A recent study published in Seminars in Arthritis and Rheumatism found that postmenopausal women with rheumatoid arthritis (RA) who had lower cumulative lifetime estrogen exposure (CLEE) experienced more severe disease, poorer patient reported outcomes, and a reduced likelihood of achieving remission. The findings highlight the potential influence of hormonal history on disease progression and therapeutic response in women with RA.
The study included 2,878 postmenopausal women with RA enrolled in the Korean Observational Study Network for Arthritis (KORONA) cohort, followed over five years. CLEE was calculated by combining each participant’s reproductive span from menarche to menopause and the duration of postmenopausal hormone replacement therapy. Using a median cutoff of 34 years, women were classified into higher and lower CLEE groups. At baseline, those in the lower CLEE group (n=1,602) showed significantly higher disease activity and greater radiographic joint erosions compared to women in the higher CLEE group (n=1,179). They also reported worse outcomes across multiple patient reported domains, including pain, fatigue, sleep disturbance, functional disability, health related quality of life, and global assessment of RA (all P<0.01).
Over the five year follow up, the lower CLEE group continued to exhibit a poorer disease trajectory, reflected by higher Simplified Disease Activity Index (SDAI) and Health Assessment Questionnaire Disability Index (HAQ DI) scores and lower EQ 5D utility values after adjustment for confounders. Among women with moderate to high disease activity (SDAI>11) at baseline, those with lower CLEE were significantly less likely to achieve remission (HR 0.597; 95% CI 0.421–0.848; p=0.004). The authors concluded that the duration of estrogen exposure had a meaningful impact on disease activity and longitudinal outcomes, suggesting a protective role of estrogen in the course of established RA.
Estrogen is known to play a complex immunomodulatory role, influencing T cell differentiation, B cell maturation, cytokine production, and osteoclast function. Experimental data show that estrogen promotes the activity of regulatory T cells while suppressing proinflammatory cytokines such as TNFα, IL6, and IL17, which are central mediators of inflammation and joint destruction in RA. The hormonal decline after menopause may therefore shift the immune system toward a proinflammatory profile, intensifying autoimmune responses and accelerating joint damage. Observational studies have previously shown that menopause is associated with worsening RA activity, increased pain scores, and reduced response to disease modifying antirheumatic drugs (DMARDs).
The current findings are consistent with results from the French E3N cohort study published in Joint Bone Spine, which examined 78,391 postmenopausal women and identified 637 validated incident RA cases. That study demonstrated that women with high lifetime estrogen exposure, summarized through a composite estrogen score that incorporated factors such as early menarche, higher parity, oral contraceptive and menopausal hormone therapy use, and later menopause, had a 63% lower risk of developing RA compared with those with low exposure (HR 0.37; 95% CI 0.2–0.8).
These studies strengthen the evidence that estrogen may exert a protective effect against both the onset and progression of rheumatoid arthritis. While hormone replacement therapy is not recommended solely for RA prevention or treatment due to associated cardiovascular and oncologic risks, understanding a patient’s hormonal and reproductive history could provide valuable insight into disease prognosis. Future research may explore selective estrogen receptor modulators or other therapeutic strategies that mimic estrogen’s immunoregulatory benefits while minimizing systemic risks.
These findings underscore the growing recognition that sex hormones influence not only the risk but also the severity and treatment outcomes of autoimmune diseases such as RA. Considering estrogen exposure as part of the clinical assessment of postmenopausal women may help clinicians tailor long term management strategies and improve quality of life in this population.
References
- Park EH, Choi ST, Song JS, Kang EH, Lee YJ, Ha YJ. Effects of cumulative lifetime estrogen exposure on the clinical characteristics and courses in postmenopausal women with rheumatoid arthritis. Semin Arthritis Rheum. 2025 Oct;74:152790.
- Salliot C, Nguyen Y, Gelot A, Mariette X, Boutron-Ruault MC, Seror R. Lifetime female hormonal exposure and risk of rheumatoid arthritis in postmenopausal women: Results from the French E3N cohort. Joint Bone Spine. 2022 Oct;89(5):105374.