Menopausal Hormone Therapy (MHT) is widely used to manage the symptoms of menopause and address long-term health risks associated with estrogen deficiency. This comprehensive review provides an in-depth analysis of MHT, encompassing its benefits, risks, and evolving clinical guidelines. The review begins by outlining the physiological changes occurring during menopause, such as decreased estrogen levels, and their impact on various bodily systems. MHT is discussed in the context of alleviating common menopausal symptoms, including vasomotor symptoms (hot flashes and night sweats), vaginal dryness, and mood disturbances. The review explores the different forms of MHT, including estrogen-only therapy and combined estrogen-progestogen therapy, and examines their indications based on patient characteristics, such as age, time since menopause, and individual risk factors. It critically evaluates the effects of MHT on bone health, cardiovascular disease, and cancer risk, drawing from evidence provided by major clinical trials like the Women’s Health Initiative and observational studies. Recent developments, such as the use of bioidentical hormones and tailored MHT regimens, are also highlighted. Current controversies, such as the balance of benefits versus risks and the impact of MHT on various health outcomes, are discussed in the context of updated clinical guidelines from leading health organizations. The review emphasizes the importance of personalized treatment strategies to optimize outcomes and minimize risks. By synthesizing current evidence and guidelines, this review aims to offer healthcare providers and patients a thorough understanding of MHT, facilitating informed decisionmaking and personalized care strategies for menopausal women.

Abstract: Menopause can influence the voice, health, and wellbeing of professional singers, making it a critical area of understanding for singing teachers. For two decades, discussion of menopausal hormone therapy (HT) was shaped by the 2002 Women’s Health Initiative study, which led to widespread concern and a decline in HT use. However, updated evidence reveals the safety of modern HT preparations, as well as non-hormonal treatment options, with emphasis on personalization of care. This article provides singing teachers with an overview of how contemporary menopause care has evolved, bridging clinical guidance with voice pedagogy to help support singers navigating this life stage.

Evidence regarding the aetiology of specific breast cancer subtypes may provide insights into the mechanisms underlying their development, and improve prevention of rarer but more aggressive subtypes. We investigated risk factor associations with surrogate molecular subtypes of breast cancer in a large cohort of UK women. In 1.2million postmenopausal women aged 50-64 recruited into the Million Women Study in 1996-2001, we estimated risks of breast cancer subtypes (defined by oestrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [HER2] status) in relation to established risk factors for breast cancer. Among 1,228,671 eligible women, followed on average for 19.8 (SD 6.5) years, there were 58,134 incident breast cancers with known ER status and 40,627 with known surrogate molecular subtype (based on ER, PR, and HER2 status). Most established risk factors were primarily either positively (age at first birth, age at menopause, BMI, height, alcohol intake, and menopausal hormone therapy use) or inversely (parity) associated with ER+ cancer (p-value for heterogeneity by ER status < = 0.002 in each case). Only prior oral contraceptive (OC) use showed a greater association with ER than with ER+ cancer (p = 0.002). Some additional differences were observed by surrogate molecular subtype including a modest positive association of parity, and inverse association of breastfeeding, with the risk of basal-like cancer. Most established risk factors for breast cancer are almost exclusively associated with hormone-sensitive cancers but some have definite associations with ER- cancers (prior OC use), or more specifically, with basal-like cancer (parity, breastfeeding).

Menopausal symptoms can disrupt women's well-being at the peak of their careers and family life. Currently, the most effective treatment for these symptoms is menopausal hormone therapy (MHT). The presence of cardiovascular and metabolic diseases does not preclude the use of MHT to relieve menopausal symptoms and improve quality of life. However, physicians' concerns about causing more harm than benefits often hinder the use of this type of hormone therapy. Caution is especially important for women with comorbidities. Moreover, it should be acknowledged that high-quality studies of the MHT safety in major chronic noncommunicable diseases and common comorbidities are insufficient. This consensus document analyzes all currently available data from clinical trials of various designs and develops a set of eligibility criteria for prescribing MHT to women with cardiovascular and metabolic comorbidities. Based on this document, physicians of various specialties who provide menopause care to women will receive an accessible algorithm that will allow them to avoid potentially dangerous situations and appropriately prescribe MHT in clinical practice.

Background: Among hormone therapy options for menopause, subcutaneous estradiol pellets offer sustained hormone release, avoid first-pass hepatic metabolism, and maintain a near-physiological estradiol-to-estrone ratio. Despite clinical use since the 1940s, standardized protocols remain lacking. Methods: We performed a critical narrative review following SANRA criteria. PubMed, Scopus, Embase, and LILACS were searched from 1949 to 2024 for randomized trials, cohort studies, and case series on estradiol pellets and outcomes in symptom control, bone health, pharmacokinetics, and safety. Animal studies, editorials, and reports without primary clinical data were excluded. Results: Following an initial peak within the first week, pellets maintain stable serum estradiol levels within the early-to-mid follicular range (50–113 pg/mL depending on dose) for four to six months, with a near-physiological E2:E1 ratio of approximately 1.5:1. The 25 mg dose achieves mean levels of 50–70 pg/mL, effectively controls vasomotor symptoms, and increases bone mineral density. Compared with oral estradiol, pellets bypass hepatic first-pass metabolism, resulting in neutral or favorable metabolic and thrombotic profiles. Compared with transdermal therapy, pellets provide more predictable pharmacokinetics, especially in women with low skin absorption. Safety concerns, including bleeding, tachyphylaxis, and supraphysiological levels, are mainly associated with excessive dosing, premature reimplantation, or lack of endometrial protection in women with a uterus. Conclusions: Estradiol pellets are an effective option for women with poor transdermal absorption, low adherence to daily regimens, or surgical menopause. Safety depends on clinical management with individualized dosing, adequate endometrial protection, and laboratory monitoring. Long-term comparative studies are needed to standardize protocols and support broader evidence-based use.

Background. The treatment of climacteric syndrome occurring during perimenopause is a pressing issue for the medical community. Currently, treatment of menopausal symptoms is aimed at correcting estrogen deficiency with menopausal hormone therapy. However, there are a number of relative and absolute contraindications for its use. In these situations, it is advisable to consider alternative methods of treating the manifestations of climacteric syndrome. Objective. To evaluate the possibilities of non-hormonal therapy during the menopausal transition. Materials and methods. This article describes the clinical case of patient K., who consulted a gynecologist with complaints of menopause, such as hot flashes, night sweats, and irritability, and who had a number of relative contraindications for menopausal hormone therapy. A combination of sulodexide and resveratrol was used as an alternative treatment for menopausal disorders. At the end of treatment, the severity of symptoms and lipid and carbohydrate metabolism indicators were assessed. Results. After combined therapy, the lipid profile after 3 years showed a 33.42% decrease in low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol decreased by 13.75%, triglyceride levels decreased by 12.6%, and total cholesterol decreased by 22.5%. The patient noted that symptoms of night sweats, hot flashes, and irritability became less pronounced, which had a positive effect on her quality of life. The combination of sulodexide and resveratrol has proven effective in relieving menopausal disorders and may be considered for the prevention of cardiometabolic complications in menopause, such as atherosclerosis, hypertension, and thrombotic complications. This aspect requires more in-depth randomized studies. Conclusion. It is expected that therapy with alternative non-hormonal drugs will not be able to demonstrate an effect completely identical to that of menopausal hormone therapy. However, combination therapy with sulodexide and resveratrol helps prevent the development of cardiometabolic complications: atherosclerosis, arterial hypertension, thrombosis, and thromboembolism. Large-scale randomized studies are needed to evaluate the properties of this combination of drugs.

Background. One of the most important consequences of changes in estrogen levels during peri- and postmenopause is the development of oxidative stress, which plays a key role in the pathogenesis of age-related diseases. The impact of menopausal hormone therapy and phytoestrogen therapy on antioxidant homeostasis is currently under active discussion. Conflicting evidence suggests that estrogen can have both pro- and antioxidant properties, making research into this issue particularly relevant. Objective. To study the effects of menopausal hormone therapy (MHT) and phytoestrogens (soy isoflavones and resveratrol) on the oxidant-antioxidant profile of plasma during peri- and postmenopause. Methods. The study included 92 patients with menopausal climacteric syndrome who were divided into MHT group (n=25), soy isoflavone therapy group (n=23), resveratrol therapy group (n=24), and control group of women who did not receive drug therapy (n=20). The severity of climacteric syndrome was assessed using questionnaires before treatment and after 3 months, and the plasma antioxidant profile was analyzed using kinetic luminol-activated chemiluminescence. Results. MHT with a combination of estradiol and dydrogesterone proved to be the most effective in reducing the severity of menopausal symptoms. Positive dynamics were also observed in the resveratrol group. Soy isoflavone therapy had no significant effect on the course of menopausal symptoms. Neither MHT nor soy isoflavone therapy affected antioxidant profile parameters. Resveratrol had a beneficial effect on the thiol antioxidant system, and a correlation was found between the thiol antioxidant system and the severity of menopausal symptoms. Conclusion. The obtained data are of high practical value and demonstrate the safety of MHT and resveratrol with respect to blood oxidant-antioxidant homeostasis, as well as their significant clinical efficacy. Further research is required to evaluate longer-term results.

Menopause is a universal physiological transition, marked by a decline in estrogen, which has important effects on skin and mucosal health. The impact of menopause and menopausal hormone therapy (MHT) on chronic dermatoses remains incompletely defined. The aim was to investigate the relationship between menopause, MHT, and common dermatological conditions. PubMed, Embase, and Web of Science were searched from inception to September 2024 in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Eligible studies evaluated menopause or MHT in relation to alopecia, psoriasis, acne, rosacea, melasma, and hidradenitis suppurativa (HS). Investigational cohorts largely consisted of menopausal women, although participant characteristics varied. Data on study design, population, hormonal status, and dermatological outcomes were extracted and synthesized. A total of 40 studies met inclusion criteria. Alopecia, particularly frontal fibrosing alopecia (FFA) and female pattern hair loss (FPHL), showed the strongest postmenopausal associations, with most cases presenting after menopause and earlier or surgical menopause conferring greater risk. Psoriasis frequently persisted or worsened after menopause, though objective assessments are limited. Acne and rosacea generally improved, whereas melasma showed mixed outcomes, including greater extra-facial involvement post menopause. HS responses to menopause were inconsistent. MHT was linked to increased risk of FFA and rosacea, whereas findings for other dermatoses were more variable or absent. Most of the studies involved MHT formulations that are less commonly used in current clinical practice. Menopause influences the onset and course of several chronic dermatoses, while data on MHT remain more limited and inconsistent. Dermatologists should consider menopausal status and hormone therapy exposure when evaluating skin disease. Longitudinal, dermatology-focused studies-particularly those integrating diverse populations and updated hormone therapies-are needed to inform individualized care.

Menopause hormone therapy and risk of mild cognitive impairment or dementia: a systematic review and meta-analysis.

BackgroundMenopause, characterized by a significant decline in ovarian hormones, represents a key transition point in the aging trajectory (Gravelsins & Galea, in press). Use of menopausal hormone therapy (MHT) has been associated with reduced risk of Alzheimer’s disease dementia as well as benefits for cognition and the brain (Kim et al., 2021). However, other studies have found MHT to have no benefit, or negative effects, on dementia risk, cognition, and the brain (Espeland et al., 2013). These inconsistencies may be explained by a failure to account for MHT formulation, MHT administration route, and cognitive domain assessed. Estradiol (E2), the most potent of the estrogens, has the greatest binding affinity to estrogen receptors (ER). Comparatively, estrone (E1) has significantly lower binding affinity. Oral E2 is largely converted to E1 via first‐pass metabolism. In contrast, transdermal E2 largely circumvents this conversion, resulting in higher circulating E2 (Gleason et al., 2005). The cognitive domains of executive functions and episodic memory may be differentially sensitive to MHT, as they rely on different brain regions. Few studies have examined the effects of E2‐ and E1‐based MHT based on administration route on different cognitive domains.MethodUsing baseline data in 4,776 mostly healthy postmenopausal females from the Canadian Longitudinal Study of Aging, we examined the influence of E2‐ and E1‐based MHT on performance in three cognitive domains: episodic memory, prospective memory, and executive functions.ResultWe found that transdermal E2 was associated with higher episodic memory scores (p=0.0084, Cohen’s d=0.228), whereas oral E2 and transdermal E1 were associated with higher prospective memory scores (E2: p=0.0353, Cohen’s d=0.296; E1: p=0.0353, Cohen’s d=0.409), compared never use of MHT. Neither MHT formulation nor route of administration influenced the executive functions composite.ConclusionThese results underscore the differential effects of E2‐ and E1‐based MHT depending on route of administration and cognitive domain tested. Notably, these results may reflect dose‐dependent effects of estrogens; episodic memory may benefit from greater ER activation than prospective memory. This work clarifies the mixed MHT literature and may inform emerging precision medicine approaches for cognitive aging in females.

BackgroundTwo‐thirds of AD patients are women, and aging‐related hormonal changes may contribute to these sex differences. Lower lifetime exposure to estrogen, a neuroprotectant, is associated with AD‐related brain atrophy. Estrogen‐based therapies are associated with better brain health, including preserved brain volume in areas that atrophy with aging. We investigated whether hormone‐based medications (birth control (BC), menopausal hormone therapy (MHT)) were associated with structural neuroimaging markers of aging and Alzheimer’s disease. We hypothesized that timing of hormone‐based therapies would be associated with larger brain volume and greater cortical thickness in older women in temporo‐limbic regions.MethodWe investigated baseline associations in Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE), a 12‐month, multi‐site, randomized aerobic exercise trial in 459 female participants aged 65‐80. We used SPM12 and CAT12 software to process 3D‐T1 MPRAGE images, and conducted voxel‐based (VBM‐gray matter volume) and surface‐based morphometry (SBM‐thickness) to investigate voxel‐wise differences between individuals that had a history of a) BC use vs. no BC use; b) MHT use vs. no MHT use and c) MHT use (no BC) vs. no MHT use (no BC), accounting for age, education, study site, and APOE4 carrier status.ResultIn the VBM analysis, BC use (average start age 22) was associated with larger left inferior frontal gyrus volume (cluster k=2613, FWE corrected p ‐value= 0.004, Figure 1). BC timing (starting age, duration) did not add significantly to the models. In the SBM analysis, combined BC and MHT use was associated with a thicker left middle temporal cortex (vertices = 496, FWE corrected p ‐value=0.019). Interestingly, when looking at MHT use without the use of BC earlier in life, there were still brain benefits of increased cortical thickness in the right lingual gyrus (vertices=459, FWE corrected p ‐value=0.032).ConclusionOur results support prior evidence that lifetime estrogen exposure is important for healthy brain aging, particularly with regard to brain volume. These findings have clinical implications for estrogen‐based therapies throughout the lifespan. Understanding sex differences in AD is critical for developing sex‐specific prevention strategies and treatments as part of a precision medicine approach.

In reply: All menopausal hormone therapy is not alike.

BackgroundThere are many menopauses, all marking a significant endocrine transition characterized by the depletion of ovarian hormones, including estradiol and progesterone. This transition, especially when it occurs earlier than average, is associated with increased risk for cardiovascular disease (CVD) and dementia. CVD contributes to cerebral small vessel disease and dementia, both partly via reduced cardiac output which can lead to cerebral hypoperfusion. Despite these established links, there is limited research examining the combined impact of age at menopause and cardiac function on brain and cognitive outcomes. This study investigated whether earlier age at menopause influences the associations between cardiac function and gray matter volume, white matter hyperintensity (WMH) burden, and cognitive performance.MethodWe analyzed data from healthy postmenopausal female participants enrolled in both the Canadian Alliance for Healthy Hearts and Minds study and the Ontario Health Study. Cardiac function was assessed using resting left ventricular ejection fraction (LVEF) measured on cardiac MRI. Brain MRI was used to quantify total gray matter volume and WMH burden. Cognition was assessed with the Montreal Cognitive Assessment (MoCA) and the Digit Symbol Substitution Test (DSST). Linear regression models assessed the interactive associations of age at menopause and LVEF on brain and cognitive outcomes, adjusting for age, race/ethnicity, education, menopausal hormone therapy, cause of menopause (surgical/spontaneous), visceral adipose tissue, systolic blood pressure, and intracranial volume (for brain outcomes).ResultWe included 708 participants (Mean age=63±5.4 years, range=45‐76; mean age of menopause=50±5.5 years, range=25‐61, mean LVEF=65±6.3%, range=45‐80%). Age at menopause moderated the association between LVEF and brain outcomes, such that earlier age at menopause strengthened the associations of lower LVEF with reduced gray matter volume (p = 0.03) and increased WMH burden (p = 0.008). The interactive associations between age at menopause and LVEF on cognitive outcomes were not significant (MoCA: p = 0.50, DSST: p = 0.26).ConclusionEarlier menopause and reduced cardiac function may have a compounding negative effect on brain health. These findings underscore the importance of integrating sex‐specific factors, such as age at menopause, into investigations of risk factors for dementia. Further research is needed to elucidate the underlying mechanisms by which earlier menopause contributes to CVD‐related dementia risk.

Granulosa-like cells (GLCs) were differentiated from human endometrium-derived induced pluripotent stem cells (heiPSCs). This study aimed to establish a GLC differentiation protocol as a defined means to produce autologous estradiol (in vitro), highlighting its therapeutic potential as an alternative to conventional menopausal hormone therapy. Endometrial cells from hysterectomy specimens were reprogrammed into iPSCs using episomal vectors encoding SOX2, OCT4, c-MYC, and KLF4. Differentiation was induced using Activin A and CHIR99021 for mesoderm induction, followed by BMP4, Follistatin, and bFGF. Gene expression, flow cytometry, and immunofluorescence were analyzed at each stage. Estradiol production was quantified by ELISA, and its effect on endometrial cell proliferation was evaluated by MTT assay. Results:The roles of small molecules and growth factors in directing stem cells toward functional chondrocytes are also discussed. Additionally, we briefly examine the emerging integration of artificial intelligence (AI) in cartilage tissue engineering. AI applications such as predicting differentiation outcomes, monitoring chondrogenic progression in real-time, and identifying small-molecule enhancers are poised to accelerate discovery and standardization in the field. GLCs expressing the key markers and capable of E2 production were successfully derived from heiPSCs, which may be developed as a novel source for menopausal hormone therapy.

Recommendations for the management of menopausal vasomotor symptoms in clinical practice

EPH26 The Impact of Menopausal Hormone Therapy on Productivity and Health Care Utilization in Women: A Finnish Claims Database Study

BackgroundMenopausal changes in adipose tissue distribution and adipokine profiles may influence immune activity in multiple sclerosis (MS). We investigated relationships between adipokines, inflammation and disease severity in menopausal women with MS and evaluated changes in adipokines during menopausal hormone therapy (MHT).Methods16 menopausal women with MS (participants with MS, PwMS) and 15 age-matched healthy controls were assessed for the associations of adipokines with inflammatory markers, and clinical, radiological and fluid biomarkers of MS severity. Adipokine levels were monitored over 1 year of oral MHT in baseline-controlled design.ResultsIn PwMS, body mass index and leptin-to-adiponectin ratio correlated with circulating high-sensitivity C reactive protein (hs-CRP), tumour necrosis factor (TNF)-α and interleukin-6 (ρ=0.51–0.66, p<0.05). The associations with hs-CRP and TNF-α were independent of age, disease duration, follicle-stimulating hormone and vitamin D. Serum vitamin D inversely correlated with hs-CRP, TNF-α and interferon-γ (ρ=–0.64–0.65, p<0.01). Adipsin showed strong correlation with neurofilament light chain (ρ=0.72, p=0.002) and decreased during MHT (3 months: p=0.007; 12 months: p=0.04).ConclusionsAdipokine imbalance and lower vitamin D levels were associated with systemic inflammation in PwMS. Adipsin emerged as a promising biomarker, with potential relevance for disease monitoring and therapeutic modulation via hormonal pathways. These findings support further exploration of multibiomarker profiling to guide personalised care in menopausal MS.

To synthesize current evidence on menopause in women living with HIV, highlighting the biological, psychosocial, and structural determinants of health, and to identify research and implementation gaps to inform integrated models of care. With increasing life expectancy, more women with HIV are transitioning through menopause. Data from international cohorts suggest that menopause may occur approximately three years earlier in women with HIV than in HIV-negative peers. Symptom burden - including vasomotor, psychological, and sexual health disturbances - appears greater and is compounded by stigma, multimorbidity, and socioeconomic disadvantage. Evidence on the safety of menopausal hormone therapy, drug-drug interactions with antiretroviral therapy, and long-term cardiometabolic and bone outcomes remains sparse, particularly in low-income and middle-income countries (LMICs). Intersectional inequities affecting racially minoritized and migrant women are increasingly recognized but under-researched. Menopause in women with HIV remains an under-prioritized aspect of care despite its significant clinical and psychosocial implications. Future efforts should focus on longitudinal and interventional studies, integration of menopause assessment within HIV services, and culturally sensitive, multidisciplinary care models that address inequities across global settings.

Women using menopausal hormone therapy who suicide have multiple risk factors.

The world of menopause is undergoing a renaissance. In recent years, medical experts have taken to social media, igniting a long overdue surge of information on the subject that helps debunk the fear of menopausal hormone therapy (MHT), which stems from the 2002 Women’s Health Initiative (WHI) study.1 The devastating consequences on health and wellness were profound: an entire generation of women was suddenly deprived of symptom relief and quality of life (QOL) due to the marked decline in hormone prescriptions in North America. These effects continue to echo today. The near extinction of medical education on mature women’s health and wellness in our academic institutions since 2002 has left healthcare professionals ill-equipped to guide the next generation of menopausal women who seek contemporary medical advice and refuse to “live their mothers’ menopause.” The creation of the Menopause Foundation of Canada in 2022, recent sold-out menopause conferences, and renewed interest from pharmaceutical companies is convincing evidence that menopause is finally receiving the recognition and attention it deserves.