Adrenal C 19-5-ene steroids induce full estrogenic responses in rat pituitary gonadotrophs

Abstract

Previous studies have shown that the C 19 adrenal steroid 5-androstene-3β,17β-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 17β-estradiol (E 2), 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 (ED 50 values) of 0.015, 45 and 115 nM. Following a 48-h preincubation with 10 nM E 2, 1 μM 5-ene-diol or 1 μM 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 ED 50 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 E 2, 5-ene-diol and DHEA are inhibited competitively by simultaneous incubation with the antiestrogen LY 156758 (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 LY 156758. in direct binding studies, 5-ene-diol and DHEA or DHEA-S have approx 85- and ⪢ 10,000 lower affinities than E 2, 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 C 19 adrenal steroids in estrogen-dependent processes, especially breast cancer.