Do mammals have menopause?

Semantics and lack of data have clouded our understanding about menopause in non-human mammals. The traditional definition of menopause based on the last menstrual bleed is limited and hinders cross-species comparison. Here, we redefine it as the permanent cessation of ovulation and show menopause to be widespread across mammalian orders.

Menopause-Biology, consequences, supportive care, and therapeutic options.

Menopause is the cessation of ovarian function, with loss of reproductive hormone production and irreversible loss of fertility. It is a natural part of reproductive aging. The physiology of the menopause is complex and incompletely understood. Globally, menopause occurs around the age of 49 years, with geographic and ethnic variation. The hormonal changes of the menopause transition may result in both symptoms and long-term systemic effects, predominantly adverse effects on cardiometabolic and musculoskeletal health. The most effective treatment for bothersome menopausal symptoms is evidence-based, menopausal hormone therapy (MHT), which reduces bone loss and may have cardiometabolic benefits. Evidence-based non-hormonal interventions are also available for symptom relief. Treatment should be individualized with shared decision-making. Most MHT regimens are not regulator approved for perimenopausal women. Studies that include perimenopausal women are needed to determine the efficacy and safety of treatment options. Further research is crucial to improve menopause care, along with research to guide policy and clinical practice.

Neurokinin 3 receptor antagonism for menopausal hot flashes.

Menopausal hot flashes are common and debilitating. Menopausal Hormone Therapy (MHT) is effective for hot flashes but has risks and side effects that limit its use. NK3 receptor antagonism has emerged as a novel therapeutic strategy, leading to the recent FDA approval of fezolinetant, a first-in-class nonhormonal treatment for menopausal hot flashes. To view this Bench to Bedside, open or download the PDF.

The evolution of menopause in toothed whales.

Understanding how and why menopause has evolved is a long-standing challenge across disciplines. Females can typically maximize their reproductive success by reproducing for the whole of their adult life. In humans, however, women cease reproduction several decades before the end of their natural lifespan1,2. Although progress has been made in understanding the adaptive value of menopause in humans3,4, the generality of these findings remains unclear. Toothed whales are the only mammal taxon in which menopause has evolved several times5, providing a unique opportunity to test the theories of how and why menopause evolves in a comparative context. Here, we assemble and analyse a comparative database to test competing evolutionary hypotheses. We find that menopause evolved in toothed whales by females extending their lifespan without increasing their reproductive lifespan, as predicted by the 'live-long' hypotheses. We further show that menopause results in females increasing their opportunity for intergenerational help by increasing their lifespan overlap with their grandoffspring and offspring without increasing their reproductive overlap with their daughters. Our results provide an informative comparison for the evolution of human life history and demonstrate that the same pathway that led to menopause in humans can also explain the evolution of menopause in toothed whales.

Genetic links between ovarian ageing, cancer risk and de novo mutation rates.

Human genetic studies of common variants have provided substantial insight into the biological mechanisms that govern ovarian ageing1. Here we report analyses of rare protein-coding variants in 106,973 women from the UK Biobank study, implicating genes with effects around five times larger than previously found for common variants (ETAA1, ZNF518A, PNPLA8, PALB2 and SAMHD1). The SAMHD1 association reinforces the link between ovarian ageing and cancer susceptibility1, with damaging germline variants being associated with extended reproductive lifespan and increased all-cause cancer risk in both men and women. Protein-truncating variants in ZNF518A are associated with shorter reproductive lifespan-that is, earlier age at menopause (by 5.61 years) and later age at menarche (by 0.56 years). Finally, using 8,089 sequenced trios from the 100,000 Genomes Project (100kGP), we observe that common genetic variants associated with earlier ovarian ageing associate with an increased rate of maternally derived de novo mutations. Although we were unable to replicate the finding in independent samples from the deCODE study, it is consistent with the expected role of DNA damage response genes in maintaining the genetic integrity of germ cells. This study provides evidence of genetic links between age of menopause and cancer risk.

Genetic insights into biological mechanisms governing human ovarian ageing.

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

Genetic insights into the age-specific biological mechanisms governing human ovarian aging.

There is currently little evidence that the genetic basis of human phenotype varies significantly across the lifespan. However, time-to-event phenotypes are understudied and can be thought of as reflecting an underlying hazard, which is unlikely to be constant through life when values take a broad range. Here, we find that 74% of 245 genome-wide significant genetic associations with age at natural menopause (ANM) in the UK Biobank show a form of age-specific effect. Nineteen of these replicated discoveries are identified only by our modeling framework, which determines the time dependency of DNA-variant age-at-onset associations without a significant multiple-testing burden. Across the range of early to late menopause, we find evidence for significantly different underlying biological pathways, changes in the signs of genetic correlations of ANM to health indicators and outcomes, and differences in inferred causal relationships. We find that DNA damage response processes only act to shape ovarian reserve and depletion for women of early ANM. Genetically mediated delays in ANM were associated with increased relative risk of breast cancer and leiomyoma at all ages and with high cholesterol and heart failure for late-ANM women. These findings suggest that a better understanding of the age dependency of genetic risk factor relationships among health indicators and outcomes is achievable through appropriate statistical modeling of large-scale biobank data.

An empowerment model for managing menopause.

Menopause eventually happens to all people with typically functioning ovaries, and almost one billion women worldwide are postmenopausal. Although the biology of typical menopause is ubiquitous, the experience varies substantially. Factors contributing to the experience include not only individual factors, such as the nature and severity of symptoms, but also psychological, social, and contextual considerations, many of which are modifiable. In this first paper in the Lancet Series on menopause, we argue for a new approach that goes beyond the treatment of specific symptoms, to encompass a broad model to support women transitioning this life stage, using the model of empowerment. WHO defines empowerment as an active process of gaining knowledge, confidence, and self-determination to self-manage health and make informed decisions about care. Rather than focusing on menopause as an endocrine deficiency, we propose an empowerment model that recognises factors modifying the experience, in which the patient is an expert in their own condition and the health-care worker supports the patient to become an equal and active partner in managing their own care.

Managing menopause after cancer.

Globally, 9 million women are diagnosed with cancer each year. Breast cancer is the most commonly diagnosed cancer worldwide, followed by colorectal cancer in high-income countries and cervical cancer in low-income countries. Survival from cancer is improving and more women are experiencing long-term effects of cancer treatment, such as premature ovarian insufficiency or early menopause. Managing menopausal symptoms after cancer can be challenging, and more severe than at natural menopause. Menopausal symptoms can extend beyond hot flushes and night sweats (vasomotor symptoms). Treatment-induced symptoms might include sexual dysfunction and impairment of sleep, mood, and quality of life. In the long term, premature ovarian insufficiency might increase the risk of chronic conditions such as osteoporosis and cardiovascular disease. Diagnosing menopause after cancer can be challenging as menopausal symptoms can overlap with other common symptoms in patients with cancer, such as fatigue and sexual dysfunction. Menopausal hormone therapy is an effective treatment for vasomotor symptoms and seems to be safe for many patients with cancer. When hormone therapy is contraindicated or avoided, emerging evidence supports the efficacy of non-pharmacological and non-hormonal treatments, although most evidence is based on women older than 50 years with breast cancer. Vaginal oestrogen seems safe for most patients with genitourinary symptoms, but there are few non-hormonal options. Many patients have inadequate centralised care for managing menopausal symptoms after cancer treatment, and more information is needed about cost-effective and patient-focused models of care for this growing population.

Promoting good mental health over the menopause transition.

The potential risk for mental health conditions over the menopause transition shapes women's expectations and informs putative physiological mechanisms regulating women's mental health. We review evidence from prospective studies reporting on associations between mental health conditions and the menopause transition. Major depressive disorder and the more prevalent subthreshold depressive symptoms are the most common conditions studied. We reviewed 12 prospective studies reporting depressive symptoms, major depressive disorder, or both over the menopause transition and found no compelling evidence for a universal increased risk for either condition. However, specific subgroups of participants, primarily defined by menopause-related risk factors (ie, vasomotor symptoms that are severe or disturb sleep, a long duration of the transition, or reproductive hormone dynamics) and psychosocial risk factors (eg, stressful life events), were vulnerable to depressive symptoms. The increased risk of major depressive disorder over the menopause transition appears predominantly in individuals with previous major depressive disorder. Greater focus on recognising risk factors in primary care is warranted. On the basis of scarce data, we found no compelling evidence that risk of anxiety, bipolar disorder, or psychosis is universally elevated over the menopause transition. Potential misattribution of psychological distress and psychiatric disorders to menopause could harm women by delaying accurate diagnosis and the initiation of effective psychotropic treatments, and by creating negative expectations for people approaching menopause. A paradigm shift is needed. We conclude with recommendations for the detection and treatment of depressive symptoms or major depressive disorder and strategies to promote good mental health over the menopause transition, while responsibly preparing and supporting those at risk.

Optimising health after early menopause.

The typical age at menopause is 50-51 years in high-income countries. However, early menopause is common, with around 8% of women in high-income countries and 12% of women globally experiencing menopause between the ages of 40 years and 44 years. Menopause before age 40 years (premature ovarian insufficiency) affects an additional 2-4% of women. Both early menopause and premature ovarian insufficiency can herald an increased risk of chronic disease, including osteoporosis and cardiovascular disease. People who enter menopause at younger ages might also experience distress and feel less supported than those who reach menopause at the average age. Clinical practice guidelines are available for the diagnosis and management of premature ovarian insufficiency, but there is a gap in clinical guidance for early menopause. We argue that instead of distinct age thresholds being applied, early menopause should be seen on a spectrum between premature ovarian insufficiency and menopause at the average age. This Series paper presents evidence for the short-term and long-term consequences of early menopause. We offer a practical framework for clinicians to guide diagnosis and management of early menopause, which considers the nature and severity of symptoms, age and medical history, and the individual's wishes and priorities to optimise their quality of life and short-term and long-term health. We conclude with recommendations for future research to address key gaps in the current evidence.

Age at Menopause, Leukocyte Telomere Length, and Coronary Artery Disease in Postmenopausal Women.

BACKGROUND: Premature menopause is a risk factor for accelerated cardiovascular aging, but underlying mechanisms remain incompletely understood. This study investigated the role of leukocyte telomere length (LTL), a marker of cellular aging and genomic instability, in the association of premature menopause with cardiovascular disease. METHODS: Participants from the UK Biobank and Women's Health Initiative with complete reproductive history and LTL measurements were included. Primary analyses tested the association between age at menopause and LTL using multivariable-adjusted linear regression. Secondary analyses stratified women by history of gynecologic surgery. Mendelian randomization was used to infer causal relationships between LTL and age at natural menopause. Multivariable-adjusted Cox regression and mediation analyses tested the joint associations of premature menopause and LTL with incident coronary artery disease. RESULTS: This study included 130 254 postmenopausal women (UK Biobank: n=122 224; Women's Health Initiative: n=8030), of whom 4809 (3.7%) had experienced menopause before age 40. Earlier menopause was associated with shorter LTL (meta-analyzed ß=-0.02 SD/5 years of earlier menopause [95% CI, -0.02 to -0.01]; P=7.2×10-12). This association was stronger and significant in both cohorts for women with natural/spontaneous menopause (meta-analyzed ß=-0.04 SD/5 years of earlier menopause [95% CI, -0.04 to -0.03]; P<2.2×10-16) and was independent of hormone therapy use. Mendelian randomization supported a causal association of shorter genetically predicted LTL with earlier age at natural menopause. LTL and age at menopause were independently associated with incident coronary artery disease, and mediation analyses indicated small but significant mediation effects of LTL in the association of menopausal age with coronary artery disease. CONCLUSIONS: Earlier age at menopause is associated with shorter LTL, especially among women with natural menopause. Accelerated telomere shortening may contribute to the heightened cardiovascular risk associated with premature menopause.

Impact of sex and reproductive status on the default mode network in early midlife: implications for aging of memory circuitry and function.

Alterations to the resting-state default mode network (rsDMN) are early indicators of memory decline and Alzheimer's disease (AD). Brain regions shared by the rsDMN and memory circuitry are highly sexually dimorphic. However, data are limited regarding the impact of sex and reproductive status on rsDMN connectivity and memory circuitry and function. In the current investigation, rsDMN connectivity was assessed in 180 early midlife adults aged 45 to 55 by sex and reproductive status (87 women; 93 men). Associations between left and right hippocampal connectivity of rsDMN and verbal memory encoding circuitry were examined using linear mixed models, controlled for age and parental socioeconomic status, testing interactions by sex and reproductive status. Relative to men, women exhibited greater rsDMN connectivity between the left and right hippocampus. In relation to rsDMN-memory encoding connectivity, sex differences were revealed across the menopausal transition, such that only postmenopausal women exhibited loss of the ability to decrease rsDMN left-right hippocampal connectivity during memory encoding associated with poorer memory performance. Results demonstrate that sex and reproductive status play an important role in aging of the rsDMN and interactions with memory circuitry/function. This suggests the critical importance of sex and reproductive status when studying early midlife indicators of memory decline and AD risk.

Complementary and Alternative Therapies for Genitourinary Syndrome of Menopause : An Evidence Map.

BACKGROUND: Women seeking nonhormonal interventions for vulvovaginal, urinary, and sexual symptoms associated with genitourinary syndrome of menopause (GSM) may seek out complementary and alternative medicine or therapies (CAMs). PURPOSE: To summarize published evidence of CAMs for GSM. DATA SOURCES: Ovid MEDLINE, EMBASE, and CINAHL from inception through 11 December 2023. STUDY SELECTION: Randomized controlled trials (RCTs) 8 weeks or more in duration that evaluated the effectiveness or harms of CAMs for postmenopausal women with GSM and reported 1 or more outcomes of interest, with sample sizes of 20 or more participants randomly assigned per group. DATA EXTRACTION: Data were abstracted by 1 reviewer and verified by a second. DATA SYNTHESIS: An evidence map approach was used to organize and describe trials. Studies were organized by type of intervention, with narrative summaries for population, study characteristics, interventions, and outcomes. Fifty-seven trials were identified that investigated 39 unique interventions. Studies were typically small (n < 200), and most were done in Iran (k = 24) or other parts of Asia (k = 9). Few trials evaluated similar combinations of populations, interventions, comparators, or outcomes. Most studies (k = 44) examined natural products (that is, herbal or botanical supplements and vitamins), whereas fewer reported on mind and body practices (k = 6) or educational programs (k = 7). Most studies reported 1 or 2 GSM symptoms, mainly sexual (k = 44) or vulvovaginal (k = 30). Tools used to measure outcomes varied widely. Most trials reported on adverse events (k = 33). LIMITATIONS: Only English-language studies were used. Effect estimates, risk of bias, and certainty of evidence were not assessed. CONCLUSION: There is a large and heterogeneous literature of CAM interventions for GSM. Trials were small, and few were done in North America. Standardized population, intervention, comparator, and outcomes reporting in future RCTs are needed. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality and Patient-Centered Outcomes Research Institute. (PROSPERO: CRD42023400684).

Escape from breast tumor dormancy: The convergence of obesity and menopause.

Obesity is associated with an increased risk of, and a poor prognosis for, postmenopausal (PM) breast cancer (BC). Our goal was to determine whether diet-induced obesity (DIO) promotes 1) shorter tumor latency, 2) an escape from tumor dormancy, and 3) an acceleration of tumor growth and to elucidate the underlying mechanism(s). We have developed in vitro assays and PM breast tumor models complemented by a noninvasive imaging system to detect vascular invasion of dormant tumors and have used them to determine whether obesity promotes the escape from breast tumor dormancy and tumor growth by facilitating the switch to the vascular phenotype (SVP) in PM BC. Obese mice had significantly higher tumor frequency, higher tumor volume, and lower overall survival compared with lean mice. We demonstrate that DIO exacerbates mammary gland hyperplasia and neoplasia, reduces tumor latency, and increases tumor frequency via an earlier acquisition of the SVP. DIO establishes a local and systemic proangiogenic and inflammatory environment via the up-regulation of lipocalin-2 (LCN2), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) that may promote the escape from tumor dormancy and tumor progression. In addition, we show that targeting neovascularization via a multitargeted receptor tyrosine kinase inhibitor, sunitinib, can delay the acquisition of the SVP, thereby prolonging tumor latency, reducing tumor frequency, and increasing tumor-free survival, suggesting that targeting neovascularization may be a potential therapeutic strategy in obesity-associated PM BC progression. This study establishes the link between obesity and PM BC and, for the first time to our knowledge, bridges the dysfunctional neovascularization of obesity with the earliest stages of tumor development.

Hormonal Treatments and Vaginal Moisturizers for Genitourinary Syndrome of Menopause : A Systematic Review.

BACKGROUND: Postmenopausal women commonly experience vulvovaginal, urinary, and sexual symptoms associated with genitourinary syndrome of menopause (GSM). PURPOSE: To evaluate effectiveness and harms of vaginal estrogen, nonestrogen hormone therapies, and vaginal moisturizers for treatment of GSM symptoms. DATA SOURCES: Medline, Embase, and CINAHL through 11 December 2023. STUDY SELECTION: Randomized controlled trials (RCTs) of at least 8 weeks' duration enrolling postmenopausal women with at least 1 GSM symptom and reporting effectiveness or harms of hormonal interventions or vaginal moisturizers. DATA EXTRACTION: Risk of bias and data extraction were performed by one reviewer and verified by a second reviewer. Certainty of evidence (COE) was assessed by one reviewer and verified by consensus. DATA SYNTHESIS: From 11 993 citations, 46 RCTs evaluating vaginal estrogen (k = 22), nonestrogen hormones (k = 16), vaginal moisturizers (k = 4), or multiple interventions (k = 4) were identified. Variation in populations, interventions, comparators, and outcomes precluded meta-analysis. Compared with placebo or no treatment, vaginal estrogen may improve vulvovaginal dryness, dyspareunia, most bothersome symptom, and treatment satisfaction. Compared with placebo, vaginal dehydroepiandrosterone (DHEA) may improve dryness, dyspareunia, and distress, bother, or interference from genitourinary symptoms; oral ospemifene may improve dryness, dyspareunia, and treatment satisfaction; and vaginal moisturizers may improve dryness (all low COE). Vaginal testosterone, systemic DHEA, vaginal oxytocin, and oral raloxifene or bazedoxifene may provide no benefit (low COE) or had uncertain effects (very low COE). Although studies did not report frequent serious harms, reporting was limited by short-duration studies that were insufficiently powered to evaluate infrequent serious harms. LIMITATIONS: Most studies were 12 weeks or less in duration and used heterogeneous GSM diagnostic criteria and outcome measures. Few studies enrolled women with a history of cancer. CONCLUSION: Vaginal estrogen, vaginal DHEA, oral ospemifene, and vaginal moisturizers may improve some GSM symptoms in the short term. Few long-term data exist on efficacy, comparative effectiveness, tolerability, and safety of GSM treatments. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality and Patient-Centered Outcomes Research Institute. (PROSPERO: CRD42023400684).

Subclinical Atherosclerosis Across the Menopausal Transition in Women With and Without HIV.

The menopausal transition is a pivotal time of cardiovascular risk, but knowledge is limited in HIV. We studied longitudinal carotid artery intima-media thickness (CIMT) in the Women's Interagency HIV Study (2004-2019; 979 women/3247 person-visits; 72% with HIV). Among women with HIV only, those who transitioned had greater age-related CIMT progression compared to those remaining premenopausal (difference in slope = 1.64 µm/year, P = .002); and CIMT increased over time in the pretransition (3.47 µm/year, P = .002) and during the menopausal transition (9.41 µm/year, P < .0001), but not posttransition (2.9 µm/year, P = .19). In women with HIV, menopause may accelerate subclinical atherosclerosis as measured by CIMT.