Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2002 Dec;24(6):635-8.
[Effects of sex hormones on serum levels of nitric oxide and plasma angiotensin II in postmenopausal women]

[Article in Chinese]

Zheng X, He FF, Nie M, Sun ML, Ge QS.

Department of Endocrinology, PUMC Hospital, CAMS, PUMC, Beijing 100730, China.

OBJECTIVE: To observe the effect of estrogen and progestin on the blood levels of nitric oxide and angiotensin II in aid of the application of hormone replacement therapy in postmenopausal women. METHODS: The serum nitric oxide and plasma angiotensin II levels in postmenopausal women were determined before and 3 months after oral intake of estradiol valerate 1 mg/day (n = 10) or estradiol valerate, 1 mg/d plus medroxyprogesterone acetate, 2 mg/d (n = 30). RESULTS: The serum nitric oxide levels of postmenopausal women were significantly increased by 3 months of oral estradiol valerate 1 mg/d (P < 0.05), whereas the plasma levels of angiotensin II tended to decrease. The positive correlation between the increases of nitric oxide and the changes of estradial 3 months after oral intake of estradiol valerate 1 mg/d was significant. Compared with the baseline, no significant changes were observed in both serum nitric oxide levels and plasma angiotensin II levels 3 months after oral intake of estradiol valerate, 1 mg/d plus medroxyprogesterone acetate, 2 mg/d (P < 0.05). CONCLUSIONS: The vascular functions can be improved through increasing the serum nitric oxide level after 3-month oral intake of estradiol valerate, 1 mg/d in postmenopausal women, and estradiol valerate plus medroxyprogesterone acetate intake may attenuate the beneficial effects.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12905695&dopt=Abstract estradiol



Int J Gynecol Cancer. 2003 Jul-Aug;13(4):485-96.
Uterine response to estradiol under action of chorionic gonadotropin in mice.

Gunin AG, Emelianov VU, Mironkin IU, Morozov MP, Ivanov VA.

Department of Histology, Medical School, Chuvash State University, Cheboksary, Russia. drguniail.ru

This work examined the effect of chorionic gonadotropin on proliferative and morphogenetic reactions in the uterus under short- and long-term estrogen treatments. Ovariectomized mice received a single injection with estradiol dipropionate (2 micro g per 100 g; subcutaneously, sc) or vehicle and injections with human chorionic gonadotropin (10 IU per 100 g; sc) or vehicle twice a day for 2 days. Other groups of animals received injections with estradiol once a week or vehicle and injections with chorionic gonadotropin or vehicle once a day for 30 days. The uteri were removed 48 h after the last estradiol or vehicle injection. In animals treated with estradiol and chorionic gonadotropin for a month, the incidence of atypical endometrial hyperplasia was significantly higher. In animals treated with estradiol and chorionic gonadotropin for 2 days or for a month, uterine mass was slightly increased, the number of mitotic cells and BrdU-labeled cells was greater in luminal epithelium, glandular epithelium, stromal and myometrial cells, whereas the expression of estrogen receptors-alpha was lower in all uterine compartments, than in control. In mice who received estradiol and chorionic gonadotropin for 2 days, levels of beta-catenin and glycogen synthase kinase-3beta in luminal and glandular epithelia were lower. In animals treated with estradiol and chorionic gonadotropin for a month, the level of beta-catenin was slightly higher, and the expression of glycogen synthase kinase-3beta was lower in luminal and glandular epithelia. Thus, chorionic gonadotropin exerts estradiol-induced proliferative and morphogenetic changes in the uterus. This action of chorionic gonadotropin is associated with decreased expression of estrog




Hypertension. 2003 Sep;42(3):349-55. Epub 2003 Aug 11.
Catecholamines block the antimitogenic effect of estradiol on human glomerular mesangial cells.

Dubey RK, Zacharia LC, Gillespie DG, Imthurn B, Jackson EK.

Department of Obstetrics and Gynecology, Clinic for Endocrinology, University Hospital Zurich, Zurich, Switzerland. Raghvendra.Dubesz.ch

Local sequential conversion of estradiol to hydroxyestradiols and methoxyestradiols by CYP450 and catechol-O-methyltransferase, respectively, contributes to the antimitogenic effects of estradiol on glomerular mesangial cell growth via estrogen receptor-independent mechanisms. Catecholamines are also substrates for catechol-O-methyltransferase and therefore, might abrogate the renoprotective effects of estradiol by inhibiting formation of methoxyestradiols. To test this hypothesis, we investigated the antimitogenic effects of estradiol on human glomerular mesangial cell proliferation and collagen synthesis in the presence and absence of catecholamines. Norepinephrine, epinephrine, and isoproterenol abrogated the inhibitory effects of estradiol on cell number, DNA synthesis, and collagen synthesis. For example, serum-induced DNA synthesis was inhibited from 100% to 62+/-1.9% by 0.1 micromol/L estradiol, and these inhibitory effects were reversed to 91+/-1.9% by 1 micromol/L epinephrine, 90.7+/-3.3% by 1 micromol/L isoproterenol, 87.5+/-2.8% by 10 micromol/L norepinephrine, and 92+/-1% by 10 micromol/L OR486 (catechol-O-methyltransferase inhibitor). The interaction of catecholamines with estradiol was not affected by phentolamine or propanolol, alpha- and beta-adrenoceptor antagonists, respectively. Similar to estradiol, the antimitogenic effects of 2-hydroxyestradiol were abrogated by epinephrine, isoproterenol, and OR486. In contrast to estradiol and 2-hydroxyestradiol, the antimitogenic effects of 2-methoxyestradiol were not attenuated by epinephrine, isoproterenol, or OR486. Norepinephrine, epinephrine, and isoproterenol inhibited the conversion of both estra




J Clin Endocrinol Metab. 2003 Aug;88(8):3515-20.
Inhibin A, inhibin B, follicle-stimulating hormone, luteinizing hormone, estradiol, and sex hormone-binding globulin levels in 473 healthy infant girls.

Chellakooty M, Schmidt IM, Haavisto AM, Boisen KA, Damgaard IN, Mau C, Petersen JH, Juul A, Skakkebaek NE, Main KM.

University Department of Growth and Reproduction, Rigshospitalet, DK-2100 Copenhagen, Denmark. rh0463h.dk

The early postnatal regulation of reproductive hormones seems to be more complex in girls than in boys. The aim of this study was to describe inhibins A and B, FSH, LH, estradiol, and SHBG in a large prospective cohort of 473 unselected, healthy, 3-month-old girls. In full term, appropriate-for- gestational-age girls (n = 355) hormones showed a marked interindividual variation, with concentrations up to pubertal values [medians (95% confidence intervals): inhibin B, 82 pg/ml (<20-175); FSH, 3.8 IU/liter (1.2-18.8); LH, 0.07 IU/liter (<0.05-1.07); estradiol, 31 pM (<18-83); SHBG, 137 nM (72-260)]. In 38%, FSH levels exceeded 4.5 IU/liter. Weight at 3 months had significant inverse relationships with estradiol and SHBG (P = 0.048 and P = 0.001, respectively). Gestational age was negatively correlated to estradiol (P = 0.001), with a similar trend for LH, FSH, and inhibin B. Inhibin B was higher in premature girls [126 pg/ml (<20-265)] than in term [80 pg/ml (<20-181), P = 0.002] and postmature girls [59 pg/ml (<20-152), P = 0.012]. Likewise, estradiol levels in prematures were higher than in mature girls [51 pM (<18-128) vs. 31 pM (<18-85), P = 0.009]. Estradiol was also higher in small-for-gestational-age than in appropriate-for-gestational-age girls (P = 0.046), with inhibin B and LH, but not FSH, showing a similar trend. In conclusion, reproductive hormones showed a large variation, and concentrations corresponded to those observed in puberty. Our findings support the concept of a minipuberty in infant girls similar to that in boys.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12915629&dopt=Abstract estradiol [




Neuroendocrinology. 2003 Aug;78(2):61-71.
Estradiol control of expression and levels of estradiol-binding proteins in the medial preoptic area, medial hypothalamus and pituitary.

Gao G, Herbert Z, Kong J, Gabrielson N, Mautz A, Wu D, Jirikowski GF, Caldwell JD.

Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota, USA.

The brains of mammals have at least three estradiol-binding proteins: estradiol receptor-alpha (ERalpha), ERbeta, and sex hormone-binding globulin (SHBG). In this study we compare the effects of estradiol treatment on the expression of mRNA for these three estradiol-binding proteins in two reproductively important brain areas, the medial preoptic area-anterior hypothalamus (MPOA-AH) and medial hypothalamus (MH) as well as in the hippocampus in ovariectomized rats, using the reverse transcriptase-polymerase chain reaction (RT-PCR). We also used surface-enhanced laser desorption ionization time of flight (SELDI-TOF) mass spectrometry (MS) to analyze the effects of estradiol in ovariectomized rats on SHBG levels in the MPOA-MH as well as the neurohypophysis. In vivo estradiol treatment in ovariectomized rats eliminated or significantly reduced expression of all three estradiol-binding proteins in both the MPOA-AH and MH. This change in ERalpha, ERbeta, and SHBG expression did not occur in the hippocampus. Both Northern blot and DNA sequence analysis confirmed the results of the RT-PCR for SHBG. SELDI-TOF MS analysis demonstrated that in vivo estradiol treatments resulted in dramatically decreased levels of SHBG in the hypothalamus and that a reduction in SHBG mRNA by estradiol treatment also resulted in a reduction in SHBG protein levels. Estradiol treatment also eliminated detectable SHBG from the neurohypophysis, suggesting that estradiol controls SHBG levels in this release site. That in vivo estradiol treatments had the same inhibitory effects on mRNA levels for SHBG and both ERs suggests similar translational control mechanisms for all thr




J Neurobiol. 2003 Sep 15;56(4):338-46.
Progesterone receptor gene and protein expression in the anterior preoptic area and hypothalamus of defeminized rats.

Arrieta I, Diaz-Ibanez LB, Morales T, Mendoza-Garces L, Morimoto S, Moreno-Mendoza N, Cerbon MA.

Departamento de Biologia, Facultad de Quimica, Universidad Nacional Autonoma de Mexico, 04510 Mexico D.F., Mexico.

Progesterone receptor (PR) plays an important role during sexual differentiation of the rat brain. The objective of the present study was to determine PR protein and gene expression pattern in preoptic-anterior hypothalamic area (POA-AHA) and hypothalamus (HYP), after estradiol or testosterone treatment during the postnatal critical period of sexual differentiation of the rat brain (defeminized animals). Three-day-old female rats were subcutaneously (s.c.) injected with a single dose of 17beta-estradiol (200 microg), or testosterone enanthate (200 microg), or vehicle (corn oil). POA-AHA and HYP were dissected 3 h, 24 h, and 14 days, as well as on the day of vaginal opening (VO) after treatments. Other animals, previously treated as above, were acutely injected with 17beta-estradiol (5 microg) on the day of VO; POA-AHA and HYP were obtained 3 h later. Total RNA was extracted and processed for semiquantitative RT-PCR and tissue slices were prepared for protein detection by immunohistochemistry. We observed that PR mRNA expression was increased in POA-AHA and HYP of the animals treated with estradiol or testosterone 3 hours after treatments, compared with the vehicle-treated control group. We also found a significant increase in PR mRNA and protein expression in POA-AHA and HYP on the day of VO in both estradiol and testosterone defeminized rats. Interestingly, the acute administration of estradiol on the day of VO (VO + E(2)) did not increase PR mRNA or protein expression in POA-AHA and HYP of either estradiol or testosterone defeminized animals, as opposed to the marked induction observed in the intact animals of the control gro




AAPS PharmSciTech. 2002;3(1):E5.
Targeted brain delivery of 17 beta-estradiol via nasally administered water soluble prodrugs.

Al-Ghananeem AM, Traboulsi AA, Dittert LW, Hussain AA.

Division of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky 40536, USA.

The utility of the nasal route for the systemic delivery of 17beta-estradiol was studied using watersoluble prodrugs of 17beta-estradiol. This delivery method was examined to determine if it will result in preferential delivery to the brain. Several alkyl prodrugs of 17beta-estradiol were prepared and their physicochemical properties were determined. In vitro hydrolysis rate constants in buffer, rat plasma, and rat brain homogenate were determined by high-performance liquid chromatography. In vivo nasal experiments were carried out on rats. Levels of 17beta-estradiol in plasma and cerebral spinal fluid (CSF) were determined with radioimunoassay using a gamma counter. The study revealed that the aqueous solubilities of the prodrugs were several orders of magnitude greater than 17beta-estradiol with relatively fast in vitro conversion in rat plasma. Absorption was fast following nasal delivery of the prodrugs with high bioavailability. CSF 17beta-estradiol concentration was higher following nasal delivery of the prodrugs compared to an equivalent intravenous dose. It was determined that water-soluble prodrugs of 17beta-estradiol can be administered nasally. These prodrugs are capable of producing high levels of estradiol in the CSF and as a result may have a significant value in the treatment of Alzheimer's disease.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12919005&dopt=Abstract estradiol




Br J Clin Pharmacol. 2003 Sep;56(3):334-6.
The effect of ketoconazole and diltiazem on oestrogen metabolism in postmenopausal women after single dose oestradiol treatment.

Annas A, Carlstrom K, Alvan G, AL-Shurbaji A.

Department of Laboratory Medicine, Division of Clinical Pharmacology Karolinska Institutet at Huddinge University Hospital, 141 86 Stockholm, Sweden.

AIMS: The effect of the CYP3A4 inhibitors ketoconazole and diltiazem on the pharmacokinetics of oestrone was studied in six healthy postmenopausal women after treatment with a single oral dose of oestradiol. METHODS: Plasma oestrone concentrations were measured following the administration of 1) oestradiol, 2) oestradiol and ketoconazole and 3) oestradiol and diltiazem. RESULTS: Treatment with ketoconazole increased the AUC of oestrone (+ 4029 nmol l-1 h; 95% CI on the difference: 1588, 6471) and its Cmax (+ 306 nmol l-1; 95% CI on the difference: 117, 496). The AUC and Cmax of oestrone tended to increase on treatment with diltiazem although this did not reach the level of statistical significance. CONCLUSIONS: The small increase in the plasma concentrations of oestrone formed from 17beta-oestradiol during co-administration with ketoconazole is unlikely to be clinically significant.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12919184&dopt=Abstract estradiol




Mol Pharmacol. 2003 Sep;64(3):610-8.
Breast cancer resistance protein exports sulfated estrogens but not free estrogens.

Imai Y, Asada S, Tsukahara S, Ishikawa E, Tsuruo T, Sugimoto Y.

Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo 170-8455, Japan.

Breast cancer resistance protein (BCRP), an ATP-binding cassette transporter, confers resistance to a series of anticancer reagents such as mitoxantrone, 7-ethyl-10-hydroxycamptothecin, and topotecan. We reported previously that estrone and 17beta-estradiol reverse BCRP-mediated multidrug resistance. In the present study, we demonstrate that BCRP exports estrogen metabolites. First, we generated BCRP-transduced LLC-PK1 (LLC/BCRP) cells, in which exogenous BCRP is expressed in the apical membrane, and investigated transcellular transport of 3H-labeled compounds using cells plated on microporous filter membranes. The basal-to-apical transport (excretion) of mitoxantrone, estrone, and 17beta-estradiol was greater in LLC/BCRP cells than in LLC-PK1 cells. Thin-layer chromatography of transported steroids revealed that the transport of estrone and 17beta-estradiol was independent of BCRP expression. Alternatively, increased excretion of estrone sulfate and 17beta-estradiol sulfate was observed in LLC/BCRP cells. BCRP inhibitors completely inhibited the increased excretion of sulfated estrogens across the apical membrane. Conversion of estrogens into their sulfate conjugates was similar between LLC/BCRP and LLC-PK1 cells, suggesting that the increased excretion of estrogen sulfates was attributable to BCRP-mediated transport. Next, the uptake of 3H-labeled compounds in membrane vesicles from BCRP-transduced K562 (K562/BCRP) cells was investigated. 3H-labeled estrone sulfate, but not 3H-labeled estrone or 17beta-estradiol, was taken up by membrane vesicles from K562/BCRP cells, and this was ATP-dependent. Additionally, BCRP inhibitors suppressed the transp