Effects of preconception lifestyle intervention in infertile women with obesity: The FIT-PLESE randomized controlled trial.

BACKGROUND: Women with obesity and infertility are counseled to lose weight prior to conception and infertility treatment to improve pregnancy rates and birth outcomes, although confirmatory evidence from randomized trials is lacking. We assessed whether a preconception intensive lifestyle intervention with acute weight loss is superior to a weight neutral intervention at achieving a healthy live birth. METHODS AND FINDINGS: In this open-label, randomized controlled study (FIT-PLESE), 379 women with obesity (BMI ≥ 30 kg/m2) and unexplained infertility were randomly assigned in a 1:1 ratio to 2 preconception lifestyle modification groups lasting 16 weeks, between July 2015 and July 2018 (final follow-up September 2019) followed by infertility therapy. The primary outcome was the healthy live birth (term infant of normal weight without major anomalies) incidence. This was conducted at 9 academic health centers across the United States. The intensive group underwent increased physical activity and weight loss (target 7%) through meal replacements and medication (Orlistat) compared to a standard group with increased physical activity alone without weight loss. This was followed by standardized empiric infertility treatment consisting of 3 cycles of ovarian stimulation/intrauterine insemination. Outcomes of any resulting pregnancy were tracked. Among 191 women randomized to standard lifestyle group, 40 dropped out of the study before conception; among 188 women randomized to intensive lifestyle group, 31 dropped out of the study before conception. All the randomized women were included in the intent-to-treat analysis for primary outcome of a healthy live birth. There were no significant differences in the incidence of healthy live births [standard 29/191(15.2%), intensive 23/188(12.2%), rate ratio 0.81 (0.48 to 1.34), P = 0.40]. Intensive had significant weight loss compared to standard (-6.6 ± 5.4% versus -0.3 ± 3.2%, P < 0.001). There were improvements in metabolic health, including a marked decrease in incidence of the metabolic syndrome (baseline to 16 weeks: standard: 53.6% to 49.4%, intensive 52.8% to 32.2%, P = 0.003). Gastrointestinal side effects were significantly more common in intensive. There was a higher, but nonsignificant, first trimester pregnancy loss in the intensive group (33.3% versus 23.7% in standard, 95% rate ratio 1.40, 95% confidence interval [CI]: 0.79 to 2.50). The main limitations of the study are the limited power of the study to detect rare complications and the design difficulty in finding an adequate time matched control intervention, as the standard exercise intervention may have potentially been helpful or harmful. CONCLUSIONS: A preconception intensive lifestyle intervention for weight loss did not improve fertility or birth outcomes compared to an exercise intervention without targeted weight loss. Improvement in metabolic health may not translate into improved female fecundity. TRIAL REGISTRATION: ClinicalTrials.gov NCT02432209.

Semen parameter thresholds and time-to-conception in subfertile couples: how high is high enough?

STUDY QUESTION: What thresholds for total sperm count, sperm concentration, progressive motility, and total progressive motile sperm count (TPMC) are associated with earlier time-to-conception in couples undergoing fertility evaluation? SUMMARY ANSWER: Values well above the World Health Organization (WHO) references for total sperm count, concentration, and progressive motility, and values up to 100 million for TPMC were consistently associated with earlier time-to-conception and higher conception rates. WHAT IS KNOWN ALREADY: Although individual semen parameters are generally not able to distinguish between fertile and infertile men, they can provide clinically useful information on time-to-pregnancy for counseling patients seeking fertility treatment. Compared to the conventional semen parameters, TPMC might be a better index for evaluating the severity of male infertility. STUDY DESIGN, SIZE, DURATION: We used data from a longitudinal cohort study on subfertile men from 2002 to 2017 and included 6061 men with initial semen analysis (SA) in the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Men from subfertile couples who underwent a SA within the study period were included, and 5-year follow-up data were collected to capture conception data. Couples were further categorized into two subgroups: natural conception (n = 5126), after separating those who achieved conception using ART or IUI; natural conception without major female factor (n = 3753), after separating those with severe female factor infertility diagnoses. TPMC was calculated by multiplying the semen volume (ml) by sperm concentration (million/ml) and the percentage of progressively motile sperm (%). Cox proportional hazard models were used to report hazard ratios (HRs) with 95% CIs before and after adjusting for male age, the number of previous children before the first SA, and income. Using the regression tree method, we calculated thresholds for total sperm count, sperm concentration, progressive motility, and TPMC to best differentiate those who were more likely to conceive within 5 years after first SA from those less likely to conceive. We also plotted continuous values of semen parameters in predicting 5-year conception rates and time-to-conception. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, the median time to conception was 22 months (95% CI: 21-23). A total of 3957 (65%) couples were known to have achieved conception within 5 years of the first SA. These patients were younger and had higher values of sperm concentration, progressive motility, and TPMC. In the overall cohort, a TPMC of 50 million best differentiated men who were more likely to father a child within 5 years. Partners of men with TPMC ≥50 million had a 45% greater chance of conception within 5 years in the adjusted model (HR: 1.45; 95% CI: 1.34-1.58) and achieved pregnancy earlier compared to those men with TPMC < 50 million (median 19 months (95% CI: 18-20) versus 36 months (95% CI: 32-41)). Similar results were observed in the natural conception cohort. For the natural conception cohort without major female factor, the TPMC cut-off was 20 million. In the visual assessment of the graphs for the continuous semen parameter values, 5-year conception rates and time-to-conception consistently plateaued at higher values of sperm concentration, total sperm count, progressive motility, and TPMC compared to the WHO reference levels and our calculated thresholds. For TPMC, values up to 100-150 million were still associated with a better conception rate and time-to-conception in the visual assessment of the curves. LIMITATIONS, REASONS FOR CAUTION: There was limited information on female partners and potential for inaccuracies in capturing less severe female infertility diagnoses. Also we lacked details on assisted pregnancies achieved outside of our healthcare network (with possible miscoding as 'natural conception' in our cohort). We only used the initial SA and sperm morphology, another potentially important parameter, was not included in the analyses. We had no information on continuity of pregnancy attempts/intention, which could affect the time-to-conception data. Finally, most couples had been attempting conception for >12 months prior to initiating fertility treatment, so it is likely that we are underestimating time to conception. Importantly, our data might lack the generalizability to other populations. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that a TPMC threshold of 50 million sperm provided the best predictive power to estimate earlier time-to-conception in couples evaluated for male factor infertility. Higher values of sperm count, concentration and progressive motility beyond the WHO references were still associated with better conception rates and time-to-conception. This provides an opportunity to optimize semen parameters in those with semen values that are low but not abnormal according to the WHO reference values. These data can be used to better inform patients regarding their chances of conception per year when SA results are used for patient counseling. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.

A higher prevalence of endometriosis among Asian women does not contribute to poorer IVF outcomes.

PURPOSE: The purpose of the study was to determine whether diagnosis of endometriosis or endometriosis with endometrioma influences in vitro fertilization (IVF) outcomes in an ethnically diverse population. METHODS: Women undergoing a first IVF cycle (n = 717) between January 1, 2008 and December 31, 2009, at a university-affiliated infertility clinic, were retrospectively assessed for an endometriosis diagnosis. Differences in prevalence of endometriosis by ethnicity were determined, as well as differences in IVF success by ethnicity, with a focus on country of origin for Asian women. A multivariate model was generated to assess the relative contributions of country of origin and endometriosis to chance of clinical pregnancy with IVF. RESULTS: Endometriosis was diagnosed in 9.5% of participants; 3.5% also received a diagnosis of endometrioma. Endometriosis prevalence in Asian women was significantly greater than in Caucasians (15.7 vs. 5.8%, p < 0.01). Women of Filipino (p < 0.01), Indian (p < 0.01), Japanese (p < 0.01), and Korean (p < 0.05) origin specifically were more likely to have endometriosis than Caucasian women, although there was no difference in endometrioma presence by race/ethnicity. Oocyte quantity, embryo quality, and fertilization rates did not relate to endometriosis. Clinical pregnancy rates were significantly lower for Asian women, specifically in Indian (p < 0.05), Japanese (p < 0.05), and Korean (p < 0.05) women, compared to Caucasian women, even after controlling for endometriosis status. CONCLUSIONS: The prevalence of endometriosis appears to be higher in Filipino, Indian, Japanese, and Korean women presenting for IVF treatment than for Caucasian women; however, the discrepancy in IVF outcomes was conditionally independent of the presence of endometriosis. Future research should focus on improving pregnancy outcomes for Asian populations whether or not they are affected by endometriosis, specifically in the form of longitudinal studies where exposures can be captured prior to endometriosis diagnoses and infertility treatment.

Sexual and physical abuse and gynecologic disorders.

STUDY QUESTION: Is sexual and/or physical abuse history associated with incident endometriosis diagnosis or other gynecologic disorders among premenopausal women undergoing diagnostic and/or therapeutic laparoscopy or laparotomy regardless of clinical indication? SUMMARY ANSWER: No association was observed between either a history of sexual or physical abuse and risk of endometriosis, ovarian cysts or fibroids; however, a history of physical abuse was associated with a higher likelihood of adhesions after taking into account important confounding and mediating factors. WHAT IS KNOWN ALREADY: Sexual and physical abuse may alter neuroendocrine-immune processes leading to a higher risk for endometriosis and other noninfectious gynecologic disorders, but few studies have assessed abuse history prior to diagnosis. STUDY DESIGN, SIZE, DURATION: The study population for these analyses includes the ENDO Study (2007-2009) operative cohort: 473 women, ages 18-44 years, who underwent a diagnostic and/or therapeutic laparoscopy or laparotomy at 1 of the 14 surgical centers located in Salt Lake City, UT, USA or San Francisco, CA, USA. Women with a history of surgically confirmed endometriosis were excluded. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Prior to surgery, women completed standardized abuse questionnaires. Relative risk (RR) of incident endometriosis, uterine fibroids, adhesions or ovarian cysts by abuse history were estimated, adjusting for age, race/ethnicity, education, marital status, smoking, gravidity and recruitment site. We assessed whether a history of chronic pelvic pain, depression, or STIs explained any relationships via mediation analyses. MAIN RESULTS AND ROLE OF CHANCE: 43 and 39% of women reported experiencing sexual and physical abuse. No association was observed between either a history of sexual or physical abuse, versus no history, and risk of endometriosis (aRR: 1.00 [95% confidence interval (CI): 0.80-1.25]); aRR: 0.83 [95% CI: 0.65-1.06]), ovarian cysts (aRR: 0.67 [95% CI: 0.39-1.15]); aRR: 0.60 [95% CI: 0.34-1.09]) or fibroids (aRR: 1.25 [95% CI: 0.85-1.83]); aRR: 1.36 [95% CI: 0.92-2.01]). Conversely, a history of physical abuse, versus no history, was associated with higher risk of adhesions (aRR: 2.39 [95% CI: 1.18-4.85]). We found no indication that the effect of abuse on women's adhesion risk could be explained by a history of chronic pelvic pain, depression or STIs. LIMITATIONS, REASONS FOR CAUTION: Limitations to our study include inquiries on childhood physical but not sexual abuse. Additionally, we did not inquire about childhood or adulthood emotional support systems, found to buffer the negative impact of stress on gynecologic health. WIDER IMPLICATIONS OF THE FINDINGS: Abuse may be associated with some but not all gynecologic disorders with neuroendocrine-inflammatory origin. High prevalence of abuse reporting supports the need for care providers to screen for abuse and initiate appropriate follow-up. STUDY FUNDING/COMPETING INTERESTS: Supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts NO1-DK-6-3428, NO1-DK-6-3427, and 10001406-02). The authors have no potential competing interests.

Controversies in the Management of Endometrioma: To Cure Sometimes, to Treat Often, to Comfort Always?

Endometriomas are common in reproductive-aged women, but controversy exists regarding their management. PubMed was searched to identify pertinent studies on outcomes of medical and surgical management of endometrioma, with focus on randomized controlled trials and meta-analyses. Surgical excision is more effective than fenestration/coagulation of endometrioma for pelvic pain but decreases antimullerian hormone. It may modestly improve the chances of spontaneous pregnancy, but does not impact chances of success with in vitro fertilization. Oral contraceptive pills improve dysmenorrhea but not dyspareunia or noncyclic pelvic pain. Management of the patient with endometrioma should be individualized based on each patient's particular symptoms and short-term and long-term fertility goals.

Pharmacodynamic evaluation of the etonogestrel contraceptive implant initiated midcycle with and without ulipristal acetate: An exploratory study.

OBJECTIVE: To estimate the incidence of ovulation suppression within five days of etonogestrel 68 mg implant insertion in the presence of a dominant follicle with and without same-day ulipristal acetate. STUDY DESIGN: This single site non-masked, exploratory randomized trial recruited people age 18-35 years with regular menstrual cycles, no pregnancy risk, and confirmed ovulatory function. We initiated transvaginal ultrasound examinations on menstrual day 7-9 and randomized participants 1:1 to etonogestrel implant alone or with concomitant ulipristal acetate 30 mg oral when a dominant follicle reached ≥14 mm in diameter. We completed daily sonography and serum hormone levels for up to seven days or transitioned to labs alone if sonographic follicular rupture occurred. We defined ovulation as follicular rupture followed by progesterone >3 ng/mL. We calculated point estimates, risk ratios and 95% confidence intervals for ovulation for each group. Ovulation suppression of ≥44% in either group (the follicular rupture suppression rate with oral levonorgestrel emergency contraception), would prompt future method testing. RESULTS: From October 2020 to October 2022, we enrolled 40 people and 39 completed primary outcome assessments: 20 with etonogestrel implant alone (mean follicular size at randomization: 15.2 mm ± 0.9 mm) and 19 with etonogestrel implant + ulipristal acetate (mean follicular size at randomization: 15.4 mm ± 1.2 mm, p = 0.6). Ovulation suppression occurred in 13 (65%) of etonogestrel implant-alone participants (Risk ratio 0.6 (95% CI: 0.3, 1.1), p = 0.08) and seven (37%) of implant + ulipristal acetate participants. CONCLUSIONS: Ovulation suppression of the etonogestrel implant alone exceeds threshold testing for future research while the implant + ulipristal acetate does not. IMPLICATIONS: Data are lacking on midcycle ovulation suppression for the etonogestrel implant with and without oral ulipristal acetate. In this exploratory study, ovulation suppression occurred in 65% of implant participants and 37% of implant + ulipristal acetate participants. Ovulation suppression of the implant alone exceeds threshold testing for future emergency contraception research.

Risk factors associated with endometriosis: importance of study population for characterizing disease in the ENDO Study.

OBJECTIVE: We sought to identify risk factors for endometriosis and their consistency across study populations in the Endometriosis: Natural History, Diagnosis, and Outcomes (ENDO) Study. STUDY DESIGN: In this prospective matched, exposure cohort design, 495 women aged 18-44 years undergoing pelvic surgery (exposed to surgery, operative cohort) were compared to an age- and residence-matched population cohort of 131 women (unexposed to surgery, population cohort). Endometriosis was diagnosed visually at laparoscopy/laparotomy or by pelvic magnetic resonance imaging in the operative and population cohorts, respectively. Logistic regression estimated the adjusted odds ratios (AORs) and 95% confidence intervals (CIs) for each cohort. RESULTS: The incidence of visualized endometriosis was 40% in the operative cohort (11.8% stage 3-4 by revised criteria from the American Society for Reproductive Medicine), and 11% stage 3-4 in the population cohort by magnetic resonance imaging. An infertility history increased the odds of an endometriosis diagnosis in both the operative (AOR, 2.43; 95% CI, 1.57-3.76) and population (AOR, 7.91; 95% CI, 1.69-37.2) cohorts. In the operative cohort only, dysmenorrhea (AOR, 2.46; 95% CI, 1.28-4.72) and pelvic pain (AOR, 3.67; 95% CI, 2.44-5.50) increased the odds of diagnosis, while gravidity (AOR, 0.49; 95% CI, 0.32-0.75), parity (AOR, 0.42; 95% CI, 0.28-0.64), and body mass index (AOR, 0.95; 95% CI, 0.93-0.98) decreased the odds of diagnosis. In all sensitivity analyses for different diagnostic subgroups, infertility history remained a strong risk factor. CONCLUSION: An infertility history was a consistent risk factor for endometriosis in both the operative and population cohorts of the ENDO Study. Additionally, identified risk factors for endometriosis vary based upon cohort selection and diagnostic accuracy. Finally, endometriosis in the population may be more common than recognized.

Tissue-specific DNA methylation variability and its potential clinical value.

Complex diseases have multifactorial etiologies making actionable diagnostic biomarkers difficult to identify. Diagnostic research must expand beyond single or a handful of genetic or epigenetic targets for complex disease and explore a broader system of biological pathways. With the objective to develop a diagnostic tool designed to analyze a comprehensive network of epigenetic profiles in complex diseases, we used publicly available DNA methylation data from over 2,400 samples representing 20 cell types and various diseases. This tool, rather than detecting differentially methylated regions at specific genes, measures the intra-individual methylation variability within gene promoters to identify global shifts away from healthy regulatory states. To assess this new approach, we explored three distinct questions: 1) Are profiles of epigenetic variability tissue-specific? 2) Do diseased tissues exhibit altered epigenetic variability compared to normal tissue? 3) Can epigenetic variability be detected in complex disease? Unsupervised clustering established that global epigenetic variability in promoter regions is tissue-specific and promoter regions that are the most epigenetically stable in a specific tissue are associated with genes known to be essential for its function. Furthermore, analysis of epigenetic variability in these most stable regions distinguishes between diseased and normal tissue in multiple complex diseases. Finally, we demonstrate the clinical utility of this new tool in the assessment of a multifactorial condition, male infertility. We show that epigenetic variability in purified sperm is correlated with live birth outcomes in couples undergoing intrauterine insemination (IUI), a common fertility procedure. Men with the least epigenetically variable promoters were almost twice as likely to father a child than men with the greatest number of epigenetically variable promoters. Interestingly, no such difference was identified in men undergoing in vitro fertilization (IVF), another common fertility procedure, suggesting this as a treatment to overcome higher levels of epigenetic variability when trying to conceive.

Meeting the demand for fertility services: the present and future of reproductive endocrinology and infertility in the United States.

The field of reproductive endocrinology and infertility (REI) is at a crossroads; there is a mismatch between demand for reproductive endocrinology, infertility and assisted reproductive technology (ART) services, and availability of care. This document's focus is to provide data justifying the critical need for increased provision of fertility services in the United States now and into the future, offer approaches to rectify the developing physician shortage problem, and suggest a framework for the discussion on how to meet that increase in demand. The Society of REI recommend the following: 1. Our field should aggressively explore and implement courses of action to increase the number of qualified, highly trained REI physicians trained annually. We recommend efforts to increase the number of REI fellowships and the size complement of existing fellowships be prioritized where possible. These courses of action include: a. Increase the number of REI fellowship training programs. b. Increase the number of fellows trained at current REI fellowship programs. c. The pros and cons of a 2-year focused clinical fellowship track for fellows interested primarily in ART practice were extensively explored. We do not recommend shortening the REI fellowship to 2 years at this time, because efforts should be focused on increasing the number of fellowship training slots (1a and b). 2. It is recommended that the field aggressively implements courses of action to increase the number of and appropriate usage of non-REI providers to increase clinical efficiency under appropriate board-certified REI physician supervision. 3. Automating processes through technologic improvements can free providers at all levels to practice at the top of their license.

Age-related differences in the reproductive and metabolic implications of polycystic ovarian syndrome: findings in an obese, United States population.

The objective of this study was to explore age-related differences in the reproductive and metabolic manifestations of polycystic ovarian syndrome (PCOS). Using a prospective cross-sectional design, we compared metabolic and reproductive findings in women attending a multidisciplinary clinic for PCOS, stratified across the following age groups: 18-25 (n = 71), 26-35 (n = 129), and 36-45 (n = 29). The study included primarily overweight and obese women, with a mean BMI of 31.1 in the entire study group. Older women had a decreased prevalence of biochemical hyperandrogenemia (p-trend: 0.0005). Of women meeting diagnostic criteria for PCOS, older women (n = 15) had larger median waist circumference and higher median diastolic blood pressure, total cholesterol, LDL cholesterol and fasting glucose compared to younger women (p-trend: 0.03, 0.01, 0.01, 0.01 and 0.06, respectively). The odds of metabolic syndrome for women ages 36-45 are increased four-fold relative to the younger groups (OR: 4.01; 95% CI: 1.04-15.4; p = 0.04). We conclude that there are significant age-related differences in both the clinical presentation and metabolic manifestations of PCOS.

Polycystic ovary syndrome and postpartum depression among Hispanics and non-Hispanics: a population-based study.

BACKGROUND: Women with polycystic ovary syndrome experience increased health complications during and after pregnancy, including a higher prevalence of postpartum depression. Although previous research has found that Hispanic women with polycystic ovary syndrome experience heightened hyperandrogenism and metabolic effects compared with non-Hispanic women, it is unknown whether they experience other polycystic ovary syndrome-related comorbidities, such as postpartum depression, to a greater degree than their non-Hispanic counterparts. OBJECTIVE: This study aimed to determine the associations among a self-reported prepregnancy diagnosis of polycystic ovary syndrome, polycystic ovary syndrome symptoms (irregular menstruation, hirsutism, and acne), and postpartum depression among a national sample of at-risk women and evaluated the potential effect modification by Hispanic ethnicity. STUDY DESIGN: The study population included 52,267 postpartum (2-6 months) women who completed the US Pregnancy Risk Assessment Monitoring System Phase 8 questionnaire (2016-2018). Data from US states that captured self-reported polycystic ovary syndrome symptoms in the 3 months before pregnancy (n=17 states) were used. Moreover, we performed a subanalysis restricted to data from the Utah Pregnancy Risk Assessment Monitoring System Phase 8 questionnaire (2016-2019; n=5814), as it was the only state that considered self-reported polycystic ovary syndrome symptoms during this period. Postpartum depressed mood and anhedonia, the postpartum depression outcome measurements, were assessed via the following questions, respectively: (1) "Since your new baby was born, how often have you felt down, depressed, or hopeless?" and (2) "Since your new baby was born, how often have you had little interest or little pleasure in doing things you usually enjoyed?" In addition, postpartum depressed mood and anhedonia were assessed separately and as a combined variable. Here, weighted adjusted prevalence ratios and 95% confidence intervals were used to assess the association between polycystic ovary syndrome and postpartum depressed mood and anhedonia among Hispanic women and non-Hispanic women while taking into account preconception sociodemographics, lifestyle, and health history confounding factors. RESULTS: The national study population was composed of 16.8% of Hispanic ethnicity, with 11.4% Hispanic women and 17.1% non-Hispanic women reporting prepregnancy polycystic ovary syndrome symptoms. The study found no association between women reporting prepregnancy polycystic ovary syndrome vs women without polycystic ovary syndrome and the prevalence of postpartum depressed mood and/or anhedonia. Moreover, the results were null when we stratified by Hispanic ethnicity. The Utah study population was composed of 15.5% of women of Hispanic ethnicity, with 5.8% of Hispanic women and 7.4% of non-Hispanic women reporting prepregnancy polycystic ovary syndrome. Symptom-based polycystic ovary syndrome (having irregular menstruation with hirsutism or irregular menstruation with acne), compared with having regular menstruation in the Utah sample, was associated with a 1.54 higher adjusted prevalence ratio (95% confidence interval, 1.14-2.09) for postpartum depressed mood and anhedonia. Stratified analyses by ethnicity indicated a 2- to 5-fold higher prevalence of postpartum depression with symptom-based polycystic ovary syndrome for Hispanic women and a 1.5-fold higher prevalence for non-Hispanic women. CONCLUSION: In this US population-based study, a self-reported prepregnancy diagnosis of polycystic ovary syndrome was not associated with postpartum depression. However, self-reported polycystic ovary syndrome symptoms, including irregular menstruation and acne and/or hirsutism, were associated with a higher probability of postpartum depression, most prominently for Hispanic women. Our findings suggested that capturing polycystic ovary syndrome symptoms among at-risk women may be important for identifying associations with postpartum depression and potentially other comorbidities.

Physical activity in women with polycystic ovary syndrome: prevalence, predictors, and positive health associations.

OBJECTIVE: The purpose of this study was to describe the prevalence and predictors of physical activity in women with polycystic ovary syndrome (PCOS) and to explore the potential health benefits that are associated with physical activity in this population. STUDY DESIGN: This was a cross-sectional assessment of 150 women with PCOS. Active women (those who met Department of Health and Human Services [DHHS] guidelines for exercise) were compared with inactive women with regards to demographic and psychosocial variables and health characteristics. RESULTS: Fifty-nine percent (88/150 women) met the DHHS guidelines for physical activity. Active women were more likely than inactive women to be nulliparous (64.1% vs 40.0%; P = .04) and white (71.6% vs 42.6%; P = .0004). Inactive women were more likely to have mild depression (adjusted odds ratio, 2.2; 95% confidence interval, 1.01-4.79; P = .048). CONCLUSION: Women with PCOS who met the DHHS guidelines for physical activity were more likely to enjoy a variety of health benefits. Our findings identify several groups that are at risk for inadequate physical activity.

Transgenerational effects of chemotherapy: Both male and female children born to women exposed to chemotherapy have fewer children.

BACKGROUND: There is little known about the transgenerational effect of chemotherapy. For example, chemotherapy is known to decrease fecundity in women. But if women are able to have offspring after chemotherapy exposure, do these children also have decreased fecundity? METHODS: This study is a retrospective cohort study utilizing the Utah Population Database (UPDB), a comprehensive resource that links birth, medical, death and cancer records for individuals in the state of Utah. The male and female children (F1 generation) of chemotherapy-exposed women (F0 generation) were identified. The number of live births (F2 generation) to this F1 generation was compared to two sets of chemotherapy-unexposed, matched controls using conditional Poisson regression models (regression coefficient, 95% confidence interval, P-value). The first unexposed was established using the general population and the second unexposed was established using first cousins to the F1 generation. RESULTS: The exposed F1 individuals had 77.2% fewer children (-1.48; -2.51 to -0.70; p = 0.001) relative to the unexposed general population. F1 males had 86.9% fewer children (-2.03; -4.91 to -0.51; p = 0.005) and F1 females had 70.5% fewer children (-1.22; -2.40 to -0.36; p = 0.016). When comparing to their unexposed cousins, the F1 generation (both sexes combined) had 74.3% (-1.36; -2.82 to -0.29; p = 0.029) fewer children. CONCLUSION: The sons and daughters (F1 generation) of chemotherapy-exposed women have fewer live births when compared to both matched, unexposed general population and cousin controls. Chemotherapy may have a transgenerational effect in exposed women which needs further investigation.

When standard genetic testing does not solve the mystery: a rare case of preimplantation genetic diagnosis for campomelic dysplasia in the setting of parental mosaicism.

OBJECTIVE: To report a rare case of somatic mosaicism with a germline component of campomelic dysplasia in a woman undergoing in vitro fertilization with preimplantation genetic diagnosis (IVF-PGD). DESIGN: Case report. SETTING: Clinic. PATIENT(S): A 28-year old G2P0110 and her 34-year old husband had two previous pregnancies complicated by fetal campomelic dysplasia with suspected germline mosaic mutation. The couple, both phenotypically normal, underwent IVF-PGD to reduce their chances of transmission. None of the embryos could initially be determined to be disease free, because all embryos shared either a maternal or a paternal short tandem repeat haplotype with the products of conception from her last pregnancy. INTERVENTION(S): Peripheral-blood cytogenomic single-nucleotide polymorphism (SNP) microarray to identify the carrier of the mutation, and IVF-PGD to identify the disease-free embryo. MAIN OUTCOME MEASURE(S): Disease-free embryo. RESULT(S): Only one of the five euploid embryos was identified as disease free. CONCLUSION(S): A woman with suspected germline mosaicism for campomelic dysplasia was found to be a somatic mosaic with a germline component via a peripheral blood SNP microarray test. This identified her solitary disease-free embryo, which was transferred to her uterus but did not result in a viable pregnancy.

Decreased fecundity and sperm DNA methylation patterns.

OBJECTIVE: To evaluate the relationship between epigenetic patterns in sperm and fecundity. DESIGN: Prospective study. SETTING: Academic andrology and in vitro fertilization laboratory. PATIENT(S): Twenty-seven semen samples from couples who conceived within 2 months of attempting a pregnancy and 29 semen samples from couples unable to achieve a pregnancy within 12 months. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Genomewide assessment of differential sperm DNA methylation and standard semen analysis. RESULT(S): We analyzed DNA methylation alterations associated with fecundity in 124 semen samples, and identified regions of interest in 27 semen samples from couples who conceived within 2 months of attempting a pregnancy and a total of 29 semen samples from couples who were unable to achieve a pregnancy within 12 months. No differences in sperm count, sperm morphology, or semen volume were observed between the patients achieving a pregnancy within 2 months of study time and those not obtaining a pregnancy within 12 months. However, using data from the human methylation 450k array analysis we did identify two genomic regions with statistically significantly decreased (false discovery rate <0.01) methylation and three genomic regions with statistically significantly increased methylation in the failure-to-conceive group. The only two sites where decreased methylation was associated with reduced fecundity are at closely related genes known to be expressed in sperm, HSPA1L and HSPA1B. CONCLUSION(S): Our data suggest that there are genomic loci where DNA methylation alterations are associated with decreased fecundity. We have thus identified candidate loci for future study to verify these results and investigate the causative or contributory relationship between altered sperm methylation and decreased fecundity.

Sperm concentration is poorly associated with hypoandrogenism in infertile men.

OBJECTIVE: To evaluate the utility of routine hormone evaluation in all men presenting for infertility by understanding the relationship between sperm concentration and hypoandrogenism. METHODS: We performed a retrospective cross-sectional study between September 2013 and May 2014 at a tertiary referral center in Utah. Ninety-four men presenting for infertility consecutively between the ages of 18 and 55 years were identified. Our primary outcome was rate of hypoandrogenism among infertile men defined as the baseline total serum testosterone levels <300 ng/dL or bioavailable testosterone (BAT) levels <155 ng/dL. Secondary outcomes included association of normospermia, oligozoospermia, or azoospermia with biochemical or clinical hypoandrogenism. RESULTS: Thirty-nine men (41%) had a total serum testosterone level of <300 ng/dL, and 41 men (43%) had a BAT level <155 ng/dL. Biochemical and symptomatic hypoandrogenism was common; 17 men (18%) had a total testosterone level <300 ng/dL and ≥ 3 positive Androgen Deficiency in Aging Male (ADAM) responses, and 18 men (19%) had a BAT level of <155 ng/dL and ≥ 3 positive ADAM responses. Sperm concentration (normospermia, oligozoospermia, and azoospermia) was not associated with biochemical hypoandrogenism (total testosterone level <300 ng/dL or BAT level <155 ng/dL), symptomatic hypoandrogenism (≥ 3 positive ADAM responses), or sexual dysfunction (Sexual Health Inventory for Men score <21). CONCLUSION: Hypoandrogenism is common among infertile men, and routine hormonal evaluation may identify hypoandrogenism in many infertile men with otherwise normal semen analysis. Sperm concentration (normospermia, oligozoospermia, and azoospermia) is not well associated with hypoandrogenism in infertile men.

Increased urinary cobalt and whole blood concentrations of cadmium and lead in women with uterine leiomyomata: Findings from the ENDO Study.

Multiple trace elements have estrogen receptor activity, but the association of these elements with uterine leiomyoma has not been defined. A cohort of 473 women aged 18-44 undergoing surgery for benign gynecologic indications provided whole blood and urine specimens for trace element analysis, which was performed by inductively coupled plasma mass spectrometry. Twenty elements were analyzed in blood and 3 in urine. The surgeon documented whether fibroids were present. Geometric mean concentrations were compared between women with and without fibroids, and logistic regression models were generated to assess the impact of the concentration of each trace element on the odds of fibroids. In multivariate regressions, odds of a fibroid diagnosis were higher with increased whole blood cadmium (AOR 1.44, 95% CI 1.02, 2.04) and lead (AOR 1.31 95% CI 1.02, 1.69), and urine cobalt (AOR 1.31, 95% CI 1.02, 1.70). Urinary cadmium and lead were not related to fibroid diagnosis. Increased exposure to trace elements may contribute to fibroid growth, and fibroids may serve as a reservoir for these elements. Differences between urinary and whole blood findings merit further investigation, as urinary cadmium has been considered a superior marker of exposure.

Comparative analysis of human CYP3A4 and rat CYP3A1 induction and relevant gene expression by bisphenol A and diethylstilbestrol: implications for toxicity testing paradigms.

Bisphenol A (BPA) and diethylstilbestrol (DES) are endocrine-disrupting chemicals that interact with the human pregnane X receptor (PXR). CYP3A4 enzyme is essential in the hydroxylation of steroid hormones and is regulated by PXR. In the present study, human and rat hepatoma cell lines were exposed to BPA and DES. Both BPA and DES (10-50µM) caused a significant activation of the CYP3A4 promoter via the PXR in the DPX2 human hepatoma cell line. No activation of rat PXR was seen. BPA and DES treated DPX2 cells demonstrated increased expression of CYP3A4 mRNA, and increased enzyme activity. In summary, BPA, in concentrations relevant to current safety levels of human exposure, activates the human PXR and demonstrates an increase in CYP3A4 mRNA expression and enzyme activity. BPA actions in this model system occur to a greater extent than DES. This study raises concerns regarding our current toxicity testing paradigms and species utilization.

Asian immigrants to the United States are less likely to donate cryopreserved embryos for research use.

OBJECTIVE: To determine whether there are ethnic differences in the proportion of IVF patients donating excess cryopreserved embryos for use in research. DESIGN: Retrospective. SETTING: University clinic. PATIENT(S): Four hundred consecutive patients undergoing IVF. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Embryo disposition plan reported on the cryopreservation consent form (disposal, donation for research, or donation for therapeutic use). RESULT(S): Compared with Europeans or Asians born in the U.S., Asians born outside the U.S. were less likely to opt to donate excess embryos. Research donation was highly associated with interest in participation in clinical research. CONCLUSION(S): Decreased donation of excess embryos for research among Asians born outside the U.S. may relate to religious, sociocultural, language, or other undescribed factors. Targeted educational strategies may be critical to the development of a diverse pool of embryos available for research.