Pharmacokinetics of dehydroepiandrosterone and its metabolites after long-term oral dehydroepiandrosterone treatment in postmenopausal women.

OBJECTIVE: Some postmenopausal women use over-the-counter dehydroepiandrosterone because of its purported beneficial effects. Although without major inherent androgenic activity, it is metabolized to potent androgens and estrogens. We investigated the pharmacokinetics of dehydroepiandrosterone and its relevant metabolites after prolonged treatment of postmenopausal women with 25 mg/d of dehydroepiandrosterone. METHODS: Twenty healthy postmenopausal women were randomized to either 25 mg/d of dehydroepiandrosterone or placebo for 6 months. Frequent blood samples were obtained over 24 hours on day 1 and after 3 and 6 months. RESULTS: Mean baseline androgen levels at day 1 and month 3 in the treated group (seven evaluable women) were the following: dehydroepiandrosterone, 1.82 and 3.56 ng/mL; dehydroepiandrosterone sulfate, 0.96 and 3.37 microg/mL; 5-androstene-3beta,17beta-diol, 0.32 and 0.66 ng/mL; androstenedione, 0.50 and 0.86 ng/mL; testosterone, 17.9 and 28.7 ng/dL; dihydrotestosterone, 6.91 and 17.4 ng/dL; and 3alpha-androstanediol glucuronide, 2.66 and 10.7 ng/mL, respectively; these increases were significant. Small changes (-6% to 16%) were observed from month 3 to month 6. Nonsignificant increases were observed in baseline estrone and estradiol levels and in Cmax and AUC0-24h values for the androgens and estrogens from day 1 to months 3 and 6 of treatment. Sex hormone-binding globulin levels were unchanged, but free testosterone increased significantly from day 1 to month 3. Baseline hormone levels did not increase in the placebo group (six evaluable women). Changes in baseline values over time differed significantly between the groups for all hormones except estrone and estradiol. CONCLUSIONS: In postmenopausal women treated orally with a commonly available dose of dehydroepiandrosterone, the daily exposure (AUC) of dehydroepiandrosterone and its principal androgenic metabolites was found to be similar during 6 months of treatment despite increased serum baseline concentrations of these androgens.

Elevated subclinical atherosclerosis associated with oophorectomy is related to time since menopause rather than type of menopause.

OBJECTIVE: To compare common carotid artery intima-media thickness (IMT) between women who had natural menopause with those who had surgical menopause and to correlate IMT with time since menopause. DESIGN: Cross-sectional study. SETTING: University-based research clinic. PATIENT(S): One hundred eighty-nine healthy postmenopausal women who were not on hormone therapy (HT), age 46 to 81 (n = 132, women who did not have a prior hysterectomy or oophorectomy; n = 57, women who had undergone hysterectomy with bilateral oophorectomy). INTERVENTION(S): B-mode ultrasonography of the carotid artery, standardized questionnaires, and fasting blood samples were completed to evaluate the relationship between type of menopause, time since menopause, and subclinical atherosclerosis. MAIN OUTCOME MEASURE(S): Carotid artery IMT. RESULT(S): Mean (SEM) carotid artery IMT measurements were 0.74 (0.01) mm among women experiencing natural menopause and 0.81 (0.02) mm among women having bilateral oophorectomy (P=.02). After adjusting for years since menopause, the mean IMT did not differ between the two groups (0.77 [0.01] mm among natural menopause and 0.76 [0.02] mm among bilateral oophorectomy groups). The age-adjusted carotid IMT was significantly positively associated with years since menopause (P=.02). CONCLUSION(S): Earlier menopause is associated with elevated subclinical atherosclerosis. Because they have on average far earlier menopause, women with bilateral oophorectomy have elevated subclinical atherosclerosis compared with women of similar age who had natural menopause.

Monozygotic twins and triplets in association with blastocyst transfer.

PURPOSE: To compare the incidence of monozygotic twins following blastocyst versus day-3 embryo transfer (ET). METHODS: A retrospective analysis of the outcome of assisted reproductive technology (ART) cycles utilizing blastocyst ET during 1999-2000 was compared to a similar group of patients undergoing day-3 ET during 1997-1998. RESULTS: Blastocyst ET was used in 75 cycles with 2.0 +/- 2 embryos transferred. The comparison group consisted of 90 cycles with day-3 ET and 3.0 +/- 2 embryos transferred. CONCLUSIONS: High pregnancy rates are maintained with blastocyst ET even though fewer embryos are transferred. The rate of monozygotic twins is higher with blastocyst ET than with day-3 ET. This increase may partially negate the benefit of reduced high-order multiple gestations attributed to blastocyst ET.

Accelerated endometrial maturation in the luteal phase of cycles utilizing controlled ovarian hyperstimulation: impact of gonadotropin-releasing hormone agonists versus antagonists.

OBJECTIVE: To evaluate the endometrium obtained during the luteal phase of controlled ovarian hyperstimulation (COH) cycles utilizing gonadotropin-releasing hormone (GnRH) antagonists, and to compare these findings with those obtained in cycles utilizing a GnRH agonist and with artificial cycles among recipients. DESIGN: Prospective evaluation of oocyte donors. SETTING: University-based in vitro fertilization (IVF) center. PATIENT(S): Fifteen oocyte donors undergoing standard COH were enrolled in 1 of 3 COH groups, and 40 recipients of oocyte donation were used as a control group. INTERVENTION(S): Controlled ovarian hyperstimulation and endometrial biopsy. MAIN OUTCOME MEASURE(S): Histological dating of endometrial biopsies, serum estradiol (E(2)) and progesterone levels. RESULT(S): On the day of oocyte retrieval, endometrial maturation was advanced by an average of 5.8 +/- 0.4 days in the antagonist group and 5.9 +/- 0.7 days in the agonist group. This advancement persisted on day 7 postoocyte retrieval. Serum progesterone levels were elevated before human chorionic gonadotropin (hCG) administration, but remained similar in both groups. CONCLUSION(S): Controlled ovarian hyperstimulation is associated with elevated progesterone levels in the late follicular phase and accelerated endometrial maturation in the subsequent luteal phase. No significant differences exist between preretrieval serial serum progesterone levels and luteal phase endometrial histology between cycles utilizing GnRH agonists or antagonists.

Treatment-associated serum FSH levels in very poor responders to ovarian stimulation.

PURPOSE: To compare treatment-associated follicle-stimulating hormone (FSH) response in patients undergoing controlled ovarian hyperstimulation with either microdose flare (MDF) leuprolide acetate or clomiphene citrate and human menopausal gonadotropin (CC/hMG). METHODS: Thirteen patients who were deemed poor responders underwent stimulation with one of two poor responder stimulation protocols (MDF group: n = 8; CC/hMG group: n = 5). Serum FSH, estrone (E1), estrone sulfate (E1S), and estradiol (E2) levels were measured at baseline, day 5 of medication, and on day of hCG administration. Ovarian and uterine responses were evaluated by ultrasound. RESULTS: Treatment-associated FSH levels were consistently higher in the group that took CC/hMG. However, serum E1, E1S, and E2 values were similar in both groups as were the number of oocytes retrieved and the endometrial echo complex. There were no differences between the two groups with regards to the quality of the oocytes obtained, fertilization rate, or the quality of the embryos. CONCLUSION: Clomiphene citrate, when administered in conjunction with exogenous hMG, is a more potent stimulator of FSH production than MDF leuprolide acetate among poor responders to ovarian stimulation. However, the number of oocytes is not increased.

Does elevated body mass modify the influence of postmenopausal estrogen replacement on atherosclerosis progression: results from the estrogen in the prevention of atherosclerosis trial.

OBJECTIVE: To determine whether the estrogen-related reduction in atherosclerosis progression demonstrated in the estrogen in the prevention of atherosclerosis trial (EPAT) is modified by body mass index (BMI). STUDY DESIGN: Subgroup analyses were performed using data from EPAT, a randomized, double-blind, placebo-controlled trial designed to determine whether unopposed 17beta-estradiol administered for a 2-year treatment period reduces the progression of subclinical atherosclerosis in healthy postmenopausal women. The primary trial endpoint was the rate of change of common carotid artery intima-media thickness (IMT). In this subgroup analysis, the sample was divided into 122 women with BMI<30 kg/m(2) and 77 women with BMI> or =30 kg/m(2). Statistical analysis was performed using mixed general linear models to evaluate whether the treatment effects on IMT progression rates differed in the two BMI groups. RESULTS: There was no significant difference in the estradiol treatment effect on IMT progression rates between postmenopausal women with BMI<30 vs. > or =30 kg/m(2) (P=0.52). In the 77 subjects who did not use lipid-lowering therapy, there was significant improvement in IMT with estradiol treatment that was evident in both BMI groups (P=0.48 for differences between BMI groups). CONCLUSIONS: In contrast to the epidemiological observation that obese postmenopausal women do not derive benefit from estrogen replacement therapy, results of this study indicate that estradiol treatment is beneficial in preventing progression of atherosclerosis regardless of initial BMI. CONDENSATION: Estradiol treatment is beneficial in preventing progression of atherosclerosis in postmenopausal women not receiving lipid-lowering therapy, regardless of their initial body mass index.

Pregnancy in the sixth decade of life: obstetric outcomes in women of advanced reproductive age.

CONTEXT: As a result of oocyte donation, women in their sixth decade of life are now able to conceive and carry pregnancies to term. However, little is known about pregnancy outcomes in this population. OBJECTIVE: To describe pregnancy outcomes in women aged 50 years or older who conceived after in vitro fertilization with donor oocytes. DESIGN AND SETTING: Retrospective analysis of cycles conducted at a US university assisted reproduction program during calendar years 1991-2001. PATIENTS: Seventy-seven postmenopausal women with no chronic medical conditions (mean [SD] age, 52.8 [2.9] years; range, 50-63 years) who underwent 121 embryo transfer procedures (89 fresh and 32 frozen). Pregnancy outcomes were ascertained by chart review and telephone follow-up. MAIN OUTCOME MEASURES: Maternal and neonatal outcomes. RESULTS: There were 55 clinical pregnancies for a total pregnancy rate of 45.5%. The live birth rate was 37.2%. Of the 45 live births, 31 were singletons, 12 were twins, and 2 were triplets, for which the mean (SD) gestational ages at delivery were 38.4 (2.1) weeks, 35.8 (2.8) weeks, and 32.2 weeks, respectively. Mean (SD) birth weights were 3039 g (703 g), 2254 g (581 g), and 1913 g, respectively. Apgar scores at 1 and 5 minutes were 8.2 (0.9) and 9.1 (0.5), respectively. Of singletons, 68% were delivered by cesarean, and all multiples were delivered by cesarean. Mild preeclampsia was noted in 25% of patients and severe preeclampsia in 10%. Gestational diabetes required diet modification in 17.5%, and 2.5% required insulin. CONCLUSIONS: Appropriately screened women aged 50 years or older can successfully conceive via oocyte donation and experience similar pregnancy rates, multiple gestation rates, and spontaneous abortion rates as younger recipients. During pregnancy, they appear at increased risk of preeclampsia and gestational diabetes. A majority can expect to deliver via cesarean. However, there does not appear to be any definitive medical reason for excluding these women from attempting pregnancy on the basis of age alone.