Melissa Wellons

OBJECTIVE: Cardiovascular disease is the number one killer of women. Identifying women at risk of cardiovascular disease has tremendous public health importance. Early menopause is associated with increased cardiovascular disease events in some predominantly white populations, but not consistently. Our objective was to determine if self-reported early menopause (menopause at an age <46 y) identifies women as at risk for future coronary heart disease or stroke. METHODS: The study population came from the Multi-Ethnic Study of Atherosclerosis, a longitudinal, ethnically diverse cohort study of US men and women aged 45 to 84 years enrolled in 2000-2002 and followed up until 2008. The association between a personal history of early menopause (either natural menopause or surgical removal of ovaries at an age <46 y) and future coronary heart disease and stroke was assessed in 2,509 women (ages 45-84 y; 987 white, 331 Chinese, 641 black, and 550 Hispanic) from the Multi-ethnic Study Atherosclerosis who were free of cardiovascular disease at baseline. RESULTS: Of 2,509 women, 693 (28%) reported either surgical or natural early menopause. In survival curves, women with early menopause had worse coronary heart disease and stroke-free survival (log rank P = 0.008 and P = 0.0158). In models adjusted for age, race/ethnicity, Multi-ethnic Study Atherosclerosis site, and traditional cardiovascular disease risk factors, this risk for coronary heart disease and stroke remained (hazard ratio, 2.08; 95% CI, 1.17-3.70; and hazard ratio, 2.19; 95% CI, 1.11-4.32, respectively). CONCLUSIONS: Early menopause is positively associated with coronary heart disease and stroke in a multiethnic cohort, independent of traditional cardiovascular disease risk factors.

Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8 × 10(-106)), PRMT6 (rs17496332, 1p13.3, p = 1.4 × 10(-11)), GCKR (rs780093, 2p23.3, p = 2.2 × 10(-16)), ZBTB10 (rs440837, 8q21.13, p = 3.4 × 10(-09)), JMJD1C (rs7910927, 10q21.3, p = 6.1 × 10(-35)), SLCO1B1 (rs4149056, 12p12.1, p = 1.9 × 10(-08)), NR2F2 (rs8023580, 15q26.2, p = 8.3 × 10(-12)), ZNF652 (rs2411984, 17q21.32, p = 3.5 × 10(-14)), TDGF3 (rs1573036, Xq22.3, p = 4.1 × 10(-14)), LHCGR (rs10454142, 2p16.3, p = 1.3 × 10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7 × 10(-08)), and UGT2B15 (rs293428, 4q13.2, p = 5.5 × 10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5 × 10(-08), women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.

The risks and benefits of structured treatment interruption (STI) in HIV-1-infected subjects are not fully understood. A pilot study was performed to compare STI with continuous highly active antiretroviral therapy (HAART) in chronic HIV-1-infected subjects with HIV-1 plasma RNA levels (VL) <400 copies per ml and CD4(+) T cells >400 per microl. CD4(+) T cells, VL, HIV-1-specific neutralizing antibodies, and IFN-gamma-producing HIV-1-specific CD8(+) and CD4(+) T cells were measured in all subjects. STIs of 1-month duration separated by 1 month of HAART, before a final 3-month STI, resulted in augmented CD8(+) T cell responses in all eight STI subjects (P = 0.003), maintained while on HAART up to 22 weeks after STI, and augmented neutralization titers to autologous HIV-1 isolate in one of eight subjects. However, significant decline of CD4(+) T cell count from pre-STI level, and VL rebound to pre-HAART baseline, occurred during STI (P = 0.001 and 0.34, respectively). CD4(+) T cell counts were regained on return to HAART. Control subjects (n = 4) maintained VL <400 copies per ml and stable CD4(+) T cell counts, and showed no enhancement of antiviral CD8(+) T cell responses. Despite increases in antiviral immunity, no control of VL was observed. Future studies of STI should proceed with caution.

PURPOSE: To assess gender differences among residents regarding their plans to have children during residency and determine the most influential reasons for these differences. METHOD: Using the Health Belief Model as a framework, the authors created an instrument to survey 424 residents from 11 residency programs at three academic medical institutions about their intentions to have children during residency. The authors developed a scale to assess the perceived career threats of having children during residency, evaluated its psychometric properties, and calculated the effect of the mediators. RESULTS: The response rate was 77% (328/424). Forty-one percent of men versus 27% of women planned to have children during residency (P = .01). The instrument measured four career threats-extended training, loss of fellowship positions, pregnancy complications, and interference with career plans-on a five-point Likert scale. The scale had a Cronbach alpha of 0.84 and an eigenvalue of 2.2. Compared with men, women had higher scores for each item and a higher mean score (2.9 versus 2.1, P = .001), signifying greater belief in the potential of pregnancy to threaten careers. After adjusting for age, institution, postgraduate year, and knowledge of parental leave policies, women were less likely to plan to have children during residency (odds ratio 0.46 [95% confidence interval 0.25-0.84]). In mediation analysis, threats to career explained 67% of the gender variance. CONCLUSIONS: Women residents intentionally postpone pregnancy because of perceived threats to their careers. Medical educators should be aware of these findings when counseling female trainees.

OBJECTIVE: To estimate whether women aged 20-32 years who fulfilled National Institutes of Health criteria for polycystic ovary syndrome (PCOS) would be at higher risk for subsequent development of incident diabetes, dyslipidemia, and hypertension, and to estimate whether normal-weight women with PCOS would have the same degree of cardiovascular risk as overweight women with PCOS. METHODS: We estimated the association of PCOS with incident diabetes, dyslipidemia, and hypertension over a period of 18 years among 1,127 white and African-American women in the Coronary Artery Risk Development in Young Adults cohort. We classified women at baseline (ages 20-32 years) based on self-reported symptoms and serum androgen measures using National Institutes of Health PCOS criteria. We estimated the association of PCOS and subsequent cardiovascular risk factors, independent of baseline body mass index (BMI), using multivariable logistic regression. Additionally, among 746 women with a second assessment of PCOS at ages 34-46 years, we estimated the association of persistent PCOS with cardiovascular risk factors. RESULTS: Of 1,127 women, 53 (4.7%) met criteria for PCOS at ages 20-32 years. Polycystic ovary syndrome was associated with a twofold higher odds of incident diabetes (23.1% compared with 13.1%, adjusted odds ratio [AOR] 2.4, confidence interval [CI] 1.2-4.9) and dyslipidemia (41.9% compared with 27.7%, AOR 1.9, CI 1.0-3.6) over the course of 18 years; the association with incident hypertension was not significant (26.9% compared with 26.3%, AOR 1.7, CI 0.8-3.3). Normal-weight women with PCOS (n=31) had a threefold higher odds of incident diabetes compared with normal-weight women without PCOS (AOR 3.1, CI 1.2-8.0). Compared with those without PCOS, women with persistent PCOS (n=11) had the highest odds of diabetes (AOR 7.2, CI 1.1-46.5). CONCLUSION: Polycystic ovary syndrome is associated with subsequent incident diabetes and dyslipidemia, independent of BMI. Diabetes risk may be greatest for women with persistent PCOS symptoms. LEVEL OF EVIDENCE: II.