ESTRADIOL ACTIVATES THE PROSTATE ANDROGEN RECEPTOR AND PROSTATE-SPECIFIC ANTIGEN SECRETION THROUGH THE INTERMEDIACY OF SEX HORMONE-BINDING GLOBULIN

These experiments were designed to examine the relationship between th e effects of steroid hormones mediated by classic intracellular steroi d hormone receptors and those mediated by a signaling system subserved at the plasma membrane by a receptor for sex hormone-binding globulin , It is known that unliganded sex hormone-binding globulin (SHBG) bind s to a receptor (R(SHBG)) on prostate membranes, The R,,, SHBG complex is rapidly activated by estradiol to stimulate adenylate cyclase, wit h a resultant increase in intracellular cAMP. In this paper we examine the effect of this system on a prostate gene product known to be acti vated by androgens, prostate-specific antigen, In serum-free organ cul ture of human prostates, dihydrotestosterone caused an increase in pro state specific antigen secretion, This event was blocked by the anti-a ndrogens cyproterone acetate and hydroxyflutamide, In the absence of a ndrogens, estradiol added to prostate tissue, whose R(SHBG) was occupi ed by SHBG, reproduced the results seen with dihydrotestosterone. Neit her estradiol alone nor SHBG alone duplicated these effects. The estra diol SHBG-induced increase in prostate-specific antigen was not blocke d by anti-estrogens, but was blocked both by anti-androgens and a ster oid (2-methoxyestradiol) that prevents the binding of estradiol to SHB G, Furthermore, an inhibitor of protein kinase A prevented the estradi ol SHBG-induced increase in prostate-specific antigen but not that whi ch followed dihydrotestosterone. These data indicate that there is a s ignaling system that amalgamates steroid-initiated intracellular event s with steroid dependent occurrences generated at the cell membrane an d that the latter signaling system proceeds by a pathway that involves protein kinase A.