Early Menopause Significantly Increases Risk of Developing RA

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Entering menopause prior to age 45 was associated with a 46% increased risk of developing RA compared with those who began menopause at ≥50 years.

Hormonal and reproductive factors, including beginning menarche at >14 years, having ≥4 children, and undergoing a hysterectomy, were associated with a higher risk of developing rheumatoid arthritis (RA), according to a study published in Rheumatic and Musculoskeletal Diseases.1 Investigators believe these factors, among others, should be considered when evaluating risk and creating management plans in female patients with RA.

Considerable efforts have been taken to better understand the individual variables of the condition, with some showing evidence RA may be sex-based, as women aged <50 years are 4 — 5 times more likely to develop the condition compared with male counterparts and the progression of the disease is adverse in females compared with males. This has led researchers to believe hormonal and reproductive factors may play a role in both the development of RA as well as disease outcomes.2

“While there is a wealth of literature linking hormonal and reproductive factors to an increased risk of RA, female-specific hormonal and reproductive factors and the gender differences in RA present a burgeoning research path that, to our understanding, has not been entirely explored,” wrote Hai-Feng Pan, MD, Department of Epidemiology and Biostatistics, Anhui Medical University School of Public Health, Hefei, China, and colleagues.

Data from a large cohort comprised of 223,526 patients extracted from the UK Biobank were used to examine the relationship between these factors and the risk of developing RA. The potential risk was evaluated using restricted cubic spline and hazard ratios (HRs) were determined using Cox proportional hazard regression.

During a follow-up period of a median of 12.39 years, 3313 women (1.5%) with RA were identified. At baseline, the mean age of female patients was 56 years and the mean age at menarche was 13 years. Most (85%) had reported being pregnant ≥1 times.

According to results, female patients who began menarche after the age of 14 years had a 17% higher risk of developing RA when compared with those who started menstruation at age 13 (HR 1.13, 95% confidence interval [CI] 1.02 — 1.26). Additionally, entering menopause prior to age 45 was associated with a 46% increased risk compared with those who began menopause at ≥50 — 51 years.

Additionally, patients with <33 reproductive years, which was defined as the time between beginning menstruation and entering menopause, had an increased risk of developing the condition compared with those with ≤33 reproductive years (HR 1.39, 95% CI 1.21 — 1.59). The risk was also higher in women with ≥4 children when compared with those with 2 children (HR 1.18, 95% CI 1.04 — 1.34).

Patients who underwent a hysterectomy or oophorectomy had a higher risk of developing RA compared with those who did not (HR 1.40, 95% CI 1.25 — 1.56; HR 1.21, 95% CI 1.08 — 1.35, respectively). Both hormone replacement therapy (HRT) use and duration were also demonstrated to increase RA risk (HR 1.46, 95% CI 1.35 — 1.57; HR 1.02, 95% CI 1.01 — 1.03, respectively).

The use of a large population-based cohort, coupled with a minimized risk of bias due to its retrospective design, were considered strengths of the study. However, investigators noted a few limitations, including collecting some self-reported data, which may have led to potential measurement error. Additionally, most patients in the UK Biobank cohort were relatively healthy, affluent, and White, making generalizability to other groups difficult to determine. Lastly, unadjusted confounders may exist despite careful efforts to adjust for strongly influential confounders.

“The findings of this study are significant and form a basis on which novel and target-specific intervention measures to curb the risk of RA in women may be developed,” investigators concluded. “Future studies should investigate the involvement of female hormones in the pathophysiology of RA.”


  1. Jiang L-Q, Zhang R-D, Musonye HA, et al. Hormonal and reproductive factors in relation to the risk of rheumatoid arthritis in women: a prospective cohort study with 223 526 participants. RMD Open 2024;10:e003338. doi:10.1136/ rmdopen-2023-003338
  2. Alpízar-Rodríguez D, Pluchino N, Canny G, et al. The role of female hormonal factors in the development of rheumatoid arthritis. Rheumatology (Oxford) 2017;56:1254–63.