Autoimmune Risk Differs by Menopausal Hormone Formulation

Estrogen Alone Shows a Modest Rise in Autoimmune Diagnoses

Systemic estrogen-only hormone therapy is associated with a slightly higher rate of composite autoimmune disease than combined estrogen and progestogen therapy. Researchers presented the findings at the 2026 Annual Meeting of The Menopause Society in San Diego.

The retrospective analysis reviewed medical records from nearly 110,000 menopausal women in the TriNetX United States (US) Collaborative Network. Across one-to-one propensity score matched cohorts, 4.9 percent of women on estrogen-only regimens developed an autoimmune condition compared to 4.5 percent on combined therapy.

That gap represents an 8 percent relative increase in hazard (hazard ratio [HR], 1.08; 95 percent confidence interval [CI], 1.02 to 1.14). The researchers tracked incident diagnoses that occurred 180 days or more after menopausal hormone therapy (MHT) initiation.

Specific Conditions Behind the Risk Gap

The elevated risk was concentrated in six individual conditions rather than distributed across every tracked disorder. The study monitored composite autoimmune disease alongside 20 specific conditions.

Women taking systemic estrogen alone had significantly higher hazards for systemic lupus erythematosus, rheumatoid arthritis, psoriasis, psoriatic arthritis, multiple sclerosis, and lichen sclerosus. Other evaluated autoimmune conditions showed no statistically meaningful differences between the two treatment groups.

Progestogen is routinely prescribed alongside estrogen to protect the uterine lining in women who retain a uterus. These findings suggest the addition of progestogen may also limit the composite autoimmune risk associated with unopposed systemic estrogen.

Small Absolute Differences in Clinical Context

The absolute difference in composite autoimmune risk between the two hormone regimens was 0.4 percentage points. Study authors noted that absolute event rates remained low across both cohorts.

Lead author Dr. Xuezhi Daniel Jiang, professor of obstetrics and gynecology at Drexel University College of Medicine, stated that the findings should be considered hypothesis-generating. Because the absolute risk difference is small, the results do not suggest an immediate clinical need to alter current prescription guidelines.

Dr. Stephanie Faubion, medical director for The Menopause Society, noted that autoimmune conditions are substantially more common in women than in men. Clarifying how different exogenous hormone regimens interact with immune function provides direction for future study design.

Observational Design and Study Limitations

Electronic health record analyses can identify statistical correlations, but they do not prove direct biological causation. While propensity score matching controls for recorded patient characteristics, unmeasured lifestyle or clinical differences may have influenced diagnosis rates.

The research evaluated systemic therapies as broad categories rather than isolating specific delivery routes, molecule types, or dosages. The study team highlighted that prospective trials are required to confirm these observations and examine the biological mechanisms involved.

Individuals considering or currently using hormone therapy for menopausal symptom management should talk to their clinician about personal autoimmune history and individual benefits and risks.