It long has been known that the presence of testis and aging are necessary for benign prostatic hyperplasia (BPH) to develop. However, we remain ignorant of the- specific factors associated with aging which are significant in the etiology of BPH. Indeed, it is puzzling that as the frequency of BPH goes up with age, the most important known stimulus to prostatic growth, plasma testosterone falls, and the concentration of its binding protein, sex hormone-binding globulin (SHBG) rises. The inconsistency between a falling plasma testosterone, together with a rising plasma SHBG, and an enlarging prostate, may be reconciled by new knowledge of the functions of the SHBG. Although for years it was believed that SHBGs sole purpose was to bind androgens and estrogens, other important functions now have been shown for this protein. It has specific receptors on human prostatic membranes that result in the accumulation of intracellular cAMP and an increased rate of growth of prostate cancer in vitro. Further, SHBG increases in concentration in the plasma of aging men at a time when the incidence of BPH is on the increase. A major goal of this application is to examine the relationship between BPH and SHBG in men having elective surgery for BPH. SHBG in plasma, seminal fluid, and prostatic tissue, and receptors for SHBG in prostatic tissue will be measured in these patients. Additionally, the effect of SHBG on cAMP and growth will be examined in explants derived from tissue from these same patients. All of these variables will be correlated with the volume of the prostate as determined by transrectal ultrasound. The other major plasma steroid-binding protein, corticosteroid-binding globulin (CBG), shares some properties with SHBG. It too has receptors on prostatic cell membranes, and its binding also results in the generation of cAMP. Further, it is uniquely negatively correlated with prostatic volume, and has been found to exist in prostatic tissue. Therefore, studies, parallel to those described for SHBG, will be undertaken for this protein. If SHBG and CBG can be shown to be involved in the etiology of BPH, then a host of potential new therapies should become available. These range from our ability to manipulate the concentration of these proteins, to already known ways in which we can interfere with their binding to their respective receptors.
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