Shruthi Mahalingaiah

Temporal Variability and Predictors of Urinary Bisphenol A Concentrations in Men and Women

Background Bisphenol A (BPA) is used to manufacture polymeric materials, such as polycarbonate plastics, and is found in a variety of consumer products. Recent data show widespread BPA exposure among the U.S. population. Objective Our goal in the present study was to determine the temporal variability and predictors of BPA exposure. Methods We measured urinary concentrations of BPA among male and female patients from the Massachusetts General Hospital Fertility Center. Results Between 2004 and 2006, 217 urine samples were collected from 82 subjects: 45 women (145 samples) and 37 men (72 samples). Of these, 24 women and men were partners and contributed 42 pairs of samples collected on the same day. Ten women became pregnant during the follow-up period. Among the 217 urine samples, the median BPA concentration was 1.20 μg/L, ranging from below the limit of detection (0.4 μg/L) to 42.6 μg/L. Age, body mass index, and sex were not significant predictors of urinary BPA concentrations. BPA urinary concentrations among pregnant women were 26% higher (–26%, +115%) than those among the same women when not pregnant (p > 0.05). The urinary BPA concentrations of the female and male partner on the same day were correlated (r = 0.36; p = 0.02). The sensitivity of classifying a subject in the highest tertile using a single urine sample was 0.64. Conclusion We found a nonsignificant increase in urinary BPA concentrations in women while pregnant compared with nonpregnant samples from the same women. Samples collected from partners on the same day were correlated, suggesting shared sources of exposure. Finally, a single urine sample showed moderate sensitivity for predicting a subject’s tertile categorization.

Serum Concentrations of Polychlorinated Biphenyls in Relation to in Vitro Fertilization Outcomes

Background: Human exposure to polychlorinated biphenyls (PCBs) remains widespread. PCBs have been associated with adverse reproductive health outcomes including reduced fecundability and increased risk of pregnancy loss, although the human data remain largely inconclusive. Objective: Our goal was to explore the relationship between serum PCB concentrations and early pregnancy loss among a large cohort of women undergoing in vitro fertilization (IVF) between 1994 and 2003. Methods: Concentrations of 57 PCB congeners were measured in serum samples collected during 827 IVF/intracytoplasmic sperm injection cycles from 765 women. Joint statistical models that accommodate multiple outcomes and multiple cycles per woman were used to assess the relationship between serum PCB quartiles and implantation failure, chemical pregnancies (human chorionic gonadotropin level > 5.0 mIU/mL) that did not result in clinical pregnancy, or spontaneous abortion, while also adjusting for confounders. Results: PCB-153 was the congener present in the highest concentration (median, 46.2 ng/g lipid). Increasing quartiles of PCB-153 and the sum of all measured PCB congeners (ΣPCBs) were associated with significantly elevated dose-dependent odds of failed implantation. Adjusted odds ratios (95% confidence interval) for highest versus lowest quartile were 2.0 (1.2–3.4) for PCB-153 and 1.7 (1.0–2.9) for ΣPCBs. There were suggestive trends for increased odds of implantation failure for PCB-118 and cytochrome P450–inducing congeners (p-values for trend = 0.06). No statistically significant associations between PCBs and chemical pregnancy or spontaneous abortion were found. Conclusions: Serum PCB concentrations at levels similar to the U.S. general population were associated with failed implantation among women undergoing IVF. These findings may help explain previous reports of reduced fecundability among women exposed to PCBs.

Prolactin can modulate CD4+ T-cell response through receptor-mediated alterations in the expression of T-bet.

Low‐dose prolactin induces proinflammatory responses and antibody production, whereas high‐dose prolactin suppresses these responses. Mechanisms for these opposing effects remain incompletely defined. We have previously demonstrated that T‐bet, a key transcription factor directing T helper type 1 inflammatory responses, is regulated by female steroid hormones in human mucosal epithelial cells via Stat1 and 5 pathways. T‐bet was also modulated in a CD4+ T cell line by prolactin exposure. Prolactin rapidly induced T‐bet transcription through phosphorylation of JAK2 and Stat5, but not Stat1. Phosphorylated Stat5 then bound to the T‐bet regulatory region. These effects were weaker with high‐dose prolactin exposures. Upon long‐term prolactin exposure, low‐dose prolactin induced T‐bet expression, whereas high‐dose prolactin tended to suppress it. Prolactin induced the suppressors of cytokine signaling (SOCS) 1 and 3 in a dose‐dependent manner. With high‐dose exposure, this was associated with an inhibition of the phosphorylation of T‐bet regulatory region‐bound Stat5. Further, the dose‐dependent prolactin effects on T‐bet expression were confirmed in murine primary CD4+ T cells. These data suggest that the divergent immune effects of low‐ and high‐dose prolactin may involve modulation of T‐bet and alterations in the balance of the prolactin/JAK2/Stat5 and the prolactin/SOCS1 and 3 pathways.

Association of hexachlorobenzene (HCB), dichlorodiphenyltrichloroethane (DDT), and dichlorodiphenyldichloroethylene (DDE) with in vitro fertilization (IVF) outcomes.

Background: Hexachlorobenzene (HCB), dichlorodiphenyltrichloroethane (DDT), and dichlorodiphenyldichloroethylene (DDE) are persistent chlorinated pesticides with endocrine activity that may adversely affect the early stages of human reproduction. Objective: Our goal was to determine the association of serum levels of HCB, DDT, and DDE with implantation failure, chemical pregnancy, and spontaneous abortion in women undergoing in vitro fertilization (IVF) from 1994 to 2003. Methods: Levels of HCB and congeners of DDT and DDE were measured in serum collected during the follicular phase. Multivariable-adjusted statistical models accommodating multiple outcomes and multiple cycles per woman were used to estimate the relation between serum pesticide levels and IVF outcomes. Results: A total of 720 women with a mean ± SD age 35.4 ± 4.2 years at enrollment contributed 774 IVF cycles. All samples had detectable levels of HCB, DDT, and DDE, with median levels of 0.087 ng/g serum for HCB, 1.12 ng/g serum for total DDT, and 1.04 ng/g serum for p,p´-DDE. Compared with the lowest quartile (Q1) of HCB, the lipid- and multivariable-adjusted odds ratio (OR) for failed implantation was significantly elevated for those with higher HCB quartiles [Q2–Q4; adjusted ORs: for Q2, 1.71; 95% confidence interval (CI): 1.03, 2.82; for Q3, 2.30; 95% CI: 1.39, 3.81; for Q4, 2.32; 95% CI: 1.38, 3.90] and showed a significantly increasing trend (p = 0.001). No statistically significant associations were observed between DDT/DDE and IVF outcomes or between HCB and chemical pregnancy or spontaneous abortion. Conclusions: Serum HCB concentrations were on average lower than that of the general U.S. population and associated with failed implantation among women undergoing IVF.

Caffeine and caffeinated beverage consumption and fecundability in a preconception cohort.

Caffeine is an adenosine receptor antagonist that may influence fertility by affecting ovulation, menstrual characteristics, or sperm quality. We studied the association between female and male preconception caffeine intake and fecundability in a North American prospective cohort study of 2135 pregnancy planners. Frequency of caffeinated beverage intake was self-reported at baseline. Outcome data were updated every 8 weeks until reported pregnancy; censoring occurred at 12 months. Adjusted fecundability ratios (FR) and 95% confidence intervals (CI) were estimated using proportional probabilities regression. Total caffeine intake among males, but not females, was associated with fecundability (FR for ≥300 vs. <100mg/day caffeine among males=0.72, 95% CI=0.54-0.96), although the association was not monotonic. With respect to individual beverages, caffeinated tea intake was associated with slight reductions in fecundability among females, and caffeinated soda and energy drink intake were associated with reduced fecundability among males.

Air pollution and risk of uterine leiomyomata.

Background: Air pollution, particularly from vehicle exhaust, has been shown to influence hormonal activity. However, it is unknown whether air pollution exposure is associated with the occurrence of uterine leiomyomata, a hormonally sensitive tumor of the uterus. Methods: For 85,251 women 25–42 years of age at enrollment in the Nurses’ Health Study II, we examined proximity to major roadways and outdoor levels of particulate matter less than 10 microns (PM10) or 2.5 microns (PM2.5) or between 10 and 2.5 microns (PM10–2.5) in diameter for all residential addresses from September 1989 to May 2007. To be eligible for this analysis, a woman had to be alive and respond to questionnaires, premenopausal with an intact uterus, and without diagnoses of cancer or prevalent uterine leiomyomata. Incidence of ultrasound- or hysterectomy-confirmed uterine leiomyomata and covariates were reported on biennial questionnaires sent through May 2007. Multivariable time-varying Cox proportional hazard models were used to estimate the relationship between distance to road or PM exposures and uterine leiomyomata risk. Results: During 837,573 person-years of follow-up, there were 7760 incident cases of uterine leiomyomata. Living close to a major road and exposures to PM10 or PM10–2.5 were not associated with an increased risk of uterine leiomyomata. However, each 10 &mgr;g/m3 increase in 2-year average, 4-year average, or cumulative average PM2.5 was associated with an adjusted hazard ratio of 1.08 (95% confidence interval = 1.00–1.17), 1.09 (0.99–1.19), and 1.11 (1.03–1.19), respectively. Conclusions: Chronic exposure to PM2.5 may be associated with a modest increased risk of uterine leiomyomata.

Air Pollution Exposures During Adulthood and Risk of Endometriosis in the Nurses’ Health Study II

Background: Particulate matter and proximity to large roadways may promote disease mechanisms, including systemic inflammation, hormonal alteration, and vascular proliferation, that may contribute to the development and severity of endometriosis. Objective: Our goal was to determine the association of air pollution exposures during adulthood, including distance to road, particulate matter < 2.5 μm, between 2.5 and 10 μm, and < 10 μm, (PM2.5, PM10–2.5, PM10), and timing of exposure with risk of endometriosis in the Nurses’ Health Study II. Methods: Proximity to major roadways and outdoor levels of PM2.5, PM10–2.5, and PM10 were determined for all residential addresses from 1993 to 2007. Multivariable-adjusted time-varying Cox proportional hazard models were used to estimate the relation between these air pollution exposures and endometriosis risk. Results: Among 84,060 women, 2,486 incident cases of surgically confirmed endometriosis were identified over 710,230 person-years of follow-up. There was no evidence of an association between endometriosis risk and distance to road or exposure to PM2.5, PM10–2.5, or PM10 averaged over follow-up or during the previous 2- or 4-year period. Conclusions: Traffic and air pollution exposures during adulthood were not associated with incident endometriosis in this cohort of women. Citation: Mahalingaiah S, Hart JE, Laden F, Aschengrau A, Missmer SA. 2014. Air pollution exposures during adulthood and risk of endometriosis in the Nurses’ Health Study II. Environ Health Perspect 122:58–64; http://dx.doi.org/10.1289/ehp.1306627

Targets to treat metabolic syndrome in polycystic ovary syndrome.

Introduction: Metabolic syndrome is comprised of a combination of the following states: increased insulin resistance, dyslipidemia, cardiovascular disease, and increased abdominal obesity. Women with polycystic ovary syndrome (PCOS) have an increased risk of developing metabolic syndrome over the course of their lives. Metabolic syndrome increases risk of major cardiovascular events, morbidity, quality of life, and overall health care costs. Though metabolic syndrome in women with PCOS is an area of great concern, there is no effective individual medical therapeutic to adequately treat this issue. Areas Covered: This article will review key aspects of metabolic syndrome in PCOS. We will discuss classic and novel therapeutics to address metabolic syndrome in women with PCOS. We will conclude with the importance of developing strategic interventions to increase the compliance to lifestyle and dietary modification, in addition to appreciation of the emerging pharmaceutical therapeutics available. Expert Opinion: Innovation in lifestyle modification, including diet, exercise, with and without dedicated stress reduction techniques is the future in treatment of metabolic syndrome in PCOS. Application of novel interventions, such as group medical care, may improve future adherence to lifestyle modification recommendations, in addition to or in combination with pharmaceutical therapeutics.

Prenatal Exposure to Endocrine Disruptors: A Developmental Etiology for Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is one of the most common and complex endocrinopathies among reproductive-age women. Polycystic ovary syndrome is characterized by symptomatology of oligomenorrhea and androgen excess, with or without presence of polycystic ovarian morphology. The etiology of PCOS is multifactorial, including genetic and environmental components. It has been previously established that prenatal androgen exposure results in a PCOS phenotype in experimental animal models and epidemiologic human studies. Investigators hypothesize that prenatal exposure to endocrine-disrupting chemicals (EDCs) may contribute to PCOS development. This review examines the emerging research investigating prenatal exposure to 3 major classes of EDCs—bisphenol A (BPA), phthalates, and androgenic EDCs—and the development of PCOS and/or PCOS-related abnormalities in humans and animal models. Highlights of this review are as follows: (1) In rodent studies, maternal BPA exposure alters postnatal development and sexual maturation;, (2) gestational exposure to dibutyl phthalate and di(2-ethylhexyl)phthalate results in polycystic ovaries and a hormonal profile similar to PCOS; and (3) androgenic EDCs, nicotine and 3,4,4’-trichlorocarbanilide, create a hyperandrogenic fetal environment and may pose a potential concern. In summary, prenatal exposure to EDCs may contribute to the altered fetal programming hypothesis and explain the significant variability in severity and presentation.

Update on Primary Ovarian Insufficiency

Purpose of reviewDespite an incidence of 1% among women under the age of 40, primary ovarian insufficiency (POI) is still poorly understood. As the variable cause and presentation of POI complicate its management, a standard regimen for treatment remains to be established. However, emerging research has provided new insight on current mainstays of treatment as well as novel management approaches and therapeutic interventions. Recent findingsRecent clinical trials in women with POI indicate that the widely used regimen of transdermal estradiol and medroxyprogesterone acetate restores bone mineral density to a level equal to women with normal ovarian function. Further research verifies that compounded bioidentical hormones and androgen supplementation are inadequate in treating POI and lowering risk for long-term sequelae. Additionally, assessing changes in bone turnover markers may be useful for monitoring bone mineral density. Alternative therapies such as acupuncture, dehydroepiandrosterone, and bupropion may be effective in treating the effects of estrogen deficiency at some level, but require further investigation. SummaryRecent updates show promise in improving management methods and reducing risk of long-term sequelae. Additional research that expands upon the most current literature is critical to achieve an evidence-based standard of best practice.