Menopausal symptoms and cardiometabolic risk factors in middle-aged women: A cross-sectional and longitudinal study with 4-year follow-up.

OBJECTIVE: To study associations of menopausal symptoms with cardiometabolic risk factors. STUDY DESIGN: A cross-sectional and longitudinal study of a representative population sample of 1393 women aged 47-55 years with a sub-sample of 298 followed for four years. The numbers of vasomotor, psychological, somatic or pain, and urogenital menopausal symptoms were ascertained at baseline through self-report. Their associations with cardiometabolic risk factors were studied using linear regression and linear mixed-effect models. Models were adjusted for age, menopausal status, body mass index, the use of hormonal preparations, education, smoking, and alcohol consumption. MAIN OUTCOME MEASURES: Cardiometabolic risk factors included total cholesterol, low-density and high-density lipoprotein cholesterol, blood pressure, glucose, triglycerides, total and android fat mass, and physical activity. RESULTS: All cholesterol and fat mass measures had modest positive associations with menopausal symptoms. The number of vasomotor symptoms, in particular, was associated with total cholesterol (B = 0.13 mmol/l, 95 % CI [0.07, 0.20]; 0.15 mmol/l [0.02, 0.28]) and low-density lipoprotein cholesterol (0.08 mmol/l [0.03, 0.14]; 0.12 mmol/l [0.01, 0.09]) in cross-sectional and longitudinal analyses, respectively. However, these associations disappeared after adjusting for confounders. The number of symptoms was not associated with blood pressure, glucose, triglycerides, and physical activity. Menopausal symptoms at baseline did not predict the changes in the risk factors during the follow-up. CONCLUSIONS: Menopausal symptoms may not be independently associated with cardiometabolic risk, and they do not seem to predict the changes in risk factors during the menopausal transition.

Associations of Sex Hormones and Hormonal Status With Arterial Stiffness in a Female Sample From Reproductive Years to Menopause.

Objective: Loss of sex hormones has been suggested to underlie menopause-associated increment in cardiovascular risk. We investigated associations of sex hormones with arterial stiffness in 19-58-years-old women. We also studied associations of specific hormonal stages, including natural menstrual cycle, cycle with combined oral contraceptives (COC) and menopausal status with or without hormone therapy (HT), with arterial stiffness. Methods: This study includes repeated measurements of 65 healthy women representing reproductive (n=16 natural, n=10 COC-users) and menopause (n=5 perimenopausal, n=26 postmenopausal, n=8 HT-users) stages. Arterial stiffness outcomes were aortic pulse wave velocity (PWVao) and augmentation index (AIx%) assessed using Arteriograph-device. Generalized estimating equation models were constructed to investigate associations of each hormone (wide age-range models) or hormonal stage (age-group focused models) with arterial stiffness. PWVao models with cross-sectional approach, were adjusted for age, relative fitness, fat mass and mean arterial pressure, while models with longitudinal approach were adjusted for mean arterial pressure. AIx% models used the same approach for adjustments and were also adjusted for heart rate. Results: Negative and positive associations with arterial stiffness variables were observed for estradiol and follicle-stimulating hormone, respectively, until adjustment for confounding effect of age. In naturally menstruating women, AIx% was higher at ovulation (B=3.63, p<0.001) compared to the early follicular phase. In COC-users, PWVao was lower during active (B=-0.33 - -0.57, p<0.05) than inactive pills. In menopausal women, HT-users had higher PWVao (B=1.43, p=0.03) than postmenopausal non-HT-users. Conclusions: When using wide age-range assessments covering reproductive to menopausal lifespan it is difficult to differentiate age- and hormone-mediated associations, because age-mediated influence on arterial stiffness seemed to overrule potential hormone-mediated influences. However, hormonal status associated differentially with arterial stiffness in age-group focused analyses. Thus, the role of sex hormones cannot be excluded. Further research is warranted to resolve potential hormone-mediated mechanisms affecting arterial elasticity.

Predicting the age at natural menopause in middle-aged women.

OBJECTIVE: To predict the age at natural menopause (ANM). METHODS: Cox models with time-dependent covariates were utilized for ANM prediction using longitudinal data from 47 to 55-year-old women (n = 279) participating in the Estrogenic Regulation of Muscle Apoptosis study. The ANM was assessed retrospectively for 105 women using bleeding diaries. The predictors were chosen from the set of 32 covariates by using the lasso regression (model 1). Another easy-to-access model (model 2) was created by using a subset of 16 self-reported covariates. The predictive performance was quantified with c-indices and by studying the means and standard deviations of absolute errors (MAE ±â€ŠSD) between the predicted and observed ANM. RESULTS: Both models included alcohol consumption, vasomotor symptoms, self-reported physical activity, and relationship status as predictors. Model 1 also included estradiol and follicle-stimulating hormone levels as well as SD of menstrual cycle length, while model 2 included smoking, education, and the use of hormonal contraception as additional predictors. The mean c-indices of 0.76 (95% CI 0.71-0.81) for model 1 and 0.70 (95% CI 0.65-0.75) for model 2 indicated good concordance between the predicted and observed values. MAEs of 0.56 ±â€Š0.49 and 0.62 ±â€Š0.54 years respectively for model 1 and 2 were clearly smaller than the MAE for predicted sample mean (1.58 ±â€Š1.02). CONCLUSIONS: In addition to sex hormone levels, irregularity of menstrual cycle, and menopausal symptoms, also life habits and socioeconomic factors may provide useful information for ANM prediction. The suggested approach could add value for clinicians' decision making related to the use of contraception and treatments for menopausal symptoms in perimenopausal women.

Video Summary:http://links.lww.com/MENO/A743 .

Role of Menopausal Transition and Physical Activity in Loss of Lean and Muscle Mass: A Follow-Up Study in Middle-Aged Finnish Women.

In midlife, women experience hormonal changes due to menopausal transition. A decrease especially in estradiol has been hypothesized to cause loss of muscle mass. This study investigated the effect of menopausal transition on changes in lean and muscle mass, from the total body to the muscle fiber level, among 47-55-year-old women. Data were used from the Estrogenic Regulation of Muscle Apoptosis (ERMA) study, where 234 women were followed from perimenopause to early postmenopause. Hormone levels (estradiol and follicle stimulating hormone), total and regional body composition (dual-energy X-ray absorptiometry (DXA) and computed tomography (CT) scans), physical activity level (self-reported and accelerometer-measured) and muscle fiber properties (muscle biopsy) were assessed at baseline and at early postmenopause. Significant decreases were seen in lean body mass (LBM), lean body mass index (LBMI), appendicular lean mass (ALM), appendicular lean mass index (ALMI), leg lean mass and thigh muscle cross-sectional area (CSA). Menopausal status was a significant predictor for all tested muscle mass variables, while physical activity was an additional significant contributor for LBM, ALM, ALMI, leg lean mass and relative muscle CSA. Menopausal transition was associated with loss of muscle mass at multiple anatomical levels, while physical activity was beneficial for the maintenance of skeletal muscle mass.

Muscle and bone mass in middle-aged women: role of menopausal status and physical activity.

BACKGROUND: Women experience drastic hormonal changes during midlife due to the menopausal transition. Menopausal hormonal changes are known to lead to bone loss and potentially also to loss of lean mass. The loss of muscle and bone tissue coincide due to the functional relationship and interaction between these tissues. If and how physical activity counteracts deterioration in muscle and bone during the menopausal transition remains partly unresolved. This study investigated differences between premenopausal, early perimenopausal, late perimenopausal, and postmenopausal women in appendicular lean mass (ALM), appendicular lean mass index (ALMI), femoral neck bone mineral density (BMD) and T score. Furthermore, we investigated the simultaneous associations of ALM and BMD with physical activity in the above-mentioned menopausal groups. METHODS: Data from the Estrogen Regulation of Muscle Apoptosis study were utilized. In total, 1393 women aged 47-55 years were assigned to premenopausal, early perimenopausal, late perimenopausal, and postmenopausal groups based on follicle-stimulating hormone concentration and bleeding diaries. Of them, 897 were scanned for ALM and femoral neck BMD by dual-energy X-ray absorptiometry and ALMI (ALM/height2 ) and neck T scores calculated. Current level of leisure-time physical activity was estimated by a validated self-report questionnaire and categorized as sedentary, low, medium, and high. RESULTS: Appendicular lean mass, appendicular lean mass index, femoral neck bone mineral density, and and T score showed a significant linear declining trend across all four menopausal groups. Compared with the postmenopausal women, the premenopausal women showed greater ALM (18.2, SD 2.2 vs. 17.8, SD 2.1, P < 0.001), ALMI (6.73, SD 0.64 vs. 6.52, SD 0.62, P < 0.001), neck BMD (0.969, SD 0.117 vs. 0.925, SD 0.108, P < 0.001), and T score (-0.093, SD 0.977 vs -0.459, SD 0.902, P < 0.001). After adjusting for potential confounding pathways, a higher level of physical activity was associated with greater ALM among the premenopausal [ß = 0.171; confidence interval (CI) 95% 0.063-0.280], late perimenopausal (ß = 0.289; CI 95% 0.174-0.403), and postmenopausal (ß=0.278; CI 95% 0.179-0.376) women. The positive association between femoral neck BMD and level of physical activity was significant only among the late perimenopausal women (ß = 0.227; CI 95% 0.097-0.356). CONCLUSIONS: Skeletal muscle and bone losses were associated with the menopausal transition. A higher level of physical activity during the different menopausal phases was beneficial, especially for skeletal muscle. Menopause-related hormonal changes predispose women to sarcopenia and osteoporosis and further to mobility disability and fall-related fractures in later life. New strategies are needed to promote physical activity among middle-aged women. Longitudinal studies are needed to confirm these results.

Patient-reported pelvic floor symptoms 5 years after hysterectomy with or without prolapse surgery.

OBJECTIVE: The aim of this study was to evaluate the effect of hysterectomy with or without concomitant prolapse surgery on subject-reported pelvic floor disorders (PFD) with a 5-year follow-up. STUDY DESIGN: This prospective longitudinal study was carried out in two Finnish central hospitals among 286 women who had undergone hysterectomy for benign reasons. The presence of urinary incontinence, urinary frequency, feeling of vaginal bulging, constipation and anal incontinence was evaluated at baseline, 1 and 5 years postoperatively. Analysis was performed on 256 (895%) patients who answered at least one of the follow-up questionnaires. RESULTS: Hysterectomy with concomitant native tissue prolapse surgery significantly reduced urinary incontinence, urinary frequency, constipation and the feeling of vaginal bulging, and the results were maintained over the following five years. Plain hysterectomy reduced urinary frequency and the feeling of vaginal bulging but did not relieve urinary incontinence. Hysterectomy had no effect on anal incontinence. The total subsequent prolapse and/or incontinence operation rate was 2,7%, and was higher among patients who underwent hysterectomy for pelvic organ prolapse. CONCLUSIONS: During a 5-years follow-up a hysterectomy alone or with native tissue prolapse surgery did not worsen pelvic floor disorders.

Design and protocol of Estrogenic Regulation of Muscle Apoptosis (ERMA) study with 47 to 55-year-old women's cohort: novel results show menopause-related differences in blood count.

OBJECTIVE: The multidisciplinary Estrogenic Regulation of Muscle Apoptosis (ERMA) study was designed to reveal how hormonal differences over the menopausal stages affect the physiological and psychological functioning of middle-aged women. This paper describes the protocol and nonrespondent analysis of ERMA and novel findings on menopausal differences in blood count variables and their association with female sex hormones. METHODS: Women aged 47 to 55 years were assigned to pre, early peri, late peri, and postmenopausal groups based on follicle-stimulating hormone (FSH) and bleeding diary. Multivariate linear regression models were constructed to estimate the association of 17ß-estradiol (E2) and FSH with the blood count variables. RESULTS: In all, 3,064 women returned the prequestionnaire (ERMA phase one), 1,393 donated blood samples and were assigned to the relevant menopausal group (phase two), and 914 completed phase three, which included physiological and psychological measurements. Nonrespondents were more likely than respondents to be obese, whereas the menopausal groups showed no mean differences in body mass index. Blood count variables, while being within clinical reference values, showed significant differences between groups. E2 and FSH were associated with the white blood cell (WBC) count and neutrophil-to-lymphocyte ratio. CONCLUSIONS: The ERMA study was successful in recruiting and characterizing the menopausal status of a cohort sample of middle-aged women. The significant group differences found in the blood count variables and their associations with E2 and FSH verifies menopause-associated changes in WBC composition potentially being an early sign of low-grade inflammation that may develop later in life.

Menopause and adipose tissue: miR-19a-3p is sensitive to hormonal replacement.

Tissue-specific effects of 17ß-estradiol are delivered via both estrogen receptors and microRNAs (miRs). Menopause is known to affect the whole-body fat distribution in women. This investigation aimed at identifying menopause- and hormone replacement therapy (HRT)-associated miR profiles and miR targets in subcutaneous abdominal adipose tissue and serum from the same women. A discovery phase using array technology was performed in 13 women, including monozygotic twin pairs discordant for HRT and premenopausal young controls. Seven miRs, expressed in both adipose tissue and serum, were selected for validation phase in 34 women from a different cohort. An age/menopause-related increase of miRs-16-5p, -451a, -223-3p, -18a-5p, -19a-3p,-486-5p and -363-3p was found in the adipose tissue, but not in serum. MiR-19a-3p, involved in adipocyte development and estrogen signaling, resulted to be higher in HRT users in comparison with non-users. Among the identified targets, AKT1, BCL-2 and BRAF proteins showed lower expression in both HRT and No HRT users in comparison with premenopausal women. Unexpectedly, ESR1 protein expression was not modified although its mRNA was lower in No HRT users compared to premenopausal women and HRT users. Thus, both HRT and menopause appear to affect adipose tissue homeostasis via miR-mediated mechanism.

Quality of life and pelvic floor dysfunction symptoms after hysterectomy with or without pelvic organ prolapse.

OBJECTIVE: To assess the effect of hysterectomy with or without pelvic organ prolapse (POP) on health-related quality of life (HRQoL) and pelvic floor disorders. STUDY DESIGN: Prospective clinical study at two central hospitals in Finland. During one year 322 women underwent elective hysterectomy for benign conditions with or without vaginal wall repair. The study population was divided in two groups, patients with and without POP. The HRQoL questionnaires RAND-36 and 15D, and questionnaires assessing urinary and bowel dysfunction symptoms were obtained preoperatively and 12 months postoperatively. POP was defined as the descent of apical, anterior or posterior compartment of vaginal wall grade ≥2 in the Baden-Walker classification at any site. Main outcome measures were HRQoL, improvement of symptoms and de novo symptoms. RESULTS: At baseline the mean 15D score of all patients was lower than that of the age-standardized population sample (p<0.001). At one year postoperatively, the mean 15D score of the patients had improved (p=0.001), this resulting mainly on dimensions of excretion (voiding and defecation), usual activities, discomfort and symptom, distress, vitality and sexual activity. HRQoL improved especially in patients with POP. They reported improvement of symptoms in urinary incontinence, urinary frequency, constipation and sense of bulging but surgery had no effect on anal incontinence. Patients without POP reported improvement in pain dimension, urinary frequency and feeling of bulging. Urinary incontinence was the most common (15.4% and 13.8%) de novo symptom in both groups. CONCLUSIONS: Hysterectomy with or without concomitant pelvic organ prolapse surgery improves health-related quality of life and reduces pelvic floor symptoms in one-year follow-up.

Five-year results of a randomized trial comparing retropubic and transobturator midurethral slings for stress incontinence.

BACKGROUND: Midurethral slings have become the most preferred surgical treatment for female urinary incontinence. OBJECTIVE: To compare the efficacy and safety of two midurethral sling procedures with a different technique of sling insertion 5 yr after intervention. DESIGN, SETTING, AND PARTICIPANTS: Multicenter randomized clinical trial conducted in seven public hospitals in Finland including primary cases of stress urinary incontinence. INTERVENTION: Surgical treatment with the retropubic tension-free vaginal tape (TVT) procedure or the transobturator tension-free vaginal tape (TVT-O) procedure. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Objective treatment success criteria were a negative stress test, a negative 24-h pad test, and no retreatment for stress incontinence. Patient satisfaction was assessed by condition-specific quality-of-life questionnaires. RESULTS AND LIMITATIONS: A total of 95% of the included women could be assessed according to the protocol 5 yr after surgery. The objective cure rate was 84.7% in the TVT group and 86.2% in the TVT-O group, with no statistical difference between the groups. Subjective treatment satisfaction was 94.2% in the TVT group and 91.7% in the TVT-O group, with no difference between groups. Complication rates were low, with no difference between groups. CONCLUSIONS: Both objective and subjective cure rates were >80% in both groups even when women lost to follow-up were included as failures. The complication rates were low, with no difference between the groups. No late-onset adverse effects of the tape material were seen. PATIENT SUMMARY: Female urinary stress incontinence can be treated surgically with minimally invasive midurethral sling procedures. Two main approaches of sling placement have been developed: the retropubic and the transobturatory. We compared both approaches and followed the patients for 5 yr. We found no difference in cure rate between the procedures, and patient satisfaction was high. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00379314.

The effect of home biofeedback training on stress incontinence.

BACKGROUND: To compare the effectiveness of pelvic floor training (PFT) with the aid of a home biofeedback device to PFT alone for urodynamic stress urinary incontinence (SUI) in women after a 1-year follow-up. METHODS: A randomized study comparing two conservative interventions was conducted in an outpatient clinic of a university hospital. Thirty-five consecutive women were randomized to either the PFT with home biofeedback group or the PFT alone group. The intensive training period lasted 12 weeks. After 1 year, 33 women could be evaluated according to the protocol. At the 1-year visit pelvic floor muscle activity was measured and the need for surgical intervention was evaluated. Logistic multivariate analysis was used to predict response to the PFT. RESULTS: In the home biofeedback training group 11/16 (68.8%) avoided surgery vs. 10/19 (52.6%) in the PFT alone group. The difference was not statistically significant. In the nonoperated home biofeedback group the increase in pelvic floor muscle activity (p = 0.005 in supine, p = 0.005 in standing) and the decrease in leakage index (p = 0.05) was significant after 12 weeks and pelvic floor activity remained constant. By contrast, in the nonoperated PFT group the increase in pelvic floor muscle activity after 12 weeks predicted a good result for conservative treatment. CONCLUSIONS: This randomized controlled trial suggests that the home biofeedback method in PFT has a good success rate of 68.8%. The change achieved in leakage index after 12 weeks of training predicted an effective outcome for conservative treatment.