Terapia de substituție hormonală la menopauză: review narativ actualizat privind beneficiile, riscurile şi recomandările clinice

Introduction

Menopause represents a physiological milestone in a woman’s life, marking the permanent cessation of menstruation for at least twelve consecutive months and reflecting the irreversible decline of ovarian follicular activity⁽¹⁾.

This transition, typically occurring between the ages of 45 and 55 years old, is driven by a progressive reduction in estrogen and progesterone production, triggering systemic hormonal changes with widespread biological implications⁽¹⁾.

While universal, the menopausal experience varies greatly among individuals, with symptom severity and duration influenced by genetic, lifestyle and psychosocial factors⁽¹⁾.

The decline in estrogen levels induces a broad range of symptoms, with vasomotor disturbances, such as hot flushes and night sweats, being the most prevalent, often accompanied by genitourinary syndromes, mood fluctuations and sleep disorders⁽²⁾. These manifestations may begin during perimenopause and persist for years beyond the final menstrual period, substantially affecting physical well-being, emotional stability and social functioning⁽²⁾.

Neurocognitive changes – including memory impairment, decreased concentration and mood lability – are in­creasingly recognized as integral components of the me­no­pausal symptom spectrum⁽²⁾.

Beyond the immediate symptomatic burden, menopause is associated with long-term health risks due to chronic estrogen deprivation⁽³⁾.

These include accelerated bone loss leading to osteoporosis and fractures, increased cardiovascular morbidity through atherogenesis and endothelial dysfunction, and adverse shifts in lipid metabolism⁽³⁾.

The absence of estrogen’s vasodilatory, anti-inflammatory and metabolic regulatory effects further contributes to heightened risks of ischemic heart disease and cerebrovascular events⁽³⁾.

Hormone replacement therapy (HRT) remains the gold standard for alleviating moderate to severe vasomotor and genitourinary symptoms, while also playing a role in bone density preservation⁽⁴⁾.

When initiated within the so-called “therapeutic window” – preferably before the age of 60 or within 10 years after menopause onset –, HRT may additionally confer cardiovascular benefits in selected patients⁽⁴⁾.

However, its widespread adoption has been hindered by persistent safety concerns, largely rooted in early interpretations of the Women’s Health Initiative (WHI) trial results⁽⁵⁾.

Subsequent re-analyses and stratified interpretations have underscored the importance of timing, formulation, route of administration and individualized risk assessment in optimizing outcomes⁽⁵⁾.

Contemporary recommendations from authoritative bodies such as the North American Menopause Society (NAMS), the National Institute for Health and Care Excellence (NICE) and the International Menopause Society (IMS) endorse a personalized, evidence-based approach, emphasizing informed decision-making and regular therapy reevaluation⁽⁶⁾.

Moreover, increasing interest in bioidentical hormone formulations – perceived by many patients as “natural” alternatives – highlights the need for rigorous research to substantiate their safety and efficacy⁽⁶⁾.

Given the evolving understanding of menopausal physiology, therapeutic safety and patient-centered preferences, a comprehensive, up-to-date synthesis of the available literature and clinical guidelines is essential to guide optimal, individualized care for women during this transitional stage⁽⁶⁾.

Materials and method

A comprehensive literature search was conducted in PubMed, MEDLINE, EMBASE and the Cochrane Library for articles published between January 2000 and April 2024, using a combination of Medical Subject Headings (MeSH) and free-text keywords related to “menopause”, “hormone replacement therapy”, “estrogen therapy”, “progestogens” and “bioidentical hormones”. Boolean operators (AND, OR) were applied to refine the search.

After removal of duplicates, 168 records were screened by title and abstract. Of these, 124 were excluded for not meeting the predefined inclusion criteria (non-hormonal interventions, studies in men or animals, narrative commentaries without primary data). The full texts of 44 articles were assessed for eligibility, and 24 were excluded after detailed evaluation due to insufficient methodological quality, limited sample size, or exclusive focus on outcomes outside the scope of this review.

A total of 20 studies were included in the qualitative synthesis, consisting of five randomized clinical trials, two systematic reviews/meta-analyses, four large observational or survey studies, and nine clinical guidelines or consensus statements. No quantitative meta-analysis was performed due to heterogeneity in study populations, hormone regimens, doses, routes of administration and outcome measures; the results were synthesized narratively.

The study selection process and reasons for exclusion are summarized in the PRISMA flow diagram (Figure 1).

Results

A broad spectrum of hormone replacement therapy (HRT) formulations and administration routes is currently available, enabling individualized regimens tailored to patient symptomatology, comorbidities and personal preferences⁽⁷⁾. Systemic options include oral, transdermal and injectable preparations, while local vaginal therapies are primarily used for targeted management of genitourinary syndrome of menopause (GSM)⁽⁷⁾.

The classification of HRT by hormonal composition, estrogen-only or estrogen-progestogen combinations, and by delivery method is summarized in Table 1⁽⁷⁾. Multiple randomized controlled trials (RCTs) and large observational studies confirm that HRT is the most effective intervention for alleviating vasomotor symptoms such as hot flushes and night sweats⁽⁸⁾. Both oral estrogen and combined estrogen-progestogen regimens demonstrate superior efficacy to placebo, with clinically significant improvement observed within 4-8 weeks of initiation⁽⁸⁾.

Transdermal estrogen formulations provide comparable symptom relief, with additional advantages in women at risk of venous thromboembolism due to the absence of first-pass hepatic metabolism⁽⁹⁾. HRT also exerts a substantial positive impact on GSM, improving vaginal epithelial maturation, lubrication and elasticity, thereby reducing dyspareunia and urinary urgency⁽¹⁰⁾. Local estrogen therapy, particularly at ultra-low doses, has demonstrated efficacy with minimal systemic absorption, making it a suitable option for women with contraindications to systemic therapy⁽¹⁰⁾.

Bioidentical hormone therapy (BHT), most commonly involving transdermal estradiol combined with micronized progesterone, is reported to have favorable tolerability in observational studies; however, high-quality randomized data remain limited⁽¹¹⁾.

Bone health outcomes are consistently improved with systemic estrogen-containing regimens, with increases in bone mineral density (BMD) at the lumbar spine and femoral neck documented across multiple trials⁽¹²⁾. Furthermore, the early initiation of HRT (within 10 years of menopause onset) has been associated with significant reductions in vertebral and hip fracture risk⁽¹²⁾. Continuous combined therapy may offer greater skeletal benefits compared to sequential regimens, although both are effective⁽¹²⁾.

Cardiovascular outcomes appear to be closely linked to the timing of therapy initiation, supporting the “window of opportunity” hypothesis⁽¹³⁾. Women commencing HRT before the age of 60 or within 10 years of menopause have demonstrated lower rates of coronary heart disease events, whereas the initiation beyond this interval is associated with neutral or increased cardiovascular risk⁽¹³⁾. These differences in benefits and risks according to age and time since menopause are summarized in Table 2, which outline the clinical advantages and potential risks across different patient categories. Evidence from trials such as the Kronos Early Estrogen Prevention Study (KEEPS) further supports the cardiovascular advantages of early, lower-dose regimens⁽¹³⁾.

Improvements in sexual function have been reported, particularly in women with GSM, where HRT enhances sexual satisfaction, reduces pain and improves overall quality-of-life scores⁽¹⁰⁾. Nevertheless, surveys such as the REVIVE study reveal that a considerable proportion of symptomatic women remain untreated despite the availability of effective options⁽¹⁰⁾.

Regarding safety, transdermal estrogen combined with micronized progesterone appears to confer a lower risk of venous thromboembolism and possibly of breast cancer compared with regimens containing synthetic progestins⁽⁹⁾. While earlier interpretations of large trials raised concerns about breast cancer risk, the subsequent analyses indicate that the magnitude of this risk is modest and dependent on factors such as duration of therapy, type of progestogen and baseline patient risk⁽⁵⁾. In hysterectomized women, estrogen-only therapy may have a neutral or even protective effect on breast cancer incidence in certain populations⁽⁵⁾.

Discussion

The synthesis of current evidence from randomized controlled trials, observational studies and expert consensus documents confirms that hormone replacement therapy remains the most effective intervention for alleviating menopausal symptoms, particularly vasomotor instability and genitourinary syndrome of menopause⁽¹⁴⁾.

These findings are consistently reinforced by international guidelines from the North American Menopause Society (NAMS), the International Menopause Society (IMS) and the National Institute for Health and Care Excellence (NICE), which recommend HRT as a first-line option for appropriately selected women^(6,15).

In clinical decision-making, the benefit-risk ratio varies significantly according to patient age, comorbidity profile and time since menopause onset, supporting the principle of individualized therapy^(16,17).

The “window of opportunity” hypothesis, supported by longitudinal data, indicates that the initiation of HRT before the age of 60 or within 10 years of menopause maximizes the cardiovascular and skeletal benefits, while minimizing thromboembolic and oncologic risks^(13,18).

Evidence from the Kronos Early Estrogen Prevention Study (KEEPS) and the Early versus Late Intervention Trial with Estradiol (ELITE) demonstrates improved endothelial function, reduced atherosclerotic progression and favorable lipid profile changes with early initiation^(13,19).

These benefits are attenuated or absent when the therapy is initiated later in the postmenopausal period, underlining the importance of timing⁽²⁰⁾.

Meta-analyses have consistently confirmed the HRT efficacy in preventing osteoporotic fractures, with vertebral fracture risk reduced by up to 35% and hip fracture risk reduced by 28% in compliant populations^(12,21).

Cardiovascular protection appears to be mediated by favorable modulation of vascular tone, inflammation and lipid metabolism, particularly with transdermal formulations that avoid first-pass hepatic metabolism^(9,22).

Furthermore, combination regimens using micronized progesterone instead of synthetic progestins are associated with lower venous thromboembolism (VTE) risk^(9,23).

Regarding the oncologic safety, updated analyses of WHI and European observational cohorts suggest that estrogen-only therapy in hysterectomized women does not increase – and may even reduce – breast cancer incidence^(5,24).

Conversely, the combined estrogen-progestogen therapy, particularly with synthetic progestins, carries a small but measurable increase in breast cancer risk, which appears related to duration of use and resolves gradually after discontinuation^(5,25).

From a clinical implementation perspective, patient-centered approaches and shared decision-making are essential to optimize adherence and satisfaction^(16,26).

Digital health tools and telemedicine platforms have emerged as valuable adjuncts for therapy monitoring, adverse event reporting and education^(27,28).

Future research should prioritize large-scale randomized trials evaluating bioidentical hormone therapy, as current evidence remains insufficient to establish definitive safety and efficacy profiles^(11,29).

Additionally, population-based preventive strategies integrating lifestyle interventions with appropriate HRT regimens may further enhance the quality of life and reduce chronic disease burden in postmenopausal women⁽³⁰⁾.

Conclusions

Hormone replacement therapy remains the most effective intervention for moderate-to-severe menopausal symptoms, particularly vasomotor disturbances and genitourinary syndrome of menopause⁽¹⁴⁾. When initiated within the “window of opportunity” – before the age of 60 or within 10 years of menopause – and individualized to patient risk, HRT also preserves bone mineral density and may confer cardiovascular benefits^(8,13,20). International guidelines from NAMS, IMS and NICE emphasize tailoring formulation, dosage and route of administration to patient needs and comorbidities^(6,15,17). Estrogen-only therapy is safest for hysterectomized women in terms of breast cancer risk^(5,24), while transdermal estrogen with micronized progesterone reduces venous thromboembolism risk compared to oral regimens with synthetic progestins^(9,23).

Effective HRT use requires balancing benefits with potential risks, regular monitoring and integration of lifestyle measures such as healthy diet, exercise and smoking cessation^(16,26,30). Bioidentical hormone therapy warrants further high-quality trials^(11,29), and digital health solutions offer opportunities to enhance adherence and safety^(27,28). Prescribed judiciously and according to current guidelines, hormone replacement therapy should be viewed as a dynamic, evidence-based, patient-centered therapy capable of improving quality of life for women during and after the menopausal transition^(6,15,16,30).   

Corresponding author: Adelina-Georgiana Vârciu E-mail: drvarciuadelina@gmail.com

Conflict of interest: none declared.

Financial support: none declared.

This work is permanently accessible online free of charge and published under the CC-BY licence.