Context Many female survivors of adolescent and young adult cancers (AYA survivors) have shortened reproductive lifespans. However, the timing and duration of ovarian function after cancer treatment are largely unknown. Objective To model the trajectory of ovarian function over two decades following cancer treatment and evaluate how trajectories vary by treatment gonadotoxicity and age. Design In a prospective cohort, AYA survivors aged 18-39 at variable times since cancer treatment completion provided dried blood spots (DBS) every 6 months for up to 18 months. Anti-Müllerian hormone (AMH) levels were measured using the Ansh DBS AMH enzyme-linked immunosorbent assay. The mean AMH trajectory was modeled for the entire cohort and separately by treatment gonadotoxicity and age using functional principal components analysis. Results 763 participants, mean (standard deviation) enrollment age 33.3 (4.7) and age at cancer diagnosis 25.9 (5.7) years, contributed 1905 DBS samples. The most common cancers were breast (26.9%), lymphoma (24.8%), and thyroid (18.0%). AMH trajectories differed among survivors by treatment gonadotoxicity (low, moderate, or high) (P < 0.001). Following low or moderately gonadotoxic treatments, AMH levels increased over 2-3 years and plateaued over 10-15 years before declining. In contrast, following highly gonadotoxic treatment, AMH levels were lower overall and declined shortly after peak at 2-3 years. Younger age at treatment was associated with higher trajectories, but a protective effect of younger age was not observed in survivors exposed to highly gonadotoxic treatments (P_interaction < 0.001). Conclusions In this large AYA survivor cohort, timing and duration of ovarian function strongly depended on treatment gonadotoxicity and age at treatment. The findings provide novel, more precise information to guide reproductive decision-making.

Context Recent studies have examined level and rate of change of anti-mullerian hormone (AMH) for predicting time to menopause. Limited prospective, longitudinal data exists evaluating measures of ovarian reserve (MOR) in cancer survivors. Purpose Determine the rate of change of MOR in survivors (15-39 years) compared to similar-aged controls and compared to late reproductive-aged controls (40-50 years). Design Prospective cohort Setting Quaternary university hospital Participants Survivors at least 1 year from therapy completion, similar-aged controls, and late reproductive-aged controls. Interventions Annual visits with early follicular-phase hormone analysis and ultrasound. Main Outcome Measure Changes in AMH and antral follicle count (AFC) were modeled using random effects linear regression. Results 170 cancer survivors and 135 similar-aged controls had annual visits for an average of 38 months, while 71 late-reproductive aged controls were followed for an average of 24 months. In models adjusted for body mass index, time since cancer therapy (for survivors), and exogenous hormone use, the geometric mean AMH and AFC levels were lower in the survivors than similar-aged controls at all ages. After age 24.5 AMH and AFC declined in both groups at rates that were similar (p=0.78 for AMH, p=0.37 for AFC). Late-reproductive aged controls declined at a much more precipitous rate of 30% per year for AMH and 16% per year for AFC (p<0.01 compared to survivors). Conclusions Though survivors had lower levels of AMH and AFC at the time of enrollment, the rate of change of AMH and AFC is not significantly different than similar-aged controls.

(Obstet Gynecol. 2016;128(6):1357–1364) Labor induction is one of the most common procedures performed during pregnancy. Studies have suggested that the use of a combination method of mechanical and pharmacologic induction agents may reduce labor time and the risk of cesarean delivery. Consequently, the authors of the present study compared the time to delivery among 4 different cervical-ripening methods, including 2 combination methods. They hypothesized that induction with a combination method would lead to a shorter time to delivery than a single agent method.

Are there improvements in the accuracy of prediction of ectopic pregnancy (EP) in women with early symptomatic pregnancy using human chorionic gonadotrophin (hCG) curves when clinicians consider visits beyond the first 48 h after initial presentation? Two hCG values, measured 48 h (2 days) apart, are often not sufficient to accurately predict the outcome of a woman with a pregnancy of unknown location (PUL), but adding a third visit on Day 4 or 7 significantly improved the prediction for 1 in 15 women. The use of serial hCG values is commonly used to aid in the prediction of the final diagnosis in women with a PUL. Initial outcome predictions based on two hCG values may often be incorrect. This retrospective multicenter cohort study included 646 women with a PUL, recruited over 2 years. Of these women, 146 were ultimately diagnosed with EP. Women presenting to the emergency room with first trimester pain or bleeding, with a PUL, at least 2 hCG values and a definitive final diagnosis from the University of Pennsylvania, University of Miami and University of Southern California, were recruited from 2007 to 2009. Using currently recommended prediction rules, adding a third hCG evaluation on Day 4 after initial presentation significantly improved the accuracy of initial prediction from the first two values (48 h apart, or Day 2) by 9.3% (P = 0.015). Adding a third value on Day 7 improved prediction significantly by 6.7% (P = 0.031), compared with prediction based on first two values. The improvement in prediction by assessing four hCG values (Days 0, 2, 4 and 7) compared with three values (Days 0, 2 and 4) was 1.3% and not statistically significant. Missing data imputation likely biased results toward the null; predicted outcomes may not match those made by clinicians; and the study does not predict intrauterine pregnancy and spontaneous miscarriage separately. This study provides useful information for the prediction of outcomes for women with a symptomatic first trimester pregnancy of unknown location, but may not be generalizable to all pregnant women. Supported by NIH grant numbers R01-HD036455 to Dr Barnhart and Dr Sammel, K24HD060687 to Dr Barnhart, and 5T32MH065218 to Ms. Zee. The authors have no conflicts of interest to declare.

Although exogenous progesterone may hold promise as a treatment for nicotine use disorders, it is unclear whether it is similarly effective in males and females. This study examined the effects of progesterone on nicotine use disorder comprehensively using behavioral, psychological, and neural measures in male and female smokers exposed to brief abstinence. Thirty-three male and 33 female non-treatment-seeking smokers participated in a double-blind, randomized, placebo-controlled crossover study of 200 mg of progesterone or placebo daily over a four-day abstinence period. Smoking behavior and subjective effects of nicotine were assessed at baseline and after final drug administration. Nicotine withdrawal, smoking urges, mood states, and neural response to smoking cues were measured at baseline, after the first drug administration, and after the final drug administration. No main effect of drug (progesterone vs. placebo) emerged for any outcome. Significant sex by drug interactions emerged for nicotine withdrawal (p = .020), perceived strength of nicotine (p = .040), and perceived bad effects of nicotine (p = .029). Males receiving progesterone reported worse nicotine withdrawal (p = .046) and a trend towards decreased bad effects of nicotine (p = .070). Males on progesterone also reported greater tension and anxiety relative to placebo (p = .021). Females on progesterone perceived nicotine’s effects as being stronger relative to placebo (p = .046). Progesterone causes sex-dependent effects on smoking-related outcomes during brief abstinence. Specifically, progesterone in males may increase rather than decrease nicotine withdrawal and negative affect during abstinence, potentially hindering efforts to quit smoking. In male and female smokers undergoing a brief period of abstinence, we examined the effects of progesterone on smoking outcomes. While progesterone had limited effects in female smokers, in males, it worsened nicotine withdrawal and negative affect. Our findings emphasize the importance of analyzing sex differences in future studies examining progesterone as a potential treatment and suggest that progesterone in males could potentially exacerbate aspects of nicotine dependence. NCT01954966. https://clinicaltrials.gov/ct2/show/NCT01954966

Ovarian aging in women can be described as highly unpredictable within individuals but predictable across large populations. We showed previously that modeling an individual woman’s ovarian reserve of primordial follicles using mathematical random walks replicates the natural pattern of growing follicles exiting the reserve. Compiling many simulations yields the observed population distribution of the age at natural menopause (ANM). Here, we have probed how stochastic control of primordial follicle loss might relate to the distribution of the preceding menopausal transition (MT), when women begin to experience menstrual cycle irregularity. We show that identical random walk model conditions produce both the reported MT distribution and the ANM distribution when thresholds are set for growing follicle availability. The MT and ANM are shown to correspond to gaps when primordial follicles fail to grow for 7 and 12 days, respectively. Modeling growing follicle supply is shown to precisely recapitulate epidemiological data and provides quantitative criteria for the MT and ANM in humans.