Coordination of early antral follicles by luteal estradiol administration provides a basis for alternative controlled ovarian hyperstimulation regimens

OBJECTIVE: To investigate whether luteal E(2) administration reduces size discrepancies of early antral follicles. DESIGN: Prospective, crossover study. SETTING: ART unit, Clamart, France. PATIENT(S): Sixty women and 120 cycles. INTERVENTION(S): On cycle day 3 (baseline day 3), all women underwent measurements of early antral follicles by ultrasound and serum FSH and ovarian hormones. From day 20 until the next cycle day 2, 30 of them received oral 17beta-E(2), whereas the remaining women served as controls. The day after E(2) discontinuation (E(2) day 3) or on subsequent cycle day 3 (control day 3), participants were reevaluated as on baseline day 3. MAIN OUTCOME MEASURE(S): Magnitude of follicular size discrepancies. RESULT(S): Follicular size discrepancies and follicular diameters were significantly attenuated on E(2) day 3 (3.7 +/- 0.5 mm) as compared with baseline day 3 (4.9 +/- 1.0 mm), but not in controls (5.0 +/- 0.8 vs. 4.9 +/- 0.8 mm). FSH (4.3 +/- 1.9 vs. 7.3 +/- 3.3 mIU/mL) and inhibin B (34 +/- 28 vs. 71 +/- 32 pg/mL) levels were consistently lower on E(2) day 3 than on baseline day 3 but remained unchanged in controls. CONCLUSION(S): Luteal E(2) administration reduces the size and improves the homogeneity of early antral follicles on day 3. This approach may be instrumental in synchronizing follicular development during controlled ovarian hyperstimulation.     

Central abdominal fat and endogenous hormones during the menopausal transition

OBJECTIVE: To investigate the effect of endogenous hormone levels on central abdominal fat during the menopausal transition in a population-based cohort of Australian-born women. DESIGN: Prospective observational study. SETTING: Population-based sample. Body composition was assessed in the Royal Melbourne Hospital, and interviews were conducted at the patient's home. SUBJECT(S): One hundred two women from the Melbourne Women's Midlife Health Project. Data, physical measures, and blood were obtained by interview when the longitudinal study commenced (baseline) and at the time of the total body scan approximately 5 years later. Body composition was measured using dual-energy X-ray absorptiometry. INTERVENTION(S): None. MAIN OUTCOME MEASURES: Total body fat and central abdominal fat. RESULT(S): The 102 women were either premenopausal or in the early menopausal transition at baseline. At the time of their dual-energy X-ray absorptiometry scan, 31 were in the early menopausal transition, 22 were in the late menopausal transition, and 49 were postmenopausal. Multiple regression analysis found that total percentage of body fat was associated with weight measures, whereas central abdominal fat was also positively associated with baseline free T index (FTI) and with the increase in FTI since baseline. CONCLUSION(S): The major hormonal change associated with central adiposity during the menopausal transition is the increase in the FTI. This effect is significant even after allowing for baseline and final weight.     

Acute and chronic effects of genistein, tyrphostin and lavendustin A on steroid synthesis in luteinized human granulosa cells

BACKGROUND: Phytoestrogens, including genistein and other inhibitors of tyrosine kinases (TKs), inhibit specific steroidogenic enzymes. This study was designed to compare the effects of genistein, with two other TK inhibitors, on steroid synthesis in human granulosa luteal (GL) cells and to identify which steroidogenic enzymes they may affect. METHODS: GL cells, obtained from women undergoing IVF procedures, were cultured for various periods of time with and without substrates for progesterone and estradiol synthesis, in the presence or absence of the TK inhibitors. RESULTS: The TK inhibitors significantly suppressed progesterone and estradiol synthesis in a dose-dependent manner over a 48 h culture period. Progesterone production in the presence of 10(-7) mol/l pregnenolone during a 4 h period was inhibited by both acute (4 h) and chronic (24 h) exposure of GL cells to 50 micromol/l genistein (P < 0.05) whilst no significant effects of 50 micromol/l tyrphostin A23 were observed. Genistein (4 and 24 h exposure) inhibited the production of estradiol using 10(-7) mol/l estrone as a substrate, but inhibition of estradiol synthesis using androstenedione or testosterone as substrates was only observed after a 24 h exposure. In contrast, tyrphostin acutely stimulated estradiol synthesis when androstenedione and testosterone were used as substrates (P < 0.05) but not estrone. CONCLUSIONS: Genistein directly inhibits 3 and 17beta-hydroxysteroid dehydrogenase activity, whilst tyrphostin has an acute stimulatory effect on aromatase activity. Over a longer time (24 and/or 48 h period), both TK inhibitors suppress steroid synthesis.     

Percentile curves of serum estradiol levels during controlled ovarian stimulation in 905 cycles stimulated with recombinant FSH show that high estradiol is not detrimental to IVF outcome

BACKGROUND: High, normal and poor responders are usually defined by reference to subjectively selected estradiol E2 levels at days 4-6 and the day of hCG administration (d-hCG). The purpose of this study was to use E2 percentile curves from day 5 until d-hCG to determine high, normal and poor responders, and to predict IVF outcome. METHODS: In this retrospective study, 762 patients underwent 905 cycles with a GnRH agonist/recombinant FSH short protocol. They were divided into three groups according to their age. Percentile E2 curves according to E2 levels were plotted. High responders were those patients with E2 levels above the 90th percentile, normal responders had E2 between the 10th and 90th percentiles, and poor responders had E2 below the 10th percentile. RESULTS: IVF outcome, expressed as number of oocytes, total embryos obtained and number of high grade embryos, was significantly better for patients with E2 above the 90th percentile at d-hCG for the three age groups and at day 5 for group A (<35 years). Pregnancy rates were higher for high responders, but the difference did not reach statistical significance. CONCLUSIONS: Percentile curves can be useful in controlled ovarian stimulation cycles to define high, normal and poor responders, and also to predict IVF outcome.     

抗早2号方治疗女童真性性早熟的临床研究

目的：观察抗早2号方治疗女童真性性早熟的疗效。并探讨其作用机制。方法：68例辨证为痰热互结型本病患儿随机分为两组。分别用抗早2号方（治疗组43例）和知柏地黄汤（对照组25例）治疗,并观察患儿临床体征,疗效,测定促卵泡生成素（FSH）,促黄体生成素（LH）,雌二醇（E2）及子宫卵巢容积,骨龄的变化。结果：临床治疗3个月后,治疗组和对照组总有效率分别为86.0%和76.0%。两组比较差异无显著性（P>0.05)。两组FSH,E2均较用药前降低（P<0.05)。而治疗组FSH,LH降低程度较对照组更显著（P<0.01)。B超显示：治疗组治疗后子宫容积和卵巢容积小于对照组（P<0.05或P<0.01)。用药后6个月骨龄显示;治疗组骨龄增长明显落后于年龄增长,其减缓骨龄增长速度优于对照组（P<0.05)。结论：提早2号方治疗痰热互结型真性性早熟的疗效确切,是治疗女童真性性早熟的一种有效药物。     

The influence of insulin on secretion of IGF-Ⅰ and IGFBP-Ⅰ in cultures of human endometrial stromal cells

Objectives To study the influence of insulin on IGF-Ⅰ and IGFBP-Ⅰ secretion of the human endometrial stromal cells. Methods Late proliferative phase endometrial stromal cells were isolated from endometrium tissues and then cultured for 24 h in Hams F-12 only as a control and in Hams F-12 with different concentrations of estradiol (E2) and insulin (INS) as treated groups. Simultaneously, the endometrial stromal cells from late secretory phase endometrium were cultured for 24 h in Hams F-12 only as a control and in Hams F-12 supplemented with different concentrations of progesterone (P) and insulin as treated groups. After 24 h of culturing, the mediums were collected for either IGF-Ⅰ or IGFBP-Ⅰ assays. Result The concentrations of IGF-Ⅰ in medium from cultured endometrial stromal cells in the proliferative phase were 0.78±0.47 ng/ml in the hormone-free control group; 1.44±0.59 ng/ml and 1.39± 0.33 ng/ml in 100 pg/ml E2 group and 20 μU/ml INS group, which was higher than that of the control group (P&lt;0.05 and P&lt;0.01, respectively). The IGF-Ⅰ concentration in the 100 μU/ml INS group was 2.03±0.53 ng/ml, which was higher than that of the 20 μU/ml INS group (P&lt;0.01). Levels of IGF-Ⅰ in the 100 pg/ml E2 plus 20 μU/ml INS group was 2.18±0.36 ng/ml, which was significantly higher than that of the 20 μU/ml INS and 100 pg/ml E2 group (P&lt;0.01), but lower than that of the 100 pg/ml E2 plus 100 μU/ml INS group (3.42±0.75 ng/ml), P&lt;0.01. The concentration of IGFBP-Ⅰ in medium from cultured endometrial stromal cells in the secretory phase was 2.50±1.39 ng/ml in the hormone-free control group and 5.44±2.09 ng/ml in the 10 pg/ml P group, which was significantly higher than that of the control (P&lt;0.01). IGFBP-Ⅰ concentration in 20 μU/ml INS group was 0.16±0.58 ng/ml, which was lower compared with control, but higher compared with the 100 μU/ml INS group (P&lt;0.01). The level of IGFBP-Ⅰ in the 10 ng/ml P plus 20 μU/ml INS group was 2.10±1.17 ng/ml, lower compared with the 10 ng/ml P group, but higher compared with the 10 pg/ml P plus 100 μU/ml INS group, P&lt;0.01. Conclusions Insulin can stimulate basal (without hormone) and E2-stimulated IGF-Ⅰ secretion in cultured stromal cells from human late proliferative endometrium in a dose-dependent manner. Insulin can suppress basal (without hormone) and P-stimulated IGFBP-Ⅰ secretions in cultured stromal cells from human secretory endometrium in a dose-dependent manner.     

An antagonist of estrogen receptors blocks the induction of adult neurogenesis by insulin-like growth factor-I in the dentate gyrus of adult female rat

Interdependence between estradiol and insulin-like growth factor-I has been documented for different neural events, including neuronal differentiation, synaptic plasticity, neuroendocrine regulation and neuroprotection. In the present study we have assessed whether both factors interact in the regulation of neurogenesis in the adult rat dentate gyrus. Wistar albino female rats were bilaterally ovariectomized and treated with estradiol, insulin-like growth factor-I and/or the estrogen receptor antagonist ICI 182,780. Estradiol was administered in a subcutaneous silastic capsule. Insulin-like growth factor-I and ICI 182,780 were delivered in the lateral cerebral ventricle. Animals received six daily injections of 5-bromo-2-deoxyuridine and were killed 24 h after the last injection. The total number of 5-bromo-2-deoxyuridine-positive neurons was significantly increased in animals treated with insulin-like growth factor-I, compared with rats treated with vehicles, while rats treated with both insulin-like growth factor-I and estradiol showed a higher number of 5-bromo-2-deoxyuridine-positive neurons than rats treated with insulin-like growth factor-I or estradiol alone. The antiestrogen ICI 182,780 blocked the effect of insulin-like growth factor-I on the number of 5-bromo-2-deoxyuridine neurons with independence of whether the animals were treated or not with estradiol. These findings suggest that estrogen receptors are involved in the induction of adult neurogenesis by insulin-like growth factor-I in the dentate gyrus, and that estradiol and insulin-like growth factor-I have a cooperative interaction to promote neurogenesis. The interaction between insulin-like growth factor-I and estradiol may participate in changes in the rate of neurogenesis during different endocrine and physiological conditions, and may be related to the decline in neurogenesis with ageing.     

Intrauterine bisphenol A exposure leads to stimulatory effects on Sertoli cell number in rats

Using the optical disector for quantifying cell numbers, we investigated whether oral treatment of rats on days 6-21 of gestation with the weakly estrogenic bisphenol A (BPA, 0.1 or 50 mg/kg) or the highly estrogenic ethinyl estradiol (EE, 0.02 mg/kg) alters testicular histology, in those offspring 9-12 month of age. Since production of male germ cells depends on Sertoli cell number, possible changes in that parameter were investigated using unbiased stereology. Spermatogenesis was qualitatively normal in all groups. BPA increases Sertoli cell number per organ but not when expressed as per gram testis. EE did not affect cell number per organ but did affect numbers on a per gram testis basis due to a lowered testis weight. In contrast to the lowering of Sertoli cell numbers that might have been expected according to the estrogen hypothesis, intrauterine administration of these xenoestrogens in fact resulted in minor increases in Sertoli cell numbers and had no qualitative effect on spermatogenesis.     

Third-generation progestogen type influences hemostatic changes caused by oral contraceptives in Brazilian women

We compared the effects of two third-generation progestogens, desogestrel (DSG) and gestodene (GSD), on coagulation and fibrinolysis in Brazilian users of oral contraceptives (OCs). Forty-six women were evaluated before treatment and after six cycles of treatment. The coagulation, anticoagulant, and fibrinolytic systems were investigated. During the use of the DSG-containing OC, the activity of factors VII, VIII, IX, X, and XII increased significantly whereas the GSD-containing OC caused no changes in coagulation parameters. Concerning the anticoagulant pathways, the DSG-containing OC increased protein C levels and decreased total protein S levels, and the GSD-containing OC only decreased total protein S. Both OCs increased plasminogen activity, although the DSG-containing OC increased fibrin degradation products levels and decreased the tissue plasminogen activator antigen. In conclusion, we have found that in Brazilian women the effects of DSG and GSD on hemostatic parameters are different and, therefore, third-generation progestogens may not contribute equally to the thrombotic risk.     

Mechanism of estrogens-induced increases in intracellular Ca(2+) in PC3 human prostate cancer cells

BACKGROUND: The effect of estrogens (diethylstilbestrol [DES], 17 beta-estradiol) on intracellular Ca(2+) concentrations ([Ca(2+)](i)) in hormone-insensitive PC3 human prostate cancer cells was examined. METHODS: [Ca(2+)](i) changes in suspended cells were measured by using the Ca(2+)-sensitive fluorescent dye fura-2. RESULTS: Estrogens (1--20 microM) increased [Ca(2+)](i) concentration-dependently with DES being more potent. Ca(2+) removal inhibited 50 +/- 10% of the signal. In Ca(2+)-free medium, pretreatment with 20 microM estrogens abolished the [Ca(2+)](i) increases induced by 2 microM carbonylcyanide m-chlorophenylhydrazone (CCCP, a mitochondrial uncoupler) and 1 microM thapsigargin (an endoplasmic reticulum Ca(2+) pump inhibitor), but pretreatment with CCCP and thapsigargin did not alter DES-induced Ca(2+) release and partly inhibited 17 beta-estradiol-induced Ca(2+) release. Addition of 3 mM Ca(2+) increased [Ca(2+)](i) in cells pretreated with 1- 20 microM estrogens in Ca(2+)-free medium. Pretreatment with 1 microM U73122 to block phospholipase C-coupled inositol 1,4,5-trisphosphate formation did not alter estrogens-induced Ca(2+) release. The effect of 20 microM estrogen on [Ca(2+)](i) was not affected by pretreatment with 0.1 microM estrogens. CONCLUSIONS: Estrogen induced significant Ca(2+) release and Ca(2+) influx in an inositol 1,4,5-trisphosphate-independent manner in PC3 cells. These effects of estrogens on Ca(2+) signaling appear to be nongenomic. Prostate 47:141-148, 2001.