Clarisa R. Gracia

Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women—2011 Update: A Guideline From the American Heart Association

Substantial progress has been made in the awareness, treatment, and prevention of cardiovascular disease (CVD) in women since the first women-specific clinical recommendations for the prevention of CVD were published by the American Heart Association (AHA) in 1999.1 The myth that heart disease is a “mans disease” has been debunked; the rate of public awareness of CVD as the leading cause of death among US women has increased from 30% in 1997 to 54% in 2009.2 The age-adjusted death rate resulting from coronary heart disease (CHD) in females, which accounts for about half of all CVD deaths in women, was 95.7 per 100 000 females in 2007, a third of what it was in 1980.3,4 Approximately 50% of this decline in CHD deaths has been attributed to reducing major risk factors and the other half to treatment of CHD including secondary preventive therapies.4 Major randomized controlled clinical trials such as the Womens Health Initiative have changed the practice of CVD prevention in women over the past decade.5 The investment in combating this major public health issue for women has been significant, as have the scientific and medical achievements. Despite the gains that have been made, considerable challenges remain. In 2007, CVD still caused ≈1 death per minute among women in the United States.6 These represent 421 918 deaths, more womens lives than were claimed by cancer, chronic lower respiratory disease, Alzheimer disease, and accidents combined.6 Reversing a trend of the past 4 decades, CHD death rates in US women 35 to 54 years of age now actually appear to be increasing, likely because of the effects of the obesity epidemic.4 CVD rates in the United States are significantly higher for black females compared with their white counterparts (286.1/100 000 versus …

Symptoms associated with menopausal transition and reproductive hormones in midlife women.

OBJECTIVE: To test the hypothesis that prevalence of women with menopausal symptoms of hot flushes; aches, joint pain, and stiffness; depressed mood; poor sleep; decreased libido; or vaginal dryness increases with progression through the menopausal transition. METHODS: Women in the Penn Ovarian Aging Study were assessed longitudinally for 9 years. Data were obtained from structured interviews, a validated symptom questionnaire, menstrual bleeding dates and early follicular hormone measures (estradiol [E2], follicle-stimulating hormone [FSH], and inhibin b). Menopausal stages were based on menstrual bleeding patterns. Other risk factors included age, race, history of depression, current smoking, body mass index, and perceived stress. Generalized linear regression models for repeated measures were used to estimate associations among the variables with each symptom. RESULTS: The prevalence of hot flushes; aches, joint pain, and stiffness; and depressed mood increased in the menopausal transition. Menopausal stage was associated with hot flushes (P<.001); aches joint pain, and stiffness (P<.001); and depressed mood (P=.002). Within-woman fluctuations of E2 were associated with hot flushes and aches. Poor sleep, decreased libido, and vaginal dryness were not associated with menopausal stages. There was 80% power to detect an absolute difference of 11% for libido and vaginal dryness and 17% for poor sleep in the prevalence of these symptoms in the late menopausal transition compared with premenopausal status. CONCLUSION: The study highlights the role of menopausal stages for some symptoms of midlife women and indicates that stages in the transition to menopause are associated with hot flushes; aches, joint pain, and stiffness; and depressed mood. Fluctuations of E2, decreased levels of inhibin b, and increased FSH levels were associated with these symptoms. LEVEL OF EVIDENCE: II

DEFINING MENOPAUSE STATUS: CREATION OF A NEW DEFINITION TO IDENTIFY THE EARLY CHANGES OF THE MENOPAUSAL TRANSITION

Objective: Several menopausal staging definitions are currently being used in ongoing studies designed to identify changes occurring during menopause. The objective of this study was to determine which definition captures the earliest hormonal changes in the menopausal transition. Design: In this prospective cohort study, women aged 35 to 47 years were followed for 5 years. Women were classified as premenopausal, early transition, late transition, and postmenopausal by 2 different menopausal staging systems defined by bleeding patterns. Definitions from the Study of Women Health Across the Nation (SWAN) and Stages of Reproductive Aging Workshop (STRAW) were compared. A new menopausal staging system (PENN-5) was also developed with five groups rather than four to distinguish among women with more subtle changes in cycle length. For each staging system, a linear regression model was created comparing mean hormone values (inhibin B, FSH, LH, E2) and menopausal stages at each assessment. Race, body mass index, cycle day, smoking, and follow-up time were included in the model. Results: Statistically significant differences in mean inhibin B and FSH levels, but not estradiol levels, were detected between the earliest menopausal stages of each definition. Significant differences in LH values were detected among the earliest stages of the SWAN and STRAW definitions, but not the PENN-5 definition. Conclusions: Subtle changes in menstrual cycle length reflect significant changes in inhibin B and FSH levels during the menopausal transition. Therefore, it appears that subtle changes in bleeding pattern may be helpful in identifying the earliest hormonal changes during menopausal transition.

Anti-Mullerian Hormone as a Predictor of Time to Menopause in Late Reproductive Age Women

CONTEXT Anti-mullerian hormone (AMH) has emerged as a marker of ovarian reserve and a possible surrogate measure of reproductive aging. OBJECTIVE The aim of the study was to evaluate the predictive value of AMH levels in determining the median time to menopause for late reproductive age women and the predictive ability of AMH compared to FSH and inhibin b. DESIGN AND SETTING A 14-yr follow-up in the Penn Ovarian Aging Study, 1996-2010, was conducted for a randomly identified population-based cohort. SUBJECTS A total of 401 late reproductive age women participated in the study. MAIN OUTCOME MEASURE Observed time to menopause was measured. RESULTS All participants were premenopausal, with a mean (SD) age of 41.47 (3.52) yr and a median AMH level of 0.68 ng/ml at baseline. AMH strongly predicted time to menopause; age further improved predictions. Among women with a baseline AMH level below 0.20 ng/ml, the median time to menopause was 5.99 yr [95% confidence interval (CI), 4.20-6.33] in the 45- to 48-yr age group and 9.94 yr (95% CI, 3.31-12.73) in the 35- to 39-yr age group. With higher baseline AMH levels above 1.50 ng/ml, the median time to menopause was 6.23 yr in the oldest age group and more than 13.01 yr in the youngest age group. Smoking significantly reduced the time to menopause (hazard ratio, 1.61; 95% CI, 1.19-2.19; P = 0.002). AMH was a stronger predictor of time to menopause than FSH or inhibin b. CONCLUSIONS AMH is a strong predictor of median time to menopause in late reproductive age women. Age and smoking are significant and independent contributors to the predictions of AMH.

Diagnosing ectopic pregnancy: decision analysis comparing six strategies ☆

Objective To compare six published methods of diagnosing ectopic pregnancy. Methods Decision analysis compared six diagnostic algorithms involving combinations of clinical examination, transvaginal ultrasound, serum progesterone, serum hCG, and D&C. The population was composed of hemodynamically stable women who presented to a tertiary care university emergency department with abdominal pain or bleeding in their first trimesters. Outcome measures included number of missed ectopic pregnancies, potentially interrupted intra-uterine pregnancies, surgical and diagnostic procedures, time until diagnosis, and cost. Results Ultrasound followed by serum hCG in women with nondiagnostic scans yielded the most favorable outcomes; no ectopic pregnancy was missed, only 1% of all potential intrauterine pregnancies were interrupted, and time to diagnosis averaged 1.46 days. Quantitative hCG measurement followed by ultrasound only in women with hCG levels above the discriminatory zone was optimal if sensitivity of ultrasound to diagnose intrauterine pregnancy was less than 93%. Serum progesterone measurement was not favored because it was associated with missed ectopic pregnancies (2.6%). Conclusion Given the current accuracy of tests for diagnosing ectopic pregnancy, algorithms using a combination of ultrasound and hCG resulted in the best outcomes. Ultrasound as the first step was the most efficient and accurate method of diagnosing ectopic pregnancies.

Obesity and reproductive hormone levels in the transition to menopause

Objective:The aim of this study was to estimate associations of obesity with reproductive hormone levels as women progress from premenopausal to postmenopausal status. Methods:This was a longitudinal study conducted in the population-based Penn Ovarian Aging Cohort (N = 436). At cohort enrollment, the women were premenopausal, ages 35 to 47 years, with equal numbers of African Americans and whites. Anthropometric measures, menopause status, and reproductive hormone measures were evaluated for 12 years. Associations of the anthropometric measures with estradiol, follicle-stimulating hormone, and inhibin B in the menopausal transition were estimated using generalized linear regression models for repeated measures. Results:Associations between obesity and hormone levels differed by menopause status as indicated by significant interactions between each hormone and menopausal stage. Premenopausal obese and overweight women had significantly lower estradiol levels compared with nonobese women, independent of age, race, and smoking (obese: 32.8 pg/mL [95% CI, 30.6-35.2] vs nonobese: 39.8 pg/mL [95% CI, 37.0-42.8], P < 0.001). The associations reversed postmenopause, with obese women having the highest estradiol levels (obese: 20.6 pg/mL [95% CI, 17.2-24.7] vs nonobese: 12.2 pg/mL [95% CI, 10.1-14.8], P < 0.001). Inhibin B levels were significantly lower in premenopausal obese compared with nonobese women but reversed in the late transition stage. Follicle-stimulating hormone levels were lowest in postmenopausal obese compared with nonobese women (P < 0.001). Measures of waist circumference (central adiposity) and waist-to-hip ratio paralleled the body mass index results. Conclusion:Obesity is an important factor in hormone dynamics independent of age, race, and smoking in midlife women, although the mechanisms remain unclear.

Body size affects measures of ovarian reserve in late reproductive age women.

Objective: To examine the association between obesity and serum and ultrasound measures of ovarian reserve in late reproductive age women. Design: Cross-sectional study of 36 healthy women, ages 40 to 52 years. Women were recruited in a 1:1 ratio of normal weight (body mass index <25) to obese women (body mass index ≥30). Early follicular phase blood draw, anthropometric measurements, and a transvaginal ultrasonography were performed. Outcome measures were serum antimullerian hormone, inhibin B, estradiol, follicle-stimulating hormone, ultrasound ovarian volume, and antral follicle count. Results: Mean antral follicle count was 7.6 for normal weight and 6.3 for obese women (P = 0.35). Proportions of normal weight (17%) versus obese women (22%) with antral follicle count less than 4 were similar. Ovarian volumes did not differ by body size. In adjusted models, antimullerian hormone levels in obese women were 77% lower on average than those in normal weight women (P = 0.02). Inhibin B levels were 24% lower in obese women compared with normal weight women (P = 0.08). Follicle-stimulating hormone and estradiol were not associated with body mass index. Conclusions: Although antral follicle count did not differ by body size, antimullerian hormone was lower in obese compared with normal weight late reproductive age women. These data suggest that lower antimullerian hormone levels in obese late reproductive age women result from physiologic processes other than decreased ovarian reserve.

Impact of cancer therapies on ovarian reserve

OBJECTIVE To determine whether measures of ovarian reserve differ between females exposed to cancer therapies in a dose-dependent manner as compared with healthy controls of similar age and late reproductive age. DESIGN Cross-sectional analysis of data from a prospective cohort study. SETTING University medical center. PATIENT(S) Seventy-one cancer survivors aged 15-39 years; 67 healthy, similarly aged unexposed subjects; and 69 regularly menstruating women of late reproductive age (40-52 years). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Early follicular-phase hormones (FSH, E(2), inhibin B, antimüllerian hormone [AMH]) and ovarian ultrasound measurements (ovarian volume and antral follicle counts [AFC]) were compared using multivariable linear regression. RESULT(S) In adjusted models, FSH, AMH, and AFC differed between exposed vs. unexposed subjects (FSH 11.12 mIU/mL vs. 7.25 mIU/mL; AMH 0.81 ng/mL vs. 2.85 ng/mL; AFC 14.55 vs. 27.20). In participants with an FSH <10 mIU/mL, survivors had lower levels of AMH and AFC compared with controls. Alkylating agent dose score was associated with increased levels of FSH and decreased levels of AMH. Exposure to pelvic radiation was associated with impairment in FSH, AMH, AFC, and ovarian volume. Antimüllerian hormone was similar in women previously exposed to high-dose cancer therapy and 40-42-year-old controls. CONCLUSION(S) Measures of ovarian reserve are impaired in a dose-dependent manner among cancer survivors compared with unexposed females of similar age. Reproductive hormone levels in menstruating survivors exposed to high-dose therapy are similar to those in late-reproductive-age women. The predictive value of measures for pregnancy and menopause must be studied. CLINICALTRIALS.GOV IDENTIFIER: NCT01143844.

Hormones and sexuality during transition to menopause

OBJECTIVE: To examine the relationship between reproductive hormonal dynamics and sexual dysfunction assessed in a cohort of women approaching menopause. METHODS: Women in the Penn Ovarian Aging Study were assessed at yearly intervals for 3 years with early follicular hormone measurements (estradiol, follicle-stimulating hormone, luteinizing hormone [LH], sex hormone binding globulin, dehyroepiandrosterone sulfate [DHEAS], total testosterone), anthropometric measures, and extensive questionnaires including the Female Sexual Function Index. Univariable analyses were performed to determine the association between hormones, menopausal status, and sexual dysfunction. Multivariable linear and logistic regression models were created to examine the influence of hormones on sexual function adjusting for the effect of potential confounders. RESULTS: The final multivariable model indicated that sexual dysfunction increased with advanced menopausal status, with postmenopausal women being 2.3 times as likely to experience sexual dysfunction compared with premenopausal women (odds ratio 2.3, 95% confidence interval [CI] 1.3–4.1). Low DHEAS serum concentrations were associated with decreased sexual function (odds ratio 1.59, 95% CI 1.19–2.14). Additional risk factors associated with sexual dysfunction included absence of a sexual partner (11.2, 95% CI 6.9–18.1), high anxiety (3.8, 95% CI 1.6–9.2), and children under the age of 18 living at home (1.6, 95% CI 1.1–5.5). Lubrication, orgasm, and pain were specific aspects of sexuality negatively affected by menopause. CONCLUSION: This study confirms the observation that sexual dysfunction increases over the menopausal transition. Several factors associated with sexual dysfunction include low DHEAS, absence of a sexual partner, anxiety, and children under the age of 18 living at home. LEVEL OF EVIDENCE: II

Symptoms in the menopausal transition: hormone and behavioral correlates.

OBJECTIVE: To estimate the association of headache, irritability, mood swings, anxiety, and concentration difficulties with menopausal stage and with reproductive hormones in the menopausal transition. METHODS: Women in the Penn Ovarian Aging Study were assessed longitudinally for 9 years. Data were obtained from structured interviews, a validated symptom questionnaire, menstrual bleeding dates, and early follicular hormone measures of estradiol (E2), follicle-stimulating hormone (FSH), and testosterone. Menopausal stages were based on menstrual bleeding patterns. Other risk factors included history of depression, perceived stress, premenstrual syndrome, current smoking, age, and race. Generalized linear regression models for repeated measures were used to estimate associations among the variables with each symptom. RESULTS: Headache decreased in the transition to menopause and was significantly associated with menopausal stage in univariable analysis (P=.002). Mood swings were inversely associated with mean FSH levels (P=.005). Irritability was inversely associated with mean levels of FSH (P=.017) and testosterone (P=.008). In multivariable models, the independent contributions of other covariates were strongly associated with these symptoms: premenstrual syndrome (P<.001) and perceived stress (P<.001) for irritability and mood swings; P=.018 for headache. There was 80% power with 0.05 alpha to detect a decrease of 13% or more in the prevalence of the symptoms in the postmenopausal stage compared with the premenopausal stage. CONCLUSION: Headache significantly decreased in the transition to menopause. Irritability and mood swings also decreased in the menopausal transition as assessed by hormone levels. The findings indicate that these symptoms that are commonly linked with menopause diminish with the physiologic changes of the menopausal transition. LEVEL OF EVIDENCE: II