Managing menopausal symptoms and associated clinical issues in breast cancer survivors

Objective: Review evidence to guide management of menopausal signs and symptoms in women after breast cancer and make recommendations accordingly. Evidence: Randomized controlled clinical trials, observational studies, evidence-based guidelines, and expert opinion from professional societies. Background: Symptoms and clinical problems associated with estrogen depletion—sleep disorders, vulvovaginal atrophy (VVA), vasomotor symptoms (VMS), mood changes, depressive symptoms, cardiovascular disease, osteopenia, and osteoporosis—confront the estimated 9.3 million breast cancer survivors globally. Recommendations: Following breast cancer, women should not generally be treated with menopausal hormone therapy or tibolone but should optimize lifestyle. Women with moderate to severe symptoms may benefit from mind–brain behavior or nonhormone, pharmacologic therapy. The selective serotonin/noradrenaline reuptake inhibitors and gabapentenoid agents improve VMS and quality of life. For osteoporosis, nonhormonal agents are available. Treatment of VVA remains an area of unmet need. Low-dose vaginal estrogen is absorbed in small amounts with blood levels remaining within the normal postmenopausal range but could potentially stimulate occult breast cancer cells, and although poorly studied, is not generally advised, particularly for those on aromatase inhibitors. Intravaginal dehydroepiandrosterone and oral ospemiphene have been approved to treat dyspareunia, but safety after breast cancer has not been established. Vaginal laser therapy is being used for VVA but efficacy from sham-controlled studies is lacking. Therapies undergoing development include lasofoxifene, neurokinin B inhibitors, stellate ganglion blockade, vaginal testosterone, and estetrol. Conclusions: Nonhormone options and therapies are available for treatment of estrogen depletion symptoms and clinical problems after a diagnosis of breast cancer. Individualization of treatment is essential

Treatment of symptoms of the menopause: an endocrine society clinical practice guideline

Objective: The objective of this document is to generate a practice guideline for the management and treatment of symptoms of the menopause. Participants: The Treatment of Symptoms of the Menopause Task Force included six experts, a methodologist, and a medical writer, all appointed by The Endocrine Society. Evidence: The Task Force developed this evidenced-based guideline using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned three systematic reviews of published data and considered several other existing meta-analyses and trials. Consensus Process: Multiple e-mail communications, conference calls, and one face-to-face meeting determined consensus. Committees of The Endocrine Society, representatives from endorsing societies, and members of The Endocrine Society reviewed and commented on the drafts of the guidelines. The Australasian Menopause Society, the British Menopause Society, European Menopause and Andropause Society, the European Society of Endocrinology, and the International Menopause Society (co-sponsors of the guideline) reviewed and commented on the draft. Conclusions: Menopausal hormone therapy (MHT) is the most effective treatment for vasomotor symptoms and other symptoms of the climacteric. Benefits may exceed risks for the majority of symptomatic postmenopausal women who are under age 60 or under 10 years since the onset of menopause. Health care professionals should individualize therapy based on clinical factors and patient preference. They should screen women before initiating MHT for cardiovascular and breast cancer risk and recommend the most appropriate therapy depending on risk/benefit considerations. Current evidence does not justify the use of MHT to prevent coronary heart disease, breast cancer, or dementia. Other options are available for those with vasomotor symptoms who prefer not to use MHT or who have contraindications because these patients should not use MHT. Low-dose vaginal estrogen and ospemifene provide effective therapy for the genitourinary syndrome of menopause, and vaginal moisturizers and lubricants are available for those not choosing hormonal therapy. All postmenopausal women should embrace appropriate lifestyle measures

Anti-Müllerian hormone for the diagnosis and prediction of menopause:a systematic review

Background: The early onset of menopause is associated with increased risks of cardiovascular disease and osteoporosis. As a woman’s circulating anti-Müllerian hormone (AMH) concentration reflects the number of follicles remaining in the ovary and declines towards the menopause, serum AMH may be of value in the early diagnosis and prediction of age at menopause. Objective and Rationale: This systematic review was undertaken to determine whether there is evidence to support the use of AMH alone, or in conjunction with other markers, to diagnose menopause, to predict menopause, or to predict and/or diagnose premature ovarian insufficiency (POI). Search Methods: A systematic literature search for publications reporting on AMH in relation to menopause or POI was conducted in PubMed®, Embase®, and the Cochrane Central Register of Controlled Trials up to 31 May 2022. Data were extracted and synthesized using the Synthesis Without Meta-analysis for diagnosis of menopause, prediction of menopause, prediction of menopause with a single/repeat measurement of AMH, validation of prediction models, short-term prediction in perimenopausal women, and diagnosis and prediction of POI. Risk-of-bias was evaluated using the Tool to Assess Risk of Bias in Cohort Studies protocol and studies at high risk of bias were excluded. Outcomes: A total of 3207 studies were identified, and 41, including 28 858 women, were deemed relevant and included. Of the three studies that assessed AMH for the diagnosis of menopause, one showed that undetectable AMH had equivalent diagnostic accuracy to elevated FSH (>22.3 mIU/ml). No study assessed whether AMH could be used to shorten the 12 months of amenorrhoea required for a formal diagnosis of menopause. Studies assessing AMH with the onset of menopause (27 publications [n = 23 835 women]) generally indicated that lower age-specific AMH concentrations are associated with an earlier age at menopause. However, AMH alone could not be used to predict age at menopause with precision (with estimates and CIs ranging from 2 to 12 years for women aged <40 years). The predictive value of AMH increased with age, as the interval of prediction (time to menopause) shortened. There was evidence that undetectable, or extremely low AMH, may aid early diagnosis of POI in young women with a family history of POI, and women presenting with primary or secondary amenorrhoea (11 studies [n = 4537]). Wider Implications: The findings of this systematic review support the use of serum AMH to study the age of menopause in population studies. The increased sensitivity of current AMH assays provides improved accuracy for the prediction of imminent menopause, but diagnostic use for individual patients has not been rigorously examined. Prediction of age at menopause remains imprecise when it is not imminent, although the finding of very low AMH values in young women is both of clinical value in indicating an increased risk of developing POI and may facilitate timely diagnosis

Association of the functional ovarian reserve with serum metabolomic profiling by nuclear magnetic resonance spectroscopy:A cross sectional study of ~400 women

Background: Women with diminished ovarian reserve are known to have increased cardiovascular risk, whether there is a continuous association between the ovarian reserve biomarkers; anti-Müllerian hormone (AMH), antral follicle count (AFC) and cardio-metabolic risk factors are unknown. Methods: A cross-sectional study of 398 women intending to undergo IVF with pre-treatment early follicular AMH and AFC measurements. Serum lipids, lipoprotein subclasses and low-molecular-weight metabolites were quantified by NMR spectroscopy (155 metabolic measures). Associations were analysed using multivariable regression. Results: Participants were mean 35.5 (SD 4.43) years old and had a median AMH of 16 pmol/l (IQR 8.8, 28.0 pmol/l) and a median AFC of 12 (IQR 7.16). AMH showed positive associations with HDL, omega-6 and polyunsaturated fatty acids and the amino acids isoleucine, leucine and tyrosine, with effects ranging from 0.11 (95%CI 0.004 to 0.21) for total lipids in small HDL to 0.16 (0.06 to 0.26) for isoleucine, for a mean difference of one SD of metabolite per one SD increment in AMH, and negatively with acetate: − 0.31(− 0.22, − 0.004) SD per 1 SD AMH. AFC was positively associated with alanine, glutamine and glycine. Results were consistent, though less precisely estimated, when restricted to those women who were preparing for treatment because of their partner’s infertility. Conclusions: In women intending to have IVF, AMH and AFC were not associated with traditional lipid measured but were associated with a number of novel cardiovascular risk factors. Prospective studies will be required for replication, determination of causality and confirmation that ovarian reserve is impacting on metabolism rather than variation in metabolism is influencing ovarian reserve

Association of the serum metabolomic profile by nuclear magnetic resonance spectroscopy with sperm parameters: a cross-sectional study of 325 men

Objective: To determine whether 155 circulating metabolic measures relevant to lifestyle and metabolic health are associated with sperm parameters, as measured by concentration, motility and total motile sperm count (TMSC). Study design: Cross-sectional. Setting: University Hospital. Patients: 325 men prospectively recruited between April 1, 2017 and March 31, 2019. Intervention(s): Non-fasting serum lipids, lipoprotein subclasses, and low-molecular weight metabolites (including amino acids, glycolysis and inflammatory markers) were quantified by NMR spectroscopy. Detailed demographic, lifestyle, fertility and medical history and semen analysis. Main Outcome Measure(s): Associations of serum metabolic profiles with sperm parameters. Results: Participants were mean 37.2 (SD 5.7) years, with a median sperm concentration of 35 million/ml (IQR 15, 69) and median motility of 53% (IQR 42,67). 76% of men had a TMSC >15 Million, 10% 5-15 Million and 14% <5 Million. In both univariate and confounder adjusted analyses an extensive range of lipids and lipoproteins, glycolysis related metabolites, amino acids, ketone bodies, creatinine or albumin, did not show strong statistical evidence of associated with sperm concentration, motility, or the odds of having a reduced or low TMSC (all PBonferroni > 0.0029). Higher levels of glycolysis metabolites and ketone bodies were associated with increased odds of TMSC <15M compared with ≥15M (odds ratios of ∼1.2 to 1.3), and several lipids/lipoprotein concentrations appeared to protect against very low TMSC (<5M compared with ≥5M) with odds ratios of ∼0.8 or greater. Conclusion: Several metabolites exhibit potentially clinically relevant strength of association with the odds of a low TMSC and warrant replication

Effects on heavy menstrual bleeding and pregnancy of uterine artery embolization (UAE) or myomectomy for women with uterine fibroids wishing to avoid hysterectomy: the FEMME randomized controlled trial

Objective: To determine treatment options (myomectomy vs uterine artery embolization [UAE]) for women wishing to avoid hysterectomy. Methods: A multicenter randomized controlled trial was conducted on 254 women and data were collected on fibroid-specific quality of life (UFS-QOL), loss of menstrual blood, and pregnancy. Results: At 4 years, the mean difference in the UFS-QOL was 5.0 points (95% confidence interval [CI] −1.4 to 11.5; P=0.13) in favor of myomectomy. This was not statistically significant as it was at 2 years. There were no differences in bleeding scores, rates of amenorrhea, or heavy bleeding. Of those who were still menstruating, the majority reported regular or fairly regular periods: 36 of 48 (75%) in the UAE group and 30 of 39 (77%) in the myomectomy group. Twelve women after UAE and six women after myomectomy became pregnant (4 years) with seven and five live births, respectively (hazard ratio 0.48, 95% CI 0.18–1.28). There was no difference between the levels of hormones associated with the uterine reserve in each group. Conclusion: Leiomyoma are common in reproductive-aged women, causing heavy menses and subfertility. Among women with uterine fibroids, myomectomy resulted in better fibroid-related quality of life at 4 years, compared with UAE but the treatments decreased menstrual bleeding equally. There was also no significant difference in the impact of treatment on ovarian reserve

Spousal associations of serum metabolomic profiles by nuclear magnetic resonance spectroscopy

Abstract Phenotype-based assortative mating is well established in humans, with the potential for further convergence through a shared environment. To assess the correlation within infertile couples of physical, social, and behavioural characteristics and 155 circulating metabolic measures. Cross sectional study at a tertiary medical center of 326 couples undertaking IVF. Serum lipids, lipoprotein subclasses, and low-molecular weight metabolites as quantified by NMR spectroscopy (155 metabolic measures). Multivariable and quantile regression correlations within couples of metabolite profiles. Couples exhibited statistical correlations of varying strength for most physical, social, and behavioural characteristics including age, height, alcohol consumption, education, smoking status, physical activity, family history and ethnicity, with correlation coefficients ranging from 0.22 to 0.73. There was no evidence of within couple associations for BMI and weight, where the correlation coefficients were − 0.03 (95% CI − 0.14, 0.08) and 0.01 (95% CI − 0.10, 0.12), respectively. Within spousal associations of the metabolite measurements were all positive but with weak to modest magnitudes, with the median correlation coefficient across all 155 measures being 0.12 (range 0.01–0.37 and interquartile range 0.10–0.18). With just four having associations stronger than 0.3: docosahexaenoic acid (0.37, 95% CI 0.22, 0.52), omega-3 fatty acids (0.32, 95% CI 0.20, 0.43) histidine (0.32, 95% CI 0.23, 0.41) and pyruvate (0.32, 95% CI 0.22, 0.43). Infertile couples exhibit spousal similarities for a range of demographic and serum metabolite measures, supporting initial assortative mating, with diet-derived metabolites suggesting possible subsequent convergence of their individual metabolic profile

Should Physical Activity Recommendations for South Asian Adults Be Ethnicity-Specific? Evidence from a Cross-Sectional Study of South Asian and White European Men and Women.

International public health guidelines recommend that adults undertake at least 150 min.week-1 of moderate-intensity physical activity. However, the underpinning evidence has largely been obtained from studies of populations of white European descent. It is unclear whether these recommendations are appropriate for other ethnic groups, particularly South Asians, who have greater cardio-metabolic risk than white Europeans. The objective of our study was to determine the level of moderate-intensity physical activity required in South Asians adults to confer a similar cardio-metabolic risk profile to that observed in Europeans of similar age and body mass index (BMI) undertaking the currently recommended levels of 150 min.week-1. 148 South Asians and 163 white Europeans aged 18 to 70 years were recruited. Physical activity was measured objectively via vertical axis accelerations from hip-worn accelerometers. Factor analysis was used to summarize the measured risk biomarkers into a single underlying latent "factor" describing overall cardio-metabolic risk. Sex did not modify the association between physical activity and the cardio-metabolic risk factor, so data for both sexes were combined and models adjusted for age, sex, BMI and accelerometer wear time. We estimated that South Asian adults needed to undertake 232 (95% Confidence interval: 200 to 268) min.week-1 in order to obtain the same cardio-metabolic risk factor score as a white European undertaking 150 minutes of moderate-equivalent physical activity per week. The present findings suggest that South Asian men and women need to undertake ~230 minutes of moderate intensity physical activity per week. This equates to South Asians undertaking an extra 10-15 minutes of moderate intensity physical activity per day on top of existing recommendations