Endocrine biomarkers and symptom clusters during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women's Health Study.

A majority of women experiencing the menopausal transition (MT) and early postmenopause (PM) report being bothered by hot flashes 1-3 and co-occurring symptoms (symptom clusters). 5-8 Cray and colleagues have identified three symptom severity clusters (latent classes) women participating in the Seattle Midlife Women's Health Study (SMWHS) experienced, which were differentially associated with stages of reproductive aging.9 The most prevalent cluster included low severity hot flashes, mood, sleep, cognitive, and pain symptoms, accounting for approximately 70% of observations. Another cluster accounting for approximately 13% of observations was characterized by high severity hot flashes and moderate severity mood, sleep, cognitive, and pain symptoms and was associated with the late menopausal transition and early postmenopause . The third cluster accounted for 17% of observations and included low severity hot flashes and moderate severity sleep, mood, cognitive and pain symptoms. 9 Several reports from longitudinal studies of the menopausal transition and early postmenopause support the association between hypothalamic-pituitary-ovarian (HPO) axis functioning and individual symptoms women experience during this period. Recently published results of the Penn Ovarian Aging and SWAN studies indicated that hot flashes were associated with variability in and levels of estradiol and follicle stimulating hormone (FSH) levels.5,10 Studies of sleep symptoms during the menopausal transition and postmenopause revealed that lower estradiol levels were associated with night-time awakening,11 and findings from the SWAN study indicated that lower estradiol levels and higher FSH were associated with difficulty falling asleep and remaining asleep.12 Moreover, these findings were supported in later studies of polysomnographic sleep in a subset of SWAN participants.13 In contrast, findings from the Penn Ovarian Aging cohort indicated that poor sleep was unrelated to estradiol, testosterone (T), and FSH.14 Studies of depressed mood symptoms revealed mixed findings: depressed mood as measured by the CESD was significantly associated with higher testosterone levels among SWAN participants.15 Among Penn Ovarian Aging participants, depressed mood was associated with increased levels of follicle stimulating hormone (FSH) and leutinizing hormone (LH) and increased variability of estradiol (E2), FSH and LH.16 Among Seattle Midlife Women's Health Study participants urinary estrone, FSH, and testosterone levels were not associated with CESD scores,17 consistent with the finding of no association between major depressive disorder and endocrine levels and change among SWAN participants.18 Cognitive symptoms were unrelated to HPO hormone levels in the SWAN, 19,20 Seattle Midlife Women's Health Study,21 and Penn Ovarian study. 22 Pain symptoms (aches, joint pain and stiffness) have been associated with estrogen levels and variability in the Penn Ovarian Aging population. Aches, joint pain and stiffness were associated with estradiol variability,5 but neither joint pain and back pain were associated with urinary levels of estrone or FSH in the SMWHS population.23 To date there has been little investigation of the role of the neuroendocrine effects associated with the hypothalamic-pituitary-adrenal (HPA) and autonomic nervous system (ANS) on symptoms women experience during the MT and early PM. A rise in cortisol during the late MT stage was found in the SMWHS population,24 but no difference in cortisol levels during the menopausal transition stages and early postmenopause in the SWAN population have been reported.25 Among the SMWHS population, cortisol was positively associated with urinary estrone, epinephrine and norepinephrine levels during the MT stages.26 Early studies of hot flashes in laboratory settings involved inducing hot flashes and measuring endocrine responses. Meldrum and colleagues27 found that ACTH levels rose shortly after women experienced hot flashes and cortisol levels rose about 15 minutes after women experienced hot flashes. Moreover, Freedman and colleagues28 demonstrated associations between brain metabolites of norepinephrine (MHPG) and hot flashes, but not peripheral metabolites of norepinephrine (VMA), suggesting a role for brain levels of norepinephrine and hot flashes. Among the SMWHS population higher cortisol levels were associated with less severe problems getting to sleep, but not night time awakening or early morning awakening; epinephrine and norepinephrine levels were not associated with sleep symptoms.11 Higher cortisol levels were associated with less back pain and higher norepinephrine and epinephrine levels were marginally associated with higher levels of joint pain.23 Depressed mood was not associated with cortisol, epinephrine or norepinephrine levels,17 nor were cognitive symptoms of difficulty concentrating and forgetfulness.21 The modulation of hypothalamic-pituitary-ovarian axis function by the hypothalamic-pituitary-adrenal axis has been demonstrated in earlier work. 29 Although it is likely that during the MT and early PM changes will occur in HPA axis and autonomic functioning when ovarian function is transitioning to a new pattern in which estrogens are increasingly of non-ovarian origin, to date there have been no investigations of HPO, HPA, and autonomic influences on symptoms report during this period, aside from hot flashes. Data from the SMWHS support women's experience of multiple co-occurring symptoms and their relationship to menopausal transition stages,9 but to date researchers have not explored the association between hypothalamic-pituitary-ovarian and hypothalamic-pituitary-adrenal and autonomic nervous system function and symptom severity clusters. The primary approach to understanding the relationship of menopause and symptoms has been motivated by hypothesizing that changes in the HPO axis such as declining estrogen levels and rising FSH are responsible for individual symptoms. Identifying symptom severity clusters and related neuroendocrine mechanisms may serve as the basis for tailoring therapy to co-occurring symptoms characterized by severity levelsexperienced by individual women and suggesting novel approaches to symptom management for women during the MT and early PM. Therefore, the purpose of this study was to test a model hypothesizing differential effects of hypothalamic-pituitary-ovarian (HPO) (urinary estrone, FSH, testosterone), hypothalamic-pituitary-adrenal (HPA) (cortisol), and autonomic nervous system (ANS) (epinephrine, norepinephrine) biomarkers on symptom severity clusters women experience during the MT and early PM.