Celia E. Dominguez

Menstrual cycle characteristics: associations with fertility and spontaneous abortion.

Background: Epidemiologists often use menstrual cycle patterns as indicators of endocrine function in environmental and occupational studies, yet few studies have considered whether menstrual cycle characteristics are associated with fertility or pregnancy outcome. Methods: We prospectively studied 470 women to determine whether cycle length or bleed length were associated with fertility or spontaneous abortion. Women completed daily diaries with information on menstrual bleeding, intercourse, birth control use, and covariates. For each menstrual cycle, women collected at least 2 urine samples, which were assayed for human chorionic gonadotropin to define early pregnancies. Women were followed for 1 year or until the end of a clinical pregnancy. Results: Cycles with lengths of 30 to 31 days preceded cycles with the highest fecundity. Shorter cycles were less likely to be followed by conception (fecundity ratio [FR] = 0.6; 95% confidence interval [CI] = 0.4–1.0). Compared with 30- to 31-day cycles, conceptions after shorter and longer cycles were more likely to be spontaneously aborted (for shorter cycles, odds ratio [OR] = 3.0 [95% CI = 0.9–9.6] and for longer cycles, OR = 3.0 [0.9–10.6]). Cycles with 5 days of menstrual bleeding had the highest fecundity. Cycles with up to 4 days of bleeding had lower fecundity (for bleed lengths of 4 days, FR = 0.5 [0.3–0.8] and for bleed lengths less than 4 days, FR = 0.6 [0.3–0.9]). Spontaneous abortion was less likely after bleeds greater than 5 days (OR = 0.4 [0.1–1.1]) when compared with 5-day bleeds. Conclusions: Menstrual cycle characteristics appear to be associated with fertility and spontaneous abortion.

Anti-Mullerian hormone indicates early ovarian decline in fragile X mental retardation (FMR1) premutation carriers: a preliminary study

BACKGROUND Women who carry the fragile X mental retardation (FMR1) premutation are at risk for fragile X-associated primary ovarian insufficiency. Past studies have shown that carriers who are still cycling have increased levels FSH compared with non-carriers. As anti-Mullerian hormone (AMH) has been shown as an excellent marker of ovarian decline, we examined AMH levels among premutation carriers to characterize their ovarian function. METHODS We determined the level of FSH and AMH in serum samples collected during early follicular phase from women who carried longer FMR1 repeat alleles (defined as >or=70 repeats, n = 40) and those with shorter repeat alleles (<70 repeats, n = 75), identified by DNA analysis. Comparisons were made stratified by age and carrier status. RESULTS For all age groups, AMH levels were significantly lower among longer repeat allele carriers compared to shorter repeat allele carriers (P = 0.002, 0.006 and 0.020 for women ages 18-30, 31-40 and 41-50 years, respectively). In contrast, increased FSH indicative of early ovarian decline was only evident for longer repeat allele carriers aged 31-40 years (P = 0.089, 0.001 and 0.261 for women ages 18-30, 31-40 and 41-50 years, respectively). CONCLUSIONS These preliminary data suggest that AMH levels indicate early ovarian decline among women with longer FMR1 repeat alleles; moreover, AMH appears to be a better marker than FSH in identifying this early decline.

Reproductive Health of Adolescent Girls Who Carry the FMR1 Premutation

The fragile X mental retardation 1 (FMR1) gene, located on the X chromosome, is characterized by a dynamic CGG repeat expansion in the 5′ untranslated region. It has long been known that female carriers of the FMR1 premutation allele (55–199 CGG) are at risk for passing the FMR1 full mutation (≥200 repeats) to their offspring, which results in a common form of mental retardation known as fragile X syndrome. The FMR1 premutation allele, however, also places female carriers at significantly increased risk for prematurely diminished ovarian function, which we refer to as fragile X–associated primary ovarian insufficiency (FXPOI). Although of particular concern for younger women, to date, studies of FXPOI have been restricted to women ≥18 years of age and have not specifically addressed ovarian reserve and menstrual cycle characteristics among adolescent carriers. We discuss the expected reproductive phenotype among FMR1 premutation carriers during adolescence, the associated health considerations based on our current understanding of FXPOI, and the directions for future studies.

Maternal exposure to a brominated flame retardant and genitourinary conditions in male offspring.

Background The upward trend in industrial nations in the incidence of male genitourinary (GU) conditions may be attributed to increased exposure to endocrine disruptors. Polybrominated biphenyl (PBB), a brominated flame retardant, is one such suspected endocrine disruptor. Objective We investigated the relationship between maternal serum levels of PBBs and GU conditions among male offspring exposed in utero. Methods In this cohort study of sons born to women accidentally exposed to PBBs during 1973–1974, we examined self-reported data on GU conditions among male offspring in relation to maternal serum PBB levels. We used generalized estimating equations to calculate odds ratios (ORs), controlling for gestational age at birth. Results Of 464 sons, 33 reported any GU condition (13 hernias, 10 hydroceles, 9 cryptorchidism, 5 hypospadias, and 1 varicocele). Four reported both hernia and hydrocele, and one both hernia and cryptorchidism. After adjustment for gestational age at birth, sons of highly exposed women (> 5 ppb) were twice as likely to report any GU condition compared with sons of the least exposed women [≤1 ppb; OR = 2.0; 95% confidence interval (CI), 0.8–5.1]. This risk was increased when we excluded sons born after the exposure but before the mother’s serum PBB measurement (OR = 3.1; 95% CI, 1.0–9.1). We found evidence of a 3-fold increase in reported hernia or hydrocele among sons with higher PBB exposure (test of trend p-value = 0.04). Neither hypospadias nor cryptorchidism was individually associated with PBB exposure. Conclusions Although cryptorchidism and hypospadias were not associated with in utero PBB exposure, this study suggests that other GU conditions may be associated with exposure to endocrine-disrupting chemicals during development.

Progression Through Puberty in Girls Enrolled in a Contemporary British Cohort

Data from the Avon Longitudinal Study of Parents and Children were used to describe initiation of secondary sexual characteristic development of girls. Tanner stages of breast and pubic hair and menarche status were self-reported via mailed questionnaires, administered from ages 8–14. Initiation pathway was categorized as breast [thelarche] or pubic hair [pubarche] development alone, or synchronous. Average ages at beginning breast and pubic hair development were estimated using survival analysis. Factors associated with initiation pathway were assessed using logistic regression. Among the 3938 participants, the median ages at beginning breast and pubic hair development were 10.19 (95% CI: 10.14–10.24) and 10.95 (95% CI: 10.90–11.00) years. Synchronous initiation was the most commonly reported pathway (46.3%), followed by thelarche (42.1%). Girls in the pubarche pathway were less likely to be obese or overweight at age 8 or have an overweight or obese mother. Girls in the thelarche pathway were less likely to be of nonwhite race or be the third born or later child.

Alcohol, Smoking, and Caffeine in Relation to Fecundability, with Effect Modification by NAT2

PURPOSE Common polymorphisms in the N-acetyltransferase-2 (NAT2) metabolic enzyme determine slow or rapid acetylator phenotypes. We investigated the effects of alcohol, smoking, and caffeine on fecundability, and determined whether the effects were modified by NAT2. METHODS Three NAT2 polymorphisms were genotyped in 319 women office workers participating in a prospective pregnancy study (1990-1994). Women were ages 20-41 and at risk for pregnancy. Discrete-time survival analysis was used to determine the effects of alcohol, smoking, and caffeine on fecundability and evaluate effect modification by NAT2. RESULTS We followed 319 women (161 slow acetylators, 158 rapid) for an average of 8 menstrual cycles, resulting in 124 pregnancies. There was no effect of caffeine on fecundability. Drinking ≥1 alcoholic drink per day and current smoking were significantly associated with reduced fecundability, but only among slow acetylators (adjusted fecundability odds ratio [FOR] for smoking = 0.34; 95% confidence interval, 0.22-0.90; adjusted FOR for ≥1 drink per day = 0.20; 0.05-0.92). There was no effect among rapid acetylators. CONCLUSIONS NAT2 status significantly modified the effects of alcohol and smoking on fecundability, emphasizing the importance of incorporating genetic and metabolic information in studies of reproductive health. Replication of this study is warranted.

Characterization of the Correlation Between Ages at Entry Into Breast and Pubic Hair Development

Purpose The timing of breast and pubic hair development in girls are related, but the degree of correlation has not been well characterized. Periodic observations also are complicated by interval censoring. Methods Data used were from the Avon Longitudinal Study of Parents and Children. Mean age at entry into breast and pubic hair development was determined by the use of parametric survival analysis. The bivariate normal cumulative distribution function was evaluated over the region containing the paired event times; the likelihood was maximized with respect to the correlation coefficient ρ. Results Among 3938 participants, estimated mean ages at entry into Tanner stage 2 for breast and pubic hair development were 10.19 and 10.95, respectively. The likelihood was maximized at ρ = 0.503 to 0.506. This value remained relatively constant among subgroups, although some heterogeneity was observed by maternal and child body mass index and birth order. Conclusions The timing of breast and of pubic hair development is moderately correlated and remain so when it is stratified by characteristics associated with puberty.

Ovulation induction in a poor responder with panhypopituitarism: a case report and review of the literature.

Background. Most women with panhypopituitarism will undergo successful ovulation induction with gonadotropin therapy. Few proven treatment options exist for those who respond poorly to such therapy. A poor response may indicate diminished ovarian reserve, or reflect a deficiency of other key components for ovarian function. Case. A 31-year-old female with panhypopituitarism and a poor response to gonadotropin therapy took growth hormone (GH) replacement for 4 months prior to restarting gonadotropins. When the serum level of insulin-like growth factor-I normalized, she began ovulation induction with gonadotropins with transdermal estradiol. After 63 days of gonadotropin therapy, she had a leading follicle of 18 mm, followed by follicles of 16.5 mm and 15.5 mm. The serum estradiol was 796 pg/ml, and human chorionic gonadotropin was administered. The patient conceived with timed intercourse. A prior attempt at ovulation induction with gonadotropins alone failed to produce follicular development. Conclusion. Prolonged gonadotropin treatment may be necessary to achieve ovulation and avoid the misdiagnosis of ovarian failure. Co-treatment with GH and estrogen may improve the follicular response in a poor responder with panhypopituitarism.