Rheumatoid arthritis, or RA, strikes when the body’s immune system goes awry and attacks healthy joints. But some scientists and doctors have long suspected that this painful form of arthritis may also be linked to another of the body’s major biological systems—the endocrine system, which regulates hormones. That theory received a boost by recent research suggesting that the age at which a woman enters menopause—which is marked by a steep drop in production of the hormone estrogen—influences not only her risk for RA, but the severity of symptoms should she develop the disease.

However, the relationship between menopause and RA remains mysterious, as rheumatologists still aren’t quite sure how changes in levels of estrogen and other key hormones might influence risk for painful joints and other symptoms. “It’s like looking through smoked glass. You get a sense that there’s something behind there, but you can’t make out the shape or the form,” says David Goddard, MD, chief of rheumatology at SUNY/Downstate Long Island College Hospital, who has studied the link between the immune and endocrine systems.

Early menopause and RA

A few past studies have suggested that women who begin menopause early have an increased risk for developing RA. Those findings were confirmed last year by a team of Swedish researchers led by Mitra Pikwer, MD, of Lund University, in Lund, Sweden. Dr. Pikwer and her colleagues examined health records for 18,326 women and found that those who entered menopause at age 45 or younger were twice as likely to develop RA as women who began menopause later. (The average age when a woman has had her last menstrual period and enters menopause is 51.) 

As they dug deeper into the data, Dr. Pikwer and her team made an intriguing discovery, which they reported at the international rheumatology conference EULAR in Berlin in June. 

“Women with early menopause have a greater risk of developing RA, but the type of RA they get is more mild,” says Dr. Pikwer. In fact, various clinical tests found that women who developed RA who had entered menopause at a relatively young age had a roughly 50 percent reduced risk for developing a more severe form of RA that results in harder-to-treat symptoms and greater joint damage.

Why would early menopause be associated with a greater overall risk for RA, but at the same time protect against developing severe symptoms? Nobody knows, but Dr. Pikwer sees no contradiction in these trends. She points out that for some reason women who begin menopause at a young age have a high susceptibility for developing other autoimmune disorders, such as lupus. Dr. Pikwer speculates that the severe and milder forms of RA may be caused by distinct and separate biological mechanisms, and that women who enter menopause early may simply be more likely to develop the latter for reasons that aren’t well understood.

Contradictions

On the other hand, apparent contradictions abound when you examine the overall relationship between RA and estrogen. As a rule, scientists believe that estrogen stimulates autoimmune disorders. To wit: Women who have not reached menopause (meaning they still produce plenty of estrogen) are three times more likely than men to develop RA.Yet a massive study of more than 120,000 women found that the risk of developing RA among women peaks between the ages 50 and 54—which is when most women enter menopause and their estrogen levels drop. After age 60, women and men have roughly the same risk for developing RA. 

If disappearing estrogen is linked to RA, then one might suspect that restoring the hormone to youthful levels with hormone-replacement therapy (HRT) might prevent or relieve RA symptoms. But studies have not consistently shown that to be true. In fact, some research suggests that women using HRT have a higher risk for developing RA. (Doctors rarely prescribe HRT to women with RA, since the medication increases the risk for heart disease, which is already elevated in RA patients.)