Increased circulating levels of immunoreactive beta-endorphin in polycystic ovary syndrome is not caused by increased pituitary secretion.

OBJECTIVE: Our purpose was to investigate the source and role of elevated levels of immunoreactive beta-endorphin in polycystic ovary syndrome. We wished to determine whether immunoreactive beta-endorphin secretion in patients with polycystic ovary syndrome is influenced by body weight and whether the pituitary release of immunoreactive beta-endorphin with corticotropin-releasing hormone is related to luteinizing hormone levels or adrenal androgen secretion. STUDY DESIGN: Eighteen patients with polycystic ovary syndrome and 10 ovulatory controls were studied. Each subject received 1 microgram/kg intravenous corticotropin-releasing hormone and an oral glucose tolerance test on alternate days. Levels of plasma immunoreactive beta-endorphin, corticotropin, luteinizing hormone, cortisol, adrenal androgens, and insulin were measured. RESULTS: Although immunoreactive beta-endorphin levels were elevated in patients with polycystic ovary syndrome (p < 0.01), incremental responses after corticotropin-releasing hormone were similar to controls and were not influenced by body weight. Serum luteinizing hormone levels were not affected by corticotropin-releasing hormone and did not correlate with immunoreactive beta-endorphin levels. Adrenal androgen responses after corticotropin-releasing hormone were increased in patients with polycystic ovary syndrome (p < 0.01) but were not correlated with immunoreactive beta-endorphin secretion. After oral glucose was given, elevated fasting insulin levels increased significantly in patients with polycystic ovary syndrome (p < 0.01), as did immunoreactive beta-endorphin levels (p < 0.05). The increases in insulin and immunoreactive beta-endorphin levels were correlated (p < 0.05). CONCLUSIONS: Pituitary secretion of immunoreactive beta-endorphin is normal in patients with polycystic ovary syndrome, and pancreatic secretion appears to be increased. Corticotropin-releasing hormone does not influence luteinizing hormone levels, and adrenal androgen sensitivity is not influenced by immunoreactive beta-endorphin secretion.

A reevaluation of estrogen status in postmenopausal women who smoke.

Hypoestrogenism in postmenopausal smokers has been suggested as the mechanism for the observed decreased risk of endometrial cancer and increased risk of osteoporosis. We have prospectively studied a well-matched group of smokers and nonsmokers and have evaluated their estrogen levels and compared them with existing data from the literature. We conclude that increased adrenal activity resulting in increased androgens, mainly androstenedione, is seen in postmenopausal smokers but that estrogen levels are not decreased. We hypothesize that in nonusers, unlike in users of estrogen, smoking is not associated with changes in estrogen levels and that other mechanisms must be responsible for the epidemiologic observations seen.

Short-term effects of smoking on the pharmacokinetic profiles of micronized estradiol in postmenopausal women.

Because smoking is associated with an increased risk of osteoporosis, yet a decreased risk of endometrial carcinoma, a state of relative hypoestrogenism induced by smoking has been suggested. However, because previous data are unclear and do not reflect current trends in smoking intensity and estrogen prescriptions, we examined the estrogen profiles of postmenopausal women, by smoking status, both before and after oral micronized estradiol. Baseline levels of estrone, estradiol, estrone sulfate, and estrone glucuronide were similar in nonsmokers and smokers, but unbound (non-sex-hormone-binding-globulin--bound) estradiol was significantly lower in smoking women (p less than 0.05) and sex-hormone-binding-globulin--binding capacity was higher (p less than 0.001). After 1 or 2 mg of micronized estradiol, estrone and estradiol serum profiles were similar but unbound estradiol was significantly lower in women who were smokers (p less than 0.05). Serum estrone glucuronide rose with treatment but was indistinguishable in nonsmokers and smokers. However, maximum changes in serum estrone sulfate were greater in smokers after administration of estrogen, suggesting a hepatic effect. Urinary estrone glucuronide levels increased after 8 hours of oral estrogen but were similar in nonsmokers and smokers with the two doses. It appears that even moderate smoking, as studied here, induces significant changes in hepatic estrogen metabolism and is best reflected by alterations in serum estrone sulfate and sex-hormone-binding-globulin--binding capacity that result in decreased serum unbound estradiol. However, these changes do not appear to require increasing the estrogen dosage to achieve physiologic levels of estrogen in postmenopausal smokers.

Effects of norethindrone on gonadotropin and ovarian steroid secretion when used for cycle programming during in vitro fertilization.

Norethindrone (NET) has been used for cycle programming and may result in attenuated responses to controlled ovarian hyperstimulation. The effects of NET on gonadotropin secretion, its bioavailability to the ovary, and its effect on ovarian steroidogenesis in vivo and in vitro were assessed. Endogenous secretion of luteinizing hormone and follicle-stimulating hormone was attenuated by 59% and 50%, respectively, after 2 weeks of orally administered NET. Twelve hours after a single 10-mg oral dose, significant levels of NET were measured in samples of peripheral (8.8 +/- 1.9 ng/mL) and ovarian venous blood (10.5 +/- 3.1 ng/mL), follicular fluid (7.1 +/- 2.1 ng/mL), and homogenates of ovarian tissue (8.0 +/- 0.6 ng/g). Furthermore, NET was detectable in follicular fluid 2 weeks after its withdrawal (863 +/- 149 pg/mL). However, there were no effects of NET on follicular fluid levels of estradiol and progesterone in vivo or on luteinized granulosa cell steroidogenesis in vitro. We conclude that when used for cycle programming in in vitro fertilization, NET does not inhibit ovarian steroidogenesis but does affect the hypothalamic-pituitary axis.

Rapid measurement of urinary pregnanediol glucuronide to diagnose ectopic pregnancy.

We investigated the ability of a single, random, urinary pregnanediol-3 alpha-glucuronide level to differentiate early intrauterine from ectopic pregnancy. Thirty-four patients with intrauterine gestations were compared with 60 patients with ectopic pregnancies. Urinary pregnanediol-3 alpha-glucuronide was measured by radioimmunoassay and enzyme immunoassay. Compared with intrauterine gestations, results demonstrate that urinary pregnanediol-3 alpha-glucuronide is significantly depressed in ectopic pregnancies: 24.5 +/- 2.2 versus 4.8 +/- 0.7 micrograms/ml (p = 0.0001). Urinary pregnanediol-3 alpha-glucuronide levels obtained by conventional radioimmunoassay correlated closely with values measured in minutes with enzyme immunoassay (r = 0.95, p = 0.0001), and with serum progesterone (r = 0.74, p = 0.0001). Urinary pregnanediol-3 alpha-glucuronide measured by enzyme immunoassay exhibited predictive values for detecting ectopic gestations comparable with random serum progesterone or serum beta-human chorionic gonadotropin values. We conclude that ectopic gestations demonstrate a reduced level of urinary pregnanediol-3 alpha-glucuronide (55/60 cases) detectable with a rapid enzyme immunoassay, which makes this assay a practical screening test in early pregnancy.

Effect of androgen on adrenal steroidogenesis in normal women.

Ovarian hyperandrogenism may induce adrenal enzymatic defects that mimic true inherited disorders of adrenal hormone biosynthesis. To assess the effect of hyperandrogenism on adrenal steroidogenesis, seven normal ovulatory women were studied on 2 days during the early follicular phase of their cycles. Plasma 17-hydroxyprogesterone (17-Prog), 17-hydroxypregnenolone, dehydroepiandrosterone (DHEA), DHEA sulfate, androstenedione (Adione), testosterone (T), 11-deoxycortisol, and cortisol concentrations were measured every 15 min for 3 h after iv injection of 0.25 mg ACTH (day 1) and pretreatment with dexamethasone on each day. On the second study day, T (80 micrograms/h) was infused iv for 5 h, and ACTH was given after 2 h of T infusion. The T infusion raised mean serum T levels from 1.2 +/- 0.3 (+/- SE) to 8.6 +/- 0.6 nmol/L. The maximum incremental (delta max) plasma Adione response to ACTH was significantly higher (2.6 +/- 0.3 to 3.2 +/- 0.4 nmol/L; P less than 0.009) during the T infusion, while the delta max responses of the other steroids did not change. There was an increase in the delta max 17-Prog to cortisol ratio (4.9 +/- 0.7 to 7.0 +/- 1.0; P less than 0.05), but no change in the delta max 17-Prog to Adione or 17-hydroxypregnenolone to DHEA ratios and no changes in the delta max delta 5- to delta 4-steroid ratios. These data suggest that acute T elevations result in subtle inhibition of 21-and/or 11 beta-hydroxylase activities, but not in 17-20-desmolase or 3 beta-ol activities.