Women who used transdermal hormone therapy (HT) to treat menopausal symptoms experienced lower rates of anxiety and depression than those who used oral HT, found a study presented at The Menopause Society 2025 Annual Meeting.

The study joins other research presented at the conference that explored the complex findings on changes in mood with HT in perimenopausal and postmenopausal women.

“Mood symptoms can be really prevalent during the menopause transition, and oftentimes those are the things that are more disruptive to one’s quality of life than other symptoms,” commented Monica Christmas, MD, associate professor of obstetrics and gynecology and director of the Menopause Program at The University of Chicago Medicine, Chicago, and associate medical director for The Menopause Society.

“Existing evidence on the broader health impact of oral HT remains inconsistent, with most research focusing on cardiovascular outcomes rather than mental or cognitive health,” Liying Wei, medical student at Drexel University College of Medicine in Philadelphia, wrote in her study comparing women using oral vs transdermal HT. “Understanding the long-term associations between HT use and these diverse health outcomes is critical for informed decision-making and personalized care.”

Wei’s retrospective cohort study used data from the TriNetX database to compare 3844 women using transdermal HT to 3844 women using oral HT. The women were aged 46-60 years, and cohorts were matched based on age, ethnicity, race, other medications they were taking, and metabolic comorbidities. They were predominantly White (88%) and non-Hispanic (68%).

While no significant differences emerged between the groups’ rates of obesity, cardiovascular disease, or Alzheimer’s disease, fewer women using transdermal HT had anxiety (7.2%) or depression (3.3%) than those taking oral HT (9.1% and 5.1%, respectively). The hazard ratio (HR) was not significant in comparing anxiety rates, but depression likelihood was modestly higher in the oral HT group (HR, 1.3; 95% CI, 1.01-1.66).

“The modest absolute risk difference of 1.8% [in depression] may be clinically meaningful in long-term management,” Wei wrote.

“We think this may be attributed by oral therapy undergoing first-pass hepatic metabolism,” Wei told Medscape Medical News.

Senior author Xuezhi (Daniel) Jiang, MD, PhD, Ob/Gyn at Reading Hospital, West Reading, Pennsylvania, and professor of Ob/Gyn at the Drexel University College of Medicine, offered more details on a potential mechanism if later research finds a causal link.

“Transdermal estradiol delivers steady, physiological estradiol levels directly to systemic circulation, avoiding hepatic fluctuations, which may result in more stable neurosteroid and neurotransmitter modulation, reducing the risk of mood disturbance,” he said.

Christmas noted, however, that while some women may experience relief from mood changes while on HT, it is important to remember that it is not a first-line treatment for mood disorders.

“Many of the [mood] symptoms of menopause seem to come from fluctuations in hormone levels in late perimenopause and early postmenopause, and often, especially in the late postmenopause timeframe, hormone therapy may not be enough to stabilize hormones,” Christmas said. “If someone comes back and says my hot flashes are better, my night sweats are gone, I’m sleeping better, but I’m still feeling anxious or down or irritable, then they need to be treated with first-line treatment for mood disorder.”

Jiang also emphasized that the findings did not suggest an increased risk for depressive symptoms in women using oral HT and that HT overall may be associated with a lower risk for depression than not using HT.

“While possible, transdermal rather than oral could be considered while we await further evidence on the subject. Emerging evidence suggests that transdermal has other proven benefits compared with oral route,” Jiang said.

The findings add to the growing research trying to understand how menopausal HT interacts with mood symptoms that frequently occur during menopause.

“Prior research on the mood effects of [menopausal] HT has yielded mixed results, with some studies demonstrating benefit in perimenopausal but not postmenopausal populations, and others showing neutral outcomes in both,” Samantha Fairweather, medical student at the NYU Grossman School of Medicine in New York City, wrote in one of the other research posters presented.

Fairweather’s research found improvements in depressive symptoms, anxiety, and irritability among women at a single institution who started menopausal HT for the first time. The 275 women in that retrospective longitudinal study were an average 52 years old, and nearly all of them (96.7%) used transdermal estrogen HT. About half (51%) had a history of anxiety or depression in their records, and 13% had also been prescribed a low-dose selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor at their first visit.

The women completed the Menopause Rating Scale (MRS) before starting HT and at a follow-up visit. Fairweather assessed changes specifically in the psychological subdomain of the MRS — asking about depressive mood, irritability, anxiety, and physical and mental exhaustion — at baseline and follow-up.

While 61.1% of patients reported “severe” symptoms (a score of at least 7) at baseline, that proportion had dropped to 25.8% at follow-up (P < .001). The women starting with severe symptoms showed the greatest improvement while those who reported moderate and low symptoms at baseline showed more modest improvements (-3.7 score change compared to -0.88 and -0.24, respectively).

“This effect was independent of a prior diagnosis of anxiety or depression, suggesting that menopausal HT may be effective in improving mood regardless of psychiatric history,” Fairweather and her colleagues wrote.

Christmas said she would not make any changes to her management based on these findings, but she underscored the importance of doing more research on managing mood issues — whether with mood stabilizers, HT, lifestyle behavioral changes, cognitive-behavioral therapy, or other modalities.

Wei’s study was funded by the Drexel University College of Medicine Medical Student Summer Research Fellowship and the Drexel University Alumni Association. Fairweather’s study did not use external funding, and none of the authors had disclosures. Christmas has done lectures for FertilityIQ and had no other disclosures.

Tara Haelle is a science/health journalist based in Dallas.