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MHT_Article_Final.pdf

MHT_Article_Final.pdf

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Overview.

Recent research (2025–2026) confirms that menopausal hormone therapy (MHT) remains the most effective treatment for vasomotor symptoms (VMS), genitourinary syndrome of menopause, and prevention of early postmenopausal bone loss, with additional modest improvements in sleep, mood, and quality of life[1-9]; however, the benefit-risk profile is highly dependent on timing, formulation, route of administration, and individual patient factors.

Initiation within 10 years of menopause or before age 60 is associated with a more favorable risk profile, especially when using transdermal estradiol at low to moderate doses [1,3,10-13]. Oral regimens, particularly those using conjugated equine estrogens, are linked to higher risks of venous thromboembolism (VTE) and stroke compared to transdermal options [1,10,14,15].

Breast cancer risk increases with longer use of combined estrogen-progestogen therapy but is lower with estrogen-only regimens after hysterectomy or when using micronized progesterone [1,12,16-18]. Cardiovascular prevention is not an indication for MHT; risks rise with older age at initiation or pre-existing comorbidities [6,11,19,20]. Newer agents like estetrol (E4) show promise but lack long-term safety data [1].

Guidelines emphasize individualized therapy, lowest effective dose, and periodic reassessment [3,20]. There remain gaps in evidence for diverse populations and long-term outcomes.

Authors & journals that appeared most frequently in the included papers:

Type

Name

Papers

Author

O. Ylikorkala

[16] [18]

Author

Heli Siitonen

[18]

Author

Johanna M Joensuu

[16] [18]

Journal

European journal of endocrinology

[20] [33] [34]

Journal

Journal of Clinical Medicine

[17] [35]

Journal

Climacteric

[31] [14]

What the research is telling us.

Efficacy for symptom relief and bone health

MHT remains the gold standard for alleviating vasomotor symptoms (hot flashes/night sweats), genitourinary syndrome of menopause (GSM), sleep disturbances, mood disorders, and quality of life [1-8]. It also prevents early postmenopausal bone loss and reduces fracture risk in appropriately selected women [3,7,8,21].

Risks: cardiovascular disease, VTE, cancer

Risks vary by regimen:

  • Cardiovascular disease: No benefit for primary prevention; increased risk if initiated >10 years after menopause or in women >60 years old [6,11,19,20]. Transdermal estradiol has a lower VTE/stroke risk than oral forms [1,10,14].

  • Venous thromboembolism: Higher with oral estrogen plus synthetic progestogens; transdermal routes confer little/no increased risk even in high-risk women [10,14].

  • Breast cancer: Risk increases with duration of combined estrogen-progestogen use; lower with estrogen-only regimens or when using micronized progesterone/dydrogesterone as progestogen [1,12,16-18].

  • Endometrial cancer: Unopposed estrogen increases risk; adding progestogen protects the endometrium but may increase breast/VTE risk [16,22].

  • Other cancers: Absolute ovarian cancer risk is small; colorectal cancer evidence is mixed [1].

Individualisation: timing, formulation & special populations

Benefits outweigh risks when MHT is started within 10 years of menopause or before age 60 at the lowest effective dose tailored to patient needs [1-3]. Transdermal estradiol/micronized progesterone are preferred for those at higher cardiovascular/VTE risk [10,12]. Special populations, such as women with diabetes or metabolic syndrome, may benefit from transdermal options but require careful screening [13].

Psychiatric & cognitive outcomes

Evidence for cognitive protection is inconsistent; some studies suggest possible benefit if started early in menopause but no effect, or even increased dementia risk, if started late (>65 years) [17,23,24]. Psychiatric adverse events are rare but may be higher in younger women or those receiving systemic rather than local HRT [25].

In summary.

The latest evidence supports MHT as the most effective intervention for menopausal symptom relief and bone health preservation when individualised according to patient characteristics, especially timing since menopause onset and baseline cardiovascular/thrombotic risk factors [1-3]. Transdermal estradiol/micronized progesterone regimens offer improved safety profiles over older oral/synthetic combinations [10,12], while newer agents like estetrol are promising but require further study.

Risks, including breast cancer (with combined regimens), VTE (especially oral/synthetic progestogens), stroke (older age/initiation >10 years post-menopause), and endometrial pathology (unopposed estrogen), necessitate careful patient selection and ongoing monitoring [1,11,22]. Most guidelines now recommend shared decision-making based on individual preferences/risks rather than blanket recommendations.

Research quality has improved through large cohort studies/meta-analyses but gaps remain regarding long-term outcomes in diverse populations (e.g., non-white ethnicities), special groups (e.g., breast cancer survivors), psychiatric/cognitive effects beyond symptom relief, and real-world adherence patterns.

While individualized menopausal hormone therapy offers substantial symptomatic relief with acceptable safety for many women when used appropriately, ongoing research is needed to address persistent uncertainties about long-term outcomes across diverse populations and evolving therapeutic options.

Claims & evidence Table

Claim

Evidence Strength

Reasoning

Papers

MHT is the most effective treatment for vasomotor/genitourinary symptoms

Evidence strength: Strong (10/10)

Supported by multiple RCTs/guidelines/meta-analyses across diverse populations

[1],[2],[3],[5],[6],[7],[8]

Early initiation (<10 yrs since menopause) improves benefit-risk ratio

Evidence strength: Strong (9/10)

Consistent findings across trials/guidelines favoring early use

[1],[3],[11],[6],[13]

Transdermal estradiol/micronized progesterone have lower VTE/breast cancer risk vs oral/synthetic regimens

Evidence strength: Strong (8/10)

Comparative studies/meta-analyses show reduced adverse events

[10],[12],[16],[17],[14]

Combined estrogen-progestogen increases breast cancer risk over time

Evidence strength: Strong (8/10)

Large cohort/nationwide studies confirm duration-dependent increase

[1],[12],[16],[17],[18]

No cardiovascular prevention benefit; possible harm if started late

Evidence strength: Moderate (7/10)

RCTs/meta-analyses show neutral/harmful effects if initiated >60 yrs or >10 yrs post-menopause

[11],[6],[19],[20]

Cognitive/psychiatric benefits are uncertain/inconsistent

Evidence strength: Moderate (5/10)

Mixed results from RCTs/observational studies; some signal for early use

[23],[17],[24],[25]

Research Gaps: Matrix showing where research is concentrated vs. lacking by topic/outcome and study attribute

Topic/
Outcome

Early Initiation (<10 yrs)

Late Initiation (>10 yrs)

Transdermal Regimens

Non-white Populations

Vasomotor symptom relief

18

2

9

2

Bone health/fracture reduction

12

2

6

GAP

Cardiovascular outcomes

9

6

5

GAP

Breast/endometrial cancer risk

11

4

3

GAP

Cognitive/psychiatric effects

6

2

2

GAP

Figure undefined: Matrix showing where research is concentrated versus lacking by topic/outcome and study attribute.

Future research

Future research should focus on long-term safety/effectiveness in underrepresented groups; regimen-specific risks/benefits; cognitive/psychiatric outcomes; real-world adherence/persistence patterns.

Question

Why

What are the long-term cardiovascular/cancer risks of newer transdermal/bioidentical hormone therapies?

Newer formulations may offer improved safety profiles but lack robust long-term outcome data

How does MHT affect cognitive function/dementia risk when initiated at different ages?

Conflicting evidence exists regarding neuroprotection versus harm depending on timing/formulation

What are optimal strategies for personalising MHT in diverse ethnic/socioeconomic populations?

Most trials underrepresent non-white/minority groups despite differing baseline risks/responses

References and other relevant publications.

  1. Arnautu, A., Nimigean, V., Nacea-Radu, C., Tilici, D., & Paun, D. Menopausal Hormone Therapy—Risks, Benefits and Emerging Options: A Narrative Review. International Journal of Molecular Sciences. 2025; 26. https://doi.org/10.3390/ijms262211098

  2. Yanachkova, V., Vasileva-Slaveva, M., Kostov, S., & Yordanov, A. Reconsidering Hormone Replacement Therapy: Current Insights on Utilisation in Premenopausal and Menopausal Women: An Overview. Journal of Clinical Medicine. 2025; 14. https://doi.org/10.3390/jcm14207156

  3. Mukherjee, A., & Davis, S. Update on Menopause Hormone Therapy; Current Indications and Unanswered Questions.. Clinical endocrinology. 2025 https://doi.org/10.1111/cen.15211

  4. Chatterjee, S., Sahoo, S., Khobragade, D., Prusty, S., Sahu, P., Tiwari, P., & Kadiri, S. Comprehensive Guide to Menopausal Therapy: Options and Outcomes. Current Women s Health Reviews. 2026 https://doi.org/10.2174/0115734048352354250406163635

  5. Church, A., & Biagi, M. Menopausal hormone therapy: Making sense of current guidelines.. JAAPA : official journal of the American Academy of Physician Assistants. 2025 https://doi.org/10.1097/01.jaa.0000000000000226

  6. Wądołowska, A., Serafin-Juszczak, B., Wydra, M., Mogilany, Z., Wojdal, J., Kusek, K., Przybył, B., Ciepłucha, K., Wilk, M., & Narożniak, D. MENOPAUSAL HORMONE THERAPHY – APPLICATION, RISKS AND BENEFITS IN CLINICAL PRACTICE. International Journal of Innovative Technologies in Social Science. 2025 https://doi.org/10.31435/ijitss.3(47).2025.3712

  7. Tang, Y., , R., Zhang, L., Sun, X., & Wang, Y. Effectiveness and safety of hormone replacement therapy in the treatment of menopausal syndrome: a meta-analysis.. American journal of translational research. 2025; 17 1. https://doi.org/10.62347/uglt3830

  8. Edelweishia, M., Christoper, A., Theresia, E., & Angelia, V. Review of hormonal replacement therapy options for the treatments of menopausal symptoms. Korean Journal of Family Medicine. 2025; 46. https://doi.org/10.4082/kjfm.25.0039

  9. Quaile, H., Hart-Kress, C., & Piasta, J. Understanding and Prescribing Menopausal Hormone Therapy for Vasomotor Symptoms. Clinical Journal for Nurse Practitioners in Women's Health. 2025 https://doi.org/10.1891/cjnpwh-2510

  10. Abdelrazeq, S., Hsieh, S., Kelly, S., Nahar, N., Skidmore, B., Brouwers, M., Najeeb, S., & Wells, G. Comparative Evidence Between Transdermal and Oral Menopausal Hormone Therapy. Canadian Journal of Health Technologies. 2025 https://doi.org/10.51731/cjht.2025.1119

  11. D’Costa, Z., Spertus, E., Hingorany, S., Patil, R., Horwich, T., Press, M., Shah, J., Watson, K., & Jafari, L. Cardiovascular Risk Associated with Menopause and Menopause Hormone Therapy: A Review and Contemporary Approach to Risk Assessment. Current Atherosclerosis Reports. 2025; 27. https://doi.org/10.1007/s11883-025-01343-6

  12. Stanczyk, F., Yang, J., Bennink, H., Sriprasert, I., Winer, S., Foidart, J., & Archer, D. Comparison of estrogens and selective estrogen receptor modulators (SERMs) used for menopausal hormone therapy.. Menopause. 2025; 32 8. https://doi.org/10.1097/gme.0000000000002547

  13. Al-Sharafi, B., & Odhaib, S. Optimizing hormone replacement therapy for postmenopausal women with type 2 diabetes: a review. Exploration of Endocrine and Metabolic Diseases. 2025 https://doi.org/10.37349/eemd.2025.101430

  14. Hicks, A., Robson, D., Tellis, B., Smith, S., Dunkley, S., & Baber, R. Safety of menopause hormone therapy in postmenopausal women at higher risk of venous thromboembolism: a systematic review. Climacteric. 2025; 28. https://doi.org/10.1080/13697137.2025.2503874

  15. Bińkowska, M., Paszkowski, T., Skrzypulec-Plinta, V., & Zgliczyński, W. Position paper of the expert panel of the Polish Society of Menopause and Andropause on the use of Oestrogel® in menopausal hormone therapy*. Przegla̜d Menopauzalny = Menopause Review. 2025; 24. https://doi.org/10.5114/pm.2025.152241

  16. Ylikorkala, O., Joensuu, J., Siitonen, H., & Mikkola, T. Progestogens in Menopausal Hormone Therapy: A Double-Edged Sword. Seminars in Reproductive Medicine. 2025; 43. https://doi.org/10.1055/s-0045-1809186

  17. Foschi, M., Groccia, G., Rusce, M., Medaglia, C., Aio, C., Sponzilli, A., Setti, V., Battipaglia, C., & Genazzani, A. Estradiol and Micronized Progesterone: A Narrative Review About Their Use as Hormone Replacement Therapy. Journal of Clinical Medicine. 2025; 14. https://doi.org/10.3390/jcm14207328

  18. Siitonen, H., Joensuu, J., Savolainen-Peltonen, H., Gissler, M., Ylikorkala, O., & Mikkola, T. Update of the impact of menopausal hormone therapy on breast cancer risk.. European journal of cancer. 2025; 220. https://doi.org/10.1016/j.ejca.2025.115340

  19. Tran, T., Phung, T., Mai, A., Ly, Q., & Nguyen, T. Menopausal Hormone Therapy: Its Role in the Prevention of Cardiovascular Diseases and the Risk of Breast Cancer in Women. Clinical and Experimental Obstetrics & Gynecology. 2025 https://doi.org/10.31083/ceog26813

  20. Lumsden, M., Dekkers, O., Faubion, S., Hirschberg, A., Jayasena, C., Lambrinoudaki, I., Louwers, Y., Pinkerton, J., Šojat, A., & Van Hulsteijn, L. European society of endocrinology clinical practice guideline for evaluation and management of menopause and the perimenopause.. European journal of endocrinology. 2025; 193 4. https://doi.org/10.1093/ejendo/lvaf206

  21. Vinogradova, Y., Iyen, B., Masud, T., Taylor, L., & Kai, J. Discontinuation of menopausal hormone therapy and risk of fracture: nested case–control studies using routinely collected primary care data. The Lancet. Healthy Longevity. 2025; 6. https://doi.org/10.1016/j.lanhl.2025.100729

  22. Schwartz, A., Sweeney, M., Dolan, M., & Lundberg, G. Menopause Hormone Therapy: 30 years of Advances and Controversies.. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2025 https://doi.org/10.1016/j.eprac.2025.10.011

  23. Fugh-Berman, A., & Mintzes, B. Menopausal Hormone Therapy: Limited Benefits, Significant Harms.. American family physician. 2025; 112 1.

  24. Mosconi, L., Nerattini, M., Williams, S., & Fink, M. New Horizons in Menopause, Menopausal Hormone Therapy, and Alzheimer's Disease: Current Insights and Future Directions.. The Journal of clinical endocrinology and metabolism. 2025 https://doi.org/10.1210/clinem/dgaf026

  25. Chen, N., Li, L., Fu, C., & Ren, Y. Psychiatric safety associated with hormone replacement therapy for menopausal symptoms: a real-world study of the FDA adverse event reporting system. Frontiers in Psychiatry. 2025; 16. https://doi.org/10.3389/fpsyt.2025.1614087

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