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.
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).
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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