Menopausal Hormone Treatment as a Preventive against the Progress of Chronic Diseases in Menopausal Women

Abstract

This review aimed to summarize the biological rationale for the protective effects of estrogen, the robust evidence supporting the benefits of menopausal hormone therapy (MHT), and the evolving regulatory and historical context shaped by the reinterpretation of the Women’s Health Initiative data. This study outlines the risk–benefit profile of contemporary MHT regimens and presented a modern clinical framework for the use of MHT as a preventive strategy to support metabolic, cardiovascular, and skeletal health across and beyond the menopausal transition. Moreover, this review emphasized that menopausal symptoms should be recognized as a critical biological inflection point necessitating proactive intervention. Furthermore, the 2025 FDA regulatory shift reinforces the safety and efficacy of individualized MHT when initiated within the “window of opportunity,” providing a definitive strategy for long-term prevention of chronic diseases in healthy women.

INTRODUCTION

A woman’s health during midlife reflects a lifelong interplay of genetic, environmental, and behavioral factors that evolve across the reproductive lifespan [1]. Although chronic diseases such as metabolic syndrome, cardiovascular disease (CVD), osteoporosis, and cognitive decline may have subclinical origins decades before menopause, their progression accelerates sharply when ovarian estrogen production declines. Menopause therefore acts as a biological inflection point, unmasking latent vulnerabilities and triggering metabolic and vascular shifts that increase disease risk. For example, data from the Study of Women’s Health Across the Nation (SWAN) demonstrate that adverse metabolic and vascular changes—including increased visceral adiposity, unfavorable lipid profiles, impaired insulin sensitivity, and carotid-intima-media thickness (CIMT) progression—emerge during the menopausal transition and are largely independent of chronological aging [2,3].

In this context, menopausal hormone therapy (MHT) is more than a treatment for vasomotor symptoms (VMS); it represents a strategic intervention that can mitigate the acceleration of cardiometabolic aging when initiated in healthy women within 10 years of menopause or before the age of 60 [4,5,6]. Clarkson’s “timing hypothesis,” supported by randomized trials such as the Early versus Late Intervention Trial with Estradiol (ELITE) and the Kronos Early Estrogen Prevention Study (KEEPS) and reinforced by age-stratified analyses of the Women’s Health Initiative (WHI), provides a strong conceptual and empirical foundation for early MHT initiation [4,5,6,7].

The recent removal of the U.S. Food and Drug Administration (FDA)’s “black box” warning on estrogen therapy marks a pivotal moment in women’s health [8]. This regulatory shift acknowledges that the original risk messaging—based largely on unstratified WHI data from older women with multiple comorbidities—did not accurately reflect the safety profile of MHT when used in appropriately selected younger postmenopausal women [9].

With this updated scientific and regulatory environment, a reassessment of MHT’s preventive potential is timely and necessary. This review integrates biological, clinical, and epidemiological evidence that MHT can diminish the upward angle of deflection of chronic disease during the menopause.

MAIN TEXT

Estrogen’s systemic protective roles

While “estrogen” refers to the broad class of steroid hormones, 17β-estradiol (E2) is the primary biological driver of the multisystem homeostatic regulation discussed in this review. A broad body of research across metabolic, cardiovascular, skeletal and neurologic systems- effects on sleep, vasomotor function, mood, and memory demonstrates that E2 is a multisystem homeostatic regulator. Throughout a woman’s life, this hormone coordinates interconnected biological pathways that sustain systemic stability. Metabolically, E2 enhances mitochondrial efficiency, reduces oxidative stress, and supports ATP production in organs with high energy demand. Through ERα-mediated PI3K–Akt signaling, it improves insulin sensitivity, promotes GLUT4 translocation, and supports β-cell function, while suppressing hepatic gluconeogenesis and lipogenesis. These actions preserve metabolic flexibility and protect against the development of insulin resistance [10,11,12,13].

E2 also has a vasoprotective effect. It activates endothelial nitric oxide synthase, maintains endothelial barrier integrity, reduces vascular inflammation, and regulates lipid metabolism. Furthermore, E2 protects against monocyte adhesion to vascular endothelium [14]. These findings help to explain the lower rates of hypertension, dyslipidemia, and atherosclerotic CVD observed in premenopausal women. With the decline in estrogen during menopause, this protective vascular tone diminishes, leading to age-independent worsening in arterial stiffness, lipid profiles, and inflammatory signaling and atherogenesis—patterns consistently shown in longitudinal cohorts [15,16,17].

Within the central nervous system, E2 supports synaptic plasticity, maintains cerebral glucose metabolism, and preserves mitochondrial function in neurons [18]. It also regulates microglial activity and neuroimmune signaling, buffering the brain against inflammatory and bioenergetic stress [19]. The sharp decline in cerebral glucose utilization seen during the menopausal transition illustrates how loss of E2 can precipitate cognitive vulnerability long before clinical symptoms appear [20,21,22,23].

E2’s role in bone is essential. It suppresses osteoclast activity, supports osteoblast and osteocyte survival, and maintains balanced bone remodeling. Menopause-driven estrogen withdrawal accelerates bone turnover and causes rapid loss of both cortical and trabecular bone. These skeletal changes are closely linked with inflammatory cytokine activation and shifts in marrow adiposity, further reflecting E2’s broad metabolic influence [24,25].

Perimenopause as a strategic window

Taken together, these multisystem alterations support menopause as a biological inflection point at which previously compensated vulnerabilities may become clinically apparent. The menopausal rise in visceral adiposity, impaired glucose control, vascular dysfunction, neuroinflammation, and skeletal deterioration reflects the disruption of estrogen-dependent regulatory networks. This interconnected mechanism explains the marked increase in metabolic syndrome, CVD, osteoporosis, and CNS/PNS symptomatology in the years following menopause [2,18,26,27].

Many of these pathophysiologic shifts begin not at the final menstrual period but during the perimenopausal transition. Longitudinal data demonstrate that visceral adiposity, impaired endothelial function, rising inflammatory cytokines, and early cognitive and metabolic vulnerabilities emerge subclinically years before overt menopause [2]. Because these alterations arise while estrogen levels are fluctuating—and before irreversible metabolic or vascular remodeling is established—the perimenopausal period represents a uniquely strategic window for intervention [2]. Early therapeutic engagement, including lifestyle optimization, cardiometabolic risk assessment, and appropriately selected hormone therapy when indicated, prevents the progression of these subclinical disturbances into chronic disease. Recognizing perimenopause as a pivotal window shifts the approach to women’s midlife health from treating diseases after menopause to actively protecting long-term systemic well-being.

Adaptive low-estrogen physiology in reproductive years becomes maladaptive postmenopause

The abrupt shift from reproductive estrogen levels to postmenopausal estrogen deficiency does not simply remove a protective hormone—it activates biological programs that were once adaptive but become maladaptive in the estrogen-depleted state. During the reproductive years, transient drops in E2 elicit short-term responses that support survival and successful reproduction. These include glucose mobilization, increased vascular tone, activation of lipoprotein lipase for lactation, calcium redistribution for fetal and neonatal needs, and modulation of thermoregulation and vigilance. These same responses persist after menopause; however, in non-reproductive situations, they manifest as glucose intolerance, arterial stiffness, atherogenic lipid remodeling, accelerated bone resorption, vasomotor instability, sleep disruption, and increased neurocognitive vulnerability. This transition from adaptive to maladaptive physiology offers a mechanistic explanation for the acceleration of metabolic, vascular, skeletal, and neurocognitive symptomatology despite stable chronological aging (Fig. 1, Table 1).

Fig. 1. Illustrating the typical chronology of estrogen deficiency effects in women. Menopausal symptoms inversely track circulating estradiol levels while the degenerative changes that reflect the ascension of new or previously subclinical disease require some time. Thus, menopausal symptoms (the inflection point) should be viewed as indicators of estrogen deficiency that may presage a multitude of related clinical problems that may be suppressed by menopausal hormone therapy.

Table 1. Physiologic actions of low estrogen in reproductive-age women that become maladaptive after menopause.

	Reproductive period	Postmenopausal period
Glucose intolerance	Physiological blood glucose	Obesity, diabetes
Arterial elasticity	Maintenance of blood flow to critical organs	Stiffness predisposes to maintained cardiovascular disease
Lipoprotein lipase increased	High blood fat for milk	Atherosclerosis
Bone remodeling cycle	Calcium for offspring	Osteoporosis, fracture
Organ turgor (genital and sex skin)	Maintenance of uterine and genital skin bulk and elasticity	Scarring and genital atrophy
Vasomotor control set-point changes	Radiant warming of the suckling newborn	Hot flushes
Sleep pattern alterations	Increased vigilance	Sleep disorders
Central nervous system alterations	Balanced affect and normal memory function	Memory defects, cognition impairment, depression, phobias
Immune response to insult/foreign antigens	Generally anti-inflammatory	Failure of immune privilege

Reconciling conflicting evidence: the central role of age and timing in menopausal hormone therapy in cardiovascular disease

Because estrogen deficiency drives the maladaptive shifts shown in Table 1, MHT offers a physiological means of restoring key metabolic, vascular, and skeletal pathways. The evidence supporting these benefits is extensive; however, the cardiovascular effects of MHT have been most completely studied [28,29,30,31].

A long-standing paradox in MHT research has been the discrepancy between observational studies and early randomized clinical trials (RCTs). Large prospective cohorts such as the Nurses’ Health Study (NHS) reported cardioprotective associations among current MHT users, with reductions in major coronary events of up to 55% (odds ratio [OR] 0.45; 95% confidence interval [CI], 0.34–0.60) [28,32]. Meta-analyses likewise demonstrated a 28%–50% reduction in coronary artery disease and all-cause mortality among appropriately selected users [29,33,34]. In contrast, the Heart and Estrogen/Progestin Replacement Study (HERS) and the initial WHI reports suggested early increases in cardiovascular events, venous thromboembolism (VTE), and stroke, generating widespread concern regarding the cardiovascular safety of MHT [4,35,36,37,38]. Critical examination of these RCTs reveals that their findings were heavily skewed by study design and enrollment characteristics [39] HERS recruited women with severe, established coronary heart disease (CHD) (mean age 67 years). It was a secondary-prevention cohort already at high thrombotic risk [35,36]. Likewise, participants in the WHI trials began therapy at a mean age of 63 years, typically more than a decade beyond menopause, with high prevalence of obesity, untreated hypertension, diabetes, and subclinical atherosclerosis [1,4,37,38]. Initiation of high-dose oral conjugated equine estrogen (CEE) with or without medroxyprogesterone acetate (MPA) in this older, comorbidity-laden population precipitated early VTE [40]. Later studies showed that VTEs are associated with aging as well as vascular insult (WHI later study), indicating that the HERS design and enrollment characteristics, rather than estrogen itself, explain the adverse outcomes and underscore the importance of age and timing in interpreting cardiovascular outcomes of MHT [4].

U.S. Food and Drug Administration’s removal of black box warning also stresses early start of menopausal hormone therapy

Hormone therapy use declined sharply in the early 2000s after the FDA applied class-wide boxed warnings in response to the initial WHI reports, which suggested increased risks of CVD, breast cancer, VTE, and probable dementia [41]. Importantly, as described above, these warnings were based on findings from a cohort whose mean age was 63 years—more than a decade beyond the typical menopausal transition—and who received formulations (particularly CEE with MPA) that are no longer representative of modern practice. The small increase in breast cancer diagnoses observed in the combined-therapy arm was also statistically non-significant and later understood to be progestogen-specific rather than a class effect [37,42].

In 2025, following an expert advisory committee review, a comprehensive evaluation of WHI and post-WHI evidence, and a public comment period, the FDA initiated removal of the “black-box” warnings from systemic and local estrogen-containing products [8,41]

Specifically, the agency removed the warnings related to CVD, breast cancer, and probable dementia from both estrogen-alone and estrogen–progestogen therapies [41]. In tandem with these removals, the FDA eliminated the long-standing recommendation to prescribe hormone therapy at the “lowest effective dose for the shortest duration,” shifting the focus to individualized treatment decisions based on clinical judgment [41].

For systemic preparations, safety data regarding cardiovascular risks is now provided within the updated prescribing information, emphasizing that risk profiles are individualized and dependent on factors such as age, time since menopause, and route of administration [41]. This shift signals a move toward tailored safety information; instead of applying identical class-based language across all products, the labeling now reflects risks most relevant to each specific type of therapy. These revisions effectively integrate the ‘timing hypothesis’ by providing specific guidance for initiating treatment in women younger than 60 years or within 10 years of menopause onset [1,41]. Notably, the FDA preserved the boxed warning for endometrial cancer in systemic estrogen-alone products for women with an intact uterus, reinforcing the essential role of progestogen co-administration in mitigating this well-established risk [41].

This regulatory revision reflects that accumulated evidence indicating that the original warnings—issued without age or timing stratification—did not accurately represent the safety profile of MHT for appropriately selected younger postmenopausal women. Given this updated regulatory framework, the present appraisal of MHT’s safety profile across key clinical domains is both timely and essential.

Risk and safety considerations of menopausal hormone therapy

While the overall benefits of MHT are substantial when treatment is initiated in menopausal women, therapy must be individualized according to age, time since menopause, comorbidities, and the specific formulation and route of administration (Table 2).

Table 2. MHT profiles and the risk/benefit ratio.

Formulation/route	Benefit	Risk	Patient profile/clinical consideration
Oral estrogen	Highly effective for VMS, GSM, bone protection	Slightly higher risk of VTE and stroke due to first-pass liver metabolism	Not recommended for patients with high VTE/stroke risk or hypertriglyceridemia
Transdermal estrogen	Highly effective for VMS, GSM, bone protection	Lower or no increased risk of VTE and stroke (avoids liver first-pass effect)	Preferred route for women with elevated VTE risk or those sensitive to oral formulations
Local/vaginal estrogen	Effective for GSM symptoms only (vaginal dryness, dyspareunia, UTIs)	Minimal to no systemic risk (absorption is negligible)	Ideal for women whose symptoms are limited to GSM, or when systemic MHT is contraindicated
Progestogen (used with intact uterus)	Prevents endometrial hyperplasia/cancer	Medroxyprogesterone acetate (MPA) may increase breast cancer risk with long-term use	Mandatory for all women with an intact uterus; choice of progestogen matters for overall risk assessment
		Micronized progesterone may carry a lower risk profile
Progestin IUD (levonorgestrel-releasing IUD)	Endometrial protection during estrogen therapy, minimal systemic progestin exposure, contraception for women initiating MHT before final menstrual period	Unscheduled bleeding, particularly during early use Limited data regarding breast cancer safety	Useful in women wishing to avoid systemic progestogen

MHT: menopausal hormone therapy, VMS: vasomotor symptoms, GSM: genitourinary syndrome of menopause, VTE: venous thromboembolism, UTIs: urinary tract infections, IUD: intrauterine device.

Data from the articles of Santen et al. (J Clin Endocrinol Metab 2010; 95: s1-66) [42] and “The 2022 Hormone Therapy Position Statement of The North American Menopause Society” advisory panel (Menopause 2022; 29: 767-94) [58].

Major safety domains include thromboembolic and cerebrovascular risk, breast and endometrial safety, gallbladder disease, and cognitive status. A meta-analysis of 19 RCTs involving oral estrogen, with or without progestogen, found a small but statistically significant increase in VTE among women under 60 who initiated MHT within 10 years of menopause [1]. There were similar effects across all age brackets. However, VTE risk varies significantly by formulation: lower-dose oral estrogen and, in particular, transdermal estrogen—especially when combined with micronized progesterone or dydrogesterone—are associated with substantially lower VTE risk. For women with prior thrombosis, obesity, or prolonged immobility, transdermal administration is preferred [43,44,45]. In women with a history of VTE, evaluation for underlying inherited or acquired prothrombic conditions, such as selected genetic abnormalities (e.g., JAK2 mutations), may be warranted as clinically indicated [33].

Breast cancer risk is similarly formulation-dependent. While the WHI reported a modest increase in breast cancer incidence with CEE plus MPA, CEE alone was associated with a long-term reduction in risk—a finding consistent across two decades of follow-up [46,47]. The magnitude of risk with MPA-containing regimens is comparable to lifestyle factors such as obesity or physical inactivity [47]. Systemic MHT is contraindicated in women with active or prior breast cancer. While non-hormonal moisturizers and lubricants are the prioritized first-line therapy for genitourinary syndrome of menopause (GSM) in these patients, ultra-low-dose vaginal E2 (4–10 µg) or estriol may be utilized for refractory symptoms to minimize both systemic absorption [48,49,50]. However, as conclusive long-term safety data are still lacking, clinicians must provide thorough counseling to patients regarding the potential for minimal systemic absorption and the theoretical risk of breast cancer recurrence.

Among women with an intact uterus, the addition of continuous or cyclic progestogen is essential to prevent endometrial hyperplasia. Combined estrogen-progestogen therapy neutralizes the proliferative effect of estrogen and does not increase endometrial cancer incidence [51]. Neither estrogen-alone nor combined therapy meaningfully increases ovarian cancer incidence [52]. Conversely, estrogen–progestin therapy has been associated with a 20%–40% reduction in colorectal cancer risk [53].

Active liver or gallbladder disease remains a contraindication, as oral estrogen increases biliary cholesterol saturation and gallstone formation via first-pass hepatic metabolism. Transdermal therapy mitigates these effects [54,55,56].

Stroke risk does not appear elevated among women starting MHT under 60 or within 10 years of menopause; risk increases with advancing age or higher-dose oral formulation and is minimized with transdermal routes [4,43].

Functional cognitive and mood changes are poorly understood. They may be responsive to changes in the MHT components or symptomatic treatment. MHT should not be prescribed solely for cognitive prevention [57,58,59,60].

The risk-benefit profile of MHT is most favorable when treatment is individualized – aligning the timing of initiation with the early menopausal window, selecting formulations with proven safety, and choosing routes of administration that minimize systemic risk. Such a personalized approach maximizes therapeutic benefit while reducing adverse outcomes, allowing MHT to be used safely and effectively in appropriately selected women (Table 2).

Menopausal hormone therapy in the Asian context: considerations for Korean and Asian women

While much of the landmark MHT data is derived from Western populations, applying these findings to Asian, and specifically Korean, women require consideration of distinct epidemiological and clinical profiles. First, the mean age of natural menopause in Korean women is reported to be between 49.3 and 49.7 years, which is slightly earlier than the 51–52 years typically observed in North American and European cohorts [61].

Beyond the age of onset, symptom presentation also differs significantly. While Western women predominantly present with VMS, Korean and East Asian women frequently report musculoskeletal symptoms—such as joint and muscle pain—and insomnia as their primary and most bothersome complaints [62]. In large epidemiologic surveys of Korean women, joint discomfort is often the most common reason for seeking medical care, whereas the overall prevalence of severe VMS is lower than that typically seen in Western cohorts [61,62].

Furthermore, Asian women exhibit unique cardiovascular risk profiles. They often manifest metabolic syndrome and vascular dysfunction at lower body mass index (BMI) levels [63]. From a safety perspective, the baseline incidence of VTE is notably lower in Asian postmenopausal women [62]. Consequently, the strict preference for transdermal over oral estrogen to avoid VTE risk may not be as rigidly applicable to clinical practice in Asia, although the rapidly increasing prevalence of obesity and metabolic syndrome in the region necessitates individualized cardiovascular risk assessments prior to MHT initiation [62].

Regarding clinical practice, although lower-than-standard doses of MHT have proven effective in Asian populations, overall utilization in South Korea remains strikingly low (approximately 6.3%–9.0%) [64,65]. When prescribed, usage is typically characterized by shorter treatment durations—averaging around one year—partly due to cultural perceptions of menopause as a natural aging process rather than a medical condition, compounded by lingering safety concerns [65]. Despite these challenges, the 2025 Korean Society of Menopause guidelines emphasize that an individualized, early-initiation approach remains the most effective strategy for optimizing long-term health [66].

Furthermore, given the slightly earlier onset of menopause and the rapidly increasing life expectancy of Korean women, they are likely to spend a greater proportion of their lives in an estrogen-deprived state. Consequently, the ‘timing hypothesis’—which advocates for the early initiation of MHT during the menopausal transition to maximize systemic and cardiovascular benefits—holds profound clinical relevance for this population.

Duration of menopausal hormone therapy

There is no conclusive data on the optimal length of MHT treatment. Historically, the FDA recommended limiting the use of hormone therapy to the “shortest duration consistent with treatment goals” [63]. However, in a landmark 2025 update, the FDA removed this restrictive language from hormone therapy labels, officially transitioning to a framework where treatment decisions are individualized and based on the clinical judgment of the physician in discussion with the patient. This shift is supported by recent evidence suggesting that arbitrary time limits may preclude long-term benefits. For instance, data from the WHI estrogen plus progestin trial suggests that a reduction in CVD risk may only become evident after 5–6 years of treatment. Consistent with this, the WHI estrogen-alone trial calculated risk ratios for CHD as 1.08 (95% CI, 0.86–1.36) during the first 6 years, dropping significantly to 0.46 (95% CI, 0.28–0.78) in years 7 to 8 and beyond [67].

Other long-term studies support the cardiovascular safety and potential benefits of extended therapy lasting 14–20 years, even in women as old as 95 years [4,68]. These findings underscore that duration should be guided by clinical evaluation rather than arbitrary time limits. Recent position statements from the North American Menopause Society (NAMS 2022) [49], the International Menopause Society (IMS) [69], and the British Menopause Society [70] emphasize that MHT should be reassessed annually. This individualized approach is particularly critical in cases of premature menopause, where untreated women face markedly increased risks of early-onset estrogen-deficiency-related diseases [29,60].

Patient education

Last, but far from least, the predictable outcome of the fall in circulating estrogen around menopause is one of the key opportunities for patient education. The occurrence of menopausal symptomatology creates an opportunity for patient education (Fig. 2). If possible, the discussion should be accomplished during the menopausal transition when the woman presents for symptoms such as hot flushes, sleeping problems or mood swings. This will not only educate the patient and encourage lifestyle changes and disease screening that will be salutary, but treatment will also give the patient confidence in the doctor’s knowledge and advice. Such educational sessions are time-consuming and visits should be scheduled for a longer duration than usual.

Fig. 2. Showing the sequence in which one can assist the patient in planning for the post reproductive period.

CONCLUSION

The menopausal transition represents a critical biological inflection point rather than a mere cessation of reproductive function. This review advocates for a refined clinical approach – moving beyond reactive symptom relief toward proactive health optimization by focusing on this strategic window. While our framework is fundamentally aligned with current clinical guidelines, which appropriately advise against the use of MHT solely for the primary prevention, we propose that the distinction between ‘symptom management’ and ‘prevention’ is bridged at the inflection point. Because menopausal symptoms often signal the acceleration of subclinical physiological shifts—including vascular stiffening, metabolic decline, and bone resorption—addressing these symptomatic needs within the ‘window of opportunity’ naturally encompasses the management of the underlying drivers of future chronic disease.

In light of the 2025 FDA regulatory shift, MHT should be recognized as a safe and effective tool when individualized and initiated in healthy women within 10 years of menopause or before age 60. Ultimately, recognizing the menopausal transition as a unique opportunity for preventive engagement through symptom-based treatment will allow clinicians to optimize the skeletal, cardiovascular, and metabolic health of aging women without departing from established clinical consensus.