Inflammation and Sex Hormone Metabolism

Abstract

The incidence of autoimmune diseases is higher in females than in males. In both sexes, adrenal hormones, that is, glucocorticoids, dehydroepiandrosterone (DHEA), and androgens, are inadequately low in patients when compared to healthy controls. Hormonally active androgens are anti-inflammatory, whereas estrogens are pro-inflammatory. Therefore, the mechanisms responsible for the alterations of steroid profiles in inflammation are of major interest. The local metabolism of androgens and estrogens may determine whether a given steroid profile found in a subject's blood results in suppression or promotion of inflammation. The steroid metabolism in mixed synovial cells, fibroblasts, macrophages, and monocytes was assessed. Major focus was on cells from patients with rheumatoid arthritis (RA), while cells from patients with osteoarthritis served as controls. Enzymes directly or indirectly involved in local sex steroid metabolism in RA are: DHEA-sulfatase, 3beta-hydroxysteroid dehydrogenase, 17beta-hydroxysteroid dehydrogenase, and aromatase (CYP19), which are required for the synthesis of sex steroids from precursors, 5alpha-reductase and 16alpha-hydroxylase, which can be involved either in the generation of more active steroids or in the pathways leading to depletion of active hormones, and 3alpha-reductase and 7alpha-hydroxylase (CYP7B), which unidirectionally are involved in the depletion of active hormones. Androgens inhibit aromatization in synovial cells when their concentration is sufficiently high. As large amounts of estrogens are formed in synovial tissue, there may be a relative lack of androgens. Production of 5alpha-reduced androgens should increase the local anti-inflammatory activity; however, it also opens a pathway for the inactivation of androgens. The data discussed here suggest that therapy of RA patients may benefit from the use of nonaromatizable androgens and/or the use of aromatase inhibitors.

Selective conversion by microglia of dehydroepiandrosterone to 5-androstenediol—A steroid with inherent estrogenic properties

“…This supports our findings with mouse microglial (BV2) cells showing a limited activity of 3␤-HSD/KSI, which is the rate-limiting enzyme for androgen (AD and T) synthesis [32]. This bi-functional enzyme responsible for the oxidation and isomerization of 5 -3␤-hydroxysteroid precursors into 4 -ketosteroids catalyzes the essential steps in the formation of most classes of active steroid hormones [33].…”

Are there reasons why adult asthma is more common in females?

“…Interestingly, the sex of the fetus being carried may influence the effect pregnancy has on the severity of asthma. Androgens have been shown to have anti-inflammatory effects [17] and spillover from a male fetus may protect the mother. Several studies have found that women pregnant with a female fetus are more likely to have increased symptoms during pregnancy than women pregnant with a male fetus [18•], although this does not appear to lead to more emergency department visits, as was shown in a recent paper [19].…”

Physical Activity and Breast Cancer Risk Among Women in the Southwestern United States

“…It has been shown that high physical activity is associated with lower levels of markers of inflammation (30). Estrogens have been shown to be proinflammatory (31); others have shown that certain estrogen, such as 17β-estradiol inhibits inflammatory gene expression that is regulated by nuclear factor κB (32). However, of interest is the observed pattern of associations; activity is most protective among those with normal body size and not exposed to estrogen.…”