Androgen Receptors and Metabolism in Cultured Human Fetal Fibroblasts

Abstract

Testosterone metabolism and dihydrotestosterone (DHT) receptor activity were studied in fibroblasts cultured fram genital and non-genital tissues of 8-to 22-week old human fetuses.AS early a s the eighth week of gestation. DHT receptar activity was detected in non-genital skin. The binding capacity (Bma,) was greater in genital skin fibroblasts (mean + SD -474 + 32 moles x lO-18/ug DNA) than non-genital skin (mean + SD = 124 fb2 moles C10-181ug DNA). DHT receptor binding (Bmax) was found in fibroblasts derived from testes (112 moles x 10-18lug DNA), but not intestine ( < 10 moles x l~-~~/ u g DNA). The DHT receptor activity of fetal skin fibroblasts of genital origin was similar to that of fibroblasts derived fram the foreskin of normal newborns. DHT receptors from fetal and newborn fibroblast cultures had similar sedimentation coefficients in sucrose density gradient centrifugation, but there were small differences in their relative affinities for 17%-estradiol and cypraterone.Low, but detectable 5a-reductase activity was observed at 8 weeks gestation in non-genital skin fibroblasts and was present in fibroblasts from a variety of tissues of older fetuses, including testes, kidneys and lung.. The highest 5o-reductase activity of 210 pgthourlug DNA was found in fibroblasts cultured from clitoral tissue from 8 10-week old fetus. In all but one specimen, the 5o-reduced products were either DHT or 5o-androstanedione.The demanstratian of 5a-reductase activity and specific DHT receptors in fetal tissues suggests that the intracellular mechanism for androgen action is present in the fetus, similar to that after birth. SPECULATIONWe have observed the conversion of testosterone into dihydrotestosterone (DHT) as well as DHT binding to a specific receptor in human fibroblasts cultured from a variety of tissue8 of fetal origin as early a s 8 weeks gestation. It is speculated that the concentration of testosterone, the rate of formation of DHT and the concentration of androgen receptors each play a role in the differentiation of the external genitalia.

Dihydrotestosterone Inhibits Fetal Rabbit Pulmonary Surfactant Production

“…Testosterone is activated locally to DHT in target cells by the enzyme 5a-reductase. This enzyme has also been found in both adult rabbit lung (27) and in human fetal lung fibroblasts (25). The human fetal lung 5a-reductase activity is higher in males (25).…”

“…This enzyme has also been found in both adult rabbit lung (27) and in human fetal lung fibroblasts (25). The human fetal lung 5a-reductase activity is higher in males (25). The effect of DHT was relatively specific to the lung.…”

“…Estrogen (22) and luteotrophic hormone (23) have been shown to augment SPC surfactant production, and lung receptors for estrogen have been demonstrated (24). Specific androgen receptors have also been identified in both adult rat lung (25) and human fetal lung fibroblasts (26). In the human fetal lung the males have more androgen receptor activity than the females, reflecting the fact that androgens stimulate their own receptors (26).…”

“…It is not surprising, therefore, that the 0.1 mg dose did not affect either the relative or absolute SPC/S ratios for either sex, despite the fact that the mean female plasma androgen level was comparable to the male control at this dose (0.32 vs. 0.31 ng/ml). The relative insensitivity of the females to DHT may be due to differences in the number and binding affinity of androgen receptors in the lung (25). The lack of any measurable effect on the male SPC/ S ratios may be because the males are already maximally inhibited by endogenous androgens.…”

Apolipoprotein A-I, A-II, C-II, and H expression in the developing lung and sex difference in surfactant lipids

“…Moreover, the sex difference in surfactant production was eliminated by administration of the antiandrogen flutamide, which resulted in an increase in male surfactant levels up to that of the females (Nielsen et al 1982). This effect of androgens depends on the presence of the androgen receptor, which has been detected in human (Sultan et al 1980), rabbit (Giannopoulos & Smith 1982) and mouse (Provost et al 2004) fetal lung tissues. In the mouse model of testicular feminization (Tfm mouse) in which male carriers of the X-linked Tfm mutation have no functional androgen receptors, the surfactant level of Tfm male fetuses is the same as that of normal female fetuses (Nielsen 1985).…”