Association between polycystic ovary syndrome and hot flash presentation during the midlife period.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in reproductive-aged women; however, the impact of PCOS on menopausal symptoms remains poorly understood. This study aims to determine the influence of PCOS on hot flash presentation in midlife women. METHODS: Participants were recruited from the Midlife Women's Health Study involving 780 women aged 45 to 54 years. All women completed detailed questionnaires on hot flash symptoms. Between June 2014 and March 2015, participants were screened for history of PCOS based on the Rotterdam criteria. Fisher's exact tests and Wilcoxon rank-sum tests were used for analysis. Multivariate logistic regression was performed to identify factors associated with hot flashes at midlife. RESULTS: In all, 453 women (69%) consented to the telephone interview and 9.3% (n = 42) met diagnostic criteria for PCOS; 411 were included as controls. Mean age was 48.0 and body mass index was 27.3 for women with PCOS. The majority of participants were white (72%). There was no difference between PCOS and control women for levels of follicle-stimulating hormone, testosterone, progesterone, or estradiol. Multivariate logistic regression demonstrated that PCOS was not associated with increased odds of hot flash incidence. Smoking was the only variable associated with experiencing hot flashes (odds ratio 2.0, 95% confidence interval 1.05-3.98). CONCLUSIONS: A history of PCOS was not associated with increased hot flash symptoms during the midlife period. Additional research should continue to investigate the health and quality of life associated with a history of PCOS in the aging population.

The Midlife Women's Health Study - a study protocol of a longitudinal prospective study on predictors of menopausal hot flashes.

BACKGROUND: The Midlife Women's Health Study (MWHS) was developed to address some of the gaps in knowledge regarding risk factors for hot flashes among generally healthy midlife women during their menopausal transition. This manuscript describes the methods from the study and the main findings that were published to date, with a focus on predictors of hot flashes. This study was initially funded to test the hypothesis that obesity is associated with an increased risk of hot flashes through mechanisms that involve ovarian failure, altered sex steroid hormone levels, and selected genetic polymorphisms. METHODS/DESIGN: The MWHS was conducted between 2006 and 2015 as a prospective longitudinal population-based study of generally healthy midlife women (ages 45 to 54 years) during their natural menopausal transition. Women were eligible if they had intact uteri and both ovaries and reported having at least 3 menstrual periods in the last 12 months. Exclusion criteria included pregnancy, cancer, and use of hormonal/hormone-like supplements. Overall, 780 women were recruited into the study. The majority of study participants were followed for 4 to 7 years. At annual visits, women donated blood and urine samples, completed questionnaires, had a vaginal ultrasound, and had their anthropometric measurements taken. DISCUSSION: Several risk factors for menopausal hot flashes were identified or confirmed, including older age, perimenopausal status, current and former cigarette smoking, lower estradiol levels, lower progesterone levels, black race, and depressive symptoms. Factors that were associated with decreased odds of hot flashes included moderate alcohol consumption and more than 5 years of cessation of cigarette smoking. Body mass index was not associated with hot flashes. The MWHS has provided important information regarding hot flashes. The study methods are rigorous and can be easily adopted by research groups investigating naturally occurring menopausal hot flashes.

Risk Factors for Extended Duration and Timing of Peak Severity of Hot Flashes.

OBJECTIVE: To identify risk factors associated with the duration of hot flashes and the time of peak hot flash severity in mid-life women. METHODS: A cohort of 647 women reporting hot flashes were followed for 1-7 years, with survey data and hormone measurements. Survival analysis determined the association of risk factors with the duration of hot flashes. Linear regression determined the association of risk factors with the time of peak severity. Final models were determined through stepwise model selection. RESULTS: Average hot flash duration was 2.5 years (range: 1-33), with peak severity on average at 2.96 years (range: 1-20). Duration of hot flashes was associated with race, education, menopause status, smoking history, BMI, alcohol consumption, leisure activity levels, and levels of estradiol and progesterone. In the final model, only race, alcohol consumption, leisure activity, and menopause were retained. White women had significantly shorter hot flash durations than non-white women. Women consuming at least 12 alcoholic drinks in the previous year had a significantly shorter duration of hot flashes with a smaller effect of hot flash duration on increasing in time to peak severity compared to those who consumed less than 12 alcoholic drinks in that year. Higher serum progesterone levels were associated with later peak severity if the duration of the hot flashes was less than 2 years and an earlier peak severity otherwise. CONCLUSIONS: These results suggest that some behaviors (such as moderate alcohol consumption) are associated with shorter durations of hot flashes, and that progesterone was associated with the dynamics of hot flash severity.

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.

The Associations Between Body Mass Index, Smoking, and Alcohol Intake with Ovarian Volume in Midlife Women.

BACKGROUND: Despite the fact that ovarian volume is a marker of reproductive aging, there is little understanding of factors related to ovarian volume among aging women. The objective of this analysis was to examine the associations between body mass index (BMI), cigarette smoking, and alcohol intake with ovarian volume among midlife women. MATERIALS AND METHODS: Data were analyzed from 771 women (45-54 years of age at baseline) enrolled in the Midlife Women's Health Study, a cohort study that was initiated in 2006. At annual clinic visits, height and weight were measured, a transvaginal ultrasound was performed to measure ovarian volume, blood was drawn to measure hormone concentrations, and a comprehensive questionnaire was administered. Generalized linear models and repeated measures mixed models were conducted to examine the associations between BMI, cigarette smoking, and alcohol intake with ovarian volume, adjusting for age and race. RESULTS: Age was significantly and negatively associated with ovarian volume. However, BMI, smoking, and alcohol use were not associated with ovarian volume either when stratified by menopausal status or when adjusting for age and race. Estradiol, but not progesterone or testosterone, was significantly and positively associated with ovarian volume overall and among both white and black participants (p < 0.05). CONCLUSIONS: This study provides insight into the associations between BMI, smoking, and alcohol use with ovarian volume among midlife women. The findings are somewhat consistent with the published literature and, thus, indicate that these factors may not be clinically important in terms of ovarian volume during the menopausal transition.

Risk factors for hot flashes among women undergoing the menopausal transition: baseline results from the Midlife Women's Health Study.

OBJECTIVE: The aim of this study was to examine the associations of demographic characteristics, health behaviors, and hormone concentrations with the experience of any, current, more severe, and more frequent midlife hot flashes. METHODS: Baseline data from 732 women aged 45 to 54 years who were enrolled in the Midlife Women's Health Study were analyzed. A clinic visit was conducted to collect blood samples for hormone assays and to measure ovarian volume using transvaginal ultrasound. A self-administered questionnaire ascertained information on demographic factors, health habits, and hot flash history. Multivariable logistic regression was conducted to examine associations between potential risk factors and hot flash outcomes. RESULTS: Approximately 45% of participants reported experiencing midlife hot flashes. In covariate-adjusted models, older age, perimenopause status, current and past cigarette smoking, and depressive symptoms were significantly associated with increased odds of all of the hot flash outcomes. In addition, history of oral contraceptive use was associated with increased odds of any hot flashes. In contrast, higher current alcohol intake was significantly associated with decreased odds of any, current, and more severe hot flashes. Higher estradiol and progesterone concentrations were significantly associated with decreased odds of all hot flash outcomes. CONCLUSIONS: Although the temporality of such associations is not known because of the cross-sectional nature of the data, these observed relationships can help to identify women at risk for hot flashes.

Change in body mass index, weight, and hot flashes: a longitudinal analysis from the midlife women's health study.

BACKGROUND: The goals of this study were to examine the associations between body mass index (BMI), as well as BMI change and weight change, with midlife hot flashes. METHODS: Data were analyzed from an ongoing 5-year cohort study of 631 midlife women (ages 45-54 years) recruited from Baltimore, Maryland, and its surrounding counties. Height and weight were measured at clinic visits conducted annually. Questionnaires administered at each clinic visit collected detailed data on hot flashes, including the severity and frequency, and other covariates. Data were analyzed using logistic regression and generalized estimated equation models, adjusting for potential confounders. RESULTS: Among women enrolled in the study, 45.2% reported hot flashes and 32.0% were categorized as being obese (BMI ≥30 kg/m(2)) at baseline. At baseline, BMI was not significantly associated with ever experiencing hot flashes (BMI ≥30 versus <25 kg/m(2): odds ratio [OR] 0.92; 95% confidence interval [CI]: 0.58, 1.15) or any of the other hot flashes outcomes (recent, frequent, or severe). In addition, no statistically significant associations between BMI, BMI change, or weight change, and the hot flash outcomes were observed in the longitudinal models (for example, any hot flashes: BMI ≥30 versus <25 kg/m(2): OR 0.81; 95% CI: 0.56, 1.17). CONCLUSION: BMI, BMI change, and weight change during midlife were not related to hot flashes in this study. The data suggest that other factors, such as smoking habits, are more important in determining hot flashes risk during midlife.

Genetic polymorphisms in the aryl hydrocarbon receptor-signaling pathway and sleep disturbances in middle-aged women.

OBJECTIVE: We aimed to determine if selected genetic polymorphisms in the aryl hydrocarbon receptor (AHR)-signaling pathway and circadian locomotor output cycles kaput (CLOCK) are associated with insomnia and early awakening in middle-aged women. METHODS: Women aged 45 to 54years (n=639) were recruited into a middle-aged health study and agreed to complete questionnaires and donate blood samples. Questionnaires were used to assess sleep outcomes. Blood samples were processed for genotyping for the selected polymorphisms: AHR (rs2066853), AHR repressor (AHRR) (rs2292596), aryl hydrocarbon nuclear translocator (ARNT) (rs2228099), and CLOCK (rs1801260). Data were analyzed using multivariable logistic regression. RESULTS: Women heterozygous for the AHRR alleles (GC) had decreased odds of insomnia compared to women homozygous for the AHRR_C allele (adjusted odds ratio [aOR], 0.69; 95% confidence interval [CI], 0.49-0.96). Women with at least one of the AHRR_G or CLOCK_C alleles had significantly decreased odds of insomnia compared to women homozygous for the AHRR_C and CLOCK_T alleles (aOR, 0.64; 95% CI, 0.43-0.96). Additionally, women homozygous for the AHRR_G and CLOCK_C alleles had significantly decreased odds of insomnia compared to women homozygous for the AHRR_C and CLOCK_T alleles (aOR, 0.56; 95% CI, 0.35-0.89). None of the selected single nucleotide polymorphisms (SNPs) or combinations of SNPs were significantly associated with early awakening. CONCLUSIONS: Selected genetic polymorphisms in the AHR-signaling pathway (i.e., AHRR) and CLOCK may play a role in decreasing the risk for experiencing insomnia during the menopausal transition.

Genetic polymorphisms in the aryl hydrocarbon receptor signaling pathway as potential risk factors of menopausal hot flashes.

OBJECTIVE: We sought to determine if genetic polymorphisms in the aryl hydrocarbon receptor signaling pathway are associated with menopausal hot flashes via hormone levels. STUDY DESIGN: Women (n = 639) aged 45-54 years completed a study survey and provided blood for genetic and hormone analyses. The associations were analyzed using multivariable logistic regression and generalized linear models. RESULTS: Women carrying CYP1B1 (rs1800440) GG genotype had 3-fold greater odds of experiencing hot flashes for ≥1 year compared to the AA genotype (adjusted odds ratio [OR], 3.05; 95% confidence interval [CI], 1.12-8.25). Adding serum estradiol concentrations to the confounder-adjusted model resulted in a nonsignificant association (adjusted OR, 2.59; 95% CI, 0.91-7.18). Carriers of both CYP1B1 (rs1800440) G and CYP1B1 (rs1058636) G alleles had higher odds of experiencing hot flashes for ≥1 year compared to women homozygous for the major alleles (adjusted OR, 1.77; 95% CI, 1.06-2.96), even after adjustment for serum estradiol. CONCLUSION: CYP1B1 is associated with menopausal hot flashes via pathways that may involve changes in serum estradiol concentration.

A genetic polymorphism in the CYP19A1 gene and the risk of hypertension among midlife women.

OBJECTIVE: To test whether a synonymous single nucleotide polymorphism (A→G; rs700518) in the CYP19A1 gene, which encodes the enzyme aromatase, is associated with an increased risk for hypertension of midlife women. METHODS: In a cross-sectional study, 639 midlife women were recruited. Eligible women had their blood pressure, weight and height measured, and donated a blood sample for hormone and genetic analyses. The participants also completed a detailed study survey. Women were grouped according to their genotype, blood pressure measurements, and medical history. The data were analyzed using logistic and linear regression models. The study had 80% power to detect small differences in mean systolic blood pressure (SBP; 4.5 mmHg) and diastolic blood pressure (DBP; 3 mmHg). RESULTS: The selected polymorphism was significantly associated with hypertension and SBP in unadjusted analyses. Interestingly, women with hypertension were more likely to be homozygous for the A allele (AA) compared to women who were not categorized as having hypertension. Further, the mean SBP was significantly higher for women who were homozygous for the A allele when compared to women carrying the other genotypes (AG or GG). The unadjusted association between DBP values and genotype was of borderline statistical significance (p=0.07). However, after adjustment for potential confounders (age, race, body mass index (BMI), smoking and physical activity), the associations between genotype and hypertension/blood pressure were attenuated and not statistically significant. CONCLUSION: The rs700518 polymorphism in the CYP19A1 is not associated with hypertension in our sample of midlife women. Other factors, including race and BMI, appear to play a greater role.

Hormonal changes throughout life in women.

The changes in hormonal milieu associated with menarche, pregnancy, lactation, and menopause are frequently accompanied by changes in the patterns and frequency of migraine. Migraine headache is more common in females and, for many women, the onset of this condition occurs at menarche. As many as 60% of women migraineurs report an association between migraine and menstruation, and evidence suggests that estrogen withdrawal may be a trigger for menstrual migraine in susceptible women. Moreover, in the majority of women, migraine frequency increases during the pill-free interval with oral contraceptive use and during the postpartum period, which are other times of decreasing estrogen levels. Migraine frequency tends to decrease during periods of increasing or stable estrogen levels. For these reasons, the numerous neuroendocrine effects elicited by estrogen have been evaluated to explain its role in migraine. Overall, estrogen appears to be a key factor in menstrual migraine, but it is likely to be only one of several factors that act in concert to trigger migraine in susceptible women. Understanding the relationship of the different hormonal milieus through the natural course of women's lives can guide diagnosis and treatment.

The association between menopausal symptoms and quality of life in midlife women.

This cross-sectional study examined 1,096 midlife women, associating menopausal symptoms, including hot flashes, vaginal dryness, sore joints, incontinence, irritability, mood changes, and headache, with quality of life (QOL), as measured using Cantril's Ladder of Life. The results showed that low QOL may be significantly associated with feeling tense and mood changes, but not the other selected symptoms.

Association between race and hot flashes in midlife women.

OBJECTIVE: Studies suggest that African American women may have a greater risk of hot flashes compared to Caucasian women, but the reasons for this are unknown. This study tested the hypothesis that African American women have an increased risk of hot flashes due to racial differences in risk factors for hot flashes, including high body mass index (BMI) and lower estrogen levels. METHODS: A population-based study was conducted among women aged 45-54 years. Participants were divided into women who reported ever experiencing hot flashes (n=356) and women who reported never experiencing hot flashes (n=257). Participants provided a blood sample for hormone assays, were weighed and measured, and completed a questionnaire. RESULTS: Among peri-menopausal women, African American women were more likely than Caucasian women to report any hot flashes (RR=2.08), severe hot flashes (RR=2.19), and hot flashes for more than 5 years (RR=1.61). The risk ratios for the associations between race and the hot flash outcomes were attenuated after controlling for other important hot flash risk factors (i.e. obesity and low estrogen levels). CONCLUSIONS: African American women have an increased risk of hot flashes compared to Caucasian women due to racial differences in a number of risk factors for hot flashes, including advanced age, obesity, current smoking, less than 12 drinks in the past year, and lower estrogen levels.

Long-term corticosteroid replacement and bone mineral density in adult women with classical congenital adrenal hyperplasia.

CONTEXT: Concern has been raised regarding the potential impact of chronic glucocorticoid therapy on the bone mineral density (BMD) of patients with congenital adrenal hyperplasia (CAH). OBJECTIVE: The purpose of this investigation was to assess the impact of chronic glucocorticoid replacement in adult women with classical CAH. PATIENTS AND DESIGN: We used dual energy x-ray absorptiometry to evaluate lumbar spine and whole body BMD in 11 women with salt-losing (SL) CAH and 15 with the simple virilizing form. Physical characteristics and serum hormone concentrations were also measured. Results were compared with those of unaffected sisters of CAH patients (n = 9). MAIN OUTCOME MEASURE: BMD was the main outcome measure. RESULTS: Osteopenia was noted in 45% of SL CAH patients, 13% of patients with the simple virilizing form, and 11% of controls. Lumbar spine and whole body BMDs of CAH subjects were lower than those of controls (P < 0.05). Compared with CAH subjects with normal BMD, those with osteopenia had reduced serum levels of dehydroepiandrosterone sulfate and dehydroepiandrosterone. Adrenal androgen levels were particularly suppressed among postmenopausal women receiving glucocorticoid replacement. CONCLUSIONS: Adult women with classical CAH treated with long-term glucocorticoids are at risk for decreased BMD, especially those with the SL form. Oversuppression of adrenal androgens is associated with increased risk for bone loss in this population.

Treatment of premenstrual dysphoric disorder with a new drospirenone-containing oral contraceptive formulation.

PURPOSE: This multicenter, double-blind, placebo-controlled crossover study evaluated the efficacy of a new oral contraceptive (OC) formulation containing drospirenone 3 mg and ethinyl estradiol (EE) 20 mug in treating symptoms of premenstrual dysphoric disorder (PMDD). METHOD: The OC formulation or placebo was administered for 24 days in a 28-day cycle (24/4), rather than the usual 21-day active treatment, 7-day inert-pill regimen. Participants (N=64) were randomized to either study treatment for three cycles and then after a washout period of one treatment-free cycle switched to the alternate treatment. RESULTS: The mean decrease from baseline for total Daily Record of Severity of Problems (DRSP) scores while using drospirenone/EE was significantly greater than for placebo (-12.47, 95% CI=-18.28, -6.66; p<.001). A positive response (i.e., a score of 1 or 2 in the Clinical Global Impressions-Improvement scale) occurred in 61.7% and 31.8% of subjects while taking drospirenone/EE and placebo, respectively (p=.009). CONCLUSION: Drospirenone/EE, given in a 24/4 regimen, was superior to placebo for improving symptoms associated with PMDD.

Prolactin gene expression in human ovarian follicular cells.

OBJECTIVE: To investigate prolactin gene expression in human ovarian follicular cells. DESIGN: RNA was isolated from follicular cells obtained at the time of transvaginal oocyte retrieval from patients after controlled ovarian hyperstimulation. The RNA was subjected to reverse transcription and polymerase chain reaction (RT-PCR) using prolactin-specific primers. The RT-PCR products were analyzed by gel electrophoresis, followed by Southern blot analysis using prolactin-specific probes. SETTING: Department of gynecology and obstetrics research laboratory. PATIENT(S): Women undergoing controlled ovarian hyperstimulation followed by transvaginal oocyte retrieval. INTERVENTION(S): Controlled ovarian hyperstimulation followed by transvaginal oocyte retrieval. Expression of prolactin mRNA by follicular cells. RESULT(S): The presence of prolactin-specific cDNA amplified by RT-PCR from RNA isolated from human follicular cells was confirmed by Southern blot analysis. CONCLUSION(S): Human ovarian follicular cells are an extrapituitary site of prolactin gene expression.

Decreased progesterone receptor expression in the intermediate trophoblastic cells of spontaneous abortions.

OBJECTIVE: To determine whether there are differences in the expression of progesterone receptor (PR) in intermediate trophoblastic cells of pregnancies ending in either spontaneous abortion (SAB) or elective abortion. DESIGN: Immunohistochemical identification of PR in intermediate trophoblastic cells. SETTING: Academic medical center. PATIENT(S): Subjects were 86 patients who either underwent first trimester SAB or elective abortion. INTERVENTION(S): All SAB and elective abortion specimens were serially sectioned and immunohistochemically stained for PR and for melanoma cell adhesion molecule. Melanoma cell adhesion molecule immunohistochemical staining was used as a sensitive and specific marker to identify intermediate trophoblastic cells on the adjacent tissue section. MAIN OUTCOME MEASURE(S): The PR staining of intermediate trophoblastic cells by semiquantitative immunostaining score. RESULT(S): The PR expression in intermediate trophoblastic cells was significantly greater in elective abortion specimens than in SAB specimens. When controlling for estimated gestational age, the difference in PR expression was even greater. CONCLUSION(S): The quantity of PR in intermediate trophoblastic cells is significantly less in SAB when compared to elective abortion pregnancies. Although it is unknown whether this is a primary or secondary event, this information may be an important finding in attempting to characterize both the molecular etiology of implantation and the molecular pathophysiology of SAB.

Integrated summary of Ortho Evra/Evra contraceptive patch adhesion in varied climates and conditions.

OBJECTIVE: To assess the adhesive reliability of the contraceptive patch (Ortho Evra/Evra). DESIGN: Pooled data of 3,319 women from three contraceptive studies of up to 13 treatment cycles; a subset of 325 women of the pooled data from warm and humid climates; and 30 women from a three-period, crossover exercise study. SETTING: 184 centers. PATIENT(S): 3,349 healthy women. INTERVENTION(S): In the contraceptive studies, each treatment cycle consisted of three consecutive 7-day patches (21 days) followed by one patch-free week. During each treatment period in the exercise study, women wore the patch for 7 days and participated in one of six activities (normal activity, excluding bathing; sauna; whirlpool; treadmill; cool-water immersion; or a combination of activities) each day at a supervised health center. MAIN OUTCOME MEASURE(S): Patch adhesion. RESULT(S): In the contraceptive studies, 4.7% of patches were replaced because they fell off (1.8% [1,297 of 70,552 patches]) or became partly detached (2.9% [2,050 of 70,552 patches]); patch replacement rates in centers from a warm, humid climate were 1.7% (85 of 4,877 patches) and 2.6% (128 of 4,877 patches), respectively. Only one of 87 patches (1.1%) completely detached in the exercise study. CONCLUSION(S): The reliability of adhesion of the contraceptive patch is excellent and consistent across all studies; only 1.8% and 2.9% of patches required replacement due to complete or partial detachment, respectively. Heat, humidity, and exercise do not affect adhesion.