Hormone Replacement Therapy for Menopause: Revisiting Evidence and Looking Ahead

For those who experience menopause, it often occurs as an unpredictable transition, diagnosed only in retrospect after 12 consecutive months without menstruation.¹ Its effects extend far beyond reproductive aging: It impacts multiple organ systems and manifests as vasomotor symptoms, mood disturbances, sexual dysfunction, and progressive loss of muscle and bone mass. Symptoms vary in severity from mild to debilitating and may arise during the peri- and postmenopausal stages, often worsening with age.^1,2

Access to preventive or early interventions is critical to helping women navigate this transition. Therapeutic options for menopause include lifestyle modifications; systemic menopausal hormone therapy (MHT), also known as hormone replacement therapy; and nonhormonal alternatives. Although multiple options exist, an estimated 85% of women in high-income countries remain untreated for menopausal symptoms.¹ Much of this gap reflects safety concerns about estrogen-containing MHT, despite evidence that MHT is the most effective treatment for disruptive menopausal symptoms.^1,3

Since its discovery in the early 20th century, estrogen has been the dominant therapy for menopause, widely prescribed beginning in the mid-1900s. MHT use grew steadily until the publication of the Women’s Health Initiative (WHI) trials in 2002 and 2004, which reported increased risks of breast cancer (HR, 1.26; 95% CI, 1.00-1.59), stroke (HR, 1.41; 95% CI, 1.07-1.85), and coronary heart disease (HR, 1.29; 95% CI, 1.02-1.63) in women older than 60 years receiving oral estrogen-containing therapies.^3,4 The resulting media coverage prompted a dramatic decline in use: 46% in the US, 28% in Canada, and a similar decline in other countries.⁴ One longitudinal study in Australia found that nearly half of American women on systemic MHT abruptly discontinued therapy, and retrospective analyses suggest that between 18,601 and 91,610 women died prematurely between 2002 and 2011 due to estrogen avoidance.²

More than 2 decades later, the legacy of the WHI studies continues to shape practice. In July 2025, the FDA convened an expert panel to reevaluate the evidence. Panelists underscored how early interpretations of WHI trial data, particularly in women who began therapy at an average age of over 60 years, were overgeneralized to all MHT formulations and age groups. Importantly, the WHI studies did not actually demonstrate a statistically significant increase in breast cancer mortality. Reanalyses of previous data discussed in this meeting revealed that women initiating therapy before age 60 years or within 10 years of menopause had reduced all-cause mortality. Estrogen monotherapy was linked to fewer breast cancers and lower mortality, whereas estrogen plus progestin conferred only a slight, nonsignificant increase in risk. Expert panelists emphasized that timing and formulation are crucial in managing menopausal symptoms, with early initiation offering cardiovascular, bone, and cognitive benefits, whereas delayed initiation may increase risk. For example, MHT can reduce fracture risk by up to 50% and has been associated with slower cognitive decline.⁵

Despite the absence of supporting clinical evidence, systemic and local vaginal estrogen products still carry boxed warnings for cardiovascular events, dementia, and breast cancer. Panelists emphasized that these warnings perpetuate fear and deprive women of safe, effective treatment, noting that as a result, approximately 4% of eligible women currently receive MHT.⁵

The panel concluded that previous interpretations of WHI findings, inconsistencies in labeling, and insufficient clinician training have collectively restricted access to evidence-based therapies. The panel supported more precise guidance, improved education, and removal of unsupported warnings to ensure women can benefit from safe and effective treatment options.⁵

Pharmacists play a critical role as educators, especially in areas where data are evolving. By applying the latest evidence-based recommendations, pharmacists can guide patients toward safe and effective options for menopausal symptom relief that also confer cardiovascular, bone, and cognitive benefits. Moving forward, pharmacists can serve as frontline advocates, ensuring patients receive accurate information and promoting evidence-based use of therapies to improve outcomes and quality of life.

REFERENCES

1. Davis SR, Pinkerton J, Santoro N, Simoncini T. Menopause—biology, consequences, supportive care, and therapeutic options. Cell. 2023;186(19):4038-4058. doi:10.1016/j.cell.2023.08.016

2. Natari RB, Hollingworth SA, Clavarino AM, Dingle KD, McGuire TM. Long term impact of the WHI studies on information-seeking and decision-making in menopause symptoms management: a longitudinal analysis of questions to a medicines call centre. BMC Womens Health. 2021;21(1):348. doi:10.1186/s12905-021-01478-z

3. Kim J, Munster PN. Estrogens and breast cancer. Ann Oncol. 2025;36(2):134-148. doi:10.1016/j.annonc.2024.10.824

4. Stute P, Marsden J, Salih N, Cagnacci A. Reappraising 21 years of the WHI study: putting the findings in context for clinical practice. Maturitas. 2023;174:8-13. doi:10.1016/j.maturitas.2023.04.271

5. FDA expert panel on menopause and hormone replacement therapy for women. FDA. July 17, 2025. Updated July 28, 2025. Accessed September 15, 2025. https://www.fda.gov/patients/fda-expert-panels/fda-expert-panel-menopause-and-hormone-replacement-therapy-women-07172025