A new study found that transdermal hormone therapy may lower anxiety and depression risk compared with oral therapy in postmenopausal women.
Hormone therapy remains the most effective treatment for menopause-related vasomotor symptoms such as hot flashes and night sweats. Although both oral and transdermal formulations are widely used, they differ in their metabolic pathways, which may affect long-term health outcomes. Findings from a new study presented at The Menopause Society’s 2025 Annual Meeting in Orlando suggest that the route of administration may influence mental health outcomes in postmenopausal women.1,2
The study, Oral vs Transdermal Hormone Therapy in Postmenopausal Women: A Comparison of Obesity, Cardiovascular, Mental Health, and Alzheimer’s Disease Risks, involved a retrospective analysis of 7,688 postmenopausal women identified in the TriNetX database. Researchers compared 3,844 women receiving oral estrogen-only hormone therapy with an equal number of women prescribed transdermal estradiol patch formulations.
Participants were between 46 and 60 years of age and had no preexisting cardiovascular disease (CVD) risk factors, including diabetes, obesity, hyperlipidemia, hypertension, tobacco use, family history of heart disease, or premature menopause. Propensity score matching was used to balance demographics, comorbidities, and medication use between cohorts, allowing for direct comparison of outcomes.
Compared with oral hormone therapy, transdermal therapy was associated with a lower incidence of anxiety (7.2% vs 9.1%; P = .009) and depression (3.3% vs 5.1%; P < .001). Oral hormone therapy was associated with a significantly increased hazard of depression over time (hazard ratio, 1.30; 95% CI, 1.01–1.66; P = .038), although no difference was observed in the hazard of anxiety (hazard ratio, 1.10; 95% CI, 0.91–1.33; P = .33).
Lead author Liying Wei, from Drexel University College of Medicine, said, “It was exciting to find statistically significant results in our study, as these findings may help shape more individualized approaches to patient care in the future.”
The study did not find significant differences between oral and transdermal hormone therapy in the risks of obesity, cardiovascular disease, or Alzheimer’s disease. These findings highlight that the primary variation between administration routes may lie in their effects on mental health rather than cardiometabolic or neurodegenerative outcomes.
According to Xuezhi (Daniel) Jiang, MD, PhD, professor of Obstetrics and Gynecology at Drexel University College of Medicine and Reading Hospital at Tower Health, “As we designed this study, we specifically excluded women with established cardiovascular disease (CVD) risk factors such as diabetes, obesity, hyperlipidemia, hypertension, tobacco use, family history of heart disease, and premature menopause to create a CVD risk–free population at baseline. This approach allowed us to more clearly examine the differences between oral and transdermal hormone therapy in relation to CVD outcomes. While our findings suggest that transdermal estrogen may offer potential mental health advantages compared with oral formulations, these results should not be generalized to the broader postmenopausal population. Hormone therapy is not a one-size-fits-all treatment, and the choice of route of administration should be individualized and made through shared decision-making, particularly for women with a history of depression.”
The authors noted that the observed differences may stem from the pharmacokinetic profiles of the two formulations. Oral estrogen undergoes first-pass hepatic metabolism, which can alter lipid metabolism, inflammatory markers, and coagulation pathways, while transdermal estrogen bypasses hepatic processing, leading to distinct systemic effects. These physiological differences may influence risks for cardiometabolic, neuropsychiatric, and neurodegenerative disorders.
While the data suggest possible advantages of transdermal therapy in relation to mental health, the investigators emphasized that further prospective studies are needed to confirm these associations and guide clinical decision-making.
Stephanie Faubion, MD, MBA, medical director for The Menopause Society, added, “It’s important to recognize the need for individualized approaches when it comes to treating menopause symptoms. Fortunately, we have many choices for women when it comes to route of administration, dose, and formulation of hormone therapy, which makes it easier to personalize treatment.”
These findings reinforce the importance of considering the route of administration when prescribing menopausal hormone therapy, especially for women with preexisting or potential mental health concerns. Although transdermal estrogen may be associated with reduced incidence of anxiety and depression, therapy selection should remain individualized, balancing symptom relief, patient preferences, and comorbidities.
Further investigation into the neuropsychiatric effects of hormone therapy delivery methods may help refine treatment recommendations and improve quality of life for postmenopausal patients.
References
Get the latest clinical updates, case studies, and expert commentary in obstetric and gynecologic care. Sign up now to stay informed.
