C19 adrenal steroids enhance prostaglandin F2 alpha output by human endometrium in vitro

Dehydroepiandrosterone sulfate significantly increased prostaglandin F2 alpha output by fragments of human secretory endometrium during the first and second 24-hour periods of incubation in Ham's F-10 medium containing 10% charcoal-treated calf bovine serum. The effects of dehydroepiandrosterone sulfate were noted at 10(-6) mol/L concentrations, which are close to the normal plasma levels of this compound. For the purpose of comparison, the effects of estradiol at 10(-8) mol/L and those of unconjugated dehydroepiandrosterone, dehydroepiandrosterone acetate, 5-androstene-3 beta, 17 beta-diol, or 5 alpha-dihydrotestosterone were evaluated at 10(-8) to 10(-8) mol/L concentrations in parallel experiments. All of the delta 5-C19 steroids tested enhanced prostaglandin F2 alpha output at 10(-6) mol/L but not at 10(-8) mol/L; 5 alpha-dihydrotestosterone was inactive at 10(-6) mol/L but showed a stimulatory effect at 10(-5) mol/L in two experiments. The stimulation of prostaglandin F2 alpha production by the adrenal steroids was significantly reduced by the antiestrogen 4-hydroxytamoxifen at 10(-6) mol/L (a finding consistent with the reported utilization of the estrogen receptor for their actions on other systems) but was not affected by the antiandrogen 4-hydroxyflutamide at 10(-6) mol/L. Progesterone (10(-7) mol/L) also lowered the effects of dehydroepiandrosterone (10(-6) mol/L) and 5-androstene-3 beta,17 beta-diol (10(-6) mol/L), as well as those of estradiol (10(-8) mol/L). delta 5-C19 steroids at 10(-6) mol/L levels did not antagonize the effect of 10(-8) mol/L estradiol, whereas 5 alpha-dihydrotestosterone reduced it by 50% at these concentrations. The significant effect of 5 alpha-dihydrotestosterone points to potential antiestrogenic effects of the C19 compounds that may be manifested in vivo at particular C19/estradiol concentration ratios. The demonstration of direct estrogenic effects of delta 5-C19 steroids, which are not significantly converted to estrogens in vivo, justifies their use in estrogen replacement preparations and indicates that aromatase inhibitors may not eliminate completely the stimulation of estrogen-responsive breast and endometrial tumors by the patient's adrenal steroids.