Penn Ovarian Aging Study Research Articles

Influences of the menopause transition and adverse childhood experiences on peripheral basal inflammatory markers

ObjectiveTo characterize the influence of early life stress on peripheral basal inflammatory markers across the menopause transition. MethodsParticipants from the longitudinal Penn Ovarian Aging study were assessed for childhood adversity at study end (14 years) using the Adverse Childhood Experiences (ACE) questionnaire. Responses were categorized as low (0–1) or high (≥2) ACE exposure. The stored blood sample catalogue was reviewed to exclude those samples collected during use of medications that could impact immune status or medications suggestive of infection or allergies. Remaining blood samples (n ​= ​640) from 167 participants were assayed for interleukin-6 (IL-6), interleukin 1-beta (IL-1β), high sensitivity C-reactive protein (hsCRP), and tumor necrosis factor alpha (TNF-α). Menopause staging (premenopause, early transition, late transition, and postmenopause) was determined by questionnaire and menstrual diaries at yearly assessments. Generalized linear models for repeated measures were used to quantify the association between outcomes of interest (i.e., IL-6, IL-1β, hsCRP, and TNF-α) and exposures (i.e., menopause stage, ACE status, their interaction) while controlling for relevant covariates (i.e., BMI, smoking, age at first blood sample, and race). Inflammatory marker levels were log-transformed for modeling. ResultsLog IL-6 levels were higher in the late perimenopause versus premenopause (p ​= ​0.035). Menopause stage ​× ​ACE interaction was observed for log IL-6, IL-1β, and TNF-α (p ​= ​0.042, p ​= ​0.054, p ​= ​0.053, respectively); for individuals with high (≥2) ACE exposure, IL-6 was higher in the late perimenopause (p ​= ​0.015) while IL-1β and TNF-α were lower in the postmenopause versus premenopause (p ​= ​0.019 and p ​= ​0.020). ConclusionsResults from this investigation indicate that the late perimenopause stage may be a window of risk for inflammation, particularly for individuals with greater childhood adversity. Prospective studies designed to address childhood stress and inflammation across the menopause transition are needed to confirm these findings. Heightened inflammation, even if transitory, may have negative impact on healthy aging.

Adverse Childhood Experiences and Risk for First-Episode Major Depression During the Menopause Transition.

Stress exposures may have a differential impact on risk and resilience for depression depending on their timing across development. We sought to determine whether adverse childhood experiences (ACEs) and their onset with respect to puberty contribute to the increased risk observed in first-episode major depressive disorder (MDD) during the menopause transition. Participants were from the Penn Ovarian Aging Study cohort, which is composed of women from Philadelphia County, Pennsylvania, who underwent behavioral, cognitive, and endocrine evaluations approximately yearly from 1996 to 2012 and completed the Adverse Childhood Experiences Questionnaire at study end point (n = 243). ACEs that first occurred 2 or more years before menarche were considered prepubertal. Incident menopause MDD was defined as first observed onset of the disorder in the perimenopause to postmenopause transition using the Structured Clinical Interview for DSM-III-R and the Primary Care Evaluation of Mental Disorders. Incident menopause MDD occurred in 48% of the 100 women who reported lifetime MDD. Women reporting ≥ 2 total ACEs were at significantly greater risk for lifetime MDD (adjusted odds ratio [aOR] = 2.05, P = .034) and incident menopause MDD (aOR = 2.58, P = .03) compared to those reporting 0 ACEs; women with ≥ 2 postpubertal ACEs were 2.3 times more likely to experience incidence menopause MDD (P = .024) after controlling for race, smoking, body mass index, and employment. Experiencing only 1 ACE in the prepubertal window, regardless of additional ACEs in postpuberty, was associated with reduced risk for lifetime and incident menopause MDD. Timing and number of adverse experiences with respect to puberty differentially impacted risk and resilience for MDD across the female life span and during the menopause transition in this community cohort.

Methods in a longitudinal cohort study of late reproductive age women: the Penn Ovarian Aging Study (POAS)

BackgroundThis report describes the methods utilized in the Penn Ovarian Aging Study (POAS), which is a longitudinal cohort study of hormone dynamics and menopausal symptoms of women in the menopause transition.Methods/DesignThe cohort is a community-based sample of generally healthy women enrolled in the late reproductive years. The study population is a stratified random sample of African-American and Caucasian women, identified by random digit dialing.Of the 1427 women who were identified as potentially eligible, 578 women were eligible after full screening; 75 % of the eligible women enrolled in the study (436/578). At Period 14 (14 years after study enrollment), 67 % remained active and were fully evaluated (293/436). Attrition was non-differential with respect to the sample characteristics.The aims of the project overall are to 1) identify within-woman trends of reproductive hormones (estradiol, follicle stimulating hormone, hormone, lutinizing hormone, inhibin B, dehydroepiandrosterone, testosterone, and anti-mullerian hormone), cofactors such as race, body mass index (BMI), age, physical and behavioral symptoms, and their predictions of menopausal symptoms, and patterns around the final menstrual period; 2) identify associations of hormone dynamics with physical and behavioral symptoms that occur with ovarian aging and identify racial differences in these factors; 3) identify associations of genetic polymorphisms with levels and longitudinal trends in menopausal symptoms. The cohort consists of 436 late reproductive-age women at enrollment, and now has 18 years of approximately annual follow-up assessments. Menopausal stage based on concurrent menstrual dates is identified at each follow-up period.DiscussionStudies of the cohort have shown that hot flashes can occur well before menopause and extend 10 or more years beyond menopause for sizeable numbers of women; provide evidence for new-onset depressed mood in the menopause transition and show that the final menstrual period is pivotal in the increases in depressive symptoms prior to menopause and decreases postmenopausal; suggest that poor sleep is common in the late reproductive years but increases in relation to the final menstrual period in only a small proportion of women; and show effects of obesity on reproductive hormones in the menopause transition. To date, more than 50 studies of the cohort are published in medical journals, demonstrating the relevance of these data to the clinical care of mid-life women.Electronic supplementary materialThe online version of this article (doi:10.1186/s40695-016-0014-2) contains supplementary material, which is available to authorized users.

Bayesian estimation of associations between identified longitudinal hormone subgroups and age at final menstrual period.

BackgroundAlthough follicle stimulating hormone (FSH) is known to be predictive of age at final menstrual period (FMP), previous methods use FSH levels measured at time points that are defined relative to the age at FMP, and hence are not useful for prospective prediction purposes in clinical settings where age at FMP is an unknown outcome. This study is aimed at assessing whether FSH trajectory feature subgroups identified relative to chronological age can be used to improve the prediction of age at FMP.MethodsWe develop a Bayesian model to identify latent subgroups in longitudinal FSH trajectories, and study the relationship between subgroup membership and age at FMP. Data for our study is taken from the Penn Ovarian Aging study, 1996–2010. The proposed model utilizes mixture modeling and nonparametric smoothing methods to capture hypothesized latent subgroup features of the FSH longitudinal trajectory; and simultaneously studies the prognostic value of these latent subgroup features to predict age at FMP.ResultsThe analysis identified two FSH trajectory subgroups that were significantly associated with FMP age: 1) early FSH class (15 %), which displayed initial increases in FSH shortly after age 40; and 2) late FSH class (85 %), which did not have a rise in FSH until after age 45. The use of FSH subgroup memberships, along with class-specific characteristics, i.e., level and rate of FSH change at class-specific pre-specified ages, improved prediction of FMP age by 20–22 % in comparison to the prediction based on previously identified risk factors (BMI, smoking and pre-menopausal levels of anti-mullerian hormone (AMH)).ConclusionsTo the best of our knowledge, this work is the first in the area to demonstrate the existence of subgroups in FSH trajectory patterns relative to chronological age and the fact that such a subgroup membership possesses prediction power for age at FMP. Earlier ages at FMP were found in a subgroup of women with rise in FSH levels commencing shortly after age 40, in comparison to women who did not exhibit an increase in FSH until after 45 years of age. Periodic evaluations of FSH in these age ranges are potentially useful for predicting age at FMP.Electronic supplementary materialThe online version of this article (doi:10.1186/s12874-015-0101-3) contains supplementary material, which is available to authorized users.

Higher serum total testosterone levels correlate with increased risk of depressive symptoms in Caucasian women through the entire menopausal transition

BackgroundDespite the high prevalence of depressive symptoms in women, the precise role of sex hormones in mood changes during the menopausal transition is unclear. Previous studies have been inconsistent with regard to identifying the association of androgens, namely total testosterone, with depressive symptoms. ObjectiveThe objectives of this study were to evaluate changes in serum total testosterone levels and depressive symptoms during the entire menopausal transition, and examine the impact of covariates on the association between concurrent serum total testosterone levels and depressive symptoms during this time period. MethodsA longitudinal cohort study (428 women at baseline with 3634 repeated measures) using data from the Penn Ovarian Aging Study, a population-based cohort of late reproductive-aged women, followed through the menopausal transition. Serum hormone parameters and depression scores using the Center for Epidemiological Studies of Depression scale (CES-D) were measured at each annual visit over a 14-year period. General linear (for testosterone) and a generalized negative-binomial model (for depressive symptoms) for repeated measures were used for analysis. ResultsSerum total testosterone levels increased progressively over the study period and were significantly associated with older age and with current smoking (p<0.001, respectively). In the post menopause total testosterone levels were significantly higher in African Americans compared to Caucasians (p=0.012). The proportion of women with CES-D ≥16 significantly decreased with increasing age and in the post-menopausal period, and were higher in women with a history of depression and hot flashes (p<0.001). The association between concurrent testosterone levels and high depressive symptoms (CES-D ≥16) differed by race (p=0.008). In Caucasians, but not African Americans, higher serum testosterone levels were associated with increased depressive symptoms after controlling for several variables including age, obesity status, hot flashes and menopausal status (RR 1.09, 95% CI 1.00–1.17, p=0.042). ConclusionIn our cohort, testosterone levels were low but progressively increased from premenopause through post menopause. In addition to age and history of depression, we identified race to have a significant interaction between the association of testosterone levels and depressive symptoms. This study further supports the associations between sex hormones and increased risk of having depressive symptoms, although the precise underlying mechanisms for this association remain unclear.

Modeling Short- and Long-Term Characteristics of Follicle Stimulating Hormone as Predictors of Severe Hot Flashes in Penn Ovarian Aging Study.

The Penn Ovarian Aging Study tracked a population-based sample of 436 women aged 35-47 years to determine associations between reproductive hormone levels and menopausal symptoms. We develop a joint modeling method that uses the individual-level longitudinal measurements of follicle stimulating hormone (FSH) to predict the risk of severe hot flashes in a manner that distinguishes long-term trends of the mean trajectory, cumulative changes captured by the derivative of mean trajectory, and short-term residual variability. Our method allows the potential effects of longitudinal trajectories on the health risks to vary and accumulate over time. We further utilize the proposed methods to narrow the critical time windows of increased health risks. We find that high residual variation of FSH is a strong predictor of hot flash risk, and that the high cumulative changes of the FSH mean trajectories in the 52.5-55 year age range also provides evidence of increased risk above and beyond that of short-term FSH residual variation by itself.

Cigarettes, genetic background, and menopausal timing

This study aims to evaluate associations between variations in genes involved in the metabolism of environmental chemicals and steroid hormones and risk of menopause in smokers. Survival analysis was performed on 410 eligible participants from the Penn Ovarian Aging study (ongoing for 14 years), a cohort study of late-reproductive-age women. Single nucleotide polymorphisms at the following loci were studied: COMT Val158Met, CYP1B1*4 Asn452Ser, CYP1B1*3 Leu432Val, and CYP3A4*1B. Significant interactions between smoking and single nucleotide polymorphisms were observed in European-American carriers of CYP3A4*1B and CYP1B1*3, supporting a greater risk of menopause entry compared with those not carrying these alleles. Among CYP1B1*3 carriers, smokers had a greater risk of menopause entry than nonsmokers (adjusted hazard ratio [HR], 2.26; 95% CI, 1.4-3.67; median time to menopause, 10.42 and 11.07 y, respectively). No association between smoking and menopause was identified in CYP1B1 wild types. Among CYP3A4*1B carriers, smokers were at greater risk for menopause entry than nonsmokers (adjusted HR, 15.1; 95% CI, 3.31-69.2; median time to menopause, 11.36 and 13.91 y, respectively). Risk of menopause entry in CYP3A4 wild types who smoked was far lower (adjusted HR, 1.59; 95% CI, 1.03-2.44). Heavily smoking CYP1B1*3 carriers (adjusted HR, 3.0; 95% CI, 1.54-5.84; median time to menopause, 10.41 y) and heavily smoking CYP3A4*1B carriers (adjusted HR, 17.79; 95% CI, 3.21-98.65; median time to menopause, 5.09 y) had the greatest risk of menopause entry. Our finding that the risk of menopause entry in European-American smokers varies depending on genetic background represents a novel gene-environment interaction in reproductive aging.

Hormone variations associated with quantitative fat measures in the menopausal transition

Objective Reproductive hormone levels are associated with body size, and the association between estradiol and body size varies over the menopausal transition. This study aims to delineate these relationships using quantitative measures of visceral and subcutaneous fat.Methods Early follicular hormones (follicle stimulating hormone (FSH), estradiol, luteinizing hormone, dehydroepiandrosterone sulfate, testosterone) and T-1 weighted abdominal MRI images were obtained in a cross-sectional assessment of 77 women in the Penn Ovarian Aging Study. Fat volume (cm3) was quantified using validated software (Amira) and divided into tertiles of visceral and subcutaneous fat volume for analysis. Multivariable linear regression models compared hormone values between tertiles adjusting for race, age, and menopausal status.Results In adjusted models, estradiol was positively associated with visceral fat tertiles (geometric mean (GM) estradiol (pg/ml): Low 13.0, Mid 17.5, High 26.7, p = 0.006) while FSH was inversely associated with visceral fat tertiles (GM FSH (mIU/ml): Low 42.8, Mid 43.2, High 30.8, p = 0.03). The association of estradiol with visceral and subcutaneous fat tertiles varied by menopausal status (p < 0.001). In the early transition, estradiol was similar across tertiles of fat; postmenopause, estradiol was positively associated with visceral fat. Other hormones were not associated with fat measures.Conclusions Estradiol was associated with quantitative measures of visceral fat and varies by menopausal status. This finding suggests that visceral fat may be an important mediator in hormone changes over the menopausal transition.

Contribution of the rate of change of antimüllerian hormone in estimating time to menopause for late reproductive-age women

To determine the rate of change of antimüllerian hormone (AMH) level in the late reproductive years and its associations with time to menopause (TTM). We hypothesized that the rate of change between two measures of AMH reflects follicular atresia and varies among women independent of age. A14-year follow-up. A randomly identified, population-based cohort (Penn Ovarian Aging Study). Two measures of AMH were evaluated in survival analysis of 293 women. None. Time to menopause. The rate of AMH change was a strong independent predictor of TTM in multivariable analysis after adjusting for AMH baseline, age, and smoking (hazard ratio for 1 SD change = 1.82, 95% confidence interval 1.56-2.14). Among women with similar AMH levels, TTM differed by approximately 2 years when compared between a slow and fast rate of AMH change. A significant interaction of AMH rate of change and age indicated that a faster decrease in AMH level was associated with an increased risk of menopause in women aged 35-39 years (hazard ratio 6.97, 95% confidence interval 3.81-12.72), with less dramatic but significant associations in women aged 40-44 and 45-48 years. The AMH rate of change was independently associated with TTM in late reproductive-age women and increased the precision of estimates of TTM when included with an AMH baseline level and age. The rate of AMH change may be a more direct surrogate than age and increases the precision of estimates of TTM during this clinically important time period.

Joint effects of smoking and gene variants involved in sex steroid metabolism on hot flashes in late reproductive-age women.

Although smoking has a known association with hot flashes, the factors distinguishing smokers at greatest risk for menopausal symptoms have not been well delineated. Recent evidence supports a relationship between menopausal symptoms and variants in several genes encoding enzymes that metabolize substrates such as sex steriods, xenobiotics, and catechols. It is currently not known whether the impact of smoking on hot flashes is modified by the presence of such variants. The objective of the study was to investigate the relationship between smoking and hot flash occurrence as a function of genetic variation in sex steroid-metabolizing enzymes. A cross-sectional analysis of data from the Penn Ovarian Aging study, an ongoing population-based cohort of late reproductive-aged women, was performed. Smoking behavior was characterized. Single-nucleotide polymorphisms in five genes were investigated: COMT Val158Met (rs4680), CYP1A2*1F (rs762551), CYP1B1*4 (Asn452Ser, rs1800440), CYP1B1*3 (Leu432Val, rs1056836), and CYP3A4*1B (rs2740574). Compared with nonsmokers, European-American COMT Val158Met double-variant carriers who smoked had increased odds of hot flashes [adjusted odds ratio (AOR) 6.15, 95% confidence interval (CI) 1.32-28.78)]; European-American COMT Val158Met double-variant carriers who smoked heavily had more frequent moderate or severe hot flashes than nonsmokers (AOR 13.7, 95% CI 1.2-154.9). European-American CYP 1B1*3 double-variant carriers who smoked described more frequent moderate or severe hot flashes than nonsmoking (AOR 20.6, 95% CI 1.64-257.93) and never-smoking (AOR 20.59, 95% CI 1.39-304.68) carriers, respectively. African-American single-variant CYP 1A2 carriers who smoked were more likely to report hot flashes than the nonsmoking carriers (AOR 6.16, 95% CI 1.11-33.91). This is the first report demonstrating the effects of smoking within the strata of gene variants involved in sex steroid metabolism on hot flashes in late reproductive-age women. The identification of individuals with a genetic susceptibility to smoking-related menopausal symptoms could contribute to interventions targeted at reducing reproductive morbidity both in the menopause and across the reproductive life course.

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

Anti-mullerian hormone (AMH) has emerged as a marker of ovarian reserve and a possible surrogate measure of reproductive aging. 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. A 14-yr follow-up in the Penn Ovarian Aging Study, 1996-2010, was conducted for a randomly identified population-based cohort. A total of 401 late reproductive age women participated in the study. Observed time to menopause was measured. 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. 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.

Higher DHEA-S (dehydroepiandrosterone sulfate) levels are associated with depressive symptoms during the menopausal transition: results from the PENN Ovarian Aging Study

The influence of sex hormones on mood during the menopausal transition has been the subject of ongoing investigation. Because dehydroepiandrosterone sulfate (DHEA-S) has been associated with several indicators of healthy aging, we conducted a population-based study of midlife women to determine the relationship between DHEA-S levels and depressive symptoms and major depression during the transition through menopause. Unexpectedly, the original report revealed a positive correlation between DHEA-S levels and depressive symptoms at baseline. The cohort was studied over 11years to determine whether the positive association between DHEA-S levels and depression persists through the menopausal transition. We conducted a longitudinal cohort study with 11 assessments during an 11-year interval in Philadelphia, Pennsylvania, using a randomly identified, population-based sample of 436 African American and Caucasian premenopausal women aged 35 to 47years at enrollment. For outcome measures, we used the Center for Epidemiologic Studies Depression Scale and standardized diagnosis of major depression. In a multivariable model, DHEA-S levels were positively associated with depressive symptoms when adjusted for age, menopausal stage, race, smoking status, and body mass index. There was no association between DHEA-S levels and a diagnosis of major depression. DHEA-S levels were positively associated with depressive symptoms through the menopausal transition. No association with major depression was apparent during the menopausal transition, but results may have limited power due to low prevalence of major depression in this cohort. These findings suggest that taking DHEA supplements may increase depressive symptoms for some women, and women and their physicians should be cautious about instituting DHEA replacement therapy during the menopausal transition.

Duration of Menopausal Hot Flushes and Associated Risk Factors

To estimate the duration of moderate-to-severe menopausal hot flushes and identify potential risk factors for hot flush duration. The Penn Ovarian Aging Study cohort was monitored for 13 years. Hot flushes were evaluated at 9-month to 12-month intervals through in-person interviews. The primary outcome was the duration of moderate-to-severe hot flushes estimated by survival analysis (n=259). Potential risk factors included menopausal stage, age, race, reproductive hormone levels, body mass index (BMI), and current smoking. A secondary analysis included women who reported any hot flushes (n=349). The median duration of moderate-to-severe hot flushes was 10.2 years and was strongly associated with menopausal stage at onset. Hot flushes that started near entry into the menopause transition had a median duration greater than 11.57 years; onset in the early transition stage had a median duration of 7.35 years (95% confidence interval [CI] 4.94-8.89; P<.001); and onset in the late transition to postmenopausal stages had a median duration of 3.84 years (95% CI 1.77-5.52; P<.001). The most common ages at onset of moderate-to-severe hot flushes were 45-49 years (median duration, 8.1 years; 95% CI 5.12-9.28). African American women had a longer duration of hot flushes than white women in adjusted analysis. The median duration of hot flushes considerably exceeded the timeframe that is generally accepted in clinical practice. The identified risk factors, particularly menopausal stage, race, and BMI, are important to consider in individualizing treatment and evaluating the risk-to-benefit ratio of hormones and other therapies.

Managing Depression During the Menopausal Transition

The menopausal transition is associated with both first onset of depression and recurrent depression. Risk factors include vasomotor symptoms, a history of premenstrual dysphoria, postpartum depression, major depression, and sleep disturbances. Hormone replacement therapy, complementary and alternative medicine approaches, and counseling implications for assessment, education, advocacy, and self-care are discussed. ********** Women are diagnosed with depression at nearly twice the rate as men are (American Psychiatric Association [APA], 2000), a trend that begins in puberty (APA, 2000) and levels off after menopause (Bebbington et al., 2003). Without question, rates of depression in women are higher during their reproductive years. Although the connections between depression and premenstrual syndrome and the postpartum period are recognized and included in the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR; APA, 2000), no such recognition exists for depression during the menopausal transition. Failing to recognize a potential biological component of a disorder and instead emphasizing psychosocial or intrapsychic factors can lead to treatment that is ineffective, if not harmful. Therefore, the purpose of this article is threefold: to discuss hormonally based factors associated with depression during the menopausal transition; to review the benefits and risks of hormone replacement therapy (HRT), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and complementary and alternative medicine (CAM) approaches to treat depression; and to offer strategies for assessment, advocacy, and intervention. THE MENOPAUSAL TRANSITION AND RISK OF DEPRESSION Efforts to understand possible relationships between depression and reproductive cycles in women consistently point to a strong connection between the menopausal transition and increased occurrences of depression. In a critical review of the research literature, Soares and Zitek (2008) concluded that the menopausal transition seems to present a unique period in which some women are more vulnerable to initial onset or recurrent depressive symptoms and major depressive episodes. Similarly, Schmidt (2005) affirmed that research studies indicate a relationship between perimenopause (the early and late stages of the menopausal transition) and the onset of depression, a relationship that did not extend to the postmenopausal stage. Deecher, Andree, Sloan, and Schechter (2008) likewise concluded that clinical studies show an increase in major depressive disorder during perimenopause compared with such occurrences during premenopause or postmenopause. The authors found that this increased risk was present even in perimenopausal women who had no prior history of major depressive disorder. Findings from longitudinal studies illustrate these conclusions. Results from the Seattle Midlife Women's Study, a prospective study that followed women for approximately fourteen years, showed that the late menopause transition stage was significantly related to depressed mood (Woods et al., 2008). Results were similar for cohorts from another prospective study, the Penn Ovarian Aging Study, an ongoing longitudinal study (as cited in E. W. Freeman et al., 2004). An examination of a 4-year cohort from this study showed that depressive symptoms increased during the menopausal transition and decreased in postmenopause (E. W. Freeman et al., 2004). E. W. Freeman, Sammel, Lin, and Nelson (2006) examined another cohort over an 8-year period from the Penn Ovarian Aging Study. They found that a woman was 4 times more likely to have high depression scores and 2 1/2 times more likely to be diagnosed with depressive disorder when she was in the menopausal transition compared with her premenopausal period. Although no direct associations have been identified in the research between depression during the menopausal transition and specific levels of hormones (e. …

Predictors of Sleep Quality in Women in the Menopausal Transition

To determine associations between menopausal status, reproductive hormone levels, menopausal symptoms, and poor sleep quality. The present study examines subjective sleep quality over an 8-year period in participants in an ongoing longitudinal study of ovarian aging in a randomly identified cohort of African American and Caucasian women. The Penn Ovarian Aging Study, a population-based cohort of 436 women from Philadelphia County who were 35 to 47 years of age and had regular menstrual cycles at enrollment. N/A. The primary outcome measure was the Sleep Quality factor score, derived from the St. Mary's Hospital Sleep Questionnaire, which was adapted for this population and collected at each assessment period over the 8-year follow-up. Associations between menopausal status, reproductive hormone levels, menopausal symptoms, sleep quality, age, and race were examined in multivariable linear mixed regression models for repeated measures. Menopausal status was not significantly associated with sleep quality (P = 0.12). In the adjusted model, independent predictors of sleep quality were hot flashes (P < 0.0001), Center for Epidemiological Studies Depression Scale scores (P < 0.0001) and levels of the reproductive hormone inhibin B (P = 0.05). Sleep quality was predicted by hormone levels and symptoms that occur in the menopausal transition but did not worsen with advancing menopausal status alone. Lower inhibin B levels, hot flashes, and symptoms of depression were all strong and independent predictors of difficulty sleeping. Race was not a significant contributor to sleep quality. Together, the findings demonstrate that women who experience other perimenopausal symptoms are likely to experience sleep problems during the menopausal transition.

Symptoms in the Menopausal Transition

To estimate the association of headache, irritability, mood swings, anxiety, and concentration difficulties with menopausal stage and with reproductive hormones in the menopausal transition. 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. 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. 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. II.

Association of Physical Activity with Reproductive Hormones: The Penn Ovarian Aging Study

Physical activity is associated with reduced risk for breast cancer, perhaps through reductions in circulating reproductive hormones (estrogens and androgens). There may also be a role for physical activity in regulating menopausal symptoms. Few studies have examined associations of physical activity on hormone levels. None have examined the potential effect of the menopausal transition on the associations between physical activity and reproductive hormone levels. Data from the Penn Ovarian Aging Study were used for this analysis. Self-reported physical activity was assessed in 391 women up to four times over 10 years and extending across the menopausal transition. Other assessments included reproductive hormones via RIA (estradiol, luteinizing hormone, follicle-stimulating hormone, testosterone, DHEA sulfate), body weight, and height. Multivariate repeated measures regression models were developed to compare reproductive hormone levels within physical activity tertiles, adjusting for age, follow-up time, smoking, and ethnicity. Activity level was inversely associated with estradiol in the subgroup in the late transition stage. Adjusted means for estradiol were 24.6 and 37.9, a relative difference of 54% in estradiol when comparing highest to lowest activity tertile (P = 0.02). Similarly, in this subgroup, there was an inverse association between physical activity and testosterone levels (means of 11.1 and 15.94 in the highest and lowest tertile, a 47% relative difference; P = 0.01). There were no significant associations of activity with any other reproductive hormone. These results identify a particular window of the menopausal transition during which physical activity is associated with reduced estradiol and/or testosterone levels.

Symptoms Associated With Menopausal Transition and Reproductive Hormones in Midlife Women

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. 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. 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. 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. II.

Hormones and Sexuality During Transition to Menopause

To examine the relationship between reproductive hormonal dynamics and sexual dysfunction assessed in a cohort of women approaching menopause. 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. 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. 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. II.

The relationship between obesity and race on inhibin B during the menopause transition

Data are lacking on the effects of obesity and race on inhibin B levels during the menopause transition. The purpose of this study was to determine the relationship among inhibin B levels, body mass index (BMI), and race during the menopause transition. In the Penn Ovarian Aging Study, a prospective cohort study of reproductive aging, 436 women aged 35 to 47 years were followed up with serial hormones, anthropometric measures, and questionnaires for 6 years. Univariate and multivariable analyses were performed comparing mean log transformed inhibin B levels among menopause stages, age groups, BMI categories, races, and smoking groups. In the univariate analyses, mean inhibin B levels were negatively associated with menopause stage, age, and BMI, but not significantly with race or smoking. Interactions of menopause status and BMI were significant (P < 0.001). Premenopausal women with a BMI of 25 or higher had significantly lower inhibin B levels compared with women with a BMI of less than 25 (41.8 pg/mL vs 58.4 pg/mL, P < 0.001), whereas postmenopausal women with a BMI of 30 or higher had significantly higher inhibin B levels compared with the postmenopausal women with a BMI of less than 25 (29.1 pg/mL vs 26.7 pg/mL, P < 0.001). Although BMI is a significant independent predictor of inhibin B levels, the relationship between BMI and inhibin B changes with advancing menopause stage. These data provide additional evidence that obesity influences hormones during the menopause transition.