Subcellular distribution of 3 alpha-hydroxysteroid dehydrogenase and antiestrogen action on androgen-metabolizing enzymes in rat pituitary gland.

Gonadectomy of male rats led to a threefold increase of 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSDH) activity in pituitary homogenates that could be completely reversed by chronic administration of estradiol or 5 alpha-dihydrotestosterone (DHT). 3 alpha-HSDH was found to be distributed mainly between the 10,000 g and 100,000 g sediments from whole homogenates. The microsomal enzyme activity showed a substantial specificity for NADH whereas the cytosolic enzyme (100,000 g supernatant) demonstrated a slight preference for NADPH. The changes in Vmax found in homogenates following gonadectomy and gonadal steroid administration reflected changes in NADH-linked activity of the microsomal, but not the cytosolic enzyme. Estradiol-induced suppression of NADH-linked 3 alpha-HSDH activity in pituitary homogenates from gonadectomized rats of either sex was accompanied by a similar suppression of NADPH-linked 5 alpha-reductase activity and a marked decrease of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release. In the ovariectomized rat chronic administration of nonsteroidal antiestrogens had strong estrogenic effects on 3 alpha-HSDH activity and LH release, but not on 5 alpha-reductase activity and FSH release. In the gonadectomized male rat, which was much less sensitive to intrinsic estrogenicity of the antiestrogens tested, nafoxidine completely blocked estradiol-induced suppression of 5 alpha-reductase activity and FSH release and partially antagonized suppression of LH release. The trans-isomeric, substituted triphenylethylenes, tamoxifen, and enclomiphene, as well as nitromifene (mixture of trans and cis isomers) were able partially to counteract estradiol-induced suppression of 5 alpha-reductase, but not 3 alpha-HSDH activity. It is concluded that estradiol action on pituitary 5 alpha-reductase, but not 3 alpha-HSDH activity, involves an estrogen receptor mechanism.