Horm Metab Res. 1985 Sep;17(9):451-3.
Ovine prolactin potentiates the action of adrenocorticotropic hormone on the secretion of dehydroepiandrosterone sulfate and dehydroepiandrosterone from cultured bovine adrenal cells.

Higuchi K, Nawata H, Kato K, Ibayashi H.

To determine the direct effect of prolactin on adrenal androgen secretion, the daily secretions of dehydroepiandrosterone sulfate (DHEA-S), dehydroepiandrosterone (DHEA), androstenedione and cortisol were determined in monolayer culture of bovine adrenal cells in the presence or absence of adrenocorticotropic hormone (ACTH) and/or prolactin. In the absence of ACTH ovine prolactin alone had no effect on steroid secretion during seven-day culture. Ovine prolactin, when administered in combination with ACTH, significantly potentiated the stimulatory effect of ACTH on DHEA-S and DHEA but not androstenedione secretion on the seventh day in culture. On the first day in culture prolactin showed no synergistic effect with ACTH on DHEA and DHEA-S secretion, although ACTH significantly increased DHEA and cortisol secretion. DHEA-S secretion increased as a function of prolactin concentration in the presence of ACTH. These results indicated that long-term treatment by ovine prolactin with ACTH caused the increase in adrenal androgen secretion from bovine adrenal cells. The site of action of prolactin was suggested to be the partial inhibition of adrenal 3 beta-hydroxysteroid dehydrogenase by the result of increases in DHEA-S and DHEA but not androstenedione secretion.

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J Steroid Biochem. 1985 Nov;23(5A):657-61.
Effect of dehydroepiandrosterone on human erythrocytes redox metabolism: inhibition of glucose-6-phosphate dehydrogenase activity in vivo and in vitro.

Niort G, Boccuzzi G, Brignardello E, Bonino L, Bosia A.

In order to elucidate the role of G6PD inhibition by DHEA on erythrocyte redox metabolism, we measured: (1) G6PD activity in erythrocytes collected at different times after injection of synthetic ACTH in 13 normal subjects; (2) G6PD activity and GSH levels in erythrocytes incubated in the presence of different DHEA concentrations; (3) DHEA distribution and metabolic clearance in red cells, together with G6PD activity; (4) GSH regeneration after hydroperoxide oxidative stress in red cells preincubated in the presence of DHEA. In vivo DHEA increase elicits a clear-cut inhibition of red cell G6PD activity. Decreasing DHEA goes in step with the recovery of enzyme activity. In vitro G6PD inhibition by DHEA reaches its maximum within 10-15 min (20-25% inhibition at 10(-7) M DHEA concentration) and the recovery time is dose-dependent. More than 2/3 of DHEA is concentrated in the red cell after 5 min incubation. GSH levels change in step with G6PD activity. After oxidative stress by BHP, DHEA-treated cells fail to restore normal GSH concentrations. These results show that DHEA inhibits human erythrocyte G6PD activity at concentrations usually observed after ACTH plasma increase and increases red cell sensitivity to oxidant agents. Moreover, it is possible that the high DHEA concentrations present in target tissues may interfere with metabolic pathways in which NADPH is the cofactor.

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Gerontology. 1986;32(1):43-51.
Adrenocortical responsiveness to graded ACTH infusions in normal young and elderly human subjects.

Ohashi M, Kato K, Nawata H, Ibayashi H.

The responses of plasma cortisol, aldosterone, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) to graded ACTH infusions (from 50 mU/h to 1,000 mU/h) in elderly subjects were compared with those in young subjects. There were no significant differences between young and elderly subjects in terms of the levels of plasma cortisol during ACTH infusion. The increment in median serum cortisol increase observed in elderly subjects was also equal to that found in young subjects. Plasma aldosterone concentration showed a gradual increase in response to ACTH infusion in both young and elderly individuals. There was no significant difference between the response of young and aged subjects. Significant increases in serum DHEA in response to ACTH infusion were observed in both young and aged individuals, however, the median increase of serum DHEA (delta DHEA) in the elderly subjects was markedly lower than that in the young ones. Serum DHEA-S concentrations prior to ACTH infusion were significantly lower in the elderly subjects. With graded infusions of ACTH, plasma DHEA-S concentrations in young subjects tended to increase gradually, whereas there was no significant increase in plasma DHEA-S concentrations in the elderly. These results are indicative that the responses of adrenal androgens in elderly subjects to small, graded doses of ACTH infusion are preferentially impaired; however, the responses of cortisol and aldosterone are well maintained.

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J Endocrinol Invest. 1986 Feb;9(1):5-9.
Increased DHEAs levels in PCO syndrome: evidence for the existence of two subgroups of patients.

Carmina E, Rosato F, Janni A.

In 49 patients affected by PCO syndrome the serum levels of dehydroepiandrosterone-sulphate (DHEAs) were determined and correlated with the clinical presentation and the endocrine pattern. Twenty-three patients (47%) had high DHEAs levels (h-DHEAs patients). They presented a milder clinical presentation (low incidence of amenorrhea) than PCO patients with normal DHEAs levels (n-DHEAs patients). In h-DHEAs patients the finding of a normal DHEAs response to ACTH and of slightly increased 170HP serum levels suggested that the elevation of serum DHEAs was not due to an adrenal enzymatic deficiency but to a tonic hyperstimulation of the adrenals. Two subgroups of h-DHEAs patients were identified: in the first subgroup, PRL and estrone levels were increased and probably explained the DHEAs hypersecretion; in the second subgroup, the endocrine pattern was very similar to that observed in n-DHEAs patients and a clear explanation for DHEAs increase was not found, although the possibility of an exaggerated secretion of some pituitary hormones with adrenal androgen stimulating activity must be considered.

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Exp Clin Endocrinol. 1986 Jun;87(1):15-25.
Adrenal function in the Mongolian gerbil (Meriones unguiculatus): influence of confinement stress upon glucocorticosteroid, progesterone, dehydroepiandrosterone, testosterone and androstenedione plasma levels, adrenal content and in-vitro secretion.

Fenske M.

The pattern of adrenal steroid secretion and the response to confinement stress were investigated in male Mongolian gerbils (Meriones unguiculatus). Steroid levels of glucocorticosteroids (GC), progesterone (P), dehydroepiandrosterone (DHEA), testosterone (T) and androstenedione (A) in plasma, adrenal tissue and superfusates of adrenals superfused in-vitro were measured by radioimmunoassay. The sensitivity of the assay systems and the low cross-reactivity of the antisera used allowed the determination of steroid levels in small samples (5-200 microliters), without prior chromatography. GC plasma levels were much higher than values of P, DHEA, T or A (176.7, 2.4, 3.3, 2.6 and 2.8 ng/ml, respectively). Confinement stress resulted in a significant increase of GC and DHEA plasma levels; similarly, adrenal content of GC, DHEA and P was markedly increased. In contrast, the applied stress factor had no significant effects on either plasma levels of P, T or A or on adrenal T or A content. Compared to plasma levels or adrenal content, amounts of steroids secreted from adrenals superfused in-vitro were very low (GC: 57.1, P: 2.1, DHEA: 23.0, T: 1.8, A: 3.0 pg/mg/min, respectively). Confinement stress significantly stimulated GC, P and DHEA secretion in-vitro but had no effects on T or A release. The secretion of GC, P, DHEA and T, but not of A was significantly increased by in-vitro stimulation with 0.01-10.0 mIU (1-24) ACTH. Interestingly, the amounts of GC and P, and of GC and DHEA secreted from incubated adrenal slices stimulated with (1-24) ACTH and from adrenals of controls and stressed gerbils superfused in-vitro were significantly correlated. By measuring steroid plasma levels and profiles of steroids secr




Fertil Steril. 1985 Feb;43(2):196-9.
Serum dehydroepiandrosterone sulfate and the use of clomiphene citrate in anovulatory women.

Hoffman D, Lobo RA.

Serum dehydroepiandrosterone sulfate (DHEA-S) is frequently elevated in anovulatory women. This study was carried out to determine whether the ovulatory response with clomiphene citrate (CC) in patients with elevated levels of serum DHEA-S is influenced by the pretreatment level. Also evaluated was whether this response rate was similar to or different from that of anovulatory patients who had normal levels of DHEA-S. CC was administered to 40 anovulatory patients who had elevated levels of DHEA-S. Rankit analysis of these 40 elevated DHEA-S levels indicated that two populations existed. These patients were, therefore, divided into two groups of 29 and 11 with DHEA-S levels of less than 5 and greater than 5 micrograms/ml, respectively. Fifty-nine anovulatory patients with normal DHEA-S levels were also treated with CC. Patients with elevated and normal DHEA-S levels had similar rates of ovulation with CC (75% and 78%). Among patients with elevated levels of DHEA-S, ovulation occurred in 55% of patients with levels greater than 5 micrograms/ml and 83% with levels less than 5 micrograms/ml. The dose of CC at which ovulation occurred was unrelated to the level of DHEA-S. Pregnancies occurred in 15 of the 40 patients after at least four ovulatory cycles and were not influenced by the level of DHEA-S. It is concluded that CC is effective in inducing ovulation in patients with elevated levels of adrenal androgens. However, in patients with DHEA-S levels greater than 5 micrograms/ml, the ovulatory response rate may be decreased.

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Metabolism. 1985 Mar;34(3):278-84.
Glucose metabolism in isolated adipocytes from lean and obese Zucker rats following treatment with dehydroepiandrosterone.

Muller S, Cleary MP.

Previous work has demonstrated that chronic administration of dehydroepiandrosterone (DHEA) to obese Zucker rats reduces the severity of hyperinsulinemia that is usually present. There were also significant decreases in body weight, fat depot weight, and adipose tissue cellularity. It was hypothesized that the decreased serum insulin was a reflection of improved tissue responsiveness to insulin. The purpose of the present study was to evaluate this hypothesis by examining the insulin response in isolated adipocytes of DHEA-treated rats. Glucose incorporation into CO2, fatty acids, and glyceride-glycerol was measured in isolated parametrial and retroperitoneal adipocytes. Cells from control and DHEA-treated lean rats and control and DHEA-treated obese rats were used, as well as cells from a group of obese rats pair-fed to the DHEA-obese rats. Increased basal and insulin-stimulated rates of incorporation of glucose into CO2 and fatty acids were found in adipocytes from DHEA-lean rats compared to control, lean rats. In contrast, cells from DHEA-treated obese rats tended to incorporate less glucose into CO2 and fatty acids than either the control or pair-fed obese rats. These data indicate that the decrease in serum insulin levels seen in DHEA-treated obese rats is not due to an improvement of adipose tissue responsiveness.

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J Clin Endocrinol Metab. 1985 Sep;61(3):564-70.
Fat tissue: a steroid reservoir and site of steroid metabolism.

Deslypere JP, Verdonck L, Vermeulen A.

Sex steroid concentrations and 17 beta-hydroxy-steroid dehydrogenase and aromatase activities were determined in fat tissue removed at surgery or, in order to allow comparisons in different sites, postmortem. Except for dehydroepiandrosterone (DHEA) sulfate (DHEAS), there existed a positive tissue/plasma gradient for all steroids studied (testosterone, androstenedione, DHEA, androstenediol, estrone, and estradiol), suggesting androgen uptake and estrogen synthesis in situ. Androgen concentrations did not vary according to site of origin of fat tissue, except that the DHEAS concentration was significantly lower in abdominal sc and omental fat than in breast, pericardial, or sc pubic fat. Tissue androgen concentrations were positively correlated with their plasma concentrations, but tissue and plasma estrogen concentrations were not correlated. All tissue steroid concentrations, with the exception of estradiol in men, decreased with age. Aromatase activity [androstenedione----estrone; mean maximum velocity, 7.4 +/- 3.7 (+/- SD) fmol estrone/mg protein . h] did not vary between sexes or with site of origin of fat tissue. 17 beta-Hydroxysteroid dehydrogenase activity (estradiol----estrone, mean maximum velocity 9.8 +/- 5.4 pmol/mg protein . h) was higher in fat from women than in that from men, higher in premenopausal than in postmenopausal women, and higher in omental than in sc fat. Its activity was noncompetitively inhibited in vitro by DHEA and DHEAS in near-physiological concentrations, and the enzyme activity was inversely correlated (P less than 0.001) with the tissue DHEA and DHEAS concentrations. We conclude that fat tissue is an important steroid hormone reservoir, that it is the site of active aromatase and 17 beta-hydroxysteroid dehydrogenase, and that tissue DHEA(S) may have a modulating effect on tissue estrogen production.

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J Clin Endocrinol Metab. 1984 Sep;59(3):422-6.
Inhibition of basal and adrenocorticotropin-stimulated plasma levels of adrenal androgens after treatment with an antiandrogen in castrated patients with prostatic cancer.

Belanger A, Dupont A, Labrie F.

The basal plasma levels of cortisol, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), and testosterone were studied in 20 patients with advanced prostatic cancer receiving combined treatment with an LHRH agonist and an antiandrogen [5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl]-2 4-imidazolidinedione]. After 60 days of combined antihormonal therapy, plasma levels of testosterone decreased from 5.44 +/- 0.44 (SEM) to 0.136 +/- 0.052 ng/ml (2.5% of control). Somewhat unexpectedly, the plasma concentrations of the adrenal androgens DHEA and DHEA-S were reduced to 45 +/- 7 and 64 +/- 4% of control, respectively. The maximal reduction in plasma adrenal androgen levels occurred between 2 and 4 weeks of treatment. Whereas the increase in serum cortisol, 17-hydroxypregnenolone, and 17-hydroxyprogesterone concentrations 2 1/2 h after the injection of 0.25 mg human ACTH 1-24 was not affected by the combined treatment, the increment of DHEA and androstenedione after the same stimulus was reduced from 3.1 +/- 0.98 and 0.73 +/- 0.11 to 1.48 +/- 0.5 and 0.31 +/- 0.05 ng/ml, respectively. The reduced levels of serum DHEA and DHEA-S were not due to the LHRH agonist by itself, since similarly low levels of serum DHEA and DHEA-S were found in patients surgically castrated and receiving the same antiandrogen. These data suggest that treatment with an antiandrogen in castrated men inhibit the formation of adrenal androgens due to a blockade at the level of 17, 20-desmolase. The efficiency of the new combined antihormonal therapy (castration and antiandrogen) aimed at complete androgen neutralization in prostate cancer is thus further facilitated.

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J Clin Endocrinol Metab. 1984 Oct;59(4):714-8.
Prolactin has a direct effect on adrenal androgen secretion.

Higuchi K, Nawata H, Maki T, Higashizima M, Kato K, Ibayashi H.

The role of PRL in the secretion of androgens by the adrenal glands was investigated in vivo and in vitro. In women with hyperprolactinemia whose pituitary-adrenal function was normal, there was significant correlation between serum PRL and dehydroepiandrosterone sulfate [(DHEA-S) gamma = 0.48, P less than 0.05, n = 34] and DHEA (gamma = 0.50, P less than 0.05, n = 34), but not with androstenedione. Long term administration of sulpiride to normal women increased both serum PRL and DHEA-S, whereas acute elevation of PRL after a single iv dose of domperidone had no influence on the serum DHEA-S levels. Monolayer cultures of human adrenal cells were used in order to study the direct effect of PRL on adrenal androgen secretion. The daily secretion of DHEA-S, DHEA, androstenedione, and cortisol was determined. In the absence of ACTH, PRL had no effect on steroid secretion in a 7-day culture period. In the presence of ACTH, there was a daily increase in the secretion of steroids. PRL, when added in combination with ACTH, potentiated the effect of ACTH on DHEA-S and DHEA but not on androstenedione and cortisol secretion on the seventh day in culture. These results indicate that PRL has a direct synergistic effect with ACTH on adrenal cells to increase adrenal androgen release. Increases in DHEA-S and DHEA but not androstenedione in vitro and correlation between serum PRL and DHEA-S and DHEA but not androstenedione in women with hyperprolactinemia suggest that the synergistic effect of PRL on adrenal androgen secretion may result from partial inhibition of adrenal 3 beta-hydroxysteroid dehydrogenase.

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Am J Physiol. 1984 Feb;246(2 Pt 1):E123-8.
Metabolic alterations after dehydroepiandrosterone treatment in Zucker rats.

Shepherd A, Cleary MP.

Dehydroepiandrosterone (DHEA) is a known noncompetitive inhibitor of glucose-6-phosphate dehydrogenase (G6PD). In the present investigation, the effects of chronic DHEA treatment on G6PD and several other enzymes involved in lipid metabolism were examined in lean and obese Zucker rats. Significant decreases in body weight were found in DHEA-treated rats in comparison with nontreated rats. In lean rats, DHEA treatment did not decrease either liver or adipose tissue G6PD and fatty acid synthetase activity, but malic enzyme activity was increased. In obese rats, decreased liver and adipose tissue G6PD and fatty acid synthetase activities were found. Malic enzyme activity in liver of obese DHEA rats was increased but not in adipose tissue. Adipose tissue lipoprotein lipase activity was decreased in both lean and obese DHEA rats. Serum insulin in obese DHEA rats was also decreased compared with control obese rats. These results indicate that the inhibition of G6PD may not be the mechanism of action of the antiobesity effect of DHEA. However, the metabolic effects of DHEA seen in obese rats may contribute to its antiobesity action.

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Fertil Steril. 1984 Jul;42(1):69-75.
Ovarian and adrenal vein steroids in patients with nonneoplastic hyperandrogenism: selective catheterization findings.

Moltz L, Schwartz U, Sorensen R, Pickartz H, Hammerstein J.

Standardized bilateral ovarian-adrenal vein catheterization was utilized to assess directly glandular steroid release in 60 androgenized women without evidence of a functional neoplasm. Testosterone (T), dihydrotestosterone (DHT), androstenedione (delta 4 A), dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), 17-hydroxyprogesterone (17-OHP), and cortisol (F) were measured by radioimmunoassay in samples obtained from a peripheral vein and the four glandular veins (all values are given as nanograms per milliliter, mean +/- standard deviation). Peripheral values were as follows: T, 0.68 +/- 0.43; DHT, 0.32 +/- 0.13; delta 4 A, 2.2 +/- 2.0; DHEA, 8.8 +/- 8.9; DHEA-S, 3137 +/- 1774; 17-OHP, 2.0 +/- 3.0; and F, 216 +/- 121. Peripheral elevations of at least one androgen were found in 80% of the 60 cases (T, 38%; DHT, 18%; delta 4 A, 50%; DHEA, 45%; and DHEA-S, 37%). Ovarian-peripheral vein gradients ( OPGs ) and adrenal-peripheral vein gradients ( APGs ) served as semiquantitative estimates of glandular secretion. OPGs were as follows: T, 0.4 +/- 1.1; DHT, 0.1 +/- 0.2; delta 4 A, 3.4 +/- 7.0; DHEA, 14.6 +/- 100; DHEA-S, -288 +/- 523; 17-OHP, 4.5 +/- 8.4; and F, -35 +/- 47. APGs were as follows: T, 0.88 +/- 1.3; DHT, 1.1 +/- 0.9; delta 4 A, 14.4 +/- 38.4; DHEA, 327 +/- 367; DHEA-S, 854 +/- 1223; 17-OHP, 20.8 +/- 41.3; and F, 1252 +/- 2023. Excess ovarian and/or adrenal androgen output was assumed in a given individual when one or more of the respective T, DHT, delta 4 A, DHEA, and DHEA-S gradients exceeded the upper 95% confidence limits of normal previously established in this laboratory.(ABSTRACT TRUNCATED AT 250 WORDS)

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