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Objective: This study was undertaken to evaluate the efficacy of metformin in women with anovulation who do not have evidence for hyperandrogenism and classic polycystic ovary syndrome. Study design: A randomized trial of metformin (1500 mg daily) and placebo in 24 anovulatory women was undertaken for 3 months. Assessments of changes in hormone levels and insulin sensitivity were carried out. Abnormal ormonal values were defined by levels exceeding the range in normal ovulatory controls. Results: Anovulatory women had normal androgen levels and luteinizing hormone but had higher serum insulin and lower insulin sensitivity compared with controls. Over 3 months, there were 16 ovulatory cycles with metformin and only 4 with placebo (P

Our purpose was to compare the pharmacokinetic parameters of oral administration of a 35 micrograms ethinyl estradiol, 1 mg norethindrone pill in peritoneal dialysis patients and normal women.A single-dose study was performed with five patients and four controls, followed by a multiple-dose study with five subjects in each group. Pharmacokinetic parameters were calculated by noncompartmental analysis and statistical analysis performed with Mann-Whitney U testing.There is no difference in the pharmacokinetic parameters for norethindrone in peritoneal dialysis patients compared with normal women. During multiple dosing an increased area under the concentration curve and decreased apparent oral clearance was observed for ethinyl estradiol in peritoneal dialysis patients compared with normal women.Peritoneal dialysis patients have decreased apparent oral clearance of ethinyl estradiol, leading to slightly higher serum concentrations compared with women with normal renal function. The clearance of norethindrone is the same in peritoneal dialysis patients and normal women.In a single-dose and multiple-dose study, gynecologists from California, North Carolina, and Texas, compared pharmacokinetic parameters of the low dose oral contraceptive (OC), Ortho-Novum 1/35, (35 mcg ethinyl estradiol and 1 mg norethindrone) in premenopausal women with renal failure on peritoneal analysis and in age and weight matched controls. They used Mann-Whitney U testing and noncompartmental analysis to calculate pharmacokinetic parameters. In the multiple-dose study, peritoneal dialysis patients had higher serum levels of ethinyl estradiol than did controls 2, 3, and 12 hours after dosing (p .05). In the same study, no significant differences in norethindrone levels existed, however. Ethinyl estradiol levels were not significantly different between the cases and controls in the single-dose study. In the multiple-dose study, the dialysis patients had a much lower apparent oral clearance and a higher area under the concentration curve than did the controls (296.1 ml/hr x kg vs. 525.8 ml/hr x kg and 1930.2 pg/ml x hr vs. 1071.4 pg/ml x hr, respectively, p = .02). For pharmacokinetics of ethinyl estradiol, multiple dosing significantly increased the elimination of half-life, area under the curve, and mean residence time in both controls and dialysis patients. As for norethindrone, no significant difference between cases and controls in any pharmacokinetic parameter occurred in both the single- and multiple-dose studies. For norethindrone in cases and controls, the area under the curve and the maximum serum concentration increased with multiple dosing. Multiple dosing significantly decreased the clearance/bioavailability of norethindrone in both cases and controls. It increased greatly the mean residence time in dialysis patients. These findings indicated that physicians may administer a low dose OC to peritoneal dialysis patients to manage dysfunctional uterine bleeding or to prevent hypoestrogenemia.

OBJECTIVE: Our purpose was to determine the pattern of reactivity to stress in premenopausal and postmenopausal women and to assess the effects of estrogen. STUDY DESIGN: A behavioral stress test was given to premenopausal ( n = 13) and postmenopausal women ( n = 36). Biophysical and neuroendocrine responses were measured during and on completion of the stress test. The postmenopausal women were then randomized to placebo or transdermal estradiol treatment for 6 weeks, at which time another behavioral stress test was given. RESULTS: Stress reactivity to math and speech tasks elicited significantly greater systolic blood pressure responses in postmenopausal women compared with premenopausal women ( p \lt 0.05). On retesting, significant biophysical responses that were present during the initial stress testing were still present ( p \lt 0.05) in the placebo group but were blunted with estrogen treatment. Plasma corticotropin, cortisol, androstenedione, and norepinephrine increased during testing to a similar degree in premenopausal and postmenopausal women; this response was maintained after placebo treatment. Postmenopausal women treated with estrogen had blunted responses. CONCLUSION: Significant differences in responses to psychologic stress exist in premenopausal and postmenopausal women. The lack of adaptation may account in part for the increased risk of cardiovascular disease in postmenopausal women. Estrogen appears to blunt the stress-induced response. (AM J OBSTET GYNECOL 1992;167:1831-6.)

The gonadotropin-releasing hormone antagonist offers several advantages over the use of the agonist and allows several physiologic questions to be addressed. In this study, we evaluated the ability of Nal-Glu to acutely inhibit the luteinizing hormone surge and prevent ovulation. We also assessed whether recovery of the follicle would be possible after several days of gonadotropin deprivation and estradiol decrement. Eight normal ovulatory women were randomized to control or Nal-Glu-treated cycles (50 micrograms/kg intramuscularly) for 3 to 4 days. Monitoring was carried out with daily vaginal ultrasonographic scans and serum estradiol levels and twice-daily serum luteinizing and follicle-stimulating hormone levels. Nal-Glu acutely inhibited the luteinizing hormone surge and ovulation, even when administered as late as the onset of the luteinizing hormone surge. Evidence was provided that spontaneous follicular rescue recurred in eight of 10 cycles after 3 to 4 days of Nal-Glu administration. Although an estradiol to follicular size dissociation occurred with Nal-Glu, subsequent ovulation occurred in 5.1 +/- 0.6 days after the last Nal-Glu dose. The decrement in estradiol after Nal-Glu administration correlated negatively with the days required for subsequent ovulation to occur (r = 0.77, p less than 0.05). The subsequent luteal phase also was normal in terms of length and progesterone levels. These data confirm the potency and efficacy of Nal-Glu in acutely inhibiting gonadotropins and extends our knowledge on the physiologic characteristics of the dominant follicle.

In the clinical practice of human in vitro fertilization, pregnancy is dependent on embryo implantation. Pregnancy is a function of the number of embryos transferred, with multiple embryos resulting in a higher likelihood of pregnancy. We formulated a mathematic model of embryo implantation. This model describes embryo implantation as dependent on three factors--transfer efficiency, embryo quality, and endometrial receptivity. Application of existing embryo implantation data to this model allows the calculation of the approximate value of each of these factors. On the basis of historic data, data obtained from our in vitro fertilization program, and these theoretic considerations, it is our hypothesis that (1) there is an inherent inefficiency associated with the mechanical transfer of embryos into the uterine cavity, which limits the maximal embryo implantation rate; (2) the quality of embryos produced by controlled ovarian hyperstimulation, follicle aspiration, and in vitro fertilization is very high and approaches that of embryos produced in natural cycles in vivo; and (3) endometrial receptivity is markedly diminished in stimulated cycles and is the current rate-limiting step of pregnancy success of in vitro fertilization.

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.

Mifepristone (RU 486), a synthetic steroid with antiprogesterone receptor activity, was given with and without naloxone hydrochloride to six women in the midluteal phase to investigate the role of progesterone in the modulation of endogenous opioid activity and the secretion of luteinizing hormone and cortisol. Subjects were evaluated during four sequential monthly admissions during which multiple blood samples were obtained every 15 minutes for 8 hours. Patients were studied during a baseline cycle, after administration of RU 486 alone (100 mg/day), naloxone with RU 486, and naloxone alone. After administration of RU 486 there was a significant decline in total luteinizing hormone secretion (p less than 0.01) and luteinizing hormone pulse amplitude (p less than 0.05), but compared with baseline there was no significant change in luteinizing hormone pulse frequency. After infusion of naloxone there was a significant increase in mean luteinizing hormone values (p less than 0.05) and luteinizing hormone pulse frequency (p less than 0.01) but no change in pulse amplitude. There was no significant difference in mean luteinizing hormone values or luteinizing hormone pulse amplitude and frequency between administration of RU 486 and naloxone plus RU 486. Administration of naloxone alone, RU 486 alone, and RU 486 plus naloxone caused a significant increase in cortisol as compared with baseline cycles (p less than 0.05). These data further support the notion that progesterone is important in the control of luteinizing hormone secretion and suggest that progesterone may primarily influence luteinizing hormone pulse amplitude and pituitary release of luteinizing hormone during the luteal phase.

Objective: Metabolic syndrome (MBS) is a significant health care problem in postmenopausal women and is driven largely by obesity. We wished to assess the prevalence of insulin resistance (IR), diagnosed using practical methods, and whether several adipocyte factors (adiponectin, leptin, resistin) or the gastric peptide ghrelin, associated with cardiovascular risk, might be abnormal and may relate to IR. Study design: We evaluated 37 obese postmenopausal women with MBS and 34 matched obese premenopausal controls, as well as 14 non-obese premenopausal controls. We measured fasting glucose and insulin, performed 75g 2 hr oral glucose tolerance and intravenous insulin tolerance tests to assess IR, and measured fasting lipids, adiponectin, leptin, resistin and ghrelin. Results: The kinetic decline in glucose after insulin (kITT) as a marker of IR was the most frequently abnormal test (abnormal in 81%), with QUICKI, HOMA, and a modification of the Matsuda-DeFronzo index (ISIM) abnormal in 76, 73, and 68%, respectively. The GIR was abnormal in only 35% of subjects. Leptin and resistin were elevated and adiponectin and ghrelin were decreased in the postmenopausal women, compared to both groups of premenopausal controls. BMI correlated strongly with markers of insulin resistance as well as adipocytokine values. After controlling for BMI, only leptin was predictive of ISIM. Conclusion: Being overweight after menopause results in worsening IR and elevations in adipocytokine levels. While BMI is the most important factor, abnormal adipocytokine secretion may enhance IR and increase cardiovascular risk in postmenopausal women. 2006 Mosby, Inc. All rights reserved.

The purpose of this study was to determine whether parameters of ovarian blood flow distinguish between women with polycystic ovary syndrome (PCOS) who ovulate and those who are anovulatory.This was a prospectively enrolled trial, carried out as a cross-sectional comparison of 12 ovulatory patients with PCOS and 20 matched subjects with classic PCOS and 10 healthy control subjects. Hormonal parameters and ovarian blood flow by color flow Doppler imaging were obtained in the early follicular phase.Characteristic elevations in luteinizing hormone (LH) and androgens were found in both groups with PCOS compared with control groups. Women with anovulatory PCOS had high insulin levels and lower Quantitative Insulin-Sensitivity Check Index (QUICKI) values compared with women with ovulatory PCOS, although both groups had values that were different from healthy control subjects (P.01). Ovarian volume was similar in the two groups with PCOS, but pulsatility and resistance indices were lower in anovulatory PCOS (P.01) compared with ovulatory PCOS and control subjects, who had similar findings. Insulin correlated negatively with the resistance index and QUICKI correlated positively (r=0.653, P.01). There was a negative correlation between the resistance index and unbound testosterone (r=-0.5, P.05).These data suggest that differences in ovarian blood flow in anovulatory versus ovulatory women with PCOS and that hormonal factors, including insulin resistance, may influence this relationship. The alterations in blood flow in anovulatory PCOS may contribute toward or result from anovulation.

OBJECTIVE: Our purpose was to examine the effect of the recipient's age on pregnancy and miscarriage rates after oocyte donation. STUDY DESIGN: A retrospective analysis of 307 consecutively performed donor oocyte cycles was undertaken. Recipients were divided into two groups: younger group ≤ 42 years old (155 cycles) versus older group >42 years old (145 cycles). Pregnancy outcomes between groups were compared. Confounding variables such as donor and cycle characteristics, recipient characteristics, and made parameters were also examined. RESULTS: Both groups had the same incidence (6%) of failed fertilization cycles. At least one embryo undertaken. Recipients were divided into two groups: younger group ≤ 42 years old (155 cycles) versus older group >42 years old (145 cycles). Pregnancy outcomes between groups were compared. Confounding variables such as donor and cycle characteristics, recipient characteristics, and male parameters were also examined. RESULTS: Both groups had the same incidence (6%) of failed fertilization cycles. At least one embryo was transferred in the remaining 286 cycles. Ongoing or delivered pregnancy rates per embryo transfer were similar for younger and older groups (30.2% vs 30.6%). Differences in miscarriage rates were not statistically significant (9.8% vs 16.3%). There were no differences in the cycle parameters related to donor age, number of oocytes aspirated, number of oocytes fertilized, and number of embryos transferred. Donor sperm was more frequently utilized in the older group (19 vs 4 cycles, p = 0.0002). In the remaining cycles male partners of older recipients were significantly older (37.9 ± 0.5 years vs 43.9 ± 0.6 years, p < 0.0001), but there were no differences in semen parameters or fertilization rates. Older recipients were more likely to be parous but also to have experienced a previous miscarriage. CONCLUSION: Recipient age does not adversely affect cycle outcome with donor oocytes. This implies that aging of the uterus is not of clinical significance to patients electing this method of infertility treatment.

The present review addresses some of the new knowledge regarding the physiology and mechanisms of action of hormonal contraceptives. Specific topics that are discussed include oral contraceptives, intravaginal rings, long-term contraception, gonadotropin-releasing hormone agonists and antagonists, and antiprogestins. It has been shown that in combined oral contraceptives, lower doses of the new progestins (desogestrel, norgestimate, and gestodene) can be used to inhibit ovulation compared with norethindrone and levonorgestrel. In addition, lower doses of ethinyl estradiol are now used with progestins. Estrogen has been added to intravaginal rings containing levonorgestrel or norethindrone acetate to reduce frequency of bleeding. A new ring containing 3-keto-desogestrel is under evaluation. The use of subdermal implants containing levonorgestrel is currently a popular and highly effective method of long-term contraception. Studies show that gonadotropin-releasing hormone agonists and antagonists can provide ovarian suppression, and antiprogestins such as RU486 effectively block the midcycle gonadotropin surge. These and other novel methods of hormonal contraception are still years away from general use.The actions of progestins largely determine the contraceptive efficacy of hormonal contraceptives (e.g., oral contraceptives [OCs]), while the estrogenic component primarily controls bleeding. Progestin contraceptive agents are derived from progesterone and testosterone. Little is known about the metabolism of norethindrone (NET), levonorgestrel (LNG), and their derivatives in OC users. The bioavailability of gestodene, LNG, 3-keto-desogestrel, and NET is about 100%, about 100%, 75%, and 65%, respectively. The mean binding of sex hormone binding globulin is 75% for gestodene, 50% for LNG, and 30-35% for 3-keto-desogestrel and NET. LNG and its derivatives appear to have a progestational potency 5-10 times that of NET. The new progestins inhibit ovulation at lower doses than do LNG and NET. Low doses of progestins thicken cervical mucus, inhibit spinnbarkeit, prevent sperm penetration, reduce the karyopyknotic index, and suppress endometrial glands. The bioavailability of ethinyl estradiol (EE2) is 40-50%. Oral EE2 is more than 200 times more potent than estradiol. Progestins and estrogens work synergistically to inhibit ovulation. They interfere with release of gonadotropin releasing hormone (GnRH) from the hypothalamus and suppress gonadotropin-producing cells of the pituitary. Progestin only and combined steroid-releasing vaginal rings are an effective method that the user can initiate and terminate herself. Problems include breakthrough bleeding, expulsion, and interference with coitus. Injectable contraceptives (depot medroxyprogesterone acetate) and subdermal contraceptive implants (levonorgestrel) are effective, long acting methods. GnRH agonists and antagonists can suppress ovulation, but often cause hypoestrogenism. They cannot be delivered orally. RU-486, an antiprogestin, interrupts early pregnancy.

We determined the independent effects of various doses of ethinyl estradiol used in oral contraceptives or norethindrone acetate, as well as their combination, on insulin sensitivity in normal women.Thirty-three normal ovulatory female volunteers were recruited for this study. Insulin tolerance tests were performed after carbohydrate loading to determine the kinetic disappearance of glucose and insulin. After initial testing the women were randomized into four groups: ethinyl estradiol 20 micrograms, 35 micrograms, and 50 micrograms and norethindrone 1 mg. Insulin tolerance tests were repeated after 1 month of treatment and again after a second month, when all ethinyl estradiol groups received the addition of norethindrone 1 mg to their doses of ethinyl estradiol. Plasma glucose and insulin were measured, and insulin sensitivity (K(itt) glucose) and the disappearance of insulin (K(itt) insulin) were calculated.All groups were comparable at baseline, and no significant changes in fasting glucose and insulin were evident with treatment. After ingestion of 50 micrograms ethinyl estradiol the K(itt) glucose value decreased significantly (p0.03) and ingestion of 20 micrograms and 35 micrograms showed individual changes, but as groups the changes were not statistically significant. All ethinyl estradiol groups combined had a significant decrease in K(itt) glucose (p0.01). Norethindrone 1 mg alone did not change K(itt) glucose values, and after the addition of norethindrone to ethinyl estradiol, K(itt) glucose values normalized. K(itt) insulin values were also lower with treatment but were lower with ethinyl estradiol plus norethindrone compared with ethinyl estradiol alone (p0.04), suggesting an attenuation of insulin clearance with the progestin.Ethinyl estradiol alone decreases insulin sensitivity, and this may occur at lower doses, but norethindrone 1 mg does not appear to do so. However, progestins may alter insulin clearance.In southern California, reproductive endocrinologists compared data on 3 normal ovulatory 19-42 year old women blindly randomized into 4 groups to determine the independent effect of ethinyl estradiol and norethindrone acetate, both of which are in oral contraceptives, on glucose tolerance and insulin sensitivity. They used the most simple and rapid of the alternatives to the oral glucose tolerance test--the insulin tolerance test. Women received either 20 mcg/day, 35 mcg/day, or 50 mcg/day of ethinyl estradiol or 1 mg/day of norethindrone acetate. For the 2nd month, all women using ethinyl estradiol also received 1 mg/day of norethindrone acetate. The women in all 4 groups had comparable plasma glucose and insulin values while fasting. Estrogen in the 3 contraceptive doses reduced insulin sensitivity (p 0.03). The effect was not significant at 20 mcg and 35 mcg ethinyl estradiol, but 22.2% and 14.3% of the women receiving 20 mcg and 35 mcg ethinyl estradiol, respectively, did experience some reduction in insulin sensitivity. One mg norethindrone acetate alone did not affect insulin sensitivity, but when it was administered with 50 mcg ethinyl estradiol, insulin sensitivity values returned close to normal. 35 mcg of ethinyl estradiol lowered insulin clearance values (19.17% min vs. 9.53%/min; p 0.03). Addition of 1 mg norethindrone acetate to all ethinyl estradiol groups resulted in even more of a reduction (10.58%/min vs. 8/81%/min; p 0.04), indicating that a progestin reduces insulin clearance. In conclusion, ethinyl estradiol, even at low doses, appears to decrease insulin sensitivity while progestins do not. Yet, progestin appear to affect insulin clearance.

Women with hypertension, angina pectoris, or mitral valve prolapse require special considerations when selecting an appropriate method of contraception. All three effective, reversible options (oral contraceptives, intrauterine devices, or progestin implants) carry some degree of added risk for these patient populations. However, pregnancy itself presents certain risks and, in the event of contraceptive failure, certain women with these disorders are at increased risk of developing serious cardiovascular sequelae that affect both mother and fetus. These negative effects can carry far into the neonatal period. This article describes the risk/benefit profiles of the currently available contraceptive options relative to their potential impact in these compromised women.Physicians should be concerned about contraception for women with mitral valve prolapse (MVP), hypertension, and angina pectoris, because pregnancy places an extra burden on the cardiovascular system (e.g., about 50% rise in blood volume and cardiac output and a large increase in extravascular fluid) and the chosen contraceptive method could cause adverse circulatory effects. Nonpregnant hypertensive should be treated with hygienic measures (e.g., weight reduction and restriction of sale) before physicians prescribe drugs (e.g., diuretics and beta blockers). Oral contraceptives (OCs) tend to induce only small increases in blood pressure. Further, hypertension in women causes less target organ damage than it does in men in the same age group. Therefore, OC use in nonsmoking, hypertensive women has little clinical effect, although physicians should monitor their blood pressure of these patients. Safe alternative contraceptives are progestin-only OCs and the IUD. MVP usually has benign clinical symptoms, so it generally does not pose a risk during pregnancy. Coagulation problems do occur, however, in a small number of MVP patients, thereby making those who use Ocs more vulnerable to thromboembolism. As long as an MVP patient does not have clinical symptoms (e.g., mitral regurgitation) or does not smoke, she can use OCs. MVP patients can use the IUD, but those with mitral regurgitation should take antibiotics during insertion to avoid systemic infection. Pregnant women with true angina are at increased risk of myocardial infarction (MI). Women who experience MI during pregnancy face an infant mortality rate of 34%. Women with angina and no other risk factors can use OCs, especially because of their potential antiatherosclerotic effect. The IUD and progestin implants are safe and effective contraceptive choices for women with angina caused by coronary atherosclerosis. In many women with cardiovascular conditions, the risk of pregnancy is frequently greater than the risks linked to contraceptive use.

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.

To determine whether the adrenal androgen 11 beta-hydroxyandrostenedione is a more sensitive and specific marker than dehydroepiandrosterone sulfate, we compared these serum androgens in 81 women with anovulatory hyperandrogenism before treatment, after corticotropin and corticotropin-releasing-factor stimulation, and after short- and long-term dexamethasone suppression. Of all subjects, 65% and 57% had elevated levels of 11 beta-hydroxyandrostenedione (greater than 2.0 ng/ml) and dehydroepiandrosterone sulfate (greater than 2.8 micrograms/ml), respectively. However, 11 beta-hydroxyandrostenedione and dehydroepiandrosterone sulfate levels did not correlate in either the women with hyperandrogenism (r = 0.12) or the 26 normal women (r = 0.29). After 0.25 mg corticotropin was administered intravenously (n = 16), 11 beta-hydroxyandrostenedione increased by 157% +/- 53% (mean +/- SEM), whereas dehydroepiandrosterone sulfate, androstenedione, dehydroepiandrosterone, and cortisol increased by 6% +/- 2%, 46% +/- 10%, 416% +/- 80%, and 2326% +/- 371%, respectively. After intravenous administration of 100 micrograms corticotropin-releasing factor to eight patients, the percent change from baseline level to peak was 148% +/- 26%, 24% +/- 5%, 61% +/- 15%, 117% +/- 15%, and 116% +/- 18% for 11 beta-hydroxyandrostenedione, dehydroepiandrosterone sulfate, androstenedione, dehydroepiandrosterone, and cortisol, respectively. After 2 mg dexamethasone for 3 days (n = 10), 11 beta-hydroxyandrostenedione, dehydroepiandrosterone sulfate, androstenedione, and testosterone were suppressed by 95% +/- 2%, 74% +/- 3%, 51% +/- 9%, and 32% +/- 9%, respectively. Suppression with 0.5 mg dexamethasone for 3 months lowered 11 beta-hydroxyandrostenedione and dehydroepiandrosterone sulfate levels equally by 50% +/- 14% and 62% +/- 12%, respectively. 11 beta-Hydroxyandrostenedione is a useful marker of adrenal androgen secretion with a calculated sensitivity and specificity greater than that of dehydroepiandrosterone sulfate. The greater sensitivity of 11 beta-hydroxyandrostenedione over dehydroepiandrosterone sulfate to adrenal stimulation and suppression suggests its unique diagnostic use.

The agonistic effect of the gonadotropin-releasing hormone agonist often necessitates an extended period of treatment, resulting in a longer treatment cycle and increased cost. We have evaluated the intermittent use of a gonadotropin-releasing hormone antagonist, Nal-Glu, and have designed a new, simplified protocol for its use in in vitro fertilization. Seven women who had previously undergone treatment with leuprolide acetate and human menopausal gonadotropins were treated with Nal-Glu. Leuprolide acetate, 1 mg/day subcutaneously, was administered in the midluteal phase until down regulation was achieved (estradiol less than 30 pg/ml). Human menopausal gonadotropins, three to four ampules per day intramuscularly, was administered in conjunction with 500 micrograms subcutaneous leuprolide acetate. In the treatment cycles Nal-Glu (50 micrograms/kg/day) was administered intramuscularly on cycle day 1 or 2 for 3 days to achieve down regulation. Human menopausal gonadotropins, three to four ampules intramuscularly, was then administered daily without the antagonist. Nal-Glu was resumed when the follicles reached 14 to 16 mm and was continued until the day of human chorionic gonadotropin administration. Compared with leuprolide acetate-human menopausal gonadotropins cycles, the days required for down-regulation with Nal-Glu were significantly shortened (20.6 +/- 4.1 vs 1.6 +/- 0.3 days, p less than 0.001), as was total cycle length (31.3 +/- 5.8 vs 11.0 +/- 1.0 days, p less than 0.01). The mean number of days of treatment with human menopausal gonadotropins, the mean number of ampules of human menopausal gonadotropins, peak estradiol levels, the number of oocytes, and the percent of oocytes fertilized were not statistically different. No luteinizing hormone surges were detected with Nal-Glu in serum or urine. Nal-Glu was well tolerated, and five pregnancies have resulted. We conclude that intermittent administration of Nal-Glu is highly effective in achieving down-regulation and blocking spontaneous luteinizing hormone surges. Compared with leuprolide acetate-human menopausal gonadotropins cycles, an equally high oocyte and embryo yield may be anticipated. This new protocol substantially decreases cycle length and increases patient convenience.

The balance between prostacyclin and thromboxane is known to be important for reproductive and cardiovascular health but has been difficult to quantify. Whereas their stable urinary metabolites, 6-keto-prostaglandin F1 alpha and thromboxane B2, may reflect in part systemic changes, it has been suggested that 2,3-dinor-6-keto-prostaglandin F1 alpha and 11-dehydro-thromboxane B2 more adequately reflect systemic production. Therefore we report for the first time the simultaneous measurements of 6-keto-prostaglandin F1 alpha, thromboxane B2, 2,3-dinor-6-keto-prostaglandin F1 alpha, and 11-dehydro-thromboxane B2 during the menstrual cycle. Timed urine collections were obtained from 18 ovulatory women, aged 22 to 40, during the midfollicular and midluteal phases. Serum estradiol, progesterone, urinary pregnanediol glucuronide, estrone glucuronide, and creatinine also were measured. Prostanoid extraction from urine by C18 and silica Bond Elut columns were then separated by high-performance liquid chromatography before radioimmunoassay. Concentrations of all urinary prostanoids were not significantly different in the follicular phase when compared with the luteal phase. A positive correlation of borderline significance was noted between luteal thromboxane B2 and pregnanediol glucuronide (r = 0.70) and between luteal estrone glucuronide and 2,3-dinor-6-keto-prostaglandin F1 alpha (r = 0.68). A significant correlation was found between follicular estrone glucuronide and the 6-keto-prostaglandin F1 alpha/11-dehydro-thromboxane B2 ratio (r = 0.83, p less than 0.04). These novel normative data suggest an influence of sex steroids on prostacyclin and thromboxane metabolism.

Progestins stimulate prolactin production from endometrial stromal cells in culture. We compared the potencies of the synthetic progestins norethindrone and medroxyprogesterone acetate to natural progesterone in inducing stromal prolactin production. Modifications of the culture system provided an increase in stromal cell yield, thus permitting multiple comparisons from the treatment of cells from a common endometrial sample. The effects of high-dose estradiol also were evaluated in this system. The findings suggest relative potencies of 50:1 for medroxyprogesterone acetate and progesterone. Norethindrone gave intermediate and more variable responses. Estradiol potentiated prolactin production from only submaximal progestins doses. The differences between the progestin effects, in large measure, were due to differential culture growth as reflected by culture mass. Compared to controls and estradiol alone, all the progestins induced much greater prolactin production. Thus during decidualization, progestins probably promote both stromal growth and intracellular prolactin production. High-dose estradiol may not interfere with these events.

This study determines whether pretreatment levels of müllerian inhibiting substance/antimüllerian hormone (MIS/AMH) would reflect ovarian response to exogenous gonadotropin in women with polycystic ovary syndrome (PCOS) and ovulatory controls matched by age and weight.Case-control study of 20 women with PCOS and 10 normoovulatory women undergoing controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF) at an academic medical center.Baseline serum MIS/AMH levels in PCOS were higher than those of normoovulatory women (P.001). MIS/AMH levels increased after gonadotropin-releasing hormone (GnRH) agonist pituitary suppression; 0.5 ng/mL in PCOS (P = .12) and 0.7 ng/mL in controls (P.02). In normoovulatory women, MIS/AMH at baseline, after pituitary suppression, and the interval change after pituitary suppression all correlated closely to the number of mature oocytes retrieved (P.005). In PCOS, however, levels of MIS/AMH at baseline and after pituitary suppression did not show this correlation, whereas only the interval change correlated with the number of mature oocytes retrieved.Baseline MIS/AMH is a good predictor of the ovarian response to COH in normoovulatory women but not in PCOS.