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Context: Female reproduction spans a developmental life arc from fetal life and childhood, through puberty to the reproductive years, and, finally, ovarian follicle depletion and the onset of menopause., Objective: This invited review highlights a selection of reports from leading journals over the past 2 yr that have significantly advanced our understanding of female reproduction from conception to menopause., Synthesis: During fetal life, in utero exposures may be important determinants of later pubertal and adult endocrine physiology. Epigenetic mechanisms are likely involved in the fetal programming of adult endocrine function. With regards to the polycystic ovary syndrome, recent clinical trials have confirmed the central role of clomiphene for ovulation induction in women with this disease. In addition, an expert panel has recommended that all women with polycystic ovary syndrome have a glucose tolerance test because of the high prevalence of impaired glucose tolerance in this population. In menopausal women the precise impact of estrogen therapy on cardiovascular biology remains to be delineated fully. Evolving data indicate that when initiated near the onset of menopause, estrogen therapy has fewer cardiovascular risks than when it is administered decades after the menopause., Conclusions: The essence of reproduction is the successful transmission of germ-line DNA to a succeeding generation. Advances in genetics and endocrinology are converging to advance significantly our understanding of the biology of reproduction and our ability to influence reproductive processes. These advances will translate into new treatments for the prevalent medical problems of reproduction.

The (basal) level of FSH measured during early menses is emerging as a predictor of ovarian competence. In this study, correlates of basal FSH were examined in 222 premenopausal women who were not using oral contraceptives and selected from either the general population or a clinic for women with family histories of ovarian cancer. Using analysis of variance, the effect on FSH by age, smoking history, and reproductive variables was examined. Dietary galactose (as a potential oocyte toxin) was estimated, and red cell activity of galactose-1-phosphate uridyl transferase (GALT) was measured. Qualitative features of GALT were described by its electrophoretic or molecular genetic patterns. Possession of GALT polymorphisms previously linked with low GALT activity, including the Q188R mutation of classic galactosemia or N314D mutation of the Duarte galactosemia variant, was associated with significantly higher FSH, even in the heterozygous state. Other factors significantly influencing FSH included age, smoking history, cycle length, and cycle regularity. No effect of current galactose consumption was found, and GALT activity was only weakly correlated (inversely) with FSH. Applying multiple linear regression, variables independently predictive of high FSH were age of 40 yr or more, current smoking, and possession of a GALT polymorphism.

In recent years, relationships of dehydroepiandrosterone and its sulfate ester dehydroepiandrosterone sulfate (DHEAS) with decreased risks of cardiovascular disease as well as a possible role in the aging process have been postulated. To explore the effects of cigarette smoking, a risk factor for cardiovascular disease, as well as age, on the levels of these adrenal androgens, we measured plasma levels of DHEAS in 543 healthy male subjects from the Physicians' Health Study. Blood specimens were collected between August 1982 and December 1984 and stored at -80 C. The overall mean DHEAS level was 3.47 mumol/L (+/- 2.12 SD). DHEAS levels were positively correlated with smoking habits (r = +0.16, P = 0.0002); current smokers had the highest age-adjusted DHEAS concentrations (4.27 mumol/L, P = 0.0005 compared with never smokers), followed by past smokers (3.47 mumol/L, P = 0.02) and never smokers (3.10 mumol/L). A marked linear decline of levels with age was observed, with an average decrease of 3% per year. These data suggest a moderate direct association with cigarette smoking and a powerful influence of age on decreasing levels of DHEAS. After adjusting for age and smoking habits, DHEAS concentrations were also inversely correlated with reported use of multivitamins (r = -0.16, P = 0.0002) and positively correlated with plasma retinol levels (r = 0.14, P = 0.002).

Leydig cell hyperplasia is a common histological finding in male infants of diabetic mothers. The functional correlates of this histological finding were investigated by measuring beta hCG, testosterone, androstenedione, dihydrotestosterone, and progesterone in mixed cord serum of male and female infants of diabetic mothers (n = 40) and normal mothers (n = 40) at term. Male and female infants of diabetic mothers had significantly higher cord serum beta hCG levels than male and female controls. Male infants of diabetic mothers had significantly higher cord serum testosterone concentrations than male controls, female controls, and female infants of diabetic mothers. Cord serum testosterone concentrations were similar in female infants of diabetic mothers and female controls. In the male infants of diabetic mothers, there was a significant positive correlation between beta hCG and testosterone (r = 0.64; P less than 0.01). There was no significant correlation between beta hCG and testosterone in the male controls (r = -0.15; P = NS). There was no significant difference in cord serum dihydrotestosterone in any group tested. Cord serum progesterone was significantly higher in the males than in the females. Cord serum androstenedione was lower in the infants of diabetic mothers than in the controls. This study suggests that the Leydig cell hyperplasia found in male infants of diabetic mothers is due, in part, to elevated concentrations of hCG and is accompanied by elevated testosterone concentrations in the fetal compartment.

The effects of nicotine and cotinine on fetal adrenal 11 beta- and 21-hydroxylase were examined using enzymatic and spectral techniques. The addition of nicotine or cotinine to preparations of adrenal mitochondria yielded a type II cytochrome P-450 binding spectrum. The apparent spectral dissociation constants (Ks) for nicotine and cotinine binding to mitochondrial cytochrome P-450 were 20 and 19 microM, respectively. The addition of nicotine to preparations of adrenal microsomes yielded a type II cytochrome P-450 binding spectrum, with an apparent Ks of 70 microM. Adrenal mitochondrial 11 beta-hydroxylase was assayed by measuring the conversion of deoxycorticosterone to corticosterone. Nicotine and cotinine competitively inhibited 11 beta-hydroxylase, with apparent Michaelis-Menten inhibition constants (Ki) of 9.9 and 9.0 microM, respectively. Nicotine competitively inhibited microsomal 21-hydroxylase, with an apparent Ki of 110 microM. Cotinine, in concentrations as high as 1 mM, did not inhibit 21-hydroxylase. These results suggest that nicotine and cotinine inhibit 11 beta-hydroxylase by binding to the heme iron of the cytochrome P-450 component of this enzyme system. Inhibition of 11 beta-hydroxylase could contribute to the altered pattern of steroidogenesis observed in smokers.

The effects of insulin and insulin-like growth factors (IGFs) on ovarian androgen production were examined in ovarian stroma obtained from four women with hyperandrogenism and three women without hyperandrogenism. In incubations of stroma obtained from all four hyperandrogenic patients, insulin alone (500 ng/ml) significantly stimulated androstenedione and testosterone release. LH alone (25 ng/ml) significantly stimulated androstenedione release in incubations of stroma obtained from three of the four hyperandrogenic patients and testosterone release in incubations of stroma obtained from one of the four hyperandrogenic patients. In stromal incubations from three of the four hyperandrogenic patients, insulin alone (500 ng/ml) resulted in a significantly greater release of androstenedione and testosterone than did LH alone (25 ng/ml). Dihydrotestosterone was released in measurable quantities in incubations of stromal tissue obtained from three of the four hyperandrogenic women. In all three instances in which dihydrotestosterone was detectable, insulin alone (500 ng/ml), but not LH alone (25 ng/ml), significantly stimulated dihydrostestosterone release. Incubations of stroma obtained from three nonhyperandrogenic, normally cycling women demonstrated low levels of androstenedione release and negligible testosterone and dihydrotestosterone release. Insulin alone (500 ng/ml) and LH alone (25 ng/ml) produced no significant increase in androstenedione release. Insulin (500 ng/ml) plus LH (25 ng/ml) significantly stimulated androstenedione accumulation in stroma obtained from two of the nonhyperandrogenic women. One insulin dose-response experiment was performed using stromal tissue obtained from a hyperandrogenic woman. In this experiment, insulin, at a dose of 50 ng/ml, was as effective as insulin at a dose of 500 ng/ml in stimulating androstenedione and testosterone release. In addition to insulin, IGF-I/somatomedin C (50 ng/ml) stimulated androstenedione and testosterone release. Relaxin (1 microgram/ml) and multiplication-stimulating activity (50 ng/ml) did not stimulate androstenedione and testosterone release. These studies suggest that human ovarian stroma may be a target tissue for insulin and IGF-I, and that hyperinsulinemia may be an important factor contributing to ovarian hyperandrogenism.

The interaction of 19-norethindrone [4-estren-17 alpha-ethinyl-17 beta-ol,3-one (NET)] with human placental microsomes was investigated using enzymatic and spectral techniques. The incubation of [6,7-3H]norethindrone with human placental microsomes, NADPH, and molecular oxygen resulted in the production of ethinyl estradiol [1,3,5-(10)estratrien-17 alpha-ethinyl-3,17 beta-diol (EE)]. The reaction was linear with respect to time and protein concentration. Androstenedione inhibited the enzymatic aromatization of NET to EE. The product was identified by thin layer chromatography, recrystallization to constant specific activity, and derivative formation. No acid or base was used in any step of product identification. To ensure that spontaneous aromatization of metabolites of NET did not contribute to our results, representative samples were treated with sodium borohydride before processing. Sodium borohydride reduces the 4-en-3-one grouping of the A-ring, thereby preventing chemical aromatization. Sodium borohydride treatment did not reduce our observed yields of EE from NET. The addition of NET to a preparation of solubilized, partially purified placental microsomal cytochrome P-450 yielded a type I cytochrome P-450 binding spectrum. The apparent spectral dissociation constant for NET binding to cytochrome P-450 was 28 microM. These results suggest that NET is enzymatically aromatized to EE by human placental microsomes.

We monitored the estrogen metabolism and menstrual function of two groups of elite oarswomen as they progressed from a phase of low intensity training (phase I), to high intensity training (phase II), and back to low intensity training (phase III). Each phase lasted 3 months. The two groups of oarswomen included five oarswomen (group A) who experienced no menstrual dysfunction during the training year, even during the phase of high intensity training, and five oarswomen (group B) who experienced normal menses during phases of low intensity training but disrupted menses during the phase of high intensity training. Four nonathletic controls were also studied. Menstrual function was monitored throughout the training year by assay for pregnanediol glucuronide in overnight 12-h urine samples collected twice weekly. Repeated measures of the extent of estradiol metabolized by 2-hydroxylase oxidation, total body water, and nutrient intake of group A and B oarswomen were made at the three phases of the training year; the extent of estradiol metabolized by 2-hydroxylase oxidation was evaluated by radiometric analysis; total body water was measured by deuterium oxide dilution and bioimpedance analysis; and nutrient intake was evaluated by food frequency questionnaire. The group B oarswomen were found to metabolize a significantly greater fraction of administered [2-3H]estradiol by 2-hydroxylase oxidation than group A oarswomen (chi 2(1) = 6.57; P = 0.01). The extent of estradiol metabolized by 2-hydroxylase oxidation among group A oarswomen did not differ from that among nonathletic controls. The extent of 2-hydroxylase activity did not change significantly with the intensity of training among either group A or group B oarswomen. Oarswomen in groups A and B lost body weight and became leaner during the phase of high intensity training (phase II). Group A and B oarswomen did not differ in the degree of weight loss or in relative fatness during phase II. Over all subjects, the extent of estradiol metabolized by 2-hydroxylase oxidation was positively correlated with the extent of leanness. These data suggest that elevated estradiol 2-hydroxylase oxidation among elite oarswomen is associated with the occurrence of menstrual disturbances during phases of high intensity training and increased relative leanness.