Female hormonal exposures and risk of rheumatoid arthritis in the French E3N-EPIC cohort study

Rheumatology (Oxford). 2021 Oct 2;60(10):4790-4800. doi: 10.1093/rheumatology/keab101.


Objective: To assess the relationships between female hormonal exposures and risk of RA in a prospective cohort of French women.

Methods: E3N (Etude Epidémiologique auprès des femmes de la Mutuelle générale de l'Education Nationale) is an on-going French prospective cohort that included 98 995 women aged 40-65 years in 1990. Every 2-3 years, women completed mailed questionnaires on their lifestyles, reproductive factors and health conditions. Cox proportional hazards regression models were used to determine factors associated with risk of incident RA, with age as the time scale, adjusted for known risk factors of RA, and considering endogenous and exogenous hormonal factors. Hazard ratios (HRs) and 95% CIs were estimated. Effect modification by smoking history was investigated.

Results: A total of 698 incident cases of RA were ascertained among 78 452 women. In multivariable-adjusted Cox regression models, risk of RA was increased with early age at first pregnancy (<22 vs ≥27 years; HR = 1.34; 95% CI 1.0, 1.7) and menopause (≤45 vs ≥53 years; HR = 1.40; 95% CI 1.0, 1.9). For early menopause, the association was of similar magnitude in ever and never smokers, although the association was statistically significant only in ever smokers (HR = 1.54; 95% CI 1.0, 2.3). We found a decreased risk in nulliparous women never exposed to smoking (HR = 0.44; 95% CI 0.2, 0.8). Risk of RA was inversely associated with exposure to progestogen only in perimenopause (>24 vs 0 months; multi-adjusted HR = 0.77; 95% CI 0.6, 0.9).

Conclusions: These results suggest an effect of both endogenous and exogenous hormonal exposures on RA risk and phenotype that deserves further investigation.

Keywords: female hormonal exposures; prospective cohort; rheumatoid arthritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Arthritis, Rheumatoid / etiology*
  • Contraceptives, Oral, Hormonal / adverse effects
  • Estrogen Replacement Therapy / adverse effects
  • Female
  • France / epidemiology
  • Humans
  • Maternal Age
  • Menopause
  • Menopause, Premature
  • Middle Aged
  • Parity
  • Proportional Hazards Models
  • Prospective Studies
  • Risk Factors
  • Smoking / adverse effects
  • Surveys and Questionnaires


  • Contraceptives, Oral, Hormonal