A risk analysis of alpelisib-induced hyperglycemia in patients with advanced solid tumors and breast cancer.

BACKGROUND: Hyperglycemia is an on-target effect of PI3Kα inhibitors. Early identification and intervention of treatment-induced hyperglycemia is important for improving management of patients receiving a PI3Kα inhibitor like alpelisib. Here, we characterize incidence of grade 3/4 alpelisib-related hyperglycemia, along with time to event, management, and outcomes using a machine learning model. METHODS: Data for the risk model were pooled from patients receiving alpelisib ± fulvestrant in the open-label, phase 1 X2101 trial and the randomized, double-blind, phase 3 SOLAR-1 trial. The pooled population (n = 505) included patients with advanced solid tumors (X2101, n = 221) or HR+/HER2- advanced breast cancer (SOLAR-1, n = 284). External validation was performed using BYLieve trial patient data (n = 340). Hyperglycemia incidence and management were analyzed for SOLAR-1. RESULTS: A random forest model identified 5 baseline characteristics most associated with risk of developing grade 3/4 hyperglycemia (fasting plasma glucose, body mass index, HbA1c, monocytes, age). This model was used to derive a score to classify patients as high or low risk for developing grade 3/4 hyperglycemia. Applying the model to patients treated with alpelisib and fulvestrant in SOLAR-1 showed higher incidence of hyperglycemia (all grade and grade 3/4), increased use of antihyperglycemic medications, and more discontinuations due to hyperglycemia (16.7% vs. 2.6% of discontinuations) in the high- versus low-risk group. Among patients in SOLAR-1 (alpelisib + fulvestrant arm) with PIK3CA mutations, median progression-free survival was similar between the high- and low-risk groups (11.0 vs. 10.9 months). For external validation, the model was applied to the BYLieve trial, for which successful classification into high- and low-risk groups with shorter time to grade 3/4 hyperglycemia in the high-risk group was observed. CONCLUSIONS: A risk model using 5 clinically relevant baseline characteristics was able to identify patients at higher or lower probability for developing alpelisib-induced hyperglycemia. Early identification of patients who may be at higher risk for hyperglycemia may improve management (including monitoring and early intervention) and potentially lead to improved outcomes. REGISTRATION: ClinicalTrials.gov: NCT01219699 (registration date: October 13, 2010; retrospectively registered), ClinicalTrials.gov: NCT02437318 (registration date: May 7, 2015); ClinicalTrials.gov: NCT03056755 (registration date: February 17, 2017).

Factors associated with self-report of polycystic ovary syndrome in the Coronary Artery Risk Development in Young Adults study (CARDIA).

BACKGROUND: Polycystic ovary syndrome (PCOS) is underdiagnosed, but factors associated with women's report of diagnosis are not well-understood, particularly social determinants of health. Therefore, in a population-based cohort, we compared the characteristics of women with self-reported PCOS vs. women who have unrecognized PCOS vs. women without PCOS. METHODS: We performed a secondary data analysis of the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a population-based, prospective cohort of Black and White women. Participants were women (n = 2028) who responded to the question, "Did a doctor or nurse ever tell you that you had polycystic ovarian syndrome or polycystic ovarian disease?" at the year 15 examination. Women who answered "yes" were defined as having self-reported PCOS. Women who answered "no or not sure" were defined as having unrecognized PCOS if they also had irregular menses and hyperandrogenemia between 20 and 30 years of age. Exposures of interest included social determinants of health, symptoms including irregular menses and hirsutism, and comorbid conditions. RESULTS: Forty-three (2.1%) of women had self-reported PCOS, 135 (6.7%) had unrecognized PCOS, and 1850 (91%) women were without PCOS. In logistic regression models adjusting for age, race, and center, women with self-reported PCOS were more likely to have obesity (OR 1.83, 95% CI 1.22, 2.75) and diabetes (OR 2.37, 95% CI 1.05, 5.33) compared to women without PCOS. Women with unrecognized PCOS were more likely to have hypertension (OR 1.68, 95% CI 1.03, 2.74) and food insecurity (OR 1.94, 95% CI 1.25, 3.01) compared to women without PCOS. CONCLUSIONS: Unrecognized PCOS is common. Self-report of PCOS is not associated with access to healthcare. Women who report PCOS are more often obese and comorbidities may contribute to recognition of PCOS.

The prospective association of hyperandrogenism, oligomenorrhea and polycystic ovary syndrome with incident gestational diabetes: The coronary artery risk development in young adults women's study.

In this 28-year prospective study of 455 women (mean age: 26 years), polycystic ovary syndrome (PCOS) was associated with a 2.6-fold elevated risk of gestational diabetes (GDM). However, hyperandrogenism or oligomenorrhea in the absence of PCOS was not associated with GDM.

Women's Reproductive Milestones and Cardiovascular Disease Risk: A Review of Reports and Opportunities From the CARDIA Study.

In 1985 to 1986, the CARDIA (Coronary Artery Risk Development in Young Adults) study enrolled 5115 Black or White participants, including 2788 women, aged 18 to 30 years. Over the following 35 years, the CARDIA study amassed extensive longitudinal data on women's reproductive milestones, spanning menarche to menopause. Although not initially conceived as a study of women's health, >75 CARDIA study publications address relationships between reproductive factors and events with cardiovascular and metabolic risk factors, subclinical and clinical cardiovascular disease, and social determinants of health. The CARDIA study was one of the earliest population-based reports to note Black-White differences in age at menarche and associations with cardiovascular risk factors. Adverse pregnancy outcomes, particularly gestational diabetes and preterm birth, have been assessed along with postpartum behaviors, such as lactation. Existing studies have examined risk factors for adverse pregnancy outcomes and lactation, as well as their relationship to future cardiovascular and metabolic risk factors, diagnoses, and subclinical atherosclerosis. Ancillary studies examining components of polycystic ovary syndrome and ovarian biomarkers, such as anti-Müllerian hormone, have facilitated examination of reproductive health in a population-based cohort of young adult women. As the cohort transitioned through menopause, examination of the importance of premenopausal cardiovascular risk factors along with menopause has improved our understanding of shared mechanisms. The cohort is now aged in the 50s to mid-60s, and women will begin to experience a greater number of cardiovascular events as well as other conditions, such as cognitive impairment. Thus, in the next decade, the CARDIA study will provide a unique resource for understanding how the women's reproductive life course epidemiology informs cardiovascular risk, as well as reproductive and chronological aging.

Antimüllerian hormone and leukocyte aging markers in the Coronary Artery Risk Development in Young Adults study.

OBJECTIVE: To examine whether premenopausal reproductive age, as indicated by serum antimüllerian hormone (AMH), is associated with leukocyte aging biomarkers. DESIGN: Prospective cohort analysis. SETTING: The Coronary Artery Risk Development in Young Adults study, a population-based study of Black and White adults from four US communities (Birmingham, AL; Chicago, IL; Minneapolis, MN; Oakland, CA). PATIENT(S): Premenopausal women with serum AMH measures at examination year 15 as well as leukocyte aging markers. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Telomere length, mitochondrial deoxyribonucleic acid (mtDNA) copy number, and intrinsic and extrinsic epigenetic age acceleration (EAA) at examination years 15, 20, and 25 as well as change between examination years. RESULT(S): Women were 40.2 (standard deviation, 3.7) years of age at examination year 15 when the AMH and initial measures of telomere length and mtDNA copy number (n = 386) were obtained and EAA occurred. After adjustment for chronological age, race, and smoking history, AMH quartile at examination year 15 was not associated with telomere length at examination years 15 and 25 or telomere length change between these years, mtDNA copy number at examination years 15 and 25 or change between these years, or intrinsic EAA at examination years 15 and 20 or change between these years. Women in the second AMH quartile had faster extrinsic EAA than women in the lowest AMH quartile (ß-coefficient, 1.84; 95% confidence interval, 0.20-3.49). CONCLUSION(S): In a population-based cohort, AMH did not have associations with leukocyte telomere length, mtDNA copy number, or intrinsic EAA.

The association of age at natural menopause with pre- to postmenopausal changes in left ventricular structure and function: the Coronary Artery Risk Development in Young Adults (CARDIA) study.

OBJECTIVE: The association between menopause and incident cardiovascular disease (CVD) is controversial. We evaluated the relationships of estrogen deficiency (ovarian reproductive aging) assessed by age at natural menopause (ANM), chronological aging, and antecedent CVD risk factors (biological aging) with left ventricular (LV) structure and function among women transitioning from pre- to postmenopause. METHODS: We studied 771 premenopausal women (37% Black) from the Coronary Artery Risk Development in Young Adults Study with echocardiographic data in 1990 to 1991 (mean age: 32 y) who later reached natural menopause by 2015 to 2016 and had repeated echocardiographic measurements. Linear regression models were used to evaluate the association of ANM with parameters of LV structure and function. RESULTS: Mean ANM was 50 (± 3.8) years and the average time from ANM to the last echocardiograph was 7 years. In cross-sectional analyses, a 1-year increase in ANM was significantly associated with lower postmenopausal LV mass (LVM), LVM indexed to body surface area, LV mass-to-volume ratio, and relative wall thickness. In age-adjusted longitudinal analyses, higher ANM was inversely associated with pre- to postmenopausal changes in LVM (ß = -0.97; 95% CI: -1.81 to -0.13, P = 0.024) and LVM indexed (ß = -0.48; 95% CI: -0.89 to -0.07, P = 0.021). Controlling for baseline LV structure parameters and traditional CVD risk factors attenuated these associations. Further adjustment for hormone therapy uses did not alter these results. CONCLUSION: In this study, premenopausal CVD risk factors attenuated the association of ANM with changes in LV structure parameters. These data suggest that premenopausal CVD risk factors may predispose women to elevated future CVD risk more than ovarian aging.

Antimüllerian hormone and F2-isoprostanes in the Coronary Artery Risk Development in Young Adults (CARDIA) Study.

OBJECTIVE: To examine whether F2-isoprostanes, a marker of systematic oxidative stress, are associated with antimüllerian hormone (AMH), an indicator of ovarian reserve, in a population-based cohort of women of black and white ethnicities. DESIGN: Cross-sectional analysis. SETTING: Not applicable. PATIENTS: The CARDIA Women's Study, a population-based cohort. Black (n = 398) and white (n = 432) late reproductive-aged women (mean age 40 ± 3.6 years) without histories of gynecologic surgery. MAIN OUTCOME MEASURES: Log-transformed serum AMH concentrations. RESULTS: Linear regression models evaluated whether plasma F2-isoprostanes were associated with log-transformed AMH after adjustment for age, race, smoking, body mass index, and oral contraceptive pill use. Higher levels of F2-isoprostanes were associated with lower AMH levels (ß -0.048 per standard deviation, 95% confidence interval -0.087, -0.01). The observed associations were stronger at younger ages (P=.04 for interaction between levels of age and F2-isoprostanes). Indicators of other steps in the oxidative stress pathway (superoxide dismutase, paraoxonase activity, oxidized low-density lipoprotein cholesterol, and carotenoids) were not associated with AMH, although lower phospholipase A2 activity (ß 0.036 per standard deviation, 95% confidence interval 0.001, 0.071) was associated with lower AMH across all ages. CONCLUSION: In a population-based cohort, higher levels of F2-isoprostanes were associated with lower ovarian reserve, particularly at younger ages.

Association of smoking with abdominal adipose deposition and muscle composition in Coronary Artery Risk Development in Young Adults (CARDIA) participants at mid-life: A population-based cohort study.

BACKGROUND: Smokers have lower risk of obesity, which some consider a "beneficial" side effect of smoking. However, some studies suggest that smoking is simultaneously associated with higher central adiposity and, more specifically, ectopic adipose deposition. Little is known about the association of smoking with intermuscular adipose tissue (IMAT), an ectopic adipose depot associated with cardiovascular disease (CVD) risk and a key determinant of muscle quality and function. We tested the hypothesis that smokers have higher abdominal IMAT and lower lean muscle quality than never smokers. METHODS AND FINDINGS: We measured abdominal muscle total, lean, and adipose volumes (in cubic centimeters) and attenuation (in Hounsfield units [HU]) along with subcutaneous (SAT) and visceral adipose tissue (VAT) volumes using computed tomography (CT) in 3,020 middle-aged Coronary Artery Risk Development in Young Adults (CARDIA) participants (age 42-58, 56.3% women, 52.6% white race) at the year 25 (Y25) visit. The longitudinal CARDIA study was initiated in 1985 with the recruitment of young adult participants (aged 18-30 years) equally balanced by female and male sex and black and white race at 4 field centers located in Birmingham, AL, Chicago, IL, Minneapolis, MN, and Oakland, CA. Multivariable linear models included potential confounders such as physical activity and dietary habits along with traditional CVD risk factors. Current smokers had lower BMI than never smokers. Nevertheless, in the fully adjusted multivariable model with potential confounders, including BMI and CVD risk factors, adjusted mean (95% CI) IMAT volume was 2.66 (2.55-2.76) cm3 in current smokers (n = 524), 2.36 (2.29-2.43) cm3 in former smokers (n = 944), and 2.23 (2.18-2.29) cm3 in never smokers (n = 1,552) (p = 0.007 for comparison of former versus never smoker, and p < 0.001 for comparison of current smoker versus never and former smoker). Moreover, compared to participants who never smoked throughout life (41.6 [41.3-41.9] HU), current smokers (40.4 [39.9-40.9] HU) and former smokers (40.8 [40.5-41.2] HU) had lower lean muscle attenuation suggesting lower muscle quality in the fully adjusted model (p < 0.001 for comparison of never smokers with either of the other two strata). Among participants who had ever smoked, pack-years of smoking exposure were directly associated with IMAT volume (ß [95% CI]: 0.017 [0.010-0.025]) (p < 0.001). Despite having less SAT, current smokers also had higher VAT/SAT ratio than never smokers. These findings must be viewed with caution as residual confounding and/or reverse causation may contribute to these associations. CONCLUSIONS: We found that, compared to those who never smoked, current and former smokers had abdominal muscle composition that was higher in adipose tissue volume, a finding consistent with higher CVD risk and age-related physical deconditioning. These findings challenge the belief that smoking-associated weight loss or maintenance confers a health benefit.

Life-Course Reproductive History and Cardiovascular Risk Profile in Late Mid-Life: The CARDIA Study.

Background Reproductive events, that is, a preterm birth (PTB), small-for-gestational-age infant (SGA), and vasomotor symptoms of menopause, are associated with subclinical atherosclerotic cardiovascular disease (ASCVD). We evaluated whether women with a past PTB and/or SGA (henceforth PTB/SGA) were more likely to have severe vasomotor symptoms of menopause and whether the estimated 10-year ASCVD risk was higher in women with PTB/SGA and vasomotor exposures. Methods and Results We assigned 1866 women (mean age=55±1 years) in the CARDIA (Coronary Artery Risk Development in Young Adults) study to the following categories of reproductive exposures: none, PTB/SGA only, vasomotor symptoms only, or both PTB/SGA and vasomotor symptoms. We used Kruskal-Wallis tests to evaluate the differences in pooled cohort equation ASCVD risk scores by category and linear regression to evaluate the associations of categories with ASCVD risk scores adjusted for study center, body mass index, education, current hormone replacement therapy use, parity, and hysterectomy. Women with PTB/SGA were more likely to have severe vasomotor symptoms, 36% versus 30%, P<0.02. ASCVD risk score was higher in women with both PTB/SGA and vasomotor symptoms (4.6%; 95% CI, 4.1%-5.1%) versus women with no exposures (3.3%; 95% CI, 2.9%-3.7%) or vasomotor symptoms only (3.8%; 95% CI, 3.5%-4.0%). ASCVD risk score was higher in women PTB/SGA (4.8%; 95% CI, 3.6%-5.9%) versus no exposures. PTB/SGA and vasomotor symptoms was associated with ASCVD risk score in white women versus no exposures (ß=0.40; 95% CI, 0.02-0.78). Conclusions Women with prior PTB/SGA were more likely to have severe vasomotor symptoms of menopause. Reproductive exposures were associated with an estimated 10-year ASCVD risk in white women.

Depression Over the Lifespan in a Population-Based Cohort of Women With Polycystic Ovary Syndrome: Longitudinal Analysis.

OBJECTIVE: To (i) determine whether women with polycystic ovary syndrome (PCOS) from a population-based cohort experience elevated depression symptoms and (ii) characterize the trajectory of symptoms over the lifespan. DESIGN: The association between PCOS and longitudinal depression scores was investigated among 1127 black and white women participating in Coronary Artery Risk Development in Young Adults study. PCOS was ascertained at baseline (ages 20 to 32) by U.S. National Institutes of Health (NIH) criteria, incorporating androgens and symptoms of oligomenorrhea and hirsutism. The Center for Epidemiologic Studies-Depression (CES-D) scale was repeated prospectively in 5-year intervals over 25 years. Mixed-effects models evaluated the association between depression scores and PCOS after adjustment for confounders and characterized the trajectory of scores. The impact of race was explored. RESULTS: Eighty-three of 1127 (7.4%) participants met NIH PCOS criteria. Of these, 33 (40%) were black and 50 (60%) were white. CES-D scores were higher among women with PCOS [coefficient (coef) 2.51; 95% CI 1.49, 3.54; P < 0.01] across the lifespan. Scores decreased across the lifespan in women with and without PCOS (coef -0.1 point per year; P < 0.001). Black women experienced higher depression burden than white women (coef 1.80; 95% CI 1.20, 2.41; P < 0.001); however, an interaction was not detected between PCOS and race (P = 0.68). CONCLUSIONS: Women with PCOS-NIH from a population-based cohort are at risk for higher depression scores across the lifespan. Depression scores decline over time in women with PCOS in a trajectory similar to that in women without PCOS. Racial differences in depression risk should be acknowledged clinically and further explored.

Uterine Fibroids and the Risk of Cardiovascular Disease in the Coronary Artery Risk Development in Young Adult Women's Study.

BACKGROUND: Uterine fibroids, the most common reproductive tract tumor in women, have been associated with hypertension and atherosclerotic cardiovascular disease (CVD). Prior studies of fibroids and CVD have examined the subset of women with symptomatic fibroids who undergo hysterectomy, itself a risk factor for CVD. We aimed to study the risk of subclinical CVD, as determined by coronary artery calcification (CAC), carotid intima media thickness (CIMT), and left ventricular (LV) mass, in women with ultrasound-diagnosed uterine fibroids. MATERIALS AND METHODS: Participants were 972 women from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a cohort recruited in 1985-1986. CARDIA screened black and white women aged 35-49 years by ultrasound for fibroids at 16 years of follow-up (2002-2004). Demographics and CVD risk factors were collected in 2000-2001 at 15 years of follow-up (baseline for this analysis). Women were tested at years 15, 20, and 25 for CAC, at year 20 for CIMT, and at year 25 for echocardiographic LV mass. Multivariable logistic regression was used to estimate the odds of CAC, CIMT, and LV mass. RESULTS: Fifty-two percent of women had fibroids (61.7% in black, 38.3% in white women). Most CVD risk factors were more common in women with fibroids. Adjusted odds of subclinical CVD, such as elevated CIMT and elevated LV mass, were not different for women with fibroids compared with those without (CIMT odds ratio [OR] = 1.03; confidence interval [95% CI] 0.7-1.5 and LV mass OR = 1.14; 95% CI 0.77-1.68), when adjusted for confounders. CONCLUSIONS: Although women with fibroids had more CVD risk factors, presence of fibroids was not associated with subclinical CVD.

Transethnic and race-stratified genome-wide association study of fibroid characteristics in African American and European American women.

OBJECTIVE: To identify, through genome-wide association studies, genetic loci that associate with differences in fibroid size and number in a population of African American and European American women. DESIGN: Cross-sectional study. SETTING: Not applicable. PATIENT(S): Using BioVU, a clinical population from the Vanderbilt University Medical Center, and the Coronary Artery Risk Development in Young Adults cohort, a prospective cohort, we identified 1520 women (609 African American and 911 European American) with documented fibroid characteristics. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Outcome measurements include volume of largest fibroid, largest fibroid dimension, and number of fibroids (single vs. multiple). RESULT(S): In race-stratified analyses we achieved genome-wide significance at a variant located between MAT2B and TENM2 (rs57542984, ß = 0.13; 95% confidence interval 0.09, 0.17) for analyses of largest fibroid dimension in African Americans. The strongest signal for transethnic analyses was at a variant on 1q31.1 located between PLA2G4A and BRINP3 (rs6605005, ß = 0.24; 95% confidence interval 0.15, 0.33) for fibroid volume. Results from MetaXcan identified an association between predicted expression of the gene ER degradation enhancing alpha-mannosidase like protein 2 (EDEM2) in the thyroid and number of fibroids (Z score = -4.51). CONCLUSION(S): This study identified many novel associations between genetic loci and fibroid size and number in both race-stratified and transethnic analyses. Future studies are necessary to further validate our study findings and to better understand the mechanisms underlying these associations.

Admixture mapping of uterine fibroid size and number in African American women.

OBJECTIVE: To evaluate the relationship between genetic ancestry and uterine fibroid characteristics. DESIGN: Cross-sectional study. SETTING: Not applicable. PATIENT(S): A total of 609 African American participants with image- or surgery-confirmed fibroids in a biorepository at Vanderbilt University electronic health record biorepository and the Coronary Artery Risk Development in Young Adults studies were included. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Outcome measures include fibroid number (single vs. multiple), volume of largest fibroid, and largest fibroid dimension of all fibroid measurements. RESULT(S): Global ancestry meta-analyses revealed a significant inverse association between percentage of European ancestry and risk of multiple fibroids (odds ratio: 0.78; 95% confidence interval 0.66, 0.93; P=6.05 × 10-3). Local ancestry meta-analyses revealed five suggestive (P<4.80 × 10-3) admixture mapping peaks in 2q14.3-2q21.1, 3p14.2-3p14.1, 7q32.2-7q33, 10q21.1, 14q24.2-14q24.3, for number of fibroids and one suggestive admixture mapping peak (P<1.97 × 10-3) in 10q24.1-10q24.32 for volume of largest fibroid. Single variant association meta-analyses of the strongest associated region from admixture mapping of fibroid number (10q21.1) revealed a strong association at single nucleotide polymorphism variant rs12219990 (odds ratio: 0.41; 95% confidence interval 0.28, 0.60; P=3.82 × 10-6) that was significant after correction for multiple testing. CONCLUSION(S): Increasing African ancestry is associated with multiple fibroids but not with fibroid size. Local ancestry analyses identified several novel genomic regions not previously associated with fibroid number and increasing volume. Future studies are needed to explore the genetic impact that ancestry plays into the development of fibroid characteristics.

The association of surgical versus natural menopause with future left ventricular structure and function: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.

OBJECTIVE: To evaluate the association between surgical menopause (SM) versus natural menopause (NM) in relation to later left ventricular (LV) structure and function, while taking into account the LV parameters and other cardiovascular disease risk factor (CVDRF) levels that predate the menopausal transition. METHODS: We studied 825 premenopausal women from the Coronary Artery Risk Development in Young Adults study in 1990 to 1991 (baseline, mean age 32 years) who later reached menopause by 2010 to 2011 and had echocardiograms at these two time points. RESULTS: During 20 years of follow-up, 508 women reached NM, whereas 317 underwent SM (34% had bilateral oophorectomy). At baseline, women who later underwent SM were more likely to be black, younger, have greater parity, and higher mean values of systolic blood pressure, body mass index, and also lower mean high-density lipoprotein cholesterol and physical activity than women who reached NM. No significant differences in LV structure/function were found between groups. In 2010 to 2011, SM women had significantly higher LV mass, LV mass/volume ratio, E/e' ratio, and impaired longitudinal and circumferential strain than NM women. SM women with bilateral oophorectomy had adverse LV measures than women with hysterectomy with ovarian conservation. Controlling for baseline echocardiographic parameters and CVDRF in linear regression models eliminated these differences between groups. Further adjustment for age at menopause/surgery and hormone therapy use did not change these results. CONCLUSION: In this study, the adverse LV structure and function observed among women with SM compared with NM were explained by their unfavorable presurgical CVDRF profiles, suggesting that premenopausal CVDRF rather than gynecologic surgery predispose SM women to elevated future cardiovascular disease risk.

Ovarian aging in women with diabetes: An overview.

Type 2 diabetes is a global epidemic, and the prevalence and incidence of type 1 diabetes are increasing. The negative effects of diabetes on kidneys, nerves, and vessels are well established. The effect of diabetes on reproductive function is less well understood, but important to characterize, given the increasing numbers of young women with diabetes. In this review, we summarize the available literature on how women with diabetes experience ovarian aging, from menarche to menopause. We report that women with type 1 diabetes appear more likely to have ovarian dysfunction, manifested by delayed menses, menstrual irregularities, and possibly earlier menopause. Studies of women with type 2 diabetes are inconsistent but suggest increased anovulation and earlier menopause. Differences in reproductive aging between women with type 1 and type 2 diabetes raise questions about potential differences in the mechanisms contributing to ovarian aging. Although there is shared glycemic dysregulation, fundamental differences in insulin presence and processing distinguish the two diseases. This review suggests that insulin, age at diagnosis, and weight play a role in ovarian dysfunction. More long-term studies are needed to evaluate the multitude of factors that may disrupt hypothalamic, pituitary, and ovarian function in women with diabetes.

Is Surgical Menopause Associated With Future Levels of Cardiovascular Risk Factor Independent of Antecedent Levels? The CARDIA Study.

In the present study, we compared changes in risk factors for cardiovascular disease (CVD) before and after natural menopause (NM), hysterectomy with at least 1 ovary conserved (HOC), or hysterectomy with bilateral oophorectomy (HBSO). Data were obtained from women 18-30 years of age who were enrolled in the Coronary Artery Risk Development in Young Adults Study (1985-2011). Piecewise linear mixed models were used to examine changes in CVD risk factors from baseline to the index visit (the first visit after the date of NM or hysterectomy) and after index visit until the end of follow-up. During 25 years of follow-up, 1,045 women reached menopause (for NM, n = 588; for HOC, n = 304; and for HBSO, n = 153). At baseline, women with either type of hysterectomy had less favorable values for CVD risk factors. When comparing the annual rates of change of all CVD risk factors from baseline until the index visit to those from the index visit to the end of follow-up, we saw a small increase in rate of change for high-density lipoprotein cholesterol (ß = 0.28 mg/dL; P = 0.002) and a decrease for triglycerides (ß =-0.006 mg/dL; P = 0.027) for all groups. Hysterectomy was not associated with risk factors for CVD after accounting for baseline values. However, antecedent young-adult levels of CVD risk factors were strong predictors of levels of postmenopausal risk factors.

Anti-mullerian hormone (AMH) is associated with natural menopause in a population-based sample: The CARDIA Women's Study.

OBJECTIVE: AMH is associated with menopausal timing in several studies. In contrast to prior studies that were restricted to women with regular cycles, our objective was to examine this association in women with either regular or irregular menstrual cycles. METHODS: CARDIA is a longitudinal, population-based study that recruited adults ages 18-30 when it began in 1985-1986. AMH was measured in serum stored in 2002-2003. Natural menopause was assessed by survey in 2005-2006 and 2010-2011. RESULTS: Among 716 premenopausal women, median [25th, 75th] AMH was 0.77 [0.22-2.02]ng/dL at a median age of 42 [39-45] years. Twenty-nine percent of the women (n=207) reported natural menopause during 9 years of follow up. In fully adjusted discrete-time hazard models, a 0.5 ng/dL AMH decrement was associated with higher risk of menopause (p<0.001). Hazard ratios varied with time since AMH measurement. The HR (95% CI) for menopause was 8.1 (2.5-26.1) within 0-3 years and 2.3 (1.7-3.3) and 1.6 (1.3-2.1) for 3-6 and 6-9 years, respectively. When restricted to women with regular menses, results were similar (e.g., HR=6.1; 95% CI: 1.9-20.0 for 0-3 years). CONCLUSION: AMH is independently associated with natural menopause. AMH appears most useful in identifying women at risk of menopause in the near future (within 3 years of AMH measurement).

Prospective association of polycystic ovary syndrome with coronary artery calcification and carotid-intima-media thickness: the Coronary Artery Risk Development in Young Adults Women's study.

OBJECTIVE: To study the independent associations of polycystic ovary syndrome (PCOS), and its 2 components, hyperandrogenism and anovulation, with coronary artery calcification (CAC) and carotid artery intima-media thickness (IMT). APPROACH AND RESULTS: At the year 20 of the Coronary Artery Risk Development in Young Adults (CARDIA) study, a population-based multicenter cohort of young adults, women (mean age, 45 years) with information on menses and hirsutism in their twenties were assessed for CAC (n=982) and IMT (n=988). We defined PCOS as women who had both irregular menses and hyperandrogenism (n=55); isolated oligomenorrhea (n=103) as women who only had irregular menses; and isolated hyperandrogenism (n=156) as women who had either hirsutism or increased testosterone levels. Logistic regressions and general linear models were used to estimate the associations between components of PCOS and subclinical CVD. The prevalence of CAC was 10.3% overall. Women with PCOS had a multivariable adjusted odds ratio of 2.70 (95% confidence interval, 1.31-5.60) for CAC. Women with either isolated oligomenorrhea or isolated hyperandrogenism had no increased risk of CAC when compared with unexposed women. Women with PCOS had significantly increased bulb and internal carotid-IMT measurements; however, no significant differences were noted in bulb or internal carotid artery IMT among women with either isolated oligomenorrhea or isolated hyperandrogenism when compared with unexposed women. There were no differences in common carotid-IMT among the 4 study groups. CONCLUSIONS: In this study, women with PCOS, manifested as both anovulation and hyperandrogenism, but not women with one of these manifestations alone, were at increased risk for the development of subclinical CVD.