Polycystic ovary syndrome (PCOS) is a familial syndrome, associated with multiple cardiovascular disease (CVD) risk factors. Thus, parents of affected women may have a higher prevalence of CVD events than the general population.
PCOS probands (n = 410) and their participating parents (n = 180 fathers and 211 mothers) were queried for CVD events in themselves and non-participating family members. In order to include the family CVD history of all parents, agreement between the proband and parental reports of CVD events was assessed. Estimated 10-year coronary heart disease (CHD) risk was calculated using the Framingham risk calculator. The National Health and Nutrition Examination Survey (NHANES) 2001–2002 database was used to generate gender, age and body mass index-relevant population parameters of CVD prevalence in the USA population.
Ninety-eight percent of the parents' self-reporting of CVD events agreed with the proband's report of parental heart attack history [Kappa = 0.82; 95% CI: (0.69, 0.94)] and 99% with parental stroke history [Kappa = 0.79; 95% CI: (0.62, 0.97)]. Fathers of women with PCOS had a higher prevalence of heart attack and stroke compared with the reference NHANES population (heart attack: 11.1 versus 5.3%, P < 0.0001; stroke: 3.0 versus 1.0%, P = 0.002). Fathers of women with PCOS had an elevated 10-year risk for CHD (11.5 versus 9.9% in NHANES, P = 0.03). No statistically significant increased prevalence of CVD events or 10-year risk was noted in probands or mothers.
Fathers, and not mothers, may be disproportionately burdened with CVD in PCOS families. The strengths of this study include the size of our cohort, the consistent phenotyping and the validation of proband's reporting of parental CVD events.
insulin resistance; androgens; dyslipidemia; hypertension; stroke
To estimate racial disparities in PCOS phenotype between White and Black women with PCOS.
Two academic medical centers
242 women off of confounding medications in otherwise good health
Phenotyping during the follicular phase or anovulation after overnight fast in women.
Main outcome measures
Biometric, serum hormones, glycemic and metabolic parameters, and body composition by DEXA.
We studied 77 White and 43 Black women with PCOS and 35 White and 87 Black controls. Black women with PCOS were very similar reproductively to White women with PCOS. Black women with PCOS had lower serum transaminases, higher HDL-C levels[mean difference (MD): 18.2; 95% CI: (14.3, 22.1) mg/dL], lower triglycerides(MD: -43.2 mg/dL; 95% CI: (-64.5, -21.9)), and enhanced insulinogenic index on the oral glucose tolerance test compared to White women with PCOS. Blacks with PCOS had higher bone mineral density(MD: 0.1 g/cm2; 95% CI: (0.1, 0.2)) and lower percent body fat on DXA (MD: -2.8%; 95% CI:(-5.1, - 0.5)), and overall a higher quality of life. While most of these findings disappeared when the differences with racially matched controls were compared, Black women with PCOS compared to Black controls had lower estradiol levels than White PCOS women compared to White controls(MD: -12.9 pg/mL; 95% CI: (-24.9, -0.8)), higher systolic blood pressure(MD: 9.1 mm Hg; 95% CI: (0.8, 17.4)), and lower fasting glucose levels(MD: -12.0 mg/dL; 95% CI: (-22.3, - 1.7)).
Racial disparities in PCOS phenotype are minor and mixed. Future studies should explore if race impacts on treatment effects.
Pregnancy outcomes and adverse outcomes in infertility trials are reported to varying extents, e.g. 35% of clinical trials reported no information on pregnancy loss, only 43% reported adverse events during the preconception treatment period and only 7% reported any serious adverse events. Incomplete reporting limits the value of these studies in counseling patients on the risk/benefit ratio of treatment to themselves and their babies.
miscarriage; multiple pregnancy; morbidity; mortality; fetal anomaly; intrauterine fetal demise; adverse event
Background: Bisphenol A (BPA), an endocrine-disrupting chemical that is routinely detected in > 90% of Americans, promotes experimental asthma in mice. The association of prenatal BPA exposure and wheeze has not been evaluated in humans.
Objective: We examined the relationship between prenatal BPA exposure and wheeze in early childhood.
Methods: We measured BPA concentrations in serial maternal urine samples from a prospective birth cohort of 398 mother–infant pairs and assessed parent-reported child wheeze every 6 months for 3 years. We used generalized estimating equations with a logit link to evaluate the association of prenatal urinary BPA concentration with the dichotomous outcome wheeze (wheeze over the previous 6 months).
Results: Data were available for 365 children; BPA was detected in 99% of maternal urine samples during pregnancy. In multivariable analysis, a one-unit increase in log-transformed creatinine-standardized mean prenatal urinary BPA concentration was not significantly associated with child wheeze from birth to 3 years of age, but there was an interaction of BPA concentration with time (p = 0.003). Mean prenatal BPA above versus below the median was positively associated with wheeze at 6 months of age [adjusted odds ratio (AOR) = 2.3; 95% confidence interval (CI): 1.3, 4.1] but not at 3 years (AOR = 0.6; 95% CI: 0.3, 1.1). In secondary analyses evaluating associations of each prenatal BPA concentration separately, urinary BPA concentrations measured at 16 weeks gestation were associated with wheeze (AOR = 1.2; 95% CI: 1.0, 1.5), but BPA concentrations at 26 weeks of gestation or at birth were not.
Conclusions: Mean prenatal BPA was associated with increased odds of wheeze in early life, and the effect diminished over time. Evaluating exposure at each prenatal time point demonstrated an association between wheeze from 6 months to 3 years and log-transformed BPA concentration at 16 weeks gestation only.
bisphenol A; BPA; child; cotinine; prenatal; tobacco; wheeze
In order to determine the effects of statins on vascular function, inflammation and androgen levels in women with polycystic ovary syndrome (PCOS), we randomized 20 women with PCOS who had LDL-cholesterol levels >100 mg/dl to atorvastatin (40 mg/day) or placebo for six weeks and found that atorvastatin reduced androgen levels, biomarkers of inflammation, and blood pressure, increased insulin levels and brachial artery conductance during reactive hyperemia, and failed to improve brachial artery flow-mediated dilation. We conclude that until additional studies demonstrate a clear risk-to-benefit ratio favoring statin therapy in PCOS, statins should only be used in PCOS women who meet current indications for statin treatment.
statin; PCOS; hyperandrogenemia; vascular function; hyperinsulinemia
To examine changes in brachial artery conductance (BAC) during reactive hyperemia in women with polycystic ovary syndrome (PCOS) compared to controls.
This is a pilot case-control study performed at a single academic medical center. Changes in BAC during reactive hyperemia were evaluated in 31 women with PCOS and 11 healthy control women. Fasting glucose, insulin, lipids and androgen levels were also determined. A mixed-effects model was used to compare the PCOS curve to the control curve for change in BAC from baseline during reactive hyperemia.
Body mass index (BMI) and testosterone levels were significantly increased in the PCOS group compared to controls (P < 0.05). In addition, the PCOS group had higher total and LDL cholesterol levels (P = 0.05 and 0.09, respectively). Change in BAC from baseline during reactive hyperemia was significantly increased in the PCOS group compared to controls even after adjusting for age, BMI and LDL cholesterol levels (P < 0.0001). There were no significant differences between the two groups in age, blood pressure, or fasting glucose or insulin levels.
Brachial artery conductance during reactive hyperemia is significantly increased in women with PCOS compared to controls and may be a novel early indicator of increased cardiovascular risk in women with PCOS.
polycystic ovary syndrome; androgen excess; brachial artery; conductance; cardiovascular risk
To determine if the combination of lifestyle(caloric restriction and exercise) and metformin(MET) would be superior to placebo and lifestyle(PBO) in improving PCOS phenotype.
Double-blind randomized 6 month trial of MET vs PBO
Two academic medical centers
Subjects collected urines daily for ovulation monitoring, had monthly monitoring of hormones/weight, and determination of body composition by DXA, glucose tolerance, and quality of life at baseline and completion.
Main outcome measures
Ovulation rates and testosterone levels
Dropout rates were high. There was no significant difference in ovulation rates. Testosterone levels were significantly lower compared to baseline in the MET group at 3 mos but not at 6 mos. There were no differences in weight loss between groups, but MET showed a significant decline at 6 mos compared to baseline(−3.4 kg, 95% CI:(−5.3, −1.5)). We noted divergent effects of MET vs PBO on OGTT indices of insulin sensitivity (increased) and secretion (worsened). Total bone mineral density (BMD) increased significantly in MET. There were no differences in QOL measures between groups. MET had increased diarrhea and headache, but fewer bladder infections and musculoskeletal complaints.
The addition of metformin to lifestyle produced little reproductive or glycemic benefit in women with PCOS, though our study had limited power due to high dropout. It is not possible at baseline to identify women likely to drop out.
ovarian function; insulin action; nutrition; exercise; androgen
In an attempt to evaluate the association between Allele 8 (A8) of D19S884 in the fibrillin-3 gene and circulating TGF-β and inhibin levels in women with polycystic ovary syndrome (PCOS), we studied 120 similarly aged women from families with PCOS and compared 40 women with PCOS who did not have A8 (A8− PCOS) to 40 women with PCOS who had A8 (A8+ PCOS) and 40 normally menstruating women who did not have either PCOS or A8 (A8− Non-PCOS). A8−PCOS is associated with higher levels of TGF-β1 compared to A8+ PCOS or A8− Non-PCOS, similar levels of TGF-β2 compared to A8+ PCOS but lower levels of TGF-β2 compared to A8− Non-PCOS, and lower levels of Inhibin B and aldosterone compared to A8+ PCOS.
polycystic ovary syndrome; TGF-β; inhibin; fibrillin; genetic association study; hyperandrogenism; insulin resistance
Dopaminergic anti-parkinsonian medications, such as levodopa (LD) cause drug-induced dyskinesias (DID) in majority of patients with Parkinson's disease (PD). Mucuna pruriens, a legume extensively used in Ayurveda to treat PD, is reputed to provide anti-parkinsonian benefits without inducing DID. We compared the behavioral effects of chronic parenteral administration of a water extract of Mucuna pruriens seed powder (MPE) alone without any additives, MPE combined with the peripheral dopa-decarboxylase inhibitor (DDCI) benserazide (MPE+BZ), LD+BZ and LD alone without BZ in the hemiparkinsonian rat model of PD. A battery of behavioral tests assessed by blinded investigators served as outcome measures in these randomized trials. In experiment 1, animals that received LD+BZ or MPE+BZ at high (6mg/Kg) and medium (4mg/Kg) equivalent doses demonstrated significant alleviation of parkinsonism, but, developed severe dose-dependent DID. LD+BZ at low doses (2mg/Kg) did not provide significant alleviation of parkinsonism. In contrast, MPE+BZ at an equivalent low dose significantly ameliorated parkinsonism. In experiment 2, MPE without any additives (12mg/Kg and 20mg/Kg LD equivalent dose) alleviated parkinsonism with significantly less DID compared to LD+BZ or MPE+BZ. In experiment 3, MPE without additives administered chronically provided long-term anti-parkinsonian benefits without causing DID. In experiment 4, MPE alone provided significantly more behavioral benefit when compared to the equivalent dose of synthetic LD alone without BZ. In experiment 5, MPE alone reduced the severity of DID in animals initially primed with LD+BZ. These findings suggest that Mucuna pruriens contains water soluble ingredients that either have an intrinsic DDCI-like activity or mitigate the need for an add-on DDCI to ameliorate parkinsonism. These unique long-term antiparkinsonian effects of a parenterally administered water extract of Mucuna pruriens seed powder may provide a platform for future drug discoveries and novel treatment strategies in PD.
basal ganglia; 6-hydroxydopamine (6-OHDA); nigrostriatal degeneration; movement disorders; complementary and alternative medicine
To determine the effect of meal composition on postprandial testosterone levels in women with polycystic ovary syndrome (PCOS).
Randomized, crossover design.
Academic research center.
Fifteen women with PCOS.
We evaluated changes in testosterone, sex hormone binding globulin (SHBG), DHEA-S, cortisol, glucose, and insulin for six hours after a high-fat, Western meal (HIFAT) (62% fat, 24% carbohydrate, 1g fiber) and an isocaloric low-fat, high-fiber meal (HIFIB) (6% fat, 81% carbohydrate, 27g fiber).
Main outcome measure
Change in testosterone.
Testosterone decreased 27% within two hours after both meals (P<0.001). However, testosterone remained below premeal values for four hours after the HIFIB meal (P<0.004) and six hours after the HIFAT meal (P<0.004). Insulin was two fold higher for two hours after the HIFIB meal compared with the HIFAT meal (P<0.03). Glucose was higher for one hour after the HIFIB meal compared with the HIFAT meal (P<0.003). DHEA-S decreased 8−10% within 2−3 hours after both meals, then increased over the remainder of the study period (P<0.001). Cortisol decreased over the 6-hour period after both meals (P<0.001).
Diet plays a role in the regulation of testosterone levels in women with PCOS. Further studies are needed to determine the role of diet composition in the treatment of PCOS. (ClinicalTrials.gov Identifier: NCT0455338).
insulin resistance; hyperandrogenism; postprandial; testosterone; fiber
To examine the relationship of male obesity and reproductive function.
Academic medical center
87 adult males, body mass index (BMI) range from 16.1 to 47.0 kg/m2 (mean = 29.3 kg/m2 ,SD=6.5 kg/m2).
Main Outcome Measures
Reproductive history, physical examination, inhibin B, FSH, LH, testosterone, unbound testosterone (uT) levels and semen-analysis.
BMI was negatively correlated with testosterone (R = −0.38, P <0.001), FSH (R = −0.22, P = 0.042) and inhibin B levels (R = −0.21, P = 0.048), and was positively correlated with estradiol levels (R = 0.34, P = 0.001). Testosterone also negatively correlated with skin fold thickness (SFT) (R = −0.30, P = 0.005). There was no correlation of BMI or SFT with semen-analysis parameters (sperm density, volume, motility or morphology). Inhibin B level correlated significantly with sperm motility (R = 0.23, P = 0.045). Males with paternity had lower BMIs (28.0 kg/m2 vs. 31.6 kg/m2; P = 0.037) and lower SFT (24.7 mm vs. 34.1 mm; P = 0.016) than males without.
Obesity is an infertility factor in otherwise normal males. Obese males demonstrate a relative hypogonadotropic hypogonadism. Reduced inhibin B levels and diminished paternity suggest compromised reproductive capacity in this population.
Male infertility; inhibin B; semen; body fat distribution
To test for associations between urine markers, bladder biopsy features and bladder ulcers in interstitial cystitis/painful bladder syndrome (IC/PBS).
Materials and Methods
Subjects were 72 patients with IC/PBS undergoing bladder distention and biopsy. Urine was collected before the procedure. Urine marker levels were correlated with biopsy and cystoscopic findings. Patients with no previous IC/PBS treatments (n=47) were analyzed separately from previously treated patients (n=25).
For untreated patients, urine IL-6 and cGMP were associated with urothelial EGF receptor staining (for IL-6 r=0.29, 95% CI (0.07, 0.51), p=0.01; for cGMP r=0.34, 95% CI (0.13, 0.55), p=0.002). Urine IL-8 was negatively associated with urothelial HB-EGF staining (r=-0.34, 95% CI (-0.55, -0.12), p=0.002) and positively associated with lamina propria mast cell count (r=0.29, 95% CI (0.06, 0.52), p=0.01). The latter association also was seen in treated patients (r=0.46, 95% CI (0.20, 0.73), p<0.001). None of the urine markers was significantly different for ulcer vs. nonulcer patients. All of the ulcer patients had extensive inflammation on bladder biopsy: severe mononuclear cell infiltration, moderate or strong IL-6 staining in the urothelium and lamina propria, and LCA staining in >10% of the lamina propria. However, these features also were seen in 24-76% of the nonulcer patients.
Overall, urine markers did not associate robustly with biopsy findings. The strongest association was a positive association between urine IL-8 levels and bladder mast cell count. Ulcer patients consistently had bladder inflammation, but the cystoscopic finding of ulcers was not a sensitive indicator of inflammation on bladder biopsy.
interstitial cystitis, urine; interstitial cystitis, pathology; interstitial cystitis, physiopathology
In neonatal trials of pre-term or low-birth-weight infants, twins may represent 10–20% of the study sample. Mixed-effects models and generalized estimating equations are common approaches for handling correlated continuous or binary data. However, the operating characteristics of these methods for mixes of correlated and independent data are not well established.
Simulation studies were conducted to compare mixed-effects models and generalized estimating equations to linear regression for continuous outcomes. Similarly, mixed-effects models and generalized estimating equations were compared to ordinary logistic regression for binary outcomes. The parameter of interest is the treatment effect in two-armed clinical trials. Data from the National Institute of Child Health & Human Development Neonatal Research Network are used for illustration.
For continuous outcomes, while the coverage never fell below 0.93, and the type I error rate never exceeded 0.07 for any method, overall linear mixed-effects models performed well with respect to median bias, mean squared error, coverage, and median width. For binary outcomes, the coverage never fell below 0.90, and the type I error rate never exceeded 0.07 for any method. In these analyses, when randomization of twins was to the same treatment group or done independently, ordinary logistic regression performed best. When randomization of twins was to opposite treatment arms, a rare method of randomization in this setting, ordinary logistic regression still performed adequately. Overall, generalized linear mixed models showed the poorest coverage values.
For continuous outcomes, using linear mixed-effects models for analysis is preferred. For binary outcomes, in this setting where the amount of related data is small, but non-negligible, ordinary logistic regression is recommended.
To evaluate changes in urine markers and symptom scores after bladder distention in interstitial cystitis (IC) patients.
Materials and Methods
Subjects were 33 new patients with no prior IC treatments. Urine specimens were taken before and one month after bladder distention. University of Wisconsin (UW) symptom scores were done the same day as the urine specimen collection. Urine marker levels and symptom scores before and after distention were compared. Changes in markers were tested for associations with changes in symptom scores and other markers. Pre-distention markers and specific pre-distention symptoms were tested for their association with post-distention symptom improvement.
After distention, the median total UW score decreased significantly (28.5 before, 10 after, p<0.001). Twelve patients (36%) had at least 30% improvement in UW score, and eight patients (24%) had at least 50% improvement. No pre-distention markers or symptoms predicted which patients would have a good response. Two of the urine markers improved significantly after distention: anti-proliferative factor (APF) activity (median −96% before, −17% after, p< 0.001) and heparin binding-epidermal growth factor-like growth factor (HB-EGF) levels (median 0.34 ng/mg creatinine before, 4.1 after, p<0.001). None of the changes in urine markers associated with changes in symptom scores.
The median symptom score for newly diagnosed IC patients decreased after distention, but only a minority of patients had at least 30% symptom improvement. Bladder distention altered urine APF activity and HB-EGF levels towards normal, but the mechanism of symptom relief after distention is still unknown.
interstitial cystitis, urine; interstitial cystitis, surgery; interstitial cystitis, therapy; interstitial cystitis, physiopathology
Inappropriate use of antibiotics by individuals worried about biological agent exposures during bioterrorism events is an important public health concern. However, little is documented about the extent to which individuals with self-identified risk of anthrax exposure approached physicians for antimicrobial prophylaxis during the 2001 bioterrorism attacks in the United States.
We conducted a telephone survey of randomly selected members of the Pennsylvania Chapter of the American College of Emergency Physicians to assess patients' request for and emergency physicians' prescription of antimicrobial agents during the 2001 anthrax attacks.
Ninety-seven physicians completed the survey. Sixty-four (66%) respondents had received requests from patients for anthrax prophylaxis; 16 (25%) of these physicians prescribed antibiotics to a total of 23 patients. Ten physicians prescribed ciprofloxacin while 8 physicians prescribed doxycycline.
During the 2001 bioterrorist attacks, the majority of the emergency physicians we surveyed encountered patients who requested anthrax prophylaxis. Public fears may lead to a high demand for antibiotic prophylaxis during bioterrorism events. Elucidation of the relationship between public health response to outbreaks and outcomes would yield insights to ease burden on frontline clinicians and guide strategies to control inappropriate antibiotic allocation during bioterrorist events.