Adrenal and gonadal steroid hormone deficiency in the etiopathogenesis of rheumatoid arthritis

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Adrenal and gonadal steroid hormone deficiency in the etiopathogenesis of

rheumatoid arthritis

Journal of Rheumatology (Canada), 1996, 23/SUPPL. 44 (10-12

Rheumatoid arthritis (RA) is a multifactonal 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-pitu itary-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 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.