Diethylstilbestrol And Steroid Hormones

The sensitivity of the thymus and T cell-mediated immunity to certain steroidal compounds, including glucocorticoids such as hydrocortisone, has been well established (Hendrickx et al. 1975; Kalland et al. 1978; Ways et al.1979). However, the role of other steroids such as sex hormones in the development of immunity remains poorly understood. A variety of reports have indicated that exogenously administered hormones, including testosterone (Warner et al. 1969), estrogen, and related compounds possessing estrogenic properties, can alter the normal development of the immune system (Luster et al. 1979; Kalland and Forsberg 1981; Ways et al. 1980; Blair 1981; Whitehead et al. 1981; Kalland 1982; Ford et al. 1983; Noller et al. 1988; Ways et al. 1987).

The use of diethylstilbestrol (DES) from the 1940s to the 1970s to prevent threatened miscarriage in pregnant women was found to cause development of genital tract anomalies and neoplasia in a number of adult women exposed in utero (Ways et al. 1987). Several lines of evidence also indicate a link between DES exposure and alterations in the development of the immune system. Perinatal DES exposure in mice results in a long-term impairment of both cell-mediated and humoral-mediated immunity (Ways et al. 1987). Postnatal immunosuppression following pre- and/or perinatal DES exposure includes altered T- and B-lymphocyte mitogen responsiveness, graft-vs.-host reaction, delayed hypersensitivity, NK cell activity, and antibody production (Ways et al. 1987; Luster et al. 1979; Kalland and Forsberg 1981; Ways et al. 1980). The consequences of immunosuppression in rodents resulting from DES exposure during development include increased susceptibility to virally induced mammary tumors and to transplanted and primary carcinogen-induced tumors (Blair 1981; Kalland 1982). In studies of women exposed in utero to DES, unconfirmed evidence exists for altered T-lymphocyte and NK cell activity (Ford et al. 1983; Ways et al. 1987), as well as an increased incidence of autoimmune diseases (Noller et al. 1988; Chapter_in this book). Several investigators have further stressed the potential relationship between prenatal DES exposure and postnatal immunocompetence and neoplastic growth in humans, including clear-cell adenocarcinoma of the vagina (Kalland et al. 1978; Luster et al. 1978).

Analysis of a variety of fetal liver markers in mice exposed prenatally to DES has indicated that fetal thymic atrophy may similarly be the result of selective prothymocyte targeting by this compound (Holladay et al. 1993). DES caused a reduction in the number of double positive CD4+ CD8+ T cells and enrichment in CD4- CD8- double negative cells. DES alters the intrathymic development of thy-mocytes in the double negative compartment at a late stage of development and may block the expression of pre-T cell receptor and its ability to respond to signals for proliferation and differentiation. It is also possible that DES causes apoptosis in cells entering the CD44- CD25- compartment (Lai et al. 1998).

Triamcinolone acetonide is a potent corticosteroid used clinically to treat a variety of inflammatory disorders. It is also immunotoxic to developing fetuses, inducing thymic hypoplasia and lymphocyte deficiency in monkeys following exposure at doses of 3 to 28 mg/kg/day during early, mid-, and late gestation (Hendrickx et al. 1975). Each group was exposed for 4 consecutive days during the following time periods: early gestation (GD 37 to 48) during the time of early proliferation of thymic tissue and separation from pharyngeal pouches, mid-gestation (GD 50 to 73) during the time of differentiation of lymphoid elements within the thymus, and late gestation (GD 100 to 133) during the time for maturation of the fetal lymphoid system. Seventy-six percent of the fetuses demonstrated a marked depletion of the thymic lymphocytes and a marked reduction in the epithelial component. A depletion of the lymphocytes from the thymic dependent areas of the spleen and lymph nodes was also observed.

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