Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 6 Suppl 9 (Suppl 9), S11-21

5alpha-reductase: History and Clinical Importance

5alpha-reductase: History and Clinical Importance

Leonard S Marks. Rev Urol.

Abstract

The treatment of men with symptomatic benign prostatic hyperplasia (BPH) has shifted dramatically from surgery to drug therapy over the past decade. The revolution in BPH treatment began with the discovery of congenital 5alpha-reductase (5AR) deficiency, leading to the appreciation of 2 different androgenic hormones: testosterone, which mediates overt masculinization in the adult male, and dihydrotestosterone (DHT), which mediates prostatic growth, acne, facial beard, and male pattern baldness. Inhibition of DHT in adults results in prostatic shrinkage and symptomatic relief in many men, without the side effects seen with conventional androgen-deprivation therapy. The 5AR inhibitor drugs (finasteride and the dual inhibitor, dutasteride) are able to ablate the accumulation of intraprostatic DHT, the mechanism most responsible for prostate growth and maintenance. Not only may these drugs relieve symptoms, but they may also alter the natural history of the BPH process. Future indications for the 5ARI drugs could include chemoprevention of prostate cancer, prophylaxis of BPH-related complications, and treatment of BPH-associated hematuria.

Figures

Figure 1
Figure 1
Definition of guevedoces.– (Also see Figure 8.)
Figure 2
Figure 2
Within prostate cells, testosterone (T) is converted to dihydrotestosterone (D or DHT), which is the major intraprostatic androgen, binding preferentially to androgen receptors (R) to effect DNA synthesis. In the prostate, tissue DHT levels are some 10 times higher than T levels, just the opposite of serum levels.
Figure 3
Figure 3
The Scotsman, John Hunter, who became known as the “Father of Scientific Surgery,” described more than 200 years ago the androgen dependence of the prostate, which he observed in castrated bulls.
FIgure 4
FIgure 4
Charles B. Huggins, working in the 1930s and early 1940s at the Ben May Laboratory at the University of Chicago, was the first to apply scientific method to a study of the relationship of prostate growth and testosterone. He observed that men with advanced prostate cancer could be markedly relieved by castration or estrogen therapy. He also noted that the glandular epithelium underwent marked involution in men with benign prostatic hyperplasia who were similarly treated. For his work, he received the Nobel Prize in Physiology and Medicine in 1966.
Figure 5
Figure 5
Photomicrographs of prostatic epithelium from men with benign prostatic hyperplasia before (above) and after (below) treatments that deprive the prostate of androgenic stimuli. On the left (black/white) are sections from Huggins’ patients circa 1940; treatment was castration. On the right (color) are sections from a contemporary treatment circa 1999: finasteride. The prostate tissue effect from the 2 treatments is similar. Reprinted with permission from Marks LS et al.
Figure 6
Figure 6
The conversion of testosterone to dihydrotestosterone is catalyzed by the enzyme 5α-reductase (5AR), which exists in 2 forms: Type 1 and Type 2, both of which are found in the prostate. Type 1 is produced primarily in liver and skin and is carried to the prostate via the systemic circulation. Type 2 is the major form in the prostate. Finasteride inhibits Type 2 5AR. Dutasteride inhibits both Type 1 and 2 5AR (dual inhibitor). DHT, dihydrotestosterone.
Figure 7
Figure 7
Distribution of messenger RNA (mRNA) for Type 2 (left) and Type 1 (right) 5α-reductase (5AR) in human prostate tissues: normal, BPH, and CaP. In BPH tissue, both types of 5AR are over-expressed; in CaP tissue, only Type 1 is over-expressed. Note difference in vertical axis scale. BPH, benign prostatic hyperplasia; CaP, cancer of the prostate; TBP, TATA-binding protein; PZ, peripheral zone; TZ, transition zone; CZ, central zone. Reprinted from Iehle C et al. with permission from Elsevier.
Figure 8
Figure 8
“Guevedoces” (literally, penis at 12) of Dominican Republic are biological males (46XY) with female-appearing external genitalia from birth until puberty; at puberty, they develop a penis, the testes descend, muscles and a male psychosexual orientation develop. Throughout life, the prostate remains small, because the congenital deficiency of 5α-reductase leaves affected individuals with markedly suppressed levels of dihydrotestosterone (DHT). DHT is the major androgenic stimulus for the prostate. Reprinted from Peterson RE et al. with permission from Elsevier.
Figure 9
Figure 9
Differences in testosterone-dependent (Wolffian duct) and DHT-dependent (urogenital sinus) structures in embryogenesis of male genitalia. The “guevedoces” are congenitally deficient in DHT, resulting in failure of the urogenital sinus derivatives to differentiate properly. At puberty, the outpouring of testosterone causes these biologic males to experience descent of testes, phallic enlargement, and development of a male body habitus. DHT, dihydrotestosterone. Reprinted from Bartsch G et al. with permission from Springer-Verlag.
Figure 10
Figure 10
Four different prostate cancers stained with a monoclonal antibody for Type 1 5AR (red color), showing that in some cancers (ie, section D above), the enzyme is highly expressed. Marginal expression of the enzyme is seen in cancer A, moderate expression in cancers B & C. 5AR, 5α-reductase. Reprinted with permission from Thomas LN et al.
Figure 11
Figure 11
Kaplan-Meier estimates of proportion of subjects experiencing a prostate cancer adverse event in the dutasteride phase III trial. Note that starting at approximately 15 months into the trial, the placebo and dutasteride groups begin to diverge. For the first 27 months, the cumulative incidence of CaP was 1.2% in the dutasteride group and 2.5% in the placebo group. The differences are highly significant (P = .002), suggesting a chemopreventive effect in the dutasteride group. CaP, cancer of the prostate. Reprinted with permission from Andriole GL et al.
Figure 12
Figure 12
10-year cumulative risk of a 60-year-old man developing one of the common conditions shown on the horizontal axis. Note that the risk of acute urinary retention (AUR) is several times greater than risk of hip fracture, stroke, or heart attack. fx, fracture; MI, myocardial infarction. Reprinted with permission from Jacobsen SJ et al.
Figure 13
Figure 13
PSA-based algorithm for treatment of men with BPH. In this schema, data from the MTOPS study is employed to suggest combination therapy with a 5ARI and an α-blocking agent for symptomatic men with high PSA levels (right side), whereas men with few symptoms and low PSA levels need only be observed (left side). Men with symptoms and low PSA levels would be treated with an α-blocker alone (right center, bottom). Men with few symptoms but elevated PSA levels would be offered preventive therapy with a 5ARI (left center, bottom), as discussed elsewhere. This schema is solely the author’s notion and does not reflect the package inserts. PSA, prostate-specific antigen; BPH, benign prostatic hyperplasia; MTOPS, Medical Therapy of Prostatic Symptoms; 5ARI, 5α-reductase inhibitor; IPSS, International Prostate Symptom Score.

Similar articles

See all similar articles

Cited by 15 PubMed Central articles

See all "Cited by" articles

LinkOut - more resources

Feedback