Rheumatoid arthritis (RA) is a multifactorial disease in which both environmental and genetic factors play a role. Data also suggest that neuroendocrine factors are involved, I briefly summarize observations that support this hypothesis. RA is characterized by striking age-sex disparities, The incidence of disease in women increases steadily from the age of menarche to its maximal incidence around menopause. The disease is uncommon in men under age 45, but its incidence increases rapidly in older men and approaches the incidence in women. These observations strongly suggest that androgens play a major suppressive role, and, in fact, testosterone levels are depressed in most men with RA. Mechanistically, many data indicate that testosterone suppresses both cellular and humoral immune: responses, Dehydroepiandrosterone (DHEA), an adrenal product, is the major androgen in women. Its production is strikingly dependent upon age, Peak production is in the 2nd and 3rd decades, but levels decline precipitously thereafter. DHEA levels are low in both men and women with RA, and recent data show that levels of this hormone may be depressed before the onset of disease, The role of DHEA in immune diseases, however, is controversial. The menopausal peak of RA onset suggests estrogen and/or progesterone deficiency play a role in the disease, and many data indicate that estrogens suppress cellular immunity but stimulate humoral immunity, i.e., deficiency promotes cellular (Th1-type) immunity. Recent data also indicate that progesterone stimulates a switch for Th1 to Th2-type immune responses. RA often develops or flares in the postpartum period, particularly if the mother breastfeeds. This is again consistent with gonadal steroid deficiency playing a role in the onset of disease. Breastfeeding is associated with blunted hypothalamic-pituitary-adrenal function and elevated prolactin synthesis, Gonadal and adrenal steroid hormone deficiency, plus elevated prolactin, probably greatly facilitates the expression of Th1-type immunity, which is widely believed to be critical in the pathogenesis of RA, By contrast, RA typically remits during pregnancy, in parallel with the increasing levels of corticosteroids, estrogens, and progesterone. Pregnancy is characterized by a shift in immune function from Th1-type to Th2-type. Oral contraceptives, which generate a condition of pseudopregnancy, also decrease the risk of RA. These data argue that adrenal and gonadal steroid hormones suppress the development of RA. Several studies indicate that corticosteroid production is inappropriately low in patients with RA, and are reminiscent of observations in Lewis rat models of chronic erosive arthritis, In summary, a growing body of data indicate that RA develops as a consequence of a deficiency in both adrenal and gonadal steroid hormone production. This hypothesis clearly has potential clinical implications.
