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Sex hormone-binding globulin (SHBG) is a plasma protein synthesized and secreted by the liver. Its initial description stemmed from its ability to bind estrogens and androgens and its capacity to regulate the free concentration of the steroids that bind to it. Additionally, it participates in signal transduction for certain steroid hormones at the cell membrane. It binds with high affinity to a specific membrane receptor (R SHBG ) in prostate stromal and epithelial cells, wherein the SHBG⅐R SHBG complex forms. An appropriate steroid binds to this complex and results in increases of intracellular cAMP. These two disparate functions of SHBG, regulation of the concentration of free steroids in plasma and signal transduction in selected tissues, raise the question of how its synthesis and secretion might be regulated so as to best perform these two disparate functions. In this paper we demonstrate that SHBG is produced in human prostate cancer cell lines (LNCaP, DU 145, and PC 3) as well as in cultured human prostate epithelial and stromal cells. In addition, in tissue sections of human prostate, we demonstrate the presence of SHBG (immunocytochemistry) and SHBG mRNA (in situ hybridization). These observations are consistent with the hypothesis that SHBG, destined to participate in signaling at the cell membrane, is locally regulated and produced.The hepatically derived (1) plasma protein, sex hormonebinding globulin (SHBG) 1 has two apparently disparate functions. It is the major regulator of free estrogens and androgens in plasma (2-4); it is an initiating component of a signaling system for estrogens and androgens at the cell membrane that functions via a G protein (5) and cAMP (6 -9). The details of the working of these systems generate a model that is in need of clarification in a number of crucial respects. In this paper we present data that deal with the source of the SHBG for signaling at the cell membrane. These data support a model in which the source of SHBG for signaling is not the plasma, but rather the target cells themselves.

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