Benign Prostatic Hyperplasia: Pathogenesis and Medical Therapy

Abstract

Epidemiologic studies in castrates strongly support the key role of the testis in the pathogenesis of benign prostatic hyperplasia (BPH). Since the testis secretes androgen and estrogen, both of these hormones have been implicated in BPH. Much information supports the important role of dihydrotestosterone (DHT) in BPH, including intraprostatic activities of enzymes that regulate DHT. Although controversy still exists, DHT levels in BPH may be higher than in normal prostate tissue. Based upon these findings and the ability to quantitate prostate size and function with reliable new techniques, suppression of androgen-mediated action has been tested to assess the validity of the DHT theory. A variety of drugs has been demonstrated to decrease prostate size by approximately 30% by either blocking secretion of circulating testosterone and adrenal androgen, inhibiting 5 alpha-reductase to prevent DHT formation, or blocking DHT binding to androgen receptors. Accompanying these changes in size was significant improvement in clinical symptoms of prostatism in about 50% of patients, when double-blind, large multicenter studies were conducted with one of these drugs. Although these results suggest a very important role for androgen, particularly DHT, in the pathogenesis of BPH, other abnormalities may coexist since significant numbers of patients do not show a total reversal of disease. There is strong indirect evidence for a possible role for estrogen in the pathogenesis of BPH, and studies are under way to test the effects of estrogen withdrawal on prostate size and symptoms. Similarly, dynamic aspects of prostatic obstruction, which are under alpha-adrenergic regulation, may also be a component of this disease and amenable to therapy with alpha-adrenergic blockers.(ABSTRACT TRUNCATED AT 250 WORDS)

Dihydrotestosterone and the Concept of 5α–Reductase Inhibition in Human Benign Prostatic Hyperplasia

“…Among these, the following obstacles will be faced by any inhibitor of 5α–reductase: heterogeneity of the disease [106]; coincidental concurrence of human benign prostatic hyperplasia and symptoms unrelated to prostatic enlargement [107]; the effect of residual, or rising testosterone levels on the prostate or prostate size [29], and the possibility that the essential developmental role of DHT in the prostate is not mirrored by regression of the developed, hyperplastic gland on removal of DHT support [108]. …”

Serum Steroids in Relation to Benign Prostatic Hyperplasia

“…For plasma DHT, the majority of case-control investigations suggest that it plays a role in the etiology of BPH [6][7][8], but studies that found no association or even inverse associations have been reported [9,19], The con sensus now is that it is DHT in the end organ rather than in plasma that dominates the pathogenesis of this disease [3,10,12]. For T, some case-control studies found a posi tive association with BPH [7,[20][21][22][23], others found an inverse association [24][25][26], while still others found no association at all [9,18,19,27,28], The fact that surgical castration largely prevents BPH [5,29] implies that T is likely to play a permissive role [12,13], Conflicting are also the results concerning the role, if any, of estrogens in the pathogenesis of BPH. Most of the studies noted posi tive associations [9,20,24,27,28,30,31 ], although these Findings were not always statistically significant.…”

Discovery and Development of GG745, a Potent Inhibitor of Both Isozymes of of 5α-Reductase

“…Benign prostatic hyperplasia (BPH) and prostate cancer are major causes of morbidity and mortality in the aging male population (Isaacs, 1990;Geller, 1991;Arrighi et al, 1991;Denis and Mahler, 1990;Geller, 1993). The clinical symptoms attributed to BPH occur in the majority of men over the age of 60 and microscopic hyperplasia is a nearly universal finding on autopsy.…”

“…BPH is a nonmalignant enlargement resulting from growth of both the stromal and glandular components of the prostate and is the most common neoplastic disease of man (Isaacs, 1990;Geller, 1991). As a consequence of the anatomical location of the prostate, surrounding the urethra just below the bladder, the growth of the prostate can produce difficulty in urination.…”