Autoimmune Disease Risk After HT: Clinical Insights From a Large Real-World Study

Hormone therapy (HT) remains a cornerstone treatment for managing menopausal symptoms, but emerging research is revealing new considerations for clinical practice. A recent study presented at The Menopause Society's annual meeting found an unexpected association between hormone therapy and increased autoimmune disease risk in postmenopausal women.

In this exclusive interview, Patient Care spoke with study author Xuezhi (Daniel) Jiang, MD, PhD, professor of obstetrics and gynecology at Drexel University College of Medicine and a practicing OBGYN at Reading Hospital Tower Health in Pennsylvania. Jiang discusses his team's analysis of the TriNetX database, which revealed increased risk across 15 of 17 autoimmune diseases studied among postmenopausal women using hormone therapy.

Despite these findings, Jiang, a self-described hormone therapy advocate, emphasizes that these results should raise clinical awareness rather than trigger hormone therapy phobia. He provides guidance on shared decision-making, identifies potential high-risk populations, and explains why further research is needed before changing clinical practice.

PCO: What led you to investigate the connection between hormone therapy and autoimmune disease risk in postmenopausal women?

Xuezhi (Daniel) Jiang, MD, PhD: As we know, autoimmune disease affects women disproportionately. Some literature reports that women had a fourfold higher risk of developing autoimmune disease than men. Menopausal transition also increases the risk of developing autoimmune disease. My original thought was, thinking about why menopausal transition increases the risk of developing autoimmune disease, most likely because of hormone change—maybe decline of estrogen level. So then I'm thinking, what if starting hormone therapy, replacing this estrogen, is that going to potentially improve or reduce incidence of autoimmune disease in postmenopausal women? Is that possible or not? That's why I started looking into this through the TriNetX database, which is a global health network that provides secure, real-time access to deidentified patient data. That's a very large database. That's the reason—I just wanted to look at whether hormone therapy can either reverse the course of autoimmune disease pathway in postmenopausal women or somehow alleviate the symptoms of autoimmune disease. This study is just the beginning of my exploration, or my team's adventure. We probably want to look at a prospective study to further validate our findings.

PCO: Great, and what were the main findings from your research?

Jiang: It's really surprising. We found actually increased risk, rather than decreased risk, of developing autoimmune disease after postmenopausal women start taking hormone therapy. Initially, when we looked at the result, it was kind of shocking, because that increased risk is across the whole spectrum of autoimmune disease, including 17 diseases. I have a long list of autoimmune disease—rheumatoid arthritis, thyroiditis, and many autoimmune diseases you probably have heard of, or maybe you're not even aware of. Among the 17 autoimmune diseases, 15 showed increased risk after postmenopausal women taking hormone therapy. That risk also increased as the time of exposure expanded. We looked at five years, 10 years, and 20 years after menopause or after hormone therapy. The risk of developing autoimmune disease increased over that time window. Twenty years is the maximum follow-up time in the TriNetX database. The risk we can see increasing, but not dramatically. For example, from 5.6% over five years, and then 10 years is 7.1%, and then 20 years, maybe 8% or 9.2%, something like that. It's not like a dramatic jump. Those are our findings, showing absolutely—it's amazing. We're seeing HT, even though my intention was trying to see benefit of HT in this disease population, but actually it's the opposite. It's kind of shocking. I'm still trying to find the explanation for the potential underlying mechanism.

PCO: How should primary care physicians, our audience, and OBGYNs like yourself, weigh these autoimmune risks against the benefits of hormone therapy when counseling postmenopausal patients?

Jiang: That's an awesome question. First of all, seeing this study's findings—I'm a menopausal practitioner, I'm a hormone therapy advocate. I still believe hormone therapy is a safe option for many women if you use it appropriately. But when I see this finding, even though I was shocked initially, I still believe the provider should take this information more like an awareness rather than a cause of hormone therapy phobia. We don't want that to happen. I think many women are miserable, and they're supposed to take hormone therapy to relieve their menopausal symptoms. But a lot of providers are hesitating or they're afraid of prescribing hormone therapy, even though they're facing the good candidate, the appropriate candidate to do it, because they have hormone therapy phobia. With these findings, I really don't want to see that happen, because right now we do need a prospective study to confirm these findings.

Also, we want to look at in the future what specific population and who may be at high risk of developing autoimmune disease in postmenopausal women. For example, a woman with family history of autoimmune disease, or some women already have personal autoimmune disease diagnosed before menopause—that could be a high-risk population. The provider may need to take precaution when they prescribe hormone therapy and may need to have shared decision-making. Talk to patients about risk-benefit. If they're miserable, maybe you can still try hormone therapy, but clinical vigilance is key, rather than routine monitoring or not monitoring, routine screening. Clinical vigilance, focus on the symptoms, and give patient education. Tell patients what are likely symptoms of autoimmune disease—arthralgia, skin rashes, fatigue, other things. I think that's important for providers to know, to be aware of this piece of information. Not to go extreme. Don't go extreme. Hormone therapy is not one size fits all. It's not for everyone. It's safe, but you have to take an individualized approach. That's all I want to say. Right now it's too premature to say, "Oh, hormone therapy is bad. It can increase risk of autoimmune disease, and don't use it for the postmenopausal woman." I think that's really premature. The provider just needs to know it's not good for everyone and know what's a high-risk population and start from there when you prescribe hormone therapy and can help them to counsel patients based on their history.

PCO: You mentioned the limitations of your study, but what research is needed to further guide clinical practice?

Jiang: It's hard to do randomized control studies on this one, but prospective study is the way to go. Also, even retrospective studies—multicenter, large datasets where investigators can access individual data. The TriNetX database, one limitation is that you're not able to access individual data. You probably can, but you have to go through a long approval process. With individual data available, it's much easier for investigators to look into the patient's history and confounding factors. When you do the analysis, you can make probably more robust adjustments for those confounding factors. More study—bottom line, we need more study to confirm, because this, to my best knowledge, is probably, if not the first one, very much the beginning of this subject. We just started looking at this.

This transcript has been lightly edited for clarity and flow.