Chunying Zhang

Estrogen Increases Endothelial Nitric Oxide Synthase via Estrogen Receptors in Rat Cerebral Blood Vessels Effect Preserved After Concurrent Treatment With Medroxyprogesterone Acetate or Progesterone

Background and Purpose— In vivo and in vitro rat models of hormone therapy were used to test the following hypotheses: (1) estrogen acts directly on cerebrovascular estrogen receptors to increase endothelial nitric oxide synthase (eNOS); (2) increased protein correlates with higher NOS activity; and (3) effects of estrogen on eNOS are altered by concurrent treatment with either medroxyprogesterone acetate (MPA) or progesterone. Methods— Blood vessels were isolated from brains of ovariectomized female rats; some were treated for 1 month with estrogen, estrogen and progesterone, or estrogen and MPA. Isolated cerebral vessels were also treated in vitro with estrogen in the absence and presence of progesterone, MPA, tamoxifen, and the estrogen receptor antagonist ICI 182 780. Levels of eNOS were measured by Western blot, and NOS activity was measured by [14C]arginine-[14C]citrulline conversion. Results— Chronic hormone treatment in vivo resulted in plasma levels of 17&bgr;-estradiol, progesterone, and MPA in the range of values found in humans. Estrogen treatment resulted in higher levels of cerebrovascular NOS activity that paralleled increases in eNOS protein. In vitro estrogen treatment for 18 hours also resulted in a concentration-dependent increase in eNOS protein (EC50 ≈300 pmol/L) that was completely prevented by estrogen receptor antagonists tamoxifen or ICI 182 780. However, cotreatment with progesterone or MPA, either in vivo or in vitro, did not alter the effect of estrogen on eNOS protein. Conclusions— Estrogen receptor activation in cerebrovascular tissue results in increased eNOS activity and protein levels. The latter effect persists in the presence of either progesterone or MPA. Thus, increased NO production by eNOS may contribute to the neuroprotective effects of estrogen.

Effects of soy foods on ovarian function in premenopausal women

It has been proposed that the high intake of soy foods among Asians may partly explain their lower rates of breast cancer, perhaps by lowering endogenous oestrogen levels, although this has been inadequately studied. Twenty healthy cycling premenopausal women (ten Asians and ten non-Asians) participated in a 7-month soy intervention study which was designed to investigate the effect of supplementation on ovarian function. Asian soy foods (tofu, soymilk, green soybean peas) in the amount of approximately 32 mg of isoflavones per day were added to the women’s diets for three menstrual cycles. The women’s baseline (two cycles) serum hormone levels were compared to levels during soy intervention (three cycles) and levels after intervention (two cycles). During the entire study period, subjects provided almost daily overnight urine samples and blood specimens during specified days of their menstrual cycles. The day of urinary luteinizing hormone (LH) peak was used as a marker for the day of ovulation. Knowledge of day of ovulation allowed comparison of hormone measurements at baseline to those obtained during intervention and recovery cycles with standardization of day of cycle. Soy intervention was associated with a statistically significant reduction in serum luteal oestradiol level (–9.3%, P< 0.05), but there were no significant changes in follicular phase oestradiol, follicular or luteal phase progesterone, sex hormone-binding globulin or menstrual cycle length. This significant reduction in luteal phase oestradiol was, however, observed only among Asian (–17.4%) but not among non-Asian (–1.2%) participants; urinary excretion of isoflavones was higher among Asians than non-Asians (29.2 vs 17.1 μmol day–1, P = 0.16) during the intervention period. Thus, supplementation using traditional soy foods reduced serum oestradiol levels among Asian participants in this study. Differences in the type of soy products (i.e. traditional soy foods versus soy protein products), amount of isoflavones, and race/ethnicity of participants may have contributed to the divergent results. Larger soy intervention studies designed specifically to include participants of different race/ethnicities and using both traditional soy foods and soy protein products providing comparable doses of isoflavones are needed to definitively determine the effect of soy on ovarian function.

Pharmacokinetics of testosterone after percutaneous gel or buccal administration

OBJECTIVE To determine the pharmacokinetics of testosterone following its administration using transdermal gel or buccal lozenges. DESIGN Pilot study. SETTING University-based hospital. PATIENT(S) Ten bilaterally oophorectomized women. INTERVENTION(S) Daily micronized testosterone gel (1 mg) and testosterone propionate lozenge (1 mg). MAIN OUTCOME MEASURE(S) Total testosterone, androstenedione, dihydrotestosterone, 3alpha-androstanediol glucuronide, and sex hormone-binding globulin were measured in serum by specific radioimmunoassays; free testosterone levels were also calculated. RESULT(S) Before treatment, serum testosterone levels in the groups using the lozenge and gel were 16 +/- 4.0 and 20 +/- 6.0 ng/dL, respectively. Mean maximum testosterone levels obtained with the lozenge occurred 1 hour after administration on days 1 (692 +/- 236 ng/dL) and 14 (836 +/- 309 ng/dL) of treatment and fell precipitously thereafter. In contrast, testosterone levels obtained with the gel showed a prolonged rise reaching maximal levels of 97 +/- 78 and 100 +/- 60 ng/dL after 18 hours. The serum level patterns of free testosterone, dihydrotestosterone, and 3alpha-androstanediol glucuronide were similar to the corresponding total testosterone levels. CONCLUSION(S) Administration of testosterone lozenge by buccal absorption produced a rapid and brief elevation of testosterone levels, with levels reaching upper limits of the male range. In contrast, transdermal testosterone gel absorption resulted in a prolonged elevation of testosterone levels, which were in the hyperandrogenic female range but resembled steady state pharmacokinetics.

Tumor Stroma as the Main Source of Inhibin Production in Ovarian Epithelial Tumors

PROBLEM: Elevated serum inhibin levels have been found in ovarian cancer patients; however, the source of the elevated inhibin is uncertain. Previous studies of activin in human ovarian cancer suggest that activin may promote the growth of the tumor. The aims of this study were to examine the source of elevated inhibin from ovarian epithelial tumors (OETs) and to preliminarily investigate the role of the gonadotropin–inhibin/activin relationship in the development of OET.
 METHOD OF STUDY: The protein and mRNA expression of α and βA subunits of inhibin/activin were examined by immunohistochemistry (IHC) and reverse transcription polymerase chain reaction (RT‐PCR) in 120 OETs, including 30 benign cystadenomas, 30 borderline tumors, and 60 carcinomas. Stromal and epithelial cells were microdissected from 23 OETs to further examine the expression of α and βA subunits by RT‐PCR. Dimeric inhibin A and activin A production were measured by using the two‐site ELISA from three OET cell lines in culture under treatment of follicle‐stimulating hormone (FSH) and luteinizing hormone (LH).
 RESULTS: βA subunit was expressed in the epithelial component of 100% of the cystadenomas, in 80% of borderline tumors, and in 75% of the carcinomas, but not in tumor stroma. Inhibin α expression was not found in the epithelium of all OETs studied, but focal inhibin α immunoreactivity was seen in the tumor stroma (mainly luteinized stromal cells) in the majority of cases. Dimeric activin A was produced by all of the three OET cell lines with a 1.5–1.9‐fold increment after FSH stimulation. However, activin A production was not augmented by LH treatment. No inhibin A was produced by the three OET cell lines with or without gonadotropin stimulation.
 CONCLUSIONS: The stroma of OET is the major source in the production of inhibin α (monomer). Dimeric inhibin A production may be the result of combined efforts of the tumor stroma (α subunit) and epithelium (βA subunit). Cellular, compartmental expression of inhibin and activin subunits may play a role in the development of OET, although the mechanism remains undefined. The unopposed activin A production stimulated by FSH in OET cell lines suggests that activin production may represent one of the cellular mechanisms of growth promotion by FSH.

Alterations in gonadotropin levels following oral and vaginal administration of the Yuzpe regimen and plan B for emergency contraception

There is increasing use of the Yuzpe regimen [500g levonorgestrel (LNG)/100g ethinyl estradiol] and Plan B (750g LNG) for emergency contraception. These regimens are believed to act by delay of ovulation in conjunction with a local effect on the endometrium; however the exact mechanism of action is unknown. Furthermore data regarding vaginal administration of both regimens are lacking. The objective of this study was to determine the effects of Plan B and Yuzpe regimens administered orally or vaginally on serum gonadotropin levels at peak and nadir LNG levels. There was no significant difference in LH and FSH suppression between Plan B and the Yuzpe regimens suggesting that when high doses of LNG are used (Plan B) the addition of EE as in the Yuzpe regimen contributes little to further gonadotropin suppression. Vaginally administered Plan B and Yuzpe regimens did not differ significantly from the same regimens administered orally in suppression of LH and FSH suggesting that vaginal administration of such regimens may be as efficacious as oral ones in delaying ovulation. (excerpt)