Phthalate metabolite levels and menopausal hot flashes in midlife women.

During the menopausal transition, a woman's reproductive capacity declines, her hormone milieu changes, and her risk of hot flashes increases. Exposure to phthalates, which can be found in personal care products, can also result in altered reproductive function. Here, we investigated the associations between phthalate metabolite levels and midlife hot flashes. Eligible women (45-54 years of age) provided detailed information on hot flashes history and donated urine samples (n=195). Urinary phthalate metabolite levels were measured by HPLC-MS/MS. A higher total sum of phthalate metabolites commonly found in personal care products was associated with an increased risk of ever experiencing hot flashes (odds ratio (OR)=1.45; 95% confidence interval (CI)=1.07-1.96), hot flashes in the past 30days (OR=1.43; 95%CI=1.04-1.96), and more frequent hot flashes (OR=1.47; 95%CI=1.06-2.05). These data suggest that some phthalate exposures from personal care products are associated with menopausal hot flashes in women.

Oxidative stress and menopause-related hot flashes may be independent events.

OBJECTIVE: At present, there is growing demand for alternative, or additional, treatments to hormone replacement therapy for menopause-related hot flashes (HF). Antioxidant supplements have been recently proposed as possible candidates for this purpose, regardless of the absence of clear evidence in support of a link between these vasomotor symptoms and oxidative stress (OxS). The aim of our study was to evaluate the association between HF and OxS serum markers in a large sample of middle-aged women. MATERIALS AND METHODS: We conducted a cross-sectional study on 245 perimenopausal and early postmenopausal women (age 45-60 years). The variables examined were presence of self-reported HF and levels of 8-iso-prostaglandin F2α, 8-OH-deoxy-2'-guanosine, advanced oxidation protein products, total antioxidant power, uric acid, thiols, and paroxonase-1. RESULTS: Seventy-six women (31%) reported to suffer from HF (either medium or high intensity). None of the peripheral markers of OxS examined was found to be significantly associated with the presence of HF. CONCLUSION: Taken together, our data suggest that systemic OxS might not be implicated with the onset of the climacteric vasomotor symptoms that most commonly affect women experiencing perimenopause and early postmenopause.

Relationship between the body iodine status and menopausal symptoms during postmenopausal period.

AIM: The aim of this study was to assess the effect of body iodine status on hot flashes and cardiovascular disease risk in postmenopausal women. METHODS: Two hundred and ten consecutive postmenopausal women without known any risk factor for cardiovascular disease risk or systemic disorder were recruited for the study. All participants underwent serum screening consisted of lipid profile including lipoprotein-a (Lp(a)) and urinary iodine excretion. Participants were also asked for the frequency and the duration of hot flashes. All parameters were assessed for the association between urine iodine excretion and other parameters. RESULTS: Urine spot iodine level was significantly correlated with Lp(a) (r = -0.287, p < 0.001), low-density lipoprotein cholesterol (LDL-C) (r = -0.187, p = 0.006), cholesterol level (r = -0.573, p < 0.001), TG level (r = -0.211, p = 0.02), frequency of hot flashes per a day (r = -0.467, p < 0.001), durations of hot flashes (r = -0.424, p < 0.001), fasting glucose level (r = 0.331, p < 0.001), and fT3 level (r = 0.475, p < 0.001). In multivariate analysis, Lp(a) levels were significantly associated with the urine iodine level (beta coefficient = -0.342, p < 0.001) after adjustment for LDL-C (beta coefficient = 0.225, p < 0.001), glucose (beta coefficient = 0.303, p < 0.001), and age (beta coefficient = 0.146, p < 0.017). CONCLUSION: Body iodine status during postmenopausal period is associated with the menopausal symptoms and lipid profile including Lp(a).

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

OBJECTIVE: During the menopausal transition and early postmenopause, participants in the Seattle Midlife Women's Health Study were likely to belong to one of three symptom severity classes: severe hot flashes with moderate sleep, mood, cognitive, and pain symptoms (high-severity hot flash); moderate levels of all but hot flashes (moderate severity); and low levels of all (low severity). We tested models of the differential effects of hypothalamic-pituitary-ovarian (HPO) axis, hypothalamic-pituitary-adrenal (HPA) axis, and autonomic nervous system (ANS) biomarkers on the three symptom severity classes. METHODS: The Seattle Midlife Women's Health Study participants recorded symptoms monthly in diaries and provided overnight urine samples several times per year that were analyzed for estrone, follicle-stimulating hormone (FSH), cortisol, testosterone, epinephrine, and norepinephrine. Multilevel latent class analysis with multinomial regression was used to determine the effects of HPO axis, HPA axis, and ANS biomarkers on symptom severity class membership. RESULTS: Having lower estrogen and higher FSH levels was significantly associated with belonging to the high-severity hot flash class versus the low-severity class. Having lower epinephrine and higher norepinephrine levels increased the likelihood of belonging to the high-severity hot flash class versus the low-severity class. Having lower epinephrine levels was significantly associated with belonging to the moderate-severity class versus the low-severity class. Cortisol and testosterone were unrelated to symptom severity class membership. CONCLUSIONS: The association of HPO axis biomarkers (estrogen and FSH) with the high-severity hot flash class is anticipated based on prior hot flash research, and the associations of HPA axis biomarkers are as expected based on earlier laboratory studies. The association of lower epinephrine levels with the moderate-severity class suggests that these symptoms may be mediated by the ANS.

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.

Sleep symptoms during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women's Health Study.

STUDY OBJECTIVES: Describe the severity of getting to sleep, nighttime awakening, and early morning awakening across the menopausal transition (MT) and early postmenopause (PM) and their relationship to age, menopausal transition factors, symptoms, stress-related factors, and health related factors. DESIGN: Cohort. SETTING: community. PARTICIPANTS: 286 women from the Seattle Midlife Women's Health Study cohort. MEASUREMENTS: Participants completed annual menstrual calendars for MT staging, diaries in which they rated their symptoms, stress levels, and perceived health multiple times per year from 1990-2007 and provided first morning urine samples assayed for E1G, FSH, cortisol, and catecholamines. Multilevel modeling (R program) was used for data analysis. RESULTS: Severity of self-reported problems going to sleep was associated with all symptoms, perceived stress, history of sexual abuse, perceived health (-), alcohol use (-) (all P < 0.001), and lower cortisol (P = 0.009), but not E1G or FSH. Severity of nighttime awakening was significantly associated with age, late MT stage, and early PM, FSH, E1G (-), hot flashes, depressed mood, anxiety, joint pain, backache, perceived stress, history of sexual abuse, perceived health (-), and alcohol use (-) (all P < 0.001, except E1G for which P = 0.030). Severity of early morning awakening was significantly associated with age, hot flashes, depressed mood anxiety, joint pain, backache, perceived stress, history of sexual abuse, perceived health (-) (all P < or = 0.001, except E1G for which P = 0.02 and epinephrine (P = 0.038), but not MT stages or FSH. Multivariate models for each symptom included hot flashes, depressed mood, and perceived health. CONCLUSION: Sleep symptoms during the MT may be amenable to symptom management strategies that take into account the symptom clusters and promote women's general health rather than focusing only on the MT.

Cortisol levels during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women's Health Study.

OBJECTIVE: Cortisol levels rise among some women during the late stage of the menopausal transition (MT), but we know little about changes in cortisol levels in relation to menopause-related factors (MT stage, urinary estrone glucuronide [E1G], testosterone, follicle-stimulating hormone [FSH]), stress-related factors (epinephrine, norepinephrine, and perceived stress), symptoms (hot flashes, mood, memory, and sleep), social factors (income adequacy, role burden, social support, employment, parenting, and history of sexual abuse), and health-related factors (depressed mood, perceived health, physical appraisal, body mass index, and smoking). The aim of the study was to examine the influence of menopause-related factors, stress-related factors, symptoms, social factors, and health-related factors on cortisol levels during the MT. METHODS: Participants were a subset of Seattle Midlife Women's Health Study who provided data during the late reproductive, early and late MT stages, or early postmenopause and who were not using hormone therapy or corticosteroids (N = 132 women, up to 5,218 observations). Data provided included menstrual calendars for staging the MT, annual health reports, health diaries, and overnight urine specimens (assayed for cortisol, catecholamines, E1G, and FSH) between 1990 and 2005 were included. Perceived stress, symptoms, and health behaviors were assessed in a health diary. Health-related and social factors were assessed in an annual health update. Multilevel modeling was used to test the effects of menopause-related and other factors on overnight cortisol levels. RESULTS: When tested with age as a measure of time, menopause-related covariates, including E1G, FSH, and testosterone, were associated with significant increases in overnight cortisol levels (P < 0.0001). Likewise, epinephrine and norepinephrine were each associated significantly with overnight cortisol levels (P < 0.0001). In multivariate analyses, E1G, FSH, and testosterone constituted the best set of predictors. CONCLUSIONS: Overnight cortisol levels during the MT were associated with E1G, testosterone, and FSH levels. In addition, they were significantly and positively associated with epinephrine and norepinephrine. MT stage, symptoms, and social, stress-related, and health-related factors had little relationship to overnight cortisol levels when other biological indicators were considered.

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.

Hot flash severity in hormone therapy users/nonusers across the menopausal transition.

OBJECTIVES: The purpose of this study was to examine the pattern of and factors that influence hot flash severity across the menopausal transition (MT) and early postmenopause (PM). METHODS: Women from the Seattle Midlife Women's Health Study (N=302) provided data for these analyses: at least one annual health questionnaire and a menstrual calendar. A subset of women provided a first morning voided urine specimen from 1997 through 2005. Urine samples were assayed for estrone glucuronide and FSH. Linear mixed effects modeling was used to identify change in hot flash severity scores over time, including the relationship to age, MT-related, psychosocial and lifestyle factors. RESULTS: Increases in hot flash severity were associated with late transition stage, early postmenopause, use of HRT, duration of early transition stage, age of entry into early PM and level of FSH. Age of entry into early transition and estrone levels were associated with decreased hot flash severity. Not associated with hot flash severity were being in early transition stage, age of entry into or duration of late transition stage and all of the psychosocial (anxiety, stress, depressed mood) and lifestyle variables (BMI, activity level, sleep, alcohol use). CONCLUSIONS: Variables associated with reproductive aging independently predicted changes in hot flash severity; psychosocial and lifestyle variables did not. The effect of age dropped out when factors associated with reproductive aging were considered. Use of HRT ameliorated but did not eliminate severe hot flashes suggesting that there is room for alternative approaches less likely to cause harm.

The association between soy nut consumption and decreased menopausal symptoms.

BACKGROUND: Epidemiological studies suggest a low incidence of hot flashes in populations that consume dietary soy. The present study examined the effect of soy nuts on hot flashes and menopausal symptoms. METHODS: Sixty healthy postmenopausal women were randomized in a crossover design to a therapeutic lifestyle changes (TLC) diet alone and a TLC diet of similar energy, fat, and protein content in which one-half cup soy nuts divided into three or four portions spaced throughout the day (containing 25 g soy protein and 101 mg aglycone isoflavones) replaced 25 g of nonsoy protein. During each 8-week diet period, subjects recorded the number of hot flashes and amount of exercise daily. At the end of each 8-week diet period, subjects filled out the menopausal symptom quality of life questionnaire. RESULTS: Compared to the TLC diet alone, the TLC diet plus soy nuts was associated with a 45% decrease in hot flashes (7.5 +/- 3.6 vs. 4.1 +/- 2.6 hot flashes day, respectively, p < 0.001) in women with >4.5 hot flashes/day at baseline and 41% in those with

Urinary excretion of calcitonin gene-related peptide in males with hot flushes after castration for carcinoma of the prostate.

OBJECTIVE: The majority of men who undergo surgical or medical castration due to prostatic carcinoma develop vasomotor symptoms with hot flushes. The mechanisms behind these symptoms are poorly understood. One possible explanation is a release of the vasodilatory peptide calcitonin gene-related peptide (CGRP) from perivascular nerves, which seem to be involved in the mechanisms behind vasomotion and sweating in postmenopausal women. The aim of this report was to investigate whether CGRP is involved in vasomotion in men after castration therapy. MATERIAL AND METHODS: Twenty-four hour urine excretion of CGRP was analysed in 15 men with prostatic carcinoma, using radioimmunoassay before and 3 months after surgical or medical castration. RESULTS: Eleven of the 15 men developed hot flushes during the observation period of 3 months. Twenty-four hour urine excretion of CGRP did not change significantly after castration, either in the group as a whole or in those 11 men who developed hot flushes. CONCLUSIONS: Even though we did not observe any significant changes in 24-h urine excretion of the potent vasodilator CGRP after castration it is possible that serum levels of CGRP increase during hot flushes, without having an effect on the 24-h urine excretion of the peptide.

Postmenopausal women with vasomotor symptoms have increased urinary excretion of calcitonin gene-related peptide.

OBJECTIVES: To establish whether 24 h urinary excretion of the potent vasodilator calcitonin gene-related peptide (CGRP) was higher in postmenopausal women with vasomotor symptoms compared to the level in women without symptoms. We also wanted to establish whether urinary excretion of CGRP changed during the menstrual cycle in women of fertile age. MATERIAL AND METHODS: Thirteen postmenopausal women with and 13 women without vasomotor symptoms were included. Urine was collected over 24 h and CGRP excretion was measured utilizing radio-immunoassay technique. Twenty-four hour CGRP excretion was also measured in ten fertile women with regular cycles in early follicular, preovulatory and midluteal phase. RESULTS: Twenty-four hour urinary excretion of CGRP was significantly higher in women with vasomotor symptoms compared to non-flushing women (median 7.16 vs 5.15 pmol/24 h; P = 0.028). CGRP concentrations were stable throughout the ovulatory cycles. CONCLUSION: The 24 h urinary excretion of CGRP is higher in women with vasomotor symptoms than in women without these symptoms. CGRP may be the mediator of vasodilator signals originating from the thermoregulatory center.