Lowered progesterone metabolite excretion and a variable LH excretion pattern are associated with vasomotor symptoms but not negative mood in the early perimenopausal transition: Study of Women's Health Across the Nation.

OBJECTIVE: The menopausal transition is characterized by progressive changes in ovarian function and increasing circulating levels of gonadotropins, with some women having irregular menstrual cycles well before their final menstrual period. These observations indicate a progressive breakdown of the hypothalamic-pituitary-ovarian axis often associated with an increase in menopausal symptoms. Relationships between vasomotor symptoms (VMS) and depressed mood and sleep as well as a bidirectional association between VMS and depressed mood in mid-life women have been reported, but the endocrine foundations and hormone profiles associated with these symptoms have not been well described. Our objective was to determine the relationship between daily urinary hormone profiles and daily logs of affect and VMS during the early perimenopausal transition. STUDY DESIGN: SWAN, the Study of Women's Health Across the Nation, is a large, mutli-ethnic, multisite cohort study of 3302 women aged 42-52 at baseline, designed to examine predictors of health and disease in women as they traversed the menopause. Inclusion criteria were: an intact uterus and at least one ovary present, at least one menstrual period in the previous three months, no use of sex steroid hormones in the previous three months, and not pregnant or lactating. A subset (n = 849) of women aged 43-53 years from all study sites in the first Daily Hormone Study collection were evaluated for this substudy. OUTCOME MEASURES: We measured daily VMS, and urinary hormones: follicle stimulating hormone (FSH), luteinizing hormone (LH), pregnanediol glucuronide (PdG) and estradiol (estrone conjugate, E1C). RESULTS: A variable pattern of LH and negative LH feedback were the hormone patterns most strongly associated with increased VMS. In contrast, no hormone pattern was significantly related to negative mood. CONCLUSION: Fluctuations of LH associated with low progesterone production were associated with VMS but not negative mood, suggesting different endocrine patterns may be related to increased negative mood than to the occurrence of VMS.

[Perimenopausal melatonin deficiency syndrome in system of personalized management of quality of life of women with climacteric syndrome.]

The aim of our study is to search diagnostic tools for early detection of prenosological melatonin deficiency in postmenopausal women and women in menopausal transition with climacteric syndrome for establishment effective personalized prevention and treatment programs. In this study 221 women were enrolled. They were divided into four groups: the 1st group - 39 women in menopausal transition with climacteric syndrome, the 2nd group - 104 menopausal women with climacteric syndrome, the 3rd group - 41 women with physiological menopause, the 4th group - 37 healthy women in reproductive-age. The study was conducted using the test for detecting melatonin deficiency, women's health questionnaire (WHQ), and morning level detection of 6-sulfatoxymelatonin in urine. A new prenosological state - perimenopausal melatonin deficiency syndrome was build on the data obtained. It is appropriate to evaluate prognosis of melatonin treatment in women with climacteric syndrome during the planning of personalized prevention and treatment programs. The assessment of prognosis is carried out with the help of the discriminant mathematical model, which is the basis of personalized management of quality of life in women with climacteric syndrome. This system is based on participatory principles.

Perimenopausal bone histomorphometry before and after menopause.

Investigators and clinicians have had few normal bone histomorphometry data available to compare with those found in diseased patients, or in the results of treatments. The Goals and Objectives of this work are two-fold: 1. to present static and dynamic bone histomorphometry data from transilial bone biopsies performed on 76 healthy, premenopausal women. 2. To present paired static and dynamic bone histomorphometry data from bone biopsies on a subset (N=51 pairs) of these same healthy women whose biopsies were repeated 12months after their last menses. Statistical comparisons between the pre- and postmenopausal data are presented. These data will shrink this important gap, both for clinicians and investigators. We enrolled 76 healthy, premenopausal women over age 46, performed transilial bone biopsies after tetracycline labeling, and during a period of 9.5years, we re-biopsied 51 of them who passed through menopause and remained healthy the entire time. We also obtained serum biochemical measurements, and serial DXA exams during the period of observation. The dynamic bone histomorphometry demonstrated a doubling of bone remodeling, and increases in serum bone markers at the time of the second biopsy. Lumbar spine bone density also declined, and there were significant correlations between serum markers and histomorphometry variables. The data demonstrate that healthy menopause results in an important increase in bone remodeling, and a loss of bone density. We do not fully understand the mechanisms of these transmenopausal changes, but the data provide some clues that are helpful.

Changes in bone mass during the perimenopausal transition in naturally menopausal cynomolgus monkeys.

OBJECTIVE: This study measured the differences in bone mineral density and content in relation to changes in serum hormone and bone marker levels during the perimenopausal transition in naturally menopausal cynomolgus monkeys. METHODS: The bone mineral density and content of premenopausal, perimenopausal, and early (0-< 5 y), mid (5-10 y), and late (> 10 y) postmenopausal monkeys were measured at the distal radius and proximal tibia in both metaphysis and diaphysis. Hormonal and bone marker levels were also measured. RESULTS: The serum 17ß-estradiol level significantly decreased during late postmenopause, whereas the serum follicle-stimulating hormone levels significantly increased from early postmenopause before declining at late postmenopause. Trabecular bone loss at metaphysis occurred once the animals entered into the perimenopausal period, whereas cortical bone loss gradually and continuously decreased, dependent on the time-course after perimenopause, and was greatest in the late postmenopausal period. Serum bone-specific alkaline phosphatase and urinary N-telopeptide of bone type-1 collagen levels were negatively correlated with the trabecular bone mineral content at metaphysis, whereas serum osteocalcin levels showed a negative correlation with the cortical bone mineral density at the diaphysis. The only positive linear correlation observed was between serum follicle-stimulating hormone and urinary N-telopeptide of bone type-1 collagen levels. CONCLUSIONS: Unlike the ovariectomized monkey models that do not retain the perimenopausal transition, naturally menopausal monkeys elicit different patterns of bone loss during the transition-an abrupt decline in the trabecular metaphysis and a gradual decline in the cortical diaphysis. Naturally menopausal cynomolgus monkeys offer an alternative model for osteoporosis research for postmenopausal women.

Urinary phytoestrogens and depression in perimenopausal US women: NHANES 2005-2008.

BACKGROUND: Fluctuating hormonal levels observed during the menopausal transition may increase vulnerability to depression in susceptible women. Thus, it is of interest to examine the effect of natural estrogens such as phytoestrogens on the risk of depression in perimenopausal women. METHODS: Our analysis included 193 perimenopausal women of the National Health and Nutrition Survey (NHANES) 2005-2008 aged 45-55 years. Urinary concentrations of phytoestrogens (isoflavones and lignans) were measured by HPLC-APPI-MS/MS. Depression was assessed using the Patient Health Questionnaire-9 (PHQ-9). Logistic regression models examined the association of phytoestrogens concentrations (creatinine-standardized and log-transformed) with depression (yes/no). RESULTS: Unadjusted odds ratios (OR) of the associations between urinary phytoestrogen concentrations and perimenopausal depression were below 1; however, only lignans were significantly inversely associated with depression. The latter findings were not attenuated in multivariate analysis including age, race, body mass index, poverty income ratio, smoking, alcohol consumption, cancer, diabetes, and cardiovascular disease (lignans: OR=0.66; 95% confidence intervals (CI) 0.50-0.87, enterodiol: OR=0.63; 95% CI 0.51-0.78, enterolactone: OR=0.75; 95% CI 0.60-0.93). LIMITATIONS: Our cross-sectional study design does not allow for causal inferences. Because information to precisely assess perimenopausal symptoms was missing, we defined perimenopause based on women's age. CONCLUSIONS: Lower lignans but not isoflavones concentrations were statistically significantly associated with an increased risk of depression in perimenopausal women. Because of medical risks associated with the use of hormone therapy, further investigation on the effect of lignans on the risk of depression in perimenopausal women is warranted.

Reproductive hormones and the menopause transition.

The hormonal correlates of reproductive aging and the menopause transition reflect an initial loss of the follicle cohort, while a responsive ovary remains, and an eventual complete loss of follicle response, with persistent hypergonadotropic amenorrhea. The physiology of the process is described, along with key findings of relevant studies, with an emphasis on the Study of Women's Health Across the Nation. A clinical framework is provided to help clinicians to forecast the major milestones of the menopausal transition and to predict potential symptoms or disease.

Enhanced hypothalamic-pituitary sensitivity to estrogen in premenopausal women with diminished ovarian reserve compared with older perimenopausal controls.

OBJECTIVE: We have previously characterized the reproductive hormone profile in infertile women with diminished ovarian reserve (DOR) as being distinct from that seen in age-comparable healthy controls. Hypothesizing that DOR reflects accelerated reproductive aging, we herein compare urinary reproductive hormone dynamics between young women with DOR and a population of chronologically older perimenopausal controls. METHODS: In this prospective observational study, urinary levels of pituitary gonadotropins (follicle-stimulating hormone and luteinizing hormone) and metabolites of estrogen (estrone conjugate) and progesterone were assessed in daily morning urine samples collected in a spontaneous menstrual cycle in 8 infertile premenopausal women with DOR and in 11 perimenopausal controls. Areas under the curves were calculated for the respective measured hormones, and comparisons were made using the Mann-Whitney U test. RESULTS: Urinary estrone conjugate levels were significantly attenuated in premenopausal women with DOR compared with the older perimenopausal cohort. Despite the relatively lower estrogen, a significantly more pronounced luteinizing hormone surge was evident in the younger population. Early follicle-stimulating hormone was lower in women with DOR, but luteal urinary progesterone excretion was comparable in the two groups. CONCLUSIONS: Our data suggest distinctions in functioning of the central (hypothalamic-pituitary) and peripheral (ovarian) components of the hypothalamic-pituitary-ovarian axis in premenopausal women with DOR compared with chronologically older perimenopausal controls. Increased hypothalamic-pituitary sensitivity to estrogen positive feedback is suggested in premenopausal women with DOR. Our observations identify DOR as a distinct entity in the paradigm of reproductive senescence.

Symptom clusters during the late menopausal transition stage: observations from the Seattle Midlife Women's Health Study.

OBJECTIVE: The aims of this study were to identify groups of women in the late menopausal transition stage who experienced the same cluster of symptoms and to identify indicators that predicted membership in these distinct groups. METHODS: The sample consisted of a subset of Seattle Midlife Women's Health Study participants who were in the late menopausal transition stage and provided self-report data on symptoms experienced between 1990 and 2005. Latent class analysis (LCA) was used to identify groups of women who experienced similar clusters of the following five symptoms: problem concentrating, hot flashes, joint ache, mood changes, and awakening at night. LCA with multivariate logistic regression was used to identify covariates that predicted membership in each group. RESULTS: Four groups of women were identified: (1) low severity for all symptoms except for joint ache, which was moderate (65%); (2) high severity for all symptoms except for hot flashes, which was moderate (13%); (3) high severity for hot flashes, joint ache, and awakening at night (12%); and (4) high severity for problem concentrating and joint ache (10%). A clear delineation between groups based on individual characteristics was not fully elucidated. CONCLUSIONS: This analysis demonstrates that LCA may be useful to identify women who may experience poorer outcomes related to a higher propensity for severe symptoms. Shifting the focus from single symptoms to symptom clusters will aid in the identification of phenotypic profiles, thus facilitating symptom management strategies that can be tailored to meet the needs of individual women.

Relation of daily urinary hormone patterns to vasomotor symptoms in a racially/ethnically diverse sample of midlife women: study of women's health across the nation.

The associations of urinary pregnanediol-glucuronide (PdG) levels and menstrual bleeding and their modification of associations of other risk factors with vasomotor symptoms (VMS) are examined. Daily urine samples were collected for 1 menstrual cycle or 50 days if no bleeding occurred. Participants (n = 742) were aged 43 to 54 years, not using exogenous hormones, not pregnant, had an intact uterus and > 1 ovary, and menstruated in the prior 3 months. Multivariate analyses were performed of urinary hormone metabolites and within-woman proportion of days reporting VMS. VMS reporting was 4-fold greater (P = .0005) in women whose urine collections ended without bleeding. In collections with PdG levels suggestive of ovulatory activity according to the work of Kassam et al, VMS are significantly associated with obesity, early perimenopause, and increasing PdG levels. In collections with lower PdG concentrations, VMS are significantly increased with no bleeding, smoking, higher age, physical activity, follicle-stimulating hormone, and luteinizing hormone and are significantly reduced with increasing estrogen concentrations.

Sequential classification of endocrine stages during reproductive aging in women: the FREEDOM study.

OBJECTIVE: Reproductive aging involves complex endocrine changes affecting women's fertility, health, and well-being; however, understanding of the specific changes involved is limited by the lack of detailed quantitative studies. We undertook a thorough study with the aim of characterizing the different endocrine stages involved in female reproductive aging. DESIGN: FREEDOM is a cohort study designed to determine the endocrine changes during reproductive aging in women. Here, we ascertained the different endocrine patterns in a representative population and developed a staging system. In this study, 112 women aged 30 to 58 years collected daily urine samples over a 6- to 18-month period and recorded their menstrual periods. A total of 36,786 samples were analyzed for follicle-stimulating hormone (FSH), luteinizing hormone, estrone 3-glucuronide, and pregnanediol 3-glucuronide. RESULTS: A classification of five sequential endocrine stages of reproductive aging was developed: stage 1, regular menstrual cycles with mean initial (day 1-5) FSH less than 5 IU/L; stage 2, regular cycles with FSH greater than 5 IU/L; stage 3, menstrual irregularity (with the appearance of "delayed-response cycles"); stage 4, acyclical ovarian activity with no evidence of ovulation and luteinization; and stage 5, ovarian quiescence and persistently raised gonadotropins. Distinct hormonal characteristics during the follicular and luteal phase were noted at each stage. CONCLUSION: This classification provides a detailed insight into the endocrinology of reproductive aging in women that could be useful for both clinical guidance and personal health care.