Research Abstracts and Links to Original Sources
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12595910&dopt=Abstract Ref: CNS Drug Rev 2003 Spring;9(1):21-40
Dehydroepiandrosterone (DHEA) and the Aging Brain: Flipping a Coin in the "Fountain of Youth".
Racchi M, Balduzzi C, Corsini E.
Department of Experimental and Applied Pharmacology, University of Pavia, Viale Taramelli 14, 27100 Pavia, Italy.
The physiological role of dehydroepiandrosterone (DHEA) and its sulphated ester DHEA(S) has been studied for nearly 2 decades and still eludes final clarification. The major interest in DHEA derives from its unique pattern of activity. Its levels exhibit a dramatic age-related decline that supports significant involvement of DHEA(S) in the aging process. Particularly relevant to the aging process is the functional decline that involves memory and cognitive abilities. DHEA is derived mainly from synthesis in the adrenal glands and gonads. It can also be detected in the brain where it is derived from a synthesis that is independent from peripheral steroid sources. For this reason DHEA and other steroid molecules have been named "neurosteroids." Pharmacological studies on animals provided evidence that neurosteroids could be involved in learning and memory processes because they can display memory-enhancing properties in aged rodents. However, human studies have reported contradictory results that so far do not directly support the use of DHEA in aging-related conditions. As such, it is important to remember that plasma levels of DHEA(S) may not reflect levels in the central nervous system (CNS), due to intrinsic ability of the brain to produce neurosteroids. Thus, the importance of neurosteroids in the memory process and in age-related cognitive impairment should not be dismissed. Furthermore, the fact that the compound is sold in most countries as a health food supplement is hampering the rigorous scientific evaluation of its potential. We will describe the effect of neurosteroids, in particular DHEA, on neurochemical mechanism involved in memory and learning. We will focus on a novel effect on a signal transduction mechanism involving a classical "cognitive kinase" such as protein kinase C. The final objective is to provide additional tools to understand the physiological role and therapeutic potentials of neurosteroids in normal and/or pathological aging, such as Alzheimer's disease.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12589391&dopt=Abstract Ref: Neuropsychopharmacology 2003 Feb;28(2):379-383
Steroid Synthesis Inhibition with Ketoconazole and its Effect upon the Regulation of the Hypothalamus-Pituitary-Adrenal System in Healthy Humans.
Deuschle M, Lecei O, Stalla GK, Landgraf R, Hamann B, Lederbogen F, Uhr M, Luppa P, Maras A, Colla M, Heuser I.
Steroid synthesis inhibitors are commonly used in the treatment of patients with Cushing's disease, but may also improve psychopathology in hypercortisolemic depressed patients. Since glucocorticoids exert a negative feedback at pituitary and supra-pituitary levels, the inhibition of steroid synthesis may lead to increased expression of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). We studied the effect of treatment with 800 mg ketoconazole (3 weeks) upon the concentrations of basal plasma cortisol in the evening, corticosteroid-binding globulin (CBG), dehydroepiandrosterone-sulfate (DHEA-S), and ACTH as well as the concentrations of cortisol, CRH, and AVP in cerebrospinal fluid (CSF) at 8.30 h in 10 healthy, male volunteers. While we found cortisol plasma concentrations to be unchanged, we noted a significant increase in ACTH (post: 45.1+/-43.5; pre: 14.2+/-5.2 pmol/l; F(1,8)=9.78, p<0.02) and CBG concentrations (post: 38.8+/-4.3; pre: 31.9+/-4.2 &mgr;g/l), but DHEA-S plasma concentrations declined (post: 1.75+/-1.83; pre: 2.75+/-2.80 mg/l; F(1,8)=7.9, p<0.03). CRH concentrations in CSF were unchanged after treatment (post: 62.5+/-15.9; pre: 63.7+/-13.9 pg/ml), while there was a trend for AVP concentrations to rise during treatment (post: 2.52+/-1.18; pre: 1.92+/-0.96 pg/ml; paired t=-1.9, p<0.1). Cortisol CSF concentrations declined in the elderly (pre: 52.5+/-23.2; post: 26.7+/-4.6 nmol/l), but not in the young subgroup (pre: 15.6+/-11.3; post: 27.7+/-9.4 nmol/l). We thus conclude that the treatment of healthy controls with steroid-synthesis inhibitors does not lead to a major increase in CRH secretion.Neuropsychopharmacology (2003) 28, 379-383. doi:10.1038/sj.npp.1300044
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12587196&dopt=Abstract Ref: World J Biol Psychiatry 2001 Jul;2(3):115-43
Stress hormone-related psychopathology: pathophysiological and treatment implications.
Wolkowitz OM, Epel ES, Reus VI.
Department of Psychiatry, University of California, School of Medicine, San Francisco, USA.
Stress is commonly associated with a variety of psychiatric conditions, including major depression, and with chronic medical conditions, including diabetes and insulin resistance. Whether stress causes these conditions is uncertain, but plausible mechanisms exist by which such effects might occur. To the extent stress-induced hormonal alterations (e.g., chronically elevated cortisol levels and lowered dehydroepiandrosterone [DHEA] levels) contribute to psychiatric and medical disease states, manipulations that normalize these hormonal aberrations should prove therapeutic. In this review, we discuss mechanisms by which hormonal imbalance (discussed in the frameworks of "allostatic load" and "anabolic balance") might contribute to illness. We then review certain clinical manifestations of such hormonal imbalances and discuss pharmacological and behavioural treatment strategies aimed at normalizing hormonal output and lessening psychiatric and physical pathology.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12587192&dopt=Abstract Ref: World J Biol Psychiatry 2001 Apr;2(2):99-102
Movement disorder, memory, psychiatric symptoms and serum DHEA levels in schizophrenic and schizoaffective patients.
Harris DS, Wolkowitz OM, Reus VI.
Department of Psychiatry, Box CPR-0984, University of California, San Francisco Medical Center, 401 Parnassus Ave., San Francisco, CA 94143-0984, USA.
OBJECTIVE: Reports of low levels of dehydroepiandrosterone (DHEA) or its sulphate (DHEA-S) in some schizophrenic patients and in some persons with poorer motoric and cognitive functioning led us to examine clinical correlates of serum DHEA and DHEA-S levels in schizophrenic patients. METHOD: Ratings of abnormal movements, memory and psychiatric symptoms in 17 medicated chronic schizophrenic or schizoaffective inpatients at a state hospital were correlated with serum DHEA and DHEA-S levels, and their ratios with serum cortisol. RESULTS: Controlling for age, higher DHEA levels and/or higher DHEA/cortisol ratios were significantly correlated with lower symptom ratings on the Brief Psychiatric Rating Scale, better performance on some measures of memory, and lower ratings of parkinsonian symptoms. CONCLUSION: Relatively low DHEA levels or DHEA/cortisol ratios may identify a particularly impaired subgroup of medicated patients with chronic schizophrenia. Potential implications are discussed.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12581618&dopt=Abstract Ref: Med Hypotheses 2003 Mar;60(3):391-7
-oxo-DHEA and Raynaud's phenomenon.
Ihler G, Chami-Stemmann H.
Department of Medical Biochemistry and Medical Genetics, Texas A&M College of Medicine, Texas, USA
Patients with Raynaud's phenomenon have abnormal digital vasoconstriction in response to cold. The pathogenesis remains unknown but may involve a local neurovascular defect leading to vasoconstriction. Diagnosis of primary Raynaud's phenomenon is based on typical symptomatology coupled with normal physical examination, normal laboratory studies and lack of observable pathology by nail fold capillaroscopy. Secondary Raynaud's phenomenon is known to occur associated with several connective tissue diseases, vascular injury due to repeated vibrational trauma, and other causes which produce demonstrable vascular and microcirculatory damage. Treatment of Raynaud's symptoms is conservative and aimed at prevention of attacks. Patients are advised to remain warm and, if possible, to live in warm climates. We suggest that an ergogenic (thermogenic) steroid, 7-oxo-DHEA (3-acetoxyandrost-5-ene-7,17-dione), which is available without prescription as the trademarked 7-keto DHEA, may be very helpful in prevention of primary Raynaud's attacks by increasing the basal metabolic rate and inhibiting vasospasm.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12579932&dopt=Abstract Ref: Yao Xue Xue Bao 2001 Aug;36(8):576-80
Studies on the anti-tumorpromotion activities of dehydroepiandrosterone and its mechanism of action
[Article in Chinese]
Yang S, Fu ZD, Han R.
Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China.
AIM: To investigate the anti-tumorpromoting activity of dehydroepiandrosterone (DHEA) and its mechanism of action. METHODS: Using croton oil-induced ear edema model and applying confocal laser scanning microscopy, flow cytometry, immuno-fluorescent techniques to investigate the inhibitory effect of DHEA on tumor promotion. RESULTS: DHEA 25 mg.kg-1 was shown to inhibit croton oil induced ear edema in mice by 51%. DHEA at dose of 40 mg.kg-1 and 10 mg.kg-1 exhibited inhibitory effects on croton oil-induced ornithine decarboxylase (ODC) activity by 64% and 53%, respectively. These results revealed that DHEA can block the change of cell cycle and the percentage of S phase was decreased to 17% at concentration of 10(-7) mol.L-1. The increase of[Ca2+]i and pH as well as PKC-activation induced by TPA stimulation were significantly inhibited by DHEA pretreatment. CONCLUSION: The present experiments demonstrate that DHEA appears to be an attractive candidate as an anti-tumorpromotion agent for tumor chemoprevention. The mechanism of its action might be related to its inhibitory effects on ODC activity and Ca(2+)-DG-PKC signal pathway.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12578430&dopt=Abstract Ref: Arch Gen Psychiatry 2003 Feb;60(2):133-41
Dehydroepiandrosterone augmentation in the management of negative, depressive, and anxiety symptoms in schizophrenia.
Strous RD, Maayan R, Lapidus R, Stryjer R, Lustig M, Kotler M, Weizman A.
Beer Yaakov Mental Health Center, P.O. Box 1, Beer Yaakov 70350, Israel.
CONTEXT: Negative symptoms of schizophrenia are a prominent feature of the illness, and frequently remain refractory to treatment. Dehydroepiandrosterone (DHEA), along with its sulfated form, DHEA-S, is an important circulating neurosteroid with several vital neurophysiological functions, including the regulation of neuronal excitability and function. OBJECTIVE: Since the administration of DHEA has demonstrated improvement in mood, sense of well-being, interest, activity, and energy in several subpopulations, we investigate the efficacy of DHEA in the management of the negative symptoms of schizophrenia. DESIGN: Thirty DSM-IV-diagnosed schizophrenic patients with prominent negative symptoms (inpatients in a large referral state hospital) were randomized to receive either DHEA or placebo in double-blind fashion, in addition to regular antipsychotic medication, dose-stabilized prior to study entry. The DHEA was titrated up to a dose of 100 mg in divided doses during 6 weeks. RESULTS: Results indicated significant improvement in negative symptoms (P<.001), as well as in depressive (P<.05) and anxiety (P<.001) symptoms in individuals receiving DHEA. This effect was especially noted in women. The improvement in negative symptoms was independent of improvement in depression. No differences were noted on the positive symptom subscale of the Positive and Negative Syndrome Scale (PANSS) or on the total PANSS score as compared with placebo. Subjects receiving DHEA demonstrated a significant increase in DHEA (P<.05) and DHEA-S (P<.01) plasma levels, without changes in cortisol levels. Increases in DHEA and plasma DHEA-S levels were correlated with improvement in negative symptoms (P<.05), but not with improvement in depressive and anxiety symptoms. No obvious adverse effects were experienced by participating subjects. CONCLUSIONS: Our preliminary observations report for the first time in double-blind fashion the efficacy of DHEA augmentation in the management of negative, depressive, and anxiety symptoms of schizophrenia. The findings from this study raise important issues regarding the role of neurosteroids in general, and DHEA in particular, in the ongoing symptomatology and pharmacotherapy of schizophrenia.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12573809&dopt=Abstract Ref: Mol Cell Endocrinol 2002 Dec 30;198(1-2):7-14
Androgen biosynthesis from cholesterol to DHEA.
Miller WL.
Department of Pediatrics, University of California, Bldg. MR IV, Room 209, 94142-0978, San Francisco, CA, USA
Androgens and estrogens are made from dehydroepiandrosterone (DHEA), which is made from cholesterol via four steps. First, cholesterol enters the mitochondria with the assistance of the steroidogenic acute regulatory protein (StAR). Mutations in the StAR gene cause congenital lipoid adrenal hyperplasia. Second, within the mitochondria, cholesterol is converted to pregnenolone by the cholesterol side chain cleavage enzyme, P450scc. Third, pregnenolone undergoes 17alpha-hydroxylation by microsomal P450c17. Finally, 17-OH pregnenolone is converted to DHEA by the 17,20 lyase activity of P450c17. The ratio of the 17,20 lyase to 17alpha-hydroxylase activity of P450c17 determines the ratio of C21 to C19 steroids produced. This ratio is regulated post-translationally by at least three factors: the abundance of the electron-donating protein P450 oxidoreductase, the presence of cytochrome b(5), and the serine phosphorylation of P450c17. Study of these and related factors may yield important information about the pathophysiology of adrenarche and the polycystic ovary syndrome (PCOS).
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12563679&dopt=Abstract Ref: J Rheumatol 2003 Feb;30(2):269-75
Serum Levels of Pregnenolone and 17-hydroxypregnenolone in Patients with Rheumatoid Arthritis and Systemic Lupus Erythematosus: Relation to Other Adrenal Hormones.
Vogl D, Falk W, Dorner M, Scholmerich J, Straub RH.
Department of Internal Medicine I, Laboratory of Neuroendocrinoimmunology, University Medical Center Regensburg, Regensberg, Germany.
OBJECTIVE: In patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), low levels of adrenal steroids have been repeatedly demonstrated, but the site of alteration has not been exactly described because measurements of serum pregnenolone and 17-hydroxypregnenolone (17OHPreg) together with other adrenal steroids have never been performed. METHODS: We measured serum levels of adrenal hormones such as pregnenolone, 17OHPreg, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), progesterone (P), 17-hydroxyprogesterone (17OHP), androstenedione (ASD), and cortisol in 24 healthy controls, 24 patients with RA, and 24 patients with SLE. RESULTS: Serum levels of pregnenolone were similar in RA and SLE patients as compared to healthy controls irrespective of prior prednisolone therapy. In all RA and SLE patients (including those with prior prednisolone treatment), serum levels of all measured hormones except pregnenolone were significantly lower as compared to controls. In RA patients without prior prednisolone treatment, serum levels of 17OHPreg, DHEA, cortisol, and ASD were similar to controls, and serum levels of P, 17OHP, and DHEAS were significantly lower as compared to controls. In SLE patients without prior prednisolone treatment, serum levels of 17OHPreg and cortisol were similar, and serum levels of P, 17OHP, ASD, DHEA, and DHEAS were significantly lower as compared to controls. CONCLUSION: The primary hormone of the adrenal steroid cascade, pregnenolone, is almost normal in RA and SLE irrespective of corticosteroid treatment. In patients with RA, we believe that there is a near normal P450scc reaction and a normal double step P450c17 reaction. In SLE patients, the P450scc reaction also seems normal but the second step of the P450c17 reaction seems to be inhibited. In both diseases, cortisol levels remain relatively stable at the expense of other adrenal hormones. This study revealed distinct changes of steroid pathways that are related to the disease entities.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12544381&dopt=Abstract Ref: J Clin Psychopharmacol 2003 Feb;23(1):96-9
Influence of DHEA administration on 24-hour cortisol concentrations.
Kroboth PD, Amico JA, Stone RA, Folan M, Frye RF, Kroboth FJ, Bigos KL, Fabian TJ, Linares AM, Pollock BG, Hakala C.
Pharmacodynamic Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
DHEA is marketed and readily available as a daily nutritional supplement to counteract the effects of aging. The effect of DHEA administration on 24-hour plasma cortisol profiles has not been investigated. In this single-blind placebo-controlled crossover study, the effect of DHEA administration on cortisol concentrations was evaluated in healthy older women and men. Once each morning, subjects took either placebo (Days 1 to 7, and 23 to 29) or oral DHEA 200 mg (Days 8 to 22: doses 1 to 15). Twenty-four hour DHEA and cortisol concentrations were measured on Day 1 (placebo), Day 8 (DHEA dose 1), Day 15 (DHEA dose 8), Day 22 (DHEA dose 15), and Day 29 (placebo washout dose 7). DHEA administration resulted in a decrease in plasma cortisol concentrations (mean, peak, and/or AUC) in healthy older women and men. The cortisol-lowering effect of DHEA was more pronounced in women than in men in our study; pairwise differences in concentrations between days showed that relative to Day 1, cortisol was lower on Days 15, 22, and 29 in women (p = 0.0001) and on Day 15 in men (p = 0.002). The mechanism by which DHEA lowers plasma cortisol concentrations merits further investigation.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12543259&dopt=Abstract Ref: Exp Gerontol 2003 Jan;38(1-2):35-46
Calorie restriction in rhesus monkeys.
Mattison JA, Lane MA, Roth GS, Ingram DK.
Intramural Research Program, Gerontology Research Center, National Institute on Aging, NIH, 5600 Nathan Shock Drive, 21224, Baltimore, MD, USA
Calorie restriction (CR) extends lifespan and reduces the incidence and age of onset of age-related disease in several animal models. To determine if this nutritional intervention has similar actions in a long-lived primate species, the National Institute on Aging (NIA) initiated a study in 1987 to investigate the effects of a 30% CR in male and female rhesus macaques (Macaca mulatta) of a broad age range. We have observed physiological effects of CR that parallel rodent studies and may be predictive of an increased lifespan. Specifically, results from the NIA study have demonstrated that CR decreases body weight and fat mass, improves glucoregulatory function, decreases blood pressure and blood lipids, and decreases body temperature. Juvenile males exhibited delayed skeletal and sexual maturation. Adult bone mass was not affected by CR in females nor were several reproductive hormones or menstrual cycling. CR attenuated the age-associated decline in both dehydroepiandrosterone (DHEA) and melatonin in males. Although 81% of the monkeys in the study are still alive, preliminary evidence suggests that CR will have beneficial effects on morbidity and mortality. We are now preparing a battery of measures to provide a thorough and relevant analysis of the effectiveness of CR at delaying the onset of age-related disease and maintaining function later into life.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12534357&dopt=Abstract Ref: Eur J Endocrinol 2003 Jan;148(1):45-53
During a corticotropin-releasing hormone test in healthy subjects, administration of a beta-adrenergic antagonist induced secretion of cortisol and dehydroepiandrosterone sulfate and inhibited secretion of ACTH.
Kizildere S, Gluck T, Zietz B, Scholmerich J, Straub RH.
Department of Internal Medicine I, University Hospital of Regensburg, 93042 Regensburg, Germany.
OBJECTIVE: In chronic inflammatory diseases, serum levels of dehydroepiandrosterone (DHEA) sulfate (DHEAS) are low. Interestingly, several non-inflammatory diseases display similarly low levels of DHEAS which points to other inhibitory factors such as an activated sympathetic nervous system (SNS) (e.g. in patients with heart failure, fibromyalgia, or cancer cachexia). We aimed to identify the influence of the SNS tone on stimulated adrenal steroid secretion in 16 male and 12 female healthy subjects. METHODS: One group were given oral propranolol 2 h before a corticotropin-releasing hormone (CRH) test, and levels of adrenocorticotropin (ACTH), cortisol, 17-hydroxyprogesterone (17OHP), androstenedione, DHEA, and DHEAS were measured. RESULTS: Propranolol treatment decreased heart rate (by 20%), diastolic blood pressure (by 20%), and plasma ACTH, and increased serum cortisol, serum DHEAS, and the molar ratio of cortisol/17OHP, cortisol/DHEA, and DHEAS/DHEA similarly in female and male subjects. CONCLUSIONS: A beta-adrenergic influence seems to decrease CRH-stimulated cortisol in relation to ACTH and 17OHP, and decreases DHEAS in relation to DHEA. Although other workers have found beta-adrenergic stimulation of steroid secretion in cultured adrenocortical cells, the overall systemic influence of the SNS via beta-adrenoceptors seems to inhibit adrenal steroids under unstimulated and stimulated conditions. Sympathetic hyperactivity may be a common denominator for low levels of DHEAS in inflammatory and non-inflammatory diseases.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12534310&dopt=Abstract Ref: Drugs Aging 2003;20(2):85-100
Effect of Reproductive Hormones and Selective Estrogen Receptor Modulators on Mood during Menopause.
Soares CN, Poitras JR, Prouty J.
Harvard Medical School, MGH Center for Women's Mental Health, Boston, Massachusetts, USA.
Periods of intense hormonal fluctuations have been associated with heightened prevalence and exacerbation of underlying psychiatric illness, particularly the occurrence of premenstrual dysphoria, puerperal depression and depressive symptoms during perimenopause. It has been speculated that sex steroids such as estrogens, progestogens, testosterone and dehydroepiandrosterone (DHEA) exert a significant modulation of brain functioning, possibly through interactions with various neurotransmitter systems. It is therefore intuitive that abrupt alterations of these hormones would interfere with mood and behaviour. On the other hand, accumulating data suggest that hormonal interventions may also promote relief or even remission of depressive symptoms, as already demonstrated in studies with patients experiencing postpartum depression and perimenopausal depressive disorders. The extent to which perimenopause, alone, may increase the risk for depression is unclear. However, existing data strongly suggest that some women are particularly vulnerable to developing significant physical and psychological disturbances when entering perimenopause. This article reviews the effect of sex hormones and selective estrogen receptor modulators (SERMs) on mood among peri- and postmenopausal women. There are preliminary, though promising, data on the use of estradiol (particularly transdermal estradiol) to alleviate depression during perimenopause, use of a combination of estrogens and selective serotonin reuptake inhibitors for depression during the postmenopausal period, and the use of testosterone to improve psychological well-being and increase libido among women with induced menopause. Further studies would help to better delineate the usage of hormones as an antidepressant strategy (monotherapy or augmenting treatment) for peri- and postmenopausal women. A brief review of some nonhormonal interventions for the treatment of menopause-related symptoms that may significantly affect a woman's quality of life is also presented. There are some preliminary data suggesting the efficacy of antidepressants for the treatment of hot flushes; existing data on diet supplements and herbal products have shown more mixed results.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12530675&dopt=Abstract Ref: Endocr Res 2002 Nov;28(4):637-40
Fibronectin, laminin, and collagen IV interact with ACTH and angiotensin II to dictate specific cell behavior and secretion in human fetal adrenal cells in culture.
Chamoux E, Narcy A, Lehoux JG, Gallo-Payet N.
Service of Endocrinology, Faculty of Medicine, University of Sherbrooke, Sherbrooke (Qc), Canada, J1H 5N4.
Whereas collagen IV is expressed throughout the fetal adrenal gland during the second trimester of human development, fibronectin, and laminin demonstrate a rather mirror-image distribution, with higher expression of fibronectin in the central portion and laminin at the periphery of the gland. In the present study, extracellular matrices were able to modulate the profile of steroid secretion in primary cultures: collagen IV favored cortisol secretion following adrenocorticotropin (ACTH) or angiotensin II (Ang II) stimulation while specific stimulation of the AT2 receptor of Ang II elicited dehydroepiandrostenedione (DHEA) production. These effects were correlated by changes in mRNA levels of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and cytochrome P450C17. In contrast, fibronectin and laminin decreased cell responsiveness to ACTH in terms of cortisol secretion, but enhanced ACTH-stimulated androgen secretion. Finally, extracellular matrices were able to orchestrate cell behavior: collagen IV and laminin enhanced cell proliferation whereas fibronectin incited cell death. These results indicate that the nature of extracellular matrix coordinates specific steroidogenic pathways and cell turnover in the developing human fetal adrenal gland.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12529194&dopt=Abstract Ref: Adolesc Med 2003 Feb;14(1):97-108
Osteopenia and osteoporosis in anorexia nervosa.
Golden NH.
Osteopenia is a frequent and severe complication of anorexia nervosa. Once established, it is difficult to treat and is only partially reversible. Osteoporosis is a preventable disease, and intervention should begin during childhood and adolescence. Optimizing peak bone mass accrual during adolescence is essential, and an episode of anorexia nervosa during adolescence interferes with that process. In anorexia nervosa, results with hormone replacement therapy have been disappointing. Calcium and vitamin D supplementation should be prescribed where necessary. Excessive exercise should be avoided and moderate weight-bearing exercise encouraged. Ongoing research studying newer modalities such as IGF-1, DHEA, and bisphosphonates looks promising. Until more effective treatment regimens become available, the mainstay of treatment remains weight gain, nutritional rehabilitation, and spontaneous resumption of menses.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12521404&dopt=Abstract Ref: Nicotine Tob Res 2002 Nov;4(4):451-8
Effects of smoking cessation or reduction on hormone profiles and bone turnover in postmenopausal women.
Oncken C, Prestwood K, Cooney JL, Unson C, Fall P, Kulldorff M, Raisz LG.
Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut, USA.
The purpose of this study was to prospectively evaluate the impact of smoking cessation on hormonal concentrations, sex hormone-binding globulin (SHBG) and markers of bone turnover in postmenopausal women. Sixty-six women who were either users or non-users of estrogen replacement therapy (ERT) were randomly assigned, using a weighted randomization scheme, to smoking cessation (SC) or to smoking cessation after 6 weeks of monitoring (wait-list control group, WLC). We measured hormones [estrone, estradiol, testosterone, parathyroid hormone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS) and androstenedione] and SHBG, markers of bone turnover [procollagen peptide (PINP), bone alkaline phosphatase (BAP), and osteocalcin (OC), N- and C-terminal collagen cross-links (NTx and CTx)], and cotinine, at baseline and again at 6 weeks in women who reported smoking cessation and in women randomized to the WLC group. Analyses included 20 subjects who quit or significantly reduced their smoking and 18 subjects in the WLC group. After controlling for differences in age and ERT use between groups, we found a significant change in SHBG in the SC vs. the WLC group (-8% vs. +5%, respectively; p = 0.01), and in DHEA (-18% vs. -5%, respectively; p = 0.04), but not in other hormonal concentrations. We also noted a significant change in NTx in the SC vs. WLC group (-5% vs. +56%, respectively, p = 0.01), but not in other markers of bone turnover. Percentage changes in SHBG and NTx were correlated with changes in plasma cotinine (r = 0.48; p = 0.004 and r = 0.36; p = 0.04, respectively). Six weeks of smoking abstinence produces reductions in SHBG and NTx. This may partly explain how smoking contributes to osteoporosis in postmenopausal women.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12515564&dopt=Abstract Ref: Drugs 2003;63(2):167-80
Newer drugs for the treatment of lupus nephritis.
Kuiper-Geertsma DG, Derksen RH.
Department of Rheumatology, Isalaklinieken, Zwolle, and Ijsselmeerziekenhuizen, Emmeloord, The Netherlands.
This article first reviews the current treatment of lupus nephritis, with a focus on the most serious forms, that is, the proliferative subtypes. Current standards for treatment have been developed empirically. Corticosteroids form the basis of all regimens. Cyclophosphamide given intravenously for prolonged periods is the current gold standard. Azathioprine can be regarded as an effective drug for maintenance treatment of lupus nephritis. Studies on its efficacy in schedules for remission induction are in progress. It has been learned from studies on 'conventional' immunosuppression that randomised, clinical trials should comprise large numbers of patients and a follow-up of many years to elucidate differences between effective strategies. These requirements are not met by any of the 'new' treatments we discuss in this review. There is only limited experience in patients with lupus nephritis with drugs that are currently used for immunosuppression in other autoimmune diseases, such as methotrexate, cyclosporin and high-dose intravenous gammaglobulins, nor with new immunosuppressive drugs that have been developed for immunosuppression in organ transplantation (mycophenolate mofetil, tacrolimus, fludarabine and cladribine). Hormonal therapy with the weak androgen prasterone (dehydroepiandrosterone; DHEA) has no role in treatment of active lupus nephritis. There are interesting experiences with agents that have evolved from progress in immunobiology and in our understanding of immunological processes. These modalities enable more specific immunosuppression and include monoclonal antibodies directed at immune cells, cytokines and components of the complement system, constructs developed to induce tolerance in pathogenic B cells, and gene therapy. Finally, we review data on autologous bone marrow transplantation in patients with systemic lupus erythematosus. We conclude that some strategies (like mycophenolate mofetil) are good candidates for further investigation in large-scale, prospective, randomised trials with prolonged follow-up (which are almost by definition hard to perform). Most new biological agents still are in a pre-clinical phase.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12508910&dopt=Abstract Ref: J Endocrinol Invest 2002;25(10 Suppl):29-35
Adrenopause: an imbalance between dehydroepiandrosterone (DHEA) and cortisol secretion.
Valenti G.
University of Parma, Parma, Italy.
Several clinical signs might be related to the decline of DHEA secretion in aged people: sarcopenia, osteopenia, atherosclerosis progression, impairment of cognitive and affective performances, deterioration of immunocompetence are the most significant evidences. In addition, in aged people this clinical condition might be worsened by the concomitant relative glucocorticoid excess which develops in an age related manner. All together, these clinical signs construct the corpus of a syndrome named adrenopause. DHEA replacement therapy might find its indication besides the obvious condition of primary and secondary corticoadrenal insufficiency in those aged patients with typical signs of adrenopause accompanied by magnified decline of DHEA and relative excess of cortisol. Two further indications for aged patients might be represented by those with chronic inflammatory diseases, especially when long term treated with glucocorticoids and those who undergo surgical procedures.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12508909&dopt=Abstract Ref: J Endocrinol Invest 2002;25(10 Suppl):24-8
Pituitary function in chronic heart failure in the elderly.
Ceda GP, Dall'Aglio E, Salimbeni I, Rocci A, Mazzoni S, Corradi F, Cattadori E, Visioli S, Banchini A, Ceresini G, Valenti G, Hoffman AR.
Department of Internal Medicine and Biomedical Sciences, Section of Geriatrics, University of Parma, Parma, Italy.
Heart failure is a complex syndrome characterized by the activation of hemodynamic, immunologic and neurohormonal systems, which have beneficial effects in the short run, but will ultimately lead to secondary end-organ damage with worsening of LV remodeling and subsequent cardiac decompensation. A very important role seems to be played by modifications of the pituitary hormone systems. Due to the neurohormonal activation there is an increase in the activity in the renin angiotensin system, in the adrenergic nervous system, and in the cytokine system. In heart failure there is a decrease in many anabolic hormones, such as a decrease of GH and IGF-I, of DHEA/DHEAS with normal or increased F, and a decrease of LH and sex steroids, resulting in an important catabolic drive, capable of contributing to the development of cardiac failure and to sarcopenia and/or cachexia, frequently observed in the advanced stages of the disease. However, these hormone alterations have been described in relatively young patients with chronic heart failure, since the mean age of all the subjects studied was of about 60 yr and none of the studies have specifically addressed this issue in the very old patients, who represent the largest portion of population affected by this pathological condition. The role of hormone replacement therapy needs to be verified in a population of elderly patients with heart failure.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12508905&dopt=Abstract Ref: J Endocrinol Invest 2002;25(10 Suppl):2-9
Replacement therapy in the aging male.
Lunenfeld B.
Faculty of Life Sciences, Bar, Ilan University Ramat Gan 52900 Israel.
In the aging male, endocrine changes and decline in endocrine function involve tissue responsiveness as well as reduced secretory output from peripheral glands and alterations in the central mechanism controlling the temporal organization of hormonal release. The latter are likely to be responsible for the dampened circadian hormonal and non-hormonal rhythms. These are in part responsible of the age dependent decrease of the peripheral levels of T, DHEA, the thyroid hormones, GH, IGF-I, and melatonin. These hormonal changes which develop in most men at about the age of 50 are in part responsible for the partial endocrine deficiencies of aging male (PEDAM). In cases of endocrine deficiencies, traditional endocrinology aims at replacing the missing hormone or hormones with substitutes. It has been demonstrated that interventions, such as hormone replacement therapies and use of antioxidant drugs may favorably influence some of the pathological conditions in aging men, by preventing the preventable and delaying the inevitable. A comprehensive medical, psycho-social and life-style history, a physical examination and laboratory testing are essential for the diagnosis and management of PEDAM. Acute, chronic or inter-current diseases must be taken into consideration prior to initiating any hormonal substitution therapy. Hormone substitution should only be performed by physicians with basic knowledge and clinical experience in diagnosis, treatment and monitoring of endocrine deficiencies. In the Era of Evidence Based Medicine, we have to acknowledge that data on hormone replacement therapy (HRT) in the aging male is mostly circumstantial, based on experience in treatment of transitional or chronic endocrine deficiencies in young men due to disease or experiments of nature. However over the past several years, there has been an increasing interest in evaluating whether male HRT might be beneficial for a specific category of older men in preventing or delaying some aspects of ageing, and a number of prospective studies on hormone replacement therapy in the aging male were performed and these are presented in detail.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12508155&dopt=Abstract Ref: J Infect Dis 2003 Jan 1;187(1):124-7
Adrenocortical hormones and interleukin patterns in paracoccidioidomycosis.
Leal AM, Magalhaes PK, Martinez R, Moreira AC.
Division of Endocrinology, Department of Internal Medicine, School of Medicine of Ribeirao Preto, University of Sao Paulo, Brazil.
The functional status of adrenocortical hormones and their relationship to the pattern of inflammatory cytokines in paracoccidioidomycosis were investigated in a prospective study. Patients were evaluated before treatment and 1 and 6 months after receiving antifungal therapy. Interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha plasma levels, C-reactive protein (CRP) concentrations, and erythrocyte sedimentation rate (ESR) were significantly higher in untreated patients than in control subjects. After 6 months of treatment, levels of the 3 cytokines, CRP concentrations, and the ESR decreased significantly. Both baseline and stimulated adrenocorticotropic hormone and cortisol plasma levels were not different between patients and control subjects. In contrast, adrenal androgen dehydroepiandrosterone sulfate (DHEA-S) plasma levels were significantly lower in patients than in sex- and age-matched control subjects. There was a significant inverse correlation between DHEA-S and IL-6 plasma levels. This finding may be of pathogenetic significance in this disease and in other inflammatory states.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12506269&dopt=Abstract Ref: Encephale 2002 Nov-Dec;28(6):563-6
A case report of mania precipitated by use of DHEA
[Article in French]
Vacheron-Trystram MN, Cheref S, Gauillard J, Plas J.
Secteur 13, Service du Docteur Caroli, Hopital Sainte-Anne, 1, rue Cabanis, 75014 Paris.
Dehydroepiandrosterone (DHEA) and its sulfate ester metabolite (DHEA-S) are precursors to testosterone and, to a lesser extent, to estrogen, and, for both sexes, they are produced in the adrenal cortex. They are among the most abundant steroids in the human body, yet their physiological roles remain unknown. DHEA and DHEA-S appear to have diverse biochemical activities, including actions within the central nervous system. So DHEA is produced in the central nervous system as well as the human adrenals and is present in the brain, concentrated in limbic regions, in levels much higher than other steroids. DHEA has been postulated to function as an excitory neuroregulator, antagonizing g-aminobutyric acid transmission. The main characteristic of DHEA is that its level of concentration in plasma varies throughout life, such level being low during the early childhood and after the age of 60 years. Adrenal production and serum concentrations of DHEA are then known to peak between ages 25 and 30 years and thereafter decrease with age, severe illness and chronic stress. The decrease of DHEA over time would appear to be responsible for morbidity related to aging process. Previous reports have found low levels of DHEA in association with physical and with frailty in the elderly (immunosenescence, increased incidence of osteoporosis, atherosclerosis and cancer, decreased cognitive functions and/or well-being). As it has been touted as a fountain of youth and a sexual tonic and promoted for a variety of illnesses associated with aging, DHEA is widely available over all the United States (since 1994) as a dietary supplement. In France, as a result of a massive advertising campaign, DHEA is already the subject of a widespread use and a growing demand although it has not yet been approved by the relevant authorities for sale as drug to the public. In practice, DHEA is prescribed and delivered under the sole responsibility of both doctor and chemist who ascertain the benefit-risk ratio and the quality of the product. DHEA may then be purchased on the internet or in the form of magistral preparations delivered on the basis of such prescription. Accordingly, there is little information or data on efficacy, drug interactions, results of long-term use, abrupt discontinuation or potential adverse effects related to the use of DHEA. We report a case of mania possibly precipitated by the use of high doses of DHEA (150-200 mg/day at the time of presentation) during several weeks in a 68 years old man who had already been hospitalized for an acute mania many years ago. Although, in this case, the patient suffered a bipolar diathesis in the past, oral DHEA may have played a role in the induction of his acute manic episode. Further research is required to assess the mood effects of DHEA, including its potential risk for patients with bipolar disorder.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12505096&dopt=Abstract Ref: Arch Med Res 2002 Nov-Dec;33(6):524-30
Relationship of insulin resistance and overweight with cortisol and dehydroepiandrosterone-sulfate levels.
Mino D, Amato D, Cuevas ML, Fonseca ME, Burbano G, Wacher N, Lifshitz A.
Coordinacion de Investigacion Medica, Division de Investigacion Clinica, Mexico City, Mexico.
BACKGROUND: Our objective was to assess the relationship of hormones such as cortisol and dehydroepiandrosterone-sulfate (DHEA-S) with insulin resistance and overweight. METHODS: We designed and conducted a cross-sectional, observational survey consisting of home visits within a previously defined area of Mexico City. The study included 303 apparently healthy volunteers from a middle-class socioeconomic urban community. We measured glucose, cholesterol, triglycerides, insulin, cortisol, and DHEA-S. Insulin resistance (IR) was defined as belonging to the first quartile of fasting glucose/insulin ratio (G/IR) distribution or fourth quartile of IR (HOMA). Overweight was defined as body mass index (BMI) > or =25 kg/m(2). RESULTS: To predict IR in women < or =35 years of age, principal component analysis (PCA) disclosed three components: 1) cholesterol, BMI, and diastolic blood pressure (DBP); 2) cholesterol, triglycerides, and cortisol, and 3) dehydroepiandrosterone-sulfate [DHEA-S]. Solely the latter (DHEA-S) was significantly associated with IR (odds ratio [OR] = 1.80, confidence interval 95% [CI 95%] 1.11-2.91, p = 0.015). For men < or =35 years of age, there were two components: 1) cholesterol, triglycerides, BMI, and DBP, and 2) DHEA-S, cholesterol, and cortisol. Component 1 was significantly associated with IR (OR = 5.65; CI 95% 1.62-19.65, p = 0.006). To predict overweight in women >35 years of age, there were three components, including 1) cholesterol and triglycerides, 2) cortisol, and 3) DHEA-S and G/IR. Component 2 was significantly associated with overweight (OR = 0.38, CI 95% 0.23-0.64, p = 0.000). CONCLUSIONS: In women < or =35 years of age, high DHEA-S levels were associated with insulin resistance, which suggests that in young women DHEA-S exerts anti-estrogenic action, perhaps caused by its competitive binding with the estrogen receptor. Additionally, in women >35 years of age, low cortisol levels were associated with overweight. These associations were not identified for the male subgroup.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12499654&dopt=Abstract Ref: Biol Pharm Bull 2002 Dec;25(12):1634-8
Serum concentrations of delta(5)-3beta-hydroxysteroids in type 2 diabetes mellitus.
Tagawa N, Ohta M, Nakamura N, Nakano K, Obayashi H, Kobayashi Y.
Clinical Chemistry Laboratory, Kobe Pharmaceutical University.
We examined the serum concentrations of Delta(5)-3beta-hydroxysteroids, pregnenolone (Preg), 17-hydroxypregnenolone (17-OH-Preg), dehydroepiandrosterone (DHEA), androstenediol (ADIOL) and their sulfates in 30 well controlled (Group I: HbA1c<7.0%) and 15 poorly controlled (Group II: HbA1c>7.1%) type 2 diabetic patients, and 30 normal controls. These patients were treated with diet therapy or anti-diabetic agent. The distribution of gender and age of the subjects were matched between the groups. The serum levels of sulfo-conjugated and unconjugated steroids described above were measured by GC-MS and enzyme immunoassay (EIA), respectively. The serum levels of the entire sulfo-conjugated steroid measured in this study were significantly lower in Groups I and II than in controls. On the other hand, Preg levels in both Groups I and II were significantly higher than those in controls, whereas the serum levels of the downstream unconjugated steroids were not different from controls. To investigate the effect of sulfonylurea (SU) on the serum levels of steroids, the serum concentrations of steroids between the patients who were treated with diet therapy and SU agent were compared in Group I. No significant differences were observed between both groups. These results suggest that (1) since increased Preg levels did not cause any changes in the downstream Delta(5)-3beta-hydroxysteroid levels, the metabolic pathway of Delta(4)-3-ketosteroids may be accelerated in type 2 diabetes; (2) serum steroid levels were not affected by SU treatment; (3) sulfo-conjugated steroid catabolism was altered in type 2 diabetes; (4) the decreased sulfo-conjugated steroids especially ADIOLS may contribute to the alteration of sex steroid levels and onset or exacerbate infectious diseases in diabetes.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12493551&dopt=Abstract Ref: Neurobiol Aging 2003 Jan-Feb;24(1):57-65
Oxidative stress-mediated DHEA formation in Alzheimer's disease pathology.
Brown RC, Han Z, Cascio C, Papadopoulos V.
The Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, 3900 Reservoir Road NW, 20007, Washington, DC, USA
An alternative pathway for dehydroepiandrosterone (DHEA) synthesis has been suggested by treating rat and human brain cells with ferrous sulfate and beta-amyloid (Abeta). To determine if this pathway exists in human brain, levels of DHEA in hippocampus, hypothalamus and frontal cortex from Alzheimer's disease (AD) patients and age-matched controls were measured. DHEA is significantly higher in AD brain than control, and was highest in AD hippocampi. Cytochrome P450 17alpha-hydroxylase, responsible for peripheral DHEA synthesis, is not present in hippocampus. DHEA levels in AD cerebrospinal fluid (CSF) were significantly higher than age-matched controls. AD serum DHEA levels are lower than CSF, and not significantly different from controls. Treatment of control hippocampus, hypothalamus and serum with FeSO(4) increases DHEA, suggesting that levels of precursor are higher in control that in AD brain. This suggests that (i) an alternative precursor is present in control brain, (ii) AD brain DHEA is formed by oxidative stress metabolism of precursor, and (iii) CSF DHEA levels and serum DHEA formation in response to FeSO(4) may serve as an indicator of AD pathology.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12488352&dopt=Abstract Ref: Endocrinology 2003 Jan;144(1):253-9
Dehydroepiandrosterone down-regulates the expression of peroxisome proliferator-activated receptor gamma in adipocytes.
Kajita K, Ishizuka T, Mune T, Miura A, Ishizawa M, Kanoh Y, Kawai Y, Natsume Y, Yasuda K.
The Third Department of Internal Medicine, Gifu University School of Medicine, Tsukasa-machi 40, Gifu 500-8705, Japan.
Dehydroepiandrosterone (DHEA) is expected to have a weight-reducing effect. In this study, we evaluated the effect of DHEA on genetically obese Otsuka Long Evans Fatty rats (OLETF) compared with Long-Evans Tokushima rats (LETO) as control. Feeding with 0.4% DHEA-containing food for 2 wk reduced the weight of sc, epididymal, and perirenal adipose tissue in association with decreased plasma leptin levels in OLETF. Adipose tissue from OLETF showed increased expression of peroxisome proliferator-activated receptor gamma (PPARgamma) protein, which was prevented by DHEA treatment. Further, we examined the effect of DHEA on PPARgamma in primary cultured adipocytes and monolayer adipocytes differentiated from rat preadipocytes. PPARgamma protein level was decreased in a time- and concentration-dependent manner, and DHEA significantly reduced mRNA levels of PPARgamma, adipocyte lipid-binding protein, and sterol regulatory element-binding protein, but not CCAAT/enhancer binding protein alpha. DHEA-sulfate also reduced the PPARgamma protein, but dexamethasone, testosterone, or androstenedione did not alter its expression. In addition, treatment with DHEA for 5 d reduced the triglyceride content in monolayer adipocytes. These results suggest that DHEA down-regulates adiposity through the reduction of PPARgamma in adipocytes.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12482595&dopt=Abstract Ref: FEBS Lett 2002 Dec 18;532(3):373-8
In vivo activation of the constitutive androstane receptor beta (CARbeta) by treatment with dehydroepiandrosterone (DHEA) or DHEA sulfate (DHEA-S).
Fujita A, Furutama D, Tanaka T, Sakai R, Koyama A, Hanafusa T, Mitsuhashi T, Ohsawa N.
Aino Institute for Aging Research, 3-9-25, Ohta, Ibaraki, 567-0018, Osaka, Japan.
We investigated whether dehydroepiandrosterone (DHEA) or DHEA-sulfate (S) affected the activities of nuclear receptors, with special reference to constitutive androstane receptor beta (CARbeta). Administration of DHEA or DHEA-S enhanced the DNA binding of hepatic nuclear extracts to responsive elements for the retinoic acid receptor, the retinoic acid receptor beta 2 and the peroxisome proliferator activated receptor. The bound complexes were shown to be the CARbeta-RXR heterodimer by antibody-supershift assays. The expression of a target gene of CARbeta, Cyp2b10, was increased in liver by DHEA or DHEA-S treatment, suggesting that DHEA or DHEA-S actually activated CARbeta in vivo. It was suggested that the metabolic conversion of DHEA, DHEA-S to CARbeta ligands could occur in vivo and the metabolites could regulate the expression of CARbeta target gene expression. Our results provide new insights into the in vivo relationship between DHEA/DHEA-S and CARbeta activation.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12475388&dopt=Abstract Ref: J Endocrinol 2002 Dec;175(3):779-92
Modulation of the peroxisomal gene expression pattern by dehydroepiandrosterone and vitamin D: therapeutic implications.
Depreter M, Vandesompele J, Espeel M, Speleman F, Roels F.
Department of Human Anatomy, Embryology, Histology and Medical Physics, Ghent University, Godshuizenlaan 4, B-9000 Ghent, Belgium.
Peroxisomes are ubiquitous organelles required for several metabolic functions. Their dysfunction is responsible for a group of human inherited disorders. In the search for endogenous factors regulating the peroxisomal compartment in normal liver, we treated female rats with dehydroepiandrosterone (DHEA) and 25-hydroxycholecalciferol for 1 and 6 days. Relative transcription levels of 39 selected genes were evaluated by real-time quantitative RT-PCR analysis. Catalase (peroxisomal marker)-specific activity was assayed in total liver homogenate and peroxisomes were visualized by catalase localization. DHEA induced peroxisome proliferation and raised catalase specific activity. Expression levels of 16 (of which 11 were peroxisomal) genes were altered. Pex 11, acyl-CoA oxidase,l - andd -multifunctional enzyme, thiolase 1, phytanoyl-CoA hydroxylase, 70 kDa peroxisomal membrane protein and very long chain acyl-CoA synthetase were upregulated, three others were downregulated. Vitamin D caused downregulation of six genes. Administration of vitamin D to peroxisomal disorder patients may be contraindicated. The adrenocortical hormone DHEA is a potential natural regulator of the peroxisomal compartment. Its therapeutic use in X-linked adrenoleukodystrophy, some other beta-oxidation defects and classical Refsum should be considered.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12471606&dopt=Abstract Ref: Proteins 2003 Jan 1;50(1):135-43
Analysis of the binding energies of testosterone, 5alpha-dihydrotestosterone, androstenedione and dehydroepiandrosterone sulfate with an antitestosterone antibody.
Nordman N, Valjakka J, Perakyla M.
Department of Chemistry, University of Kuopio, Kuopio, Finland.
Molecular dynamics simulations and molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) free energy calculations were used to study the binding of testosterone (TES), 5alpha-dihydrotestosterone (5ADHT), androstenedione (AND), and dehydroepiandrosterone sulfate (DHEAS) to the monoclonal antitestosterone antibody 3-C(4)F(5). The relative binding free energy of TES and AND was also calculated with free energy perturbation (FEP) simulations. The antibody 3-C(4)F(5) has a relatively high affinity (3 x 10(8) M(-1)) and on overall good binding profile for testosterone but its cross-reactivity with DHEAS has been the main reason for the failure to use this antibody in clinical immunoassays. The relative binding free energies obtained with the MM-PBSA method were 1.5 kcal/mol for 5ADHT, 3.8 kcal/mol for AND, and 4.3 kcal/mol for DHEAS, as compared to TES. When a water molecule of the ligand binding site, observed in the antibody-TES crystal structure, was explicitly included in MM-PBSA calculations, the relative binding energies were 3.4, 4.9, and 5.4 kcal/mol for 5ADHT, AND, and DHEAS, respectively. The calculated numbers are in correct order but larger than the corresponding experimental energies of 1.3, 1.5, and 2.6 kcal/mol, respectively. The fact that the MM-PBSA method reproduced the relative binding free energies of DHEAS, a steroid having a negatively charged sulfate group, and the neutrally charged TES, 5ADHT, and AND in satisfactory agreement with experiment shows the robustness of the method in predicting relative binding affinities. The 800-ps FEP simulations predicted that the antibody 3-C(4)F(5) binds TES 1.3 kcal/mol tighter than AND. Computational mutagenesis of selected amino acid residues of the ligand binding site revealed that the lower affinities of AND and DHEAS as compared to TES are due to a combined effect of several residues, each contributing a small fraction to the tighter binding of TES. An exception to this is Tyr99H, whose mutation to Ala lowered the binding of DHEAS 0.7 kcal/mol more than the binding of TES. This is probably due to the hydrogen bonding interaction formed between the OH group of Tyr99H and the sulfate group of DHEAS. Computational mutagensis data also showed that the affinity of the steroids to the antitestosterone antibody 3-C(4)F(5) would be enhanced if Trp47H were repositioned so that it would make more extensive contacts with the bound ligands. In addition, the binding of steroids to antitestosterone, antiprogesterone, and antiestradiol antibodies is discussed.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12466638&dopt=Abstract Ref: Psychother Psychosom 2003 Jan-Feb;72(1):49-58
A longitudinal study of hormonal reactions accompanying life events in recently resettled refugees.
Sondergaard HP, Theorell T.
National Swedish Institute for Psychosocial Factors and Health, Stockholm, Sweden.
Background: Refugees constitute a growing section of the general population in many countries. It is therefore important to study which factors in everyday life are important to recently resettled refugees after they have been granted residence. Methods: Life events from a checklist, as well as categories derived from written responses to open-ended questions were analysed (repeated-measures ANOVA). Changes over time in mean serum/plasma concentrations of cortisol, thyroxine, prolactin, and dehydroepiandrosterone sulphate (DHEA-S) were compared in subjects with and without the reported events. Results: Distress in significant others (close friends or first-degree relatives) and a perception of excessive demands in everyday life were associated with increases in serum cortisol. Events associated with decreased levels of prolactin were typically situations of strain in relation to authorities or individuals to which the subjects were in a position of dependency. DHEA-S changed in opposite directions in post-traumatic stress disorder (PTSD) and non-PTSD subjects. DHEA-S also changed with positive events. Conclusions: Distress in significant others and a too demanding everyday life lead to significant changes in the stress-responsive hormones cortisol, prolactin and DHEA-S. Since DHEA-S behaves differently in PTSD, this condition is a potential confounder in studies of DHEA-S with an unknown proportion of PTSD among participants.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12463448&dopt=Abstract Ref: Clin Exp Rheumatol 2002 Nov-Dec;20(6 Suppl 28):S52-9
No alterations of serum levels of adrenal and gonadal hormones in patients with ankylosing spondylitis.
Straub RH, Struharova S, Scholmerich J, Harle P.
Department of Internal Medicine I, University Hospital Regensburg, Germany.
Ankylosing spondylitis (AS) is a chronic inflammatory disease with a marked preponderance of affected males compared to females of approximately 6 to 1. During the last two decades, this circumstance stimulated several research groups to investigate serum levels of gonadal and adrenal sex hormones. From available results of cross-sectional studies, there seems to be no particular defect in secretion or production of adrenal, gonadal, and pituitary hormones. This is in striking contrast to diseases such as rheumatoid arthritis and other chronic inflammatory diseases. In the latter diseases, low serum levels of dehydroepiandrosterone (DHEA), DHEA sulphate (DHEAS), and testosterone have been described in an advanced chronic disease stage, whereas estrogen serum levels remain normal. Although AS is an inflammatory disease with signs of systemic inflammation such as elevated erythrocyte sedimentation rate or increased circulating proinflammatory cytokines, serum levels of adrenal and gonadal androgens are normal. It is unclear whether this can be considered as unexpected. It may be that inflammation does not reach the pituitary, adrenal, and gonadal glands or does not alter the aromatase complex in peripheral tissue. Furthermore, the inflammation-induced changes may be subtle so that only specific endocrine examination of these axes may reveal signs of alterations. In conclusion, current data on sex steroid hormones provide no straightforward explanation for the male predominance in AS. At the moment, there is no rationale to treat AS patients with sex steroid hormones.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12459481&dopt=Abstract Ref: FEBS Lett 2002 Dec 4;532(1-2):153-8
Synergistic effect of retinoic acid and dehydroepiandrosterone on differentiation of human neuroblastoma cells.
Silvagno F, Guarnieri V, Capizzi A, Pescarmona GP.
Dipartimento di Genetica, Biologia e Biochimica, Facolta' di Medicina e Chirurgia, Universita' di Torino, Sezione di Biochimica, Via Santena 5 bis, 10126 Turin, Italy.
Retinoic acid (RA) affects many cell types by either promoting their survival or inducing their differentiation. Dehydroepiandrosterone (DHEA), a precursor for both androgenic and estrogenic steroids and abundantly produced by brain, is known as an inhibitor of cell proliferation. Differentiation of a human neuroblastoma cell line (SK-N-BE) was evaluated measuring growth rate, motility, neurite extension and GAP-43 expression. We report that DHEA enhances the differentiating effect of RA on neuroblastoma cells via a signalling that is not RA receptor-mediated. Instead, we show a differential expression of matrix metalloproteinases: RA enhances the activity of MMP-2, whereas MMP-9 expression is up-regulated by DHEA. The concerted modulation of these proteinases may support the neurite outgrowth observed after co-treatment with the two drugs.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12428484&dopt=Abstract Ref: Rev Med Interne 2002 Oct;23(10):819-27
Relation between physical activity, muscle function and IGF-1, testosterone and DHEAS concentrations in the elderly
[Article in French]
Bonnefoy M, Patricot MC, Lacour JR, Rahmani A, Berthouze S, Kostka T.
Service de medecine geriatrique, centre hospitalier Lyon-Sud, 69495 Pierre-Benite, France.
OBJECTIVE: Lower amounts of circulating anabolic hormones are thought to accelerate the age related decline in muscle mass and function. Replacement therapies are promising interventions but there are problems with these therapies. Thus alternative strategies should be developed. The age related changes in hormonal status may be probably influenced by exercise. The purpose of this study was: a) to confirm with other methods, more adapted for elderly people, the results of a previous study that has shown relationship between physical activity (PA) and quadriceps muscle function with dehydroepiandrosterone sulphate (DHEAS), insulin like growth factor-1 (IGF-1). Quadriceps muscle power (Pmax) is measured in this new work with a recently developed leg extensor machine and, b) to complete the results of the first study examining simultaneously the relationship between PA, Pmax and cardiorespiratory fitness (VO2max) with DHEAS, IGF-1 and testosterone in a group of healthy elderly people. METHODS: Fifty independent, community dwelling elderly subjects (25 mens and 25 womens) aged from 66 to 84 volunteered to participate in the study. PA was evaluated by the questionnaire and expressed using two activity indices: mean habitual daily energy expenditure (MHDEE) and the daily energy expenditure corresponding to leisure time sports activities (Sports Activity). Pmax and optimal shortening velocity (vopt) were measured on a Ergopower dynamometer. The Pmax was expressed relative to body mass, Pmax/kg (W kg-1), and relative to the mass of the two quadriceps muscles, Pmax/Quadr (W.kgQuadr-1). VO2max has been measured during a maximal treadmill exercise. RESULTS: In women, IGF-1 correlated significantly with MHDEE (r = 0.54, P = 0.004), Pmax/kg (r = 0.54, P = 0.004) and Pmax/Quadr (r = 0.46, P = 0.02), whereas DHEAS with MHDEE (r = 0.54, P = 0.004), Sports Activity (r = 0.65, P < 0.001), VO2max (r = 0.46, P = 0.02), Pmax/kg (r = 0.46, P = 0.02) and Pmax/Quadr (r = 0.55, P = 0.004). No such correlation was found in men. CONCLUSION: These findings confirm that in healthy elderly women physical activity, cardiorespiratory fitness and quadriceps muscle function are similarly related to levels of circulating DHEAS and IGF-1 suggesting a favourable influence of exercise on anabolic hormonal production in the elderly.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12428233&dopt=Abstract Ref: Arthritis Rheum 2002 Nov;46(11):2924-7
Dehydroepiandrosterone treatment of women with mild-to-moderate systemic lupus erythematosus: a multicenter randomized, double-blind, placebo-controlled trial.
Chang DM, Lan JL, Lin HY, Luo SF.
Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China.
OBJECTIVE: To evaluate the efficacy and tolerability of dehydroepiandrosterone (DHEA) at a dosage of 200 mg/day in adult women with active systemic lupus erythematosus (SLE). METHODS: In a multicenter randomized, double-blind, placebo-controlled trial, 120 adult women with active SLE received oral DHEA (200 mg/day; n = 61) or placebo (n = 59) for 24 weeks. The primary end point was the mean change from baseline in the Systemic Lupus Activity Measure (SLAM) score at 24 weeks of therapy. Secondary end points included time to first flare, change in SLE Disease Activity Index (SLEDAI) score, and physician's and patient's global assessment scores at week 24. RESULTS: The two groups were well balanced for baseline characteristics. Mean reductions in SLAM scores from baseline were similar and were not statistically significantly different between treatment groups (DHEA -2.6 +/- 3.4 versus placebo -2.0 +/- 3.8, mean +/- SD). The number of patients with flares was decreased by 16% in the DHEA group (18.3% of DHEA-treated patients versus 33.9% of placebo-treated patients; P = 0.044, based on time to first flare). The mean change in the patient's global assessment was statistically significant between the two groups (DHEA -5.5 versus placebo 5.4; P = 0.005). The number of patients with serious adverse events, most of which were related to SLE flare, was significantly lower in DHEA-treated patients compared with placebo-treated patients (P = 0.010). Expected hormonal effects, including increased testosterone levels and increased incidence of acne, were observed. No life-threatening reactions or serious safety issues were identified during this study. CONCLUSION: The overall results confirm that DHEA treatment was well-tolerated, significantly reduced the number of SLE flares, and improved patient's global assessment of disease activity.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12425955&dopt=Abstract Ref: Mech Ageing Dev 2002 Sep;123(11):1477-86
Changes in peripheral blood lymphocyte subsets in elderly subjects are associated with an impaired function of the hypothalamic-pituitary-adrenal axis.
Martinez-Taboada V, Bartolome MJ, Amado JA, Blanco R, Garcia-Unzueta MT, Rodriguez-Valverde V, Lopez-Hoyos M.
Services of Rheumatology, Immunology, and Endocrinology, Santander, Spain.
A growing body of evidence indicates that ageing brings a progressive disruption in the immune and endocrine systems. However, very few reports have correlated the changes in the immune system with the endocrine function in the elderly. The aim of the present study was to investigate the changes occurring in the peripheral blood lymphocyte subpopulations with age and correlate them with the hypothalamic-pituitary-adrenal (HPA) function. We determined the peripheral blood lymphocyte phenotype and the T cell receptor usage by flow cytometry analysis. The HPA function was evaluated by the basal serum levels of adrenal steroids and the response to stimulation with a low-dose ACTH. In the elderly, we observed a decrease of major T subsets together with an increase of NK cells and activated T cells. With regard to the HPA function, the most significant decline was found in dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulphate (DHEAS). A close correlation between immune changes with ageing and DHEA response to ACTH stimulation was found. The present study showed an inverse correlation of lymphocyte changes with the plasma levels of steroids, especially DHEA and its metabolite, DHEAS. This association was not found for other steroids and points for the possibility of using DHEA to correct the immunological decline associated with ageing.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12422680&dopt=Abstract Ref: MMW Fortschr Med 2002 Sep 26;144(39):24-7
Hormonal "rejuvenation". Warning your patients from false claims!
[Article in German]
Bruckel J.
Abt. f. Innere Medizin, Bereich Endokrinologie und Diabetes, Krankenhaus Wangen, Oberschwaben-Klinik GmbH.
No intervention, including drugs and hormones, has been proven to slow or even reverse aging. Such promises, as well as the term "anti-aging medicine", are misleading. On the other hand, remarkable progress has been made in the prevention and treatment of age-related diseases. The use of hormones constitutes a potentially new option in the prevention and treatment of age-related diseases, but is not an established therapy. The status of scientific evidence for the treatment of seniors with growth hormone, melatonin, DHEA or testosterone is critically reviewed.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12422368&dopt=Abstract Ref: Synapse 2003 Jan;47(1):10-4
Dehydroepiandrosterone (DHEA) such as 17beta-estradiol prevents MPTP-induced dopamine depletion in mice.
D'Astous M, Morissette M, Tanguay B, Callier S, Di Paolo T.
Molecular Endocrinology and Oncology Research Center, Laval University Medical Center (CHUL), Quebec, Qc, G1V 4G2, and Faculty of Pharmacy, Laval University, Quebec, Qc, G1K 7P4, Canada.
Previous work from our laboratory has shown prevention of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced striatal dopamine (DA) depletion in mice by 17beta-estradiol, progesterone, and raloxifene. Dehydroepiandrosterone (DHEA), a neurosteroid, was shown to have neuroprotective activities in various paradigms of neuronal death but its effect in vivo in mice on MPTP toxicity has not been reported. We investigated the effects of 17beta-estradiol (2 microg/day) and DHEA (3 mg/day) for 5 days before and after an acute treatment of four MPTP (10 mg/kg) injections in male C57Bl/6 mice. Striatal DA concentrations and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured by HPLC. MPTP mice that received 17beta-estradiol or DHEA had striatal DA, DOPAC, and HVA concentrations comparable to intact animals and higher than striatal DA, DOPAC, and HVA levels in saline-MPTP-treated mice. MPTP treatment led to an increase of striatal DA turnover (assessed with the HVA/DA ratio); DHEA and 17beta-estradiol prevented this increase. 17beta-Estradiol did not affect striatal DA and metabolites concentrations in intact mice in this paradigm. Furthermore, in the substantia nigra DHEA and 17beta-estradiol prevented the MPTP-induced dopamine transporter and tyrosine hydroxylase mRNA decreases measured by in situ hybridization. Therefore, DHEA such as 17beta-estradiol is active in preventing the catecholamine-depleting effect of MPTP and our results suggest that this involves neuroprotection of DA neurons.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12421607&dopt=Abstract Ref: Neuroscience 2002;115(2):415-24
Dehydroepiandrosterone and alpha-estradiol limit the functional alterations of rat brain mitochondria submitted to different experimental stresses.
Morin C, Zini R, Simon N, Tillement JP.
Departement de Pharmacologie, Faculte de Medecine de Paris XII, 8 rue du General Sarrail, F-94010 Creteil, France.
The effects of dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), alpha-estradiol and beta-estradiol on the main functions of purified rat brain mitochondria were investigated in basal conditions and after being submitted to various stresses including anoxia-reoxygenation, uncoupling and apoptosis. In basal conditions, DHEA (1 microM) and alpha-estradiol (1 microM) inhibited the respiratory control ratio (RCR) from 3.1 to 2.3 (25%). After anoxia-reoxygenation, DHEA (1 microM) and alpha-estradiol (1 microM) reversed significantly (P<0.01) the RCR decrease from 1.4 to 2.0 (21.5%) by restoring the state 4. This effect was observed when DHEA was added either before anoxia or before reoxygenation and when alpha-estradiol was added before anoxia. The mitochondrial membranes damaged after the anoxia-reoxygenation were 70 and 50%, respectively, protected by DHEA and alpha-estradiol at 1 microM. They also limited by about 50%, the cytochrome c release induced by the anoxia-reoxygenation. The oxygen consumption of mitochondria in presence of NADH (130 microM) and cytochrome c (5 microM) was significantly inhibited by DHEA and alpha-estradiol with high EC(50) of 30 and 22 pM, respectively. At 1 microM, they also inhibited the 10 microM carbonyl cyanide m-chlorophenylhydrazone-induced uncoupling to about 35% whereas beta-estradiol only decreased it to 9%.Our results indicated that DHEA and alpha-estradiol partly preserved the mitochondrial functions altered by an anoxia-reoxygenation with a concentration-dependent effect. The mechanism involved was independent of the classical genomic effect of steroids, the antioxidant properties but implicated a direct action on the mitochondrial membranes.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12420152&dopt=Abstract Ref: Psychopharmacology (Berl) 2003 Jan;165(2):97-110
Neurosteroids in depression: a review.
Van Broekhoven F, Verkes RJ.
Department of Psychiatry, Unit for Clinical Psychopharmacology and Neuropsychiatry, University Medical Centre Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands,
RATIONALE. A deregulation in concentrations of the neurosteroids (allo)pregnanolone and 3alpha,5alpha-tetrahydrodeoxycorticosterone (3alpha,5alpha-TH DOC) has been found in depressed patients. These levels normalize following treatment with selective serotonin reuptake inhibitors (SSRIs). Furthermore, administration of the neurosteroid dehydroepiandrosterone (DHEA) to depressed patients is associated with an improvement in the symptoms of depression. OBJECTIVE. The aim of the present review is to clarify the mechanisms whereby neurosteroids, particularly allopregnanolone and DHEA, are involved in depression and to discuss the effect of SSRIs on allopregnanolone concentration. METHODS. Literature on preclinical and clinical research has been analyzed in relation to the pathophysiology of depression. RESULTS. Decreased plasma and cerebrospinal fluid concentrations of allopregnanolone in depressed patients increase to normal levels following effective psychopharmacological treatment. This might either be a physiological aspect of improvement in the symptoms of depression or a pharmacologically induced alteration. Several findings support the hypothesis of an antidepressant effect of allopregnanolone. These include an antidepressant effect demonstrated in an animal model of depression and a suppressing effect on corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP) gene expression. SSRIs increase levels of allopregnanolone, but this effect is not confined to this class of drugs alone. The beneficial effect of DHEA administration in depressed patients might result from its sigma 1 receptor-mediated enhancement of noradrenaline and serotonin neurotransmission, antiglucocorticoid effects, and cognition enhancing effects. CONCLUSIONS. Indirect genomic (allopregnanolone) and non-genomic (allopregnanolone and DHEA) mechanisms are involved in the neurosteroidogenic pathophysiology of depression. Clinical studies in homogeneous groups of non-pharmacologically treated depressed patients are required to elucidate this relationship further.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12414884&dopt=Abstract Ref: J Clin Endocrinol Metab 2002 Nov;87(11):5138-43
Neurosteroid quantification in human brain regions: comparison between Alzheimer's and nondemented patients.
Weill-Engerer S, David JP, Sazdovitch V, Liere P, Eychenne B, Pianos A, Schumacher M, Delacourte A, Baulieu EE, Akwa Y.
INSERM U-488, Steroides et Systeme Nerveux, 80 rue du General Leclerc, 54276 Le Kremlin-Bicetre, France.
Some neurosteroids have been shown to display beneficial effects on neuroprotection in rodents. To investigate the physiopathological significance of neurosteroids in Alzheimer's disease (AD), we compared the concentrations of pregnenolone, pregnenolone sulfate (PREGS), dehydroepiandrosterone, dehydroepiandrosterone sulfate (DHEAS), progesterone, and allopregnanolone, measured by gas chromatography-mass spectrometry, in individual brain regions of AD patients and aged nondemented controls, including hippocampus, amygdala, frontal cortex, striatum, hypothalamus, and cerebellum. A general trend toward decreased levels of all steroids was observed in all AD patients' brain regions compared with controls: PREGS and DHEAS were significantly lower in the striatum and cerebellum, and DHEAS was also significantly reduced in the hypothalamus. A significant negative correlation was found between the levels of cortical beta-amyloid peptides and those of PREGS in the striatum and cerebellum and between the levels of phosphorylated tau proteins and DHEAS in the hypothalamus. This study provides reference values for steroid concentrations determined by gas chromatography-mass spectrometry in various regions of the aged human brain. High levels of key proteins implicated in the formation of plaques and neurofibrillary tangles were correlated with decreased brain levels of PREGS and DHEAS, suggesting a possible neuroprotective role of these neurosteroids in AD.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12414869&dopt=Abstract Ref: J Clin Endocrinol Metab 2002 Nov;87(11):5038-43
Pubertal and gender-related changes in the sympathoadrenal system in healthy children.
Weise M, Eisenhofer G, Merke DP.
Developmental Endocrinology Branch, National Institute of Child Health and Human Development/NIH, Building 10, 10 Center Drive, Bethesda, MD 20892-1932, USA.
A critical amount of body fat is necessary for the initiation of puberty, and leptin, an adipocyte-derived hormone, is necessary for pubertal development. The sympathoadrenal system modulates body fat stores and leptin secretion and interacts with adrenocortical androgen production, suggesting a possible role in sexual maturation. We studied sympathetic nerve and adrenomedullary activity at rest in 80 healthy children (ages, 5-17 yr; 37 boys and 43 girls) in relation to age, pubertal stage, gender, physical activity, body mass index, and serum levels of sex steroids, dehydroepiandrosterone sulfate, cortisol, leptin, and insulin. Plasma concentrations of the adrenomedullary hormone, epinephrine (E), and its metabolite metanephrine (MN), decreased significantly with advancing puberty and were higher in boys than in girls. E and MN correlated significantly and inversely with dehydroepiandrosterone sulfate, estradiol, testosterone, leptin, and insulin. Plasma norepinephrine, which is primarily derived from sympathetic nerve endings, increased significantly with advancing puberty and increasing testosterone levels in boys. Stepwise multiple regression analysis revealed that E was best predicted by pubertal stage and leptin, and MN by estradiol and leptin. Our data suggest that sympathoadrenal hormones may play a role in the complex process of sexual maturation. Further studies are needed to investigate a possible modulatory role of the adrenal medulla in the body weight-related timing of adrenarche and/or gonadarche.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12414853&dopt=Abstract Ref: J Clin Endocrinol Metab 2002 Nov;87(11):4935-41
Effects of oral dehydroepiandrosterone on bone density in young women with anorexia nervosa: a randomized trial.
Gordon CM, Grace E, Emans SJ, Feldman HA, Goodman E, Becker KA, Rosen CJ, Gundberg CM, LeBoff MS.
Division of Adolescent/Young Adult Medicine, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
Young women with anorexia nervosa (AN) have subnormal levels of dehydroepiandrosterone (DHEA) and estrogen that may be mechanistically linked to the bone loss seen in this disease. The purpose of this study was to compare the effects of a 1-yr course of oral DHEA treatment vs. conventional hormonal replacement therapy (HRT) in young women with AN. Sixty-one young women were randomly assigned to receive oral DHEA (50 mg/d) or HRT (20 micro g ethinyl estradiol/0.1 mg levonorgestrel). Anthropometric, nutrition, and exercise data were acquired every 3 months, and bone mineral density (BMD) and body composition were measured by dual energy x-ray absorptiometry (DXA) every 6 months over 1 yr. Serum samples were obtained for measurements of hormones, proresorptive cytokines, and bone formation markers, and urine was collected for determinations of bone resorption markers at each visit. In initial analyses, total hip BMD increased significantly and similarly (+1.7%) in both groups. Hip BMD increases were positively correlated with increases in IGF-I (r = 0.44; P = 0.030) and the bone formation marker, bone-specific alkaline phosphatase increased significantly only in the DHEA treatment group (P = 0.003). However, both groups gained significant amounts of weight over the year of therapy, and after controlling for weight gain, no treatment effect was detectable. There was no significant change in lumbar BMD in either group. Both bone formation markers, bone-specific alkaline phosphatase and osteocalcin, increased transiently at 6-9 months in those subjects receiving DHEA compared with the estrogen-treated group (P < 0.05). Both DHEA and HRT significantly reduced levels of the bone resorption markers, urinary N-telopeptides (P < 0.05). There was a positive correlation between changes in IGF-I and changes in weight, body fat determined by DXA, and estradiol for both groups. In addition, patients receiving DHEA exhibited improvement on three validated psychological instruments (Eating Attitudes Test, Anorexia Nervosa Subtest, and Spielberger Anxiety Inventory). Both DHEA and HRT had similar effects on hip and spinal BMD. Over the year of treatment, maintenance of both hip and spinal BMD was seen, but there was no significant increase after accounting for weight gain. Compared with HRT, DHEA appeared to have anabolic effects, evidenced by the positive correlation between increases in hip DXA measurements and IGF-I and significant increases in bone formation markers. Both therapies significantly decreased bone resorption. Replicating results from studies of the elderly, DHEA resulted in improvements in specific psychological parameters in these young women.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12413984&dopt=Abstract Ref: Fertil Steril 2002 Nov;78(5):1001-4
Use of dexamethasone and clomiphene citrate in the treatment of clomiphene citrate-resistant patients with polycystic ovary syndrome and normal dehydroepiandrosterone sulfate levels: a prospective, double-blind, placebo-controlled trial.
Parsanezhad ME, Alborzi S, Motazedian S, Omrani G.
Division of Infertility, Department of Obstetrics and Gynecology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
OBJECTIVE: To evaluate the effects of short-course administration of dexamethasone (DEX) combined with clomiphene citrate (CC) in CC-resistant patients with polycystic ovary syndrome (PCOS) and normal DHEAS levels. DESIGN: Prospective, double-blind, placebo-controlled, randomized study. SETTING: Referral university hospitals. PATIENT(S): Two hundred thirty women with PCOS and normal DHEAS who failed to ovulate after a routine protocol of CC. INTERVENTION(S): The treatment group received 200 mg of CC from day 5 to day 9 and 2 mg of DEX from day 5 to day 14 of the menstrual cycle. The control group received the same protocol of CC combined with placebo. MAIN OUTCOME MEASURE(S): Follicular development, hormonal status, ovulation rate, pregnancy rate. RESULT(S): Mean follicular diameters were 18.4124 +/- 2.4314 mm and 13.8585 +/- 2.0722 mm for the treatment and control groups, respectively. Eighty-eight percent of the treatment group and 20% of the control group had evidence of ovulation. The difference in the cumulative pregnancy rate in the treatment and control groups was statistically significant. CONCLUSION(S): Hormonal levels, follicular development, and cumulative pregnancy rates improved with the addition of DEX to CC in CC-resistant patients with PCOS and normal DHEAS. This regimen is recommended before any gonadotropin therapy or surgical intervention.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12412624&dopt=Abstract Ref: Shock 2002 Nov;18(5):445-9
Dehydroepiandrosterone (DHEA) modulates the activity and the expression of lymphocyte subpopulations induced by cecal ligation and puncture.
van Griensven M, Dahlweid FM, Giannoudis PV, Wittwer T, Bottcher F, Breddin M, Pape HC.
Department of Trauma Surgery, Hannover Medical School, Germany.
Dehydroepiandrosterone (DHEA) exerts a variety of positive effects on the immunologic alterations after trauma and sepsis. We therefore measured the therapeutic efficacy of DHEA after cecal ligation and puncture (CLP) on the expression of lymphocyte subpopulations and on the delayed type hypersensitivity (DTH) reaction. Male NMRI-mice were randomly assigned to four different treatment groups. Treatment consisted of DHEA or saline (S) administration after CLP or laparotomy only. Flow cytometry was performed (CD4+, CD8+, and CD56 lymphocytes) after 96 hours. DTH-reaction, activity and mortality rate were documented. The CLP-induced reduction in activity and survival (mortality: 34/40) was significantly (p < 0.03) less sustained in CLP-DHEA (mortality: 22/40). The DTH-ratio (before vs. after secondary challenge) was significantly lowered in CLP-S (1.01 +/- 0.15) compared to CLP-DHEA (1.35 +/- 0.1) after 48 hours (p < 0.01). CLP-DHEA (22.2 +/- 7.9%) was associated with a statistically significant less sustained increase of CD56+ cells (p < 0.01) compared with CLP-S (49.0 +/- 6.9%). DHEA-treatment after CLP was associated with less reduction in the CD8+ T-lymphocyte subsets (p < 0.01 vs. all other groups). DHEA treatment after CLP was associated with fewer alterations in the changes of CD8+ and CD56, cells, and the DTH reaction compared with animals submitted to CLP without any treatment. This difference was associated with improved outcome (reactivity, mortality). These results suggest a modulation at specific immune reactions by DHEA treatment.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12409283&dopt=Abstract Ref: Am J Physiol Endocrinol Metab 2003 Feb;284(2):E390-8
Characterization and identification of steroid sulfate transporters of human placenta.
Ugele B, St-Pierre MV, Pihusch M, Bahn A, Hantschmann P.
I. Frauenklinik Innenstadt and Medizinische Klinik II Grosshadern, Klinikum der Universitat Munchen, D-80337 Munich, Germany.
Human trophoblasts depend on the supply of external precursors, such as dehydroepiandrosterone-3-sulfate (DHEA-S) and 16 alpha-OH-DHEA-S, for synthesis of estrogens. The aim of the present study was to characterize the uptake of DHEA-S by isolated mononucleated trophoblasts (MT) and to identify the involved transporter polypeptides. The kinetic analysis of DHEA-(35)S uptake by MT revealed a saturable uptake mechanism (K(m) = 26 microM, V(max) = 428 pmol x mg protein(-1) x min(-1)), which was superimposed by a nonsaturable uptake mechanism (diffusion constant = 1.2 microl x mg protein(-1) x min(-1)). Uptake of [(3)H]DHEA-S by MT was Na(+) dependent and inhibited by sulfobromophthalein (BSP), steroid sulfates, and probenecid, but not by steroid glucuronides, unconjugated steroids, conjugated bile acids, ouabain, p-aminohippurate (PAH), and bumetanide. MT took up [(35)S]BSP, [(3)H]estrone-sulfate, but not (3)H-labeled ouabain, estradiol-17beta-glucuronide, taurocholate, and PAH. RT-PCR revealed that the organic anion-transporting polypeptides OATP-B, -D, -E, and the organic anion transporter OAT-4 are highly expressed, and that OATP-A, -C, -8, OAT-3, and Na(+)-taurocholate cotransporting polypeptide (NTCP) are not or are only lowly expressed in term placental tissue and freshly isolated and cultured trophoblasts. Immunohistochemistry of first- and third-trimester placenta detected OAT-4 on cytotrophoblast membranes and at the basal surface of the syncytiotrophoblast. Our results indicate that uptake of steroid sulfates by isolated MT is mediated by OATP-B and OAT-4 and suggest a physiological role of both carrier proteins in placental uptake of fetal-derived steroid sulfates.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12406027&dopt=Abstract Ref: Eur J Clin Invest 2002 Oct;32(10):775-84
Longitudinal evolution of HIV-1-associated lipodystrophy is correlated to serum cortisol:DHEA ratio and IFN-alpha.
Christeff N, De Truchis P, Melchior JC, Perronne C, Gougeon ML.
Institut Pasteur, Hopital Raymond Poincare, Garches, CHU Bichat Claude Bernard, Paris Cedex, France.
BACKGROUND: We have previously shown that lipid alterations in HIV-1-associated lipodystrophy (LD) are correlated with decreased serum dehydroepiandosterone (DHEA) and increased cortisol:DHEA ratio and IFN-alpha levels. OBJECTIVE: To evaluate in a longitudinal study whether steroid and cytokine modifications are associated with the evolution of physical changes and lipid alterations associated with LD. METHODS: Thirty-four HIV-1-positive men were followed during 32.5 +/- 4.0 months and tested at four time-points. The patients were subdivided into five groups according to physical changes and anthropometric measurements: LD-negative, initially LD-negative becoming LD-positive, LD-positive unchanged, aggravated or improved. Serum lipids, apolipoproteins, adrenal steroids and cytokines were measured and compared with baseline values. RESULTS: (1) LD aggravation is associated with persistent elevated lipids, a decrease in serum DHEA, an increase in cortisol:DHEA ratio and persistent high levels of IFN-alpha. (2) LD improvement is associated with normalization of serum lipids, an increase in serum DHEA leading to normalization in cortisol:DHEA ratio, and normalization of IFN-alpha levels. (3) In LD-positive men evolution of VLDL cholesterol is negatively correlated with DHEA (r = -0.56, P < 0.01) and positively with cortisol:DHEA ratio (r = 0.62, P < 0.004) and with IFN-alpha (r = 0.57, P < 0.01). (4) The switch to LD is associated with a decrease in serum DHEA. (5) Patients who remained LD-negative maintained normal lipids, elevated cortisol and DHEA, and normal cortisol:DHEA ratio and normal levels of IFN-alpha. CONCLUSIONS: This study indicates that cortisol:DHEA ratio and serum IFN-alpha levels are closely associated with clinical evolution and atherogenic lipid alterations in LD.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12404198&dopt=Abstract Ref: Metabolism 2002 Nov;51(11):1458-62
Low circulating estradiol and adrenal androgens concentrations in men on glucocorticoids: a potential contributory factor in steroid-induced osteoporosis.
Hampson G, Bhargava N, Cheung J, Vaja S, Seed PT, Fogelman I.
Department of Chemical Pathology, St Thomas' Hospital, London, UK.
Reductions in circulating estradiol concentrations could be implicated in the pathogenesis of steroid-induced osteoporosis (SIOP) in men. We assessed serum estradiol and adrenal androgens (dehydroepiandrosterone sulfate [DHEAS] and androstenedione) in 77 men (group A: idiopathic osteoporosis [IOP], n = 38, aged [mean +/- SD] 57.7 +/- 12.1 years; group B: SIOP, n = 39, aged 55.3 +/- 13.1 years). We also studied the relationship between bone mineral density (BMD) and serum estradiol in the group of men with SIOP. In group B, we observed a higher prevalence of low serum testosterone concentrations (<9.0 nmol/L) (P =.0052), which was significantly correlated with steroid dosage (r = -0.42, P =.0089) and estradiol concentrations (r = 0.42, P =.012). There was a significant positive association between BMD at the lumbar spine and serum estradiol (P =.004) in the men with SIOP (group B). A high proportion of subjects had low serum estradiol concentrations (<48 pmol/L) in both groups (group A: 44.7 %, group B: 36 %). Serum adrenal androgens concentrations were also significantly suppressed in group B (serum androstenedione-group A: 4.99 +/- 1.8; Group B: 2.1 +/- 1.6 nmol/L; P =.0001). Serum DHEAS was undetectable in 59% of patients in group B versus 6% in group A (P =.001). Reductions in androstenedione also correlated with steroid dosage (r = -0.35, P =.01). In conclusion, the data show that adrenal androgens synthesis is markedly suppressed in men with SIOP. The clinical relevance of this finding remains to be determined. This study also shows a positive association between serum estradiol and BMD and a high prevalence of low serum estradiol in men with SIOP. Low serum estradiol may contribute to bone loss in men with SIOP.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12402184&dopt=Abstract Ref: Int J Sports Med 2002 Oct;23(7):510-5
Cortisol, DHEA, Performance and Training in Elite Swimmers.
Chatard JC, Atlaoui D, Lac G, Duclos M, Hooper S, Mackinnon L.
Laboratoire de Physiologie, GIP Exercice, Faculte de Medecine Jean Monnet, Saint-Etienne, France.
Salivary cortisol (C) and DHEA concentrations were measured in 9 elite swimmers (4 female and 5male) over a 37-week period, 5 to 12 times per swimmer, before 68 competitions. For female and male swimmers, no significant relationship was found between C, DHEA and performance. For the whole group, C was negatively correlated with week number of training (r = -0.31, p < 0.01). The incorporation of the cumulated distance swum as a second variable in the regression increased r to 0.56 (p < 0.01). The higher the cumulated distance swum, the higher C. No significant relationship was found between DHEA and distance swum. For individual swimmers, 3 of 4 females showed a significant negative relationship between C and cumulated dry-land training. No equivalent relationship was found for DHEA. The 2 males practicing dry-land training showed a significant and negative relationship between DHEA and cumulated dry-land training. No equivalent relationship was found for C. Thus, C and DHEA were not good predictors of swimming performance. C for individual females, and DHEA for individual males were considered useful markers for dry-land training stress.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12401940&dopt=Abstract Ref: Horm Res 2002;58(5):215-22
Increased adrenal androgen levels in patients with prader-willi syndrome are associated with insulin, igf-I, and leptin, but not with measures of obesity.
L'Allemand D, Eiholzer U, Rousson V, Girard J, Blum W, Torresani T, Gasser T.
Foundation Growth Puberty Adolescence, Zurich, Switzerland.
Background/Aim: Since hyperandrogenism in simple obesity is assumed to arise from hyperinsulinism and/or increased insulin-like growth factor I (IGF-I) or leptin levels, we examined how in patients with Prader-Willi syndrome (PWS), the most frequent form of syndromal obesity, the accelerated adrenarche can be explained despite hypothalamic-pituitary insufficiency with low levels of insulin and IGF-I. Methods: In 23 children with PWS and a mean age of 5.6 years, height, weight, fat mass, fasting insulin concentration, insulin resistance (by HOMA-R; see text), and leptin and IGF-I levels were determined to test whether they explain the variance of the levels of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), of androstenedione, and of cortisol before and during 42 months of therapy with growth hormone. Results: The baseline DHEAS, DHEA, and androstenedione concentrations were increased as compared with age-related reference values, whereas the cortisol level was always normal. During growth hormone treatment, the DHEA concentration further rose, and the cortisol level decreased significantly. The insulin and IGF-I concentrations were low before therapy, while fat mass and leptin level were elevated. The hormonal covariates provided alone or together between 24 and 60% of the explanation for the variance of adrenal androgen levels, but the anthropometric variables did not correlate with them. Conclusions: In children with PWS, elevated androgen levels correlate with hormones that are usually associated with adiposity. However, the lack of direct correlations between disturbed body composition and androgen levels as well as the increased sensitivity to insulin and IGF-I are abnormalities specific to PWS, potentially caused by the underlying hypothalamic defect.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12398993&dopt=Abstract Ref: Steroids 2002 Nov;67(12):967-77
Steroid and sterol 7-hydroxylation: ancient pathways.
Lathe R.
Division of Biomedical Sciences, University of Edinburgh, George Square, EH9 9XD, Edinburgh, UK
B-ring hydroxylation is a major metabolic pathway for cholesterols and some steroids. In liver, 7alpha-hydroxylation of cholesterols, mediated by CYP7A and CYP39A1, is the rate-limiting step of bile acid synthesis and metabolic elimination. In brain and other tissues, both sterols and some steroids including dehydroepiandrosterone (DHEA) are prominently 7alpha-hydroxylated by CYP7B. The function of extra-hepatic steroid and sterol 7-hydroxylation is unknown. Nevertheless, 7-oxygenated cholesterols are potent regulators of cell proliferation and apoptosis; 7-oxygenated derivatives of DHEA, pregnenolone, and androstenediol can have major effects in the brain and in the immune system. The receptor targets involved remain obscure. It is argued that B-ring modification predated steroid evolution: non-enzymatic oxidation of membrane sterols primarily results in 7-oxygenation. Such molecules may have provided early growth and stress signals; a relic may be found in hydroxylation at the symmetrical 11-position of glucocorticoids. Early receptor targets probably included intracellular sterol sites, some modern steroids may continue to act at these targets. 7-Hydroxylation of DHEA may reflect conservation of an early signaling pathway.
Crit Care. 2002; 6 (5): 434–438
Decreased levels of dehydroepiandrosterone sulphate in severe critical illness: a sign of exhausted adrenal reserve?
Beishuizen A, Thijs LG, Vermes I.
Department of Intensive Care, VU University Medical Center, Amsterdam, The Netherlands.
INTRODUCTION: Dehydroepiandrosterone (DHEA) and its sulphate (DHEAS) are pleiotropic adrenal hormones with immunostimulating and antiglucocorticoid effects. The present study was conducted to evaluate the time course of DHEAS levels in critically ill patients and to study their association with the hypothalamic-pituitary-adrenal axis. MATERIALS AND METHOD: This was a prospective observational clinical and laboratory study, including 30 patients with septic shock, eight patients with multiple trauma, and 40 age- and sex-matched control patients. We took serial measurements of blood concentrations of DHEAS, cortisol, tumour necrosis factor-alpha and IL-6, and of adrenocorticotrophic hormone immunoreactivity over 14 days or until discharge/death. RESULTS: On admission, DHEAS was extremely low in septic shock (1.2 +/- 0.8 mol/l) in comparison with multiple trauma patients (2.4 +/- 0.5 micromol/l; P < 0.05) and control patients (4.2 +/- 1.8; P < 0.01). DHEAS had a significant (P < 0.01) negative correlation with age, IL-6 and Acute Physiology and Chronic Health Evaluation II scores in both patient groups. Only during the acute phase did DHEAS negatively correlate with dopamine. Nonsurvivors of septic shock (n = 11) had lower DHEAS levels (0.4 +/- 0.3 micromol/l) than did survivors (1.7 +/- 1.1 micromol/l; P < 0.01). The time course of DHEAS exhibited a persistent depletion during follow up, whereas cortisol levels were increased at all time points. CONCLUSION: We identified extremely low DHEAS levels in septic shock and, to a lesser degree, in multiple trauma patients as compared with those of age- and sex-matched control patients. There appeared to be a dissociation between DHEAS (decreased) and cortisol (increased) levels, which changed only slightly over time. Nonsurvivors of sepsis and patients with relative adrenal insufficiency had the lowest DHEAS values, suggesting that DHEAS might be a prognostic marker and a sign of exhausted adrenal reserve in critical illness.
Introduction
Dehydroepiandrosterone (DHEA) and its sulphate (DHEAS) are the most abundant steroids secreted by the adrenal cortex [1]. The concentration of DHEA in the blood oscillates in parallel with cortisol, in response to levels of adrenocorticotrophic hormone (ACTH), but without feedback control at the hypothalamic–pituitary level.
The physiological role and biological actions of DHEA(S) are not well known but studies in humans suggest a positive impact on sense of well-being [2], and DHEA has recently been recognized as a potent modulator of the immune response [1]. DHEA improved host defences by restoring immune cell function and reversed susceptibility to infection [3].
Serum DHEA(S) concentration was low in patients with primary adrenal insufficiency, and short-term oral DHEA replacement improved the clinical condition of these patients [2,4]. Functional or relative adrenal insufficiency frequently occurs in critically ill patients, with possible fatal consequences, although diagnostic criteria for this entity still pose problems [5]. We hypothesize that the serum DHEAS level has utility as a diagnostic tool and a prognostic marker in such patients. Furthermore, low serum concentrations of DHEAS might be a more sensitive marker of hypothalamic–pituitary–adrenal (HPA) hypofunction than is glucocorticoid secretion.
The present study was conducted to evaluate the time course of DHEAS levels (an immunostimulator) as compared with those of cortisol (an immunosuppressor), ACTH (an inducer of DHEAS) and cytokines (stimulators of the HPA axis) in patients with critical illness and in age- and sex-matched control patients.
Discussion
We found a clear dissociation between high blood levels of cortisol and extremely low levels of DHEAS in critically ill patients in both the acute and prolonged phases. Parker and coworkers [7] demonstrated such a divergence in adrenal steroid secretion; in that study serum cortisol was increased in adult men with burn injuries, whereas serum DHEAS was reduced. Luppa and coworkers [8] studied serum androgens in a large group of critically ill patients and also found markedly decreased DHEAS levels in both males and females, mainly in those patients with a prolonged clinical course. These data indicate a shift in adrenal steroid synthesis away from mineralocorticoids and androgens and toward excessive cortisol production. The dissociation between blood levels of cortisol and DHEAS appears to be a contradiction because both hormones are synthesized and secreted mainly by the adrenal cortex. However, DHEAS is produced mainly in the zona reticularis of the adrenal cortex, possibly indicating that a differential alteration in the cortical zone is responsible for DHEAS deficiency during severe critical illness.
The sustained hypercortisolism, as opposed to the marked DHEAS depletion, during severe critical illness could theoretically result in an imbalance between immunosuppressive and immunostimulatory pathways, and may therefore play a role in susceptibility to infectious complications [1].
Interestingly, we found the lowest DHEAS and the highest cortisol levels in nonsurvivors and the most severely ill patients, indicating that the DHEAS : cortisol ratio might be a prognostic indicator for outcome of critical illness, in particular septic shock. Interpretation of cortisol levels measured in seriously ill patients is difficult. Serum cortisol levels that are regarded as high in control individuals may be inappropriately low in patients who are severely ill. We recently showed that functional or relative adrenal insufficiency can be present in critically ill patients despite 'high' initial serum cortisol levels [5]. By using the low-dose ACTH stimulation test and Thorn test, we demonstrated the relative lack of adrenocortical response to extra stimulation by ACTH in some critically ill patients, because their HPA axis is already maximally stimulated. In the present study the low-dose ACTH test identified four patients out of eight with a clinical suspicion for relative adrenal insufficiency. These patients had very low serum concentrations of DHEAS, which may also be a sign of limited adrenocortical reserve arising during the course of critical illness [6].
In both septic and trauma patients we found a similar degree of stimulation of the HPA axis; however, patients with septic shock were more severely ill than were patients with multiple trauma, as reflected by their APACHE II scores, and TNF-a and IL-6 levels. One could argue that this also indicates a state of exhausted adrenal reserve.
We found a relation between dopamine use and DHEAS levels, but only during the acute phase. Therefore, acute depletion of DHEAS might reflect the liberal use of dopamine [9]. In addition, we found a negative correlation between IL-6 and DHEAS during the acute phase. In healthy persons, serum IL-6 correlated inversely with DHEAS, and DHEA administration led to inhibition of IL-6 secretion from monocytes, indicating a functional link between DHEAS and IL-6 [10]. IL-6 can act synergistically with ACTH on the adrenal glands to release cortisol [11]. Therefore, IL-6 may be an important regulator of DHEAS in (acute) critical illness. However, the dopamine dosage and IL-6 levels decreased significantly over time whereas DHEAS concentrations remained low, suggesting different mechanisms for the prolonged DHEAS depletion during critical illness.
We found a negative correlation between age and DHEAS concentrations. DHEAS concentrations exhibit a biphasic time course following the onset of adrenarche, reaching a peak between the ages 20 and 30 years, and with the greatest decline occurring by age 50–60 years [12,13]. This dramatic age-related reduction might be caused by a specific defect in the desmolase activity in the reticular zone of the adrenal gland. Most of patients studied here, including control patients, were aged approximately 50–60 years.
In conclusion, we found extremely low DHEAS levels in virtually all critically ill patients, in both septic shock and multiple trauma. DHEAS depletion was associated with a worse outcome and represents a prognostic marker. Acute depletion of DHEAS is probably related to the use of dopamine and high IL-6 levels. The prolonged depletion of DHEAS might reflect an exhausted adrenal adaptation. Whether DHEA should be administered in DHEAS-deficient states remains to be elucidated. However, theoretically, beneficial effects on immunity, susceptibility for infections and well-being may be expected.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12390533&dopt=Abstract Ref: J Neurochem 2002 Nov;83(3):713-26
Characterization of the dehydroepiandrosterone (DHEA) metabolism via oxysterol 7alpha-hydroxylase and 17-ketosteroid reductase activity in the human brain.
Steckelbroeck S, Watzka M, Lutjohann D, Makiola P, Nassen A, Hans VH, Clusmann H, Reissinger A, Ludwig M, Siekmann L, Klingmuller D.
Department of Clinical Biochemistry, University of Bonn, Sigmund-Freud-Strasse 25, D-53105 Bonn, Germany.
Dehydroepiandrosterone and its sulphate are important factors for vitality, development and functions of the CNS. They were found to be subjects to a series of enzyme-mediated conversions within the rodent CNS. In the present study, we were able to demonstrate for the first time that membrane-associated dehydroepiandrosterone 7alpha-hydroxylase activity occurs within the human brain. The cytochrome P450 enzyme demonstrated a sharp pH optimum between 7.5 and 8.0 and a mean KM value of 5.4 micro m, corresponding with the presence of the oxysterol 7alpha-hydroxylase CYP7B1. Real-time RT-PCR analysis verified high levels of CYP7B1 mRNA expression in the human CNS. The additionally observed conversion of dehydroepiandrosterone via cytosolic 17beta-hydroxysteroid dehydrogenase activity could be ascribed to the activity of an enzyme with a broad pH optimum and an undetectably high KM value. Subsequent experiments with cerebral neocortex and subcortical white matter specimens revealed that 7alpha-hydroxylase activity is significantly higher in the cerebral neocortex than in the subcortical white matter (p < 0.0005), whereas in the subcortical white matter, 17beta-hydroxysteroid dehydrogenase activity is significantly higher than in the cerebral neocortex (p < 0.0005). No sex differences were observed. In conclusion, the high levels of CYP7B1 mRNA in brain tissue as well as in a variety of other tissues in combination with the ubiquitous presence of 7alpha-hydroxylase activity in the human temporal lobe led us to assume a neuroprotective function of the enzyme such as regulation of the immune response or counteracting the deleterious effects of neurotoxic glucocorticoids, rather than a distinct brain specific function such as neurostimulation or neuromodulation.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12390344&dopt=Abstract Ref: Clin Endocrinol (Oxf) 2002 Nov;57(5):677-83
Dehydroepiandrosterone, 17alpha-hydroxyprogesterone and aldosterone responses to the low-dose (1 micro g) ACTH test in subjects with preclinical adrenal autoimmunity.
Laureti S, Candeloro P, Aglietti MC, Giordano R, Arvat E, Ghigo E, Santeusanio F, Falorni A.
Department of Internal Medicine and Endocrine and Metabolic Sciences, University of Perugia, Italy.
OBJECTIVE: The appearance of 21-hydroxylase autoantibodies (21OHAbs) identifies subjects with preclinical adrenal insufficiency. In 21OHAb-positive subjects, the adrenocortical function is best evaluated by peak cortisol (F) levels after the low-dose (1 micro g) ACTH stimulation test (LDT). No information is currently available on the correlation between F and other adrenocortical hormone responses to the LDT in subjects with an ongoing autoimmune adrenal process. In this study, we tested the hypothesis that the dehydroepiandrosterone (DHEA), 17alpha-hydroxyprogesterone (17OHP) and aldosterone (A) responses to the LDT are consensual to that of F during the preclinical phase of autoimmune adrenal insufficiency. DESIGN AND PATIENTS: We studied 12 subjects positive for 21OHAb, in the absence of clinical signs of adrenal insufficiency. On the basis of peak F levels after the LDT, and according to the lower level of normal observed in 15 healthy volunteers (510.4 nmol/l), patients were subdivided into two groups: group A, n = 6 subjects with normal F response; and group B, n = 6 subjects with impaired F response. Results were expressed as absolute delta increase (Delta) between peak and basal levels. RESULTS: DeltaF was significantly higher in group A (314.5 +/- 115.8 nmol/l) than in group B (151.7 +/- 88.2 nmol/l) (P = 0.041). DeltaDHEA and Delta17OHP were also significantly higher in group A (17.0 +/- 13.5 nmol/l and 6.1 +/- 4.4 nmol/l, respectively) than in group B (0.69 +/- 2.25 nmol/l and 1.9 +/- 1.7 nmol/l, respectively) (P = 0.002 and P = 0.041). The difference in DeltaA between the two groups did not reach statistical significance (group A 321.8 +/- 272.0 pmol/l vs. group B 157.0 +/- 154.0 pmol/l). DeltaDHEA, Delta17OHP and DeltaA tended to correlate positively with DeltaF (P = 0.039, P = 0.039 and P = 0.044, respectively), but the correlations did not reach significance after correction of the P-value. CONCLUSIONS: Our study demonstrates a high concordance between F and DHEA, 17OHP and A responses to the LDT in subjects with preclinical adrenal autoimmunity, thus strengthening the concept that the LDT is an accurate test to identify early adrenal dysfunction.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12387582&dopt=Abstract Ref: Scand J Clin Lab Invest 2002;62(5):361-8
Diurnal rhythm and effects of oral contraceptives on serum dehydroepiandrosterone sulfate (DHEAS) are related to alterations in serum albumin rather than to changes in adrenocortical steroid secretion.
Carlstrom K, Karlsson R, Von Schoultz B.
Department of Obstetrics and Gynecology, Clinical Research Center, Karolinska Institutet, Huddinge University Hospital, Sweden.
Dehydroepiandrosterone sulfate (DHEAS), which is of almost exclusive adrenal origin, is important for the androgen status in women and prepubertal children, and DHEAS assays are used in the investigation of hyperandrogenism. There are conflicting reports concerning a diurnal variation in serum DHEAS. Although of adrenocortical origin, serum DHEAS levels are decreased by oral contraceptives (OCs). DHEAS is strongly bound to serum albumin and has a very low metabolic clearance rate. The present study was performed in order to investigate whether a diurnal variation in serum DHEAS exists and, if so, whether this diurnal variation and the decreased DHEAS levels following OC use are related to alterations in adrenocortical steroids or to changes in serum albumin. Serum concentrations of DHEAS, dehydroepiandrosterone (DHEA), cortisol and albumin were determined in blood samples taken every half hour over a 24-h period in 10 healthy women before and during use of combined OCs. Significant and frequently synchronous diurnal variations in serum DHEAS and albumin were found before as well as during OC use. These variations were not synchronous with the diurnal variation in DHEA. OCs significantly decreased serum DHEAS and albumin levels. A multiple regression analysis showed changes in albumin to be the most decisive factor for the diurnal variation as and for OC-induced changes in DHEAS. Changes in serum DHEAS during the day and following OC use are related to alterations in its main binding protein, serum albumin, rather than to changes in adrenocortical steroid secretion.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12387516&dopt=Abstract Ref: J Pediatr Endocrinol Metab 2002 Sep-Oct;15(8):1173-81
Precocious puberty: clinical and endocrine profile and factors indicating neurogenic precocity in Indian children.
Bajpai A, Sharma J, Kabra M, Kumar Gupta A, Menon PS.
Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi.
The objective of this study was to evaluate the clinical and endocrine profile of patients with precocious puberty followed up in a tertiary care hospital. Records of 140 patients (114 girls, 26 boys) with precocious puberty were reviewed. Clinical features including age of onset, stage of pubertal development, presenting symptoms, features suggestive of CNS involvement and family history were analyzed. Endocrine investigations included basal and GnRH-stimulated levels of LH and FSH as well as 17OHP, DHEA, hCG and thyroid profile. Abdominal and pelvic ultrasonography and CNS imaging were correlated with clinical features. Girls outnumbered boys in this series (4.4:1). Neurogenic central isosexual precocious puberty (CIPP) was more common in boys (10 out of 18, 55.6%) than girls (16 out of 77, 20.8%). The most common cause of neurogenic CIPP was hypothalamic hamartoma present in five girls and four boys. Other causes of neurogenic CIPP included neurotuberculosis, pituitary adenoma, hydrocephalus, post radiotherapy, CNS tumors and malformations. Peripheral precocious puberty (PPP) was secondary to adrenal causes in boys and ovarian cysts in girls. Benign variants of precocious puberty, such as premature thelarche and premature adrenarche, were present in 23 and six girls, respectively. Hypothyroidism was present in four girls and McCune-Albright syndrome in one girl. Girls with neurogenic CIPP had a lower age of onset as compared to idiopathic CIPP (3.6 +/- 2.7 years vs 5.4 +/- 2.5 years, p = 0.014). The lowest age of onset was seen in girls with hypothalamic hamartoma (1.6 +/- 0.9 years). Forty-seven girls with CIPP (seven neurogenic and 40 idiopathic) presented after the age of 6 years. Features of CNS involvement, in the form of seizures, mental retardation, raised intracranial tension or focal neurological deficits, were present in seven girls (43.8%) and four boys (40%), and gelastic seizures were present in three children. Girls with CIPP had greater bone age advancement (3.4 +/- 1.5 years) and negative height standard deviation for bone age (-2.7 +/- 1.5) than those with PPP (1.9 +/- 1.6 years and -1.3 +/- 1.3) and premature thelarche (0.4 +/- 0.4 years and -0.8 +/- 0.8). Patients with neurogenic CIPP had significantly higher levels of baseline and GnRH-stimulated levels of LH and FSH and LH:FSH ratio than those with idiopathic CIPP. Occurrence of neurogenic CIPP in seven girls with an age of onset after 6 years emphasizes the need for CNS imaging in these girls contrary to the current recommendations. The fact that 65.6% cases of idiopathic CIPP presented after the age of 6 years raises the possibility that these patients may be physiological variants of normal puberty. Pointers to neurogenic CIPP included early age of onset in girls, clinical features of CNS involvement, and elevated basal and stimulated LH levels and LH:FSH ratio.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12385014&dopt=Abstract Ref: Int J Cancer 2002 Nov 10;102(2):172-8
Relationship between serum hormone concentrations, reproductive history, alcohol consumption and genetic polymorphisms in pre-menopausal women.
Garcia-Closas M, Herbstman J, Schiffman M, Glass A, Dorgan JF.
Division of Cancer Epidemiology and Genetics, National Cancer Institute/NIH, 6120 Executive Boulevard, Bethesda, MD 20852-7234, USA.
Reproductive characteristics, alcohol intake and polymorphisms in genes encoding sex-steroid metabolizing enzymes might influence the risk of hormone-related cancers by changing circulating concentrations of sex hormones. The relationship between these factors and serum concentrations of estradiol, progesterone, androstenedione, testosterone and DHEA was evaluated in a cross-sectional study of 218 pre-menopausal women from Kaiser Permanente Health Plan in Portland, Oregon. Risk factor information was obtained from questionnaires and hormone serum concentrations were determined by radioimmunoassays. Genotypes for CYP11A 5'UTR(tttta)n, CYP17 5'-UTR -34 T>C, CYP19 IVS4(ttta)n, CYP1B1 (L432V and S453N) and COMT (V158M) were determined from genomic DNA samples. Increasing number of full-term pregnancies was associated with a significant decrease in late-follicular progesterone levels (p-trend = 0.03). Increasing alcohol consumption was associated with higher estradiol levels averaged through the menstrual cycle (p-trend = 0.009) and higher progesterone levels during luteal phase (p-trend = 0.04). Androstenedione and testosterone levels were higher among light to moderate drinkers compared to non-drinkers, although we only observe a significant trend with increasing levels of alcohol consumption for androstenedione. Women heterozygous or homozygous for the CYP1B1 L432V or the S453N polymorphisms had increased luteal estradiol levels (p-value = 0.04 for L432V and 0.04 for S453N). None of the other factors evaluated was significantly associated with serum concentration of hormones. In conclusion, results from this cross-sectional study of pre-menopausal women provide support for an association between light to moderate alcohol intake and elevated levels of estrogen and androgen levels. Our data suggest that circulating levels of progesterone might be related to parity and alcohol consumption, however the biological plausibility of the observed associations is unclear. We found little support for an influence of the evaluated genetic polymorphisms in the steroid synthesis and metabolism pathway on serum hormone levels, except for a possible effect of the CYP1B1 L432V and S453N polymorphisms on serum estradiol levels.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12384998&dopt=Abstract Ref: J Cell Physiol 2002 Nov;193(2):208-18
Polarized glucose transporters and mRNA expression properties in newly developed rat syncytiotrophoblast cell lines, TR-TBTs.
Kitano T, Iizasa H, Terasaki T, Asashima T, Matsunaga N, Utoguchi N, Watanabe Y, Obinata M, Ueda M, Nakashima E.
Department of Pharmaceutics, Kyoritsu College of Pharmacy, Tokyo, Japan.
In this study, we have established new syncytiotrophoblast cell lines (TR-TBTs) from the recently developed transgenic rat harboring temperature-sensitive simian virus 40 large T-antigen gene (Tg-rat). Four conditionally immortalized syncytiotrophoblast cell lines (TR-TBT 18d-1 approximately 4) were obtained from pregnant Tg-rats at gestational day 18. These cell lines had a syncytium-like morphology, could be prepared as monolayers, expressed cytokeratins and rat syncytiotrophoblast markers, and exhibited apical or basal GLUT1 localizations and apical GLUT3 localizations. TR-TBTs express large T-antigen and grow well at 33 degrees C with a doubling time of about 30 h. TR-TBTs have processes for the uptake of dehydroepiandrosteron-3-sulfate (DHEAS) and these are predominantly located on the basal side, and this is the first report of an in vitro model of blood placental barrier (BPB) able to incorporate DHEAS. Therefore, TR-TBTs are an appropriate in vitro model for investigating carrier-mediated transport functions at the BPB. Moreover, TR-TBTs express betaine/GABA transporter (GAT-2/BGT-1), concentrative nucleoside transporter 2 (CNT2), equilibrative nucleoside transporter 1 (ENT1), and ENT2 and the expression of these transporters has been reported in blood-brain barrier (BBB). Thus, the expression patterns of nucleoside and neurotransmitter transporters examined are quite similar in both the BPB and BBB.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12383452&dopt=Abstract Ref: Psychoneuroendocrinology 2002 Nov;27(8):907
Basal plasma hormone levels in depressed perimenopausal women.
Schmidt P, Murphy J, Haq N, Danaceau M, St Clair L.
NIMH, Building 10, Room 3N-238, 10 Center Drive MSC 1276, 20892-1276, Bethesda, MD, USA
BACKGROUND: An association between abnormal changes in reproductive endocrine function during the perimenopause and the onset of depression in some women has been suggested but remains controversial.METHODS: We examined basal plasma hormone levels in two samples of women with well characterized, first onset depression (major or minor) during the perimenopause and matched comparison groups of asymptomatic women. Results were compared by analysis of variance.RESULTS: No significant diagnosis-related differences were observed in plasma hormone measures of the following: follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), estrone (E1), total (T) or free testosterone (FT), or the E2/LH ratio. We did identify significantly lower morning plasma dehydroepiandrosterone (DHEA) and its sulphated metabolite DHEA-S (but not cortisol) levels in the depressed women compared to the non-depressed comparison group. Women with hot flushes (regardless of the presence of depression) were significantly older than women without flushes, had significantly higher plasma levels of FT, LH and FSH, and had significantly lower E2/LH ratios.CONCLUSIONS: Women with first onset depression during the perimenopause are not distinguished from controls on the basis of basal hormone measures of ovarian estrogens, testosterone, or gonadotropins. However, perimenopause-related changes in E2 may interact with low levels of DHEA in some women to increase their vulnerability to develop depression. In contrast to perimenopause-related vasomotor symptoms, depression during the perimenopause is not associated with a simple hormone deficiency state. The relatively low levels of E2 and E1 in the depressed women may have met statistical significance in a much larger and homogenous sample.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12380796&dopt=Abstract Ref: J Microbiol Immunol Infect 2002 Sep;35(3):199-202
Dehydroepiandrosterone (DHEA) attenuates allergic airway inflammation in Dermatophagoides farinae-sensitized mice.
Yu CK, Liu YH, Chen CL.
Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
Dehydroepiandrosterone or DHEA, an androgen abundant in circulation, has important immunomodulating effects. In this study the therapeutic effect of dehydroepiandrosterone on established allergic inflammation was examined in a dust mite (Dermatophagoides farinae)-induced asthma model. Airway inflammation was provoked in D. farinae-sensitized BALB/c mice by repetitive intratracheal challenge (3 times, once a week). Three days after the first challenge, mice were fed a diet incorporated with 1.5% (w/w) dehydroepiandrosterone and were examined at days 3 and 6 after the last challenge. Airway challenge resulted in pulmonary eosinophilic inflammation accompanied by elevated blood eosinophil counts and elevated serum and bronchoalveolar lavage immunoglobulin E antibody levels in control diet-fed mice. However, the D. farinae-induced airway inflammation and blood eosinophilia was significantly reduced in dehydroepiandrosterone-fed mice, which was associated with a decrease in serum interleukin-4, interleukin-5, and interferon-gamma levels. Total immunoglobulin E antibody concentrations in serum and bronchoalveolar lavage fluids were not affected by the dehydroepiandrosterone treatment. These results demonstrated that dehydroepiandrosterone could suppress preexisting allergic airway inflammation.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12379925&dopt=Abstract Ref: J Pharm Sci 2002 Nov;91(11):2399-407
Skin permeation study of dehydroepiandrosterone (DHEA) compared with its alpha-cyclodextrin complex form.
Ceschel GC, Mora PC, Borgia SL, Maffei P, Ronchi C.
Dipartimento di Scienze Farmaceutiche, Universita di Bologna, via San Donato 19/2, 40100 Bologna, Italy.
Several studies have shown that dehydroepiandrosterone (DHEA) has promising uses in a large range of pathologies including age-related illnesses (osteoporosis, atherosclerosis), immune dysfunctions, and cancer. A long-term oral dosage form would be favorable, but this type of medication has not been developed yet because of the important first-pass effect and low and variable bioavailability. A proposed alternative strategy is the preparation of DHEA for transdermal permeation, allowing direct absorption in the systemic circulation. DHEA has shown good permeation properties through the stratum corneum, however its poor water solubility limits its dosage form concentration and represents the major obstacle to the formulation of a reservoir transdermal system. However, alpha-cyclodextrins have been shown to improve the solubility, the dissolution properties, and the partition coefficient of DHEA. This paper deals with the formulation and evaluation of a transdermal gel containing an alpha-cyclodextrin complex with DHEA. In in vitro permeation tests on porcine skin, the formulation containing the complex improved the permeation flux of DHEA. The study also shows that a gel formulation improved drug permeation with respect to simple water suspension.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12378185&dopt=Abstract Ref: J Pediatr 2002 Oct;141(4):477-82
Increased adrenocortical and adrenomedullary hormonal activity in 12-year-old children born small for gestational age.
Tenhola S, Martikainen A, Rahiala E, Parviainen M, Halonen P, Voutilainen R.
Departments of Pediatrics and Clinical Chemistry, Kuopio University Hospital, and the Computing Centre, Kuopio University, Kuopio, Finland.
OBJECTIVES: To determine whether adrenal hormonal activity is altered in children born small for gestational age (SGA), and whether concentrations of adrenal hormones relate to those of serum lipids or to anthropometric measures. STUDY DESIGN: We studied 55 SGA children and 55 appropriate for gestational age (AGA) children at the age of 12 years in a case-control setting. The concentrations of fasting serum cortisol, dehydroepiandrosterone sulfate (DHEAS), plasma epinephrine (E), and norepinephrine (NE) were analyzed. RESULTS: The SGA children had significantly higher mean concentrations of serum DHEAS (3.53 vs 2.89 micromol/L, P =.009) and plasma E (0.33 vs 0.25 nmol/L, P =.005) than their age- and sex-matched control subjects. The mean serum cortisol and plasma NE concentrations did not differ significantly between the groups. However, the SGA children in the highest quartile for serum cortisol had significantly higher concentrations of plasma E (0.50 vs 0.28 nmol/L, P <.001), serum LDL (3.21 vs 2.73 mmol/L, P =.025) and total cholesterol (5.06 vs 4.42 mmol/L, P =.021) than the SGA children in the lower cortisol quartiles. The factors associating with high levels of plasma E in the SGA children were high level of serum cortisol [odds ratio (OR) = 3.8, 95% confidence interval (95% CI) = 1.5-10], LDL cholesterol (OR = 3.9, 95% CI = 1.3-12), male sex (OR = 8.3, 95% CI = 1.0-68) and low birth weight (OR = 1.4, 95% CI = 1.0-1.8) in multiple logistic regression analysis. CONCLUSIONS: Twelve-year-old children born SGA had increased DHEAS and epinephrine levels in circulation. High serum cortisol concentrations are associated with high epinephrine, LDL, and total cholesterol levels.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12376336&dopt=Abstract Ref: Am J Physiol Endocrinol Metab 2002 Nov;283(5):E1067-75
Effect of treatment of diabetic rats with dehydroepiandrosterone on vascular and neural function.
Yorek MA, Coppey LJ, Gellett JS, Davidson EP, Bing X, Lund DD, Dillon JS.
Veterans Affairs Medical Center, Diabetes Endocrinology Research Center, and Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52246, USA.
Nutritional supplementation with dehydroepiandrosterone (DHEA) may be a candidate for treating diabetes-induced vascular and neural dysfunction. DHEA is a naturally occurring adrenal androgen that has antioxidant properties and is reportedly reduced in diabetes. Using a prevention protocol, we found that dietary supplementation of streptozotocin-induced diabetic rats with 0.1, 0.25, or 0.5% DHEA caused a concentration-dependent prevention in the development of motor nerve conduction velocity and endoneurial blood flow impairment, which are decreased in diabetes. At 0.25%, DHEA significantly prevented the diabetes-induced increase in serum thiobarbituric acid-reactive substances and sciatic nerve conjugated diene levels. This treatment also reduced the production of superoxide by epineurial arterioles of the sciatic nerve. DHEA treatment (0.25%) significantly improved vascular relaxation mediated by acetylcholine in epineurial vessels of diabetic rats. Sciatic nerve Na+-K+-ATPase activity and myoinositol content was also improved by DHEA treatment, whereas sorbitol and fructose content remained elevated. These studies suggest that DHEA, by preventing oxidative stress and perhaps improving sciatic nerve Na+-K+-ATPase activity, may improve vascular and neural dysfunction in diabetes.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12375289&dopt=Abstract Ref: Microsurgery 2002;22(6):234-41
Dehydroepiandrosterone as an enhancer of functional recovery following crush injury to rat sciatic nerve.
Gudemez E, Ozer K, Cunningham B, Siemionow K, Browne E, Siemionow M.
Department of Plastic Surgery, A60, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
This study was designed to investigate the effect of dehydroepiandrosterone (DHEA) on the recovery of the rat sciatic nerve following crush injury. A standard hemostat system was used to create the injury, with a length of 1.5 mm in three groups of 18 animals each. In group I, the crush injury was applied without any treatment. In groups II and III, vehicle (ethylene glycol) and DHEA solutions were injected subepineurally 30 min following the crush injury. Sciatic function index (SFI), toe contracture measurement, gastrocinemius muscle weight, total number of myelinated fibers, fiber diameters, myelin thickness, and axon/fiber cross-sectional ratio were measured at 3, 6, and 12 weeks. The SFI values in the DHEA group showed a faster return to normal values confirmed at 3 and 6 weeks (P < 0.05). The number of myelinated fibers and fiber diameters at 6 and 12 weeks were significantly higher in the DHEA group (P < 0.05). In this study, the subepineural injection of DHEA following crush injury was found to enhance functional recovery of the rat sciatic nerve.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12370113&dopt=Abstract Ref: Eur J Endocrinol 2002 Oct;147(4):503-6
Apolipoprotein E gene determines serum testosterone and dehydroepiandrosterone levels in postmenopausal women.
Zofkova I, Zajickova K, Hill M, Horinek A.
Institute of Endocrinology, Narodni 8, Prague 1 116 94, Czech Republic.
OBJECTIVE: Apolipoprotein E (ApoE) is believed to play an important role in lipid metabolism and has been found to be related to diseases associated with ageing, the important characteristic of which is decline in circulating sex steroids, including androgen. DESIGN: To find the relationships of levels of serum testosterone and its precursor, dehydroepiandrosterone (DHEA), to ApoE polymorphism in 113 postmenopausal Caucasian women. METHODS: The ApoE genotype was assessed by polymerase chain reaction and CfoI endonuclease digestion. ApoE genotype distribution was as follows: E2/3, 15%; E3/3, 71.7%; E2/4, 1.8%; E3/4, 10.6; and E4/4, 0.89%. The differences in serum androgen levels between genotypes were evaluated by ANCOVA and least significant difference (LSD) multiple comparisons test after adjustment for body mass index, age and/or years since menopause. RESULTS: Significant intergroup differences between the most frequent allele combination (2/3, 3/3 and 3/4) in serum DHEA levels were found (P<0.05, ANCOVA). DHEA levels were higher in women with the E3/4 allele combination than in the E3/3 genotype (P<0.01, LSD multiple comparisons). In serum testosterone levels, borderline intergroup differences were found (P<0.07, ANCOVA). Higher testosterone levels were found in the E3/4 allele combination as compared with E3/3 (P<0.05, LSD multiple comparisons). Dose effect of E4 allele analysis indicated higher serum DHEA and testosterone levels in women with the E4 allele present than in women with the E4 allele absent (P<0.003 for DHEA, P<0.007 for testosterone, ANCOVA). CONCLUSIONS: Circulating testosterone and DHEA are associated with the ApoE genotype, which may render women missing the allele E4 more susceptible to the development of some diseases associated with ageing and menopause.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12269389&dopt=Abstract Ref: Life Sci 2002 Apr 19;70(22):2623-30
Chemoprevention of precursors to colon cancer by dehydroepiandrosterone (DHEA).
Osawa E, Nakajima A, Yoshida S, Omura M, Nagase H, Ueno N, Wada K, Matsuhashi N, Ochiai M, Nakagama H, Sekihara H.
The Third Department of Internal Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan.
Although dehydroepiandrosterone (DHEA) is recognized as one of the major adrenal androgens, its precise physiological role in the human endocrine system remains to be elucidated. In particular, the effect of DHEA on carcinogenesis has not been fully characterized. We undertook this study to determine whether DHEA has a chemopreventative effect on the precursors of colon cancer in a murine model of azoxymethane (AOM)-induced aberrant crypt foci (ACF). The number of ACF was significantly decreased in mice treated with 0.4% (p < 0.001) and 0.8% DHEA (p < 0.001), but there were no significant differences between DHEA-treated and control mice in terms of the ACF size, 3-catenin expression or level of dysplasia. This is the first study of colon cancer carcinogenesis demonstrating that DHEA treatment can decrease the number of ACF without apparently modifying their malignant potential. These data strongly suggest that DHEA might be a potential chemopreventative agent against human colon cancer.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12233218&dopt=Abstract Ref: Rev Med Liege 2002 Jul;57(7):438-42
DHEA and rejuvenating intracrinology? Between reason and magic
[Article in French]
Bourguignon R, Uhoda I, Henry F, Pierard-Franchimont C, Pierard GE.
Service, Universite de Liege, Service de Dermatopathologie.
Slowing down ageing is a goal for a large part of the population. Some mercantile claims hold out bright prospects to DHEA. The effects of this hormone manifest themselves after intracrine conversion. In the skin, sebaceous glands enlarge and seborrhoea increases in post-menopausal women. No other effect is clinically discernable on the skin. At this level, DHEA does not show efficacy comparable to that of other anti-ageing compounds.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12231116&dopt=Abstract Ref: Steroids 2002 Sep;67(10):815-9
The estrogen receptor alpha gene determines serum androstenedione levels in postmenopausal women.
Zofkova I, Zajickova K, Hill M.
Institute of Endocrinology, Narodni 8, 116 94 1, Prague, Czech Republic.
Estrogen receptors (ER) are expressed not only in the reproductive system and ovaries but also in some other tissues, including the adrenal gland. The purpose of this study was to assess the association between the estrogen receptor (ER) alpha gene polymorphisms XbaI and PvuII and circulating levels of androstenedione, a precursor of sex-steroids synthetized in the ovary and adrenal. After adjustment for years since menopause, body mass, and dehydroepiandrosterone (DHEA) levels, a highly significant relationship was demonstrated between androstenedione and XbaI or PvuII polymorphisms, the highest levels of the hormone being found in the xx and pp genotypes (P<0.05 as compared to XX or PP, ANCOVA followed by least significant difference (LSD) multiple comparisons). This suggests that the ER genotype may determine the function of the sex-steroid system not only at the receptor level but also at the level of hormone synthesis. The pathogenetic role of this association in diseases related to menopause, such as osteoporosis, remains to be determined.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12207110&dopt=Abstract Ref: Psychother Psychosom 2002 Sep-Oct;71(5):298-303
Elevated blood levels of dehydroepiandrosterone sulphate vary with symptom load in posttraumatic stress disorder: findings from a longitudinal study of refugees in Sweden.
Sondergaard HP, Hansson LO, Theorell T.
CTD (Center for Torture and Trauma Survivors), Karolinska Vagen, Stockholm, Sweden.
BACKGROUND: The present study is part of a longitudinal study of recently resettled refugees with the aim of learning which factors in their daily life influence health as measured by self-report and stress-responsive hormones. METHODS: In a group of recently resettled refugees with a high incidence of posttraumatic stress disorder (PTSD), diagnosed by structured interview, self-rated symptoms of PTSD were followed three times over a period of 9 months after inclusion in the study. Eighty-six individuals were included in the study and 58 subjects (67.4%) completed it. Blood samples were drawn at each examination for assessment of hormone levels. RESULTS: After adjustment for age, dehydroepiandrosterone sulphate (DHEA-s) was observed to be higher in non-depressed PTSD cases than in non-PTSD without depression. There was an interaction between PTSD and depression regarding DHEA-s levels. DHEA-s correlated significantly with changes in self-rated symptoms of PTSD at last follow-up; the greater the increase in PTSD symptoms, the greater the increase in plasma DHEA-s. The variation of DHEA-s levels in relation to changes in self-rated health in non-PTSD showed the opposite pattern, although not reaching significance. CONCLUSIONS: The finding of changes in DHEA-s should encourage further studies of the role of altered steroid metabolism in PTSD.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12208665&dopt=Abstract Ref: J Endocrinol 2002 Sep;174(3):447-54
Dehydroepiandrosterone treatment attenuates oestrogen-induced pituitary hyperplasia.
Suarez C, Garcia Tornadu I, Khalil W, Becu-Villalobos D.
Instituto de Biologia y Medicina Experimental, CONICET V, Obligado 2490 (1428) Buenos Aires, Argentina.
The physiological importance of and therapeutic interest in dehydroepiandrosterone (DHEA) has been predominantly in relation to its action as an inhibitor of the promotion and progression of several kinds of tumours, including those of breast, prostate, lung, colon, liver and skin tissues. The aim of the present study was to determine the role of DHEA in diethylstilboestrol (DES)-induced pituitary hyperplasia. Female Sprague-Dawley rats were divided into four treatment groups: DES (implanted s.c. with a 20 mg DES pellet), DHEA (two 50 mg DHEA pellets), DHEA/DES (both DHEA and DES pellets), and controls (not implanted). Every week, all rats were weighed and cycled, and jugular blood samples were obtained. After 7 weeks, rats were killed. Hypophyses were removed and weighed, and serum prolactin, GH, IGF-I and leptin levels were assayed by RIA. DHEA cotreatment reduced pituitary enlargement by 39% in DES-treated rats. It also reduced the hyperprolactinaemia (280.4+/-43.6 ng/ml for DHEA/DES vs 823.5+/- 127.1 ng/ml for DES) and partially reversed the loss of body weight induced by DES. DHEA treatment did not modify the effects of DES on serum GH, IGF-I and leptin levels. But DHEA per se also increased pituitary weight and induced hyperprolactinaemia, although to a lesser degree than DES. We conclude that DHEA administration has beneficial effects on oestrogen-induced pituitary hyperplasia and hyperprolactinaemia, but the fact that DHEA per se also induces diverse hormonal effects and a slight pituitary enlargement limits its use as a possible therapeutic drug.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12208664&dopt=Abstract Ref: J Endocrinol 2002 Sep;174(3):435-46
Detection of oestrogenic activity of steroids present during mammalian gestation using oestrogen receptor alpha- and oestrogen receptor beta-specific in vitro assays.
Lemmen JG, van den Brink CE, Legler J, van der Saag PT, van der Burg B.
Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
Numerous steroid hormones are present in the foetus but their potential to activate oestrogen receptor (ER) alpha and/or beta is largely unknown. In this study, in vitro assays were developed to rapidly and specifically detect ERalpha or ERbeta activation by these steroid hormones. Our results showed that several oestrogen precursors and androgens are able to activate both ERalpha and ERbeta. Of special interest is that some of these precursors are able to activate ERalpha and ERbeta at concentrations that are present during human gestation. Moreover, some precursors (dehydroepiandrosterone (DHEA) and 17-hydroxylated pregnenolone sulphate) and androgens (5-androsten-3beta,16alpha,17beta-triol and testosterone) showed a more than 100-fold relative preference for ERbeta transactivation over ERalpha transactivation when compared with 17beta-oestradiol. Due to their relatively high levels, the precursor steroids DHEA and pregnenolone may be of particular importance in the regulation of ERbeta activity in vivo. To obtain information about the oestrogenic activity of the total pool of steroid hormones present during mammalian gestation, steroids were extracted from mouse embryos at different prenatal stages and assayed for oestrogenic activity in the established in vitro assays. Oestrogenic activity was detected in steroid extracts from all stages tested. This study has demonstrated that oestrogen receptor agonists are present in the murine embryo and that oestrogen precursors may contribute to the total pool of agonists during foetal life.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12207557&dopt=Abstract Ref: Endocr Regul 2002 Jun;36(2):79-86
Steroid hormones in human semen with particular respect to DHEA (dehydroepiandrosterone) and its immunomodulatory metabolites.
Pohanka M, Hampl R, Sterzl I, Starka L.
Institute of Endocrinology, Narodni 8, 116 94 Praha 1, Czech Republic.
OBJECTIVE: In addition to many components, seminal fluid contains also hormonal steroids. So far, the studies were focused mostly to androgens, their precursors, estrogens and also cortisol, in most instances in relation to sperm abnormalities. Our group detected for the first time in the ejaculate 7-hydroxylated metabolites of dehydroepiandrosterone (DHEA), believed to function as immunomodulatory and immunoprotective agents. Occurrence of steroids in seminal fluid and their possible role is reviewed in the first part of the article. METHODS: In a group of 34 men (age 21-46 years) with various problems of fertility the presence of 7-hydroxydehydroepiandrosterone isomers and dehydroepiandrosterone in seminal fluid was found. The concentrations of steroids in seminal fluid and plasma were determined by recently developed radioimmunoassay. In brief, the ejaculate was extracted twice with diethyl ether and the water phase was separated by freezing in solid carbon dioxide and evaporating the solvent to dryness. The dry residue was dissolved in methanol:water:light petroleum ether (1.3:1.0:0.3 ml) and mixed. After separation the water-methanolic phase was evaporated, the dry residue was re-dissolved in phosphate buffer and aliquots were used for RIA. The results were corrected for losses by counting the residual radioactivity of [(3)H] testosterone added initially to the sample of seminal fluid. RESULTS: The concentrations of 7-hydroxydehydroepiandrosterone varied from 1.08 to as much as 15.7 nmol/l, while those of dehydroepiandrosterone were about five times higher. The concentrations of both 7-hydroxydehydroepiandrosterone isomers were close to or even higher than recently reported levels of these substances in blood serum. CONCLUSION: The presence of steroids derived from dehydroepiandrosterone by 7-hydroxylation with recently reported immunomodulatory activity was for the first time demonstrated in seminal fluid of normal men.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12199273&dopt=Abstract Ref: Prescrire Int 2002 Aug;11(60):118-23
DHEA: the last elixir.
(1) DHEA, or dehydroepiandrosterone, is an adrenal steroid. Its physiological role is unclear, but it is known to be an intermediate in sex hormone synthesis. DHEA replacement therapy is not currently indicated in adrenal insufficiency. (2) Plasma DHEA levels are so low in most animal species that they are difficult to measure, hindering studies of the impact of DHEA on ageing. Most animal studies are based on administration of pharmacological doses. (3) Clinical data have been obtained in a very large number of observational studies, in which plasma concentrations of DHEA were measured in various situations. The only established fact is that circulating concentrations show wide interpersonal variability and a tendency to fall with age. Low DHEA levels have not so far been linked to any specific health disorders. (4) Clinical trials of DHEA have focused on cognitive function, well-being, libido, immunostimulation, etc. There is no proof that DHEA is beneficial in these areas. (5) The side effects of DHEA are linked to its androgenic effects (acne, hirsutism), its unfavourable effects on lipid metabolism (a cardiovascular risk factor), and a possible growth-stimulating effect on hormone-dependent malignancies (prostate, breast). (6) In practice, there is currently no scientific reason to prescribe DHEA for any purpose whatsoever.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12195234&dopt=Abstract Ref: Neuroendocrinol Lett 2002 Aug;23(4):321-4
Dehydroepiandrosterone regulation of prolactin gene expression in the anterior pituitary does not depend on galanin induction.
Piroli GG, Pietranera L, Grillo CA, De Nicola AF.
Laboratorio de Bioquimica Neuroendocrina, Instituto de Biologia y Medicina Experimental, UBA-CONICET, Buenos Aires, Argentina.
OBJECTIVES: The effects of dehydroepiandrosterone (DHEA) on galanin (GAL) and prolactin (PRL) mRNA expression in the anterior pituitary of Fischer 344 rats were studied, taking in consideration that: (1) DHEA is an androgen with estrogenic activity on pituitary lactotrophs; (2) estrogens induce prolactinomas in Fischer 344 rats; and (3) GAL has been considered the main mediator of estrogen-induced lactotroph proliferation. DESIGN: Female rats were ovariectomized and used as controls or treated during 2 weeks with DHEA (500 mg/kg/day or 5 mg/kg/day or 50 mg/kg/day) or estradiol (E2, 50 microg/kg/day), as a positive control for pituitary growth and GAL induction. GAL and PRL mRNA expression were studied by in situ hybridization. RESULTS: Both DHEA and E2 induced PRL mRNA synthesis. However, DHEA neither produced pituitary enlargement nor GAL induction, in contrast to E2. CONCLUSIONS: Our results shows that GAL is not involved in the estrogenic activity of DHEA on pituitary lactotrophs, and suggest that DHEA effects are exerted directly on the PRL gene or through another mechanism(s) not related to GAL.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12193536&dopt=Abstract Ref: Endocrinology 2002 Sep;143(9):3250-8
Dehydroepiandrosterone modulates nuclear factor-kappaB activation in hippocampus of diabetic rats.
Aragno M, Mastrocola R, Brignardello E, Catalano M, Robino G, Manti R, Parola M, Danni O, Boccuzzi G.
Department of Experimental Medicine and Oncology, General Pathology Section, University of Turin, Turin 10126, Italy.
Oxidative stress induced by chronic hyperglycemia contributes to cerebrovascular complications in diabetes. Reactive oxygen species activate the transcription factor nuclear factor-kappaB (NF-kappaB), which in turn activates a variety of target genes linked to the development of diabetic complications. Dehydroepiandrosterone, an adrenal steroid, which possesses a multitargeted antioxidant effects, is also synthesized de novo by the brain. Normoglycemic and streptozotocin-diabetic rats were either treated with dehydroepiandrosterone (DHEA) for 7, 14, or 21 d (4 mg/d per rat) or left untreated. Oxidative state, antioxidant balance and activation of nuclear transcriptional redox-sensitive factor NF-kappaB were evaluated in the hippocampus area. In streptozotocin-treated rats, besides the strong increase in oxygen reactive species, there is also a persistent activation of NF-kappaB. The derangement of the oxidative balance in the brain induced by diabetes improves with DHEA. Moreover, DHEA completely counteracts NF-kappaB activation, measured as DNA binding activity, and hinders the increase of IkappaB-alpha inhibitory subunit induced by oxidative stress. The time-lag of DHEA's effects on NF-kappaB activation parallels its effects on oxidative balance. Results indicate that DHEA might protect hippocampus from chronic activation of NF-kappaB-dependent genes by reducing NF-kappaB nuclear translocation. This could result in protection from diabetes-dependent brain damage.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12193187&dopt=Abstract Ref: Eur J Neurosci 2002 Aug;16(3):445-53
Dehydroepiandrosterone (DHEA) stimulates neurogenesis in the hippocampus of the rat, promotes survival of newly formed neurons and prevents corticosterone-induced suppression.
Karishma KK, Herbert J.
Department of Anatomy, University of Cambridge, Cambridge, CB2 3DY, UK.
Treating adult male rats with subcutaneous pellets of dehydroepiandrosterone (DHEA) increased the number of newly formed cells in the dentate gyrus of the hippocampus, and also antagonized the suppressive of corticosterone (40 mg/kg body weight daily for 5 days). Neither pregnenolone (40 mg/kg/day), a precursor of DHEA, nor androstenediol (40 mg/kg/day), a major metabolite, replicated the effect of DHEA (40 mg/kg/day). Corticosterone reduced the number of cells labelled with a marker for neurons (NeuN) following a 28-day survival period, and this was also prevented by DHEA. DHEA by itself increased the number of newly formed neurons, but only if treatment was continued throughout the period of survival. Subcutaneous DHEA pellets stimulated neurogenesis in a small number of older rats ( approximately 12 months old). These results show that DHEA, a steroid prominent in the blood and cerebral environment of humans, but which decreases markedly with age and during major depressive disorder, regulates neurogenesis in the hippocampus and modulates the inhibitory effect of increased corticoids on both the formation of new neurons and their survival.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12181608&dopt=Abstract Ref: World J Surg 2002 Sep;26(9):1079-82
Dehydroepiandrosterone sulfate and growth axis hormones in patients after surgery.
Osorio A, Vara-Thorbeck R, Rosell J, Osorio C, Ortega E, Ruiz-Requena E.
Department of Biochemistry and Molecular Biology, Clinico Hospital, University of Granada, Avenida de Madrid s/n, 180012 Granada, Spain.
We selected 38 patients scheduled for cholecystectomy and studied their serum concentrations of dehydroepiandrosterone (DHEA) and growth axis hormones [growth hormone/insulin-like growth factor-1 (GH/IGF-1)]. We aimed to determine whether alterations in these concentrations resulted from surgical stress or, on the contrary, preceded surgery and were themselves a cause of chronic diseases that reduce life expectancy. We measured the serum concentrations of DHEA sulfate (DHEA-S), ACTH, cortisol, human GH (hGH), IGF-1, and IGF-1 binding protein-3 (IGFBP-3) preoperatively and then 2 and 7 days after surgery; we also compared the preoperative findings with those of a healthy control group. The results were analyzed by gender because DHEA and GH/IGF-1 are known to present sexual dimorphism. There were no significant differences between the preoperative and control results for any of the parameters studied. We found a significant reduction in the concentrations of DHEA-S and IGF-1 on days 2 and 7 after surgery versus the preoperative values. We conclude that the decrease in DHEA-S in patients after surgery is a result of surgical trauma and does not precede surgical stress. The decrease in hormone levels observed in patients with chronic disease may therefore be a result, not a cause, of disease, as some have claimed. Further studies with a later endpoint would be of interest to assess any subsequent return of DHEA-S levels to baseline measurements.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12176784&dopt=Abstract Ref: Ann Oncol 2002 Jul;13(7):1059-66
Biological activity of anastrozole in postmenopausal patients with advanced breast cancer: effects on estrogens and bone metabolism.
Bajetta E, Martinetti A, Zilembo N, Pozzi P, La Torre I, Ferrari L, Seregni E, Longarini R, Salvucci G, Bombardieri E.
Medical Oncology Unit B and Nuclear Medicine Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
BACKGROUND: To study the short-term biological effect of anastrozole on serum estrogens, androgens, 17-hydroxyprogesterone (17OH-PGR), gonadotrophins, sex hormone binding globulin (SHBG) and bone metabolism markers. MATERIALS AND METHODS: Thirty-four consecutive patients with advanced breast cancer received anastrozole 1 mg/day. Blood samples were taken before commencement of treatment and at 2, 4, 8 and 12 weeks during treatment to measure serum levels of estrogens (E(1), E(2) and E(1)-S), androgens [androstenedione (Delta(4)), dihydrotestosterone (DHT), testosterone (TST), free TST, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S)], 17OH-PGR, SHBG and gonadotrophins. As an indicator of bone resorption, we measured serum levels of C-terminal telopeptide of type I collagen (ICTP) and the cross-linked N-telopeptide of type I collagen (NTx), and for osteoblastic activity, intact osteocalcin (BGP) and bone alkaline phosphatase (BAP). RESULTS: After 2 weeks E(1 )and E(1)-S levels decreased on average by 56% (range 23.1-88.8%) and 75.8% (range 52.4-87.2%), respectively; E(2) decreased on average by 62% (range 31.4-89.6%). No significant changes were detected in levels of androgens or 17OH-PGR. There was a significant increase in gonadotrophins over time (P = 0.0001 for both luteinizing hormone and follicle-stimulating hormone), and a significant decrease in SHBG (P = 0.0001). A progressive significant increase in bone metabolism serum markers was detected in all patients: BAP, P = 0.039; BGP, P = 0.016; ICTP, P = 0.0021; and NTx, P = 0.0013. In particular, patients with bone metastases had a statistically significant increase of bone resorption markers (ICTP, P = 0.0019; NTx, P = 0.025) and borderline for bone formation markers. In patients without bone disease, BAP, BGP and ICTP remained unchanged, whereas serum NTx significantly increased (P = 0.019). CONCLUSIONS: Anastrozole is a selective aromatase inhibitor as it does not modify serum levels of androgens and 17OH-PGR. In our experience no relationship was found in the short-term period between serum estrogen suppression and bone metabolism.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12168817&dopt=Abstract Ref: Anticancer Res 2002 May-Jun;22(3):1409-11
Effect of castration on dehydroepiandrosterone-induced hepatocarcinogenesis in male rats.
Rao MS, Kashireddy P.
Department of Pathology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Dehydroepiandrosterone (DHEA), a peroxisome proliferator, is a hepatocarcinogen in male and female rats. The incidence of DHEA-induced hepatic tumors was much higher in males compared to females, although the peroxisome proliferative effect is similar in both sexes. In this study, we have evaluated the effect of castration in male rats on DHEA-induced hepatocarcinogenesis. Orchiectomy resulted in a significant reduction in hepatocellular carcinomas (15% in castrated rats versus 81% in control rats). However, the incidence of neoplastic nodules was comparable in both orchiectomized and control groups (84% versus 94% in orchiectomized and control groups, respectively). Sixty-two percent of livers in the control group contained tumors larger than 10 mm compared to 8% in the orchiectomized group. These findings indicate that testosterone promotes the growth of neoplastic lesions induced by DHEA.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12163335&dopt=Abstract Ref: Cancer Epidemiol Biomarkers Prev 2002 Aug;11(8):785-9
Reproducibility studies and interlaboratory concordance for androgen assays of male plasma hormone levels.
Fears TR, Ziegler RG, Donaldson JL, Falk RT, Hoover RN, Stanczyk FZ, Vaught JB, Gail MH.
Biostatistics Branch, National Cancer Institute, Bethesda, Maryland 20892, USA.
To help us identify appropriate techniques and laboratories for measuring hormones, we studied the variability and reproducibility of assay measurements of androstanediol glucuronide, androstenedione, dehydroepiandrosterone (DHEA), DHEA sulfate, dihydrotestosterone, testosterone, androstanediol, androsterone glucuronide, and androsterone sulfate for five men. Four sets of two aliquots from each sample were sent to participating laboratories, and one set was used for analyses monthly for four consecutive months. For each assay, estimates of components of variance were then used to estimate the coefficient of variation, the intraclass correlation between measurements on different days from a given individual, and the minimum detectable relative difference for a standard design. These data indicate that for at least one of the laboratories a single sample with two laboratory replicates per sample of androstanediol glucuronide, androstenedrone, DHEA, DHEA sulfate, and dihydrotestosterone yields an intraclass correlation coefficient exceeding 0.80 and can be used to discriminate reliably among men. The results for testosterone, androstanediol, androsterone, glucuronide, and androsterone sulfate do not meet this test. These data do not allow us to estimate the component of variation that corresponds to repeated blood samples taken over time from the same man. This reliability study design is, however, entirely appropriate for the typical case-control study which utilizes only one sample per subject.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12163230&dopt=Abstract Ref: Trends Endocrinol Metab 2002 Sep;13(7):288-94
DHEA treatment: myth or reality?
Allolio B, Arlt W.
Dept Medicine, Endocrine and Diabetes Unit, University of Wurzburg, Josef-Schneider-Str. 2, 97080 Wurzburg, Germany.
Dehydroepiandrosterone (DHEA) and its sulfate ester are major secretory products of the human adrenal. Serum DHEA concentrations decline with advancing age and DHEA supplementation in elderly people has been advertized as anti-aging medication. However, such claims are based on experiments in rodents with a fundamentally different DHEA physiology. In humans, DHEA is a crucial precursor of sex steroid biosynthesis and exerts indirect endocrine and intracrine actions following conversion to androgens and estrogens. In addition, it acts as a neurosteroid via effects on neurotransmitter receptors in the brain. DHEA has considerable effects on mood, well-being and sexuality in patients with adrenal insufficiency, and also in those with mood disorders. However, subjects with a physiological, age-related decline in DHEA secretion show little benefit from DHEA administration. Future research should focus on DHEA treatment for adrenal insufficiency, and DHEA administration in both patients receiving chronic glucocorticoid treatment and women with androgen deficiency.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12163136&dopt=Abstract Ref: J Steroid Biochem Mol Biol 2002 Jul;81(3):249-53
Accumulation of 4- and 5-ene steroid sulfates in human breast cyst fluids.
Maeda Y, Tanaka E, Fujiwara M, Watanabe R, Furusawa H, Matsu T, Nakahara H, Nanba K, Higashi S, Setoguchi T.
Department of Surgery I, Miyazaki Medical College, Japan.
Gross cystic disease of the breast is one of the most common diseases of adult females. Breast cyst fluid contains various steroid hormones. In order to obtain more information about the concentrations of 4- and 5-ene steroids in human breast cyst fluids, levels of pregnenolone sulfate (PREGS), pregnenolone (PREG), dehydroepiandrosterone sulfate (DHEAS) and dehydroepiandrosterone (DHEA) were determined by high-performance liquid chromatography (HPLC). A total of 35 human breast cyst fluid samples, obtained from 35 patients (28-54 years old) were analyzed. Cyst fluid electrolytes were simultaneously determined. Levels of PREGS (mean+/-S.D.) were 26.9+/-20.0 micromol/l (N=35) and of PREG were <0.1 micromol/l. Levels of DHEAS and DHEA were 89.1+/-111.7 micromol/l (N=35) and 0.3+/-0.2 micromol/l (N=35), respectively. Cyst fluids were divided into two groups (types I and II) according to their electrolyte ratio (K(+)/Na(+)). The cysts of the type I group (K(+)/Na(+) >1.5) contained significantly higher levels of PREGS (39.9+/-21.1 micromol/l) and DHEAS (133.2+/-87.9 micromol/l) than those of the type II group (K(+)/Na(+) <1.5), the mean levels of which were 19.8+/-16.2 micromol/dl for PREGS, and 36.3+/-29.0 micromol/dl for DHEAS (P<0.05). PREGS and DHEAS levels in the cysts were significantly correlated (r=0.49; P<0.01). Human breast cyst fluids contain high concentration of DHEAS and PREGS, especially in the cyst fluids containing high K(+)/Na(+) ratios.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12161507&dopt=Abstract Ref: J Clin Endocrinol Metab 2002 Aug;87(8):3760-7
The relationship of circulating dehydroepiandrosterone, testosterone, and estradiol to stages of the menopausal transition and ethnicity.
Lasley BL, Santoro N, Randolf JF, Gold EB, Crawford S, Weiss G, McConnell DS, Sowers MF.
Department of Population Health and Reproduction, University of California, Davis, California 95616, USA.
In this report, 3029 women between the ages of 42 and 54 yr from five ethnic groups were studied for 2 yr. Log circulating dehydroepiandrosterone sulfate (DHEAS) concentrations were highest among Chinese and Japanese and lowest among African Americans and Hispanics, and this pattern persisted after adjustment for age, smoking, and log body mass index (BMI). With the exception of Japanese women, log BMI was negatively related to log circulating DHEAS. The magnitude of this association varied by ethnic group, and the decline in log circulating DHEAS levels with higher log BMI was steepest for Chinese and least steep for Hispanics. The relationship between log DHEAS and log BMI was positive for Japanese. DHEAS levels did not decline at a steady rate during the menopausal transition and transiently increased in some women and increased, on average, during the transition to late perimenopause. These increases tended to be larger for Chinese, Hispanic, and Japanese than for African Americans and Caucasians, although the interactions were not statistically significant. Changes in circulating testosterone and, to a lesser extent, estradiol were correlated to changes in DHEAS. These data have importance in understanding the endocrinology of the menopausal transition, defining the relationship of adrenal steroid production during declining ovarian function and determining a rationale regarding DHEAS supplementation for older women.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12161487&dopt=Abstract Ref: J Clin Endocrinol Metab 2002 Aug;87(8):3632-9
Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: the Rotterdam study.
Hak AE, Witteman JC, de Jong FH, Geerlings MI, Hofman A, Pols HA.
Department of Epidemiology & Biostatistics, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands.
In both men and women, circulating androgen levels decline with advancing age. Until now, results of several small studies on the relationship between endogenous androgen levels and atherosclerosis have been inconsistent. In the population-based Rotterdam Study, we investigated the association of levels of dehydroepiandrosterone sulfate (DHEAS) and total and bioavailable testosterone with aortic atherosclerosis among 1,032 nonsmoking men and women aged 55 yr and over. Aortic atherosclerosis was assessed by radiographic detection of calcified deposits in the abdominal aorta, which have been shown to reflect intimal atherosclerosis. Relative to men with levels of total and bioavailable testosterone in the lowest tertile, men with levels of these hormones in the highest tertile had age-adjusted relative risks of 0.4 [95% confidence interval (CI), 0.2-0.9] and 0.2 (CI, 0.1-0.7), respectively, for the presence of severe aortic atherosclerosis. The corresponding relative risks for women were 3.7 (CI, 1.2-11.6) and 2.3 (CI, 0.7-7.8). Additional adjustment for cardiovascular disease risk factors did not materially affect the results in men, whereas in women the associations diluted. Men with levels of total and bioavailable testosterone in subsequent tertiles were also protected against progression of aortic atherosclerosis measured after 6.5 yr (SD +/- 0.5 yr) of follow-up (P for trend = 0.02). No clear association between levels of DHEAS and presence of severe aortic atherosclerosis was found, either in men or in women. In men, a protective effect of higher levels of DHEAS against progression of aortic atherosclerosis was suggested, but the corresponding test for trend did not reach statistical significance. In conclusion, we found an independent inverse association between levels of testosterone and aortic atherosclerosis in men. In women, positive associations between levels of testosterone and aortic atherosclerosis were largely due to adverse cardiovascular disease risk factors.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12161011&dopt=Abstract Ref: Mol Cell Endocrinol 2002 Jul 31;193(1-2):121-8
Breast cancer: from estrogen to androgen receptor.
Ando S, De Amicis F, Rago V, Carpino A, Maggiolini M, Panno ML, Lanzino M.
Department of Cell Biology, University of Calabria, Via P. Bucci, 87036 Rende (CS), Italy.
To investigate the link existing between androgens and human breast cancer, the hormonal milieu present in pre- and post-menopausal women has been translated in an in vitro model utilizing a hormone dependent breast cancer cell line MCF-7 exposed to DHEA, DHEAS, androstenediol, T, DHT with or w/o E(2). DHEAS and androstenediol stimulate the growth of MCF-7 cell line but reduce cell proliferation induced by E(2) (1 nM). T and DHT (1-100 nM) instead inhibit MCF-7 cell proliferation independently on E(2) presence. When we focused our study on the most powerful androgen, DHT alone (100 nM) consistently inhibits MCF-7 cell proliferation by 50% of the basal growth rate and counteracts E(2) proliferative action by 68%. These data correlate well with cell cycle analysis showing an enhanced number of cells in G(0)/G(1) phase after 6 days of DHT treatment. Upon prolonged DHT exposure, Western blotting analysis shows a markedly increased AR content, while immunohistochemistry indicates that it was mostly translocated into the nucleus. So we assumed that the enhanced activation of the AR might inhibit MCF-7 cells proliferation. This assumption is corroborated by the fact that the inhibitory effects induced by DHT on MCF-7 cell proliferation are abrogated in the presence of hydroxyflutamide. Therefore to better investigate the role of AR in inhibiting E(2) action at genomic level, MCF-7 cells were transiently cotransfected with the reporter plasmid XETL carrying firefly luciferase sequence under the control of an estrogen responsive element and the full length AR or with an AR carrying a mutation (Cis 574-->Arg 574) which abolishes its binding to DNA. The over-expression of the AR markedly decreases E(2) signalling which furthermore appears inhibited by simultaneous exposure to DHT but reversed by addition of hydroxyflutamide. The inhibitory effect was no longer noticeable when MCF-7 cells were cotransfected with XETL and the mutant AR. Taken together these data demonstrate that gonadal androgens antagonize MCF-7 proliferation induced by E(2). This seems to be related to the inhibitory effects of the over-expressed AR on E(2) genomic action.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12148690&dopt=Abstract Ref: Life Sci 2002 Mar 15;70(17):1979-88
ATP depletion is an important factor in DHEA-induced growth inhibition and apoptosis in BV-2 cells.
Yang NC, Jeng KC, Ho WM, Hu ML.
Department of Food Science, National Chung-Hsing University, Taichung, Taiwan.
Dehydroepiandrosterone (DHEA), a major steroid secreted by the adrenal gland, is known to have antiproliferative effects but the mechanism is unclear. We recently reported that DHEA induces growth inhibition and apoptosis in BV-2 cells and these effects are inversely associated with glucose concentrations in the medium. Here, we further showed that incubation of BV-2 cells with DHEA under glucose deprivation (G0) led to dose- and time-dependent decrease in cellular ATP levels. The decrease in ATP preceded growth inhibition and apoptosis induced by DHEA and all these effects of DHEA (i.e., loss of ATP, antiproliferation and apoptosis) were prevented by glucose added at 4.5 mg/ml (G4.5) during incubation. In addition, two ATP-depleting agents, iodoacetic acid (IAA) and 2,4-dinitrophenylhydrazine (2,4-DNP), potentiated the antiproliferative and apoptotic effects of DHEA. We also determined whether decrease in nucleic acid synthesis (due to glucose-6-phosphate dehydrogenase inhibition by DHEA) contributes to DHEA-induced antiproliferation and apoptosis. Using a mixture of deoxyribonucleotides (DN) and ribonucleotides (RN), we showed that DNRN had little or no effect on DHEA-induced growth inhibition and apoptosis. We also showed that mevalonic acid (MVA) did not affect DHEA-induced antiproliferation and apoptotic effects, indicating that protein isoprenylation and membrane association are not affected by DHEA in BV-2 cells. Taken together, the present results demonstrate that depletion of ATP by DHEA plays an important role in DHEA-induced antiproliferation and apoptosis of BV-2 cells.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12137806&dopt=Abstract Ref: J Steroid Biochem Mol Biol 2002 Jun;81(2):159-64
Pharmacokinetics of oral dehydroepiandrosterone (DHEA) in the ovariectomised cynomolgus monkey.
Leblanc M, Labrie C, Belanger A, Candas B, Labrie F.
Laboratory of Molecular Endocrinology and Oncology, Laval University Medical Center (CHUL), Laval University, Que., Canada.
Humans and primates are unique in having adrenals that secrete large amounts of DHEA and DHEA-S in the circulation. These steroids act as precursors of active androgens and estrogen's in a long series of peripheral target intracrine tissues. The marked decline of serum DHEA and DHEA-S concentrations with age in men and women has been incriminated in the development of various pathologies. This study provides detailed information on the effect of a single 50mg oral dose of DHEA on circulating estrogen's as well as androgens and their metabolites over 10h in adult ovariectomised (OVX) Cynomolgus monkeys. Serum DHEA, DHEA-S, testosterone (Testo) and androstenedione (4-dione) concentrations increased rapidly with a maximal value at approximately 1h after DHEA administration followed by a 60-80% decrease during the next 2-6h. An important sulfatation of DHEA occurs through first hepatic pass, thus, leading to a marked increase in serum DHEA-S. Serum androst-5-ene-3beta,17beta-diol and androsterone glucuronide (ADT-G) levels remained elevated on a plateau for 6h. Androstan-3alpha,17beta-diol-glucuronide, estradiol and estrone levels remained unchanged. The present data indicate the predominant transformation of the adrenal precursor DHEA into active androgens in peripheral tissues and support the importance of measurement of circulating glucuronide derivatives as index of peripheral or intracrine androgen formation and action.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12131057&dopt=Abstract Ref: Clin J Sport Med 2002 Jul;12(4):236-41
DHEA and sport.
Corrigan B.
Institute of Sport, Concord Hospital, Sydney, New South Wales, Australia.
Dehydroepiandrosterone (DHEA), a 19-carbon steroid, is situated along the steroid metabolic pathway. It is the most abundant circulating hormone in the body and can be converted to either androgens or estrogens. It is readily conjugated to its sulphate ester DHEAS, and they are designated as DHEA(S) here when used together. Its secretion reaches a peak in early adulthood and thereafter decreases, until approximately age 70 years when it reaches a concentration of approximately 20%. Many hormonal changes may take place with aging but none is as marked as this. This "relative DHEA deficiency" resulted in DHEA being enthusiastically labelled by some as a fountain of youth or an antidote to aging that would prove to be the panacea they are seeking. Its use was also taken up enthusiastically by the athletic community and used as a prohormone in the belief or hope that it would be converted mainly to testosterone in the body.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12128283&dopt=Abstract Ref: Trends Endocrinol Metab 2002 Aug;13(6):234-9
Dissecting human adrenal androgen production.
Rainey WE, Carr BR, Sasano H, Suzuki T, Mason JI.
Department Obstetrics and Gynecology, Division of Reproductive Endocrinology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9032, USA.
The human adrenal cortex produces aldosterone, cortisol and the so-called adrenal androgens, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Within the adult adrenal, the zona glomerulosa produces aldosterone, the zona fasciculata cortisol and the zona reticularis both DHEA and DHEAS. The processes regulating aldosterone and cortisol synthesis are well defined; however, the mechanisms regulating the production of DHEA(S) remain elusive. The emphasis of this review is based on increasing evidence that cytochrome b(5), DHEA sulfotransferase and 3 beta-hydroxysteroid dehydrogenase play crucial roles in regulating production of DHEA(S). Insight into the mechanisms that regulate the synthesis of these key components of DHEA(S) synthesis should provide important clues to the regulation of adrenal androgen biosynthesis.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12125405&dopt=Abstract Ref: Zh Vyssh Nerv Deiat Im I P Pavlova 2002 May-Jun;52(3):371-3
Effects of dehydroepiandrosterone on passive avoidance in ovariectomized female rats of different age
[Article in Russian]
Goncharov NP, Fedotova IuO, Sapronov NS.
Institute for Experimental Medicine, Russian Academy of Medical Sciences, St. Petersburg.
The aim of the present work was to study the influence of long-term treatment with dehydroepiandrosterone (DHEA) in doses of 0.1 and 0.7 mg/kg, i.p. on the passive avoidance performance in the ovariectomized female rats of 5- and 18-month old. The results obtained indicated that DHEA administration during 7 days in dose of 0.1 mg/kg normalized the passive avoidance performance in the ovariectomized rats of 5-month old while DHEA administration during 7 days in dose of 0.7 mg/kg restored passive avoidance performance in the ovariectomized rats of 18-month old.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12124866&dopt=Abstract Ref: Arthritis Rheum 2002 Jul;46(7):1820-9
Effects of prasterone on corticosteroid requirements of women with systemic lupus erythematosus: a double-blind, randomized, placebo-controlled trial.
Petri MA, Lahita RG, Van Vollenhoven RF, Merrill JT, Schiff M, Ginzler EM, Strand V, Kunz A, Gorelick KJ, Schwartz KE; GL601 Study Group.
Department of Medicine, John Hopkins Medical Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
OBJECTIVE: To evaluate whether treatment with prasterone (dehydroepiandrosterone [DHEA]) would allow the dosage of prednisone (or an equivalent corticosteroid) to be reduced to < or = 7.5 mg/day for 2 months or longer while maintaining stable or reduced disease activity in steroid-dependent women with systemic lupus erythematosus (SLE). METHODS: In a double-blind, randomized trial, 191 female SLE patients receiving prednisone (10-30 mg/day) were treated daily with either placebo, 100 mg of oral prasterone (an adrenal androgen), or 200 mg of oral prasterone for 7-9-months. At monthly intervals, corticosteroid dosages were reduced by algorithm in patients whose SLE Disease Activity Index (SLEDAI) score was stable or improved. Patients for whom a sustained reduction in the dosage of prednisone (< or = 7.5 mg/day) was achieved for at least the last 2 months of the 7-9-month treatment period were classified as responders. RESULTS: Response rates were 41% in the placebo group, 44% in the 100-mg prasterone group, and 55% in the 200-mg group (P = 0.110, 200 mg versus placebo). Among the 137 subjects (45 in the placebo group, 47 in the 100-mg group, and 45 in the 200-mg group) who had active disease at baseline (defined as SLEDAI score >2), 29%, 38%, and 51%, respectively, were responders (P = 0.031 for 200 mg prasterone versus placebo). Acne was the most common adverse event but was generally mild. Clinical and laboratory changes primarily reflected androgenic effects of prasterone. CONCLUSION: Among women with lupus disease activity, reducing the dosage of prednisone to < or = 7.5 mg/day for a sustained period of time while maintaining stabilization or a reduction of disease activity was possible in a significantly greater proportion of patients treated with oral prasterone, 200 mg once daily, compared with patients treated with placebo.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12122537&dopt=Abstract Ref: Intensive Care Med 2002 Jul;28(7):963-8
The effect of dehydroepiandrosterone on hemorrhage-induced suppression of cellular immune function.
Oberbeck R, Nickel E, von Griensven M, Tschernig T, Wittwer T, Schmitz D, Pape HC.
Department of Trauma Surgery, University Hospital of Essen, Hufelandstrasse 55, 45122 Essen
OBJECTIVE: To determine whether the steroid hormone dehydroepiandrosterone (DHEA) improves cellular immune functions after hemorrhagic shock. DESIGN AND SETTING: Prospective controlled study in a research laboratory at an university medical center. SUBJECTS: Male NMRI mice. INTERVENTIONS: Animals received 0.9% saline or DHEA (20 mg/kg subcutaneously) before induction of a volume-controlled hemorrhagic shock (55% of estimated circulating blood volume) by retro-orbital puncture. One hour after hemorrhage mice underwent fluid resuscitation by intravenous infusion of lactated Ringer's solution (300% of the shed blood). Separate groups of mice were killed to obtain whole blood and spleen 1 h after hemorrhage, 1 h after fluid resuscitation, and 24 h after hemorrhage to determine lymphocyte distribution (CD4(+), CD8(+), NK1.1-AG(+)), splenocyte apoptosis, and plasma concentrations of tumor necrosis factor-alpha and interleukin-10. MEASUREMENTS AND RESULTS: Hemorrhage in control mice was associated with a rapid increase in circulating NK cell numbers. Elevated splenocyte apoptosis, an increased CD4/CD8 ratio, and decreased number of circulating CD8(+) T-cells was observed 24 h after hemorrhagic shock. DHEA administration was accompanied by a normalization of splenocyte apoptosis and lymphocyte migration. Induction of hemorrhagic shock did not affect TNF-alpha or IL-10 plasma concentrations in either treatment group. CONCLUSIONS: DHEA administration improves cellular immune function after hemorrhage and may therefore be beneficial in patients with hemorrhagic shock.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12114270&dopt=Abstract Ref: Ann N Y Acad Sci 2002 Jun;966:166-86
Influence of cytokines and growth factors on distinct steroidogenic enzymes in vitro: a short tabular data collection.
Herrmann M, Scholmerich J, Straub RH.
Institute of Sports and Preventive Medicine, University of Saarland, 66041 Saarbrucken, Germany.
Cytokines (IL-1, IL-6, IL-8, IL-11, TNF, IFN-gamma, and TGF-beta) and growth factors (EGF, bFGF, aFGF, and KGF) play an important role in modulation of hormone secretion by directly influencing specific enzyme steps of steroidogenesis in various endocrine cell types. For this tabular data collection, the following enzyme steps were considered: steroidogenic acute regulatory protein (StAR), side chain cleavage enzyme (P450scc), 3 beta-hydroxysteroid dehydrogenase, 17-alpha-hydroxylase/17,20-lyase (P450c17), 17-beta-hydroxysteroid-dehydrogenase, aromatase complex, 5-alpha-reductase, P450c21, DHEAS sulfatase, and DHEA sulfotransferase. This collection summarizes the current information on how the mentioned cytokines and growth factors influence particular enzyme steps.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12112241&dopt=Abstract Ref: Yeast 2002 Jul;19(10):873-86
Dehydroepiandrosterone (DHEA) metabolism in Saccharomyces cerevisiae expressing mammalian steroid hydroxylase CYP7B: Ayr1p and Fox2p display 17beta-hydroxysteroid dehydrogenase activity.
Vico P, Cauet G, Rose K, Lathe R, Degryse E.
Transgene SA, 11 Rue de Molsheim, 67000 Strasbourg, France.
We have engineered recombinant yeast to perform stereospecific hydroxylation of dehydroepiandrosterone (DHEA). This mammalian pro-hormone promotes brain and immune function; hydroxylation at the 7alpha position by P450 CYP7B is the major pathway of metabolic activation. We have sought to activate DHEA via yeast expression of rat CYP7B enzyme. Saccharomyces cerevisiae was found to metabolize DHEA by 3beta-acetylation; this was abolished by mutation at atf2. DHEA was also toxic, blocking tryptophan (trp) uptake: prototrophic strains were DHEA-resistant. In TRP(+) atf2 strains DHEA was then converted to androstene-3beta,17beta-diol (A/enediol) by an endogenous 17beta-hydroxysteroid dehydrogenase (17betaHSD). Seven yeast polypeptides similar to human 17betaHSDs were identified: when expressed in yeast, only AYR1 (1-acyl dihydroxyacetone phosphate reductase) increased A/enediol accumulation, while the hydroxyacyl-CoA dehydrogenase Fox2p, highly homologous to human 17betaHSD4, oxidized A/enediol to DHEA. The presence of endogenous yeast enzymes metabolizing steroids may relate to fungal pathogenesis. Disruption of AYR1 eliminated reductive 17betaHSD activity, and expression of CYP7B on the combination background (atf2, ayr1, TRP(+)) permitted efficient (>98%) bioconversion of DHEA to 7alpha-hydroxyDHEA, a product of potential medical utility.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12102568&dopt=Abstract Ref: Comp Med 2002 Jun;52(3):233-7
Effects of ketamine-xylazine and isoflurane on insulin sensitivity in dehydroepiandrosterone sulfate-treated minipigs (Sus scrofa domestica).
Heim KE, Morrell JS, Ronan AM, Tagliaferro AR.
Department of Animal and Nutritional Sciences, University of New Hampshire, Durham 03824-3505, USA.
Isoflurane and ketamine-xylazine (KX) combinations are widely used veterinary anesthetics, KX being the particularly common agent for immobilizing swine. Results of previous studies indicate that KX and xylazine suppress insulin release. The steroid hormones, dehydroepiandrosterone (DHEA) and its sulfated form, dehydroepiandrosterone-sulfate (DHEAS), have variable effects on insulin sensitivity in animals. We evaluated the effect of DHEAS on plasma glucose and insulin concentrations in female Yucatan swine under KX and isoflurane anesthesia. A 2 x 2 factorial design was used. Twenty-four 17-week-old gilts were randomly assigned to receive vehicle (placebo) or DHEAS as part of an ongoing study. The KX was given intramuscularly to all animals prior to blood sample collection at weeks two and four. At week three, all animals received isoflurane by inhalation. During KX anesthesia, mean insulin concentration in DHEAS-treated and control groups approximated half the postisoflurane values (P < 0.001). While under isoflurane, the DHEAS group had significantly higher mean plasma insulin concentration and mean insulin-to-glucose ratio, compared with values for controls (P < 0.05). These findings are consistent with changes in insulin values following DHEAS treatment observed previously in nonanesthetized swine. The effect of DHEAS treatment was absent in animals under KX anesthesia. These results suggest that KX significantly decreases plasma insulin concentration and blunts DHEAS-associated insulin resistance in female minipigs.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12095951&dopt=Abstract Ref: Ann N Y Acad Sci 2002 Jun;963:247-67
Diet and breast cancer.
Bradlow HL, Sepkovic DW.
David and Alice Jurist Institute for Research, Hackensack University Medical Center, Hackensack, New Jersey 07601, USA.
The preponderance of evidence suggests a role for fat and alcohol as risk factors for breast cancer. The role of milk is more controversial with some studies suggesting that milk is a risk factor and others that consumption of milk is protective against breast cancer. No other major nutrient appears to play a significant role in increasing breast cancer risk. On the other hand, there is increasing evidence that a variety of micronutrients and hormones appear to have significant anticancer activity. These range from steroids such as dehydroepiandrosterone (DHEA) and its analysis to indoles, isothiocyanates, and isoflavone derivatives. These compounds act directly by interfering with cyclins and promoting apoptosis as well as indirectly by altering estrogen metabolism in a favorable direction. These effects are not merely theoretical actions in cell culture and tissue explants; they have been demonstrated in human patients as a range of studies have demonstrated.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12091857&dopt=Abstract Ref: J Pediatr 2002 Jul;141(1):91-8
Premature pubarche in girls is associated with functional adrenal but not ovarian hyperandrogenism.
Mathew RP, Najjar JL, Lorenz RA, Mayes DE, Russell WE.
Department of Pediatrics, Vanderbilt University, Nashville, Tennessee 37232, USA.
OBJECTIVE: We hypothesized that there would be evidence of functional ovarian hyperandrogenism in girls with premature pubarche (PP) at diagnosis. METHODS: White girls <8 years of age and black girls <6 years with PP (n = 15) were studied. Prepubertal girls (n = 13; 5.3-10.9 years) and early pubertal girls (n = 8) served as control subjects. The biochemical marker for functional ovarian hyperandrogenism was the 17-hydroxyprogesterone (17-OHP), androstenedione (AD), and estradiol (E2) response to subcutaneous leuprolide during adrenal suppression with dexamethasone. This was studied in girls with PP and in control subjects. RESULTS: ACTH stimulated 17-hydroxypregnenolone (17-OH Preg), dehydroepiandrosterone (DHEA), and AD levels, and 17-OH Preg:17-OHP and DHEA:AD ratios were significantly higher in girls with PP than in prepubertal control subjects (n = 18) (P < or =.003). The ovarian response to leuprolide stimulation was comparable in girls with PP and prepubertal control subjects, but the response in prepubertal study subjects was significantly lower than in pubertal control subjects (P =.016 for Delta17-OHP, P =.001 for DeltaAD, and P =.026 for DeltaE2). CONCLUSIONS: Contrary to the hypothesis, PP in girls was not associated with prepubertal evidence of ovarian hyperandrogenism but was associated with functional adrenal hyperandrogenism.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12091208&dopt=Abstract Ref: Am J Psychiatry 2002 Jul;159(7):1237-9
Elevation of the cortisol-dehydroepiandrosterone ratio in drug-free depressed patients.
Young AH, Gallagher P, Porter RJ.
Department of Psychiatry, Leazes Wing, Royal Victoria Infirmary, University of Newcastle upon Tyne, Newcastle upon Tyne NE1 4LP, UK.
OBJECTIVE: Elevated basal cortisol levels are a feature of depressive illness and cause deficits in learning and memory. The adrenal steroid dehydroepiandrosterone (DHEA) has antiglucocorticoid properties that may offer protection against the deleterious effects of cortisol. The authors examined the ratio of cortisol to DHEA in drug-free depressed patients and a matched comparison group. METHOD: Cortisol and DHEA were measured in saliva samples from 39 patients with unipolar depression who had been medication free for at least 6 weeks and 41 healthy comparison subjects. RESULTS: The molar cortisol-DHEA ratio was significantly higher in the depressed patients than in the healthy comparison subjects. Cortisol-DHEA ratios from saliva samples taken at 8:00 p.m. correlated positively with length of current depressive episode. CONCLUSIONS: Elevated cortisol-DHEA ratios may be a state marker of depressive illness and may contribute to the associated deficits in learning and memory. Administration of DHEA or other antiglucocorticoid treatments may reduce neurocognitive deficits in major depression.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12088188&dopt=Abstract Ref: World J Urol 2002 May;20(1):4-10
The ageing male.
Schulman C, Lunenfeld B.
Department of Urology, Erasme Hospital University, Brussels, Belgium.
With prolonged life expectancy, men and women can expect to live one-third of their lives with some form of hormone deficiency. The ageing male, in particular, has the added problem of developing urological diseases, such as benign prostatic hyperplasia (BPH), prostate cancer, continence disorders and erectile dysfunction. When discussing age-related problems, it is often difficult to separate and to distinguish between the natural ageing process, ageing amplifiers and an acute or chronic illness, or inter-current diseases. Partial endocrine deficiencies of ageing are associated with a decrease in the peripheral levels of testosterone, dehydroepiandrosterone (DHEA), DHEA sulphate (DHEA-S), growth hormone, insulin-like growth factor and melatonin. There is also a concomitant increase in luteinising hormone and follicle stimulating hormone. The concentration of free biologically active testosterone is lowered further by an increase in sex hormone binding globulin (SHBG). Hormonal changes in the ageing male are associated with changes in the body mass index, osteoporosis, sleep and mood disorders. A number of testosterone replacement therapies are available. These therapies should maintain physiological levels not only of serum testosterone, but also of its metabolites, including dihydrotestosterone (DHT) and estradiol. Men on testosterone therapy should be monitored at 3-month intervals during the first year of use and, thereafter, at 1-year intervals if they are stable. The association of testosterone replacement with development of prostate cancer has not been determined.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12085256&dopt=Abstract Ref: Br J Cancer 2002 Jul 1;87(1):54-60
Does place of birth influence endogenous hormone levels in Asian-American women?
Falk RT, Fears TR, Hoover RN, Pike MC, Wu AH, Nomura AM, Kolonel LN, West DW, Ziegler RG.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, MD 20892, USA.
In 1983-87, we conducted a population-based case-control study of breast cancer in Asian women living in California and Hawaii, in which migration history (a composite of the subject's place of birth, usual residence in Asia (urban/rural), length of time living in the West, and grandparents' place of birth) was associated with a six-fold risk gradient that paralleled the historical differences in incidence rates between the US and Asian countries. This provided the opportunity to determine whether endogenous hormones vary with migration history in Asian-American women. Plasma obtained from 316 premenopausal and 177 naturally premenopausal study controls was measured for levels of estrone (E1), estradiol (E2), estrone sulphate (E1S), androstenedione (A), testosterone (T), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS), progesterone (PROG) and sex hormone-binding globulin (SHBG). Levels of the oestrogens and sex hormone-binding globulin did not differ significantly between Asian- and Western-born women, although among premenopausal women, those least westernised had the lowest levels of E1, E2, and E1S. Androgen levels, particularly DHEA, were lower in women born in the West. Among premenopausal women, age-adjusted geometric mean levels of DHEA were 16.5 and 13.8 nmol l(-1) in Asian- and Western-born women respectively; in postmenopausal women these values were 11.8 and 9.2 nmol l(-1), (P<0.001) respectively. Among postmenopausal women, androgens tended to be highest among the least westernised women and declined as the degree of westernisation increased. Our findings suggest that aspects of hormone metabolism play a role in population differences in breast cancer incidence.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12074401&dopt=Abstract Ref: Eur Urol 2002 Feb;41(2):144-53; discussion 153-4
Age dependent secretion of LH and ACTH in healthy men and patients with erectile dysfunction.
Derouet H, Lehmann J, Stamm B, Luhl C, Romer D, Georg T, Isenberg E, Gebhardt T, Stoeckle M.
Department of Urology and Pediatric Urology, University of Saarland, Homburg/Saar, Germany.
OBJECTIVES: Age dependent secretion of testicular and adrenal androgens was examined in healthy men and patients with erectile dysfunction (ED). METHODS: In 95 healthy men (age 20-74 years) and 739 patients with ED, luteineizing hormone (LH, n = 739), adrenocorticotropic hormone (ACTH, n = 480) and the secretion products of testis and adrenal gland testosterone (T, n = 750), free testosterone (fT, n = 718), dehydroepiandrosteronesulfate (DHEAS, n = 598) and cortisol (n = 538) were measured. RESULTS: In healthy men, LH was measured from 0.75-8.58 mIU/ml and ACTH from 10.59-121.7 pg/ml. Statistically, age was not correlated to LH (P = 0.573) and ACTH (P = 0.833) in healthy men. The secretion products T (P < 0.05), fT (P < 0.001), DHEAS (P < 0.001) and cortisol (P < 0.05) declined significantly with age in healthy persons. In patients with ED, a significant age dependent increase of LH (P < 0.05, n = 739), but not ACTH (P = 0.469, n = 480) was found. T (P < 0.001, n = 736), fT (P < 0.001, n = 718) and DHEAS (P < 0.001, n = 598), but not cortisol (P = 0.307, n = 538) declined in age dependent patients with ED. Age matching revealed a statistical significant elevation (P < 0.05) only for LH (n = 659) in comparison to healthy men (n = 94), all other hormones were not different in both groups. CONCLUSION: An LH-increase in patients with erectile dysfunction underlines the importance of Leydig cell degeneration in this disease, but age dependent decline of T secretion was comparable to healthy men, demonstrating a working hypophyseal-testicular-axis. Indication of androgen replacement is therefore limited to selected cases.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12073659&dopt=Abstract Ref: Orv Hetil 2002 May 19;143(20):1121-8
The role of adrenal and gonadal hormones in the pathogenesis of autoimmune polyarthritis
[Article in Hungarian]
Toth E, Horvath C.
Flor Ferenc korhaz, Reumatologiai Osztaly, Kistarcsa,
A growing body of recently published results suggest the role of adrenal androgens in the onset and development of chronic inflammatory process due to autoantigens. Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulphate (DHEA)--the major androgen products of the adrenal gland--have immunosuppressive effect inhibiting interleukin-6 production and substantially determining acute phase reaction. Decreased serum levels of DHEA and DHEAS has been observed in most of autoimmune diseases. Recent data suggest that adrenal hypoandrogenism comes from disturbed neuroendocrine, regulation due to hypothalamic effect of the inflammatory cytokines. On the other side, decreased adrenal androgen activity negatively influences the anabolic tonus of steroid hormone system while a relative enhancement of catabolic pressure occurs by the glucocorticoids. Moreover, the hypothalamus-hypophysis-gonadal axis can also be involved, resulting shifts in serum levels of prolactin, estrogens and gonadal androgens. All these hormonal changes can be summarised in decreasing the immunosuppressive tonus. This hypothesis connects the endocrine dysregulation with the development of autoimmune disorders. The new results promise not only a basically different theory of chronic inflammation but they will permit using new diagnostic tools as well as inducing substantially new and more effective therapeutic approaches.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12073561&dopt=Abstract Ref: Mycoses 2002;45 Suppl 1:37-40
Dehydroepiandrosterone metabolism by Epidermophyton floccosum
[Article in German]
Brasch J, Flader S, Roggentin P, Wudy S, Homoki J, Shackleton CH, Sipell W.
Universitats-Hautklinik, Schittenhelmstr. 7, D-24105 Kiel, Germany.
Steroid hormones may be relevant for the fungus-host relation in dermatophytoses. In contrast to most other hosts of dermatophytes, humans are characterized by a high cutaneous concentration of the adrenal androgen dehydroepiandrosterone (DHEA) and its sulphate (DHEAS). To investigate whether the strictly anthropophilic dermatophyte Epidermophyton floccosum can metabolize this steroid hormone, cultures of E. floccosum were supplemented with DHEA. After 5 days of incubation the steroids in the culture supernatants were extracted and differentiated by gaschromatography and massspectrometry (GC-MS). The results show that a nearly complete metabolization of DHEA by E. floccosum leads to the formation of multiple new steroids/metabolites some of which have not been reported before. Therefore, this fungus could possibly mediate the hormone regulated cutaneous defense mechanisms of the host by an intraepidermal metabolization of DHEA.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12065890&dopt=Abstract Ref: Neuroendocrinology 2002 Jun;75(6):375-83
A role for hypothalamic astrocytes in dehydroepiandrosterone and estradiol regulation of gonadotropin-releasing hormone (GnRH) release by GnRH neurons.
Zwain IH, Arroyo A, Amato P, Yen SS.
Department of Reproductive Medicine, University of California, San Diego, La Jolla, CA, USA.
Molecules of astrocyte origin influence gonadotropin-releasing hormone (GnRH) release and GnRH neuronal growth and differentiation. Furthermore, type 1 astrocytes express steroid receptors, presenting the possibility that steroid actions on GnRH neurons might occur via astrocytes. Utilizing GT1-7 cells, a GnRH-secreting cell line, the present study demonstrates that astrocytes mediate dehydroepiandrosterone (DHEA) or estradiol (E2) stimulated GnRH secretion. Conditioned media (CM) from astrocytes cultured for 48 h alone, with DHEA (DHEA-CM), or with E2 (E2-CM) were collected, treated with charcoal to remove steroids, and added to GT1-7 cells in culture for 12 h to test the effect on GnRH secretion. DHEA-CM and E2-CM stimulated GnRH secretion by GT1-7 cells by 4- and 3-fold, respectively. The effect of DHEA-CM on GnRH secretion by GT1-7 cells appears to be related to both DHEA and its metabolite, E2, since blocking the metabolism of DHEA into estrogen in the DHEA-treated astrocytes partially reversed the stimulatory effect of DHEA-CM. Addition of transforming growth factor (TGF)-beta1-neutralizing antibody to the astrocyte cultures reversed the stimulatory effects of both DHEA-CM and E2-CM on GnRH secretion by GT1-7 cells, suggesting that TGF-beta1 derived from astrocytes may be the principle mediator of E2 and DHEA effects. These data provide evidence for a novel mechanism by which circulating steroids and/or neurosteroids may modulate GnRH secretion.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12064215&dopt=Abstract Ref: Rev Med Interne 2002 May;23(5):436-46
DHEA: an unknown star
[Article in French]
Schlienger JL, Perrin AE, Goichot B.
Service de medecine interne et nutrition, hopital de Hautepierre, 67098 Strasbourg, France.
PURPOSE: To clarify the physiological function of dehydroepiandrosterone (DHEA), the most abundant steroid in human plasma, which remains poorly understood. To analyse the beneficial effects of a supplementation in order to alleviate its decrease in ageing and improve well-being. CURRENT KNOWLEDGE AND KEY POINTS: DHEA (and its sulfate) acts on peripheral tissues as an androgenic and estrogenic precursor. It is also considered as a neurosteroid. DHEA administration in several pathological animal models is promising, especially in metabolic diseases such as obesity and insulin resistance. It appears like a factor of immunomodulation and facilitates cognitive acquisition. In humans there is little evidence that DHEA may be useful in characterized pathologies apart from adrenal insufficiency. An interesting effect was also noted in severe systemic lupus erythematosus. The effects on cognitive and neuropsychiatric diseases such as midlife dysthymia are not yet convincing. Prospective studies of supplementation versus placebo indicate inconstant improvement in well-being in the post-menopausal state. DHEA is not a panacea against ageing despite there being a well-established aging-related decrease of DHEA. Contrary to some assertions there are no proven relations between cardiovascular or cancer risk. FUTURE PROSPECTS AND PROJECTS: Until now adrenal insufficiency has been the only well-documented indication of an oral DHEA supplementation. However, DHEA may be a good way for androgen supplementation in menopausal men. Further investigations are needed to better know the anti-inflammatory and immunomodulation properties of DHEA. At the least, prospective studies on large populations are necessary to assess the true benefits and dangers of DHEA in prevention of ageing.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12055703&dopt=Abstract Ref: Nutr Metab Cardiovasc Dis 2001 Dec;11(6):388-93
Adrenal C19 steroids and serum lipoprotein levels in healthy men.
Vatalas IA, Dionyssiou-Asteriou A.
Department of Biological Chemistry Medical School, Athens University, Greece.
BACKGROUND AND AIM: It has become apparent that dehydroepiandrosterone (DHEA) plays a protective role in atherosclerosis, but its influence on serum lipids has not yet been clarified. The aim of this study was to evaluate the association of endogenous adrenal C19 steroid hormones [(DHEA) and androstenedione (ASD)] and serum lipoprotein levels. METHODS AND RESULTS: The serum concentrations of dehydroepiandrosterone sulphate (DHEA-S), ASD, total and free testosterone, estradiol, total cholesterol, LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), triglycerides, apolipoprotein AI (ApoAI) and apolipoprotein B100 (ApoB100) were measured in a sample of 88 healthy men. Statistical analysis using Spearman's correlation coefficient showed a positive correlation between DHEA-S levels and ApoAI (p = 0.034), a negative correlation between ASD and triglycerides (p = 0.005), a positive correlation between ASD and LDL-C (p = 0.005), and a negative correlation between estradiol and HDL-C (p = 0.042). Multiple regression analysis revealed that DHEA-S is an independent factor for ApoAI, ASD an independent factor for triglycerides and LDL-C, and age an independent factor for ApoB100; estradiol was found to be a suggestive factor for HDL. CONCLUSIONS: The results suggest that the plasma levels of DHEA-S and ASD (adrenal C19 steroid hormones) correlate with the plasma lipid profiles of healthy men. It remains to be seen whether this profile is favourable.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12054746&dopt=Abstract Ref: Biochem Biophys Res Commun 2002 May 31;294(1):95-100
Gender differences in steroid modulation of angiotensin II-induced protein kinase C activity in anterior pituitary of the rat.
Lachowicz A, Rebas E.
Department of Experimental Endocrinology and Hormone Research, Institute of Endocrinology, Medical University of Lodz, Poland.
To investigate whether the various steroid hormones can modulate the basal and angiotensin II-induced protein kinase C (PKC) activity in the anterior pituitary of the rat, female and male intact and ovariectomized female Wistar rats were treated in vivo with estradiol (E2), progesterone (P), dehydroepiandrostendione sulfate (DHEA-S), and pregnenolone sulfate (PREG-S). Estradiol caused the increase of basal PKC activity in intact and ovariectomized females, but did not change the enzyme activity in males. In ovariectomized animals the increase of PKC activity was lower than in intact females. Progesterone decreased PKC activity only in intact animals. DHEA-S strongly enhanced activity of PKC in ovariectomized females. Pregnenolone sulfate did not significantly change PKC function of all studied groups. Incubation with AngII enhanced the PKC activity in intact (without steroid treatment) animals of both genders. In females, AngII and estradiol together rise the PKC-stimulated phosphorylation in greater degree than used separately. Treatment with other investigated steroids reduced the effect of AngII. In intact males every examined hormone turned back the stimulatory effect of AngII on PKC activity. These data suggest that gender differences in PKC activity are likely related to hormonal milieu of experimental animals and may depend in part on the basic plasma level of estrogens.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12053088&dopt=Abstract Ref: Horm Res 2002;57(5-6):165-9
Dehydroepiandrosterone sulfate and growth axis hormones in patients with ischemic heart disease.
Osorio A, Gutierrez MA, Ortega E, Ruiz-Requena E.
Department of Biochemistry and Molecular Biology, Clinico Hospital, University of Granada, Spain.
BACKGROUND: The present study aimed to determine whether decreases in dehydroepiandrosterone sulfate (DHEA-S) and growth axis components precede cardiovascular disease or are a consequence of it. METHODS: We measured the concentrations in serum of DHEA-S, ACTH, cortisol, growth hormone, insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 in 30 male controls and also in 37 male patients on days 0, 2, 5, 7 and 9 after suffering a myocardial infarction (MI). RESULTS: There was no significant variation in any of these parameters between the controls and the patients on day 0. However, we found a significant (p < 0.001) reduction in the DHEA-S concentrations of the patients between day 0 and subsequent days (days 2, 5, 7 and 9). CONCLUSION: We conclude that the decrease in DHEA-S in patients with MI is a consequence and not a cause of the disease.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12050224&dopt=Abstract Ref: J Clin Endocrinol Metab 2002 Jun;87(6):2611-22
Newly proposed hormonal criteria via genotypic proof for type II 3beta-hydroxysteroid dehydrogenase deficiency.
Lutfallah C, Wang W, Mason JI, Chang YT, Haider A, Rich B, Castro-Magana M, Copeland KC, David R, Pang S.
Department of Pediatrics, College of Medicine, University of Illinois at Chicago, 840 South Wood Street, Chicago, IL 60612, USA.
To define the hormonal criteria via genotypic proof for 3beta-hydroxysteroid dehydrogenase (3beta-HSD) deficiency in the adrenals and gonads, we investigated the type II 3beta-HSD genotype in 55 patients with clinical and/or hormonal presentation suggesting compromised adrenal with or without gonadal 3beta-HSD activity. Fourteen patients (11 males and 3 females) had ambiguous genitalia with or without salt wasting and with or without premature pubarche. One female neonate had salt wasting only. Twenty-five children (4 males and 21 females) had premature pubarche only. Fifteen adolescent and adult females had hirsutism with or without menstrual disorder. The type II 3beta-HSD gene, including the promoter region up to -1053 base, all exons I, II, III, IV, and exon and intron boundaries, was sequenced in all subjects. Eight patients had a proven or predictably deleterious mutation in both alleles of the type II 3beta-HSD gene, and 47 patients had no apparent mutation in the gene. ACTH-stimulated (1 h post iv bolus of 250 microg Cortrosyn) serum 17-hydroxypregnenolone (Delta5-17P) levels and basal and ACTH-stimulated ratios of Delta5-17P to cortisol (F) in the genotypic proven patients were unequivocally higher than those of age-matched or pubic hair stage matched genotype-normal patients or control subjects (n = 7-30 for each group). All other baseline and ACTH-stimulated hormone parameters, including dehydroepiandrosterone (DHEA) levels, ratios of Delta5-17P to 17-OHP and DHEA to androstenedione in the genotype-proven patients, overlapped with the genotype-normal patients or control subjects. The hormonal findings in the genotype-proven patients suggest that the following hormonal criteria are compatible with 3beta-HSD deficiency congenital adrenal hyperplasia (numeric and graphic reference standards from infancy to adulthood are provided): ACTH-stimulated Delta5-17P levels in 1) neonatal infants with ambiguous genitalia at or greater than 378 nmol/liter equivalent to or greater than 5.3 SD above the control mean level [95 +/- 53 (SD) nmol/liter]; 2) Tanner I children with ambiguous genitalia at or greater than 165 nmol/liter equivalent to or greater than 35 SD above the control mean level [12 +/- 4.3 (SD) nmol/liter]; 3) children with premature pubarche at or greater than 294 nmol/liter equivalent to or greater than 54 SD above Tanner II pubic hair stage matched control mean level [17 +/- 5 (SD) nmol/liter]; and 4) adults with at or greater than 289 nmol/liter equivalent to or greater than 21 SD above the normal mean level [25 +/- 12 (SD) nmol/liter]. ACTH-stimulated ratio of Delta5-17P to F in 1) neonatal infants at or greater than 434 equivalent to or greater than 6.4 SD above the control mean ratio [88 +/- 54 (SD)]; 2) Tanner I children at or greater than 216 equivalent to or greater than 23 SD above the control mean ratio [12 +/- 9 (SD)]; 3) children with premature pubarche at or greater than 363 equivalent to or greater than 38 SD above the control mean ratio [20 +/- 9 (SD)]; and 4) adults at or greater than 4010 equivalent to or greater than 221 SD above the normal mean ratio [29 +/- 18 (SD)]. Conversely, the hormonal data in the genotype-normal patients suggest the following hormonal criteria are not consistent with 3beta-HSD deficiency congenital adrenal hyperplasia: ACTH-stimulated Delta5-17P levels in children with premature pubarche up to 72 nmol/liter equivalent to up to 11 SD above the control mean level, and in hirsute females up to 150 nmol/liter equivalent to up to 12 SD above the normal female mean level [28 +/- 10 (SD) nmol/liter]; and ACTH-stimulated Delta5-17P to F ratio in children with premature pubarche up to 67 equivalent to up to 5 SD above the control mean ratio, and in hirsute females up to 151 equivalent to up to 10 SD above the normal mean ratio [32 +/- 12 (SD)]. These findings help define newly proposed hormonal criteria to accurately predict inherited 3beta-HSD deficiency.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12044968&dopt=Abstract Ref: Mech Ageing Dev 2002 Apr 30;123(8):1191-201
Effects of aging on hypothalamic-pituitary-adrenal system function in non-human primates.
Goncharova ND, Lapin BA.
Laboratory of Endocrinology, Institute of Medical Primatology of the Russian Academy of Medical Sciences, 354376, Veseloye 1, Sochi-Adler, Russia.
The study was aimed at characterizing the changes in hypothalamic-pituitary-adrenal (HPA) axis function during aging in monkey models (Papio hamadryas and Macaca mulatta). It has been established by specific radioimmunoassay and enzyme immunoassay that basal plasma levels of adrenal androgenes (dehydroepiandrosterone-DHEA, dehydroepiandrosterone sulfate-DHEAS) and the early precursors of steroid hormones (pregnenolone and 17-hydroxypregnenolone) progressively decrease with age in baboons and macaques, while cortisol and 11-desoxycortisol concentrations do not change. The old female rhesus monkeys exhibited a higher cortisol and corticosterone response, but a lower DHEAS response to corticotropin-releasing hormone (CRH) administration then the young monkeys. The aged rhesus monkeys also exhibited a decrease of the adrenal cortex resiliency, that was manifested in the deceleration of the decrease of cortisol concentrations after the peak values had been reached in response to ACTH 1-39 administration. At the same time the ACTH 1-24 depot test revealed no age-related changes in the maximum capacity of monkey adrenals to synthesize and secrete cortisol. The aged monkeys also developed less sensitivity of the HPA axis to dexametasone suppression test. The age-related hormonal changes may play an important role in the age-related involutive processes and in the disorders of the adaptive ability of old organisms.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12044960&dopt=Abstract Ref: Mech Ageing Dev 2002 Apr 30;123(8):1107-14
Dehydroepiandrosterone (DHEA) as a possible source for estrogen formation in bone cells: correlation between bone mineral density and serum DHEA-sulfate concentration in postmenopausal women, and the presence of aromatase to be enhanced by 1,25-dihydroxyvitamin D3 in human osteoblasts.
Takayanagi R, Goto K, Suzuki S, Tanaka S, Shimoda S, Nawata H.
Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, Japan.
A significant positive correlation between bone mineral density (BMD) and serum dehydroepiandrosterone sulfate (DHEA-S) was found in 120 postmenopausal women (51-99 years old) but no correlation was seen between BMD and serum estradiol. In subset analysis, strong positive correlation of serum DHEA-S and estrone with BMD was observed in postmenopausal women aged less than 69 years old. To study a possible role of DHEA-S in preventing osteoporosis, we characterized aromatase activity converting androgens to estrogens in human osteoblasts, because postmenopausal women maintain considerable levels of adrenal androgens. Glucocorticoids at 10(-9) to 10(-7) M induced transiently the expression of and the enzymatic activity of aromatase cytochrome P450 (P450AROM) in primary cultured osteoblasts. 1,25-Dihydroxyvitamin D3 (1,25-(OH)(2)D(3)) alone did not induce the aromatase activity, but enhanced and maintained the glucocorticoid-induced P450AROM gene expression. Analysis of the activity of P450AROM gene 1b (I.4) promoter, which is used dominantly in human osteoblasts, indicated that the region from -888 bp to -500 bp, which does not contain a typical vitamin D responsive element, is responsible for the enhancing effect of 1,25-(OH)(2)D(3). These results may suggest that adrenal androgen, DHEA, is converted to estrone in osteoblast by P450AROM, which is positively regulated by glucocorticoid and 1,25-(OH)(2)D(3), and is important in maintaining BMD in the sixth to the seventh decade, after menopause.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12044959&dopt=Abstract Ref: Mech Ageing Dev 2002 Apr 30;123(8):1101-6
Mechanism of action of anti-aging DHEA-S and the replacement of DHEA-S.
Nawata H, Yanase T, Goto K, Okabe T, Ashida K.
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku,Fukuoka 812-8582, Japan.
The plasma ACTH and cortisol levels do not change during aging. On the other hand, the plasma dehydroepiandrosterone sulfate (DHEA-S) changes remarkably during aging. Before puberty, the plasma DHEA-S level both in males and females is very low, however, it rapidly increases at puberty, and thereafter significantly decreases both linearly and age-dependently. Cytochrome P450c17 has two enzyme activities, 17-alpha-hydroxylase and 17,20-lyase. Cortisol is synthesized by 17-alpha-hydroxylase, and DHEA is synthesized by 17,20-lyase. The mechanism of dissociation of cortisol and DHEA synthesis in aging depends on another regulator of 17,20-lyase of cytochrome P450c17 such as cytochrome P450 reductase. We demonstrated significant decrease in cytochrome P450 reductase activity in bovine aged adrenal glands. We clarified the beneficial effects of DHEA as an anti-aging steroid based on both in vitro and in vivo experiments, such as the stimulatory effect of immune system, anti-diabetes mellitus, anti-atherosclerosis, anti-dementia (neurosteroid), anti-obesity and anti-osteoporosis. It is very important to identify the mechanism of action of DHEA. We clarified the conversion of DHEA to estrone by cytochrome P450 aromatase in primary cultured human osteoblasts. We indentified high affinity of DHEA binding with K(d)=6.6 nM in antigen and DHEA stimulated human T lymphocytes. We searched for the target genes that are specifically induced in activated T lymphocytes in the presence of DHEA by subtractive hybridization screening for differentially expressed transcripts. The double blind, randomized human replacement therapies utilizing DHEA are also reviewed.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12041914&dopt=Abstract Ref: Endocrine 2002 Mar;17(2):129-34
Dehydroepiandrosterone regulates insulin-like growth factor-1 system in adult rat hypothalamus.
Ribeiro MF, Garcia-Segura LM.
Departamento de Fisiologia, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEA-S) exert multiple effects in rodent and human brain. Several findings suggest that insulin-like growth factor-1 (IGF-1) is involved in the actions of DHEA. In this study, we assessed whether systemic administration of DHEA regulates the IGF-1 system in the hypothalamus, hippocampus, cerebral cortex, and cerebellum of adult rats. DHEA resulted in a significant reduction in IGF-1 receptor protein levels. This effect was dose dependent and restricted to the hypothalamus. In contrast to IGF-1 receptor, IGF-1-binding protein 2 levels were unaffected by DHEA treatment. IGF-1 levels were significantly increased in the hypothalamus of the rats treated with DHEA, whereas IGF-1 serum levels were not affected by DHEA. The effects of DHEA on the hypothalamic IGF-1 system may be highly relevant to the control and maintenance of hypothalamic neuroendocrine function.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12039447&dopt=Abstract Ref: Ageing Res Rev 2002 Feb;1(1):29-41
Uses of DHEA in aging and other disease states.
Johnson MD, Bebb RA, Sirrs SM.
Division of Endocrinology, University of British Columbia, 262-575 West 8th Avenue, Vancouver BC, Canada V5Z 1C6.
Dehydro-3-epiandrosterone is a steroid hormone synthesized in large quantities by the adrenal gland whose physiologic role remains unclear. The effects of DHEA could be estrogenic or androgenic, depending on the hormonal milieu. Low levels of DHEA are associated with aging, cardiovascular disease in men, and an increased risk of pre-menopausal breast and ovarian cancer. High levels of DHEA might increase the risk of postmenopausal breast cancer. Therapeutically DHEA might be useful for improving psychological well-being in the elderly, reducing disease activity in people with mild to moderate systemic lupus erythematosus and myotonic dystrophy, improving mood in those clinically depressed, and improving various parameters in women with adrenal insufficiency. Although many other claims have been made for DHEA in diverse conditions, such as aging, dementia, and AIDS, no well-designed clinical trials have clearly substantiated the utility and safety of long-term DHEA supplementation.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12039440&dopt=Abstract Ref: Ageing Res Rev 2002 Apr;1(2):229-42
Aging of the human adrenal cortex.
Hornsby PJ.
Department of Physiology, Sam and Ann Barshop Center for Longevity and Aging Studies, University of Texas Health Science Center, 15355 Lambda Drive STCBM 2.200, San Antonio, TX 78245, USA.
The aging of the human adrenal cortex presents several problems of interest to the cell biologist, as the interplay of changes in growth, differentiation, apoptosis and cellular senescence affect the properties of the tissue over the life span. The human adrenal cortex also presents an interesting case of tumor progression, as nodules and adenomas are very common in aging, although carcinomas are rare. A specific puzzle for the gerontologist is the loss of biosynthesis of dehydroepiandrosterone (DHEA) and its sulfate by the human adrenal cortex in aging. The reason for the development of a specific zone of DHEA-secreting cells, the zona reticularis, in childhood and the later involution of this zone is completely unknown. This review explores these issues, the underlying basic cell and molecular biology, and the techniques that can address these questions.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12037127&dopt=Abstract Ref: Exp Biol Med (Maywood) 2002 Jun;227(6):382-8
Decrease of core body temperature in mice by dehydroepiandrosterone.
Catalina F, Milewich L, Frawley W, Kumar V, Bennett M.
Departments of Pathology, Obstetrics and Gynecology, and Academic Computing Services, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9072, USA.
Dietary dehydroepiandrosterone (DHEA) reduces food intake in mice, and this response is under genetic control. Moreover, both food restriction and DHEA can prevent or ameliorate certain diseases and mediate other biological effects. Mice fed DHEA (0.45% w/w of food) and mice pair-fed to these mice (food restricted) for 8 weeks were tested for changes in body temperature. DHEA was more efficient than food restriction alone in causing hypothermia. DHEA injected intraperitoneally also induced hypothermia that reached a nadir at 1 to 2 hr, and slowly recovered by 20 to 24 hr. This effect was dose dependent (0.5-50 mg). Each mouse strain tested (four) was susceptible to this effect, suggesting that the genetics differ for induction of hypophagia and induction of hypothermia. Because serotonin and dopamine can regulate (decrease) body temperature, we treated mice with haloperidol (dopamine receptor antagonist), 5,7-dihydroxytryptamine (serotonin production inhibitor), or ritanserin (serotonin receptor antagonist) prior to injection of DHEA. All of these agents increased rather than decreased the hypothermic effects of DHEA. DHEA metabolites that are proximate (5-androstene-3beta, 17beta-diol and androstenedione) or further downstream (estradiol-17beta) were much less effective than DHEA in inducing hypothermia. However, the DHEA analog, 16alpha-chloroepiandrosterone, was as active as DHEA. Thus, DHEA administered parentally seems to act directly on temperature-regulating sites in the body. These results suggest that DHEA induces hypothermia independent of its ability to cause food restriction, to affect serotonin or dopamine functions, or to act via its downstream steroid metabolites.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12032350&dopt=Abstract Ref: Proc Natl Acad Sci U S A 2002 May 28;99(11):7722-7
Opposing actions of adrenal androgens and glucocorticoids on alternative splicing of Slo potassium channels in bovine chromaffin cells.
Lai GJ, McCobb DP.
Department of Neurobiology and Behavior, Cornell University, Ithaca, NY 14853, USA.
Pituitary ablation (hypophysectomy) in rats was previously reported to cause a precipitous change in the relative abundance of two alternative splice variants of the "BK"- or "Maxi K"-encoding Slo gene in adrenal chromaffin cells. Inclusion of the optional "STREX" exon (STRess axis-regulated EXon) in a C-terminal splice site was reduced, in preference to the variant lacking an insert at this site. Adrenocorticotropic hormone (ACTH) injections prevented the drop in STREX inclusion, implicating stress-axis function, as opposed to other pituitary functions. Because ACTH promotes synthesis and release of glucocorticoids (corticosterone or cortisol, depending on species), we hypothesized that glucocorticoids applied directly would promote STREX inclusion. Contrary to predictions, we report that direct application of glucocorticoids to bovine cells in vitro decreased STREX inclusion. This effect was blocked by the glucocorticoid receptor antagonist RU38486. As with glucocorticoids, synthesis and release of the adrenal androgen dehydroepiandrosterone (DHEA) increases in response to stress or elevated ACTH levels in some species. We report that direct application of DHEA increased expression of the STREX variant in cultured bovine cells. Two other androgens, androstenedione and testosterone, had similar effects. We hypothesize that Slo splicing in adrenal chromaffin cells in vivo is differentially regulated by the integrative, concentration- and time-dependent actions of glucocorticoids and androgens, with potentially important ramifications for stress-evoked catecholamine secretion.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12027876&dopt=Abstract Ref: Eur J Clin Invest 2002 May;32(5):354-9
LDL-receptors expression in HIV-infected patients: relations to antiretroviral therapy, hormonal status, and presence of lipodystrophy.
Petit JM, Duong M, Duvillard L, Florentin E, Portier H, Lizard G, Brun JM, Gambert P, Verges B.
Hopital Universitaire du Bocage, 21000 Dijon, France.
BACKGROUND: Abnormalities in lipid levels and lipodystrophy (LD) have been commonly reported after commencement of highly active antiretroviral therapy (HAART). A major mechanism by which plasma low-density lipoprotein (LDL) cholesterol levels may be influenced is via the regulation of hepatic LDL receptor expression. The activity of LDL receptors is under hormonal control. Moreover, HIV infection and HAART are associated with important modifications of hormonal status. As the cause of these adverse reactions is unknown, the effects of HAART and lipodystrophy on LDL receptors were evaluated. MATERIALS AND METHODS: Thirty-nine HIV treated patients (21 with a protease inhibitor (PI) containing regimen, 18 without PI use) and 22 control subjects were tested for insulin resistance (HOMA model assessment), lipid profile, serum concentration of dehydroepiandrosterone (DHEA) and LDL-R expression. LDL-R on mononuclear cells were quantified by flow cytrometry. RESULTS: Among the 39 HIV infected patients, 14 patients had a lipodystrophy (LD). Patients with LD had significantly higher levels of triglyceride (TG) and insulin resistance compared to patients without LD. There was no significant difference in LDL-R count between patients with or without PI use. In contrast, LDL-R count was significantly lower in patients with LD compared with those without (8504 +/- 3901 vs. 13 200 +/- 4532, P = 0.001). There was no difference in LDL-R count between patients without LD and control subjects. Patients with LD had lower levels of DHEA compared to patients without LD. In HIV-infected patients, we found a significant correlation between LDL-R expression and TG (r = -0.32; P = 0.04) and LDL cholesterol (r = -0.33; P = 0.04). In contrast, we did not observe a correlation between DHEA level and LDL-R count or LDL cholesterol level. CONCLUSIONS: HIV-lipodystrophy is associated with a lower expression of LDL-R. This decreased expression of LDL-R seems independent of DHEA or insulin secretion.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12027057&dopt=Abstract Ref: Psychol Med 2000 Sep;30(5):1227-31
Elevated circulatory level of GABA(A)--antagonistic neurosteroids in patients with combat-related post-traumatic stress disorder.
Spivak B, Maayan R, Kotler M, Mester R, Gil-Ad I, Shtaif B, Weizman A.
Research Unit, Ness Ziona Mental Health Center, Israel.
BACKGROUND: Post-traumatic stress disorder (PTSD) is a multisystem neurobiological disorder with chronic alterations in various neurochemical systems. Levels of the GABA(A)--antagonistic neurosteroids plasma dehydroepiandrosterone (DHEA) and its sulphate derivate, dehydroepiandrosterone sulphate (DHEAS) may be relevant to depressive and anxiety disorders, including PTSD. METHODS: We assessed the circulatory levels of morning plasma DHEA and DHEAS in 21 male outpatients with untreated chronic combat-related PTSD (CR-PTSD), and 18 healthy control male subjects. RESULTS: Compared with the control subjects, the PTSD patients showed significantly higher plasma DHEA and DHEAS levels. CONCLUSIONS: Chronic CR-PTSD may be associated with increased circulatory level of neuroactive steroids with inhibitory activity at the GABA(A) receptors. Neurosteroid-induced decreased GABAergic tone may be relevant to the symptomatology and pathophysiology of chronic PTSD, as well as to the frequent co-morbidity of PTSD with depression and anxiety disorders.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12019346&dopt=Abstract Ref: Neuroendocrinol Lett 2002 Apr;23 Suppl 1:17-9
Effects of six months melatonin treatment on sleep quality and serum concentrations of estradiol, cortisol, dehydroepiandrosterone sulfate, and somatomedin C in elderly women.
Pawlikowski M, Kolomecka M, Wojtczak A, Karasek M.
Department of Experimental Endocrinology and Hormone Diagnostics, Institute of Endocrinology, Medical University of Lodz, 91-425 Lodz, Sterling Str.3, Poland.
OBJECTIVES: The role of melatonin is aging is still under debate. Therefore, an open pilot study on the effects of melatonin administration on some sleep parameters, routine hematological and biochemical parameters, and concentrations of hormones was performed in elderly women. SUBJECTS AND METHODS: The study was performed on 14 women (volunteers), aged from 64 to 80 years (mean age 71+/-4.6 years). Melatonin (2 mg daily at 19:00 h) was administered during 6 months. Before and after melatonin treatment the peripheral venous blood samples were taken in the morning (approx. at 08:00 h) after the overnight fast. The total blood count, glucose, total cholesterol, LDL, HDL, and triglycerides were estimated by routine laboratory methods. The serum concentrations of the following hormones were determined: 17-beta-estradiol, dehydroepiandrosterone sulfate (DHEAS), cortisol, and somatomedin C (IGF-I). Additionally, before and after 6 months of melatonin therapy the investigated subjects answered to a questionnaire dealing with sleep parameters and self-estimation of general health status. RESULTS: In 35.7% of investigated subjects an improvement in general sleep quality and in such sleep parameters as sleep initiation, sleep latency, number of awakenings episodes, wake time after sleep onset, was observed. A significant decrease of estradiol concentrations was observed after 6 months of the melatonin treatment in comparison to initial levels. IGF-I was found to be slightly but significantly increased after the 6 months melatonin therapy. Cortisol levels did not change significantly, during the melatonin treatment. DHEAS concentrations increased after melatonin therapy. Moreover, a tendency towards a higher DHEAS/cortisol ratio was found after 6 months of treatment. Melatonin treatment did not influence significantly either the parameters of total blood count or glucose and serum lipids levels. CONCLUSIONS: On the basis of this preliminary open study it seems that melatonin administration may be beneficial for elderly subjects.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12018773&dopt=Abstract Ref: Neural Plast 2001;8(4):255-70
Task- and time-dependent memory enhancement by dehydroepiandosterone in day-old chicks.
Johnston AN, Migues PV.
Brain and Behavior Research Group, The Open University, Milton Keynes, UK.
We have previously reported the presence of dehydroepiandosterone (DHEA) in the day-old-chick brain, and a role for it in enhanced memory formation. Here we confirm that intracerebral injections of DHEA 5 min before training on the weak passive avoidance task enhanced recall 24 hours after training. Recall per se on an appetitive visual categorization task was not altered by administration of DHEA 5 min before training. However administration of DHEA 5 min before limited or very limited training on a visual categorization task (20 or 10 pecks only) appeared to enhance consolidation of this task at test 24 h after training; reducing the latency and total time taken to complete the test (60 pecks), while not detrimentally altering accuracy. Moreover, DHEA is unlikely to induce this effect via possible anxiolytic effects because it did not alter behavior in the open field test. We also examined diffusion of DHEA throughout the brain at various stages following intracerebral injection.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12017547&dopt=Abstract Ref: Recent Prog Horm Res 2002;57:257-75
Hormonal changes in the menopause transition.
Burger HG, Dudley EC, Robertson DM, Dennerstein L.
Prince Henry's Institute of Medical Research at Monash Medical Centre, Clayton, Victoria, Australia.
The menopause is the permanent cessation of menstruation resulting from the loss of ovarian follicular activity. It is heralded by the menopausal transition, a period when the endocrine, biological, and clinical features of approaching menopause begin. A common initial marker is the onset of menstrual irregularity. The biology underlying the transition to menopause includes central neuroendocrine changes as well as changes within the ovary, the most striking of which is a profound decline in follicle numbers. Follicle-stimulating hormone (FSH) is an established indirect marker of follicular activity. In studies of groups of women, its concentration, particularly in the early follicular phase of the menstrual cycle, begins to increase some years before there are any clinical indications of approaching menopause. The rise in FSH is the result of declining levels of inhibin B (INH-B), a dimeric protein that reflects the fall in ovarian follicle numbers, with or without any change in the ability of the lining granulosa cells to secrete INH-B. Estradiol levels remain relatively unchanged or tend to rise with age until the onset of the transition and are usually well preserved until the late perimenopause, presumably in response to the elevated FSH levels. During the transition, hormone levels frequently vary markedly - hence, measures of FSH and estradiol are unreliable guides to menopausal status. Concentrations of testosterone have been reported to fall by about 50% during reproductive life, between the ages of 20 and 40. They change little during the transition and, after menopause, may even rise. Dehydroepiandrosterone (DHEA) and DHEAS, its sulphate, on the other hand, decline with age, without any specific influence of the menopause. Symptoms of the menopause can be interpreted as resulting primarily from the profound fall in estradiol, occurring over a 3- to 4-year period around final menses, a fall that presumably contributes importantly to the beginning, in the late perimenopause, of loss of bone mineral density.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12016909&dopt=Abstract Ref: Yao Xue Xue Bao 1998 Jun;33(6):413-7
Effects of dehydroepiandrosterone sulfate on mimetic aging actions of cerebral cortex of fetal rats in vitro
[Article in Chinese]
Wang Y, Rao M.
Department of Cardiovascular Pharmacology, Nanjing Medical University, Nanjing 210029.
The effects of dehydroepiandrosterone sulfate (DHEAS) on mimetic aging action of cultured neurons were studied in two models: the cultured cerebral cortex neurons were exposed to the xanthine oxidase-hypoxanthine(XO-HPX) system; serum free culture of cerebral cortex neurons. The results indicated that when cultured neurons were incubated for 6 h with XO-HPX system or 24 h serum free cultures, LDH release and MDA content increased while the number of surviving neurons decreased. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) decreased and morphological injury developed. DHEAS (25, 50, 100 micrograms.L-1) concentration-dependently increased the number of surviving neurons and the activities of SOD and GSH-Px. It also inhibited the elevation of LDH and MDA induced by free radical and serum free cultures. The results suggest that DHEAS prevent the toxicity of free radical and serum free culture insults by suppressing the generation of lipid peroxide and increasing the activities of antioxidant enzymes.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12015034&dopt=Abstract Ref: Zhonghua Zhong Liu Za Zhi 2002 Mar;24(2):137-40
Anti-mutagenicity activity of dehydroepiandrosterone
[Article in Chinese]
Yang S, Fu Z, Wang F, Cao Y, Han R.
Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China.
OBJECTIVE: The chemopreventive activity and mechanism of dehydroepiandrosterone (DHEA) were studied. METHODS: Model of 7, 12-dimethylbenz (alpha) anthracene (DMBA) induced breast carcinoma in Sprague-Dawley rats, uitra-violet (UV)-induced DNA damage and Salmonella mutation assay were used. RESULTS: In DMBA-induced rat mammary tumor model, the rats were orally given daily DHEA for 2 weeks before DMBA and continued for 10 weeks after DMBA administration. The results showed significant inhibition of tumor development by DHEA. The incidence of mammary carcinoma also decreased significantly on daily dose of oral 25 mg/kg DHEA with the mean tumor volume per rat also remarkably reduced by 92%. Moreover, 25 mg/kg DHEA treatment could significantly increase the carcinoma latency for about 3.5 weeks as compared with the control. Using polymerase chain reaction (PCR) assay, in vitro 10(-9) mol/L DHEA showed significant inhibitory effect on UV-induced DNA damage by 90%. In Ames test, DHEA was found to decrease DMBA and benzo (alpha) pyrene-induced TA98 and TA100 His(+) revertants markedly and the number of Salmonella clones were significantly reduced by 53.2% and 73.0% on dose of 5 microgram DHEA/plate. It was also shown that in vitro 10(-7) mol/L DHEA could also effectively inhibit the G-6-PDH activity, which might play an important role in its chemoprophylaxis activities. CONCLUSION: The results strongly prove that DHEA is a potent cancer chemoprophylaxis agent, which exhibits inhibitory potential on mutation and chemical carcinogen in vivo and in vitro.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12014422&dopt=Abstract Ref: Int J Colorectal Dis 2002 Mar;17(2):63-6
Association of dehydroepiandrosterone sulfate and testosterone deficiency with bone turnover in men with inflammatory bowel disease.
Szathmari M, Vasarhelyi B, Treszl A, Tulassay T, Tulassay Z.
First Department of Medicine, Semmelweis University, Budapest, Hungary.
BACKGROUND AND AIMS: We investigated the coexistence of dehydroepiandrosterone sulfate (DHEAS) and testosterone deficiency in men with inflammatory bowel disease (IBD) and their relationship with bone homeostasis. PATIENT AND METHODS: In 45 men with IBD (25 with ulcerative colitis, 20 with Crohn's disease) the testosterone and DHEAS levels were examined in relationship to bone mineral density, osteocalcin levels, and urinary deoxypyridinoline excretions. RESULTS: We detected osteoporosis in 10 and osteopenia in 22 patients at the lumbar spine and/or femoral neck. Lower testosterone levels were measured in 20. Lower DHEAS levels were present in 23 patients; these had higher deoxypyridinoline excretion and lower lumbar spine and femoral neck BMD T scores than patients with normal DHEAS. DHEAS and BMD were correlated at the lumbar spine and the femoral neck. Associations remained significant after adjustment for age, weight, steroid use, and inflammatory activity. No independent effect of testosterone deficiency was detected on bone parameters. CONCLUSION: DHEAS deficiency may contribute to the bone loss of men with IBD. This putative action of DHEAS on bone turnover is contrary to the common effect of testosterone deficiency and steroid therapy.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12008748&dopt=Abstract Ref: Endocr J 2002 Feb;49(1):35-40
Twenty-four hour 17-hydroxyprogesterone response to adrenocorticotropine in adrenal incidentalomas: augmented response after adrenalectomy in two patients.
Kamel N, Erdogan MF, Tonyukuk V, Ilgin SD, Erdogan G.
Department of Endocrinology and Metabolism, Ankara University, Medical Faculty, Turkey.
The current study aimed to investigate the midterm (24 hour) response of 17-hydroxyprogesterone (17-OHP) and dehydroepiandrosterone sulphate (DHEA-S) to synthetic high-dose adrenocorticotropin (ACTH) in adrenal incidentalomas (Al). Seventeen patients with Al and 40 age- and sex-matched controls received synthetic ACTH (tetracosactide, 1000 microg, IM). Plasma, 17-OHP and DHEA-S were collected in basal conditions and after 1, 4, 6, 8 and 24 hours. (HPA) axis was also evaluated using circadian serum cortisol, urinary free cortisol and over-night 2 mg dexamethasone suppression. Basal plasma 17-OHP levels did not differ among the groups. However, the increment in plasma 17-OHP in patients both in terms of peak [13.76 +/- 2.52, 4.77 +/- 0.30ng/ml, mean +/- S.E.M, p < 0.001] and area under the curve [190 +/- 46, 96.75 +/- 32 ng/ml/h, p < 0.001] were significantly higher than that of the controls. Stimulated 17OH-P levels never reached 9.1 ng/ml in controls. Sixty-five (11/17) % of the patients were found to have exaggerated response. Three of the patients were found to have subclinical Cushing's syndrome and interestingly, two augmented their 17-OHP response to ACTH after unilateral adrenalectomy and normalisation of their HPA axis. Basal DHEA-S levels of the patients were significantly lower [99.21 +/- 45, 230.18 +/- 34 microg/dl, p < 0.01] and stayed persistently lower than that of the controls. Evidence of a heterozygous 21 hydroxylase deficiency, as indicated by the exaggerated 17-OHP response to ACTH, has been widely reported in Al patients. However, to our knowledge to date there is no report on augmented 17-OHP response to ACTH after adrenalectomy. Possible reasons for the augmentation were discussed.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12007900&dopt=Abstract Ref: Fertil Steril 2002 Apr;77 Suppl 4:34-41
Androgen effects on bone and muscle.
Notelovitz M.
Adult Women's Medicine, Gainesville, Florida, USA
Bone health and strength are dependent on the coupling of cone resorption and bone formation. This process is governed by the interaction of osteoclasts and osteoblasts plus the modulating influence of the bone mechanicosensory cells-the osteocytes. Both sex steroids-estrogen (E) and testosterone (T)- have receptors on all bone cells, with androgen dominance on osteoblasts and osteocytes. Specific receptors for the weaker androgens, such as DHEA have also been identified. The activity of the sex steroids, influenced by various enzymes found in bone, is reflective of the hormone ligand before its binding to the bone cells. As a result, T acts both directly and via its aromatization to estradiol. The activity of the androgens also varies with the bone surface; periosteal cells, for example, do not have 5alpha-reductase activity, indicating that T is the active metabolite at this clinically important site. Androgens influence bone cell function via local and systemic growth factors and cytokines. By enhancing osteoblast differentiation, androgens regulate bone matrix production, organization, and mineralization. Androgens also regulate osteoclast recruitment and activity. Endogenous androgens increase bone mineral density (BMD) in both adolescent and adult premenopausal women. Women with excess endogenous androgen-for example, those with hirsutism and polycystic ovary syndrome (PCOS)-have increased BMD compared with normal young women. E and androgen therapy increases BMD to a greater degree than does E therapy alone. This is true for both oral combinations of esterified E and methyltestosterone and for subcutaneous T implants. Androgenic progestins have an additive effect on BMD when combined with E therapy and have the further advantage of being protective to the endometrium in E-treated women. Androgens increase muscle mass and strength. The resulting improvement in physical activity leads to the activation of bone-forming sites and the stimulation of the bone formation-modulating cells, the osteocytes. Mechanical loading, when combined with hormone therapy, results in greater osteogenic response than does either alone.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12007898&dopt=Abstract Ref: Fertil Steril 2002 Apr;77 Suppl 4:19-25
Dehydroepiandrosterone: a springboard hormone for female sexuality.
Spark RF.
Department of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
OBJECTIVE: To determine the role of adrenal androgenic hormone precursors in female sexual function.DESIGN: A review of current literature on sexual function and the androgen precursor hormone dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS).RESULT(S): The C(19) steroid DHEA is both an ovarian and adrenal androgen precursor hormone, whereas DHEAS is only synthesized in the adrenal cortex. Dehydroepiandrosterone sulfate secretion begins at age 10, peaks at age 20, and then wanes. Low DHEAS levels occur in men and women with adrenal insufficiency and in the elderly. Dehydroepiandrosterone, 50 mg/d, increases DHEAS levels. In women but not men, the increased DHEAS levels facilitate additional production of downstream androgens, testosterone, dihydrotestosterone, androstenedione, and androstenediol glucuronide. With the improved female androgenic profile women with adrenal insufficiency have increased sexual thoughts and fantasies as well as an enhancement in mood and well-being. In the elderly >age 65 - DHEAS levels increase in both men and women with DHEA 50 mg/d but only in women were the higher DHEAS levels accompanied by a surge in testosterone levels and in women >age 70 increased libido and enhanced sexual satisfaction as well as a 26% diminution in bone resorption, and a 10% decrease in skin pigmentation.CONCLUSION(S): The female adrenal androgen deficiency syndrome, characterized low serum DHEAS levels may be corrected by DHEA supplements that increase levels of DHEAS and downstream androgens of importance to female sexuality.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12007896&dopt=Abstract Ref: Fertil Steril 2002 Apr;77 Suppl 4:6-10
Aromatization of androgens in women: current concepts and findings.
Simpson ER.
Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia
OBJECTIVE: To review the role of circulating C(19) steroids as precursors of estrogens in postmenopausal women.DESIGN: Review of current published literature.RESULT(S): In postmenopausal women as in men, estradiol no longer functions as a circulating hormone, because it ceases to be formed by the ovaries at the time of menopause. Estradiol continues to be formed in a number of extragonadal sites, however, including breast, bone, vascular smooth muscle, and various sites in the brain. At these sites of formation, local estradiol levels can be quite high, but the production rate is insufficient to affect the body in a global fashion; thus, estrogen action at these extragonadal sites of synthesis is primarily at a local level and serves a paracrine or even intracrine role.Because of this, in postmenopausal women as in men, circulating estrogen levels do not drive growth and development of target tissues. Instead, they reflect the metabolism of estradiol at these extragonadal sites. Estrogen that is not metabolized at these sites reenters the circulation, and, consequently, circulating levels of estradiol reflect its synthesis and action in extragonadal sites. Thus, they are reactive instead of proactive. An important difference between estrogen production at these extragonadal sites and estrogen that is synthesized in the ovary is that the former is absolutely dependent on a supply of circulating C(19) androgenic substrate.CONCLUSION(S): Circulating levels of testosterone begin to decline in the mid-reproductive years, and the levels of adrenal androgenic steroids, namely adrostenedione and DHEA, decrease throughout postmenopausal life. Therefore, the circulating levels of these adrogenic steroids may serve an important role in the maintenance of local estrogen synthesis, for example, in the bone and brain where estrogen has a profound influence on the maintenance of mineralization on the one hand, and possible cognitive function on the other.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12007895&dopt=Abstract Ref: Fertil Steril 2002 Apr;77 Suppl 4:3-5
Androgen production in women.
Burger HG.
Prince Henry's Institute of Medical Research, Monash Medical Centre, Clayton, Victoria, Australia
OBJECTIVE: To describe the sources, production rates, circulating concentrations, and regulatory mechanisms of the major androgen precursors and androgens in women.DESIGN: Review of the major published literature.RESULT(S): Quantitatively, women secrete greater amounts of androgen than of estrogen. The major circulating steroids generally classified as androgens include dehydroepiandrosterone sulphate (DHEAS), dehydroepiandrosterone (DHEA), androstenedione (A), testosterone (T), and dihydrotestosterone in descending order of serum concentration, though only the latter two bind the androgen receptor. The other three steroids are better considered as pro-androgens. Dehydroepiandrosterone is primarily an adrenal product, regulated by adrenocorticotropic hormone (ACTH) and acting as a precursor for the peripheral synthesis of more potent androgens. Dehydroepiandrosterone is produced by both the ovary and adrenal, as well as being derived from circulating DHEAS. Androstenedione and testosterone are products of the ovary and the adrenal. Testosterone circulates both in its free form, and bound to protein including albumin and sex steroid hormone-binding globulin (SHBG), the levels of which are an important determinant of free testosterone concentration.CONCLUSION(S): The postmenopausal ovary is an androgen-secreting organ and the levels of testosterone are not directly influenced by the menopausal transition or the occurrence of menopause. Dihydrotestosterone (DHT) is primarily a peripheral product of testosterone metabolism. Severe androgen deficiency occurs in hypopituitarism, but other causes may lead to androgen deficiency, including Addison's disease, corticosteroid therapy, chronic illness, estrogen replacement (leads to elevated SHBG and, therefore, low free testosterone), premenopausal ovarian failure, or oophorectomy.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11994353&dopt=Abstract Ref: J Clin Endocrinol Metab 2002 May;87(5):2134-8
Elevated dehydroepiandrosterone sulfate levels as the reproductive phenotype in the brothers of women with polycystic ovary syndrome.
Legro RS, Kunselman AR, Demers L, Wang SC, Bentley-Lewis R, Dunaif A.
Division of Women's Health, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
There is an inherited susceptibility to polycystic ovary syndrome (PCOS). Some investigators have suggested that premature male-pattern balding is a male phenotype in PCOS families, but this remains controversial. We recently reported evidence for an autosomal monogenic abnormality in ovarian and adrenal steroidogenesis in the sisters of women with PCOS. We performed this study to determine whether we could identify a clinical or biochemical phenotype in the brothers of women with PCOS. One hundred nineteen brothers of 87 unrelated women with PCOS and 68 weight- and ethnicity-comparable unrelated control men were examined and had fasting blood samples obtained. The odds of balding (Hamilton score > or = V) did not differ in the brothers of PCOS women compared with control men. Brothers of women with PCOS had significantly elevated dehydroepiandrosterone sulfate (DHEAS) levels [brothers 3035 +/- 1132 ng/ml (mean +/- SD) vs. control men 2494 +/- 1172 ng/ml; P < 0.05]. There was a significant positive linear relationship between DHEAS levels in PCOS probands and their brothers (r = 0.35; P = 0.001). There was no significant bimodal distribution in DHEAS levels, and there were no significant differences in other parameters in brothers of PCOS women with high DHEAS levels compared with those with low DHEAS levels. There is familial clustering of elevated DHEAS levels in the brothers of women with PCOS, suggesting that this is a genetic trait. This might reflect the same underlying defect in steroidogenesis that we found in the sisters of women with PCOS. Balding was not increased in the brothers of women with PCOS. We conclude that there is a biochemical reproductive endocrine phenotype in men in PCOS families.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11994339&dopt=Abstract Ref: J Clin Endocrinol Metab 2002 May;87(5):2046-52
Low dose dehydroepiandrosterone affects behavior in hypopituitary androgen-deficient women: a placebo-controlled trial.
Johannsson G, Burman P, Wiren L, Engstrom BE, Nilsson AG, Ottosson M, Jonsson B, Bengtsson BA, Karlsson FA.
Research Center for Endocrinology and Metabolism, Sahlgrenska University Hospital, SE-413 45 Goteborg, Sweden.
Thirty-eight women, aged 25-65 yr, with androgen deficiency due to hypopituitarism were treated with oral dehydroepiandrosterone (DHEA; 30 mg/d if <45 yr of age and 20 mg if > or =45 yr of age) for 6 months in a randomized, placebo-controlled, double blind study, followed by a 6-month open treatment period. The administration of DHEA raised the serum levels of DHEAS to normal age-related reference ranges and increased androstenedione and T to subnormal levels. Androgen effects on skin and/or pubic and/or axillary hair were observed in 84% (32 of 38) of the women after all received 6 months of DHEA treatment. No such effects were observed after the placebo treatment. These effects after 6 months were correlated with the serum levels of DHEAS (r = 0.37; P = 0.03), androstenedione (r = 0.42; P = 0.01), and T (r = 0.37; P = 0.03). The percentages of partners who reported improved alertness, stamina, and initiative by their spouses were 70%, 64%, and 55%, respectively, in the DHEA group and 11%, 6%, and 11%, respectively, in the placebo group (P < 0.05). According to the partners, sexual relations tended to improve compared with placebo (P = 0.06). After 6 months of treatment, increased sexual interest or activity was reported by 50% of the women taking 30 mg DHEA, by none taking 20 mg DHEA, and by two women taking placebo (P = NS). Compared with levels after placebo administration, high density lipoprotein cholesterol and apolipoprotein A-1 levels decreased after DHEA. Serum concentrations of IGF-I, serum markers of bone metabolism, and bone density did not change. In conclusion, oral administration of a low dose of DHEA to adult hypopituitary women induced androgen effects on skin and axillary and pubic hair as well as changes in behavior, with only minor effects on metabolism.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11988089&dopt=Abstract Ref: Biochem J 2002 May 15;364(Pt 1):165-71
Crystal structure of human dehydroepiandrosterone sulphotransferase in complex with substrate.
Rehse PH, Zhou M, Lin SX.
Oncology and Molecular Endocrinology Research Center, Laval University Medical Center CHUL (CHUQ), 2705 Boul. Laurier, Quebec City, Quebec, G1V 4G2, Canada.
Dehydroepiandrosterone sulphotransferase (DHEA-ST) is an enzyme that converts dehydroepiandrosterone (DHEA), and some other steroids, into their sulphonated forms. The enzyme catalyses the sulphonation of DHEA on the 3alpha-oxygen, with 3'-phosphoadenosine-5'-phosphosulphate contributing the sulphate. The structure of human DHEA-ST in complex with its preferred substrate DHEA has been solved here to 1.99 A using molecular replacement with oestradiol sulphotransferase (37% sequence identity) as a model. Two alternative substrate-binding orientations have been identified. The primary, catalytic, orientation has the DHEA 3alpha-oxygen and the highly conserved catalytic histidine in nearly identical positions as are seen for the related oestradiol sulphotransferase. The substrate, however, shows rotations of up to 30 degrees, and there is a corresponding rearrangement of the protein loops contributing to the active site. This may also reflect the low identity between the two enzymes. The second orientation penetrates further into the active site and can form a potential hydrogen bond with the desulphonated cofactor 3',5'-phosphoadenosine (PAP). This second site contains more van der Waal interactions with hydrophobic residues than the catalytic site and may also reflect the substrate-inhibition site. The PAP position was obtained from the previously solved structure of DHEA-ST co-crystallized with PAP. This latter structure, due to the arrangement of loops within the active site and monomer interactions, cannot bind substrate. The results presented here describe details of substrate binding to DHEA-ST and the potential relationship to substrate inhibition.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11975863&dopt=Abstract Ref: J Womens Health Gend Based Med 2002 Mar;11(2):155-62
Acute dehydroepiandrosterone (DHEA) effects on sexual arousal in postmenopausal women.
Hackbert L, Heiman JR.
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, USA.
BACKGROUND: The age-related decline of dehydroepiandrosterone (DHEA) has prompted research on its experimental replacement in women. Although no relationship to sexual functioning in healthy women has been shown to date, DHEA replacement has potential for affecting sexual response. METHODS: To investigate DHEA effects, 16 sexually functional postmenopausal women participated in a randomized, double-blind, crossover protocol in which oral administration of DHEA (300 mg) or placebo occurred 60 minutes before the presentation of an erotic video segment. Blood DHEA sulfate (DHEAS) changes, subjective and physiological sexual responses, as well as affective responses were measured in response to videotaped neutral and erotic video segments. RESULTS: The concentration of DHEAS increased 2-5-fold following DHEA administration in all 16 women. Subjective ratings across DHEA and placebo conditions showed significantly greater mental (p < 0.016) and physical (p < 0.036) sexual arousal to the erotic video with DHEA vs. placebo. Positive affect also increased during the erotic video across drug conditions. Vaginal pulse amplitude (VPA) and vaginal blood volume (VBV) demonstrated a significant increase (p < 0.001) between neutral and erotic film segments within both conditions (DHEA and placebo) but did not differentiate drug conditions. CONCLUSION: In sum, increases in mental and physical sexual arousal ratings significantly increased in response to an acute dose of DHEA in postmenopausal women.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11972301&dopt=Abstract Ref: Horm Metab Res 2002 Mar;34(3):127-31
Dehydroepiandrosterone status in postmenopausal women is determined by the gene for the vitamin D receptor.
Zofkova I, Hill M, Zajickova K.
Institute of Endocrinology, Prague, Czech Republic.
Data documenting the indirect interaction of vitamin D and bone metabolism via hormonal systems are rare. The authors analysed the predictive role of the vitamin D receptor (VDR) gene for circulating sex steroids and their precursors in postmenopausal women. Using the PCR technique, the polymorphic FokI, ApaI, TaqI and BsmI sites of the VDR gene were determined in relation to serum dehydroepiandrosterone sulphate (DHEAS), androstenedione (AD), testosterone, and estradiol levels. After adjustment to body mass and years since menopause, circulating DHEAS was higher in the Ff genotype than in ff (p < 0.001) and FF genotypes (p < 0.05, ANCOVA followed by least significant difference multiple comparison tests). The Ff genotype also contributed to the highest BMD at the hip (p < 0.01 as compared to ff genotype) and at the spine (p < 0.05). No significant associations were found between ApaI, TaqI and BsmI polymorphisms and serum DHEAS or between FokI, ApaI, TaqI or BsmI and serum androstenedione, testosterone or estradiol. The study shows that the VDR gene predicts synthesis and/or metabolism of sexual steroid preursor DHEA in parallel with bone mineral density (BMD). The results indicate that DHEA production and bone mass share a common genetic control through VDR.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11972299&dopt=Abstract Ref: Horm Metab Res 2002 Mar;34(3):116-20
Evidence for the biosynthesis of DHEA from cholesterol by first-trimester human placental tissue: source of androgens.
Loganath A, Peh KL, Wong PC.
University Department of Obstetrics and Gynecology, National University Hospital, Singapore.
With a view to establishing whether first-trimester human placentas possess the ability to synthesize DHEA from cholesterol, homogenates of this tissue obtained from two groups of women undergoing elective termination of normally progressing pregnancy between 10 - 12 weeks gestation (n = 5, age 23 - 29 years and n = 5, age 21 - 27 years) were incubated separately with [26-(14)C]cholesterol for the generation of [14C]isocaproic acid + pregnenolone and [7n-3H]pregnenolone for the biosynthesis of [3H]DHEA. Controls consisted of homogenates heated in a boiling water bath for 10 min. Using the reverse-isotope dilution analysis, desmolase efficiency expressed as mean specific activity of [14C]isocaproic acid varied from 282 to 725 dpm/mmol, while that of 17 alpha-hydroxylase and steroid C-17,20-lyase, catalyzed conversion of [7n-3H]pregnenolone to [3H]DHEA varied from 3498 to 26 258 dpm/mmol. The corresponding efficiencies of enzymicconversion varied between 5.8 x 10( -2) and 1.5 x 10( -1) % for [14C]isocaproic acid, but between 5.5 x 10( -2) and 4.1 x 10( -1) % for [3H]DHEA. No such metabolite was evident in the controls of heat-denatured homogenates. These are the first study results to demonstrate that early placentas are capable of converting cholesterol to pregnenolone to DHEA, contrary to the widely held concept of DHEA production by fetal and maternal adrenal glands. This finding has important physiological implications and could provide a new dimension to the concept of fetoplacental steroidogenesis.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11972140&dopt=Abstract Ref: Encephale 2002 Mar-Apr;28(2):139-46
Study of the stress response: role of anxiety, cortisol and DHEAs
[Article in French]
Boudarene M, Legros JJ, Timsit-Berthier M.
Bat G, N 266, Cite Djurdjura, Ville Nouvelle, Tizi Ouzou 15010, Algerie, France.
AIM OF THE STUDY: Several studies have exhibited the psychological processes that are implied in the stress response and have shown, according to Selye's research, the participation of the hypothalamic-pituitary-adrenal axis and the major role of cortisol. The possible action of another adrenal steroid, dehydroepiandrosterone (DHEA), is increasingly documented. The beneficial effect of the latter and his antistress role would be related to an antagonistic action to that of cortisol. The aim of our study was, first to assess biological and psychological aspects of the stress response, then to define the relationships that exist between these two processes. POPULATION AND METHODOLOGY: 40 subjects (21 women) aged 42 +/- 12 years, who consulted within a clinic of stress (CITES Prevert, Liege, Belgium) were studied. They all felt stressed but, according to DSM IV, were without mental disorders and drug free when examined. Subjects were asked to accomplish simple cognitive tasks: 1 - to distinguish two different auditory stimulations. The first one was a high-pitched sound of 1 470 Hz, which was presented unfrequently (20%). The second one, a low frequency tone of 800 Hz, was presented more frequently (80%). The interval between both stimuli was 1 s. The subject had to press a button when the rare stimulus was recognized. 2 - to extinguish a light after a warning tone of 64 dB, 50 ms and 1 000 Hz. The light, which followed one second later the tone, consisted of a series of flashes of 18 c/s that the subject had to stop by pressing a button. The purpose of this second procedure was that the subject was warned and had to prepare and anticipate the most rapid response. After that, subjects were submitted to self-evaluation psychological tests. The impact of psychosocial factors was assessed by Amiel-Lebigre life events questionnaire. Personality features and emotional response (state anxiety, related to experimental situation) were assessed by Spielberger inventory (STAI: State and Trait Anxiety Inventory). Psychological tests are practised immediately after experimental situation. Cortisol and DHEAs (dehydroepiandrosterone sulfate) were measured in blood samples taken before (t1) and after (t2) the experimental test. Cortisol was measured by radio-immunology and expressed as ng/ml of plasma. DHEAs was measured by radio-immunoassay and expressed as g/liter of plasma. RESULTS AND DISCUSSION: The majority of subjects displayed high scores of trait anxiety (37 subjects had a score>42) and life events impact (35 subjects had a score>200). These data confirmed that the subjects were fragile and were obviously stressed. In response to the cognitive tasks, that constituted for each subject a new event with which it was necessary to cope, 25 subjects exhibited high level of state anxiety (score>42) and an increase of cortisol plasmatic concentrations occurred solely in 11 persons. Ten among them were in the group of subjects which displayed a score of state anxiety>42 (p=0,0223, Chi square). Base on these data three types of stress response were identified: 1 - the experimental situation was experienced without anxiety ( psychological silence ) and without any increase in cortisol level ( biological silence ). There was no stress and these subjects were, despite their vulnerability, close to a normal health state . 2 - high emotional reaction (high level of state anxiety) was observed. This response reveals a psychological vulnerability that can be considered as the expression of a consecutive psychological distress induced by a threatening experimental situation. There were no biological manifestations ( biological silence ). 3 - high state anxiety and increased plasma cortisol levels were observed. The corresponding subjects were obviously more vulnerable. CONCLUSION: These results allow us to propose that the emergence of state anxiety is the first stress response and the primary protest . Up to a certain level, a plateau level, anxiety remains stable. Then, nature of the stress response changes and takes a biological aspect. Increased of cortisol plasma levels, the secondary protest , is observed and gives evidence of an intensified and sustained stress response. Such a gradual phenomenon is particularly reported in elevated psychological distress which is associated with loss of control. It is important to note that identical scores of state anxiety (Mann Whitney test) were observed in anxious subjects with or without rise of plasma cortisol levels. DHEAs was also implied in the stress response. The enhancement of plasma levels of DHEAs were dependent on cortisol, as shown by the close correlation between both hormones (r=0,433, p=0,0033, Spearman test). The hypothesis of an antagonism between these two hormones is based on the fact that DHEAs opposes the action of cortisol and exerts a true anticortisol effect. This antagonism might be related to a competition in their synthesis and release by the adrenal gland. In the present case, high level of anxiety (state and trait) was associated with an increase of cortisol, while low level (of anxiety) was related to an exclusive rise of DHEAs. Intermediate anxious score was observed in subjects who showed increases of both cortisol and DHEAs (p=0,0225, Kruskall Wallis test). Furthermore, a close relationship (negative correlation: Spearman test), was observed between increases in DHEAS and scores of state anxiety (r=- 0,382, p=0,06) and trait anxiety (r=- 0,0097, p=0,527). This means that the worriness and the underlying anxious ruminations and negative anticipations, which characterize trait anxiety, were less important in subjects who increased plasma DHEAs levels. In addition, emotional tension and uneasiness, which accompanies state anxiety, were also less marked. There are no studies reporting a relation between DHEA(s) and state or trait anxiety. Nevertheless, many authors have proposed a beneficial action of DHEA on the feeling of well-being. This beneficial role could be related to a double action of DHEA: a direct effect provided by its transformation into sexual hormones, an indirect one mediated by its competition with cortisol, of which the synthesis and consequently the activity decrease.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11969408&dopt=Abstract Ref: Biochemistry 2002 Apr 30;41(17):5473-82
Molecular differences caused by differentiation of 3T3-L1 preadipocytes in the presence of either dehydroepiandrosterone (DHEA) or 7-oxo-DHEA.
Gomez FE, Miyazaki M, Kim YC, Marwah P, Lardy HA, Ntambi JM, Fox BG.
Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin, Madison, Wisconsin 53706, USA.
The effects of dehydroepiandrosterone (DHEA) and 7-oxo-DHEA on the cell size, adiposity, and fatty acid composition of differentiating 3T3-L1 preadipocyte cells are correlated with stearoyl-CoA desaturase (SCD) expression (mRNA and protein levels) and enzyme activity. Fluorescence-activated cell sorting shows that preadipocyte cells treated with methylisobutylxanthine, dexamethasone, and insulin (MDI) plus DHEA comprise a population distribution of predominantly large cells with reduced adiposity. In contrast, cells treated with MDI plus 7-oxo-DHEA comprise a population distribution of almost equal proportions of small and large cells that have an adiposity equivalent to cells differentiated with MDI alone. The cells treated with MDI plus DHEA have significantly reduced levels of total fatty acid, mainly due to a dramatic reduction in the level of palmitoleic (Delta(9)-16:1) acid. The cells treated with MDI plus 7-oxo-DHEA have a significantly increased level of total fat, primarily due to increased levels of Delta(9)-16:1 and palmitic (16:0) acids. At the molecular level, the DHEA-treated cells contain lowered amounts of SCD1 mRNA and antibody-detectable desaturase protein, while 7-oxo-DHEA-treated cells contained elevated levels of SCD1 mRNA and protein. Inhibition of differentiation in DHEA-treated cells was also suggested by a reduction in the mRNA level of the adipogenic gene aP2. At the level of microsomal enzymatic activity, SCD activity was decreased in DHEA-treated cells while the SCD activity was increased in 7-oxo-DHEA-treated cells. The changes in mRNA levels and enzyme activity were concentration-dependent and appeared as early as day 3 of the differentiation protocol. The results show that DHEA and 7-oxo-DHEA have distinct modes of action with respect to the complex transcriptional cascade required for differentiation. Furthermore, differences in the insulin-stimulated uptake of 2-deoxyglucose and in the activity of carnitine palmitoyl transferase observed from either DHEA- or 7-oxo-DHEA-treated cells support the ability of DHEA to produce a thermogenic effect in differentiating preadipocytes, while 7-oxo-DHEA promotes differentiation without other changes typical of thermogenesis.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11958788&dopt=Abstract Ref: Steroids 2002 Apr;67(5):333-8
A simple, accurate, and sensitive assay method of dehydroepiandrosterone sulfate: application for quantitative determination in human breast cyst and duct fluids.
Maeda Y, Kamimura R, Higashi S, Namba K, Tanaka E, Iwamura T, Setoguchi T.
Department of Surgery I, Miyazaki Medical College, Kiyotake, Miyazaki, Japan.
Radioimmunoassay (RIA) is the most prevalent method for measuring small amounts of hormones, peptides, and other compounds in human body fluids. The method, however, has several problems, such as cross reactions or non-specific reactions of the antibody used. In order to establish an improved method for assaying dehydroepiandrosterone sulfate (DHEAS) and cholesterol, which are the largest components of human breast cyst and duct fluids, we describe a simple, accurate, and sensitive method using high-performance liquid chromatography (HPLC). The samples were treated with cholesterol oxidase for quantitation of dehydroepiandrosterone (DHEA) and free cholesterol, and the respective oxidized substances, 4-androstene-3,17-dione and 4-cholesten-3-one, were extracted with n-hexane. The extracts were analyzed by straight phase HPLC. Effluents were monitored by measuring absorption at 240 nm, where a newly introduced chromophoric group, an alpha,beta-unsaturated ketone, showed intense absorption (epsilon = 16,000). When the total amount of DHEA (DHEAS plus DHEA) was measured, the sample had been solvolyzed by sulfatase beforehand. The amounts of DHEAS were quantified by comparing the amounts of DHEA before and after solvolysis. Levels of free cholesterol, DHEAS, and DHEA in human breast cyst fluids (n = 30) were 1.77 +/- 1.12 mmol/dl, 8.27 +/- 10.24 micromol/dl, and 0.02 +/- 0.02 micromol/dl (means +/- SD), respectively. The levels of sterol and steroid measured in breast duct fluids that were turbid, brown, dark green, or milky in color (n = 9) (mean levels, 3.20 +/- 2.97 mmol/dl for free cholesterol and 14.77 +/- 13.75 micromol/dl for DHEAS) were significantly (P < 0.01) higher than the levels in clear or serous breast fluids (n = 21) (mean levels, 0.14 +/- 0.13 mmol/dl for free cholesterol and 0.04 +/- 0.07 micromol/dl for DHEAS).
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11954015&dopt=Abstract Ref: Arthritis Rheum 2002 Apr 15;47(2):202-9
Steroid hormones and disease activity during pregnancy in systemic lupus erythematosus.
Doria A, Cutolo M, Ghirardello A, Zampieri S, Vescovi F, Sulli A, Giusti M, Piccoli A, Grella P, Gambari PF.
Division of Rheumatology, University of Padova, Padua, Italy.
OBJECTIVES: To analyze the variation of steroid hormone levels during pregnancy in patients with systemic lupus erythematosus (SLE). Moreover, to investigate whether, during gestation, there is any relationship between steroid concentration and SLE activity. METHODS: Seventeen consecutive pregnant SLE patients and 8 matched healthy pregnant controls were studied prospectively. Disease activity was evaluated by European Consensus Lupus Activity Measure (ECLAM) score modified for pregnancy. The following hormones were evaluated: testosterone, 17beta-estradiol (estradiol), cortisol, dehydroepiandrosterone sulfate (DHEAS), and progesterone. RESULTS: Disease activity score significantly varied during pregnancy and postpartum (P< 0.05), being decreased in the third trimester and increased in the second trimester and postpartum. Serum levels of all steroids varied significantly during pregnancy and the postpartum period both in patients and in healthy subjects. In SLE patients, estradiol, progesterone, and DHEAS concentrations were found to be significantly reduced compared with controls. Serum level profiles of estradiol and progesterone were different from those observed in controls. No differences in the steroid levels were observed between patients taking prednisone 5 mg/day, apart from cortisol, which was, as expected, lower in the latter group. CONCLUSIONS: The major hormonal alteration observed during pregnancy in SLE patients was an unexpected lack of estrogen serum level increase, and, to a lesser extent, progesterone serum level increase, during the second and-even more-the third trimester of gestation. This lack of increase probably was due to placental compromise. Therefore, these steroid hormone variations may result in a lower humoral immune response activation, probably related to a change in the estrogen/androgen balance, that in turn could account for the decrease in disease activity observed during the third trimester in pregnant SLE patients.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11950789&dopt=Abstract Ref: Drug Metab Dispos 2002 May;30(5):570-5
Induction of CYP3A expression by dehydroepiandrosterone: involvement of the pregnane X receptor.
Ripp SL, Fitzpatrick JL, Peters JM, Prough RA.
Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky 40292, USA.
Dehydroepiandrosterone (DHEA) is a steroid produced by the human adrenal gland. Administration of pharmacological doses of DHEA to rats changes expression of many genes, including the cytochrome P450 family members CYP4A1 and CYP3A23. It is known that induction of CYP4A expression by DHEA requires the peroxisome proliferator-activated receptor alpha (PPAR(alpha)). In the current study, PPAR(alpha)-null mice were used to examine the role of PPAR(alpha) in expression of CYP3A. In wild-type mice, 150 mg/kg DHEA-sulfate induced Cyp4a and Cyp3a11 mRNAs by 5- and 2-fold, respectively. Induction of Cyp4a expression by DHEA-sulfate was not observed in PPAR(alpha)-null mice, whereas induction of Cyp3a11 expression by DHEA-sulfate was similar between genotypes. This suggests that PPAR(alpha) is not involved in induction of Cyp3a11 expression by DHEA. Because expression of CYP3A family members can be induced by activation of another member of the nuclear receptor superfamily, the pregnane X receptor (PXR), we examined the ability of DHEA to activate PXR. In transient transfection assays, DHEA and its metabolites androst-5-ene-3beta,17beta-diol (ADIOL), androst-5-ene-3,17-dione, and androst-4-ene-3,17-dione were activators of PXR. Maximal induction of a PXR-responsive reporter gene of approximately 3-fold was observed at concentrations of 50 to 100 microM, indicating that these steroids are relatively weak activators of PXR. Human and murine PXR exhibited different specificities for DHEA and its metabolites. ADIOL activated reporter gene expression in the presence of murine but not human PXR. Results of these studies suggest that the induction of rodent CYP3A expression upon treatment with high doses of DHEA occurs through activation of PXR.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11940375&dopt=Abstract Ref: Chin Med J (Engl) 2002 Mar;115(3):402-4
Treatment of osteoporosis in men using dehydroepiandrosterone (DHEA) sulfate.
Sun Y, Mao M, Sun L, Feng Y, Yang J, Shen P.
Department of Gerontology, Shanghai Sixth People's Hospital, Shanghai 200233, China.
OBJECTIVE: To study the effect of dehydroepiandrosterone sulfate (DHEAS) treatment of osteoporosis in men with T(BMD) > or = 2.5SD. METHODS: Eighty-six patients were randomly divided into two groups: treatment group (n = 44) and control group (n = 42). DHEAS (100 mg q.d.) was given to the treatment group for 6 months. Bone mineral density, (BMD), biochemical markers of bone absorption and formation and other serum biochemical markers were measured before and after DHEAS treatment. Drug side effects were also evaluated. RESULTS: After oral administration of DHEAS (100 mg q.d.) for 6 months, the serum concentrations of DHEAS and IGF-I in the treatment group were 93.75% +/- 16.1% and 17.71% +/- 4.2% higher respectively than those in the control group (P < 0.01). The BMD of L2, L3, L4, L2 - 4 and Neck sections increased in the treatment group by 2.65% +/- 0.65%, 2.70% +/- 0.48%, 3.10% +/- 0.41%, 2.82% +/- 0.37% and 2.32% +/- 0.31%, respectively, as compared with that the control group (P < 0.05 or 0.01). No significant changes were observed in serum FT, E(2) and PSA concentrations in the treatment group as compared with the control group. CONCLUSION: The treatment of osteoporosis in men with DHEAS is safe and effective.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11934890&dopt=Abstract Ref: J Biol Chem 2002 Jun 14;277(24):21379-88
Dehydroepiandrosterone activates endothelial cell nitric-oxide synthase by a specific plasma membrane receptor coupled to Galpha(i2,3).
Liu D, Dillon JS.
Division of Endocrinology, Department of Internal Medicine, University of Iowa College of Medicine and Veterans Administration Medical Center, Iowa City, Iowa 52246, USA.
The adrenal steroid dehydroepiandrosterone (DHEA) has no known cellular receptor or unifying mechanism of action, despite evidence suggesting beneficial vascular effects in humans. Based on previous data from our laboratory, we hypothesized that DHEA binds to specific cell-surface receptors to activate intracellular G-proteins and endothelial nitric-oxide synthase (eNOS). We now pharmacologically characterize a putative plasma membrane DHEA receptor and define its associated G-proteins. The [3H]DHEA binding to isolated plasma membranes from bovine aortic endothelial cells was of high affinity (K(d) = 48.7 pm) and saturable (B(max) = 500 fmol/mg protein). Structurally related steroids failed to compete with DHEA for binding. The putative DHEA receptor was functionally coupled to G-proteins, because guanosine 5'-O-(3-thio)triphosphate (GTPgammaS) inhibited [3H]DHEA binding to plasma membranes by 69%, and DHEA increased [35S]GTPgammaS binding by 157%. DHEA stimulated [35S]GTPgammaS binding to Galpha(i2) and Galpha(i3), but not to Galpha(i1) or Galpha(o). Pretreatment of plasma membranes with antibody to Galpha(i2) or Galpha(i3), but not to Galpha(i1), inhibited the DHEA activation of eNOS. Thus, DHEA receptors are expressed on endothelial cell plasma membranes and are coupled to eNOS activity through Galpha(i2) and Galpha(i3). These novel findings should allow us to isolate the putative receptor and reevaluate the physiological role of DHEA activity.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11932311&dopt=Abstract Ref: J Clin Endocrinol Metab 2002 Apr;87(4):1750-3
Intranasal administration of adrenocorticotropin-(1-24) stimulates adrenocortical hormone secretion.
Hiroi N, Ichijo T, Ueshiba H, Miyachi Y.
First Department of Internal Medicine, Toho University School of Medicine, Tokyo 143-0015, Japan.
To determine the efficiency of transmucosal absorption of ACTH, we measured serum cortisol, aldosterone, dehydroepiandrosterone (DHEA), and DHEA sulfate (DHEA-S) levels after intranasal (in) vs. iv administration of ACTH-(1-24) (250 microg) in 12 healthy adult men (mean age, 24.3 +/- 3.2 yr; range, 21-31 yr), who had received no prior medication and had no symptoms of rhinitis. Blood was collected at 0, 30, 60, 120, and 180 min after administration of ACTH-(1-24), and the levels of adrenocortical steroids were measured by specific RIAs. There were no side-effects associated with in or iv ACTH administration. After in administration, serum cortisol and aldosterone increased rapidly by 224.7 +/- 39.2% and 147.2 +/- 50.5%, respectively, peaking 30 min after ACTH-(1-24) administration, and decreasing to basal levels within 120 min. These increases in serum cortisol and aldosterone were lower than those obtained after iv administration. Thirty minutes after in or iv administration of ACTH-(1-24), DHEA increased by 49.1 +/- 27.2% and 81.6 +/- 17.1%, respectively, and remained elevated for 180 min. Serum DHEA-S levels did not change after in administration of ACTH-(1-24) and increased only slightly after iv injection. Adrenocortical steroid levels did not increase after in administration of saline. These data demonstrate that adrenocortical steroids are stimulated by in administration of ACTH-(1-24). We suggest that intranasal administration of ACTH offers both a diagnostic approach as an adrenal function test and a therapeutic approach as ACTH replacement therapy in patients with ACTH deficiency. The latter may be more physiological than glucocorticoid replacement.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11932279&dopt=Abstract Ref: J Clin Endocrinol Metab 2002 Apr;87(4):1544-9
Dehydroepiandrosterone supplementation and bone turnover in middle-aged to elderly men.
Kahn AJ, Halloran B.
Department of Growth and Development, University of California at San Francisco, California 94143-0438, USA.
In the present placebo-controlled, double-blind study, we assessed the effect of dehydroepiandrosterone (DHEA) supplementation (90 mg orally/d) on bone turnover in 43 healthy men, 56-80 yr old. Placebo or steroid was given for 6 months, followed by a 1-month washout period and then a further 6 months of the opposite agent. Serum samples were collected at baseline 3, 6, 7, and 13 months and assayed for procollagen peptide, bone-specific alkaline phosphatase, and osteocalcin, all markers of bone formation. Measurements were also made of serum cortisol, DHEA/DHEA-S, E2 and free and total T. First void, fasting urine was collected at baseline, 6, 7, and 13 months and assessed for deoxypyridinoline, a marker of bone resorption. Mean serum DHEA and DHEA-S levels in treated men were increased approximately 3-fold ( approximately 2.2 ng/ml to approximately 6 ng/ml) and 4.5-fold ( approximately 1000 ng/ml to approximately 4500 ng/ml), respectively, after 6 months and returned to baseline after washout. Similarly, circulating E2 concentrations were also increased 1.4-fold (from approximately 16-23 pg/ml; P < 0.001), a finding not observed with any other measured hormone. Bone marker levels remained remarkably constant at each sampling interval; procollagen peptide at approximately 8.0 ng/ml; bone-specific alkaline phosphatase at approximately 21.0 U/liter; deoxypyridinoline at approximately 4.5 nmol/mmol Cr. Osteocalcin showed a transient reduction from approximately 10.2- 6.2 ng/ml, P < 0.005 to P < 0.001, at 3 months, but this decline was observed in both treated and controls. Stratifying the marker levels by age or baseline DHEA/DHEA-S levels did not affect the findings. We conclude that oral DHEA does not affect bone turnover in middle-aged to elderly men when used for a 6-month period at doses targeted to restore circulating levels of the steroid to that seen in young adults.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11928558&dopt=Abstract Ref: Wiad Lek 2001;54(11-12):693-704
Dehydroepiandrosterone (DHEA)--youth hormone?
[Article in Polish]
Zdrojewicz Z, Kesik S.
Katedry i Kliniki Endokrynologii i Diabetologii Akademii Medycznej we Wroclawiu.
Dehydroepiandrosterone (DHEA) and its sulphated metabolite (DHEA-S) are endogenous steroid hormones, synthesized by the adrenal cortex, gonads and CNS. The secretion profile changes with age and depends on the sex. Human DHEA and DHEA-S levels decline linearly and systematically with age and suggest the potential importance of that parameter as a biomarker of ageing. The counteraction of DHEA against atherosclerotic disease, cancer growth, diabetes mellitus, insulin resistance, obesity and the influence on immunological functions are observed in researches. DHEA influences the condition of mind, cognition functions, memory and well-being. DHEA hormonal replacement therapy is expected to lengthen human life by the stoppage of physiological degeneration changes and prevention of age-related clinical disorders.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11928179&dopt=Abstract Ref: J Sex Marital Ther 2002 Jan-Feb;28(1):53-60
Acute dehydroepiandrosterone effects on sexual arousal in premenopausal women.
Meston CM, Heiman JR.
Department of Psychology, University of Texas at Austin, Mezes Hall 330, Austin, TX 78712, USA.
The present investigation was designed to provide the first empirical examination of the effects of acute dehydroepiandrosterone (DHEA) administration on subjective and physiological sexual arousal in women. The primary purpose was to assess whether DHEA influences vaginal blood flow response in sexually functional women. Subjective (self-report) and physiological (vaginal photoplethysmograph) sexual responses to erotic stimuli were measured following DHEA (300 mg) and placebo administration in 12 sexually functional, premenopausal women, using a single-blind protocol. Acute DHEA significantly increased blood levels of dehydroepiandrosterone sulfate (DHEA-S) 30 min following drug administration but had no significant effect on either vaginal pulse amplitude responses or subjective responses to the erotic films. Acute DHEA does not appear to substantially influence sexual responding among sexually functional, premenopausal women.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11927388&dopt=Abstract Ref: Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11927388&dopt=Abstract
Adrenopause or decline of serum adrenal androgens with age in women living at sea level or at high altitude.
Gonzales GF, Gonez C, Villena A.
Department of Physiological Sciences, Faculty of Sciences and Philosophy and Instituto de Investigaciones de la Altura, Universidad Peruana Cayetano Heredia, PO Box 1843, Lima, Peru.
The present study aimed to determine adrenopause or reduction of serum adrenal androgens with age at high altitude and at sea level. It was a cross-sectional study performed in 210 women resident at high altitude (4340 m) and 123 women living in Lima (150 m), aged 20-70 years. Fasting early morning blood samples were obtained. Serum dehydroepiandrosterone (DHEA), DHEA sulphate (DHEAS), androstenedione, testosterone and estradiol were measured by radioimmunoassay. Serum testosterone concentrations were greater in women living at high altitude than in those resident at sea level. Serum concentrations of DHEA, DHEAS and androstenedione were lower in women living at high altitude than in those living at sea level. The DHEAS/DHEA ratio was significantly greater, and the androstenedione/testosterone ratio was lower in samples from women living at high altitude. Among women older than 50 years of age, a greater decline in serum concentrations of DHEA was observed in those living at high altitude than in those living at sea level. Among women 60-70 years of age, serum concentrations of DHEA at high altitude were 46.9% of those in women of the same age living at sea level. Decay of DHEAS at sea level and at high altitude occurred from the age of 40 years. The decline was faster at high altitude than at sea level, and in women aged 60-70 years serum values of DHEAS at high altitude were 56% of those at sea level. In the same age group, serum concentrations of androstenedione among those native to high altitudes were 27.34% of the value at sea level. At sea level, serum testosterone concentrations did not change with age from 20 to 70 years. In women aged 20-39 years and 50-59 years, serum testosterone concentrations were greater at high altitude than at sea level (P<0.05). In those aged 60-70 years, the concentrations were similar in those living at sea level and at high altitude. At sea level and at high altitude, the serum testosterone/estradiol ratio increased with age (P<0.0034 and P<0.0001 respectively). This ratio increased at an earlier age among those living at high altitude (40-49 years) than among those living at sea level (50-59 years). Multivariate analysis showed that altitude (P<0.0001) and greater chronological age (P<0.001) were associated with lower serum DHEAS concentrations. DHEAS was related to chronological age (P<0.0001). Low serum androstenedione concentrations were related to living at high altitude at birth and greater chronological age (P<0.0001). In conclusion, adrenopause is attained earlier and is of greater magnitude at high altitude than at sea level.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11925670&dopt=Abstract Ref: Cas Lek Cesk 2002 Feb 15;141(3):89-95
Role of the steroids, SHBG, IGF-1, IGF BP-3 and growth hormone in glucose metabolism disorders during long-term treatment with low doses of glucocorticoids
[Article in Czech]
Vondra K, Hampl R, Nemcova D, Hill M, Hoza J, Kot'atkova A, Starka L, Vrbikova J, Zamrazil V.
Endokrinologicky ustav, Praha.
BACKGROUND: The relationships between selected steroids, SHBG, growth hormone, IGF-1, IGF BP-3 and indicators of glucose metabolism were studied in the group of 20 female patients (15-20 yrs) on long-term treatment with low prednisone doses (< 0.3 mg/kg/day) (baseline phase) and after adding 1000 mg of metformin per day for following 6 months to improve impaired glucose metabolism (control phase). METHODS AND RESULTS: Lower basal DHEAS and DHEA (DHEA/S) levels were found as compared with reference values. Only DHEAS level returned into the reference range after the treatment with metformin. Decrease of DHEA/S depended on the doses (DHEAS -0.7621, DHEA -0.7685). Positive correlations between DHEA/S and of the results insulin tolerance were found as at the baseline (+0.4452, resp. +0.4455) as well as in the control period after the metformin administration (+0.7549, resp. +0.6073). Testosterone (T) and dihydrotestosterone(DHT) values were within the reference range during the whole study. Due to very low SHBG levels higher free androgen index (FAI) was recorded in more than half of the patients. Significant relationships were revealed between former gonadal androgens and indicators of glucose metabolism deterioration at the control phase: T correlated: with fasting insulin (+0.6005), with HOMAIR (+0.5380), with insulin/glucose (+0.5261), with fasting glucose (+0.9268), with AUC glucose (+0.6792), FAI: with fasting insulin (+0.5560), with HOMAIR (+0.5269), with fasting glucose (+0.9025), with AUC glucose (+0.7143), DHT: with fasting C peptide (+0.7921), with AUC C peptide (+0.7143). SHBG correlated: with fasting glucose (-0.6519), and with AUC glucose (-0.5868). The tendency of GH to lower, and IGF-1, IGF BP-3 to higher values at the baseline changed at the control phase: fasting and AUC value of GH increased (signif.), while were IGF-1 (nonsignif.) and IGF BP-3 (signif.) levels decreased. Surprisingly, no correlation was observed between GH and parameters of glucose metabolism. Contrary to GH, baseline IGFBP-3 values correlated: with HOMAIR (+0.5002), with insulin/glucose (+0.4860). The same relationships were found between AUC IGF BP-3 (+0.5676, +0.5559), IGF-1 (HOMAIR only +0.5412), IGF-1/IGF BP-3 (+0.5059, +0.5716) and parameters of insulin sensitivity (HOMAIR, insulin/glucose) in the control period. For the first time negative correlations between IGF-1, IGF-1 AUC, IGF BP-3, IGF-1/IGF BP-3 and somatostatin blood levels were discovered at the control phase. CONCLUSIONS: The study brought a number of new information about the importance of the "non-classical" glucoregulatory hormones in impairment of glucose metabolism, during long-term administration of low prednisone doses. The results suggest, that without normalisation of low DHEA/S, SHBG and high FAI levels it would not be possible to correct glucose metabolism properly in patients with long-term glucocorticoid therapy.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11921506&dopt=Abstract Ref: J Int Med Res 2002 Jan-Feb;30(1):9-14
The effects of cardiopulmonary bypass on androgen hormones in coronary artery bypass surgery.
Canbaz S, Ege T, Sunar H, Cikirikcioglu M, Acipayam M, Duran E.
Department of Cardiovascular Surgery, Medical Faculty, Trakya University, Edirne, Turkey.
The effects of testosterone on coronary vasomotor regulation have been described by several recent reports. Here we investigated changes in serum androgen levels during and after cardiopulmonary bypass (CPB) in patients who had undergone coronary artery bypass surgery. Serum luteinizing hormone, free testosterone and dihydroepiandrestenedione sulphate (DHEA sulphate) levels were evaluated in 38 male coronary artery bypass surgery patients using a chemical immunoassay technique. All hormone levels were corrected to account for haemodilution. Serum-free testosterone level decreased significantly during weaning from CPB (from 15.7 +/- 4.2 nmol/l to 6.2 +/- 2.8 nmol/l), and an even greater decrease was observed in the first post-operative day (5.4 +/- 3.1 nmol/l). On the seventh post-operative day, free testosterone levels reached a normal value (11.8 +/- 5.5 nmol/l), although they were still significantly lower compared with the pre-operative value. There were slight alterations in serum DHEA sulphate levels, although the only significant decrease occurred from the first to the seventh day post-operation (from 4.7 +/- 2.2 mumol/l to 3.7 +/- 1.8 mumol/l, respectively). Serum luteinizing hormone levels were decreased during weaning from CPB (from 4.8 +/- 2.1 mIU/ml to 3.9 +/- 1.8 mIU/ml), but increased rapidly to the pre-operative value (5.5 +/- 2.5 mIU/ml) at the first post-operative day. These results show that CPB affects serum luteinizing hormone, free testosterone and dihydroepiandrestenedione sulphate levels. The free testosterone level decreases significantly both during and after CPB surgery.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11920401&dopt=Abstract Ref: Arthritis Rheum 2002 Mar;46(3):654-62
Inadequately low serum levels of steroid hormones in relation to interleukin-6 and tumor necrosis factor in untreated patients with early rheumatoid arthritis and reactive arthritis.
Straub RH, Paimela L, Peltomaa R, Scholmerich J, Leirisalo-Repo M.
Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
OBJECTIVE: To compare levels of steroid hormones in relation to cytokines and to study levels of cortisol or dehydroepiandrosterone (DHEA) in relation to other adrenal hormones in untreated patients with early rheumatoid arthritis (RA) and reactive arthritis (ReA) compared with healthy controls. METHODS: In a retrospective study with 34 RA patients, 46 ReA patients, and 112 healthy subjects, we measured serum levels of interleukin-6 (IL-6), tumor necrosis factor (TNF), adrenocorticotropic hormone (ACTH), cortisol, 17-hydroxyprogesterone (17-OH-progesterone), androstenedione (ASD), DHEA, and DHEA sulfate (DHEAS). RESULTS: RA patients had higher serum levels of IL-6, TNF, cortisol, and DHEA compared with ReA patients and healthy subjects, but no difference was noticed with respect to ACTH and DHEAS. However, in RA and ReA patients compared with healthy subjects, levels of ACTH, cortisol, ASD, DHEAS, and 17-OH-progesterone were markedly lower in relation to levels of IL-6 and TNF. Furthermore, the number of swollen joints correlated inversely with the ratio of serum cortisol to serum IL-6 in RA (R(Rank) = -0.582, P = 0.001) and, to a lesser extent, in ReA (R(Rank) = -0.417, P = 0.011). In RA patients, the mean grip strength of both hands was positively correlated with the ratio of serum cortisol to serum IL-6 (R(Rank) = 0.472, P = 0.010). Furthermore, in these untreated patients with RA and ReA, there was a relative decrease in the secretion of 17-OH-progesterone, ASD, and DHEAS in relation to DHEA and cortisol. This indicates a relative predominance of the nonsulfated DHEA and cortisol in relation to all other measured adrenal steroid hormones in the early stages of these inflammatory diseases. CONCLUSION: This study indicates that levels of ACTH and cortisol are relatively low in relation to levels of IL-6 and TNF in untreated patients with early RA and ReA compared with healthy subjects. The study further demonstrates that there is a relative increase of DHEA and cortisol in relation to other adrenal hormones, such as DHEAS. This study emphasizes that adrenal steroid secretion is inadequately low in relation to inflammation. Although changes in hormone levels are similar in RA and ReA, alteration of steroidogenesis is more pronounced in RA patients than in ReA patients.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11911290&dopt=Abstract Ref: Anticancer Res 2001 Nov-Dec;21(6A):4051-4
Serum dehydroepiandrosterone and dehydroepiandrosterone sulfate and risk of melanoma or squamous cell carcinoma of the skin.
Alberg AJ, Gordon GB, Genkinger JM, Hoffman SC, Selvin E, Comstock GW, Helzlsouer KJ.
Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA.
BACKGROUND: Dehydroepiandrosterone (DHEA) and its analogs have potent chemoprotective actions in mouse skin tumorigenesis models. To assess this association in humans, we investigated the relationship of prediagnostic serum concentrations of DHEA and dehydroepiandrosterone sulfate (DHEAS) to the subsequent risk of developing malignant melanoma and squamous cell carcinoma of the skin in residents of Washington County, Maryland, USA. PATIENTS AND METHODS: In a nested case-control study, serum that had been stored in 1974 was thawed and assayed for DHEA and DHEAS for 23 cases of malignant melanoma and 28 cases of squamous cell carcinoma and 1-2 matched controls per case. RESULTS: The mean serum concentrations of DHEA or DHEAS were similar in cases and controls. There were no statistically significant trends in the risk of developing malignant melanoma or squamous cell skin cancer by concentration of either steroid (all p-for-trends >0.30). CONCLUSION: The results of this study do not support the hypothesis that physiological concentrations of DHEA or DHEAS protect against skin cancer in humans.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11907709&dopt=Abstract Ref: Calcif Tissue Int 2002 Mar;70(3):137-45
Predictors of bone mineral density in aging healthy men varies by skeletal site.
Clarke BL, Ebeling PR, Jones JD, Wahner HW, O'Fallon WM, Riggs BL, Fitzpatrick LA.
Division of Endocrinology and Endocrine Research Unit, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.
Factors contributing to the pathogenesis of osteoporosis in women are well defined. However, changes in bone mineral metabolism in aging men and the role of various factors in the pathogenesis of age-related bone loss in men are less well understood. To further clarify these changes, serum and urine biochemical parameters, and lumbar spine, hip, and total body bone mineral density (BMD) were evaluated in a small sample of 45 healthy men aged 20-80 years, and multiple regression models were developed to predict age-related bone loss. Serum calcium, phosphate, albumin, creatinine clearance, osteocalcin, C-terminal propeptide of type I procollagen, log-free androgen index, dehydroepiandrosterone sulfate (DHEA-S), and androstenedione decreased with age, and serum sex hormone binding globulin and urine total and free pyridinoline increased with age. Femoral neck BMD decreased with age, but remained stable at the other sites measured. Multiple regression analysis indicated that serum phosphate, DHEA-S, and intact parathyroid hormone (PTH) predicted lumbar spine BMD. Age, serum phosphate, and PTH predicted femoral neck BMD. Urine-free deoxypyridinoline alone predicted femoral greater trochanter BMD. Weight, serum creatinine, and urine-free deoxypyridinoline predicted total body BMD. We conclude that predictor variables of bone density vary by skeletal site in healthy men. Alterations in adrenal androgens, phosphate, and PTH may be important in the pathogenesis of bone loss with aging in men.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11898698&dopt=Abstract Ref: J Sex Marital Ther 2002;28 Suppl 1:165-73
Androgen replacement therapy with dehydroepiandrosterone (DHEA) for androgen insufficiency and female sexual dysfunction: androgen and questionnaire results.
Munarriz R, Talakoub L, Flaherty E, Gioia M, Hoag L, Kim NN, Traish A, Goldstein I, Guay A, Spark R.
Boston University School of Medicine, Boston, Massachusetts, USA.
During our evaluations of women with sexual dysfunction, we have seen many with low interest, arousal, and orgasmic capabilities with associated personal distress and diminished genital sensation and blood flow following sexual stimulation. Laboratory evaluation of these women has revealed normal estrogen but androgen values that were either below or in the lower quartile of the physiologic range. Androgen insufficiency and sexual dysfunction have been the working diagnoses in these women. Although many treatment options currently are available for this syndrome, there are limited data concerning safety and efficacy. The aim of this retrospective, Institutional Review Board (IRB)--approved, single-institution study was to report on the androgen and questionnaire results from a series of patients who underwent androgen replacement therapy with dehydroepiandrosterone for treatment of androgen insufficiency and sexual dysfunction. This study revealed that there was a significant decrease in sexual distress, a significant increase in sexual function in the domains of desire, arousal, lubrication, satisfaction, and orgasm, and a normalization to values within the physiologic range in the following androgens measured: total testosterone, free or bioavAilable testosterone, DHEA, DHEA-S, and androstenedione. Side effects included increased facial hair (11%), weight gain (7%), acne (5%), temporary breast tenderness (1%), loss of head hair (1%) and skin rash (1%). Preliminary results suggest that androgen replacement therapy with dehydroepiandrosterone is a safe and effective treatment for androgen insufficiency and female sexual dysfunction. However, further research is needed, including prospective, multi-institution, placebo-controlled double-blind studies.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11898695&dopt=Abstract Ref: J Sex Marital Ther 2002;28 Suppl 1:129-42
Decreased free testosterone and dehydroepiandrosterone-sulfate (DHEA-S) levels in women with decreased libido.
Guay AT, Jacobson J.
Center for Sexual Function, Lahey Clinic Northshore, One Essex Center Drive, Peabody, MA 01960, USA.
A prior study has shown that premenopausal women could have decreased testosterone levels and still have regular menstrual cycles (Guay, 2001). Since ovarian function in such women was normal, the question of a possible adrenal dysfunction causing androgen deficiency was considered. If this was true, the question then arose as to whether the same defect could be seen in postmenopausal women. We studied 105 women who presented during a 6-month period of time with the chief complaint of decreased sexual desire. On subsequent testing, 74 of the women (70%) were found to have decreased total testosterone, free testosterone, and dehydroepiandrosterone sulfate (DHEA-S). Thirty-six of these women were premenopausal (ages range 24-50 years), and 38 were postmenopausal (ages range 47-78 years). All androgen levels for the women were lower than age-matched control groups found in the literature. The decreased DHEA-S levels suggest a a defect in adrenal steroidogenesis, which was seen in both premenopausal and postmenopausal women. Possible defects in regulatory mechanisms of adrenal steroidogenesis are discussed.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11895222&dopt=Abstract Ref: Clin Endocrinol (Oxf) 2001 Dec;55(6):797-803
Dehydroepiandrosterone sulphate (DHEA-S) is increased and dehydroepiandrosterone-response to corticotrophin-releasing hormone is decreased in the hyperthyroid state compared with the euthyroid state.
Yamakita N, Murai T, Kokubo Y, Hayashi M, Akai A, Yasuda K.
Department of Internal Medicine, Matsunami General Hospital, Kasamatsu, Gifu-Prefecture, Japan.
OBJECTIVE: Dehydroepiandrosterone (DHEA) and DHEA-sulphate (S) have been suggested to play protective roles in many pathological states, some of which are observed in hyperthyroidism. If DHEA and DHEA-S levels change in hyperthyroidism, they might participate as a possible causative link with such pathophysiological changes in hyperthyroidism. However, the CRH-ACTH-DHEA system in hyperthyroidism has not been clearly defined. We examined plasma levels of DHEA and DHEA-S together with ACTH and cortisol in both hyperthyroid (Hyper) and euthyroid states (Eu). METHODS: Eighteen patients (5 men and 13 women, aged 46.9 +/- 2.8 years) with Graves' disease were studied before treatment and again in the euthyroid state following treatment with methimazole. A 100 microg hCRH stimulation test and a low-dose (0.5 microg) 1-24 ACTH stimulation test were performed on separate days. Basal levels and A area under the response curve (AUC) were compared between Hyper and Eu. RESULTS: DHEA-S was higher in Hyper than in Eu. However, basal DHEA did not differ between Hyper and Eu. The ratio of DHEA to DHEA-S was lower in Hyper than in Eu. AAUC of DHEA during a CRH test was lower in Hyper than in Eu. However, AAUC of DHEA during an ACTH test was similar in both Hyper and Eu. Basal ACTH was higher in Hyper than in Eu. In both CRH and ACTH tests, AAUC of cortisol response was lower in Hyper than in Eu, although the basal cortisol level was not different. CONCLUSION: The balance of the conversion between DHEA-S and DHEA in the hyperthyroid state favoured DHEA-S. Similar to cortisol, the DHEA response in the CRH test in hyperthyroidism seemed to be insufficiently compensated for by increased ACTH, although the DHEA response to low-dose ACTH was similar in the hyperthyroid and euthyroid states. Increased DHEA-S might play some role in the pathological states in many organs in hyperthyroidism.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11892912&dopt=Abstract Ref: Curr Opin Investig Drugs 2001 Aug;2(8):1045-53
Novel therapies in the treatment of systemic lupus erythematosus.
Dequet CR, Wallace DJ.
Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
This review highlights the advances made in the use of biological and immunomodulatory agents in systemic lupus erythematosus. Although there have been disappointments (eg, anti-CD40 ligand, DNAse), it is clear that DHEA and mycophenolate mofetil will have a place in the management of the disease. In our opinion, leflunomide and LJP-394 are the most promising therapies currently, under study.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11888844&dopt=Abstract Ref: Eur J Endocrinol 2002 Mar;146(3):375-80
Decreased steroidogenic enzyme 17,20-lyase and increased 17-hydroxylase activities in type 2 diabetes mellitus.
Ueshiba H, Shimizu Y, Hiroi N, Yakushiji F, Shimojo M, Tsuboi K, Miyachi Y.
First Department of Internal Medicine, Toho University School of Medicine, 6-11-1 Ohmori-nishi, Ohta-ku, Tokyo 143-0015, Japan.
OBJECTIVE: To analyze activities of adrenal steroidogenic enzymes in type 2 diabetes mellitus, serum levels of 11 steroid hormones were measured simultaneously. SUBJECTS: We studied 130 patients with type 2 diabetes mellitus (74 men and 56 women between the ages of 40 and 69 years), whose blood glucose control had been poor (more than 10% in HbA(1c)). Age-matched normal subjects served as the control group. METHODS: Serum levels of steroid hormones (pregnenolone (Preg), progesterone (Prog), deoxycorticosterone (DOC), corticosterone (B), 17-hydroxypregnenolone (17-OH-Preg), 17-hydroxyprogesterone (17-OHP), 11-deoxycortisol (S), cortisol (F), dehydroepiandrosterone (DHEA) and Delta4-androstenedione (Delta4A)) were measured by HPLC/RIA methods. Fasting plasma glucose (FPG), HbA(1c), ACTH, serum immunoreactive insulin (IRI) and DHEA sulfate (DHEA-S) were also measured. We analyzed product/precursor ratios to assess relative activities of adrenal steroidogenic enzymes. RESULTS: Serum levels of ACTH and F were high and DHEA and DHEA-S were low in both male and female patients under poor blood glucose control. Following 6-months treatment with diet only or with sulfonylurea, FPG and HbA(1c) improved, and blood concentrations of ACTH and F decreased while DHEA and DHEA-S levels increased to within the normal range. DHEA/17-OH-Preg and Delta4A/17-OHP ratios, reflecting 17,20-lyase activity, were low before treatment and recovered to the normal range after treatment, and 17-OH-Preg/Preg and 17-OHP/Prog ratios, reflecting 17-hydroxylase activity, were high before treatment, and fell within the normal range after treatment. 3beta-Hydroxysteroid dehydrogenase, 21-hydroxylase and 11beta-hydroxylase activities remained within the normal range both before and after treatment. CONCLUSIONS: These data suggest that the decrease in DHEA and DHEA-S concentrations together with the high F levels that occur in patients with type 2 diabetes mellitus is associated with low 17,20-lyase and high 17-hydroxylase activity in the adrenal steroidogenic enzymes. High insulin concentrations may further lower DHEA and DHEA-S levels.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11888843&dopt=Abstract Ref: Eur J Endocrinol 2002 Mar;146(3):365-74
Dehydroepiandrosterone in relation to other adrenal hormones during an acute inflammatory stressful disease state compared with chronic inflammatory disease: role of interleukin-6 and tumour necrosis factor.
Straub RH, Lehle K, Herfarth H, Weber M, Falk W, Preuner J, Scholmerich J.
Department of Internal Medicine I, University Hospital Regensburg, 93042 Regensburg, Germany.
OBJECTIVE: Serum levels of dehydroepiandrosterone (DHEA) and DHEA sulphate (DHEAS) are low in chronic inflammatory diseases, although the reasons are unexplained. Furthermore, the behaviour of serum levels of these hormones during an acute inflammatory stressful disease state is not well known. SUBJECTS AND METHODS: In this study in patients with an acute inflammatory stressful disease state (13 patients undergoing cardiothoracic surgery) and patients with chronic inflammation (61 patients with inflammatory bowel diseases (IBD)) vs. 120 controls, we aimed to investigate adrenal hormone shifts looking at serum levels of DHEA in relation to other adrenal hormones. Furthermore, we tested the predictive role of serum tumour necrosis factor (TNF) and interleukin-6 (IL-6) for a change of serum levels of DHEA in relation to other adrenal hormones. RESULTS: The molar ratio of serum levels of DHEA/androstenedione (ASD) was increased in patients with an acute inflammatory stressful disease state and was decreased in patients with chronic inflammation. The molar ratio of serum levels of DHEAS/DHEA was reduced during an acute inflammatory stressful disease state and was increased in patients with chronic inflammation. A multiple linear regression analysis revealed that elevated serum levels of TNF were associated with a high ratio of serum levels of DHEA/ASD in all groups (for IL-6 in patients with an acute inflammatory stressful disease state only), and, similarly, elevated serum levels of TNF were associated with a high ratio of serum levels of DHEAS/DHEA only in IBD (for IL-6 only in healthy subjects). CONCLUSIONS: This study indicates that changes of serum levels of DHEA in relation to serum levels of other adrenal hormones are completely different in patients with an acute inflammatory stressful disease state compared with patients with chronic inflammation. The decrease of serum levels of DHEAS and DHEA is typical for chronic inflammation and TNF and IL-6 play a predictive role for these changes.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11887177&dopt=Abstract Ref: Metabolism 2002 Mar;51(3):376-9
Effects of dehydroepiandrosterone on rat apolipoprotein AI gene expression in the human hepatoma cell line, HepG2.
Deleon MJ, Horani MH, Haas MJ, Wong NC, Mooradian AD.
Division of Endocrinology, Diabetes, and Metabolism, Saint Louis University School of Medicine, St Louis, MO 63104, USA.
Serum apolipoprotein AI (apoAI) levels correlate with the risk of developing atherosclerosis. Previous studies have suggested that dehydroepiandrosterone (DHEA) lowers high-density lipoprotein (HDL)-cholesterol levels. We investigated whether or not DHEA may lower HDL-cholesterol levels by suppressing apoAI gene transcription in hepatocytes. ApoAI mRNA levels, assessed by Northern blotting, were suppressed in HepG2 cells treated with DHEA (34%) (10 microg/mL) or testosterone (36%) (T, 1 microg/mL). Estradiol alone (E2, 1 microg/mL) had relatively little effect on apoAI mRNA levels, while E2 in combination with DHEA prevented a decrease in apoAI mRNA levels compared to DHEA alone. To determine whether these effects were due to changes in apoAI gene transcription, HepG2 cells were transfected with a plasmid carrying the full-length promoter of the rat apoAI gene ligated into a chloramphenicol acetyltransferase (CAT) reporter construct. The plasmid pCMV.SPORT-beta-gal was included in each transfection to normalize the data to transfection efficiency. Cells were then cultured in the presence or absence of DHEA (10 microg/mL), T (1 microg/mL), 17alpha-methyltestosterone (MTT, 1 microg/mL), 5alpha-dihydrotestosterone (DHT, 1 microg/mL), E2 (1 microg/mL), or a combination of DHEA plus E2, T plus E2, MTT plus E2, and DHT plus E2, for 24 hours. CAT activity, relative to beta-galactosidase activity, was reduced by 19.6%, 57.6%, 38.6%, and 54.6% with DHEA, T, DHT, and MTT addition, respectively. E2 increased CAT activity by 43.8%. When the androgens (ie, DHEA, T, DHT, or MTT) were combined with E2, apoAI promoter activity was suppressed. We conclude, therefore, that androgens downregulate apoAI promoter activity in the presence or absence of E2. However, the changes in mRNA levels do not always reflect changes in promoter activity, suggesting that these steroids may have additional post-transcriptional effects on steady-state apoAI mRNA levels. It remains to be established if the transcriptional effects we observed are mediated through an androgen response element.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11886764&dopt=Abstract Ref: Maturitas 2002 Mar 25;41(3):187-92
Cytokine pattern in postmenopause.
Cioffi M, Esposito K, Vietri MT, Gazzerro P, D'Auria A, Ardovino I, Puca GA, Molinari AM.
Patologia clinica, Dipartimento di Patologia Generale, Facolta di Medicina e Chirurgia, Seconda Universita degli Studi di Napoli, Via S. Andrea delle Dame, 2-80138, Naples, Italy.
OBJECTIVE: The present study was undertaken to evaluate the pattern of serum cytokine production in postmenopausal women and the relationship with the hormonal status. A group of fertile women served as controls. METHODS: Eighty-two women in apparent good health, non-smokers and without a history of hormone replacement therapy, were enrolled for the study. The women were divided in two groups according to their hormonal status: fertile women (n=34, age 32 +/- 7 years) and postmenopausal women (n=48, age 54 +/- 8 years). Blood samples were withdrawn in the morning, after an overnight fast. RESULTS: Sex hormones (LH, FSH, Estradiol, Progesterone, DHEA, DHEA-S), as well as GH and IGF-1 levels, were significantly higher in the serum of fertile women as compared with their postmenopausal counterparts. Unlike IL-2, IL-4, IL-5, IL-10, IL-12 and IFN-gamma, significant differences were observed in serum IL-6, IL-18, TNFalpha and TNFbeta between groups: both IL-6 and IL-18 were higher in postmenopausal women, while TNFalpha and TNFbeta were significantly lower. There was an inverse relationship between serum DHEA and DHEA-S levels and both IL-6 (r= -0.46, P<0.02) or IL-18 (r= -0.38, P<0.05) serum concentrations. CONCLUSIONS: Compared with fertile counterparts, women in postmenopause present an alteration in serum cytokine profile suggesting a prevalence of Th2 lymphocytes.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11885858&dopt=Abstract Ref: J Chromatogr B Analyt Technol Biomed Life Sci 2002 Feb 15;767(2):285-99
Ergosteroids. VI. Metabolism of dehydroepiandrosterone by rat liver in vitro: a liquid chromatographic-mass spectrometric study.
Marwah A, Marwah P, Lardy H.
University of Wisconsin-Madison, Institute for Enzyme Research and Department of Biochemistry, 53705-4908, USA.
Because relatively large amounts of dehydroepiandrosterone (DHEA) are required to demonstrate its diverse metabolic effects, it is postulated that this steroid may be converted to more active molecules. To search for the possible receptor-recognized hormones. DHEA was incubated with whole rat liver homogenate and metabolite appearances were studied by LC-MS as a function of time to predict the sequence of their formation. An array of metabolites has been resolved, identified and characterized by highly specific and accurate technique of LC-MS, and several of these steroids were analyzed quantitatively. Their identities were established by comparison with pure chemically synthesized compounds and by chemical degradation of isolated fractions. In the present study, we have reasonably established that DHEA was converted to 7alpha-OH-DHEA, 7-oxo-DHEA, and 7beta-OH-DHEA in sequence. These metabolites were further reduced at position 7 and/or 17 to form their respective diols and triols, which were also sulfated at 3beta-position. DHEA and its 7-oxygenated derivatives were also converted to their respective 3beta-sulfate esters. Several of these steroids are being reported for the first time. 16Alpha-hydroxy-DHEA, androst-5-ene-3beta,16alpha,17beta-triol, androst-4-ene-3,17-dione, 11-hydroxy-androst-4-ene-3,17-dione, androst-5-ene-3,17-diol and testosterone were also identified and characterized. In all, 19 metabolites of DHEA are being reported in this extensive study. We have also detected the formation of 12 additional metabolites including several conjugates, which are the subject of current investigation.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11883869&dopt=Abstract Ref: J Endocrinol Invest 2002 Jan;25(1):73-83
Dementia: a neuroendocrine perspective.
Polleri A, Gianelli MV, Murialdo G.
Department of Endocrinological and Metabolic Sciences, University of Genoa, Italy.
The etiology of Alzheimer's disease (AD) has not been as yet completely defined. Genetic, environmental and neurophysiological aspects should all be taken into account. The disease has also neuroendocrine implications, some of which are discussed in this review. It is known that stress and glucocorticoids may affect neurone survival. On the contrary, some data indicate that DHEA and DHEAS exert a neuroprotective action. In AD, changes in hypothalamic-pituitary-adrenal axis function have been reported. Experimental and clinical evidence indicates that glucocorticoid hypersecretion and DHEAS levels decrement may add to hippocampal dysfunction in aging and in AD. Glucocorticoid and beta-amyloid concur in the mechanism of neurone damage, as well as excitatory amino acids (EAA), Ca++ and reactive oxygen species (ROS). The neuroprotective effects exerted by IGFs are also hindered in aging and even more in AD. Production and biological actions of IGFs are negatively influenced by cortisol hypersecretion and DHEAS decrease in patients with AD.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11875781&dopt=Abstract Ref: Postepy Hig Med Dosw 2001;55(6):835-54
Dehydroepiandrosterone (DHEA)--structure, clinical importance and the role in human body
[Article in Polish]
Zdrojewicz Z, Ciszko B.
Katedra i Klinika Endokrynologii i Diabetologii Akademii Medycznej we Wroclawiu.
DHEA and DHEA-S are hormones synthetized primarily by the adrenal cortex. The levels oh this hormones are systematically decreased, beginning from the fourth life decade. The levels of this hormones are also abberrated as a consequence of divorce systematical diseases like cardiovascular diseases, skeletal diseases, diabetes mellitus or obesity. This hormones, probably, have antiaheromatic facilities. There are also data suggesting their influence on stimulation of immunological system. It is already confirmed that the levels of this hormones are modified in congenital function disorders that are present in different diseases, like Alzheimer diseases, and oral administration of DHEA can improves the memory. Presumably DHEA-S have also anticarcinogenic facilities. The levels of this hormones can be also a marker monitoring the course of pregnancy. There are still a lot of discrepancies between results of different studies and it is very difficult to describe their role in human body. Because their levels are decreased with ageing process, this observation makes the researchers call them as the "youth hormones".
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11873519&dopt=Abstract Ref: Mil Med 2002 Feb;167(2 Suppl):60-3
Inhibition of adjuvant-induced arthritis by 16 alpha-fluoro-5-androsten-17-one.
Schwartz AG, Pashko LL.
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 North Broad Street, Philadelphia, PA 19140, USA.
The adrenal steroid dehydroepiandrosterone (DHEA) produces cancer-preventive, antiatherosclerotic, antidiabetic, immunomodulating, and anti-inflammatory effects in laboratory animals. The clinical use of DHEA is limited by its androgenicity. We have developed a synthetic congener of DHEA called fluasterone that, in animal tests, lacks the androgenicity, estrogenicity, and peroxisome-proliferating effects of DHEA but retains the cancer-preventive, antidiabetic, and anti-inflammatory efficacy. This report discusses how fluasterone ameliorates the development of joint inflammation in an adjuvant-arthritis model in Lewis rats.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11865961&dopt=Abstract Ref: J Clin Pharmacol 2002 Mar;42(3):247-66
The influence of hormones and pharmaceutical agents on DHEA and DHEA-S concentrations: a review of clinical studies.
Salek FS, Bigos KL, Kroboth PD.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pennsylvania 15261, USA.
Low endogenous levels of dehydroepiandrosterone (DHEA) and/or its sulfoconjugated derivative DHEA-S have been associated with diseases such as lupus, cancer, and diabetes. Circulating concentrations of DHEA and DHEA-S resulting from endogenous production or hormone supplementation may also be relevant in psychiatric illness. Drugs may significantly increase or decrease circulating concentrations of these adrenal androgens by various mechanisms. Some agents, such as dexamethasone, affect the HPA axis by inhibiting ACTH and therefore decrease DHEA and DHEA-S concentrations. Central nervous system agents, including carbamazepine and phenytoin, induce the P450 enzymes that metabolize DHEA and DHEA-S and therefore decrease circulating concentrations of these hormones. Danazol alters the ratio between DHEA and DHEA-S by inhibiting sulfatase. As research moves forward to better understand the relationships of these adrenal androgens with health and disease, it is essential that studies be designed to control for the influence of administered pharmaceuticals on DHEA and DHEA-S.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11858769&dopt=Abstract Ref: Endocr Regul 2001 Dec;35(4):217-22
Circadian serum levels of dehydroepiandrosterone sulphate in postmenopausal asthmatic women before and after long-term hormone replacement.
Kos-Kudla B, Ostrowska Z, Marek B, Ciesielska-Kopacz N, Kudla M, Kajdaniuk D, Siemidska L, Strzelczyk J.
Department of Pathophysiology and Endocrinology, Silesian Medical University, Katowice, Poland.
OBJECTIVE: To assess mean 24-h serum concentrations of dehydroepianrosterone (DHEAS) in postmenopausal women with asthma before and after hormone replacement therapy (HRT). METHODS: Studies were performed in 55 asthmatic and 20 healthy postmenopausal women aged 48-60 before HRT and after 6 months of transdermal 17b-estradiol (E2) and medroxyprogesterone acetate treatment (cyclical method). Serum DHEAS concentrations were assessed with the use of RIA method. RESULTS: In the group of postmenopausal asthmatic women treated with glucocorticoids the mean 24 h DHEAS serum levels were lower than in a similar group not treated with glucocorticoids and a control group of healthy postmenopausal women. However, in both groups of asthmatic women (e.g. glucocorticoid treated and untreated) a significant increase of mean daily DHEAS levels after 6 months of HRT was observed. The hormone concentrations did not change in control group. CONCLUSIONS: Postmenopausal asthmatic women show diminished circadian dehydroepiandrosterone sulphate serum concentrations irrespective whether they were treated with glucocorticoids or not. However, after 6 months of hormonal replacement therapy in these groups increased levels of DHEA were found.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11856546&dopt=Abstract Ref: Steroids 2002 Mar;67(3-4):221-33
Ergosteroids V: preparation and biological activity of various D-ring derivatives in the 7-oxo-dehydroepiandrosterone series.
Reich IL, Reich HJ, Kneer N, Lardy H.
Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, WI 53706, USA.
Our previous finding that D-ring seco derivatives of dehydroepiandrosterone retained biologic activity (Reich et al., Steroids 1998;63:542-53) motivated us to synthesize and test a number of steroids in which the D-ring is retained but altered in various ways. Several new steroids were synthesized and characterized by (1)H and (13)C NMR spectroscopy. The availability of a number of closely related compounds allowed detailed (13)C chemical shift correlations. Using the induction of two thermogenic enzymes in rats, liver mitochondrial glycerophosphate dehydrogenase (GPDH) and cytosolic malic enzyme, as criteria of biologic activity some 30 compounds were assayed. Hydroxylation of dehydroepiandrosterone (DHEA) at the 16 alpha position was previously shown to diminish activity (Lardy et al., Steroids 1998;63:158-65); the corresponding 7-oxo compound is fully active. Hydroxylation at the 15 beta position of DHEA, 7-oxo-DHEA, or 16 alpha-hydroxy-7-oxo-DHEA greatly diminished the induction of GPDH but induction of malic enzyme was retained. Most 5,15 diene steroids tested had 2 weak, or no, ability to enhance the formation of GPDH but did increase malic enzyme.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11855905&dopt=Abstract Ref: Horm Behav 2002 Mar;41(2):203-12
Dehydroepiandrosterone (DHEA) increases territorial song and the size of an associated brain region in a male songbird.
Soma KK, Wissman AM, Brenowitz EA, Wingfield JC.
Department of Zoology, University of Washington, Seattle, Washington 98195, USA.
In many species, male territorial aggression is tightly coupled with gonadal secretion of testosterone (T). In contrast, in song sparrows (Melospiza melodia morphna), males are highly aggressive during the breeding (spring) and nonbreeding (autumn and early winter) seasons, but not during molt (late summer). In aggressive nonbreeding song sparrows, plasma T levels are basal (< or = 0.10 ng/ml), and castration has no effect on aggression. However, aromatase inhibitors reduce nonbreeding aggression, indicating a role for estrogen in wintering males. In the nonbreeding season, the substrate for brain aromatase is unclear, because plasma T and androstenedione levels are basal. Aromatizable androgen may be derived from plasma dehydroepiandrosterone (DHEA), an androgen precursor. DHEA circulates at elevated levels in wintering males (approximately 0.8 ng/ml) and might be locally converted to T in the brain. Moreover, plasma DHEA is reduced during molt, as is aggression. Here, we experimentally increased DHEA in wild nonbreeding male song sparrows and examined territorial behaviors (e.g., singing) and discrete neural regions controlling the production of song. A physiological dose of DHEA for 15 days increased singing in response to simulated territorial intrusions. In addition, DHEA treatment increased the volume of a telencephalic brain region (the HVc) controlling song, indicating that DHEA can have large-scale neuroanatomical effects in adult animals. The DHEA treatment also caused a slight increase in plasma T. Exogenous DHEA may have been metabolized to sex steroids within the brain to exert these behavioral and neural effects, and it is also possible that peripheral metabolism contributed to these effects. These are the first results to suggest that exogenous DHEA increases male-male aggression and the size of an entire brain region in adults. The data are consistent with the hypothesis that DHEA regulates territorial behavior, especially in the nonbreeding season, when plasma T is basal.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11853289&dopt=Abstract Ref: J Med Assoc Thai 2001 Oct;84 Suppl 2:S605-12
DHEA(S): the fountain of youth.
Leowattana W.
Department of Clinical Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) are weak androgens produced primarily by the adrenal gland. Although their plasma concentrations by far exceed those of any other adrenal product, their physiological roles have not yet been determined. In plasma, where the major portion of these hormones is present in the sulfate form, it is possible that DHEAS serves as a reservoir for DHEA. Since various tissues have been shown to contain steroid sulfatases. The peak plasma levels of DHEA and DHEAS occur at approximately age 25 years, decrease progressively thereafter, and diminish by 95 per cent around the age of 85 years. The decline of DHEAS concentrations with aging has led to the suggestion that DHEAS could play a role in itself and be implicated in longevity. Moreover, the epidemiological evidence has shown that adult men with high plasma DHEAS levels are less likely to die of cardiovascular disease. DHEA has also been shown to increase the body's ability to transform food into energy and burn off excess fat. Another recent finding involves the anti-inflammatory properties of DHEA. It has been known that DHEA can lower the levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha). It should be pointed out that chronic inflammation is known to play a critical role in the development of the killer diseases of aging: heart disease, Alzheimer's disease and certain types of cancer. In conclusion, DHEA or DHEAS administration combined with conventional treatment may be implicated in particular conditions to improve the quality of life.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11853283&dopt=Abstract Ref: J Med Assoc Thai 2001 Oct;84 Suppl 2:S570-5
Serum dehydroepiandrosterone sulfate, testosterone, and biochemical markers of bone turnover in elderly Thai men.
Leowattana W, Bunyaratavej N, Puangvarin N, Pokum S, Arechep N, Chutchawal S.
Department of Clinical Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
The most abundant human steroid, dehydroepiandrosterone sulfate (DHEAS), may have a multitude of beneficial effects, but declines with age. It is unclear whether DHEAS deficiency is an important factor contributing to increased bone resorption and impaired bone formation or not that leads to their bone loss. Thus, we investigated serum DHEAS, testosterone, osteocalcin (N-MID osteocalcin) and C-terminal telopeptides (beta-CrossLaps) in 121 healthy Thai males without bone diseases. Thirty-nine males (mean age 31.5 +/- 8.2, range 23-42 years) were recruited as the normal adult group and 82 males (mean age 61.2 +/- 7.0, range 52-77 years) were assigned as the elderly group. DHEAS levels were higher in the adult group compared with the elderly subjects (296.8 +/- 93.4 vs 172.6 +/- 99.8 microg/dL, p < 0.0001). Serum osteocalcin concentrations were also higher in the adult group compared with the elderly males (27.9 +/- 11.1 vs 23.2 +/- 7.9 ng/ml, p = 0.0091). However, serum testosterone and C-terminal telopeptides levels were not significantly different between the two groups. We concluded that low DHEAS concentrations are commonly encountered in elderly males and may relate to low osteocalcin levels due to the osteoblast stimulation effects of DHEAS. These findings may be implicated in the treatment of osteoporosis in elderly men by using DHEAS.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11851726&dopt=Abstract Ref: Eur J Clin Invest 2002 Jan;32(1):43-50
Increased serum interferon alpha in HIV-1 associated lipodystrophy syndrome.
Christeff N, Melchior JC, de Truchis P, Perronne C, Gougeon ML.
Institut Pasteur, Paris, France.
BACKGROUND: A syndrome of lipodystrophy (LD) associated with peripheral lipoatrophy and central/visceral adiposity has been reported in HIV-1-infected patients treated by combined antiretroviral therapy (ART). Lipid metabolism is partly regulated by both steroid hormones and cytokines and we have previously reported that dyslipidaemia in LD-positive men is correlated to an increase in cortisol : DHEA ratio (Christeff et al., AIDS 1999;13:2251). In this study we questioned whether it is also related to cytokine perturbations. MATERIALS AND METHODS: A cross-sectional study was performed on 42 HIV-1-positive men on ART, 27 of whom had symptoms of LD, defined by computed tomography scan. Serum cytokines (IFN-alpha, TNF-alpha, sTNF-RI, sTNF-RII, IL-6, IL-1beta and IL-2) and lipids [cholesterol, triglycerides (TG) and their subclasses], and apolipoproteins (Apo), were determined. RESULTS: Serum IFN-alpha was markedly increased in LD-positive compared with LD-negative men and controls. IL-6 and TNF-alpha concentrations were also significantly elevated in HIV-positive men compared to controls but the levels of these cytokines did not differ between the two groups of patients. A significant positive correlation was found between accumulation of IFN-alpha and increased levels of cholesterol, TG, VLDL cholesterol, VLDL TG, ApoB and ApoB-ApoA1 ratio. A multivariate forward-performed analysis revealed that IFN-alpha is the best marker for lipid perturbations associated to LD, followed by insulin and cortisol : DHEA ratio. CONCLUSIONS: This study demonstrates an association between serum IFN-alpha and lipid alterations in LD-positive men. The concomittant action of IFN-alpha and cortisol : DHEA ratio is probably one of the mechanisms responsible for hyperlipidaemia in LD syndrome.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11847477&dopt=Abstract Ref: Horm Res 2001;56(3-4):134-9
Dehydroepiandrosterone sulfate treatment for atrichia pubis.
Wit JM, Langenhorst VJ, Jansen M, Oostdijk WA, van Doorn J.
Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
OBJECTIVE: To evaluate the efficacy of oral dehydroepiandrosterone sulfate (DHEAS) treatment for atrichia pubis in female adolescents. STUDY DESIGN: Two XY female adolescents with 17-hydroxylase deficiency and 2 XX females with panhypopituitarism presenting with atrichia pubis were treated with a daily dosage of DHEAS 10 mg/m2 body surface in addition to their regular substitution therapy. The dosage was increased according to clinical response. Pubic hair stages, growth and serum DHEAS were evaluated and in 1 case also serum IGFs and IGFBPs. RESULTS: A dosage of 10 mg/m2 for 1 year led to serum DHEAS levels at the lower limit of the normal range. 15 mg/m2 was needed to achieve pubic hair stage 4-5 and axillary hair in patients with 17-hydroxylase deficiency. In panhypopituitarism, pubic hair developed at a slower pace and reached stage 4 on a dosage of 25-30 mg/m2. Baseline serum IGF-I SDS was -0.67 and did not change on the initial dosage of DHEAS, in combination with submaximal estrogen substitution (10 microg ethinyl estradiol). On the combination of 15 mg/m2 DHEAS and full estrogen substitution, IGF-I SDS increased to an average of -0.15. IGFBP-3 SDS increased from 1.4 to a mean of 2.6 in the first year, and went back to 1.4 in the second year. IGFBP-6 SDS was low at baseline (-2.5) and rose to -1.9 and -1.7 IGF-II and IGFBP-1 showed an irregular pattern. CONCLUSIONS: Oral administration of DHEAS in a dosage of 15 mg/m2 o.d. is an efficacious treatment for atrichia pubis. For females with a panhypopituitarism a higher dosage appears needed. Given this and other biological actions of DHEAS, substitution therapy with DHEAS or DHEA to females with adrenal androgen deficiency appears rational.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11846992&dopt=Abstract Ref: In Vitr Mol Toxicol 2001 Fall;14(3):191-207
Comparative tissue-specific toxicities of 20 cancer preventive agents using cultured cells from 8 different normal human epithelia.
Elmore E, Luc TT, Steele VE, Redpath JL.
Department of Radiation Oncology, Medical Sciences I, University of California-Irvine, Irvine, CA 92697, USA.
Comparative toxicity was determined for twenty potential chemopreventive agents in the Human Epithelial Cell Cytotoxicity (HECC) Assay using epithelial cell cultures from eight different tissues including: skin, kidney, breast, bronchus, cervix, prostate, oral cavity, and liver. The endpoints assessed were inhibition of: growth at 3 and 5 days; mitochondrial function; and proliferating cell nuclear antigen or albumin expression. Difluoromethylornithine (DFMO), s-allylcysteine, dehydroepiandrosterone (DHEA) analogue 8543, l-selenomethionine, and vitamin E acetate were not toxic or only produced mild toxicity with all endpoints in all eight cell types. N-acetyl-l-cysteine, calcium chloride, DHEA, genistein, ibuprofen, indole-3-carbinol, 4-hydroxyphenylretinamide (4-HPR), oltipraz, piroxicam, phenylethyl isothiocyanate, 9-cis-retinoic acid, and p-xylylselenocyanate each showed at least a 10-fold decrease in their TC(50) (toxic concentration that inhibited growth by 50%) for at least one endpoint with one or more cell types. For some agents such as DHEA and piroxicam, the TC(50)s for growth inhibition were 10-fold lower after 5 days compared with 3 days. Unique tissue-specific toxicity was observed for each toxic agent suggesting that tissue-specific effects are the rule rather than the exception. The HECC Assay is effective in identifying tissue-specific toxicity for chemopreventive agents and may help to identify potential toxicity problems in phase I human clinical trials.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11844949&dopt=Abstract Ref: Psychother Psychosom 2002 Mar-Apr;71(2):117-22
Physiological changes associated with downsizing of personnel and reorganisation in the health care sector.
Hertting A, Theorell T.
Institute for Psychosocial Factors and Health, Karolinska Institute, Stockholm, Sweden.
BACKGROUND: The objective of this study was to assess potential physiological changes associated with downsizing/reorganisation in the health care sector. The personnel reductions (1995-1997) in the studied regional hospital corresponded to one fifth of the personnel. METHODS: In a longitudinal study, female personnel had blood sampled twice (8 a.m. and 4 p.m.) during a working day in 1997 (in connection with the last completed round of personnel redundancies) and 1 year later in 1998. The participants were 31 women (82% of those initially sampled ); there were 14 registered nurses, 11 assistant nurses and 6 medical secretaries. No additional drop outs took place during follow-up. Outcome variables were changes in the difference in serum cortisol levels between the morning and afternoon and in serum/plasma concentrations of immunoglobulin G (IgG), oestradiol, dehydroepiandrosterone sulphate (DHEAS), prolactin and apolipoproteins AI and B. RESULTS: Significantly decreased serum/plasma concentrations of IgG (p < 0.001), apolipoprotein AI (p < 0.001) and oestradiol (p < 0.001) were found. The difference between morning and afternoon serum cortisol decreased, with a change at the significance level of p = 0.05. No significant changes were observed regarding prolactin, DHEAS and apolipoprotein B. CONCLUSIONS: These results could be an indication that protective and anabolic functions had suffered in these remaining 'ageing' female work groups. The circadian cortisol rhythm was possibly flattened, which could be a sign of physiological dysfunction associated with the long-lasting adaptation process. These conclusions are tentative, given the small size of the sample and the lack of a control group. However, the findings point to the significance of studies of physiological changes possibly associated with restructuring of the health care sector.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11844888&dopt=Abstract Ref: Dement Geriatr Cogn Disord 2002;13(2):74-9
Increased levels of adrenocortical and gonadal hormones in mild to moderate Alzheimer's disease.
Rasmuson S, Nasman B, Carlstrom K, Olsson T.
Department of Geriatric Medicine, Umea University Hospital, Umea, Sweden.
Hormonal changes during normal aging include decreasing levels of gonadal hormones and adrenal androgens. These hormones influence multiple nervous functions, including cognition and mood. Related to this, abnormalities at several levels of the hypothalamic-pituitary-adrenal axis (HPA) have been reported in patients with Alzheimer's disease (AD). We studied steroid hormones in 33 patients with mild to moderate AD (12 men; 21 women, 76.4 +/- 7.8 years) and 22 healthy elderly controls (10 men; 12 women, 75.4 +/- 7.5 years old, respectively). Basal levels of serum cortisol, dehydroepiandrosterone (DHEA) and androstenedione were significantly increased in AD patients. Women with AD had significantly higher levels of DHEA and androstenedione. Serum estradiol levels were non-significantly increased in women with AD. After adjustment for age and BMI women with AD had significantly increased levels of androstenedione and DHEA. Increased gonadal hormone levels in mild to moderate AD may reflect an increased secretion, and/or alterations in metabolism of these hormones. This may influence the symptomatology and progression of the disease.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11836304&dopt=Abstract Ref: J Clin Endocrinol Metab 2002 Feb;87(2):682-6
Genetics of serum dehydroepiandrosterone sulfate and its relationship to insulin in a population-based cohort of twin subjects.
Nestler JE, Whitfield JB, Williams TY, Zhu G, Condon J, Kirk KM, Heath AC, Montgomery GW, Martin NG.
Division of Endocrinology, Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23398, USA.
Previous studies have shown a significant effect of insulin administration on serum dehydroepiandrosterone sulfate (DHEA-S) concentration and its metabolic rate, with evidence for the effect in men, but not in women. This could lead to differences in the sources of variation in serum DHEA-S between men and women and in its covariation with insulin concentration. This study aimed to test whether these hypotheses were supported in a sample of healthy adult twins. Serum DHEA-S (n = 2287) and plasma insulin (n = 2436) were measured in samples from adult male and female twins recruited through the Australian Twin Registry. Models of genetic and environmental sources of variation and covariation were tested against the data. DHEA-S showed substantial genetic effects in both men and women after adjustment for covariates, including sex, age, body mass index, and time since the last meal. There was no significant phenotypic or genetic correlation between DHEA-S and insulin in either men or women. Despite the experimental evidence for insulin infusion producing a reduction in serum DHEA-S and some effect of meals on the observed DHEA-S concentration, there were no associations between insulin and DHEA-S at the population level. Variations in DHEA-S are due to age, sex, obesity, and substantial polygenic genetic influences.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11834296&dopt=Abstract Ref: Brain Res Mol Brain Res 2002 Jan 31;98(1-2):58-66
Dehydroepiandrosterone (DHEA) and its sulfated derivative (DHEAS) regulate apoptosis during neurogenesis by triggering the Akt signaling pathway in opposing ways.
Zhang L, Li B, Ma W, Barker JL, Chang YH, Zhao W, Rubinow DR.
Behavioral Endocrinology Branch, National Institute of Mental Health, Building 36, Room 2C02, Bethesda, MD 20892, USA.
Dehydroepiandrosterone (DHEA) can function to protect neural precursors and their progeny targeted with toxic insults; however, the molecular mechanisms underlying the neuroprotective effects of DHEA are not understood. We cultured neural precursors from the embryonic forebrain of rats and examined the effects of DHEA and its sulfated derivative (DHEAS) on the activation of the serine-threonine protein kinase Akt, which is widely implicated in cell survival signaling. We found that DHEA activated Akt in neural precursor culture, in association with a decrease in apoptosis. In contrast, DHEAS decreased activated Akt levels and increased apoptosis. The effects of DHEA on neural cell survival and activation of Akt were not blocked by the steroid hormone antagonists flutamide and tamoxifen, but both were blocked by a PI3-K inhibitor, LY294002. These findings suggest that during neurogenesis in the developing cortex, DHEA and DHEAS regulate the survival of neural precursors and progeny through the Akt signaling pathway.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11834092&dopt=Abstract Ref: Lipids 2001 Dec;36(12):1383-6
Dehydroepiandrosterone alters phospholipid profiles in Zucker rat muscle tissue.
Abadie JM, Malcom GT, Porter JR, Svec F.
Department of Pathology, Louisiana State University Medical Center, New Orleans 70112, USA.
Insulin-resistant muscle tissue contains low proportions of arachidonic acid (AA), and increased proportions of muscle AA correlate with improved insulin sensitivity. Dehydroepiandrosterone (DHEA) and AA, like the thiazolidinedione drugs that decrease insulin resistance (IR), are peroxisome proliferators. Long-chain fatty acids (FA) have been named the "one true" endogenous ligand for activating the peroxisome proliferator-activator receptor (PPAR), and DHEA has been named a "good candidate" as a naturally occurring indirect activator of PPAR. This study was conducted to determine DHEA's effects on lipid profiles of skeletal and cardiac muscle in lean and obese Zucker rats (ZR), a model of IR, type 2 diabetes mellitus, and obesity. We hypothesize that DHEA may alter long-chain FA profiles in muscle tissue of obese rats such that they more closely resemble that of the lean. In our experiments, we employed a DHEA and a pair-fed (PF) group (n = 6) for 12 lean and 12 obese ZR. For 30 d, the diet of the two DHEA groups was supplemented with 0.6% DHEA; PF groups were given the average daily calories consumed by their corresponding treatment group. Hearts and gastrocnemius muscles were assayed for phospholipid (PL), free FA, and triglyceride (TG) FA profiles. The proportion of PL AA was significantly greater in both muscle types of lean compared to obese rats. Hearts from both DHEA groups had greater PL proportions of AA and less oleic (18:1) acid than their PF controls. Likewise, 18:1 proportions were significantly lower in the gastrocnemius; however, AA proportions were not significantly different. Similar phenotypic profile differences were observed in the TG fraction of both muscle types. There were no DHEA-related TG FA profile alterations.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11823507&dopt=Abstract Ref: J Immunol 2002 Feb 15;168(4):1753-8
In vivo dehydroepiandrosterone restores age-associated defects in the protein kinase C signal transduction pathway and related functional responses.
Corsini E, Lucchi L, Meroni M, Racchi M, Solerte B, Fioravanti M, Viviani B, Marinovich M, Govoni S, Galli CL.
Department of Pharmacological Sciences, University of Milan, Milan, Italy.
Elderly subjects are at increased risk of pneumonia, influenza, and tuberculosis. Besides the known age-related decrease in mechanisms for mechanical clearance of the lungs, impaired alveolar macrophage function contributes to the increased risk of illness in the elderly. We have previously shown that age-induced macrophage immunodeficiencies are associated with a defective system for anchoring protein kinase C. Castration of young male rats produces effects on alveolar macrophages similar to those of aging, suggesting a relationship between circulating sex hormones, particularly androgens, and the decreases in the receptor for activated C kinase (RACK-1) and macrophage function observed. The aging process in humans and rats is associated with a decline in the plasma concentrations of dehydroepiandrosterone (DHEA) and its sulfate, among other steroid hormones. We report here that in vitro and in vivo administration of DHEA to rats restores the age-decreased level of RACK-1 and the LPS-stimulated production of TNF-alpha in alveolar macrophages. DHEA in vivo also restores age-decreased spleen mitogenic responses and the level of RACK-1 expression. These findings suggest that the age-related loss in immunological responses, linked to defective pathways of signal transduction, are partially under hormonal control and can be restored by appropriate replacement therapy.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11823067&dopt=Abstract Ref: Neuroscience 2002;109(3):569-84
Comparative study of the neuroprotective effect of dehydroepiandrosterone and 17beta-estradiol against 1-methyl-4-phenylpyridium toxicity on rat striatum.
Tomas-Camardiel M, Sanchez-Hidalgo MC, Sanchez del Pino MJ, Navarro A, Machado A, Cano J.
Departmento de Bromatologia y Toxicologia, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.
The effects of dehydroepiandrosterone (DHEA), estradiol and testosterone on 1-methyl-4-phenylpyridium (MPP+)-induced neurotoxicity of the nigrostriatal dopaminergic system were examined in rat. They were subjected to a unilateral intrastriatal infusion of the following treatment conditions: MPP+ alone or co-injection of MPP+ plus each hormone. Four days after injection, concentrations of dopamine and their metabolites were determined from the corpus striatum. To corroborate the neurochemical data an immunohistochemical analysis of tyrosine hydroxylase-immunoreactive fibers and acetylcholinesterase histochemistry in the striatum was performed. Moreover, we performed a dose-response study of the three hormones on the high-affinity dopamine transport system in rat striatal synaptosomes.Rats co-injected within the striatum with MPP+ and either DHEA or estradiol had significantly greater concentrations of dopamine and less tyrosine hydroxylase-immunoreactive fibers and acetylcholinesterase fiber density loss compared with their respective controls. In addition, 4 days after injection, the brain was fixed and cut into coronal sections, and was immunostained with major histocompatibility complex class II antigens for activated microglia, and glial fibrillary acidic protein for activated astrocytes. DHEA also attenuated microglial cell activation. In contrast, testosterone showed reductions in dopamine concentrations similar to those obtained by MPP+. The protective effect of DHEA against the MPP+ neurotoxic dopaminergic system may be produced by its partial prevention of MPP+ inhibition of NADH oxidase activity, whereas the estradiol may function as a neuroprotectant by reducing the uptake of MPP+ into dopaminergic neurons.Our findings we suggest indicate that dehydroepiandrosterone and estradiol by a non-genomic effect may have an important modulatory action, capable of attenuating degeneration within the striatum, and in this way serve as neuroprotectants of the nigrostriatal dopaminergic system.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11820328&dopt=Abstract Ref: Eur J Appl Physiol 2001 Nov;86(1):85-91
Leptin and steroid hormone responses to exercise in adolescent female runners over a 7-week season.
Kraemer RR, Acevedo EO, Synovitz LB, Hebert EP, Gimpel T, Castracane VD.
Southeastern Louisiana University, Department of Kinesiology and Health Studies, Hammond 70402, USA.
The purpose of the study was to investigate the responses of leptin and steroid hormones to maximal exercise in adolescent female runners over a competitive season. Seven adolescent female distance runners completed three testing trials during weeks 1.4 and 7 of their high-school track season. Blood samples were collected before and after a discontinuous graded exercise test to exhaustion (GXT) for each trial. Tests were administered during the subjects' normal training time (3:30 p.m.-5:00 p.m.). Compared to week 1, peak O2 uptake rose significantly during the season and was 10% and 7% higher at weeks 4 and 7, respectively. Levels of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), cortisol, testosterone, and leptin increased significantly in response to the graded exercise tests. Testosterone levels were also changed over the course of the study. Resting testosterone levels and testosterone responses to exercise in weeks 4 and 7 were both higher than in week 1. Resting concentrations and acute increases of the other hormones were not changed over the season. It appears, therefore, that DHEA, DHEAS, cortisol, testosterone and leptin concentrations increase in response to running in adolescent female runners. Data also suggest that training and/or maturation increases resting testosterone concentrations and testosterone responses to running in adolescent female runners during a training season.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11809345&dopt=Abstract Ref: Maturitas 2002 Jan 30;41(1):69-77
Androgens and estrogens in relation to hot flushes during the menopausal transition.
Overlie I, Moen MH, Holte A, Finset A.
Department of Behavioural Sciences in Medicine, University of Oslo, P.O. Box 1111, Blindern, N-0317 Oslo, Norway.
In this paper, the association of hormones to vasomotor complaints during the menopausal transition is discussed. Fifty-seven regularly menstruating women without history of hormone replacement therapy (HRT) were selected for a longitudinal, prospective study around the menopausal transition. The mean age at the start of the study was 51.3 (+/-2.0) years. At intervals of 12 months all women went through a semi-structured interview and filled in questionnaires. Venous blood samples were collected every 12-month for analyses of estradiol (E2), testosterone, androstendione, dehydroepiandrosterone-sulphate (DHEA-S), follicle stimulating hormone (FSH), thyrotropin (TSH), and luteinizing hormone (LH). Vasomotor complaints were tested using questions about hot flushes and bouts of sweating in terms of occurrence, frequency and degree of distress. Forty-six percent of the subjects reported hot flushes and bouts of sweating before menopause, increasing to 67% during the first year after menopause and 49% in the second year postmenopause. Low levels of estradiol and high levels of FSH were associated with vasomotor complaints before menopause. During menopause high levels of TSH were related to vasomotor complaints. The first year after menopause, women, who at this point achieved hot flushes, were characterised by high levels of E2, but declining and low levels of FSH, but increasing. Postmenopausal, high levels of testosterone and DHEA-S seemed to protect against vasomotor symptoms. Our most important finding was, that among women who achieved hot flushes at the first assessment postmenopause, the high androgen levels was a significant predictor of recovery from hot flushes at the last assessment, 1 year later.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11809003&dopt=Abstract Ref: Joint Bone Spine 2001 Dec;68(6):588-94
DHEA in bone and joint diseases.
Cormier C, Souberbielle JC, Kahan A.
Rheumatology Department A, Hopital Cochin, AP-HP, Paris, France.
Serum concentrations of dehydroepiandrosterone (DHEA) and its sulfate ester (sDHEA) decrease dramatically with age in parallel with the appearance of age-related health problems, leading to the suggestion that DHEA replacement therapy may be beneficial in older patients. Daily oral doses that restore sDHEA levels to the values seen in young adults are well tolerated in the short-term (6 months to 1 year) and seem to have a positive although modest beneficial effect on bone in elderly women, particularly those with low pretreatment sDHEA levels. This effect seems ascribable to both decreased bone resorption and increased bone formation, which are probably related mainly to conversion of DHEA into active sex steroids, i.e., estradiol and testosterone; this explains why there is no effect on bone in men, whose testes continue to produce testosterone throughout life. Other mechanisms of action, including an increase in insulin growth factor-1, may be operative also. DHEA cannot be recommended as a treatment for osteoporosis at present given the absence of studies evaluating possible efficacy in reducing the fracture rate and possible long-term side effects.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11801361&dopt=Abstract Ref: Neuroscience 2002;109(2):243-51
Dehydroepiandosterone and its sulphate enhance memory retention in day-old chicks.
Migues PV, Johnston AN, Rose SP.
Department of Biological Sciences, The Open University, Walton Hall, Milton Keynes MK7 6AA, UK.
We report the presence of dehydroepiandosterone (DHEA) and DHEA sulphate (DHEA-S) in the day-old-chick brain, and their possible role in memory formation. DHEA and DHEA-S were present in the brain at higher concentrations than in the plasma. Radioimmunoassay examination of the intermediate medial hyperstriatum ventrale 5 or 30 min after training or the lobus parolfactorius 60 or 120 min after training on the passive avoidance task did not show learning-related differences in absolute levels of DHEA or DHEA-S. However, bilateral intracerebral injections of DHEA or DHEA-S before or after training on the weak passive avoidance task enhanced recall 24 h after training. Memory retention was enhanced by administration of DHEA and DHEA-S 15 min before training or 30 and 60 but not 180 min after training. Neurosteroids are present in high concentrations in regions of the chick brain known to be associated with learning and memory for an aversive one-trial task. Our study demonstrates that memory retention for this task is enhanced by administration of the neurosteroids DHEA-S and DHEA. These findings provide additional evidence that these neurosteroids have memory-enhancing properties and, thus, if common to other tasks and species, that DHEA-S and DHEA may constitute potential therapeutic tools for the treatment of cognitive deficits.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11797418&dopt=Abstract Ref: Nihon Shinkei Seishin Yakurigaku Zasshi 2001 Nov;21(5):157-62
Neuroactive steroid and stress response
[Article in Japanese]
Nagai T, Noda Y, Nozaki A, Nabeshima T.
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, 466-8560 Japan.
Dehydroepiandrosterone sulfate (DHEAS), a neuroactive steroid, has been demonstrated to bind to sigma 1 receptors, and it has antidepressive effects in the forced swimming test. We used the conditioned fear stress, which is useful for investigating the pathogenesis of mood disorders. DHEAS attenuated the conditioned fear stress response in mice, the effects being antagonized by a sigma 1 receptor antagonist. It is interesting that, the DHEAS contents and number of apoptotic cells in the brain of mice showing conditioned fear stress response were decreased and increased, respectively, compared with those in the nonstressed mice. DHEAS prevented the expression of apoptosis induced by conditioned fear stress. These findings suggest that the imbalance of neuroactive steroids and the expression of apoptosis play an important role in the expression of conditioned fear stress response and that the use of DHEAS is a novel therapeutic approach for at least some mood disorders.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11788644&dopt=Abstract Ref: J Clin Endocrinol Metab 2002 Jan;87(1):176-81
Dehydroepiandrosterone inhibits human vascular smooth muscle cell proliferation independent of ARs and ERs.
Williams MR, Ling S, Dawood T, Hashimura K, Dai A, Li H, Liu JP, Funder JW, Sudhir K, Komesaroff PA.
Baker Medical Research Institute and Alfred Hospital, Melbourne, Victoria 3181, Australia.
Dehyroepiandrosterone (DHEA), an adrenal-derived steroid, has been clinically implicated in protection against coronary artery disease and experimentally in inhibition of atherosclerosis and plaque progression. Because DHEA is enzymatically metabolized to androgens or estrogens, it is not clear whether DHEA exerts effects directly or after conversion to these hormones, both of which are associated with well-characterized pathways of action. We therefore examined the effects of DHEA on proliferation of human vascular smooth muscle cells (VSMCs) in culture in the presence or absence of the ER antagonist ICI 182,780 and the AR antagonist flutamide and compared them with the effects of 17beta-estradiol, androstenedione, and T. We also determined the affinity of DHEA for ERs and ARs in VSMC and its specific binding in intact cells. To explore a possible mechanism for DHEA action in these cells, we measured the phosphorylation of ERK-1, c-jun N-terminal protein kinase, and p38 (three members of the MAPK superfamily). Both DHEA and 17beta-estradiol significantly inhibited platelet derived growth factor (PDGF)-BB-induced increases in VSMC proliferation, whereas androstenedione and T increased proliferation. Although E2-induced inhibition of the PDGF effect was abolished by ICI 182,780 and T-induced stimulation was abolished by flutamide, neither receptor antagonist altered the inhibitory effect of DHEA. Binding studies confirmed the presence of both ERs and ARs; DHEA showed minimal affinity for either receptor but bound specifically and with high affinity to putative receptors in intact cells. Following 4-h incubation with DHEA (1-100 nM), ERK1 phosphorylation was significantly reduced in a dose-dependent manner, whereas neither c-jun N-terminal protein kinase nor p38 kinase activity was altered by either PDGF-BB or DHEA. DHEA inhibits human VSMC proliferation by a mechanism independent of either ARs or ERs, presumably via a DHEA-specific receptor that involves ERK1 signaling pathways.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11787951&dopt=Abstract Ref: Pol J Pharmacol 2001 Mar-Apr;53(2):125-30
Increase in NAD but not ATP and GTP concentrations in rat liver by dehydroepiandrosterone feeding.
Swierczynski J, Slominska E, Smolenski RT, Mayer D.
Department of Biochemistry, Medical University of Gdansk, Poland.
Dehydroepiandrosterone (5-androsten-3beta-ol-17-one; DHEA), the main circulating steroid in humans, has been described to exert varied beneficial effects including antiobesity, anti-aging and anticancer action when used at pharmacological doses in experimental animals. To elucidate the mechanism of the pleiotropic effects of DHEA, we studied the effect of this steroid on concentrations of NAD and adenine and guanine nucleotides in rat liver. Administration of DHEA at 0.3% in the diet for 7 consecutive days caused an increase in liver NAD and NADP, but was without effect on NADH concentrations. This indicates a shift of the redox couple (NAD/NADH) towards oxidation in the DHEA-treated rats. Moreover, there was no change in adenine and guanine nucleotide concentrations, which disproves the hypothesis that the DHEA anticancer actions are due to a decrease in the availability of nucleosides for DNA synthesis. The findings indicate that an increase in liver NAD pool and/or altered redox status, but no changes in adenine or guanine nucleotide content, may be involved in the pleiotropic effects of DHEA.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11787268&dopt=Abstract Ref: Invest Clin 2001 Dec;42(4):235-40
In mice the efficiency of immunization with Venezuelan Equine Encephalomyelitis virus TC-83 is transiently increased by dehydroepiandrosterone.
Negrette B, Bonilla E, Valero N, Giraldoth D, Medina-Leendertz S, Anez F.
Instituto de Investigaciones Clinicas, Facultad de Medicina, Universidad del Zulia.
To determine whether treatment with dehydroepiandrosterone (DHEA) improves the efficiency of immunization against the Venezuelan Equine Encephalomyelitis (VEE) virus, mice were vaccinated with the TC-83 VEE virus. DHEA (10 mg/kg) was administered in a single dose, 4 hours before vaccination. IgM antibody titers were determined at days 7, 14 and 21 post-immunization. Treatment with DHEA increased antibody titers at day 14 after immunization. Mice were challenged with live VEE virus at day 21, and viral titers were plaque assayed in chicken embryo fibroblasts from days 2 to 5 post-infection. After the challenge, viremia decreased on day 2 and brain virus levels were reduced at day 4 in mice treated with DHEA. These results suggest that DHEA treatment could enhance the efficiency of immunization against VEE virus in mice.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11780316&dopt=Abstract Ref: Chin Med J (Engl) 2001 Mar;114(3):291-3
Effects of sex hormones on apoptosis in peripheral blood mononuclear cells from patients with systemic lupus erythematosus.
Liu C, Zhou H, Qu R, Liu Z.
Department of Dermatology, Affiliated Taihe Hospital, Yunyang Medical College, Shiyan 442000, China.
OBJECTIVE: To study the effects of dehydroepiandrosterone (DHEA) and/or estradiol (E2) on apoptosis in peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE). METHODS: The percentage of apoptosis of PBMCs from SLE patients and healthy blood donors were examined by means of AO staining 48 h after culture with DHEA and/or E2 at physiologic or pathologic concentrations. RESULTS: The percentage apoptosis of PBMCs from SLE patients is higher than that of healthy blood donors (P < 0.01). E2, whether at physiological or at pathological concentrations, had no effects no apoptosis of PBMCs from both SLE patients and healthy donors (P > 0.05). Both DHEA and DHEA plus E2 at physiologic concentrations, had no effect on apoptosis of PBMCs from healthy donors (P > 0.05), but significantly inhibited that of SLE patients (P < 0.05); at pathologic concentrations, they promoted apoptosis of PBMCs from SLE patients as well as healthy blood donors (P < 0.05). There were no significant differences between the effects of DHEA and that of DHEA plus E2 (P > 0.05). CONCLUSION: DHEA plays an important role in the apoptosis of PBMCs from SLE patients; low serum levels of DHEA may cause accelerated apoptosis.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11779609&dopt=Abstract Ref: Fertil Steril 2002 Jan;77(1):167-72
Ovarian hyperandrogenism in adult female rhesus monkeys exposed to prenatal androgen excess.
Eisner JR, Barnett MA, Dumesic DA, Abbott DH.
Wisconsin Regional Primate Research Center, University of Wisconsin-Madison, 53715, USA.
OBJECTIVE: To determine whether there is an ovarian thecal cell component to hyperandrogenism exhibited in adult female rhesus monkeys exposed to androgen excess during prenatal life. DESIGN: Prospective nonrandomized study. SETTING: An academic research environment. ANIMAL(S): Eleven adult female rhesus monkeys. INTERVENTION(S): Five female rhesus monkeys exposed prenatally to T propionate and six normal females underwent blood sampling immediately before and 24 h after a 200-IU IM injection of recombinant hCG. MAIN OUTCOME MEASURE(S): Serum T, 17alpha-hydroxyprogesterone, DHEAS, and cortisol concentrations determined by RIA. RESULT(S): Prenatally androgenized females exhibited increased T and 17alpha-hydroxyprogesterone response to recombinant hCG stimulation, compared to control females. Although serum adrenal DHEAS concentrations were elevated in comparison to control females, the increased levels of DHEAS were not dependent on recombinant hCG stimulation. CONCLUSION(S): Prenatal androgen excess in female rhesus monkeys causes perturbations in ovarian and adrenal steroidogenesis during adulthood, which may both contribute to hyperandrogenism.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11772330&dopt=Abstract Ref: Expert Opin Pharmacother 2002 Jan;3(1):23-31
Dehydroepiandrosterone for the treatment of systemic lupus erythematosus.
van Vollenhoven RF.
Department of Rheumatology, Karolinska Hospital, 17176 Stockholm, Sweden.
The adrenal steroidal hormone dehydroepiandrosterone (DHEA) has been studied as a potential pharmacological agent in the treatment of the autoimmune disease systemic lupus erythematosus (SLE). Both the endocrine effects (the ability to be converted peripherally to androgenic and oestrogenic sex steroids) and the immunomodulatory effects of DHEA (the production of the Th(1) cytokines, such as IL-2) suggest that this hormone could be of benefit for patients with SLE. During the past decade, five controlled clinical trials and a number of additional observational studies have been performed investigating these possibilities. The results from these studies suggest that 200 mg/day of DHEA for 7 - 12 months decreases corticosteroid requirement for the patients, the frequency of disease flares, has an anti-osteoporotic effect and has an overall beneficial effect on SLE disease activity in female patients. A small study suggested benefits for cognitive function in such patients. The side effects acne and hirsutism were seen relatively frequently (30 - 40% and 10 - 12% of patients, respectively) but in most instances were deemed mild. DHEA treatment resulted in changes in lipid profile and may have endocrine effects, the consequences of which will need to be ascertained through longer-term follow-up studies.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11765058&dopt=Abstract Ref: J Endocrinol Invest 2001 Nov;24(10):RC28-30
Serum DHEAS levels correlate with platelet cGMP in normal women.
Martina V, Origlia C, Bruno GA, Messina M, Ferri M, Pescarmona GP.
Department of Internal Medicine, University of Turin, Italy.
Several studies suggest that DHEAS is a protective factor against atherosclerosis and coronary artery disease in man, but the mechanism of its biological role is unclear. Recently, it has been suggested that DHEAS can retard atherosclerosis formation through an increase in nitric oxide (NO) production by increasing E2 synthesis. The aim of the study was to evaluate the platelet cGMP concentrations (i.e. a marker of NO production) and the serum levels of DHEAS and E2 in normal females. Blood samples were taken from 51 normal women (age 42.3+/-1.9 yr, range: 22-67 yr, BMI 23.0+/-0.6 kg/m2) to evaluate platelet cGMP concentrations and serum levels of DHEAS and E2. To determine the platelet cGMP content, platelet rich plasma (PRP) was incubated at 37 C (30 min) in the presence of IBMX. The amount of platelet cGMP was measured by a cGMP (3H) assay kit. In all subjects the mean of platelet cGMP was 536.2+/-45.3 fmol/10(6) platelets and the mean of serum DHEAS and E2 was 151.4+/-13.9 microg/dl and 34.7+/-6.1 pg/ml, respectively. In all subjects DHEAS positively correlates with cGMP (p<0.001, r=0.513) and with E2 (p<0.001, r=0.650); furthermore E2 positively correlates with cGMP (p<0.001, r=0.663). In conclusion our data support the hypothesis that DHEAS exerts its antiatherogenic effect by increasing the NO production directly and/or by increasing the E2 synthesis.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11765025&dopt=Abstract Ref: J Anal Toxicol 2001 Nov-Dec;25(8):685-90
Human nutritional supplements in the horse. Dehydroepiandrosterone versus androstenedione: comparative effects on the androgen profile and consequences for doping analysis.
Dehennin L, Bonnaire Y, Plou P.
Laboratoire de la Federation Nationale des Courses Francaises, Chatenay-Malabry, France.
Dehydroepiandrosterone (DHEA) and androstenedione are weak androgens, which need conversion to more potent testosterone in order to enhance anabolic action. Consequences of oral dosing at 1 mg/kg on the urinary and plasma androgen profile of mare and gelding have been evaluated with an analytical method involving conjugate fractionation and selective hydrolysis, group separation, and quantitation by gas chromatography-mass spectrometry with selected ion monitoring of trimethylsilyl ethers. Peak levels of testosterone total conjugates in urine (range 300-6000 microg/L) were attained a few hours after dosing. Renal clearance was fast, so the testosterone detection period lasted only 20 to 33 h, the longest time being generated by androstenedione. The urinary testosterone/epitestosterone ratio for detection of exogenous testosterone in the mare was inoperative after DHEA administration because there was a concomitant increase of epitestosterone, which thereby acted as a masking agent. Androstanediols and androstenediols, as well as some 17-ketosteroids, were additional markers. A transient increase of circulating free testosterone has been evidenced, and this would support possible anabolic/androgenic action by supplementation with DHEA and androstenedione along the oral route.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11762781&dopt=Abstract Ref: J Chromatogr A 2001 Nov 23;935(1-2):297-307
7-Hydroxydehydroepiandrosterone epimers in human serum and saliva. Comparison of gas chromatography-mass spectrometry and radioimmunoassay.
Hill M, Lapcik O, Havlikova H, Morfin R, Hampl R.
Institute of Endocrinology, Prague, Czech Republic.
Recent reports demonstrated that 7-hydroxylated metabolites of dehydroepiandrosterone (DHEA) possess immunomodulatory and antiglucocorticoid properties. Increased 7alpha-OH-DHEA levels were found in patients with Alzheimer's disease. Hence, measurement of steroids in patients with autoimmune diseases or disturbances in the central nervous system could be of interest. A new sensitive GC-MS method for the determination of 7-hydroxydehydroepiandrosterone epimers was developed and compared with previously developed radioimmunoassays. Besides serum, these steroids were, for the first time, measured in saliva where their concentrations were about five times lower. 7alpha- and 7beta-epimer levels correlated well in both body fluids and they were larger in male.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11753752&dopt=Abstract Ref: Horm Metab Res 2001 Dec;33(12):691-5
Differential gene expression profile of glucocorticoids, testosterone, and dehydroepiandrosterone in human cells.
Maurer M, Trajanoski Z, Frey G, Hiroi N, Galon J, Willenberg HS, Gold PW, Chrousos GP, Scherbaum WA, Bornstein SR.
Institute of Biomedical Engineering, Graz University of Technology, Graz, Austria.
Glucocorticoids are the major immunomodulating hormones in the human body. Recently, increasing interest in androgens as immunomodulators has emerged. In particular, Dehydroepiandrosterone (DHEA) has been suggested as beneficial in the treatment of some autoimmune disorders. However, the action and role of testicular and adrenal androgens on human immune cells remains unclear. This is the first study to provide large-scale gene expression data on the action of different steroids (DHEA, glucocorticoids, and testosterone) on human peripheral blood mononuclear cells using the recently developed genomic-scale technology of microarrays. Novel computational tools and techniques such as Principal Component Analysis (PCA) were used for analysis, clustering and visualization. We have demonstrated that each steroid has its distinct gene expression profile, although DHEA and testosterone co-regulated most genes in a similar direction while glucocorticoids frequently regulated the same genes in an opposite direction. Our data suggest an important and a complex regulatory role for androgens on human immune cells that should be considered in androgen replacement or treatment strategies.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11750771&dopt=Abstract Ref: Psychoneuroendocrinology 2002 Jan-Feb;27(1-2):83-97
Perturbations of plasma cortisol and DHEA-S following discontinuation of cocaine use in cocaine addicts.
Buydens-Branchey L, Branchey M, Hudson J, Dorota Majewska M.
New York Harbor Healthcare System, Brooklyn Campus, 800 Poly Place, Brooklyn, NY 11209, USA.
Changes in plasma levels of cortisol and dehydroepiandrosterone sulfate (DHEA-S) following cocaine discontinuation were assessed in hospitalized chronic cocaine users. Measurements were performed after 6, 9, 18 and 21 days of abstinence. Repeated measures ANOVAs revealed significant time effects for cortisol (P<0.02) and DHEA-S (P<0.001). Changes in the two hormones did not follow the same course. Levels of cortisol were highest on day 6 and then subsequently decreased, whereas DHEA-S levels were low on day 6 and highest on day 18. Repeated measures ANCOVAs were used to test the overall effects of total duration of cocaine use, daily or weekly cocaine amounts consumed, or frequency of use on cortisol secretion. Analyses revealed a significant effect of frequency of use only (P<0.04). More sustained cocaine use was associated with higher cortisol levels and less pronounced cortisol decline after discontinuation of cocaine use, but drug intake variables had no influence on DHEA-S. The effects of presence or absence of life-long histories of aggression were also assessed. Repeated measures ANOVAs revealed a near significant group x time interaction for cortisol, which declined more dramatically in aggressive addicts than in non-aggressive addicts after day 6. DHEA-S was consistently higher in aggressive cocaine addicts, although this effect did not reach statistical significance. There was a noticeable difference in the dynamics of normalization of adrenal hormones between the two groups, with DHEA-S/cortisol ratios rising more dramatically during cocaine abstinence in aggressive than in non-aggressive addicts. In conclusion, lingering neuroendocrine perturbations persist after discontinuation of cocaine use in addicts. Some of these changes could be associated with an increased relapse risk.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11744095&dopt=Abstract Ref: Brain Res Brain Res Rev 2001 Nov;37(1-3):301-12
Role of pregnenolone, dehydroepiandrosterone and their sulfate esters on learning and memory in cognitive aging.
Vallee M, Mayo W, Le Moal M.
Institut F. Magendie-INSERM U259, Domaine de Carreire, Rue Camille Saint Saens, 33077, Cedex, Bordeaux, France.
Aging is a general process of functional decline which involves in particular a decline of cognitive abilities. However, the severity of this decline differs from one subject to another and inter-individual differences have been reported in humans and animals. These differences are of great interest especially as concerns investigation of the neurobiological factors involved in cognitive aging. Intensive pharmacological studies suggest that neurosteroids, which are steroids synthesized in the brain in an independent manner from peripheral steroid sources, could be involved in learning and memory processes. This review summarizes data in animals and humans in favor of a role of neurosteroids in cognitive aging. Studies in animals demonstrated that the neurosteroids pregnenolone (PREG) and dehydroepiandrosterone (DHEA), as sulfate derivatives (PREGS and DHEAS, respectively), display memory-enhancing properties in aged rodents. Moreover, it was recently shown that memory performance was correlated with PREGS levels in the hippocampus of 24-month-old rats. Human studies, however, have reported contradictory results. First, improvement of learning and memory dysfunction was found after DHEA administration to individuals with low DHEAS levels, but other studies failed to detect significant cognitive effects after DHEA administration. Second, cognitive dysfunctions have been associated with low DHEAS levels, high DHEAS levels, or high DHEA levels; while in other studies, no relationship was found. As future research perspectives, we propose the use of new methods of quantification of neurosteroids as a useful tool for understanding their respective role in improving learning and memory impairments associated with normal aging and/or with pathological aging, such as Alzheimer's disease.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11744094&dopt=Abstract Ref: Brain Res Brain Res Rev 2001 Nov;37(1-3):294-300
Age-related changes of the adrenal secretory pattern: possible role in pathological brain aging.
Ferrari E, Casarotti D, Muzzoni B, Albertelli N, Cravello L, Fioravanti M, Solerte SB, Magri F.
Department of Internal Medicine and Medical Therapy, Chair of Geriatrics, University of Pavia, Piazza Borromeo 2, 27100, Pavia, Italy.
The biosynthetic dissociation of the adrenocortical secretion occurring with age may have a pathogenetic role in the pathophysiology of brain aging. We studied cortisol and DHEAS secretion in healthy old and young subjects, in senile dementia, in major depression of elderly subjects and in healthy centenarians. A clear age-related decline of DHEAS secretion was well evident in healthy centenarians, and a further decrease in DHEAS concentration was found in old depressed patients and moreover in the demented ones, by comparison with age-matched controls. The circadian profile of serum cortisol was clearly flattened in old subjects, due to the selective increase in the cortisol nocturnal levels, particularly evident in demented subjects; on the other hand, the morning serum cortisol levels were not significantly different among centenarians, young and old controls. The molar ratio between cortisol and DHEAS showed a significant age-related increase; the occurrence of senile dementia and of major depression played an additive role, by comparison to physiological aging. The qualitative and quantitative modifications of the adrenocortical secretion occurring with aging seem mainly dependent on age itself, but the occurrence of pathological conditions may amplify these changes. Since cortisol and DHEAS play opposite effects on the central nervous system, the evaluation of the ratio between cortisol and DHEAS seems to be a good marker of the neuroendocrine features in old subjects.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11744093&dopt=Abstract Ref: Brain Res Brain Res Rev 2001 Nov;37(1-3):287-93
Dehydroepiandrosterone (DHEA) and the relationship with aging and memory: a possible link with protein kinase C functional machinery.
Racchi M, Govoni S, Solerte SB, Galli CL, Corsini E.
Department of Experimental and Applied Pharmacology, University of Pavia, Viale Taramelli 14, 27100, Pavia, Italy.
A progressive decline of cognitive and memory functions, compared to the average young-life performance, characterizes brain aging. The changes in performance may depend upon altered activity of neurotransmitters acting on attention and memory trace formation (acetylcholine, catecholamines, glutamate, for example) or the failure of the transduction mechanisms linked to receptor activation. One of the fundamental cellular changes associated with brain aging is the alteration of mechanisms involving the activity of the calcium-phospholipid-dependent protein kinase C (PKC). A crucial event for the activation of protein kinase C is its translocation from the cytosol to different intracellular sites and recent studies have demonstrated the key role played by several anchoring proteins in this mechanism. The defective activation of PKC-dependent pathways during aging is due to a defective mechanism of translocation of the kinase because of reduced levels of the major anchoring protein RACK-1 (receptor for activated C kinase). Pharmacological strategies aimed at the correction of age-associated memory deficits have been mostly focused on neurotransmitters using direct or indirect agonists. More recently, attention has been paid to the memory enhancing properties of some steroid hormones, namely 'neurosteroids'. Among these the activities of dehydroepiandrosterone (DHEA), pregnenolone (PREG) and their sulfates, have been extensively studied. These neuroactive steroids, can regulate neuronal function through their concurrent influence on transmitter-gated ion channels and gene expression. We addressed the possibility that DHEA, among other neurosteroids, could modulate directly the age-associated impairment of PKC signal transduction and provide experimental evidence that DHEA can revert the alteration of RACK-1 anchoring protein expression.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11723706&dopt=Abstract Ref: Rev Med Suisse Romande 2001 Sep;121(9):649-54
Is there an indication for dehydroepiandrosterone (DHEA) treatment in elderly women with Addison disease? Beneficial and adverse effects of DHEA
[Article in French]
Martin-Du Pan RC.
DHEA is a cetosteroid secreted by the adrenal gland. Serum levels of DHEA decline by an average of 10% per decade whereas cortisol levels remain stable. The relative lack of DHEA secretion in elderly people has been called adrenopause. The daily administration of 50 mg of DHEA to women over 60 years old results in a two-fold increase in serum level of testosterone and androstenedione and in a 10% increase of estradiol in men. A 10 to 20% increase of IGF-1 is observed in both sexes. In women over 70 years old treated by 50 mg/day of DHEA for 6 months an improvement of bone turnover and of skin status was observed as well as an increase of overall well-being and of libido. These beneficial psychological effects have also been observed in younger men and women with adrenal insufficiency. In men 50 to 65 years old, 100 mg/day of DHEA for 6 months could slightly increase the lean body mass and the muscle strength. Moreover DHEA could increase immune function and NK cell activity. As there are no actual data about cardio-vascular and oncological risks of a prolonged treatment with DHEA, the administration of this steroid must still be considered experimental. Previous or present cancer of the breast or of the prostate is an absolute contraindication to DHEA treatment.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11720695&dopt=Abstract Ref: Biol Psychiatry 2001 Nov 15;50(10):767-74
Endogenous concentrations of DHEA and DHEA-S decrease with remission of depression in older adults.
Fabian TJ, Dew MA, Pollock BG, Reynolds CF 3rd, Mulsant BH, Butters MA, Zmuda MD, Linares AM, Trottini M, Kroboth PD.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pennsylvania 15261, USA.
BACKGROUND: Clinical studies of endogenous concentrations of dehydroepiandrosterone (DHEA) and its sulfated conjugate DHEA-S in depression are limited. This study was designed to evaluate the influence of successful pharmacological treatment of late-life depression on concentrations of DHEA, DHEA-S and cortisol. METHODS: We determined endogenous concentrations of DHEA, DHEA-S and cortisol in elderly control subjects (n = 16) and in elderly depressed patients who remitted (n = 44) or failed to remit (n = 16) with pharmacological treatment. Depressed patients were treated for 12 weeks with either nortriptyline or paroxetine. RESULTS: In remitters, DHEA and DHEA-S concentrations were lower at week 12 than at week 0 (p =.002 and p =.0001, respectively). In the nonremitters and control subjects, neither DHEA nor DHEA-S concentrations changed. Decreases in hormone concentrations were associated with improvement in mood and functioning in depressed patients. Although cortisol concentrations decreased in remitters and nonremitters, the change was not significant. CONCLUSIONS: Our data suggest that the decrease in DHEA and DHEA-S in remitters is related to remission of depression rather than to a direct drug effect on steroids, as nonremitters had no change in hormone concentrations.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11717007&dopt=Abstract Ref: J Steroid Biochem Mol Biol 2001 Oct;78(4):367-72
7-Hydroxydehydroepiandrosterone epimers in the life span.
Hampl R, Hill M, Starka L.
Institute of Endocrinology, Narodni 8, 116 94 1, Praha, Czech Republic.
Evidence has been accumulated that 7-hydroxyepimers of dehydroepiandrosterone (7-OH-DHEA), may act as locally active immunomodulatory and immunoprotective agents, counteracting exaggerated actions of glucocorticoids. Since Skinner et al. (1977) developed the first unspecific RIA, it has been known that 7alpha-OH-DHEA is present in near nanomolar concentration in human blood. No data have been available, however, on its changes during the human life. Using recently developed specific radioimmunoassays for determination of both 7-OH-DHEA epimers, 7alpha- and 7beta-OH-DHEA were measured in sera from 252 males and 172 females, representing age groups from 10 to 91 years (males) and from 10 to 72 years (females). The dependence of 7-OH-DHEA levels on age was evaluated by using polynomial fitting of the 4th or 5th degree. In contrast to men, where a distinct decline with age occurred, two local maxima have been recorded round the age 22 and 53, respectively, in females. The curves of age dependence of 7-OH-DHEA levels in both sexes resembled those of previously determined unconjugated DHEA, but in the latter case the second maximum in women was found about 10 years earlier than 7-OH-DHEA, in a premenopausal period. The levels of both 7-OH-DHEA epimers correlated excellently with each other.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11717001&dopt=Abstract Ref: J Steroid Biochem Mol Biol 2001 Oct;78(4):313-7
Metabolism of dehydroepiandrosterone by rat hippocampal cells in culture: possible role of aromatization and 7-hydroxylation in neuroprotection.
Jellinck PH, Lee SJ, McEwen BS.
Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
The rate of metabolism of the multifunctional neurosteroid, dehydroepiandrosterone (DHEA), by embryonic rat hippocampal cells maintained in culture was compared to that of 4-androstenedione (AD), the immediate precursor of estrone (E1). The experiments were carried out to assess the relative contribution of DHEA, its 7-hydroxylated metabolites and estrogen on their reported effects on memory and neuroprotection. The 3H-labeled steroids of high specific radioactivity were incubated for 1, 8, 24 and 48 h and the putative metabolites extracted from the culture medium with acetone-ethyl acetate before separation by TLC for radioassay. [3H]DHEA (2.0 ng/5x10(5) cells) yielded primarily the 7alpha- and 7beta-hydroxylated steroids in an almost equal ratio under conditions that resembled those used by others to study the protection of neurons by hippocampal astrocytes against excitatory amino acid-induced toxicity. The rate of conversion of DHEA to AD, and particularly to E1, was much lower. With [3H]AD as substrate, significant aromatization to estrogen occurred only after 24 h when most of [3H]DHEA had already been converted to its 7-hydroxylated products and the hydroxylase and aromatase systems would no longer be competing for the same coenzyme (NADPH). The hippocampal cells were still viable after 48 h of incubation with the steroids and were able to oxidize estradiol (E2) to E1 and reduce E1 to E2 and AD to testosterone (T). It is suggested that 7alpha- and 7beta-OHDHEA, the main metabolites formed in the rat hippocampus, might be responsible for some of the functions previously ascribed to estrogens in the brain and the reasons for this proposal are discussed.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11702658&dopt=Abstract Ref: Riv Biol 2001 May-Aug;94(2):345-62
Androgens in human evolution. A new explanation of human evolution.
Howard J.
Human evolution consists of chronological changes in gene regulation of a continuous and relatively stable genome, activated by hormones, the production of which is intermittently affected by endogenous and exogenous forces. Periodic variations in the gonadal androgen, testosterone, and the adrenal androgen, dehydroepiandrosterone (DHEA), significantly participated in all hominid transformations. The hominid characteristics of early Australopithecines are primarily a result of increased testosterone. The first significant cold of the early Pleistocene resulted in an increase in DHEA that simultaneously produced Homo and the robust Australopithecines. Subsequent Pleistocene climatic changes and differential reproduction produced changes in DHEA and testosterone ratios that caused extinction of the robust Australopithecines and further changes and continuation of Homo. Changes in testosterone and DHEA produce allometric and behavioral changes that are identifiable and vigorous in modern populations.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11672993&dopt=Abstract Ref: Exp Gerontol 2001 Nov;36(10):1739-47
Dehydroepiandrosterone, ageing and immune activation.
Ledochowski M, Murr C, Jager M, Fuchs D.
Department of Clinical Nutrition, Leopold-Franzens University, A-6020 Innsbruck, Austria.
The age-related decline in dehydroepiandrosterone (DHEA) production is currently attracting attention because of its possible relevance to the etiology and management of a number of age-related clinical disorders. Various abnormalities of immune system function have been described in the elderly. Among them, increased concentrations of neopterin have been reported, which is produced by human monocytes/macrophages upon stimulation by interferon-gamma. In order to examine the relation of serum DHEA to serum neopterin, we studied 281 otherwise healthy outpatients, who visited the physician's office for a medical health check-up. 10% presented with increased neopterin concentrations, 0.4% had increased DHEA sulfate (DHEAs) concentrations. DHEAs concentrations were significantly higher in patients with lower neopterin concentrations (Mann-Whitney test: U=4793, P<0.0001). There existed a rather strong inverse correlation between DHEAs concentrations and serum neopterin concentrations (Spearman's rank correlation: r(s)=-0.221, P<0.0001). The data support the concept that the decrease of DHEA with increasing age is related to immune system activation. Oxidative stress which accompanies immune response may diminish DHEA synthesis.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11605430&dopt=Abstract Ref: Zh Vyssh Nerv Deiat Im I P Pavlova 2001 Jul-Aug;51(4):502-6
Is dehydroepiandrosterone sulfate an anxiolytic agent?
[Article in Russian]
Obut TA, Lipina TV, Koriakina LA, Kudriavtseva NN.
Institute of Physiology, Russian Academy of Medical Sciences, Siberian Branch, Institute of Cytology and Genetics, Russian Academy of Sciences, Siberian Branch, Novosibirsk.
Effects of dehydroepiandrosterone sulfate (DHEAS, 30 mg/kg, i.p., 4 and 28 hours after the injection) were studied in CBA/Lac male mice different in the level of anxiety resulting from repeated social victories (winners) or social defeats (losers) in 10 daily agonistic confrontations. The losers demonstrated high level of anxiety estimated by the "partition" test. The DHEAS and saline injections had different effects on winners, losers, and intact mice. DHEAS prevented the development of anxiety in losers 28 hours after the injection. In these experimental conditions DHEAS exerted no effect on winners. It was concluded that the DHEAS effect depends on the psychoemotional state of an animal. The anxiolytic effect of the exogenous DHEAS may be also characteristic of the endogenous hormone secreted by the adrenal glands and in the central nervous system.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11600195&dopt=Abstract Ref: Immunol Lett 2001 Dec 3;79(3):177-9
Dehydroepiandrosterone attenuates the spontaneous elevation of serum IgE level in NC/Nga mice.
Sudo N, Yu XN, Kubo C.
Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, 812-8582, Fukuoka, Japan.
Dehydroepiandrosterone (DHEA) and its sulfate derivatives are known to affect host immune function; however if such hormones influence the development of atopic dermatitis has not yet been clarified. In this study, we examined the effects of DHEA on the allergic process using NC/Nga mouse, a model animal of human atopic dermatitis. The administration of DHEA profoundly suppressed the spontaneous elevation of both serum IgE and interleukin-6 levels in NC/Nga mice during the observation period. These results indicate that DHEA promotes a shift in Thl/Th2 balance toward Th1-dominant immunity, and thus may be one of the effective alternatives in treating atopic dermatitis.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11549645&dopt=Abstract Ref: J Clin Endocrinol Metab 2001 Sep;86(9):4171-7
Dehydroepiandrosterone sulfate and mortality in elderly men and women.
Trivedi DP, Khaw KT.
Clinical Gerontology Unit, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom.
Dehydroepiandrosterone sulfate levels have been inversely related with cardiovascular mortality in men, but findings have been inconsistent, and there are few data in women. We examined the relationship between baseline circulating dehydroepiandrosterone sulfate levels and subsequent all-cause and cardiovascular mortality in 963 men and 1171 women, 65-76 yr old, surveyed in 1991-1995, and followed up until August 2000 (when 296 deaths had occurred). All-cause and cardiovascular disease mortality rates were highest in the lowest dehydroepiandrosterone sulfate quartile in men; and thereafter, rates did not differ significantly in the upper three quartiles. This pattern remained after excluding those with previous history of cardiovascular disease and, in multivariate analyses, was independent of age, cigarette smoking habit, systolic blood pressure, body mass index, blood cholesterol, and steroid use. There was no significant association of dehydroepiandrosterone sulfate and mortality in women. The multivariate adjusted relative risks for all-cause mortality by sex-specific increasing quartile of dehydroepiandrosterone sulfate were 1.00, 0.66 (95% confidence interval, 0.44-1.01), 0.70 (0.46-1.07), 0.73 (0.48-1.10), respectively, for men and 1.00, 0.71 (95% confidence interval, 0.41-1.24), 0.97 (0.58-1.62), and 1.14 (0.69-1.88), respectively, for women. In older men and women, there is no consistent relationship between dehydroepiandrosterone sulfate and all-cause or cardiovascular mortality. The highest mortality rates were observed in the lowest quartile in men, but the highest rates were in the highest quartile in women.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11506809&dopt=Abstract Ref: Mutat Res 2001 Sep 1;480-481:153-62
Reduction in DNA damage in brain and peripheral blood lymphocytes of elderly dogs after treatment with dehydroepiandrosterone (DHEA).
Shen S, Cooley DM, Glickman LT, Glickman N, Waters DJ.
Department of Veterinary Clinical Sciences, Purdue University, West Lafayette, IN 47907, USA.
Steady state levels of DNA damage are substantial in vertebrate animals as a consequence of exposure to endogenous and environmental mutagens. DNA damage may contribute to organismal senescence and an increased risk for specific age-related diseases. In this study, we determined if treatment with the neuroactive adrenal steroid, dehydroepiandrosterone (DHEA), which exhibits antioxidant and anticarcinogenic properties in rodents, would reduce DNA damage in the brain and peripheral blood lymphocytes (PBLs) of elderly dogs. Elderly male dogs, physiologically equivalent to 59-69-year-old men, were randomly assigned to receive no treatment (n=9 dogs) or DHEA at 100mg/kg PO daily (n=8 dogs). Extent of DNA damage in brain cells and PBLs was measured using alkaline comet assay. The effect of DHEA treatment on the susceptibility of PBLs to H(2)O(2)-induced DNA damage was also measured. We found that elderly male dogs receiving daily DHEA treatment for 7 months had significantly less DNA damage detectable in their brain compared to age-matched control dogs. After 7 months treatment, DHEA-treated dogs also had a significant reduction in DNA damage in PBLs compared to pre-treatment levels. We also found that PBLs of dogs treated with DHEA were more resistant to H(2)O(2)-induced DNA damage than PBLs of untreated dogs. Our results did not show that basal DNA damage in PBLs was strongly correlated with DNA damage within the brain. The results of this study suggest that DHEA supplementation can significantly reduce steady state levels of DNA damage in the mammalian brain. Further evaluation of DHEA as a neuroactive agent and its effects on DNA damage and gene expression in other tissues and species is warranted.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11456468&dopt=Abstract Ref: Front Neuroendocrinol 2001 Jul;22(3):185-212
DHEA and its transformation into androgens and estrogens in peripheral target tissues: intracrinology.
Labrie F, Luu-The V, Labrie C, Simard J.
Oncology and Molecular Endocrinology Research Center, Laval University Medical Center (CHUL), Quebec, G1V 4G2, Canada.
A new understanding of the endocrinology of menopause is that women, at menopause, are not only lacking estrogens resulting from cessation of ovarian activity but have also been progressively deprived for a few years of androgens and some estrogens originating from adrenal DHEA and androstenedione (4-dione). In fact, serum DHEA decreases by about 60% between the maximal levels seen at 30 years of age to the age of menopause. This decreased secretion of DHEA and DHEA-S by the adrenals is responsible for a parallel decrease in androgen and estrogen formation in peripheral tissues by the steroidogenic enzymes specifically expressed in each cell type in individual target tissues. This new field of endocrinology, called intracrinology, describes the local synthesis of androgens and estrogens made locally in each cell of each peripheral tissue from the adrenal precursors DHEA and 4-dione. These androgens and estrogens exert their action in the same cells where their synthesis takes place and they are released from these target cells only after being inactivated. To further understand the effect of DHEA in women, DHEA has been administered in postmenopausal women for 12 months. Such treatment resulted in increased bone formation and higher bone mineral density accompanied by elevated levels of osteocalcin, a marker of bone formation. Vaginal maturation was stimulated, while no effect was observed on the endometrium. Preclinical studies, on the other hand, have shown that, due to its predominant conversion into androgens, DHEA prevents the development and inhibits the growth of dimethylbenz(a)anthracene-induced mammary carcinoma in the rat, a model of breast cancer. DHEA also inhibits the growth of human breast cancer ZR-75-1 xenografts in nude mice. The inhibitory effect of DHEA on breast cancer is due to an androgenic effect of testosterone and dihydrotestosterone made locally from DHEA. When used as replacement therapy, DHEA is free of the potential risk of breast and uterine cancer, while it stimulates bone formation and vaginal maturation and decreases insulin resistance. The combination of DHEA with a fourth generation SERM, such as EM-652 (SCH 57068), a compound having pure and potent antiestrogenic activity in the mammary gland and endometrium, could provide major benefits for women at menopause (inhibition of bone loss and serum cholesterol levels) with the associated major advantages of preventing breast and uterine cancer. A widely used application of intracrinology is the treatment of prostate cancer where the testicles are blocked by an LHRH agonist while the androgens made locally in the prostate from DHEA are blocked by a pure antiandrogen. Such treatment, called combined androgen blockade, has led to the first demonstration of a prolongation of life in prostate cancer.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11445999&dopt=Abstract Ref: Riv Biol 2001 Jan-Apr;94(1):177-83
Hormones in mammalian evolution.
Howard J.
Animals that produced increased levels of prolactin and dehydroepiandrosterone (DHEA) survived the period of mass extinctions at the end of the Cretaceous period. DHEA increases thermogenesis and supported existence through the extended episode of cold and dark. Further increases in DHEA and prolactin produced continual physiological and anatomical changes which eventually produced all of the characteristics of mammals.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11435018&dopt=Abstract Ref: Eur J Obstet Gynecol Reprod Biol 2001 Jul;97(1):96-7
Dehydroepiandrosterone replacement in addison's disease.
Kim SS, Brody KH.
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 98105, USA.
Addison's disease is a rare endocrine disorder which can be life-threatening. It can also interfere with the normal development of adrenarche, resulting in the absence of pubic and axillary hair growth. We report a case of satisfactory restoration of adrenarche through DHEA administered in conjunction with the standard glucocortisone and fluorocortisone replacement.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11435994&dopt=Abstract Ref: Ann Med Interne (Paris) 2001 Apr;152 Suppl 3:IS43-9
Neuropsychic effects of dehydroepiandrosterone
[Article in French]
Rigaud AS, Pellerin J.
Service de Medecine Interne et de Gerontologie, Hopital Broca, CHU Cochin Port-Royal, Universite Rene-Descartes - Paris-V, 54-56, rue Pascal, 75013 Paris.
Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) are secreted primarily by the adrenal glands. DHEA could also be a neuroactive steroidal hormone. Because basal levels of DHEA and DHEA-S in humans decrease significantly with age, these hormones have been assumed to be involved in the aging process and in a number of pathologies which develop with aging: immunosenescence, increased mortality, increased incidence of cancer, osteoporosis and cardiovascular diseases. However, its role is still unknown. In humans, cross sectional and longitudinal studies have shown that DHEA might be associated with global measures of well-being and functioning, but positive effects on measures of memory and attention could not be found. Studies investigating DHEA and DHEA-S levels in dementia have produced controversial results. Short-term experimental studies have not shown significant improvement in global measures of well-being and functioning in healthy subjects but have revealed preliminary evidence for mood enhancing and antidepressant effects of DHEA. There is no evidence that DHEA could induce addiction in human beings.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11405958&dopt=Abstract Ref: Cochrane Database Syst Rev 2001;(2):CD000304
Dehydroepiandrosterone (DHEA) supplementation for cognitive function .
Huppert FA, Van Niekerk JK.
Department of Psychiatry, University of Cambridge, Box 189, Addenbrooke's Hospital, Cambridge, UK, CB22 2QQ.
BACKGROUND: In view of the theoretical rationale for beneficial effects of DHEA and DHEAS on cognitive function in ageing and dementia, we have undertaken a thorough investigation of well-conducted studies in this area. This will provide a basis for confirmation of any effect of DHEA/S administration in humans in properly controlled trials. The review will also provide a scientific basis for effective dosage, acceptable route and duration of administration, and side effect profiles. This review is especially pertinent at this time as DHEA is currently being sold in large quantities in health food stores, particularly in the USA. In some cases the recommended dose is different for men and women (50mg/day for men and 25mg/day for women) and the basis for this recommendation needs to be explored. OBJECTIVES: To establish whether administration of DHEA, or its sulphate, DHEAS, improves cognitive function or reduces the rate of decline of cognitive function in normal older adults or in individuals with dementia. SEARCH STRATEGY: Relevant electronic databases, journals, personal communications and conference abstracts were searched for randomised controlled trials investigating the effects of DHEA/S on cognition in older adults. SELECTION CRITERIA: All relevant randomised controlled trials of DHEA/S were considered for inclusion in the review. DATA COLLECTION AND ANALYSIS: Data for the specified outcomes were independently extracted by two reviewers (FAH & JvN) and cross-checked. Any discrepancies were discussed and resolved. No data pooling was undertaken owing to the lack of availability of the relevant statistics. MAIN RESULTS: There are four included studies, three cognition in normal older people, and Barnhart 1999 in perimenopausal women with decreased well-being. There were no studies in dementia. There were a few significant findings. Wolf 1997 found significant improvement following DHEA compared with placebo in both immediate recall (MD 0.8, 95% CI 0.16, 1.44) and delayed recall (MD 0.9, 95% CI 0.09, 1.71) of a visual memory test in women, estimated in a crossover trial after 2 weeks of treatment with each of DHEA and placebo. However there was no significant improvement in men, nor a significant effect on a verbal memory test. There was also no significant effect on four other cognitive tests. Wolf 1998 (2) found that placebo group performance deteriorated significantly on a test of selective attention following a psychosocial stressor (p<0.05), while deterioration was not evident in the DHEA group (p=0.85) after two weeks of treatment. However, when compared to placebo, DHEA produced a significant impairment on a visual memory test (p<0.01) following the stressor. No significant effect was found on a third cognitive task. Effects were not found on tasks when administered in the absence of a stressor. Barnhart 1999 employed three cognitive measures and found no significant effect of DHEA compared with placebo at 3 months. Findings to date suggest that DHEA replacement seems to be well tolerated with an absence of significant side-effects. REVIEWER'S CONCLUSIONS: The data offer no support at present for an improvement in memory or other aspects of cognitive function following DHEA treatment in normal older people. In view of the growing public enthusiasm for DHEA supplementation, particularly in the USA, and the possibility that any neuroprotective effect of DHEA/S may only be evident in the long term, there is a need to undertake high quality trials in which the duration of DHEA treatment is longer than one year, and the number of participants is large enough to detect effects if they exist. Recently, trials of DHEA supplementation in Alzheimer's Disease (USA), post-menopausal women (USA), normal older men (UK), and a one-year trial in normal older men and women (France) have been completed. As soon as the results are available these studies will be included in the review.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11404052&dopt=Abstract Ref: Exp Gerontol 2001 Jul;36(7):1075-82
Hormonal changes in aging men: a therapeutic indication?
Hermann M, Berger P.
Institute for Biomedical Aging Research, Austrian Academy of Sciences, Endocrinology Unit, Rennweg 10 A-6020 Innsbruck, Austria.
The rise in male life expectancy is paralleled by increased age-related clinical signs and symptoms such as muscle weakness, osteoporosis, benign prostatic hyperplasia, changes in body composition, fatigue, decreased sexual interest and activity, and increased prevalence of erectile dysfunction, all of which limit the quality of life. Many of these symptoms are similar to those of clinically well-defined hormone deficiencies, e.g. Kallman syndrome, Prader--Labhart--Willi syndrome or deficiencies due to treatment of pituitary tumors. Three male endocrine axes are characterized by age-related changes in concentrations of circulating hormones: (i) the hypothalamic--pituitary--testicular axis with lower serum levels of testosterone (T) and higher serum levels of luteinizing and follicle-stimulating hormone, (ii) the hypothalamic--pituitary--adrenal axis with its gradual decline in dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS), (iii) the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis showing decreased hormone production concomitant with symptoms similar to those of GH-deficient adults. The beneficial effects of hormone replacement in nonelderly hormone-deficient individuals and in postmenopausal women raised hope that hormone substitution might prevent or even reverse some of the symptoms of male aging. However, this approach is hampered by the lack of individual age-related hormone reference values and reliable clinical read-out parameters. The findings so far do not support the need for widespread hormone replacement in elderly men. Larger long-term prospective studies are needed to identify clinically useful read-out parameters, and then demonstrate that hormone replacement can translate into functional parameters, thereby providing the individual benefit of treatment for aging men.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11378605&dopt=Abstract Ref: Crit Care Med 2001 May;29(5):965-70
Dehydroepiandrosterone, dehydroepiandrosterone-sulfate, and cortisol concentrations in intensive care unit patients.
Folan MM, Stone RA, Pittenger AL, Stoffel JA, Hess MM, Kroboth PD.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.
STUDY OBJECTIVE: This purpose of this study was to determine whether severity of illness, as defined by the intensive care unit (ICU) admission APACHE II (updated Acute Physiology and Chronic Health Evaluation) score, is correlated with early morning cortisol, dehydroepiandrosterone (DHEA), and/or dehydroepiandrosterone-sulfate (DHEA-S) concentrations. DESIGN: Early morning concentrations of DHEA, DHEA-S, and cortisol were determined within 24 hrs of admission and compared with admission APACHE II scores. SETTING: Medical (MICU), neurologic (NICU), and surgical (SICU) intensive care units of the University of Pittsburgh Medical Center. PATIENTS: A total of 191 men and women ranging in age from 16 to 93 yrs. All had been admitted to an ICU. MEASUREMENTS AND MAIN RESULTS: Statistically significant correlations between APACHE II scores and cortisol were observed for women in the MICU and SICU (r = .68, p = .0001; r = .35 p = .017, respectively) and for men in the NICU (r = .55, p = .003) and the SICU (r = .29, p = .036). The correlations between APACHE II scores and DHEA concentration data were statistically significant for women in the MICU (r = .37, p = .047) and SICU (r = .43, p = .002), as was the correlation between APACHE II and DHEA-S concentrations among women in the SICU (r = .38, p = .008). Although not statistically significant, a similar relationship was observed in the smaller group of NICU women (r = .40, p = .099). Each correlation was essentially unchanged when adjusted for age. CONCLUSION: These data show a positive correlation between APACHE II and cortisol concentrations in all groups except the MICU men. Also evident is the positive correlation between APACHE II scores and DHEA and DHEA-S concentrations in women, but not in men.
Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11341799&dopt=Abstract Ref: J Surg Res 2001 May 15;97(2):196-201
Dehydroepiandrosterone restores hepatocellular function and prevents liver damage in estrogen-deficient females following trauma and hemorrhage.
Kuebler JF, Jarrar D, Wang P, Bland KI, Chaudry IH.
Center for Surgical Research, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama 35294-0019, USA.
INTRODUCTION: Recent studies have shown that administration of the sex steroid dehydroepiandrosterone (DHEA) in males following trauma-hemorrhagic shock has salutary effects on the depressed cardiovascular and immunological functions under those conditions. Since the effects of sex steroids are gender specific, we examined whether administration of DHEA has any beneficial effects on hepatocellular function in female rats with low estrogen levels following trauma-hemorrhage. METHODS: Ovariectomy was performed in female Sprague-Dawley rats 14 days prior to the experiments. The animals then underwent a 5-cm midline laparotomy and were subjected to hemorrhagic shock (40 mm Hg for 90 min). This was followed by fluid resuscitation (Ringer's lactate over 60 min) and administration of DHEA (30 mg/kg BW) or vehicle subcutaneously at the end of resuscitation. At 24 h after resuscitation hepatocellular function, i.e., clearance of indocyanine green (ICG), and hepatocyte damage (serum alanine aminotransferase) were measured. Plasma levels of DHEA and 17beta-estradiol were also assayed. RESULTS: Vehicle-treated rats had significantly reduced hepatocellular function, increased ALT activity, and decreased levels of 17beta-estradiol following trauma-hemorrhage compared to sham-operated animals (P < 0.05, ANOVA and Student-Newman-Keuls test). In animals receiving DHEA following trauma-hemorrhage, hepatocellular function and ALT activity were similar to those of shams. However, administration of DHEA did not influence the plasma levels of 17beta-estradiol. CONCLUSIONS: Administration of DHEA following trauma-hemorrhage restored hepatocellular function and reduced hepatic damage that was observed in ovariectomized female rats under such conditions. This salutary effect of DHEA did not appear to be due to elevated levels of plasma 17beta-estradiol. We therefore propose that DHEA should be considered a novel, safe, and useful adjunct in the treatment of trauma-induced hepatocellular dysfunction in ovariectomized and postmenopausal females.
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