title: Adrenal C19-5-ene steroids induce full estrogenic responses in rat pituitary gonadotrophs.
abstract: Previous studies have shown that the C19 adrenal steroid 5-androstene-3 beta, 17 beta-diol (5-ene-diol), a metabolite of dehydroepiandrosterone (DHEA), can stimulate typical estrogenic responses in target tissues. Since estrogens are known to cause a specific stimulatory effect on LHRH-induced LH release in rat anterior pituitary cells in culture, we have taken advantage of the precision of this system to study the effect of 5-ene-diol or DHEA on this precise estrogen-sensitive parameter. Pretreatment for 48 h with 17 beta-estradiol (E2), 5-ene-diol or DHEA induces a 2.4-, 2.7- and 2.6-fold stimulation of LH release induced by 0.3 nM LHRH, the effect being exerted at respective 50% maximally effective concentrations (ED50 values) of 0.015, 45 and 115 nM. Following a 48-h preincubation with 10 nM E2, 1 microM 5-ene-diol or 1 microM DHEA, the maximal LH and FSH responses to LHRH are increased by approx 50% above control. On the other hand, the sensitivities of the LH and FSH responses to LHRH as assessed by ED50 values of LHRH action are increased by 3.3- to 7.5-fold. As further proof of the estrogenic nature of the effect of 5-ene-diol and DHEA, the effects of E2, 5-ene-diol and DHEA are inhibited competitively by simultaneous incubation with the antiestrogen LY156758 (keoxifene). The 2-fold stimulation of LHRH-induced LH release caused by DHEA-S, at concentrations within the range found in the plasma of women, is also completely blocked by 120 nM LY156758. In direct binding studies, 5-ene-diol and DHEA or DHEA-S have approx 85- and greater than 10,000 lower affinities than E2, respectively, for the estrogen receptor in rat anterior pituitary homogenate and human breast carcinoma cytosol. The present data clearly show that 5-ene-diol, DHEA and DHEA-S can exert full estrogenic activity in rat gonadotrophs, thus supporting the potential estrogenic role of these C19 adrenal steroids in estrogen-dependent processes, especially breast cancer.
mesh_terms: D015114:Androstenediol / Q000378:metabolism / Q000494:pharmacology*; D000734:Androstenediols / Q000494:pharmacology*; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D002478:Cells, Cultured; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D019314:Dehydroepiandrosterone Sulfate; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism*; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D006801:Humans; D007986:Luteinizing Hormone / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000378:metabolism*; D020849:Raloxifene Hydrochloride; D051381:Rats; D011919:Rats, Inbred Strains; D011960:Receptors, Estrogen / Q000378:metabolism
chemical_list: D000734:Androstenediols; D010880:Piperidines; D011960:Receptors, Estrogen; D007987:Gonadotropin-Releasing Hormone; D003687:Dehydroepiandrosterone; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D019314:Dehydroepiandrosterone Sulfate; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D015114:Androstenediol