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A retrospective study of more than 100,000 women using systemic menopause hormone therapy found a slightly higher incidence of autoimmune disease among those taking estrogen alone than among those taking estrogen with a progestogen. The absolute difference was small, the study cannot establish cause and effect, and researchers say the finding needs replication.
A retrospective study of 109,384 women using systemic menopause hormone therapy found a slightly higher incidence of autoimmune disease among those taking estrogen alone than among those taking estrogen with a progestogen. The difference was small, and the researchers said the findings do not show that either treatment causes or prevents autoimmune disease.
The study reported a composite autoimmune disease incidence of 4.9% in the estrogen-only group and 4.5% in the estrogen-progestogen group. The association was statistically significant (hazard ratio 1.076, 95% confidence interval 1.015–1.141; P=0.022), but the authors cautioned that the absolute difference may not be clinically meaningful.
Researchers examined 20 individual autoimmune diseases and reported statistically higher hazards for five in the estrogen-only group: systemic lupus erythematosus, psoriasis, psoriatic arthritis, multiple sclerosis and lichen sclerosus. Reported incidences were low. For example, multiple sclerosis occurred in 0.2% versus 0.1%, while psoriatic arthritis was 0.2% in both groups despite a higher estimated hazard in the estrogen-only group.
Medical student Hadia Saroya and Xuezhi (Daniel) Jiang, MD, PhD, of Drexel University College of Medicine presented the findings in a poster at the Menopause Society annual meeting. The team used the TriNetX U.S. Collaborative Network to identify women ages 45 to 70. After matching participants on demographic and medical characteristics, including hysterectomy and surgical menopause, each treatment group contained 54,692 women. Outcomes were assessed at least 180 days after therapy began.
A Small Difference, Not a Treatment Verdict
The findings highlight a possible difference between two commonly used forms of systemic hormone therapy, a distinction that studies treating hormone therapy as a single exposure may not capture. Estrogen-only therapy is commonly used after hysterectomy; estrogen-progestogen therapy is generally used when a patient needs endometrial protection. The results may prompt further study of whether the type of regimen is associated with autoimmune outcomes.
They do not provide a reason for patients to stop or change treatment on their own. The observed absolute difference was 0.4 percentage points, and the researchers did not compare hormone users with women taking no hormone therapy. The study therefore cannot determine whether either regimen raises or lowers autoimmune risk compared with no treatment. Treatment decisions should be discussed with a qualified health professional in light of an individual’s needs and medical history.
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How the Study Compared Regimens
The analysis was retrospective, meaning it used existing health-record data rather than assigning participants to treatments. Researchers excluded women with a prior autoimmune disease and those with several other factors, including chemotherapy or immunotherapy exposure, premature ovarian insufficiency, organ transplantation, HIV, or vaginal estrogen use. They compared systemic estrogen-only therapy with systemic estrogen-progestogen therapy.
The results add to a mixed research record. JoAnn E. Manson of Harvard Medical School, a past president of the Menopause Society, told MedPage Today that findings from the Women’s Health Initiative did not show a significant difference in rheumatoid arthritis risk or severity between women receiving postmenopausal hormone therapy or placebo. Manson also cited a randomized trial in women with lupus that found no increase in severe flares, though it reported a small risk of increased mild-to-moderate flares.
“The clinical message is to encourage informed discussions and individualized care rather than immediate changes in treatment.”
— Xuezhi (Daniel) Jiang, MD, PhD, speaking to MedPage Today
Limits of the Available Evidence
Because the study was retrospective, it can identify an association but cannot establish that estrogen-only therapy caused the higher incidence. Residual confounding may remain despite matching, and diagnoses in electronic medical records may have been misclassified. The study also lacked information on route of administration, dosage, and specific estrogen or progestogen formulations.
The report does not establish whether the result applies to all patients or treatment regimens. It also cannot say how hormone therapy compares with no hormone treatment, or whether the associations vary by age, timing of therapy, type of menopause, or underlying autoimmune susceptibility. The small absolute differences mean the clinical importance remains uncertain.
Prospective Studies Could Clarify Risk
The researchers described the analysis as a starting point for prospective research. Future studies could compare hormone therapy with no treatment and examine whether outcomes differ between natural micronized progesterone and synthetic progestins, as well as by age, treatment timing, surgical versus natural menopause, and pre-existing susceptibility to autoimmune disease.
Large-scale randomized trials would offer stronger evidence about cause and effect, although the current report does not specify a trial or timeline. For now, the study’s authors and outside experts say the result should inform research and individualized discussions, not prompt immediate treatment changes.
Key Questions
What did the study find?
Among systemic hormone therapy users, composite autoimmune disease incidence was 4.9% with estrogen-only therapy and 4.5% with estrogen-progestogen therapy. The retrospective comparison found a small association, not proof that treatment caused the difference.
Which conditions had higher reported hazards with estrogen-only therapy?
The researchers reported statistically higher hazards for systemic lupus erythematosus, psoriasis, psoriatic arthritis, multiple sclerosis and lichen sclerosus. The reported incidences were low, and the study does not establish causation.
Does this mean patients should stop estrogen-only therapy?
No. The study authors said the findings support informed, individualized discussions rather than immediate treatment changes. Anyone considering a change should speak with a qualified health professional.
Can the study show whether hormone therapy increases autoimmune risk compared with no treatment?
No. It compared estrogen-only therapy with estrogen-progestogen therapy and did not establish how either regimen compares with no hormone therapy.
What are the main limitations?
The retrospective design cannot establish cause and effect, and electronic health records may contain misclassified diagnoses or leave residual confounding. Researchers also lacked data on treatment route, dose and specific hormone formulations.
Source: rss
