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British women whose capability of bearing children either started late or ended early -- naturally or otherwise -- were at increased risk for developing rheumatoid arthritis (RA), compared with women with earlier menarche or later menopause, researchers found.

In an analysis of more than 220,000 female participants in the , those with menarche after age 14 were 13% more likely than those with menarche at age 13 to ultimately receive an RA diagnosis (95% CI 2%-26%), according to Hai-Feng Pan, MD, of Anhui Medical University in China, and colleagues.

And those beginning menopause before age 45 were 46% more likely to develop RA compared with women experiencing it at ages 50-51, the researchers .

Age 13 for menarche and 50-51 for menopause were chosen to serve as the respective references because they were the medians in the Biobank sample. There were no significant associations with RA risk for other menarche/menopause ages besides those given above, when statistics were adjusted for 12 covariates including age, affluence, certain comorbidities, smoking and alcohol drinking status, body mass index, and physical activity.

Pan and colleagues found that early-onset menopause because of oophorectomy or hysterectomy also appeared to raise RA risk (by 21% and 40%, respectively), as did peri- or postmenopausal hormone replacement therapy (by 46%). But use of hormonal oral contraceptives had no effect on RA rates.

Overall, women with fewer than 33 reproductive years were 39% more likely to develop RA than those with 38-39 (also the Biobank median). It was the only group stratified in this way to show even a hint of association with RA risk.

Because women comprise around three-quarters of all RA cases, it's long been assumed that female biology and, specifically, reproductive hormones play a prominent role. Pan's group said their study supports that view, but unfortunately it sheds little new light on the exact mechanisms. Their best guess was that estrogen -- particularly its lack prior to menarche and after menopause -- is a major driver of RA. Pan and colleagues noted other research suggesting that estrogen "seems to support regulatory T cells and TH2 cell-associated cytokine production," whereas low levels following menopause "lead to chronic activation of the immune system, altering cytokines and immune cell profiles, directly or indirectly affecting the phenotype of fibroblast-like synoviocytes, osteoblasts or osteoclasts, and thereby damaging the skeletal system." (This same pathway is often cited as the basis for age-related osteoporosis.)

This is not the first time that researchers have looked at menarche and/or menopause in relation to RA development. However, earlier studies came to different conclusions, particularly with regard to menarche: Pan and colleagues cited two case-control studies that suggested "early menarche is a protective factor," whereas a Nurses' Health Study analysis found the opposite.

As well, previous research yielded conflicting results on the degree to which pregnancies might increase or decrease RA risk. Pan's group felt that this somewhat confusing landscape meant that further exploration in a large, well-managed prospective cohort could be fruitful.

The U.K. Biobank project enrolled more than half a million men and women from 2006 to 2010, gathering extensive health and socioeconomic data at baseline; participants' subsequent medical outcomes were tracked via records in Britain's National Health Service (NHS). The latter was a potential limitation to the new study, in that Britons can receive care outside the NHS either through private insurance or paying out of pocket. RA diagnoses made in private clinics might therefore not be seen in NHS records. Also, Biobank participants tended to be more affluent with a higher percentage of whites than the general British population, and probably not representative of other countries' populations either. There remains, too, the possibility of unmeasured confounders.

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