Critical data gaps remain regarding infertility treatment and child development. We assessed the utility of a birth certificate registry for developing a population cohort aimed at answering such questions.
We utilized the Upstate New York live birth registry (N=201,063) to select births conceived with (n=4,024) infertility treatment or exposed infants, who were then frequency-matched by residence and plurality to a random sample of infants conceived without (n=14,455) treatment or unexposed infants, 2008–2010. Mothers were recruited at 2–4 months postpartum and queried about their reproductive histories including infertility treatment for comparison with birth certificate data. Overall, 1,297 (32%) mothers of exposed and 3,692 of unexposed (26%) infants enrolled.
Twins represented 22% of each infant group. The percentage of infants conceived with/without infertility treatment was similar whether derived from the birth registry or maternal report: 71% none, 16% drugs or intrauterine insemination, and 14% ART. Concordant reporting between the two data sources was 93% for no treatment, 88% for ART and 83% for fertility drugs, but differed by plurality. Exposed infants had slightly (p<0.01) earlier gestations than unexposed infants (38.3±2.8 and 38.7±2.7 weeks, respectively) based upon birth certificates but not maternal report (38.7±2.7 and 38.7±2.9, respectively). Conversely, mean birthweight was comparable using birth certificates (3157±704 and 3194±679 grams, respectively), but differed using maternal report (3167±692 and 3224±661, respectively p<0.05).
The birth certificate registry is a suitable sampling framework as measured by concordance with maternally reported infertility treatment. Future efforts should address the impact of factors associated with discordant reporting on research findings.
There has been limited study of trace elements and endometriosis. Using a matched cohort design, 473 women aged 18–44 years were recruited into an operative cohort, along with 131 similarly-aged women recruited into a population cohort. Endometriosis was defined as surgically visualized disease in the operative cohort, and magnetic resonance imaging diagnosed disease in the population cohort. Twenty trace elements in urine and three in blood were quantified using inductively coupled plasma mass spectrometry. Logistic regression estimated the adjusted odds (aOR) of endometriosis diagnosis for each element by cohort. No association was observed between any element and endometriosis in the population cohort. In the operative cohort, blood cadmium was associated with a reduced odds of diagnosis (aOR=0.55; 95% CI: 0.31, 0.98), while urinary chromium and copper reflected an increased odds (aOR=1.97; 95% CI: 1.21, 3.19; aOR=2.66; 95% CI: 1.26, 5.64, respectively). The varied associations underscore the need for continued research.
arsenic; cadmium; chromium; endometriosis; lead; metals; mercury; trace elements
Limited study of persistent organochlorine pesticides (OCPs) and endometriosis has been conducted. One hundred women aged 18-40 years who were undergoing laparoscopy provided 20 cc of blood for toxicologic analysis and surgeons completed operative reports regarding the presence of endometriosis. Gas chromatography with electron-capture was used to quantify (ng/g serum) six OCPs. Logistic regression was utilized to estimate the adjusted odds ratios (aOR) and 95% confidence intervals (CI) for individual pesticides and groups based on chemical structure adjusting for current cigarette smoking and lipids. The highest tertile of aromatic fungicide was associated with a five-fold risk of endometriosis (aOR = 5.3; 95% CI, 1.2-23.6) compared to the lowest tertile. Similar results were found for t-nonachlor and HCB. These are the first such findings in a laproscopic cohort that suggest an association between OCP exposure and endometriosis. More prospective studies are necessary to ensure temporal ordering and confirm these findings.
Endometriosis; Environment; Fecundity; Organochlorines; Pesticides; Reproductive toxicant
Environmental chemicals may be associated with endometriosis. No published research has focused on the possible role of perfluorochemicals (PFCs) despite their widespread presence in human tissues.
We formulated two samples. The first was an operative sample comprising 495 women aged 18–44 years scheduled for laparoscopy/laparotomy at one of 14 participating clinical sites in the Salt Lake City or San Francisco area, 2007–2009. The second was a population-based sample comprising 131 women matched to the operative sample on age and residence within a 50-mile radius of participating clinics. Interviews and anthropometric assessments were conducted at enrollment, along with blood collection for the analysis of nine PFCs, which were quantified using liquid chromatography-tandem mass spectrometry. Endometriosis was defined based on surgical visualization (in the operative sample) or magnetic resonance imaging (in the population sample). Using logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for each PFC (log-transformed), adjusting for age and body mass index, and then parity.
Serum perfluorooctanoic acid (PFOA; OR = 1.89 [95% CI = 1.17–3.06]) and perfluorononanoic acid (2.20 [1.02–4.75]) were associated with endometriosis in the operative sample; findings were moderately attenuated with parity adjustment (1.62 [0.99–2.66] and 1.99 [0.91–4.33], respectively). Perfluorooctane sulfonic acid (1.86 [1.05–3.30]) and PFOA (2.58 [1.18–5.64]) increased the odds for moderate/severe endometriosis, although the odds were similarly attenuated with parity adjustment (OR = 1.50 and 1.86, respectively).
Select PFCs were associated with an endometriosis diagnosis. These associations await corroboration.
We sought to identify risk factors for endometriosis and their consistency across study populations in the Endometriosis: Natural History, Diagnosis, and Outcomes (ENDO) Study.
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, populationcohort). 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.
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.
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.
Body mass index; dysmenorrhea; endometriosis; epidemiology; infertility; laparoscopy; magnetic resonance imaging; risk factors
To assess in utero exposures and the odds of an endometriosis diagnosis.
Matched cohort design.
Fourteen participating clinical centers in geographically defined areas in Utah and California.
The operative cohort comprised 473 women undergoing laparoscopy/laparotomy, and was matched on age and residence to a population cohort comprising 127 women undergoing pelvic magnetic resonance imaging (MRI), 2007–2009.
Main outcome measures
Women completed standardized interviews prior to surgery or MRI regarding in utero exposures: mothers’ lifestyle during the index pregnancy, and the index woman’s gestation and birth size. Endometriosis was defined as visually confirmed disease in the operative cohort, and MRI visualized disease in the population cohort. The odds of an endometriosis diagnosis and corresponding 95% confidence intervals (AOR; 95% CI) were estimated for each exposure by cohort using logistic regression and adjusting for current smoking, age at menarche, body mass index, and study site.
Endometriosis was diagnosed in 41% and 11% of women in the operative and population cohorts, respectively. In the primary analysis, AORs were elevated for maternal vitamin usage (1.27; 95% CI =0.85–1.91), maternal cigarette smoking (1.16; 95% CI=0.61–2.24), and low birth weight (1.1; 95% CI=0.92–1.32). Reduced odds were observed for maternal usage of caffeine (0.99; 95% CI=0.64–1.54), alcohol (0.82; 95% CI=0.35–1.94), paternal cigarette smoking (0.72; 95% CI=0.43–1.19) and preterm delivery (0.98; 95% CI=0.47–2.03). Sensitivity analyses mostly upheld the primary results except for a decreased AOR for preterm birth (0.41; 95% CI=0.18–0.94) when restricting to visualized and histologically-confirmed endometriosis in the operative cohort.
In utero exposures were not significantly associated with the odds of an endometriosis diagnosis in either cohort.
endometriosis; epidemiology; in utero; ovarian dysgenesis hypothesis
Initial reports suggested that children conceived with assisted reproductive technologies (ART) may be at increased risk for a spectrum of developmental disabilities. Evolving evidence suggests that some of the early risks may have been overstated when not taking plurality of birth or gestational age at delivery into consideration, since both are independent risk factors for neurodevelopmental disabilities arising from alterations in structure and function or limitations in activities. Continued research is needed to overcome lingering data gaps in light of the equivocal literature for many neurodevelopmental disabilities relative to ART, increasing utilization of services and changes in the clinical management of infecund couples such as the adoption of natural cycles or in vitro maturation treatment options. Population-based cohorts with longitudinal assessment of the multifaceted nature of neurodevelopment across critical and sensitive windows is paramount for the development of empirically based guidance for clinical and population health.
Assisted reproductive technology; children; epidemiology; neurodevelopment; impairments
To determine whether body size and perceived figure, both current and historical, are associated with a diagnosis of endometriosis on laparoscopy.
Cohort study of consecutively identified patients undergoing laparoscopy for tubal sterilization or as a diagnostic procedure.
Two university-affiliated hospitals.
A cohort of 84 women ages 18–45 years. Endometriosis was visualized in 32 cases; 52 women (controls) had no visualized endometriosis, including 22 undergoing tubal sterilization and 30 with other gynecologic pathology.
Main Outcome Measure(s):
Body mass index (kg/m2) from self-report and perception of body figure were compared for their ability to predict case status (diagnosed endometriosis), using logistic regression models. Longitudinal trends in BMI based on perceived figure at 5-year intervals from age 15 years were compared using mixed linear models.
Based on self-report, women diagnosed with endometriosis were taller, thinner, and had a significantly lower BMI. In this series, cases were more likely to be late maturers (menarche ≥ 14 y) and late to initiate sexual activity (≥ 21 y), while they were less likely to be gravid, parous, and a current smoker. Adjusting for age (in years), being tall (height ≥ 68 in), and parity (yes, no), a higher current BMI was statistically protective for a diagnosis of endometriosis, regardless of whether BMI was determined by self-report (adjusted odds ratio [AOR]=0.88, 95% confidence interval [CI] 0.79–0.99) or from perceived figure (AOR=0.86, 95% CI 0.75–0.99). For every unit increase in BMI (kg/m2), there was an approximate 12–14% decrease in the likelihood of being diagnosed with endometriosis. In an adjusted repeated measures model, BMI was 21.3 ± 0.6 kg/m2 (estimate ± SE) for women with endometriosis, compared with 23.2 ± 0.4 kg/m2 for the controls, a difference over all ages of –1.9 ± 0.8 kg/m2 (P = .045). This is a consistent difference of about 10 lb at every age, assuming an average height of about 64.5 in.
In a laparoscopy cohort, women diagnosed with endometriosis were found to have a lower BMI (leaner body habitus), both at the time of diagnosis and historically. That women diagnosed with endometriosis may have a consistently lean physique during adolescence and young adulthood lends support to the suggestion of there being an in utero or early childhood origin for endometriosis.
body figure; body mass index; endometriosis; fetal origin; silhouette
Evaluate inhibin B and luteinizing hormone (LH) levels in a large, representative cross-sectional sample of U.S. girls and characterize the relationships of these laboratory values with age, clinical signs of puberty, and other correlates.
Cross-sectional analysis of LH and inhibin B in banked serum from 720 girls aged 6-11 years who participated in the Third National Health and Nutrition Examination Survey (NHANES III).
Levels of inhibin B and LH, race, ethnicity, and anthropometric measurements were compared for all girls. Visual assessment of pubertal stage was performed on girls 8 years and older. A two-part model was used to establish normative data and tobit regression models were used to evaluate associations with participant characteristics. Receiver operating characteristic (ROC) analysis was performed to identify optimum cut points predictive of puberty onset.
Mean hormone levels progressively increased with age. LH levels progressively increased with pubertal stage. Inhibin B levels increased gradually from breast stage I to II, then more sharply to peak at stage III, followed by a plateau at stages IV and V. ROC curves indicated both hormones were consistent with pubertal onset as indicated by breast stage II.
This study characterizes inhibin B and LH values in a large, representative cross-sectional sample of U.S. girls. Inhibin B can be a useful tool in combination with other clinical and biochemical parameters to evaluate gonadal function as a reflection of pubertal progression in girls.
Inhibin B; luteinizing hormone; NHANES; puberty; girls
Obesity is a growing public health problem among reproductive-aged women, with consequences for chronic disease risk and reproductive and obstetric morbidities. Evidence also suggests that body shape (i.e., regional fat distribution) may be independently associated with risk, yet it is not known if women adequately perceive their shape. This study aimed to assess the validity of self-reported body size and shape figure drawings when compared to anthropometric measures among reproductive-aged women.
Self-reported body size was ascertained using the Stunkard nine-level figures and self-reported body shape using stylized pear, hourglass, rectangle, and apple figures. Anthropometry was performed by trained researchers. Body size and body mass index (BMI) were compared using Spearman's correlation coefficient. Fat distribution indicators were compared across body shapes for nonobese and obese women using analysis of variance (ANOVA) and Fisher's exact test. Percent agreement and kappa statistics were computed for apple and pear body shapes.
The 131 women studied were primarily Caucasian (81%), aged 32 years, with a mean BMI of 27.1 kg/m2 (range 16.6–52.8 kg/m2). The correlation between body size and BMI was 0.85 (p<0.001). Among nonobese women, waist-to-hip ratios (WHR) were 0.75, 0.75, 0.80, and 0.82 for pear, hourglass, rectangle, and apple, respectively (p<0.001). Comparing apples and pears, the percent agreement (kappa) for WHR≥0.80 was 83% (0.55).
Self-reported size and shape were consistent with anthropometric measures commonly used to assess obesity and fat distribution, respectively. Self-reported body shape may be a useful proxy measure in addition to body size in large-scale surveys.
Benzophenone (BP)-type ultraviolet (UV) filters are widely used in a variety of personal care products for the protection of skin and hair from UV irradiation. Despite the estrogenic potencies of BP derivatives, few studies have examined the occurrence of these compounds in human matrices. Furthermore, associations among exposure to these compounds and estrogen-dependent diseases (such as endometriosis) have not been examined previously. In this study, we determined the concentrations of five BP derivatives, 2-hydroxy-4-methoxybenzophenone (2OH-4MeO-BP), 2,4-dihydroxybenzophenone (2,4OH-BP), 2,2’-dihydroxy-4-methoxybenzophenone (2,2’OH-4MeO-BP), 2,2’,4,4’-tetrahydroxybenzophenone (2,2’,4,4’OH-BP) and 4-hydroxybenzophenone (4OH-BP), in urine collected from 625 women in Utah and California, using liquid chromatography (LC)-tandem mass spectrometry (MS/MS). The association of urinary concentrations of BP derivatives with an increase in the odds of a diagnosis of endometriosis was examined in 600 women who underwent laparoscopy/laparotomy (n = 473: operative cohort) or pelvic magnetic resonance imaging (n = 127: population cohort), during 2007-2009. 2OH-4MeO-BP, 2,4OH-BP, and 4OH-BP, respectively, were detected in 99.0%, 93.3%, and 83.8% of the urine samples analyzed, whereas the detection rates for 2,2’,4,4’OH-BP and 2,2’OH-4MeO-BP were below 6.0%. Significant regional differences (higher concentrations in California) and monthly variations (higher concentrations in July and August) were found for urinary concentrations of 2OH-4Me O-BP and 2,4OH-BP. In addition, urinary concentrations of 2OH-4MeO-BP and 2,4OH-BP tended to be higher in more affluent, older, and leaner women. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for the urinary concentrations of BP derivatives and the odds of an endometriosis diagnosis; ORs increased across quartiles of 2OH-4MeO-BP and 2,4OH-BP concentrations, but a significant trend was observed only between 2,4OH-BP and the odds of an endometriosis diagnosis in the operative cohort (OR = 1.19; 95% CI = 1.01, 1.41). When women in the highest quartile of 2,4OH-BP concentrations were compared with women in the first three quartiles, the OR increased considerably (AOR = 1.65; 95% CI = 1.07, 2.53). Given that 2,4OH-BP possesses an estrogenic activity higher than that of 2OH-4MeO-BP, our results invite the speculation that exposure to elevated 2,4OH-BP levels may be associated with endometriosis.
Benzophenone derivatives; UV filters; sunscreen agents; estrogenic activity; endometriosis; epidemiology
To estimate the incidence of endometriosis in an operative cohort of women seeking clinical care and in a matched population cohort to delineate more fully the scope and magnitude of endometriosis in the context of and beyond clinical care.
Matched exposure cohort design.
Surgical centers in the Salt Lake City, Utah and San Francisco, California areas.
The operative cohort comprised 495 women undergoing laparoscopy/laparotomy between 2007–2009, while the population cohort comprised 131 women from the surgical centers’ catchment areas.
Main Outcome Measure(s)
Incidence of endometriosis by diagnostic method in the operative cohort and by pelvic magnetic resonance imaged (MRI) disease in the population cohort.
Endometriosis incidence in the operative cohort ranged by two orders of magnitude by diagnostic method: 0.7% for only histology, 7% for only MRI and 41% for visualized disease. Endometriosis staging was skewed toward minimal (58%) and mild disease (15%). The incidence of MRI-diagnosed endometriosis was 11% in the population cohort.
Endometriosis incidence is dependent upon the diagnostic method and choice of sampling framework. Conservatively, 11% of women have undiagnosed endometriosis at the population level with implications for the design and interpretation of etiologic research.
Endometriosis; epidemiology; histology; incidence; laparoscopy; magnetic resonance imaging
Background: An equivocal literature exists regarding the relation between persistent organochlorine pollutants (POPs) and endometriosis in women, with differences attributed to methodologies.
Objectives: We assessed the association between POPs and the odds of an endometriosis diagnosis and the consistency of findings by biological medium and study cohort.
Methods: Using a matched cohort design, we assembled an operative cohort of women 18–44 years of age undergoing laparoscopy or laparotomy at 14 participating clinical centers from 2007 to 2009 and a population-based cohort matched on age and residence within a 50-mile catchment area of the clinical centers. Endometriosis was defined as visualized disease in the operative cohort and as diagnosed by magnetic resonance imaging in the population cohort. Logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for each POP in relation to an endometriosis diagnosis, with separate models run for each medium (omental fat in the operative cohort, serum in both cohorts) and cohort. Adjusted models included age, body mass index, breast-feeding conditional on parity, cotinine, and lipids.
Results: Concentrations were higher in omental fat than in serum for all POPs. In the operative cohort, γ-hexachlorocyclohexane (γ-HCH) was the only POP with a significant positive association with endometriosis [per 1-SD increase in log-transformed γ-HCH: adjusted OR (AOR) = 1.27; 95% CI: 1.01, 1.59]; β-HCH was the only significant predictor in the population cohort (per 1-SD increase in log-transformed β-HCH: AOR = 1.72; 95% CI: 1.09, 2.72).
Conclusions: Using a matched cohort design, we found that cohort-specific and biological-medium–specific POPs were associated with endometriosis, underscoring the importance of methodological considerations when interpreting findings.
endocrine-disrupting chemicals; organochlorine pesticides; persistent organochlorine pollutants; polybrominated diphenyl ethers; polychlorinated biphenyls
Sporadic anovulation among regularly menstruating women is not well understood. It is hypothesized that cholesterol abnormalities may lead to hormone imbalances and incident anovulation. The objective was to evaluate the association between lipoprotein cholesterol levels and endocrine and metabolic disturbances and incident anovulation among ovulatory and anovulatory women reporting regular menstruation.
The BioCycle Study was a prospective cohort study conducted at the University at Buffalo from September 2005 to 2007, which followed 259 self-reported regularly menstruating women aged 18–44 years, for one or two complete menstrual cycles. Sporadic anovulation was assessed across two menstrual cycles.
Mean total and low-density lipoprotein cholesterol and triglycerides levels across the menstrual cycles were higher during anovulatory cycles (mean difference: 4.6 (P = 0.01), 3.0 (P = 0.06) and 6.4 (P = 0.0002) mg/dl, respectively, adjusted for age and BMI). When multiple total cholesterol (TC) measures prior to expected ovulation were considered, we observed a slight increased risk of anovulation associated with increased levels of TC (odds ratio per 5 mg/dl increase, 1.07; 95% confidence interval, 0.99, 1.16). Sporadic anovulation was associated with an increased LH:FSH ratio (P = 0.002), current acne (P = 0.02) and decreased sex hormone-binding globulin levels (P = 0.005).
These results do not support a strong association between lipoprotein cholesterol levels and sporadic anovulation. However, sporadic anovulation among regularly menstruating women is associated with endocrine disturbances which are typically observed in women with polycystic ovary syndrome.
anovulation; lipoproteins; menstrual cycle; endocrine disturbances
Children with autism spectrum disorder (ASD) are reported to have decreased bone cortical thickness (BCT). Vitamin D plays an important physiological role in bone growth and development, so deficiency of vitamin D could contribute to decreased BCT. The goal of this study was to compare plasma 25(OH)D concentration in three groups of Caucasian males age 4 to 8 years old: (1) ASD and an unrestricted diet (n=40), (2) ASD and a casein-free diet (n=9), and (3) unaffected controls (n=40). No significant group differences were observed (p=0.4). However, a total of 54 (61%) of the children in the entire cohort had a plasma 25(OH)D concentration of less than 20ng/mL, similar to findings of low 25(OH)D concentrations in population-based studies. Children with ASD should be monitored for vitamin D deficiency.
To assess the associations between measures of adiposity and sex hormone– binding globulin (SHBG) and to evaluate whether such associations differ by race.
RESEARCH DESIGN AND METHODS
Adiposity was measured by anthropometry and dual-energy X-ray absorptiometry among women (146 white, 50 black, and 25 Asian) aged 18–44 years in the BioCycle study. SHBG was repeatedly measured over one to two menstrual cycles. The ratio of trunkal to leg fat (T/L) was used to assess upper to lower body adiposity.
Among whites, all adiposity measures were significantly and inversely associated with SHBG. Among blacks, BMI (β = −0.032), waist circumference (β = −0.016), and T/L (β = −0.033) were significantly associated with SHBG, whereas total and trunkal fat were not (P interaction with race <0.04). Among Asians, measures of central and upper body fat were significantly associated with SHBG (e.g., T/L, β = −0.84) but not BMI.
Associations between SHBG and adiposity differ by race among premenopausal women.
To determine whether the initial physical findings of puberty are accompanied by hormonal evidence of pubertal activation of the hypothalamic–pituitary–gonadal (HPG) axis and whether racial/ethnic differences exist, we have analysed hormone levels in relation to age, onset of puberty and race/ethnicity.
Cross-sectional analysis of luteinizing hormone (LH), testosterone (T) and inhibin B from banked sera from a representative sample of US boys aged 6·0–11·99 years who participated in the National Health and Nutrition Examination Survey (NHANES) III.
Eight hundred and twenty-eight boys having sera including 228 non-Hispanic white (NHW), 266 non-Hispanic black (NHB), 288 Mexican-American (MA) and 46 ‘other’.
Using analysis of variance and linear regression techniques, concentrations of LH, T and inhibin B were compared by race/ethnicity for all boys and pubertal status (Tanner's Staging 1, 2 and 3+) for boys aged 8 years and older. Receiver operating curves were utilized to identify cut-points predictive of pubertal HPG status.
Mean hormones levels progressively increased with age. Receiver operating characteristic (ROC) curves indicate hormones are consistent with pubertal onset as indicated by Tanner stage 2, except for T and genital stage 2. Inhibin B and LH levels increased significantly by genital stage after adjusting for age and race/ethnicity, while LH and T concentrations increased significantly across pubic hair stages. Levels of inhibin B were significantly higher for NHB boys compared with other racial/ethnic groups.
In these cross-sectional findings, hormone levels rise gradually as boys approach the peripubertal age, whereas an abrupt rise was not associated with the onset of physical changes of puberty.
Emerging hypotheses suggest a causal role for prenatal androgen exposure in some cases of autism spectrum disorders (ASD). The ratios of the lengths of the bones of the 2nd to the 4th digit (2D:4D) are purported to be markers for prenatal androgen exposure and to be established early in gestation. Elongation of the 4th digit in response to testosterone is said to reduce 2D:4D in males versus females. We examined the ratios of bones from the left hand radiographs of 75 boys and 6 girls 4–8 years of age, diagnosed with ASD, to evaluate digit ratio as a marker for gestational androgen exposure. Contrary to our expectations, girls had reduced 2D:4D compared to boys but the difference was not significant (Cohen’s D 0.51–0.66, P>0.05). The limited sample size for this study and the absence of a referent group precluded providing robust estimates for girls and identifying possible statistical differences between the sexes. Tanner-Whitehouse 3 (TW3) rating of finger bone growth suggested relative immaturity of the 4th relative to the 2nd digits. Positive correlations were detected for 2D:4D ratios, body mass index (r=0.23, P=0.039), chronologic age (r=0.35, P=0.001), and skeletal age (r=0.42, P<0.0001). The TW3 ratings and associations between 2D:4D ratios and indicators of growth suggest that digits develop at different rates. This asynchronous development may produce differences in 2D:4D over time which could lead to erroneous interpretation of androgen exposure in utero among young ASD children.
Autism spectrum disorder; digit ratio; hyperandrogenic hypothesis; measurement error
To examine the longitudinal relation between perceived stress in the previous month and perimenstrual symptom severity across two cycles among regularly menstruating, healthy women (n = 259).
At baseline (11 days before the first cycle), participants completed the 4-item Perceived Stress Scale (PSS) for the previous month (first cycle exposure) and questionnaires on lifestyle factors. On cycle day 22 of a standardized 28-day cycle, participants again completed the PSS for the previous week (second cycle exposure) and each week rated the severity (none, mild, moderate, severe) of 17 psychological and physical symptoms (e.g., crying, cramping, pain). Mixed models estimated the association between perceived stress scores and number of moderate/severe symptoms and symptom severity scores, allowing both stress and perimenstrual symptoms to vary by cycle.
Adjusting for age, education, passive and active smoking, and waist/height ratio (WHtR), high stress (fourth quartile PSS) was associated with an increased risk of reporting ≥8 or more (OR 7.2, 3.3-15.8) and ≥5 (OR 2.5, 1.6-4.1) symptoms as moderate/severe during the perimenstrual period compared with lower stress (quartiles one, two, and three). Stress scores were positively (p < 0.0001) associated with increased symptom severity scores for total, psychological, and physical symptoms.
These analyses show that higher perceived stress precedes an increased severity of perimenstrual symptoms. Stress reduction programs may be an effective, nonpharmaceutical treatment for physical and psychological symptom relief.
Habitual energy expenditure appears to favorably alter oxidant/antioxidant balance. Sparse evidence suggests that hormones that fluctuate during the menstrual cycle, particularly estrogens, may influence concentrations of oxidative biomarkers and their relation to energy expenditure.
We investigated the relation between energy expenditure and plasma free F2-isoprostane concentrations in 259 healthy, regularly menstruating 18 to 44 year old participants of the BioCycle Study. Habitual energy expenditure was measured using a baseline International Physical Activity Questionnaire and categorized as low, moderate, or high. Women were followed for one or two subsequent menstrual cycles. Past-week and past-day physical activity were measured during follow-up using questionnaires and diaries, respectively. F2-isoprostane concentrations were measured in blood samples collected at both menses (approximate cycle day 2; low serum estradiol concentration) and the late follicular phase (approximate cycle day 12; peak estradiol concentration). Generalized estimating equations were used to model the energy expenditure/isoprostane association, adjusting for confounders.
Habitual energy expenditure was positively associated with F2-isoprostane concentration (adjusted difference in median F2-isoprostane, high versus low energy expenditure: 17.4%; 95% confidence interval [CI] 3.3, 31.4%). This association was not modified by cycle phase (interaction p=0.61) or differences in peak estradiol concentration across women (interaction p=0.20). Past-week and past-day physical activity measures were not associated with F2-isoprostane concentration (category trend p-values 0.50 and 0.18, respectively).
These results suggest that higher habitual energy expenditure may be associated with higher concentration of F2-isoprostanes in healthy reproductive-aged women. Estradiol concentration changes during the menstrual cycle do not appear to influence this relationship.
physical activity; menses; exercise; oxidative stress; premenopause; women
The authors investigated the association between age at menarche and risk of type 2 diabetes mellitus (T2DM) among 101,415 women from the Nurses’ Health Study (NHS) aged 34–59 years (1980–2006) and 100,547 women from Nurses’ Health Study II (NHS II) aged 26–46 years (1991–2005). During 2,430,274 and 1,373,875 person-years of follow-up, respectively, 7,963 and 2,739 incident cases of T2DM were documented. Young age at menarche was associated with increased risk of T2DM after adjustment for potential confounders, including body figure at age 10 years and body mass index (BMI; weight (kg)/height (m)2) at age 18 years. Relative risks of T2DM across age-at-menarche categories (≤11, 12, 13, 14, and ≥15 years) were 1.18 (95% confidence interval (CI): 1.10, 1.27), 1.09 (95% CI: 1.02, 1.17), 1.00 (referent), 0.92 (95% CI: 0.83, 1.01), and 0.95 (95% CI: 0.84, 1.06), respectively, in the NHS (P for trend < 0.0001) and 1.40 (95% CI: 1.24, 1.57), 1.13 (95% CI: 1.00, 1.27), 1.00 (referent), 0.98 (95% CI: 0.82, 1.18), and 0.96 (95% CI: 0.78, 1.19), respectively, in NHS II (P for trend < 0.0001). Associations were substantially attenuated after additional control for updated time-varying BMI. These data suggest that early menarche is associated with increased risk of T2DM in adulthood. The association may be largely mediated through excessive adult adiposity. The association was stronger among younger women, supporting a role for sex hormones in younger onset of T2DM, in addition to BMI.
adiposity; body mass index; diabetes mellitus, type 2; menarche; risk factors; weight gain
Lead (Pb) and cadmium (Cd) are known reproductive toxicants thought to disrupt hormone production throughout sensitive developmental windows, although this has not been previously examined in nationally representative peripubertal children.
We examined the association between blood Pb and urinary Cd concentrations and the reproductive hormones inhibin B and luteinizing hormone (LH) in girls 6–11 years of age who participated in the cross-sectional Third National Health and Nutrition Examination Survey (NHANES III) (1988–1994).
Pb (micrograms per deciliter) was measured in whole blood, and Cd was measured in urine (nanograms per milliliter). Inhibin B (picograms per milliliter) and LH (milli–International units per milliliter) were measured in residual sera for 705 girls. Survey logistic regression was used to estimate associations with pubertal onset based on inhibin B concentration > 35 pg/mL or LH concentration > 0.4 mIU/mL, and multinomial logistic regression was used to estimate the association between Pb and increasing categories of hormone concentrations.
High Pb (≥ 5 μg/dL) was inversely associated with inhibin B > 35 pg/mL [odds ratio (OR) = 0.26; 95% confidence interval (CI), 0.11–0.60; compared with Pb < 1 μg/dL]. At 10 and 11 years of age, girls with low Pb (< 1 μg/dL) had significantly higher inhibin B than did girls with moderate (1–4.99 μg/dL) or high Pb (≥ 5 μg/dL). In the subsample of 260 girls with levels of inhibin B above the level of detection and using survey regression modeling, inhibin B levels were lower among girls with both high Pb and high Cd (β = −0.52; 95% CI, −0.09 to −1.04) than among girls with high Pb alone (β = −0.35; 95% CI, −0.13 to −0.57), relative to girls with low Pb and low Cd.
Higher Pb was inversely associated with inhibin B, a marker of follicular development, and estimated effects suggestive of pubertal delays appeared to be stronger in the context of higher Cd concentrations. These data underscore the importance of Pb and Cd as reproductive toxicants for young girls.
heavy metals; inhibin B; luteinizing hormone; NHANES; puberty
Matching control selection strategies are often employed in PCOS case-control studies; however, they are infrequently used in an appropriate fashion. When properly applied, matching may offer improved study precision, but this is highly contingent on the causal pathway under consideration, strength of the associations between the matching variable and both the risk factor of interest and PCOS, and use of an appropriate stratified data analysis.
DDT (dichlorodiphenyltrichloroethane), a pesticide once used widely in agriculture and now limited to public health use, remains a controversial chemical because of a combination of benefits and risks. DDT or its breakdown products are ubiquitous in the environment and in humans. Compounds in the DDT family have endocrine actions and have been associated with reproductive toxicity. A previous study reported associations between prenatal exposure to p,p′-DDE [1,1-dichloro-2,2-bis(p-chlorophenyl)-ethylene] and increased height and weight in adolescent boys. We examined a group with higher exposures to see whether similar associations would occur. Our study group was 304 males born in Philadelphia in the early 1960s who had participated in a previous study. Anthropometric and pubertal measures from one to six visits during their adolescent years were available, as were stored maternal serum samples from pregnancy. We measured p,p′-DDE, p,p′-DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)-ethane], and o,p′-DDT [1,1,1-trichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)-ethane] in the maternal serum. Outcomes examined in the boys were height, ratio of sitting height to height, body mass index, triceps skinfold thickness, ratio of subscapular to the sum of triceps and subscapular skinfold thicknesses, skeletal age, serum testosterone, and serum dehydroepiandrosterone sulfate. No associations between prenatal exposure to any of the DDT compounds and any outcome measure were seen.
child development; DDE; DDT; growth; prenatal exposure delayed effects; puberty