madman
Super Moderator
Introduction:
Five-alpha reductase (5-AR) deficiency was first identified by Imperato-McGinley and Walsh as the cause of pseudohermaphroditism in two separate studies. The discoveries led to the development of finasteride (inhibitor of type 2 isoenzyme of 5-AR) and dutasteride (inhibitor of type 1 and type 2 isoenzymes of 5-AR.Both drugs have been proven effective for the treatment of benign prostatic hyperplasia and improve voiding symptoms, reduce the risk of urinary retention, and the need for prostate surgery.
Five-alpha reductase inhibitors 5-ARIs have been demonstrated to be chemopreventive agents and reduce the risk of prostate cancer, although the risk of selecting out or mediating higher-grade prostate cancer remains uncertain. A lower dose of finasteride has been shown to be effective in the treatment of male pattern baldness.
Materials and methods:
A Medline search was performed using mesh terms, benign prostatic hypertrophy, prostate cancer, male pattern baldness, female and 5-AR.Results:
The Prostate Long Term Efficacy and Safety Study (PLESS) was a randomized double-blind study that established that finasteride resulted in a 22% increase in maximum flow rate and a 19% decrease in prostate volume. Further studies demonstrated that finasteride caused a significant reduction in the risk of the need for surgery and urinary retention in a 4 year period. Additional studies showed similar beneficial results with dutasteride.The potential benefits of 5-ARIs as chemopreventive agents were examined in the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) studies. In the 7-year PCPT trial, 18.4% of the finasteride group developed prostate cancer compared to 24.4% in the placebo group. In the 4-year REDUCE trial, there was a 22.8% reduction of prostate cancer at the conclusion of the study.
Despite the reduction of prostate cancer in both the PCPT and REDUCE trials, each study showed an increased risk of prostate cancer in the treatment arms. The explanation for these observations remains an area of investigation. Low-dose finasteride has also been used successfully for the treatment of male pattern baldness.
Conclusions:
The use of 5-ARIs has been a major advance in urologic clinical practice. Urologists should be familiar with the underlying pharmacology of 5-ARIs as well as the clinical indications for their use.History-the Guevedoces
In 1972, Julianne Imperato-McGinley was a young endocrinologist at Cornell Medical College in New York City who was interested in studying children with intersexuality and ambiguous genitalia. She investigated a cohort of children in an isolated village, Salinas, in the southwestern Dominican Republic. These children appeared to be females at birth, but at puberty, these “girls” developed muscles, testicles, and a penis. They were referred to locally as “Guevedoces”- penis at twelve. They then continued their lives as men.
Imperato-McGinley studied these children and identified their underlying defect as 5-AR deficiency, an inherited form of male pseudohermaphroditism.1 That same year, Walsh et al identified the same defect in Texas.2 Roy Vagelos was then the chief of research at Merck when he read the findings, “ The prostate, however, remains small” and was struck by the possibility of drug development to impair the growth of benign prostatic hyperplasia (BPH).3
*5-ARIs: biochemistry, physiology, and side effects
5-ARIs blocks the conversion of testosterone to dihydrotestosterone. There are three commercially available 5-ARIs in the United States. Finasteride (Proscar) is an orally active, competitive inhibitor of nicotinamide adenine dinucleotide phosphate, reduced from (NADPH) -dependent 5AR enzyme’s type 2 isoenzyme.4 Despite its steroid structure, it has no affinity for any steroid receptors, including androgens, estrogens, and progesterone.5 Finasteride has been shown to suppress serum DHT to approximately 70% of baseline levels in human males.5-7 Propecia is a 1 mg formulation of finasteride used for male pattern hair loss.
Dutasteride (Avodart) is an inhibitor of both isoenzymes (type 1 and type 2) of 5-AR. Nonselective inhibition of both isoenzymes produces more than a 90% reduction in serum DHT.4,8 Type 2 5-AR is the predominant isoenzyme within the prostate. Its inhibition by finasteride may lead to upregulation of type 1 5AR in extraprostatic sites (liver and skin) with consequent paracrine effects and elevated serum DHT on the prostate.4,8 The half-life of finasteride is 5 to 8 hours, whereas the half-life of dutasteride is about 180 hours.8,9
Some investigators have reported increases in both or either serum testosterone and estrogens in patients receiving 5-ARIs.10-12 However, a recent meta-analysis concluded that reported increases in T levels with finasteride or dutasteride in men with low baseline serum T may be attributed, in part, to increased trapping of T by unsaturated sex hormone-binding globulin (SHBG) due to the dissociation of 5 alpha dihydrotestosterone. In men with high baseline T levels, there appears to be no change in serum T levels.13 Ten studies reported LH, FSH, SHBG, and estradiol values and none reported significant changes in these levels, suggesting that observed changes in serum T levels are unlikely mediated by gonadotropins or peripheral conversion of T to estradiol.13
The most common side effects of 5-ARIs include impotence, decreased libido, ejaculatory disorders, and gynecomastia.14 Less common side effects that have been reported include infertility, breast tenderness, depression, anxiety, dementia, and suicide. 15-18
Finasteride has also been associated with intraoperative floppy iris syndrome and cataract formation.19,20
