The first step of androgen biosynthesis, catalyzed by P450scc, occurs in Leydig cell mitochondria, and subsequent steps occur in the SER. After synthesis, testosterone, which is lipophilic, moves out of the Leydig cell by passive diffusion, down a concentration gradient. There is no evidence of packaging testosterone into secretory granules (8). In the testis, testosterone diffuses freely into the interstitial space and associates in rodents with androgen-binding protein (ABP) produced by Sertoli cells (75,76) as a transport vehicle to the seminiferous tubules and epididymis.
Testosterone enters the testicular blood capillaries that are immediately adjacent to Leydig cells. Once a part of the systemic circulation, secreted testosterone binds to plasma proteins and is present in both bound and unbound forms. In humans, more than 95% of testosterone is complexed with proteins, both the high-affinity (KD = 1 nM) sex hormone-binding globulin (SHBG) and the low-affinity (KD = 1000 nM) albumin (Alb). The proportion of testosterone that is unbound or loosely bound represents the biologically active fraction, which freely diffuses from capillaries into cells. In contrast, the SHBG-bound fraction is believed to act as a reservoir for the steroid.
SHBG is a plasma protein synthesized and secreted by the liver. As its name suggests, SHBG has the ability to bind androgens and estrogens and the capacity to regulate the free concentrations of the steroids that bind to it. SHBG also participates in signal transduction for sex steroids at the cell membrane. SHBG binds with high affinity to a specific membrane receptor (RSHBG) in prostate stromal and epithelial cells, wherein the SHBG / Rshbg complex forms. Once an appropriate steroid, e.g., 3a-androstanediol or estradiol, binds to this complex, an increase of intracellular cyclic adenosine monophosphate (cAMP) occurs and intracellular signal transduction is initiated. Moreover, SHBG not only is a plasma protein secreted by the liver but also is expressed in the prostate tissue itself, specifically by prostate stromal and epithelial cells (77). (See Chapter 17.) The process of testosterone secretion and regulation of Leydig cell function are illustrated in Fig. 5.
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