Type of Menopause Hormone Therapy Tied to Small Autoimmune Disease Risk

— Estrogen-only therapy singled out in retrospective study

Estrogen-only menopausal hormone therapy was associated with a slightly higher incidence of autoimmune disease compared with estrogen-progestogen therapy, a retrospective cohort study suggested.

Among over 100,000 women taking systemic menopausal hormone therapy, the incidence of composite autoimmune disease was 4.9% with estrogen-only therapy versus 4.5% with estrogen-progestogen therapy (HR 1.076, 95% CI 1.015-1.141, P=0.022), reported medical student Hadia Saroya and Xuezhi (Daniel) Jiang, MD, PhD, of Drexel University College of Medicine in Philadelphia, in a poster presentation at the Menopause Societyopens in a new tab or window annual meeting.

Of the 20 individual autoimmune diseases assessed, there were significantly increased hazards for five:

• Systemic lupus erythematosus: 0.3% vs 0.2% (HR 1.332, 95% CI 1.033-1.718)
• Psoriasis: 0.8% vs 0.7% (HR 1.160, 95% CI 1.008-1.336)
• Psoriatic arthritis: 0.2% vs 0.2% (HR 1.430, 95% CI 1.078-1.897)
• Multiple sclerosis: 0.2% vs 0.1% (HR 1.693, 95% CI 1.206-2.377)
• Lichen sclerosis: 0.6% vs 0.5% (HR 1.192, 95% CI 1.012-1.403)

While statistically significant, the absolute differences were small and may not be clinically meaningful, the authors noted.

"The clinical message is to encourage informed discussions and individualized care rather than immediate changes in treatment," Jiang told MedPage Today, noting that this study "does not establish whether either regimen increases or decreases risk relative to women who do not use hormone therapy."

Much of the existing literature on autoimmune disease risk considers menopausal hormone therapy as a single exposure, Jiang explained. However, estrogen and progesterone influence immune function through different mechanisms.

"We hope these findings will stimulate greater dialogue between menopause specialists, rheumatologists, and other healthcare professionals about the complex relationship between sex hormones and immune function," he said.

JoAnn E. Manson, MD, MPH, DrPH, of Harvard Medical School in Boston and past president of the Menopause Society, told MedPage Today that "these findings are provocative but need replication and testing in large-scale randomized trials."

"The effects of menopausal hormone therapy on the immune system are complex and inconsistent in previous studies," she pointed out.

For instance, data from the pivotal Women's Health Initiative (WHI) study, for which Manson was an investigator, didn't show a significant differenceopens in a new tab or window in the risk of developing rheumatoid arthritis or the severity of the disease between women taking postmenopausal hormone therapy or placebo. Another randomized trialopens in a new tab or window of women with lupus found that hormone replacement therapy didn't increase the risk of severe flares, though it was associated with a small risk of increasing mild to moderate flares.

Stephanie Faubion, MD, MBA, medical director of the Menopause Society, noted in a press releaseopens in a new tab or window that studies like this one "are important to better inform future prospective studies investigating the association of hormone therapy with risk of autoimmune diseases, which are more common in women than in men."

For this study, the researchers sought to compare the incidence of autoimmune diseases among women receiving systemic estrogen-only therapy or estrogen-progestogen therapy. Combined estrogen-progestogen therapy is generally used in women who require endometrial protection, while estrogen-only therapy is commonly used following hysterectomy.

Saroya and Jiang used the TriNetX U.S. Collaborative Network to identify women ages 45 to 70 on systemic menopausal hormone therapy. Those with prior autoimmune disease, chemotherapy or immunotherapy exposure, premature ovarian insufficiency, organ transplantation, HIV, or vaginal estrogen use were all excluded.

Women were propensity score-matched 1:1 on demographic and medical characteristics, including hysterectomy and surgical menopause. Each group included 54,692 women.

The primary outcome was composite autoimmune disease assessed ≥180 days after hormone therapy initiation, as well as 20 individual autoimmune diseases. Follow-up duration was comparable between groups.

Jiang noted limitations to their study, including its retrospective nature, risk of residual confounding, and the possibility for misclassification within electronic medical record data. TriNetX also did not have available data on the hormone therapy route of administration, dosage, and specific estrogen or progestogen formulations.

This study is a jumping-off point for future prospective research, he emphasized, which should explore whether menopausal hormone therapy increases autoimmune disease risk compared with no treatment. It's also worth investigating whether natural micronized progesterone and synthetic progestins have different results, and if the observed associations differ by age, timing of initiation, surgical versus natural menopause, and underlying autoimmune susceptibility.