Occupation and Semen Parameters in a Cohort of Fertile Men.

OBJECTIVE: We examined associations between occupation and semen parameters in demonstrably fertile men in the Study for Future Families. METHODS: Associations of occupation and workplace exposures with semen volume, sperm concentration, motility, and morphology were assessed using generalized linear modeling. RESULTS: Lower sperm concentration and motility were seen in installation, maintenance, and repair occupations. Higher exposure to lead, and to other toxicants, was seen in occupations with lower mean sperm concentrations (prevalence ratio for lead: 4.1; pesticides/insecticides: 1.6; solvents: 1.4). Working with lead for more than 3 months was associated with lower sperm concentration, as was lead exposure outside of work. CONCLUSIONS: We found evidence in demonstrably fertile men for reduced sperm quality with lead, pesticide/herbicide, and solvent exposure. These results may identify occupations where protective measures against male reproductive toxicity might be warranted.

Associations Between Prenatal Urinary Biomarkers of Phthalate Exposure and Preterm Birth: A Pooled Study of 16 US Cohorts.

Importance: Phthalate exposure is widespread among pregnant women and may be a risk factor for preterm birth. Objective: To investigate the prospective association between urinary biomarkers of phthalates in pregnancy and preterm birth among individuals living in the US. Design, Setting, and Participants: Individual-level data were pooled from 16 preconception and pregnancy studies conducted in the US. Pregnant individuals who delivered between 1983 and 2018 and provided 1 or more urine samples during pregnancy were included. Exposures: Urinary phthalate metabolites were quantified as biomarkers of phthalate exposure. Concentrations of 11 phthalate metabolites were standardized for urine dilution and mean repeated measurements across pregnancy were calculated. Main Outcomes and Measures: Logistic regression models were used to examine the association between each phthalate metabolite with the odds of preterm birth, defined as less than 37 weeks of gestation at delivery (n = 539). Models pooled data using fixed effects and adjusted for maternal age, race and ethnicity, education, and prepregnancy body mass index. The association between the overall mixture of phthalate metabolites and preterm birth was also examined with logistic regression. G-computation, which requires certain assumptions to be considered causal, was used to estimate the association with hypothetical interventions to reduce the mixture concentrations on preterm birth. Results: The final analytic sample included 6045 participants (mean [SD] age, 29.1 [6.1] years). Overall, 802 individuals (13.3%) were Black, 2323 (38.4%) were Hispanic/Latina, 2576 (42.6%) were White, and 328 (5.4%) had other race and ethnicity (including American Indian/Alaskan Native, Native Hawaiian, >1 racial identity, or reported as other). Most phthalate metabolites were detected in more than 96% of participants. Higher odds of preterm birth, ranging from 12% to 16%, were observed in association with an interquartile range increase in urinary concentrations of mono-n-butyl phthalate (odds ratio [OR], 1.12 [95% CI, 0.98-1.27]), mono-isobutyl phthalate (OR, 1.16 [95% CI, 1.00-1.34]), mono(2-ethyl-5-carboxypentyl) phthalate (OR, 1.16 [95% CI, 1.00-1.34]), and mono(3-carboxypropyl) phthalate (OR, 1.14 [95% CI, 1.01-1.29]). Among approximately 90 preterm births per 1000 live births in this study population, hypothetical interventions to reduce the mixture of phthalate metabolite levels by 10%, 30%, and 50% were estimated to prevent 1.8 (95% CI, 0.5-3.1), 5.9 (95% CI, 1.7-9.9), and 11.1 (95% CI, 3.6-18.3) preterm births, respectively. Conclusions and Relevance: Results from this large US study population suggest that phthalate exposure during pregnancy may be a preventable risk factor for preterm delivery.

Does an endocrinology subspecialty residency rotation enhance resident endocrine clinical knowledge?

BACKGROUND: Internal Medicine (IM) programs offer elective subspecialty rotations in which residents may enroll to supplement the experience and knowledge obtained during general inpatient and outpatient rotations. Objective evidence that these rotations provide enhanced subspecialty specific knowledge is lacking. The purpose of this study was to determine whether exposure to an endocrinology subspecialty rotation enhanced a resident's endocrinology-specific knowledge beyond that otherwise acquired during IM residency. METHODS: Data were collected on internal medicine resident scores on the American College of Physicians Internal Medicine In-Training Examinations (IM-ITE) for calendar years 2012 through 2018 along with enrollment data as to whether residents had completed an endocrinology subspecialty rotation prior to sitting for a given IM-ITE. Three hundred and six internal medicine residents in the University of Minnesota Internal Medicine residency program with 664 scores total on the IM-ITE for calendar years 2012 through 2018. Percentage of correct answers on the overall and endocrine subspecialty content areas on the IM-ITE for each exam were determined and the association between prior exposure to an endocrinology subspecialty rotation and percentage of correct answers in the endocrinology content area was analyzed using generalized linear mixed-effects models. RESULTS: Two hundred and thirty-three residents (76%) completed an endocrinology subspecialty rotation at some point during their residency; 121 (40%) residents had at least one IM-ITE both before and after exposure to an endocrine subspecialty rotation. Exposure to an endocrinology subspecialty rotation exhibited a positive association with the expected IM-ITE percent correct on the endocrinology content area (5.5% predicted absolute increase). Advancing year of residency was associated with a predicted increase in overall IM-ITE score but did not improve the predictive model for endocrine subspecialty score. CONCLUSIONS: Completion of an endocrinology subspecialty elective was associated with an increase in resident endocrine specific knowledge as assessed by the IM-ITE. These findings support the value of subspecialty rotations in enhancing a resident's subspecialty specific medical knowledge.

Semen and reproductive hormone parameters in fertile men with and without varicocele.

Although varicoceles are a widely accepted identifiable male factor in infertile couples, the benefit of varicocele repair in improving pregnancy and live birth rates remains uncertain. The Study for Future Families obtained semen and reproductive hormone samples from US men whose partners were currently pregnant. In our analysis cohort of 709 men, a varicocele was detected by clinical examination in 56 (8%) of men. Men with varicocele had smaller left testis, and lower total and total motile sperm counts than men without varicocele. Gonadotropin levels were higher as well in men with varicocele. Interestingly, testosterone levels were also slightly higher in men with varicocele. Despite these differences, there was no difference between the groups in the time to achieve the study pregnancy or percentage of men with a previous pregnancy. We conclude that even in fertile men, varicoceles are associated with some degree of testicular hypofunction. This would support current recommendations to consider varicocele repair in male partners in infertile couples who demonstrate both a varicocele and abnormal semen parameters and after evaluation for treatable female factors.

Predictors of Steroid Hormone Concentrations in Early Pregnancy: Results from a Multi-Center Cohort.

Objectives To identify factors predicting maternal sex steroid hormone concentrations in early pregnancy. Methods The Infant Development and the Environment Study recruited healthy pregnant women from academic medical centers in four US cities. Gold standard liquid chromatography-tandem mass spectrometry was used to measure maternal sex steroids concentrations (total testosterone [TT], free testosterone [FT], estrone [E1], estradiol [E2], and estriol [E3] concentrations) in serum samples from 548 women carrying singletons (median = 11.7 weeks gestation). Women completed questionnaires on demographic and lifestyle characteristics. Results In multivariable linear regression analyses, hormone concentrations varied in relation to maternal age, body mass index (BMI), race, and parity. Older mothers had significantly lower levels of most hormones; for every year increase in maternal age, there was a 1-2% decrease in E1, E2, TT, and FT. By contrast, each unit increase in maternal BMI was associated 1-2% lower estrogen (E1, E2, E3) levels, but 1-2% higher androgen (TT, FT) concentrations. Hormone concentrations were 4-18% lower among parous women, and for each year elapsed since last birth, TT and FT were 1-2% higher (no difference in estrogens). Androgen concentrations were 18-30% higher among Black women compared to women of other races. Fetal sex, maternal stress, and lifestyle factors (including alcohol and tobacco use) were not related to maternal steroid concentrations. Conclusions for Practice Maternal demographic factors predict sex steroid hormone concentrations during pregnancy, which is important given increasing evidence that the prenatal endocrine environment shapes future risk of chronic disease for both mother and offspring.

Evaluation and Management of Testosterone Deficiency: AUA Guideline.

PURPOSE: There has been a marked increase in testosterone prescriptions in the past decade resulting in a growing need to give practicing clinicians proper guidance on the evaluation and management of the testosterone deficient patient. MATERIALS AND METHODS: A systematic review utilized research from the Mayo Clinic Evidence Based Practice Center and additional supplementation by the authors. Evidence-based statements were based on body of evidence strength Grade A, B, or C and were designated as Strong, Moderate, and Conditional Recommendations with additional statements presented in the form of Clinical Principles or Expert Opinions (table 1 in supplementary unabridged guideline, http://jurology.com/). RESULTS: This guideline was developed by a multi-disciplinary panel to inform clinicians on the proper assessment of patients with testosterone deficiency and the safe and effective management of men on testosterone therapy. Additional statements were developed to guide the clinician on the appropriate care of patients who are at risk for or have cardiovascular disease or prostate cancer as well as patients who are interested in preserving fertility. CONCLUSIONS: The care of testosterone deficient patients should focus on accurate assessment of total testosterone levels, symptoms, and signs as well as proper on-treatment monitoring to ensure therapeutic testosterone levels are reached and symptoms are ameliorated. Future longitudinal observational studies and clinical trials of significant duration in this space will improve diagnostic techniques and treatment of men with testosterone deficiency as well as provide more data on the adverse events that may be associated with testosterone therapy.

First-Trimester Urinary Bisphenol A Concentration in Relation to Anogenital Distance, an Androgen-Sensitive Measure of Reproductive Development, in Infant Girls.

INTRODUCTION: Evidence from animal models suggests that prenatal exposure to bisphenol A (BPA), a ubiquitous endocrine-disrupting chemical, is associated with adverse reproductive outcomes in females. Exposure during early gestation, a critical period for reproductive development, is of particular concern. Anogenital distance (AGD) is a sensitive biomarker of the fetal hormonal milieu and a measure of reproductive toxicity in animal models. In some studies, the daughters of BPA-exposed dams have shorter AGD than controls. Here, we investigate this relationship in humans. METHODS: BPA was assayed in first-trimester urine samples from 385 participants who delivered infant girls in a multicenter pregnancy cohort study. After birth, daughters underwent exams that included two measures of AGD (AGD-AC: distance from center of anus to clitoris; AGD-AF: distance from center of anus to fourchette). We fit linear regression models to examine the association between specific gravity-adjusted (SPG-adj) maternal BPA concentrations and infant AGD, adjusting for covariates. RESULTS: BPA was detectable in 94% of women. In covariate-adjusted models fit on 381 eligible subjects, the natural logarithm of SpG-adj maternal BPA concentration was inversely associated with infant AGD-AC [ß=−0.56, 95% confidence interval (CI): −0.97, −0.15]. We observed no association between maternal BPA and infant AGD-AF. CONCLUSION: BPA may have toxic effects on the female reproductive system in humans, as it does in animal models. Higher first-trimester BPA exposure was associated with significantly shorter AGD in daughters, suggesting that BPA may alter the hormonal environment of the female fetus. https://doi.org/10.1289/EHP875.

The Effect of Intentional Weight Loss on Fracture Risk in Persons With Diabetes: Results From the Look AHEAD Randomized Clinical Trial.

Intentional weight loss is an important treatment option for overweight persons with type 2 diabetes mellitus (DM), but the effects on long-term fracture risk are not known. The purpose of this Look AHEAD analysis was to evaluate whether long-term intentional weight loss would increase fracture risk in overweight or obese persons with DM. Look AHEAD is a multicenter, randomized clinical trial. Recruitment began in August 2001 and follow-up continued for a median of 11.3 years at 16 academic centers. A total of 5145 persons aged 45 to 76 years with DM were randomized to either an intensive lifestyle intervention (ILI) with reduced calorie consumption and increased physical activity designed to achieve and maintain ≥7% weight loss or to diabetes support and education intervention (DSE). Incident fractures were ascertained every 6 months by self-report and confirmed with central adjudication of medical records. The baseline mean age of participants was 59 years, 60% were women, 63% were white, and the mean BMI was 36 kg/m2 . Weight loss over the intervention period (median 9.6 years) was 6.0% in ILI and 3.5% in DSE. A total of 731 participants had a confirmed incident fracture (358 in DSE versus 373 in ILI). There were no statistically significant differences in incident total or hip fracture rates between the ILI and DSE groups. However, compared to the DSE group, the ILI group had a statistically significant 39% increased risk of a frailty fracture (HR 1.39; 95% CI, 1.02 to 1.89). An intensive lifestyle intervention resulting in long-term weight loss in overweight/obese adults with DM was not associated with an overall increased risk of incident fracture but may be associated with an increased risk of frailty fracture. When intentional weight loss is planned, consideration of bone preservation and fracture prevention is warranted. © 2017 American Society for Bone and Mineral Research.

Prenatal Stress as a Modifier of Associations between Phthalate Exposure and Reproductive Development: results from a Multicentre Pregnancy Cohort Study.

BACKGROUND: Prenatal phthalate exposure is associated with altered male reproductive tract development, and in particular, shorter anogenital distance (AGD). AGD, a sexually dimorphic index of prenatal androgen exposure, may also be altered by prenatal stress. How these exposures interact to impact AGD is unknown. Here, we examine the extent to which associations between prenatal phthalate exposure and infant AGD are modified by prenatal exposure to stressful life events (SLEs). METHODS: Phthalate metabolites [including those of diethylhexyl phthalate (DEHP) and their molar sum (ΣDEHP)] were measured in first trimester urine from 738 pregnant women participating in The Infant Development and the Environment Study (TIDES). Women completed questionnaires on SLEs, and permitted infant AGD measurements at birth. Subjects were classified as 'lower' and 'higher' stress (0 first trimester SLEs vs. 1+).We estimated relationships between phthalate concentrations and AGD (by infant sex and stress group) using adjusted multiple regression interaction models. RESULTS: In the lower stress group, first trimester ΣDEHP was inversely associated with two measures of male AGD: anoscrotal distance (AGD-AS; ß = -1.78; 95% CI -2.97, -0.59) and anopenile distance (AGD-AP; ß = -1.61; 95% CI -3.01, -0.22). By contrast, associations in the higher stress group were mostly positive and non-significant in male infants. No associations were observed in girls. CONCLUSIONS: Associations between prenatal phthalate exposure and altered genital development were only apparent in sons of mothers who reported no SLEs during pregnancy. Prenatal stress and phthalates may interact to shape fetal development in ways that have not been previously explored.

Comprehensive Cardiovascular Risk Factor Control Improves Survival: The BARI 2D Trial.

BACKGROUND: It is unclear whether achieving multiple risk factor (RF) goals through protocol-guided intensive medical therapy is feasible or improves outcomes in type 2 diabetes mellitus. OBJECTIVES: This study sought to quantify the relationship between achieved RF goals in the BARI 2D (Bypass Angioplasty Investigation Revascularization 2 Diabetes) trial and cardiovascular events/survival. METHODS: We performed a nonrandomized analysis of survival/cardiovascular events and control of 6 RFs (no smoking, non-high-density lipoprotein cholesterol <130 mg/dl, triglycerides <150 mg/dl, blood pressure [systolic <130 mm Hg; diastolic <80 mm Hg], glycosylated hemoglobin <7%) in BARI 2D. Cox models with time-varying number of RFs in control were adjusted for baseline number of RFs in control, clinical characteristics, and trial randomization assignments. RESULTS: In 2,265 patients (mean age 62 years, 29% women) followed up for 5 years, the mean ± SD number of RFs in control improved from 3.5 ± 1.4 at baseline to 4.2 ± 1.3 at 5 years (p < 0.0001). The number of RFs in control during the trial was strongly related to death (global p = 0.0010) and the composite of death, myocardial infarction, and stroke (global p = 0.0035) in fully adjusted models. Participants with 0 to 2 RFs in control during follow-up had a 2-fold higher risk of death (hazard ratio: 2.0; 95% confidence interval: 1.3 to 3.3; p = 0.0031) and a 1.7-fold higher risk of the composite endpoint (hazard ratio: 1.7; 95% confidence interval: 1.2 to 2.5; p = 0.0043), compared with those with 6 RFs in control. CONCLUSIONS: Simultaneous control of multiple RFs through protocol-guided intensive medical therapy is feasible and relates to cardiovascular morbidity and mortality in patients with coronary disease and type 2 diabetes mellitus. (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes [BARI 2D]; NCT00006305).

Human Chorionic Gonadotropin Partially Mediates Phthalate Association With Male and Female Anogenital Distance.

CONTEXT: Prenatal exposure to phthalates disrupts male sex development in rodents. In humans, the placental glycoprotein hormone human chorionic gonadotropin (hCG) is required for male development, and may be a target of phthalate exposure. OBJECTIVE: This study aimed to test the hypothesis that phthalates disrupt placental hCG differentially in males and females with consequences for sexually dimorphic genital development. DESIGN: The Infant Development and Environment Study (TIDES) is a prospective birth cohort. Pregnant women were enrolled from 2010-2012 at four university hospitals. PARTICIPANTS: Participants were TIDES subjects (n = 541) for whom genital and phthalate measurements were available and who underwent prenatal serum screening in the first or second trimester. MAIN OUTCOME MEASURES: Outcomes included hCG levels in maternal serum in the first and second trimesters and anogenital distance (AGD), which is the distance from the anus to the genitals in male and female neonates. RESULTS: Higher first-trimester urinary mono-n-butyl phthalate (MnBP; P = .01), monobenzyl phthalate (MBzP; P = .03), and mono-carboxy-isooctyl phthalate (P < .01) were associated with higher first-trimester hCG in women carrying female fetuses, and lower hCG in women carrying males. First-trimester hCG was positively correlated with the AGD z score in female neonates, and inversely correlated in males (P = 0.01). We measured significant associations of MnBP (P < .01), MBzP (P = .02), and mono-2-ethylhexyl phthalate (MEHP; P < .01) with AGD, after adjusting for sex differences. Approximately 52% (MnBP) and 25% (MEHP) of this association in males, and 78% in females (MBzP), could be attributed to the phthalate association with hCG. CONCLUSIONS: First-trimester hCG levels, normalized by fetal sex, may reflect sexually dimorphic action of phthalates on placental function and on genital development.

Systolic Blood Pressure Control Among Individuals With Type 2 Diabetes: A Comparative Effectiveness Analysis of Three Interventions.

BACKGROUND: The relative effectiveness of 3 approaches to blood pressure control-(i) an intensive lifestyle intervention (ILI) focused on weight loss, (ii) frequent goal-based monitoring of blood pressure with pharmacological management, and (iii) education and support-has not been established among overweight and obese adults with type 2 diabetes who are appropriate for each intervention. METHODS: Participants from the Action for Health in Diabetes (Look AHEAD) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) cohorts who met criteria for both clinical trials were identified. The proportions of these individuals with systolic blood pressure (SBP) <140 mm Hg from annual standardized assessments over time were compared with generalized estimating equations. RESULTS: Across 4 years among 480 Look AHEAD and 1,129 ACCORD participants with baseline SBPs between 130 and 159 mm Hg, ILI (OR = 1.46; 95% CI = [1.18-1.81]) and frequent goal-based monitoring with pharmacotherapy (OR = 1.51; 95% CI = [1.16-1.97]) yielded higher rates of blood pressure control compared to education and support. The intensive behavioral-based intervention may have been more effective among individuals with body mass index >30 kg/m2, while frequent goal-based monitoring with medication management may be more effective among individuals with lower body mass index (interaction P = 0.047). CONCLUSIONS: Among overweight and obese adults with type 2 diabetes, both ILI and frequent goal-based monitoring with pharmacological management can be successful strategies for blood pressure control. CLINICAL TRIALS REGISTRY: clinicaltrials.gov identifiers NCT00017953 (Look AHEAD) and NCT00000620 (ACCORD).

Environmental exposure to di-2-ethylhexyl phthalate is associated with low interest in sexual activity in premenopausal women.

Phthalates, a ubiquitous class of environmental chemicals, may interfere with typical reproductive hormone production both in utero and in adulthood. Although they are best known as anti-androgens, increasingly, evidence suggests that phthalates, particularly di-2-ethylhexyl phthalate (DEHP), may also suppress estrogen production. Given that both androgens and estrogens are essential for sexual function, particularly sexual interest, it is plausible that adult exposure to phthalates alters sexual function. To this end, we used data from 360 women participating in a pregnancy cohort study (the Study for Future Families) to examine whether urinary phthalate metabolite concentrations were associated with two dimensions of self-reported sexual dysfunction in the months prior to conception: lack of sexual interest and vaginal dryness. Women in the highest quartile of urinary concentrations of mono-2-ethyl-5-hydroxyhexyl phthalate, a DEHP metabolite, had 2.58 (95% CI 1.33, 5.00) times the adjusted odds of reporting that they almost always or often lacked interest in sexual activity, and results were similar for mono-2-ethyl-5-oxohexyl phthalate (aOR: 2.56, 95% CI 1.32, 4.95), another DEHP metabolite. Self-reported vaginal dryness was not associated with any phthalate metabolite concentration. This study is novel in its focus on sexual function in relation to environmentally relevant (rather than occupational) exposure to phthalates in adult women and these preliminary findings merit replication in a large, prospective study. Better understanding how adult exposure to phthalates may affect reproductive health, including sexual function, is of public health interest given that virtually all Westerners are exposed to phthalates.

Impact of an intensive lifestyle intervention on use and cost of medical services among overweight and obese adults with type 2 diabetes: the action for health in diabetes.

OBJECTIVE: To assess the relative impact of an intensive lifestyle intervention (ILI) on use and costs of health care within the Look AHEAD trial. RESEARCH DESIGN AND METHODS: A total of 5,121 overweight or obese adults with type 2 diabetes were randomly assigned to an ILI that promoted weight loss or to a comparison condition of diabetes support and education (DSE). Use and costs of health-care services were recorded across an average of 10 years. RESULTS: ILI led to reductions in annual hospitalizations (11%, P = 0.004), hospital days (15%, P = 0.01), and number of medications (6%, P < 0.001), resulting in cost savings for hospitalization (10%, P = 0.04) and medication (7%, P < 0.001). ILI produced a mean relative per-person 10-year cost savings of $5,280 (95% CI 3,385-7,175); however, these were not evident among individuals with a history of cardiovascular disease. CONCLUSIONS: Compared with DSE over 10 years, ILI participants had fewer hospitalizations, fewer medications, and lower health-care costs.

Environmental health attitudes and behaviors: findings from a large pregnancy cohort study.

OBJECTIVE: Environmental chemicals are widely found in food and personal care products and may have adverse effects on fetal development. Our aim was to examine women's attitudes about these chemicals and ask whether they try to limit their exposure during pregnancy. STUDY DESIGN: A multi-center cohort of women in the first trimester of pregnancy completed questionnaires including items on attitudes and behaviors related to environmental chemicals. Multivariable logistic regression models were used to examine: (1) whether sociodemographic variables predict environmental health attitudes and behaviors; and (2) whether women's attitudes about environmental chemicals affect their lifestyle behaviors, particularly diet and personal care product use. RESULTS: Of the 894 subjects, approximately 60% strongly agreed that environmental chemicals are dangerous and 25% strongly felt they were impossible to avoid. Adjusting for covariates, educated women were more likely to believe that environmental chemicals are dangerous (OR 1.74, 95% CI 1.13, 2.66), and that belief, in turn, was associated with a number of healthy behaviors including choosing organic foods, foods in safe plastics, and chemical-free personal care products, and limiting fast food intake. Younger women were more likely to believe that environmental chemicals are impossible to avoid (OR 1.04, 95% CI 1.00, 1.08). CONCLUSIONS: Women's attitudes about environmental chemicals may impact their choices during pregnancy. Overcoming a lack of concern about environmental chemicals, particularly among certain sociodemographic groups, is important for the success of clinical or public health prevention measures.

Exposure to prenatal life events stress is associated with masculinized play behavior in girls.

Previous research has shown that prenatal exposure to endocrine-disrupting chemicals can alter children's neurodevelopment, including sex-typed behavior, and that it can do so in different ways in males and females. Non-chemical exposures, including psychosocial stress, may disrupt the prenatal hormonal milieu as well. To date, only one published study has prospectively examined the relationship between exposure to prenatal stress and gender-specific play behavior during childhood, finding masculinized play behavior in girls who experienced high prenatal life events stress, but no associations in boys. Here we examine this question in a second prospective cohort from the Study for Future Families. Pregnant women completed questionnaires on stressful life events during pregnancy, and those who reported one or more events were considered "stressed". Families were recontacted several years later (mean age of index child: 4.9 years), and mothers completed a questionnaire including the validated Preschool Activities Inventory (PSAI), which measures sexually dimorphic play behavior. In sex-stratified analyses, after adjusting for child's age, parental attitudes toward gender-atypical play, age and sex of siblings, and other relevant covariates, girls (n=72) exposed to prenatal life events stress had higher scores on the PSAI masculine sub-scale (ß=3.48, p=0.006) and showed a trend toward higher (more masculine) composite scores (ß=2.63, p=0.08). By contrast, in males (n=74), there was a trend toward an association between prenatal stress and higher PSAI feminine sub-scale scores (ß=2.23, p=0.10), but no association with masculine or composite scores. These data confirm previous findings in humans and animal models suggesting that prenatal stress is a non-chemical endocrine disruptor that may have androgenic effects on female fetuses and anti-androgenic effects on male fetuses.

Evidence for sexually dimorphic associations between maternal characteristics and anogenital distance, a marker of reproductive development.

Data from animal models, historical cohorts, and modern epidemiologic studies have suggested that maternal characteristics can affect reproductive health of offspring; however, distinguishing between prenatal and postnatal contributions is difficult. Anogenital distance (AGD), the distance from the anus to the genitals, is believed to be a biomarker of prenatal androgen exposure in many species, and in humans it has been associated with several adult reproductive health outcomes. We used data from a pregnancy cohort study conducted in 4 US cities from 1999-2005 to examine whether AGD measurements in infants were associated with maternal self-reported age at conception, age at menarche, age at first birth, parity, and gravidity. AGD was measured in 289 infants (140 male, 149 female) born to study participants. After adjustment for relevant covariates, in linear regression models stratified by infant sex, maternal age was positively associated with AGD in male infants (AGD, anus to penis: ß = 0.50, P = 0.002; AGD, anus to scrotum: ß = 0.29, P = 0.02) but not female infants. Parity was inversely associated with AGD (anus to scrotum; ß = -1.68, P = 0.03) in male infants. No other maternal characteristic predicted AGD in either sex. The mechanism underlying the unexpected relationship between maternal characteristics and AGD is unknown; however, we suggest several possibilities for future study.

Low-fat diet with omega-3 fatty acids increases plasma insulin-like growth factor concentration in healthy postmenopausal women.

The insulin-like growth factor pathway plays a central role in the normal and abnormal growth of tissues; however, nutritional determinants of insulin-like growth factor I (IGF-I) and its binding proteins in healthy individuals are not well defined. Three test diets-high-fat diet (40% energy as fat), low-fat diet (LF; 20% energy as fat), and a diet with low fat and high omega-3 fatty acid (LFn3; 23% energy as fat)--were tested in a randomized crossover designed controlled feeding trial in healthy postmenopausal women. Plasma IGF-I, IGF binding protein-3 (IGFBP-3), insulin, glucose, and ratio of IGF-I/IGFBP-3 concentrations were measured in response to diets. Insulin sensitivity was calculated using the homeostatic model assessment of insulin resistance We hypothesized that IGF-I, insulin, and glucose concentrations would decrease and IGFBP-3 concentration would increase in response to the low-fat diets. Eight weeks of the LFn3 diet increased circulating IGF-I (P < .001) and IGFBP-3 (P = .01) and the LF diet increased IGFBP-3 (P = .04), resulting in trends toward an increased IGF-I/IGFBP-3 ratio with the LFn3 diet and a decreased IGF-I/IGFBP-3 ratio with the LF diet (P = .13 for both comparisons). No statistically significant differences were detected between treatments at baseline or 8 weeks for IGF-1, IGFBP-3, or the ratio of IGF-1/IGFBP-3. Insulin, glucose, and the homeostatic model assessment of insulin resistance were not altered by the interventions. Low-fat diet with high n-3 fatty acids may increase circulating IGF-I concentrations without adversely affecting insulin sensitivity in healthy individuals.

Total dietary fat and omega-3 fatty acids have modest effects on urinary sex hormones in postmenopausal women.

BACKGROUND: Total fat and omega-3 fatty acids in the diet may affect breast cancer risk by altering estrogen metabolism. The purpose of this study was to elucidate the effects of differing total fat and omega-3 fatty acid content of diets on a panel of urinary estrogens and metabolites. FINDINGS: A controlled, cross-over feeding trial was conducted in postmenopausal women using three test diets: high fat diet (HF; 40% energy from fat), low fat diet (LF; 20% of energy from fat) and low fat, high omega-3 diet (LFn3; 23% energy from fat; 3% omega-3 fatty acids) for 8 week periods. Urinary hormone concentrations for 16 women were compared among diets using a linear mixed model, and within diet comparisons were made using paired t-tests. Urinary excretion of estrone was greater after the LF and LFn3 compared to the HF (P = 0.004). Estrone excretion was increased from baseline within the LF only (P = 0.02). Total estrone + estradiol + estriol increased from baseline with LF (P = 0.02) and was greater than the other two diets at 8 weeks (P = 0.03). There were no effects on estrogen metabolites, including the 2-hydroxy estrone:16α-hydroxy estrone ratio. CONCLUSIONS: The results of this study indicate that urinary sex hormone metabolism was modestly altered in postmenopausal women by a low fat dietary intervention.

Prenatal exposure to stressful life events is associated with masculinized anogenital distance (AGD) in female infants.

In animal models, prenatal stress programs reproductive development in the resulting offspring, however little is known about effects in humans. Anogenital distance (AGD) is a commonly used, sexually dimorphic biomarker of prenatal androgen exposure in many species. In rodents, prenatally stressed males have shorter AGD than controls (suggesting lower prenatal androgen exposure), whereas prenatally stressed females have longer AGD than controls (suggesting greater prenatal androgen exposure). Our objective was to investigate the relationship between stressful life events in pregnancy and infant AGD. In a prospective cohort study, pregnant women and their partners reported exposure to stressful life events during pregnancy. Pregnancies in which the couple reported 4+ life events were considered highly stressed. After birth (average 16.5 months), trained examiners measured AGD in the infants (137 males, 136 females). After adjusting for age, body size and other covariates, females born to couples reporting high stress had significantly longer (i.e. more masculine) AGD than females born to couples reporting low stress (p=0.015). Among males, high stress was weakly, but not significantly, associated with shorter AGD. Our results suggest prenatal stress may masculinize some aspects of female reproductive development in humans. More sensitive measures of prenatal stress and additional measures of reproductive development are needed to better understand these relationships and clarify mechanisms.