A recent study conducted by researchers from Anhui Medical University in China has shown that British women who experience late menarche or early menopause are at an increased risk of developing rheumatoid arthritis (RA). The study, which analyzed data from over 220,000 female participants in the U.K. Biobank project, found that women with menarche after the age of 14 were 13% more likely to receive an RA diagnosis compared to those with menarche at age 13. Additionally, women who began menopause before the age of 45 were 46% more likely to develop RA compared to those who experienced it at ages 50-51. These findings illustrate the significant impact that reproductive factors can have on a woman’s susceptibility to RA.
The researchers chose the ages of 13 for menarche and 50-51 for menopause as the respective references in their analysis because they were the medians in the Biobank sample. They found no significant associations between RA risk and other menarche or menopause ages when adjusting for various covariates, including age, affluence, comorbidities, smoking and alcohol consumption, BMI, and physical activity. However, the study did suggest that early-onset menopause due to oophorectomy or hysterectomy, as well as peri- or postmenopausal hormone replacement therapy, were associated with an increased risk of RA. Surprisingly, the use of hormonal oral contraceptives had no effect on RA rates. These findings further emphasize the complex relationship between reproductive factors and RA risk.
The study conducted by Pan and colleagues provides support for the long-held belief that female biology and reproductive hormones play a significant role in the development of RA. However, the exact mechanisms underlying this association remain unclear. The researchers hypothesize that estrogen, especially its deficiency before menarche and after menopause, may be a major driver of RA. Estrogen is thought to support regulatory T cells and TH2 cell-associated cytokine production, whereas low levels following menopause can lead to chronic activation of the immune system and alterations in cytokines and immune cell profiles. These changes may directly or indirectly affect the phenotype of cells in the skeletal system, potentially leading to damage and inflammation characteristic of RA. The same pathway has also been implicated in age-related osteoporosis.
Previous studies examining the relationship between menarche, menopause, and RA risk have yielded conflicting results, which adds to the complexity of this topic. Some case-control studies have suggested that early menarche may be a protective factor against RA, while others have found the opposite. The Nurses’ Health Study, for example, reported conflicting findings regarding the impact of menarche on RA risk. Similarly, research on the influence of pregnancy on RA risk has produced conflicting results. Given this apparent contradiction in the literature, Pan and colleagues believed that further investigation in a large prospective cohort, such as the U.K. Biobank project, was necessary to provide more clarity on the relationship between reproductive factors and RA risk.
The U.K. Biobank project, which enrolled over half a million men and women between 2006 and 2010, collected extensive health and socioeconomic data at baseline and tracked participants’ subsequent medical outcomes using records from Britain’s National Health Service (NHS). However, the reliance on NHS records may have limited the study’s findings, as RA diagnoses made in private clinics would not be captured. Additionally, the Biobank participants were more affluent and had a higher percentage of white individuals compared to the general British population. Therefore, the findings may not necessarily be generalizable to other populations or countries. Furthermore, there is always a possibility of unmeasured confounders that could influence the observed associations.
The study conducted by Pan and colleagues sheds light on the relationship between menarche, menopause, and the risk of developing rheumatoid arthritis among British women. The findings emphasize the importance of reproductive factors in the pathogenesis of RA, with late menarche and early menopause being associated with an increased risk. However, further research is necessary to elucidate the exact mechanisms underlying this association and to explore potential interventions that could reduce the risk of developing RA in vulnerable populations of women.