A large TriNetX analysis found hormone therapy use in postmenopausal women was linked to a higher incidence of autoimmune diseases.
In a TriNetX analysis of nearly 1.8 million postmenopausal women, hormone therapy use was linked to a higher incidence of autoimmune diseases.
Increased risks were seen for most autoimmune conditions except Graves’ disease and autoimmune hepatitis.
Authors emphasized the need for further research and individualized hormone therapy decisions while reaffirming its safety when appropriately used.
Autoimmune diseases disproportionately affect women, with incidence patterns shifting after menopause and suggesting a potential role of sex hormones in immune regulation. A new large-scale analysis presented at The Menopause Society’s 2025 Annual Meeting, held October 21–25 in Orlando, Florida, found a significantly higher incidence and risk of developing autoimmune diseases in postmenopausal women who used hormone therapy compared with those who did not.1,2
Hormone therapy remains the most commonly used and effective treatment for managing a range of menopause-related symptoms, including vasomotor symptoms such as hot flashes. However, the relationship between hormone therapy and the development of autoimmune diseases in postmenopausal women has remained unclear.
The study, “Association of Hormone Therapy with Autoimmune Disease Risk in Postmenopausal Women: A TriNetX-Based Analysis,” analyzed health data from the TriNetX Global Health Research Network within the US Collaborative Network. Investigators identified adult females with ICD-10 codes indicating menopause (N95, Z78.9, or E28.31) and compared those prescribed estrogen (VA class HS300) after menopause diagnosis (the hormone therapy cohort) with women without estrogen use (the non-hormone therapy cohort).
After excluding women with a prior diagnosis of any of 17 predefined autoimmune diseases, the researchers analyzed a total of nearly 1.8 million postmenopausal women. Each cohort included 889,413 women with a mean age of 60.5 years. Propensity score matching was performed to balance baseline characteristics such as age, ethnicity, and comorbidities, including obesity, type 2 diabetes, essential hypertension, and major depressive disorder.
Compared with non-users, hormone therapy users had a higher incidence of autoimmune disease at multiple time points—6.7% vs 5.3% at 5 years, 8.6% vs 6.7% at 10 years, and 9.0% vs 7.1% across the full postmenopausal period. Hormone therapy use was significantly associated with increased risk of developing any autoimmune disease at 5 years (risk ratio [RR] 1.29; 95% CI, 1.27–1.30; P < .0001), 10 years (RR 1.28; 95% CI, 1.27–1.29; P < .0001), and overall (RR 1.27; 95% CI, 1.25–1.28; P < .0001). The hazard of developing an autoimmune disease over the full follow-up period was also elevated among hormone therapy users (hazard ratio 1.33; 95% CI, 1.32–1.35; P < .001).
When evaluating 17 individual autoimmune diseases, statistically significant increases in risk were observed for all except Graves’ disease and autoimmune hepatitis, with risk ratios ranging from 1.03 for psoriasis to 2.90 for lichen sclerosis.
“Our study found a statistical link between hormone therapy and autoimmune diseases, but the actual increase in absolute risk is relatively small and varies by condition. Because this was a retrospective database study, more research is needed before drawing firm conclusions. Hormone therapy remains a safe and important option for many women when used appropriately, but like any treatment, it should be individualized while we await more research on its possible links to autoimmune disease,” said Xuezhi (Daniel) Jiang, MD, PhD, professor of obstetrics and gynecology at Drexel University College of Medicine and lead author.
Autoimmune diseases have been increasing globally, and women remain the primary population affected. Prior studies have suggested that women may have up to a fourfold higher risk of being diagnosed with an autoimmune disease compared with men. Environmental factors, stress, and hormonal influences have all been implicated, though the mechanisms underlying these associations remain uncertain.
These findings underscore the need for further prospective studies to confirm the associations and clarify potential mechanisms and timing of autoimmune disease onset in women receiving hormone therapy. According to Jiang and colleagues, such research will be critical to guide individualized risk–benefit discussions in menopause care.
“Since more and more women are affected by autoimmune diseases, it's important to consider all potential associations,” said Stephanie Faubion, MD, medical director for The Menopause Society. “That's why we continue to recommend that healthcare professionals take a very individualized approach when prescribing hormone therapy. Although hormone therapy continues to be the first-line therapy for managing menopause symptoms, it is not for everyone.”
The study adds to ongoing discussions about the safety and long-term effects of hormone therapy use in postmenopausal women. As clinicians balance the benefits of symptom relief with emerging data on autoimmune risk, individualized patient assessment remains central to optimizing menopause management.
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