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Symptoms Associated With Menopausal Transition and Reproductive Hormones in Midlife Women

Freeman, Ellen W. PhD; Sammel, Mary D. ScD; Lin, Hui MS; Gracia, Clarisa R. MD; Pien, Grace W. MD; Nelson, Deborah B. PhD; Sheng, Li PhD

doi: 10.1097/01.AOG.0000270153.59102.40
Original Research
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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

The prevalence of hot flushes, aches, joint pain, stiffness, and depressed mood increases in the menopausal transition.

From the 1Departments of Obstetrics/Gynecology, 2Psychiatry, the 3Center for Clinical Epidemiology and Biostatistics, the 4Center for Research in Reproduction and Women’s Health, and 5Department of Medicine, University of Pennsylvania; 6Temple University College of Health Professions; and 7Department of Mathematics, Drexel University, Philadelphia, PA.

See related editorial on page 228.

Supported by grants from the National Institutes of Health: RO1-AG-12745 (Dr. Freeman, Principal Investigator) and RR024134 (Clinical and Translational Research Center).

Corresponding author: Dr. Ellen W. Freeman, Department of Obstetrics/Gynecology, 3701 Market Street, Suite 820 (Mudd), Philadelphia, PA 19104; e-mail: freemane@mail.med.upenn.edu.

Financial Disclosure

Dr. Freeman has current grant support for other studies from Wyeth-Ayerst Laboratories (Philadelphia, PA), Pfizer US Pharmaceutical Group (New York, NY), and Xanodyne Pharmaceuticals (Newport, KY). In the past 3 years she has received honoraria for consulting and presentations from Wyeth-Ayerst Laboratories, Forest Laboratories (New York, NY), and Pherin Pharmaceuticals, Inc. (Redwood City, CA) for work not associated with this project.

Both clinicians and women identify the approach of menopause by changes in menstrual bleeding or by the experience of hot flushes or night sweats that occur around menopause. Other symptoms that occur in this same period, such as poor sleep, depressed mood, and decreased libido, are commonly attributed to menopause but have lacked evidence of association with menopausal status as distinct from general aging or other problems that occur in midlife.

The paucity of scientific data on menopausal symptoms was confirmed by the report of the 2005 State-of-Science Conference on Management of Menopause-Related Symptoms.1 This conference concluded that much more information is needed about associations of symptoms with clinically defined menopause to inform medical management of symptoms that are disruptive or signal other significant health problems.

We previously demonstrated that early changes in menstrual bleeding patterns, particularly cycle-length changes, were associated with reproductive hormone levels in the menopausal transition.2,3 We also identified associations of menstrual bleeding patterns with measures of depression and anxiety in our population-based cohort of premenopausal women as they entered the menopausal transition.4–6

The present report examines six common symptoms of midlife women over a 9-year time period that encompasses the transition from premenopausal to postmenopausal status: hot flushes; aches, joint pain, and stiffness; depressed mood; poor sleep; decreased libido; and vaginal dryness. The symptoms were assessed by women’s self-reports, which are analogous to reports to a clinician, using a validated menopausal symptom questionnaire.7 Our cohort is designed to evaluate age and prospectively identify menopausal stages, which enables us to look at age and menopausal stage both separately and jointly to identify whether and which of these factors are associated with symptoms.

We examined each of the six menopausal symptoms separately. We hypothesized that the prevalence of women with the symptom increased with progression through the menopausal transition, and that reproductive hormone levels or fluctuations were associated with the symptom. The specific aims were to 1) estimate the association of each symptom with menopausal stages as defined by menstrual bleeding patterns; 2) estimate the association of each symptom with levels and fluctuations of reproductive hormones; and 3) estimate the independent associations of menopausal stage and reproductive hormones with the severity of each symptom after adjusting for other demographic and behavioral risk factors.

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PARTICIPANTS AND METHODS

Data are from the Penn Ovarian Aging Study, a population-based cohort identified by random-digit dialing to households in Philadelphia County, Pennsylvania and described in previous reports.2,4 At enrollment in the cohort, the ages of the participants were 35 to 47 years, all participants were premenopausal as defined by regular menstrual cycles in normal range (22–35 days) for the past three cycles, had an intact uterus and at least one ovary. Exclusion criteria for cohort enrollment included current use of psychotropic or hormonal medications, including hormonal contraception and hormone therapies; pregnancy or breastfeeding; serious health problems known to compromise ovarian function (eg, diabetes mellitus, liver disease, and breast or endometrial cancer); and alcohol or drug abuse within the past year. The Institutional Review Board of the University of Pennsylvania approved the study, and written informed consent was obtained from all enrolled women. All women in the cohort who provided symptom assessments between Period 2 (when the symptom list was first included in the assessments) and Period 11, a span of approximately 9 years, were included in the present study (n=404).

The data at the study baseline were compared between the participants who continued throughout the study and the 105 women who discontinued during the study interval. These comparisons showed no significant baseline differences in the variables under study (Table 1). We had previously examined demographic and hormonal characteristics of the sample through phase 1 (the first 5 years of the study) and found no substantial differences in racial group or any of the studied characteristics compared between the active and inactive participants.8 Only 36 participants (8%) discontinued in the subsequent 5 years, and we believe that our previous observation, that dropout was spread equally across study characteristics, remains valid.

Table 1

Table 1

The data were collected in 10 assessment periods between 1997 and 2006. Periods 2–6 were at 9-month intervals, periods 7–10 were at annual intervals, and period 11 was approximately 2 years after the previous assessment, for a total of 9 years per participant. Each assessment period included two visits, scheduled in the first 6 days of two consecutive menstrual cycles or 1 month apart in noncycling women to obtain blood samples for the hormone assessments (yielding a possible maximum of 20 samples per participant).

Trained research interviewers obtained all data in individual in-person interviews at the participants’ homes. The study was described to the participants as a general women’s health study. The structured interview questionnaire focused on overall health and included demographic background information, menstrual cycle dates, reproductive experience, general health status, current medications, and health behaviors including smoking and alcohol use.

Each of the study symptoms was queried using a validated symptom list that was embedded in the structured interview questionnaire.7 The participants were asked to indicate whether each of the symptoms occurred in the past month, the frequency of its occurrence and its severity rated on a four-point scale from 0 (none) to 3 (severe). The symptoms included in this report are hot flushes; aches, joint pain, and stiffness; depressed mood; poor sleep; decreased libido or interest in sex; and vaginal dryness.

Menopausal stage was identified at each assessment period using the menstrual dates at each study visit (visits were conducted within 6 days of bleeding) and the two previous menstrual dates obtained at each visit. Other confirmatory data were obtained from the daily symptom diaries that participants recorded for one menstrual cycle at each assessment period, (the diary date was used in cases of disagreement), the reported number of menstrual periods between assessments, cycle length, and number of bleeding days.

The definitions of menopausal stage were from the consensus statement on a staging system for reproductive aging in women (Stages of Reproductive Aging Workshop).9 The following categories were used in this study: premenopausal (regular menstrual cycles in the 22–35-day range); late premenopausal (a change in cycle length of 7 days or more either direction from the participant’s personal baseline at enrollment in the cohort and observed for at least one cycle in the study); early transition (changes in cycle length of 7 days or more from the participant’s personal baseline at enrollment in the cohort, observed for at least two cycles in the study or 2 months amenorrhea; late transition (3–11 months amenorrhea); postmenopausal (12 months or more amenorrhea excluding hysterectomy). We previously demonstrated that these Stages of Reproductive Aging Workshop stages were significantly associated with reproductive hormone levels and differentiated the earliest stages in the menopausal transition in this cohort.2,3

Nonfasting blood samples for hormone assays were collected at each study visit. More than 98% of the samples from women with identifiable menstrual cycles were collected within the first 6 days of bleeding, with a mean cycle day of 3.5 for the samples in this report.

Assays of estradiol (E2) and follicle-stimulating hormone (FSH) were conducted in the General Clinical Research Center using commercially available kits (Coat-a-Count; Diagnostic Products, Los Angeles, CA). All interassay and intra-assay coefficients were less than 5%. The dimeric inhibin b level was measured in serum by Patrick Sluss, PhD, Massachusetts General Hospital, Boston, MA, using a sensitive, two-site nonisotopic immunoassay (Serotec, Oxford, England). The intra-assay and interassay coefficients were less than 5% and 8.5%, respectively (range 15–500 pg/mL). Values below the sensitivity threshold (15 pg/mL) were given the threshold value.

In addition to menopausal stage and hormones, the following potential risk factors were selected, based on their significance in previous studies of menopausal symptoms10–13 and the goals of this study: age, race, history of depression, body mass index (BMI; calculated as weight in kilograms divide by the square of height in meters), current smoking (yes, no), and perceived stress (the total score from a validated questionnaire of Cohen et al14; higher scores indicate greater stress). Potentially changing variables were assessed at each assessment period.

Estimates of statistical power to detect a change in the prevalence of symptoms in the menopausal transition compared with premenopausal status were conducted. For 80% power with 0.05 alpha, assuming within-subject correlations of 0.29 to 0.36, power is sufficient to detect an absolute difference 0.165 or more in prevalence of the symptom in the late menopausal transition compared with premenopausal status for symptoms with a premenopausal prevalence of 0.24 or higher (depressed mood; aches, join pain, and stiffness; and poor sleep). For symptoms with a premenopausal prevalence lower than 0.24 (hot flushes, decreased libido, and vaginal dryness), power is sufficient to detect an absolute difference of 0.11 or more between late menopausal transition and premenopausal status.

The statistical analyses used generalized linear regression models for repeated measures to estimate the bivariable association of menopausal stage and symptom prevalence (none compared with any).15 These extensions of linear regression address among-women associations, while taking into account the longitudinal data collection. The same generalized linear regression models for repeated measures were used to estimate the association of menopausal stage and each of the other explanatory variables (age, race, history of depression, current smoking, body mass index, perceived stress, E2, FSH, and inhibin B) with the severity of each symptom (moderate, severe compared with none, mild). The outcome of symptom severity was dichotomized as moderate or severe compared with none or mild to examine the level of symptom severity that is likely to be reported in a clinical setting.

The generalized linear regression models for repeated measures were also used to estimate the association of each hormone with symptom severity adjusted for menopausal stage. We then examined menopausal stage and the other risk factors simultaneously in multivariable models to estimate the independent associations of menopausal stage with symptom severity adjusted for all other variables in the model. Each hormone was added separately in the multivariable models because of the biologic correlation of the hormones. The same set of covariates was modeled for each symptom and all covariates were retained in the final model.

The hormone measures were transformed to natural log values to accommodate assumptions of the statistical models. Two important factors were used to describe the hormone values: the average (mean) of two measurements from each assessment period and the standard deviation from the mean level. In cases where two hormone values were not obtained in an assessment period, the single value was used for the mean, and the standard deviation was set at missing for that period. This approach was used to provide a measure of the women’s hormone fluctuations apart from the hormone levels.

In the tables, the associations between the hormones and symptoms are expressed as odds ratios (ORs) with 95% confidence intervals. For hormone levels, an OR represents the increased odds of reporting the symptom for a one-unit increase in the log-transformed hormone value, or a one-unit increase in the hormone standard deviation (SD).

All available data for each participant were included in the repeated measures models. Observations of pregnancy, breastfeeding, or hormone use were censored at the times of their occurrence. Observations of hysterectomy or cancer treatment were set to missing from the time of occurrence forward. Premenopausal observations were used as the reference group. In all models, variance estimates for the statistical tests on the regression coefficients were adjusted for the repeated observations from each participant using generalized estimating equations.16

Comparisons of baseline variables between continuers and subsequent dropouts used two-sample t or Pearson χ2 tests of association as appropriate for the distributions of the data. All analyses were conducted using the SAS V.9 statistical package (SAS Institute, Cary, NC). Statistical tests were two-tailed. To adjust for multiple symptom outcomes, a Bonferroni adjustment to the type one, alpha error rate results in a significant P value ≤.008 (P=.05 divided by the six symptoms of the study).

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RESULTS

At the study baseline (Period 2, n=404), the women were ages 36–49 years, with a mean of 42.3 (SD 3.5) years. Sixty-nine percent were premenopausal, 22% were late premenopausal, 7% were early transition, 2% were late transition, and none were postmenopausal. Of the observations at endpoint 9 years later, 2% were premenopausal, 3% were late premenopausal, 38% were early transition, 22% were late transition and 35% were postmenopausal. Table 1 shows the variables of the study at the Period 2 baseline.

Figure 1 shows the prevalence of each symptom (the percent of cohort women who reported the presence of the symptom) and the percent of women who reported the symptom as moderate or severe at each menopausal stage. The most prevalent symptoms were aches, joint pain, and stiffness and hot flushes. The prevalence of aches, joint pain, and stiffness peaked in the late transition stage when these were reported by 75% of the women. The prevalence of hot flushes peaked in the postmenopausal stage when it was reported by 73% of the women. The prevalence of depressed mood was higher through the late premenopausal, early transition, and late transition stages (reported by 56–59% of the women) and decreased postmenopause. The prevalence of poor sleep, decreased libido, and vaginal dryness increased only slightly across the menopausal transition.

Fig

Fig

The frequency of moderate or severe symptoms was consistently lower than the overall prevalence, as would be expected (shown in Fig. 1). For example, 72% reported aches, joint pain, and stiffness in the postmenopausal stage, but only 40% of the women reported a moderate or severe degree of these symptoms. Likewise, 73% of the women reported hot flushes in the postmenopausal stage but only 40% reported hot flushes at a moderate or severe degree. Fifty-nine percent of the women reported depressed mood in the early transition periods, but only 32% reported depressed mood at a moderate or severe degree.

Moderate or severe hot flushes (P<.001), aches, joint pain, and stiffness (P<.001), and depressed mood (P=.002) were significantly associated with menopausal stages in bivariable analysis (data shown in Table 2). Although decreased libido was not significantly associated with menopausal stages overall, there was a marginal association with the late transition stage (P=.05, data not shown). Poor sleep and vaginal dryness were not significantly associated with menopausal stages.

Table 2

Table 2

Table 2

Table 2

Age was associated only with the severity of hot flushes (P<.001) and aches, joint pain, and stiffness (P<.001). The significant associations of age with these symptoms were observed only in age groups 45 years or older.

The mean and standard deviation of the participant’s two hormone measures were calculated at each of the nine assessment periods, and the association of these measures with each symptom adjusted for menopausal stage was then estimated (Table 3). The repeated point-in-time measures of E2 fluctuations (standard deviation) were associated with hot flushes (P=.004) and with aches, joint pain, and stiffness (P=.03). Lower mean levels of E2 were associated with decreased libido (P=.04). Estradiol levels were not significantly associated with hot flushes, aches, depression, poor sleep, or vaginal dryness in the menopausal transition of this cohort. We observed that a relatively small number of women reported vaginal dryness before menopause, and E2 levels in the transition stages were not lower than the premenopausal levels for most women.

Table 3

Table 3

Lower levels of inhibin b were associated with hot flushes (P=.006), depressed mood (P=.05), and poor sleep (P=.01). In contrast to E2, inhibin b levels significantly decreased early in the menopausal transition and were previously shown to be significantly associated with menopausal stages.2,3

Higher FSH levels were associated with hot flushes (P<.001) and aches, joint pain, and stiffness (P=.002). Fluctuations of FSH were also associated with hot flushes in bivariable analysis (P=.02).

We then estimated the association between menopausal stage and symptom severity adjusted for other risk factors of the study: age, race, history of depression, current smoking, BMI, and perceived stress. Estimates were obtained for each symptom using the same set of covariates, and each variable was adjusted for all other variables in the model (shown in Table 2).

Menopausal stage was associated with hot flushes (P<.001), aches, joint pain, and stiffness (P<.001), and depressed mood (P=.002) after adjusting for other risk factors. The risk of hot flushes increased throughout the menopausal transition and was greatest in the postmenopausal group (OR 2.87, 95% confidence interval [CI] 1.76–4.67, P<.001). The risk of aches, joint pain, and stiffness was greatest in the late transition stage (OR 1.63, 95% CI 1.23–2.17, P<.001). The risk of depressed mood was greatest in the late premenopausal stage compared with the premenopausal group (OR 1.48, 95% CI 1.11–1.99, P=.009). Depressed mood decreased postmenopause (OR 0.64, 95% CI 0.41–1.00), P=.05). There was no significant association of menopausal stage with the remaining symptoms: poor sleep, decreased libido, and vaginal dryness.

After adjusting for all other risk factors in the multivariable model, greater fluctuations of E2 were associated with hot flushes (OR 1.27, 95% CI 1.05–1.53, P=.01) and aches, joint pain, and stiffness (OR 1.18, 95% CI 1.01–1.38, P=.04). Lower mean levels of E2 were associated with decreased libido (OR 0.82, 95% CI 0.70–0.97, P=.02). Lower mean levels of inhibin b were associated with hot flushes (OR 0.83, 95% CI 0.71–0.99, P=.03), poor sleep (OR 0.84, 95% CI 0.72–0.97, P=.02) and depressed mood at a trend level (OR 0.87, 95% CI 0.75–1.02, P=.08). Higher mean FSH levels were associated with hot flushes (OR 1.19, 95% CI 1.03–1.34, P=.02).

Of the other risk factors in the multivariable model, the measure of perceived stress had the strongest association with symptoms. Higher stress was associated with all symptoms of the study: hot flushes (P=.007), aches, joint pain, and stiffness (P<.001), depressed mood (P<.001), poor sleep (P<.001), decreased libido (P<.001), and vaginal dryness (P=.06).

A history of depression was associated with hot flushes (P=.01), depressed mood (P<.001), poor sleep (P<.001), and vaginal dryness (P=.03). Women with a history of depression were nearly 1.6 times more likely to report hot flushes than women with no history of depression. Women with a history of depression were nearly two times more likely to report depressed mood and 1.7 times more likely to have poor sleep than women with no history of depression.

Higher BMI was associated with hot flushes (P=.02), aches, joint pain, and stiffness (P<.001), and poor sleep (P=.01) in the multivariable model.

Race remained marginally associated with hot flushes (P=.05) and aches, joint pain, and stiffness (P=.05). African American women were 1.4 times more likely to report hot flushes and 1.31 times more likely to report aches, joint pain, and stiffness compared with the white women after adjusting for other risk factors. Age was associated only with hot flushes after adjusting for menopausal stage and other risk factors. The strongest association of age with hot flushes was in the 50–54 year group (OR 2.06, 95% CI 1.91–3.55, P=.01).

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DISCUSSION

This study demonstrates that reports of hot flushes, aches, joint pain, and stiffness, and depressed mood significantly increase in the transition to menopause. The association of these symptoms with menopausal stage was independent of age and other known risk factors such as stress and a history of depression. Women’s reports of poor sleep, decreased libido, and vaginal dryness were not associated with the stages in the transition to menopause in either bivariable or multivariable analyses in this population-based cohort.

Reproductive hormones, particularly within-woman fluctuations of E2, decreased levels of inhibin b, and increased FSH levels, were significantly and independently associated with these symptoms. The hormones measured in the study reflect different aspects of ovarian aging. For example, E2 fluctuations measure cycle to cycle changes, whereas mean inhibin b levels provide a slightly different measure of ovarian reserve, and mean FSH levels reflect an integrated central nervous system–pituitary response to both circulating E2 and inhibin b levels. The findings further support the possibility that changes in reproductive hormone levels and destabilizing effects of hormone fluctuations, particularly E2, are important risk factors for some menopausal symptoms.17,18 Although these hormone factors are unlikely to be detected with single hormone measures in clinical practice, women and clinicians can observe the changes in bleeding patterns that define menopausal stages to help determine whether a women is in the menopausal transition.

Hot flushes are the most commonly reported menopausal symptom and a primary reason that midlife women seek medical care. These findings clearly show that hot flushes increased in both prevalence and severity from the premenopausal stage, with peaks in the late transition and postmenopausal stages. After adjusting for other risk factors, menopausal stage had the strongest association with hot flushes, as was also found in the Study of Women’s Health Across the Nation.19

African American women were more likely than white women to report hot flushes. This result is consistent with our previous findings in this cohort5,20 and also with reports from the Study of Women’s Health Across the Nation studies.10,19 Although earlier studies of hot flushes, particularly those of treatment-seeking women, concluded that thin white women had the greatest risk of hot flushes, it may be that these studies had few or no African American participants. Another possible reason for racial differences is that there are major confounders of the association of race and hot flushes, particularly BMI20,21 and anxiety,5 both of which are measurably greater in the African American participants. It should be noted that all covariates of this study remained significantly associated with hot flushes in the adjusted model, indicating the multifactorial nature of this symptom. Although the reasons for racial differences are still not well-understood, it is clearly important in clinical care to evaluate the presence and severity of hot flushes regardless of race.

The robust association of aches, joint pain, and stiffness with menopausal stages was not expected. The National Institutes of Health State-of-Science Panel concluded that the majority of studies showed no association between menopausal stage and the prevalence of somatic symptoms, including back pain, stiff or painful joints.1 However, aches, joint pain, and stiffness were reported as frequently as hot flushes in this cohort, were associated with menopausal stage as well as fluctuations of E2, FSH, and inhibin b levels, and remained significantly associated with menopausal stage after adjusting for other risk factors of age, BMI, smoking, depressed mood, and perceived stress. A high prevalence of aches, joint pain, and stiffness that increased significantly compared with premenopausal women was also recently reported in the Study of Women’s Health Across the Nation study.22 Our hormone findings suggest that fluctuations of E2 may be involved in the aches, joint pain, and stiffness reported by perimenopausal women and add to limited findings of a positive relationship between E2 levels and aches, joint pain, and stiffness in the interval around menopause.23

The risk of depressed mood increased in the early menopausal transition and remained significantly associated with menopausal stage after adjusting for other risk factors, including a history of depression. These findings that are based on self-reported mood add support to previous studies that obtained in-depth assessments or a diagnosis of depression.4,6,24,25 The evidence for the association of dysphoric mood with menopause is conflicting, and the association continues to be controversial.1 However, five other recent population-based studies have consistently reported a significant association of depression with menopausal stages with odds ratios ranging from 1.8 to 2.9 compared with premenopausal women.2,4,11,12,24 Another prospective study similarly found a significantly greater risk for episodes of diagnosed depression around menopause compared with when the women were premenopausal.25 The present results further indicate that reports of depressed mood significantly decreased postmenopause compared with the premenopausal group.

The prevalence of poor sleep ranged from 43% to 53% in this report, but was not associated with menopausal stages in either bivariable or multivariable analyses. However, poor sleep was significantly associated with lower inhibin b levels, which decline rapidly in the early menopausal transition.2,26 The findings are consistent with our in-depth study of sleep quality, which did not worsen with menopausal stage alone, but was associated with reproductive hormones, hot flushes, depressed mood, and higher BMI (submitted for publication). The findings are also in agreement with several studies that used objective measurements and found no associations of sleep quality with menopausal stage, although other reports are conflicting.27,28

Stress was a strong covariate of menopausal symptoms and was significantly associated with all six symptoms in both bivariable and multivariable analyses. Perceived stress is highly correlated with anxiety, which is very common and frequently persistent, although often not recognized in clinical practice.29 We previously reported that anxiety preceded hot flushes in this cohort, and that the women with high anxiety scores were nearly five times more likely to report hot flushes.5 Further longitudinal analysis to determine whether higher stress at baseline predicts other menopausal symptoms is needed.

Another strong covariate of menopausal symptoms was a history of depression. A previous study identified history of depression as the single most important factor in perimenopausal depression in a population-based cohort.30 In our cohort, women who had a history of depression were nearly five times more likely to have a diagnosis of depression during the study interval.6 Women with a history of depression were also more likely to report hot flushes and poor sleep than women with no history of depression, as others have reported.31,32 Harlow et al11 found that a lifetime history of major depression was associated with an earlier perimenopause. Although a history of depression is clearly associated with menopausal symptoms, it is also important to recognize that women with no history of depression have an increased risk of depression in the menopausal transition6,24 and carefully evaluate depressive symptoms when presented for clinical care.

The associations of age with menopausal symptoms were weak. Age was significantly associated only with hot flushes after adjusting for menopausal stage and other risk factors.

Menopausal symptoms frequently coexist, and an important question that is not addressed in this study is the temporal relationships of these symptoms to each other. For example, hot flushes are widely believed to be the precipitating event that leads to poor sleep, which in turn may lead to depressed mood, although data that demonstrate a causal relationship among these variables are lacking. Another example is that vaginal dryness is a significant risk factor for decreased libido, as we previously reported,33 but the temporal relationship of these symptoms has not been demonstrated. This study also did not address within-woman patterns of symptom changes. We plan to conduct further follow-up to address these important questions.

Other limitations should be considered. The findings are based on participants’ self-reports of the occurrence and severity of the symptoms, rather than in-depth assessments or diagnoses of the symptoms. A strength of self-reported symptoms is that they are analogous to the clinical office visit. It is particularly noteworthy that these results are consistent with our previous studies that employed in-depth assessments of the symptoms, particularly for depressed mood and poor sleep,4–6 although the “yes or no” responses for decreased libido or interest in sex were not associated with menopausal stages, in contrast to our previous in-depth assessment of sexuality.34 This suggests that some symptoms, such as those relating to sexual behavior, require in-depth assessment to determine their associations with the menopausal transition.

The statistical model employed in these analyses evaluated each symptom independently. A Bonferroni adjustment was made to adjust for multiple comparisons, but it should also be noted that standard methods of adjustment are too conservative for outcomes that are positively correlated.35 The hormone measures were obtained in the early follicular phase, which is identified as the most reliable phase for hormone measurement in cycling women, but do not address questions that require luteal phase or full cycle measures. We selected risk factors based on evidence in previous studies and the design of this cohort, but other risk factors for menopausal symptoms may well exist. The study did not examine treatment modalities, although the findings suggest that clinical trials to determine the efficacy and dose levels of hormone treatments for these symptoms are important. Finally, our findings are from a population-based cohort of urban, generally healthy, African American and white women and may not be generalizable to other geographic or racial groups.

The strengths of this study are its long-term, prospective examination of symptoms in the transition to menopause that captures the early stages of the transition in late reproductive-age women. All women were premenopausal when they enrolled in the cohort, and subsequent menopausal stages were identified by carefully assessed bleeding patterns at each assessment period. The enrollment of women ages 35–47 years with regular menstrual cycles allows us to assess the independent contributions to symptoms of both age and menopausal stage. Sampling was stratified to obtain equal numbers of African American and white women for the evaluation of racial associations. The longitudinal hormone measures were obtained in two menstrual cycles at each assessment period for 9 years and were concurrent with the symptom measures. Strong follow-up and participation rates over the 9-year interval provide a wealth of longitudinally measured data to determine associations with changing hormones bleeding patterns in the menopausal transition.

In summary, the data indicate that stages in the transition to menopause are associated with some symptoms of midlife women, specifically hot flushes, aches, joint pain, and stiffness, and depressed mood. The symptoms are also associated with reproductive hormone levels and fluctuations that characterize the menopausal transition. Although this study did not address treatment, it is possible that hormone therapies may stabilize the changing hormonal milieu and potentially alleviate these symptoms. The findings of this study point to the need to investigate hormone treatments in the menopausal transition and to evaluate and treat menopausal symptoms that are distressing or disruptive.

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REFERENCES

1. National Institutes of Health. National Institutes of Health State-of-the-Science Conference statement: management of menopause-related symptoms. Ann Intern Med 2005;142:1003–13.
2. Freeman EW, Sammel MD, Gracia CR, Kapoor S, Lin H, Liu L, et al. Follicular phase hormone levels and menstrual bleeding status in the approach to menopause. Fertil Steril 2005;83:383–92.
3. Gracia CR, Sammel MD, Freeman EW, Lin H, Langan E, Kapoor S, et al Defining menopausal status: creation of a new definition to identify the early changes of the menopausal transition. Menopause 2005;12:128–35.
4. Freeman EW, Sammel MD, Liu L, Gracia CR, Nelson DB, Hollander L. Hormones and menopausal status as predictors of depression in women in transition to menopause. Arch Gen Psychiatry 2004;61:62–70.
5. Freeman EW, Sammel MD, Lin H, Gracia CR, Kapoor S, Ferdousi T. The role of anxiety and hormonal changes in menopausal hot flashes. Menopause 2005;12:258–66.
6. Freeman EW, Sammel MD, Lin H, Nelson DB. Associations of hormones and menopausal status with depressed mood in women with no history of depression. Arch Gen Psychiatry 2006;63:375–82.
7. Freeman EW, Sammel MD, Liu L, Martin P. Psychometric properties of a menopausal symptom list. Menopause 2003;10:258–65.
8. Nelson DB, Sammel MD, Freeman EW, Liu L, Langan E, Gracia CR. Predicting participation in prospective studies of ovarian aging. Menopause 2004;11:543–8.
9. Soules MR, Sherman S, Parrott E, Rebar R, Santoro N, Utian W, et al. Executive summary: Stages of Reproductive Aging Workshop (STRAW). Fertil Steril 2001;76:874–8.
10. Santoro N, Lasley B, McConnell D, Allsworth J, Crawford S, Gold EB, et al. Body size and ethnicity are associated with menstrual cycle alterations in women in the early menopausal transition: The Study of Women’s Health across the Nation (SWAN) Daily Hormone Study. J Clin Endocrinol Metab 2004;89:2622–31.
11. Harlow BL, Wise LA, Otto MW, Soares CN, Cohen LS. Depression and its influence on reproductive endocrine and menstrual cycle markers associated with perimenopause: the Harvard Study of Moods and Cycles. Arch Gen Psychiatry 2003;60:29–36.
12. Bromberger JT, Assmann SF, Avis NE, Schocken M, Kravitz HM, Cordal A. Persistent mood symptoms in a multiethnic community cohort of pre- and perimenopausal women. Am J Epidemiol 2003;158:347–56.
13. Guthrie JR, Dennerstein L, Taffe JR, Lehert P, Burger HG. Hot flushes during the menopause transition: a longitudinal study in Australian-born women. Menopause 2005;12:460–7.
14. Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. J Health Soc Behav 1983;24:385–96.
15. Laird NM, Donnelly C, Ware JH. Longitudinal studies with continuous responses. Stat Methods Med Res 1992;1:225–47.
16. Liang KY, Zeger SL. Longitudinal data analysis using generalized linear models. Biometrika 1986;73:13–22.
17. Rubinow DR, Schmidt PJ, Roca CA. Estrogen-serotonin interactions: implications for affective regulation. Biol Psychiatry 1998;44:839–50.
18. Joffe H, Cohen LS. Estrogen, serotonin, and mood disturbance: where is the therapeutic bridge? Biol Psychiatry 1998;44:798–11.
19. Gold EB, Colvin A, Avis N, Bromberger J, Greendale GA, Powell L, et al. Longitudinal analysis of the association between vasomotor symptoms and race/ethnicity across the menopausal transition: study of women’s health across the nation. Am J Public Health 2006;96:1226–35.
20. Freeman EW, Sammel MD, Grisso JA, Battistini M, Garcia-Espagna B, Hollander L. Hot flashes in the late reproductive years: risk factors for African American and Caucasian women. J Womens Health Gend Based Med 2001;10:67–76.
21. Hyde Riley E, Inui TS, Kleinman K, Connelly MT. Differential association of modifiable health behaviors with hot flashes in perimenopausal and postmenopausal women. J Gen Intern Med 2004;19:740–6.
22. Dugan SA, Powell LH, Kravitz HM, Everson Rose SA, Karavolos K, Luborsky J. Musculoskeletal pain and menopausal status. Clin J Pain 2006;22:325–31.
23. Finset A, Overlie I, Holte A. Musculo-skeletal pain, psychological distress, and hormones during the menopausal transition. Psychoneuroendocrinology 2004;29:49–64.
24. Cohen LS, Soares CN, Vitonis AF, Otto MW, Harlow BL. Risk for new onset of depression during the menopausal transition: the Harvard study of moods and cycles. Arch Gen Psychiatry 2006;63:385–90.
25. Schmidt PJ, Haq N, Rubinow DR. A longitudinal evaluation of the relationship between reproductive status and mood in perimenopausal women. Am J Psychiatry 2004;161:2238–44.
26. Burger HG, Dudley EC, Hopper JL, Groome N, Guthrie JR, Green A, et al. Prospectively measured levels of serum follicle-stimulating hormone, estradiol, and the dimeric inhibins during the menopausal transition in a population-based cohort of women. J Clin Endocrinol Metab 1999;84:4025–30.
27. Young T, Rabago D, Zgierska A, Austin D, Laurel F. Objective and subjective sleep quality in premenopausal, perimenopausal, and postmenopausal women in the Wisconsin Sleep Cohort Study. Sleep 2003;26:667–72.
28. Freedman RR, Roehrs TA. Lack of sleep disturbance from menopausal hot flashes. Fertil Steril 2004;82:138–44.
29. Kessler RC. The global burden of anxiety and mood disorders: putting the European Study of the Epidemiology of Mental Disorders (ESEMeD) findings into perspective. J Clin Psychiatry 2007;68 suppl:10–9.
30. Dennerstein L. Well-being, symptoms and the menopausal transition. Maturitas 1996;23:147–57.
31. Joffe H, Hall JE, Soares CN, Hennen J, Reilly CJ, Carlson K, et al. Vasomotor symptoms are associated with depression in perimenopausal women seeking primary care. Menopause 2002;9:392–8.
32. Glazer WM. Overview: importance of recognizing and treating insomnia. J Clin Psychiatry 2006;67 suppl:3–4.
33. Gracia CR, Sammel MD, Freeman EW, Liu L, Hollander L, Nelson DB. Predictors of decreased libido in women during the late reproductive years. Menopause 2004;11:144–50.
34. Gracia CR, Freeman EW, Sammel MD, Lin H, Mogul M. Hormones and sexuality during transition to menopause. Obstet Gynecol 2007;109:831–40.
35. Savitz DA, Olshan AF. Multiple comparisons and related issues in the interpretation of epidemiologic data. Am J Epidemiol 1995;142:904–8.
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