The prostate gland is dependent on androgens that are produced exogenously by the testicles to facilitate normal development and to maintain normal structure and function (1). Briefly, the testes are stimulated to produce and secrete testosterone and other steroids by an exogenous protein, luteinizing hormone, which is made in the pituitary gland. Testosterone (T) is converted to its reduced form, dihydrotestosterone (DHT), by the enzyme 5a-reductase in the prostate. Both T and DHT bind to and activate the androgen receptor, causing a cascade of events that results in stimulation and maintenance of prostatic epithelial and stromal growth and secretion. DHT has a greater affinity for the androgen receptor than T and is normally the major prostate growth stimulant. Currently, attempts to interrupt or alter the stimulatory effects of exogenous factors that control prostate growth target aspects of the pituitary-testis-prostate axis. One approach is to alter the production and secretion of testosterone by altering pituitary function or removing the testis. Another method is inhibition of the prostate stimulatory effects of local conversion of T to the more biologically active DHT. A final method is prevention of activation of the anabolic metabolic cascade by interference with DHT/T androgen-receptor binding.
Androgen deprivation by any of these mechanisms leads to dramatic changes in both prostate anatomy and function. Flutamide, an oral non-steroidal androgen-receptor antagonist, competitively inhibits testosterone and DHT binding to androgen receptor sites. This results in significant histologic changes in prostate tissue, including squamous metaplasia, fibrosis, basal cell hypertrophy, and lymphocytic infiltration (2). Functional prostatic changes represented by decreases in prostate secretions have also been noted in the ejaculate of patients treated with flutamide androgen blockade (3). It is known that surgical castration by means of orchiectomy also results in profound changes in prostate anatomy and physiology. In the 1940s, Huggins and Stevens demonstrated that significant prostatic atrophy occurred in patients with BPH within 3 mo after orchiectomy (4). Subsequent work has shown that castration results in increased DNA synthesis within the prostate,
with an approx 90% decrease in the epithelial glandular component and an approx 20% involution of the stromal glandular component (5,6). Medical and surgical castration lead to inducible gene expression, which is an active process that results in apoptosis in androgen-dependent prostate cells (7,8). Impairment in prostate growth and function are changes associated with androgen depletion. Androgen levels can be restored in medically treated patients with cessation of therapy and in postorchidectomy patients who are given androgen-replacement therapy (9).
T, the primary androgen secreted by the testis, has a direct stimulatory effect on androgen-dependent activities in skeletal muscle, in the brain, and in testicular seminiferous tubules. However, DHT is the primary androgen present in the prostate gland (10). T is converted to DHT by 5a-reductase (Fig. 1). Two isozymes for 5a-reductase exist: type I and type II. Type I 5a-reductase is present in the liver and in the skin (sebaceous glands), and in small amounts in the prostate. Type II 5a-reductase is present in the prostate, liver, chest skin, beard, and scalp (hair follicles). Within the prostate gland, 90% of androgens are in the form of DHT. In 1970, Siiteri et al. postulated that DHT secretion might be associated with the development of BPH (11). Although T and DHT both bind to the same androgen receptor, DHT binds with greater affinity and forms a more stable complex than T. Additionally, the DHT-receptor complex stimulates a greater increase in androgen-receptor concentration. The binding of the DHT-receptor complex to nuclear DNA initiates a cascade of androgen-dependent gene transcription and protein synthesis (Fig. 2).
The critical role of 5a-reductase in normal male development was documented in two important independent publications in 1974. These papers reported observations in two geographically separate groups in Texas and in the village of Salinas in the Dominican Republic (12,13). The investigators described the development of male primary and secondary sexual characteristics within individuals with congenital
deficiencies in 5a-reductase production. Men affected by this auto-somal-recessive disorder have impaired embryonic differentiation of the external genitalia and prostate glands. Phenotypically, these individuals, born as pseudohermaphrodites with a 46,XY karyotype, have normal testes (presenting as inguinal or labial masses), a scrotum resembling a labia, and normal epididymides and vas deferens. Although their underdeveloped phallus resembles a clitoris, they have severe hypospadias and a urogenital sinus with a blind-ending vaginal pouch. They routinely have a prostate gland that is poorly formed.
Walsh et al. examined a group of patients from Texas, and Imperato-McGinley studied a group of patients from a single village in the Dominican Republic, Salinas, where inbreeding was common (12,13). Both studies are experiments of nature observed by two insightful groups, and the anatomic features as well as the natural history of the condition are detailed in these papers. Both groups of patients had congenital deficiency in 5a-reductase activity. The children from the Dominican Republic were typically raised as girls from birth until puberty, when they underwent virilizing changes. These changes included scrotal rugation and hyperpigmentation, penile growth and function, increase in skeletal muscle mass, deepening voice, testicular descent, and development of the ability to ejaculate. Testicular biopsies revealed complete spermatogenesis and normal Leydig cells. These individuals demonstrated male psychosocial orientation. Despite these masculinizing changes, several other hallmark features of puberty were missing in these individuals. Specifically, they developed a scanty beard, if any at all. Also, the 5a-reductase-deficient group experienced neither male-pattern baldness nor acne. More importantly, it was observed that their prostate glands, which were poorly developed at birth, grew minimally after puberty despite other masculinizing changes. It was this observation, which is directly tied to the deficiency in 5 a-reductase activity, that led researchers to consider the possibility of therapeutic inhibition of 5 a-reductase enzymes in the treatment of symptomatic BPH.
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