The Hormonal Tug-of-War: Estrogen-Only Therapy and the Risk of Autoimmune Disease

By Rachael Robertson, Enterprise & Investigative Writer
October 23, 2026

The intricate relationship between sex hormones and the human immune system has long been a subject of intense scientific scrutiny. For millions of women entering menopause, hormone therapy (HT) serves as a vital tool to mitigate the vasomotor symptoms and physiological shifts that define this transitional period. However, a new study presented at the annual meeting of the Menopause Society suggests that the specific formulation of that therapy—whether it includes progestogen or consists of estrogen alone—may carry distinct implications for the development of autoimmune conditions.

The retrospective cohort study, led by researchers at Drexel University College of Medicine, found a statistically significant, albeit modest, increase in the incidence of autoimmune diseases among women utilizing estrogen-only therapy compared to those on combined estrogen-progestogen regimens. As clinicians continue to navigate the complexities of menopausal care, these findings offer a new variable to consider in the ongoing pursuit of personalized, risk-stratified medicine.

The Core Findings: A Closer Look at the Data

The study, spearheaded by medical student Hadia Saroya and Xuezhi (Daniel) Jiang, MD, PhD, analyzed data from more than 100,000 women aged 45 to 70 who were prescribed systemic menopausal hormone therapy. The primary goal was to determine whether the absence or presence of progestogen altered the trajectory of immune system health over time.

When comparing the two cohorts, the researchers observed that the incidence of composite autoimmune disease was 4.9% in women receiving estrogen-only therapy, compared to 4.5% in those receiving a combination of estrogen and progestogen. The hazard ratio (HR) of 1.076 (95% CI 1.015-1.141) with a P-value of 0.022 indicates a statistically significant difference.

Of the 20 distinct autoimmune conditions evaluated, five showed a significantly increased hazard for those on estrogen-only therapy. While the authors were careful to note that the absolute differences were small, the consistency of the signal across the data set warrants further investigation.

Chronology of the Research: From Retrospective Analysis to Clinical Query

The investigation utilized the TriNetX U.S. Collaborative Network, a massive, real-world database that allows researchers to sift through electronic medical records (EMR) to find correlations across large populations.

Selection and Matching: The researchers identified women aged 45 to 70 currently on systemic HT. To ensure a robust comparison, they applied stringent exclusion criteria, filtering out individuals with prior autoimmune diagnoses, histories of chemotherapy or immunotherapy, premature ovarian insufficiency, organ transplantation, HIV, or those using vaginal estrogen, which acts locally rather than systemically.
Propensity Score Matching: To mitigate bias, the study team matched the groups 1:1 based on demographic and medical characteristics, including whether the women had undergone a hysterectomy or experienced surgical menopause. This resulted in two balanced cohorts, each comprising 54,692 women.
Outcome Assessment: The primary endpoint was the development of composite autoimmune disease occurring 180 days or more after the initiation of hormone therapy. Follow-up durations were closely monitored and found to be comparable across both groups, ensuring that the observation period did not skew the results.

Expert Perspectives: Provocative Findings vs. Clinical Reality

The medical community’s reaction to the study has been characterized by a blend of intellectual curiosity and professional caution. Dr. Jiang, the study’s lead investigator, emphasized that the findings should not trigger panic or immediate changes in clinical practice.

"The clinical message is to encourage informed discussions and individualized care rather than immediate changes in treatment," Dr. Jiang stated in an interview with MedPage Today. He noted that the study’s architecture is fundamentally limited: it cannot establish whether either regimen increases or decreases risk relative to women who do not use hormone therapy at all.

The Role of Progesterone

Dr. Jiang pointed out that the scientific literature often treats "menopausal hormone therapy" as a monolithic category. However, he argues that this is a conceptual error. "Estrogen and progesterone influence immune function through entirely different mechanisms," he explained. "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."

The Call for Large-Scale Trials

Dr. JoAnn E. Manson, a prominent figure in the field and past president of the Menopause Society, echoed the need for temperance. "These findings are provocative but need replication and testing in large-scale randomized trials," Dr. Manson said.

She highlighted the historical inconsistency in this field. The Women’s Health Initiative (WHI), a landmark study in which Dr. Manson was a key investigator, notably found no significant difference in the risk of developing rheumatoid arthritis for women taking postmenopausal hormones compared to those taking a placebo. Furthermore, research on women with systemic lupus erythematosus (SLE) has shown that while hormone therapy might trigger mild-to-moderate flares, it does not necessarily increase the risk of severe, life-threatening complications.

Implications for Future Practice

As the population ages, the number of women requiring menopausal symptom management is expected to grow. Understanding the interplay between exogenous hormones and the immune system is therefore not merely academic; it is a public health necessity.

Why This Research Matters

Autoimmune diseases disproportionately affect women. Given that these conditions often emerge or exacerbate during the perimenopausal and postmenopausal years, identifying potential triggers—or protective factors—within hormonal regimens is essential. Stephanie Faubion, MD, MBA, medical director of the Menopause Society, noted that while this study is retrospective, it serves as a critical "jumping-off point."

"Studies like this are important to better inform future prospective studies," Dr. Faubion remarked in a press release. "We need to understand if the association is causative or if it is a result of underlying patient characteristics that we haven’t yet accounted for."

Limitations and Next Steps

The research team at Drexel acknowledged several inherent limitations:

Data Granularity: The TriNetX database, while expansive, lacks granular data regarding specific hormone dosages, the route of administration (e.g., transdermal patches versus oral pills), and the specific types of progestogens used.
Confounding Variables: As with any retrospective EMR study, there is the risk of residual confounding—variables that may influence both the decision to prescribe a specific therapy and the likelihood of developing an autoimmune disease.
The "No-Treatment" Gap: The study compares two types of treatment but does not establish a baseline against women who forgo hormone therapy entirely.

Future research, according to Dr. Jiang, must pivot toward prospective designs. Key areas for exploration include:

Formulation Differences: Distinguishing between natural micronized progesterone and synthetic progestins.
Timing and Age: Investigating whether the age at which a woman starts therapy—or the timing relative to the onset of menopause—alters the autoimmune risk profile.
Biological Susceptibility: Determining whether women with a family history of autoimmune disorders respond differently to specific HT regimens than those without.

Conclusion

The study presented by Saroya and Jiang adds a nuanced layer to the ongoing discussion regarding menopausal health. While the data suggests that estrogen-only therapy may carry a slightly higher risk of autoimmune emergence compared to combined therapy, the findings are currently preliminary. For the clinician in the exam room, the takeaway remains unchanged: prioritize individualized care, engage in shared decision-making, and remain vigilant in monitoring the evolving medical literature. As the field moves toward more robust, prospective research, women can feel empowered to discuss these risks with their healthcare providers, ensuring their path through menopause is as safe and symptom-free as possible.