Howard A. Zacur

Ethinyl estradiol acutely attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women.

BACKGROUND Estrogen administration in postmenopausal women is associated with a 50% reduction in the clinical manifestations of coronary artery disease. The mechanisms are not known, although one potential explanation is estrogen-induced modulation of coronary vasoreactivity. Acetylcholine is an endothelium-dependent vasodilator that may be used to assess coronary vasoreactivity and elicits coronary responses that parallel those found with common daily vasomotor stimuli. Therefore, we tested whether estrogen attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women. METHODS AND RESULTS Acetylcholine-induced changes in coronary flow, resistance, and cross-sectional area were determined before and 15 minutes after intravenous administration of ethinyl estradiol (EE, 35 micrograms) in 15 postmenopausal women. The influence of estrogen on basal coronary flow, resistance, and epicardial cross-sectional area was also assessed by measuring these parameters before and after EE or placebo administration in 33 women. Estrogen altered basal coronary vasomotor tone in 22 women as manifested by an EE-induced 23.3 +/- 4.5% (mean +/- SEM) increase (P < .01) in coronary flow, a 15.0 +/- 3.2% decrease (P < .01) in resistance, and a 20.0 +/- 6.5% increase (P = .02) in epicardial cross-sectional area. Placebo administration in 11 women did not change these parameters. Estrogen also attenuated abnormal coronary vasomotor responses to acetylcholine. Seven women who exhibited a paradoxical acetylcholine-induced decrease in coronary flow (-33.5 +/- 12.3%, P < .01) and increase in resistance (38.9 +/- 14.1%, P = .05) and seven who had an abnormal acetylcholine-induced decrease in epicardial cross-sectional area (-14.2 +/- 4.4%; P = .04) did not have acetylcholine-induced changes in these parameters after EE administration. Acetylcholine-induced flow, resistance, and cross-sectional area responses before and after EE were significantly different (P < .01, P = .02, and P = .02, respectively). Normal coronary responses to acetylcholine were not affected by EE administration. CONCLUSIONS EE attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women. EE also decreases basal coronary vasomotor tone as manifested by increased coronary flow, decreased resistance, and increased epicardial cross-sectional area. These acute effects of estrogen on coronary vasoreactivity may explain, in part, the cardioprotective effects of estrogen in postmenopausal women.

Disappearance of exogenously administered human chorionic gonadotropin

Concentrations of human chorionic gonadotropin (hCG) were measured after intramuscular hCG administration in 34 patients undergoing ovarian stimulation in an in vitro fertilization program. Serum hCG levels were detectable by an immunoenzymetric assay up to 14 days after injection. Individual variation in hCG concentration after injection could be minimized by expressing the daily hCG level as a fractional distribution of the value observed 36 hours after hCG administration (hCG0). In nonpregnant patients, less than 10% of the hCG0 value was found on day 10. The disappearance rate measured 36 hours after injection of hCG was exponential with a mean half-life of 2.32 days. These findings are significant for ovarian stimulation protocols, including exogenous hCG, with respect to timing and accuracy of quantitative pregnancy testing.

Alcohol and caffeine consumption and decreased fertility

OBJECTIVE To examine the effects of alcohol and caffeine on conception. DESIGN Prospective observational study. SETTING Healthy volunteers in two manufacturing facilities. PATIENT(S) One hundred twenty-four women who provided daily urine samples for measurement of steroid hormones and hCG, and prospective information about alcohol and caffeine consumption. MAIN OUTCOME MEASURE(S) Probability of conception per 100 menstrual cycles. RESULT(S) There was >50% reduction in the probability of conception during a menstrual cycle during which participants consumed alcohol. Caffeine consumption did not independently affect the probability of conception but may enhance alcohols negative effect. Women who abstained from alcohol and consumed less than one cup of coffee or its equivalent per day conceived 26.9 pregnancies per 100 menstrual cycles compared with 10.5 per 100 menstrual cycles among those who consumed any alcohol and more than one cup of coffee per day. CONCLUSIONS This study revealed an independent dose-related negative effect of alcohol consumption on the ability to conceive. Our results suggest that women who are attempting to conceive should abstain from consuming alcohol.

Success following vaginal creation for Müllerian agenesis

Eighty-eight women with Müllerian agenesis underwent vaginal dilatation (n = 21) and/or vaginal creation using a modified McIndoe technique (n = 79). Patient and family counseling was considered an essential component of the therapy regimen. An initial trial of vaginal dilatation was successful in 9 of 21 patients (43%). Failure was associated with a prior vaginal exploration in eight women. All of the 79 women experienced satisfactory sexual activity and were satisfied with vaginal depth following vaginal creation using a split thickness graft technique. However, anatomic success, as judged by the surgeon, was noted in 72 patients (91%). Our experience suggests an initial trial of vaginal dilatation coupled with careful instruction and family counseling is appropriate in the motivated patient. However, vaginoplasty using a split thickness graft technique is highly successful and should be offered to those patients unwilling or unable to obtain an adequate neovagina with dilatation.

Infertility and early pregnancy loss

OBJECTIVES We describe the epidemiologic characteristics of conception, including subclinical early pregnancy loss, in a population of healthy women volunteers who had heterogeneous fertility experiences, and we describe the conception experience of women within this group who had evidence of impaired fertility. STUDY DESIGN This was a prospective observational study of a cohort of women employed in two semiconductor manufacturing facilities. A total of 148 volunteers completed interviews and daily diaries and collected daily urine specimens for an average of 7 months. Conception, including subclinical losses and clinical pregnancies, was determined with a highly sensitive and specific assay for urinary human chorionic gonadotropin, and ovulation was determined with assays of urinary ovarian steroid hormones. RESULTS There were 679 menstrual cycles at risk for pregnancy contributed by 124 (84%) of the 148 women. Women with evidence of subfertility before or during the study period had a rate of early pregnancy loss of 70% compared with 21% in women without fertility problems (relative risk 2.6, 95% confidence interval 1.8 to 3.8). The risk of pregnancy loss associated with subfertility increased with age and remained the same in women treated with clomiphene citrate. CONCLUSIONS These results suggest that subfertile women have increased subclinical pregnancy losses regardless of fertility treatment and that the association between reduced fertility and advancing age may be related, in part, to early subclinical pregnancy loss.

Integrated summary of ORTHO EVRA™/EVRA™ contraceptive patch adhesion in varied climates and conditions.

OBJECTIVE To assess the adhesive reliability of the contraceptive patch (Ortho Evra/Evra). DESIGN Pooled data of 3,319 women from three contraceptive studies of up to 13 treatment cycles; a subset of 325 women of the pooled data from warm and humid climates; and 30 women from a three-period, crossover exercise study. SETTING 184 centers. PATIENT(S) 3,349 healthy women. INTERVENTION(S) In the contraceptive studies, each treatment cycle consisted of three consecutive 7-day patches (21 days) followed by one patch-free week. During each treatment period in the exercise study, women wore the patch for 7 days and participated in one of six activities (normal activity, excluding bathing; sauna; whirlpool; treadmill; cool-water immersion; or a combination of activities) each day at a supervised health center. MAIN OUTCOME MEASURE(S) Patch adhesion. RESULT(S) In the contraceptive studies, 4.7% of patches were replaced because they fell off (1.8% [1,297 of 70,552 patches]) or became partly detached (2.9% [2,050 of 70,552 patches]); patch replacement rates in centers from a warm, humid climate were 1.7% (85 of 4,877 patches) and 2.6% (128 of 4,877 patches), respectively. Only one of 87 patches (1.1%) completely detached in the exercise study. CONCLUSION(S) The reliability of adhesion of the contraceptive patch is excellent and consistent across all studies; only 1.8% and 2.9% of patches required replacement due to complete or partial detachment, respectively. Heat, humidity, and exercise do not affect adhesion.

Cellular proliferation, estrogen receptor, progesterone receptor, and bcl-2 expression in GnRH agonist-treated uterine leiomyomas

Gonadotropin-releasing hormone (GnRH) agonists are commonly used in the treatment of uterine leiomyomas, but little is known about their histological and cellular effects on these neoplasms. We examined a cellular proliferation index as determined by the nuclear antigen Ki-67 and proliferating cell nuclear antigen (PCNA) expression, estrogen receptor (ER), and progesterone receptor (PR) expression in 27 leiomyomas from patients treated with the GnRH agonist leuprolide acetate (LA) and compared them with 33 untreated controls. All leiomyomas were removed by myomectomies from premenopausal woman after 2 to 6 months of LA treatment or in the follicular phase of the menstrual cycle in the untreated controls. Histological features examined included cellularity, nuclear atypia, vascular changes (dilated, thickened, or thrombosed vessels), edema, calcification, hemorrhage, necrosis, hyalinization, and mitotic activity. Although no difference was found between GnRH-treated and nontreated groups with respect to most histological features examined, immunohistochemical studies showed a significant decrease in the cellular proliferation index, ER, and PR expression in the LA-treated cases compared with nontreated controls. The cellular proliferation index, ER, and PR expression decreased by 85%, 49%, and 36%, respectively, in the LA-treated group as compared with controls (P < .001). A subset of cases from the LA-treated and nontreated groups were also analyzed with respect to bcl-2 (an inhibitor of apoptosis) expression, and no significant difference between the LA-treated and nontreated groups was observed with both groups showing a strong (> 75% of cells) cytoplasmic staining pattern. Results of this study show that LA treatment of leiomyomas results in a decrease in number of cycling cells.

Neuroendocrine dysfunction in galactorrhea-amenorrhea after oral contraceptive use.

Nonpuerperal alactorrhea and amenorrhea have been reported following the use of oral contraceptives. Treatment of this condition with ergot alkaloids has proved to be of great therapeutic value. Pretreatment plasma hLH and hFSH concentrations in 13 women with postqill galactorrhea-amenorrhea (PPGA) were 6.6 plus or minus 0.6 (SE.) and 5.0 plus or minus 0.8 mlU/ml, respectively. The mean prolactin concentration was 80.7 plus or minus 13.2 ng/ml. After complete evaluation in which diagnostic evidence of pituitary tumor was absent, the patients were treated with ergocryptine (CB-154). The mean hPRL concentration at 14 days of therapy was 7.8 p;us or minus 1.9 ng/ml. Cyclic gonadotropin secretion resumed in all but one instance; ovulation was confirmed on the basis of a biphasic temperature chart and in 5 cases, endometrial biopsy. Measurement of serum dopamine-beta-hydroxylase (DBH) activity indicated a significant decline at the end of 8 weeks of CB-154 therapy. The fall in hPRL was not necessarily associated with a fall in DBH. The majority of women in this study exhibited a consistent personality suggesting varying degrees of anxiety unrelated to the PPGA and usually antedating the use of oral contraceptives. PPGA was found in women without hyperprolactinemia, but altered hPRL secretion was evident in all instances. The data suggest that the disorder of cyclic gonadotropin secretion is related to altered hPRL secretion, but the mechanism is possibly related to a catecholamine abnormality. The data support the presence of an inherent cyclic mechanism for the secretion of gonadotropins. CB-154 therapy does not affect conception, and no teratogenic effects were observed in 2 infants born to women who had received CB-154 during the first 40 days of gestation.

Tubal anastomosis: pregnancy success following reversal of Falope ring or monopolar cautery sterilization *

The present study reviews pregnancy outcome following tubal anastomosis in 80 previously sterilized women. Thirty of 58 women (52%) sterilized by monopolar cautery techniques delivered a living child as compared to 19 of 22 women (86%) sterilized using the Falope ring method. Cumulative pregnancy curves were calculated for the Falope ring and cautery groups using life-table methods. Following reversal of Falope ring sterilization, the estimated cumulative probability of pregnancy 6, 12, 24, and 36 months after surgery was 28.4%, 48.8%, 69.3%, and 87.2% respectively. The corresponding estimates following reversal of cautery sterilization were lower at 6, 12, 24, and 36 months following surgery: 22.7%, 37.8%, 52.4%, and 57.9%, respectively. The ectopic tubal pregnancy and spontaneous abortion rate were higher among women sterilized with monopolar cautery. A decreased pregnancy rate was associated with ampullary-isthmic anastomosis in the cautery group; however, pregnancy was least likely to occur in women with shortened oviducts of less than 4 cm.

Correlates of sexual functioning among mid-life women

Objective Studies have reported a decline in sexual functioning among women undergoing the menopausal transition. Few studies, however, have examined the associations between hormones and sexual dysfunction during this time period. Therefore, the purpose of this study was to examine the associations between participant characteristics and endogenous hormones with sexual functioning in mid-life women. Methods Data were analyzed from a community-based sample of 441 women aged 45–54 years who stated that they were sexually active at the time of the study. Each participant completed a survey that included questions pertaining to sexual functioning and provided a blood sample that was used to measure estrogen and androgen concentrations. Results Among women who reported being sexually active, poorer self-reported health and the experiencing of depressive symptoms were significantly associated with not being satisfied with sexual relations after adjustment for other covariates. None of the hormones examined were significantly associated with overall sexual satisfaction. However, statistically significant associations between both total testosterone levels and the free testosterone index with satisfaction with the frequency of sexual relations were observed. Conclusions Our findings indicate that the experiencing of depressive symptoms and the reporting of poor overall health are important correlates of sexual dysfunction. Further, our results suggest that higher total and free testosterone levels are significantly associated with a desire for increased frequency of sexual relations among mid-life women.