Diffuser44
Banned
- Reaction score
- 24
[h=2]Pseudohermaphrodites (“Guevedocesâ€) of the Dominican Republic[/h]The pseudohermaphrodites of the Dominican Republic, having a congenital deficiency of 5AR Type 2, provided a model to confirm the DHT theory of prostate growth. In the isolated village where the mutation was discovered, approximately 2% of live births were males (46 XY karyotype), with apparent female genitalia at birth. These children were raised as girls until puberty, at which time the microphallus developed into a functional penis (hence the name “guevedoce†or penis at 12), the normal testes descended into a developed scrotum, the body became muscular, the voice deepened, and a male psychosexual orientation evolved. Throughout life thereafter, the guevedoces are in most ways like the other males of the village except beard growth remains scanty, no acne occurs, the temporal hair line does not recede, and the prostate remains small. At about the same time, Walsh and colleagues co-discovered the syndrome in 2 siblings in Dallas. Later studies of the guevedoces as adults revealed that the prostate was rudimentary by MRI evaluation; biopsy of the gland showed only stromal tissue, no epithelium, and serum PSA level was undetectable.
The unusual features of the guevedoces are explained by differential functions of testosterone, which in these individuals is normal, and DHT, which is markedly suppressed. In utero, testosterone is responsible for differentiation of the Wolffian duct derivatives (ie, seminal vesicles, vasa, epididymis, and ejaculatory ducts); after puberty testosterone causes masculinization (ie, muscle mass, voice change, libido, growth of external genitalia, and spermatogenesis). In utero, DHT is responsible for normal differentiation of the male external genitalia; after puberty, however, DHT may be considered a “bad†hormone, as it is responsible for facial hair, acne, male pattern baldness, and prostate growth.
[h=2]Drugs to Inhibit 5AR Enzymes[/h]Scientists in the pharmaceutical industry reasoned that if 5AR could be targeted for inhibition after the external genitalia were fully formed and mature, then a safe drug to shrink the prostate, relieve LUTS, and ameliorate baldness and acne might be developed. Eighteen years after Imperato-McGinley’s first publication,1 the “prostate pill†arrived; the US Food and Drug Administration (FDA) approved finasteride June 19, 1992 for the treatment of men with symptomatic BPH. FDA approval for male pattern hair loss (in men only) followed, and in October 2002, the dual 5ARI dutasteride was approved. Both drugs currently claim to improve symptoms, reduce the risk of acute urinary retention (AUR), and reduce the risk of the need for BPH-related surgery. A comparison of finasteride and dutasteride is shown in Table 3. In recognition of data from the Medical Therapy of Prostatic Symptoms study,6 an additional indication for finasteride is: “in combination with the α-blocker doxazosin, to reduce the risk of symptomatic progression of BPH.â€
[h=3]Finasteride[/h]Soon after the guevedoces’ story became known, and the implications of 5AR deficiency became clear, Merck began an ambitious development program in the research laboratories at Rahway, New Jersey. Following synthesis of many potential 4-aza steroid molecules that would inhibit 5AR, a drug known as MK-906 was selected as the best therapeutic molecule. After successful testing in experimental animals, where the drug was found to sharply reduce DHT levels and prostate volume, 27 MK-906 (later finasteride) went into human trials in 1986. A few years later, reports of phase I testing were reported by Stoner,28Gormley and colleagues,29 Rittmaster and colleagues,30 and others. As expected, men treated with finasteride developed a marked suppression of DHT, no change or slight elevation in serum testosterone, and no change in all other serum components studied. In 1992, the phase III studies, demonstrating safety and efficacy over 1 year of treatment in men with symptomatic BPH, were published in the New England Journal of Medicine,5concomitant with FDA approval.
The unusual features of the guevedoces are explained by differential functions of testosterone, which in these individuals is normal, and DHT, which is markedly suppressed. In utero, testosterone is responsible for differentiation of the Wolffian duct derivatives (ie, seminal vesicles, vasa, epididymis, and ejaculatory ducts); after puberty testosterone causes masculinization (ie, muscle mass, voice change, libido, growth of external genitalia, and spermatogenesis). In utero, DHT is responsible for normal differentiation of the male external genitalia; after puberty, however, DHT may be considered a “bad†hormone, as it is responsible for facial hair, acne, male pattern baldness, and prostate growth.
[h=2]Drugs to Inhibit 5AR Enzymes[/h]Scientists in the pharmaceutical industry reasoned that if 5AR could be targeted for inhibition after the external genitalia were fully formed and mature, then a safe drug to shrink the prostate, relieve LUTS, and ameliorate baldness and acne might be developed. Eighteen years after Imperato-McGinley’s first publication,1 the “prostate pill†arrived; the US Food and Drug Administration (FDA) approved finasteride June 19, 1992 for the treatment of men with symptomatic BPH. FDA approval for male pattern hair loss (in men only) followed, and in October 2002, the dual 5ARI dutasteride was approved. Both drugs currently claim to improve symptoms, reduce the risk of acute urinary retention (AUR), and reduce the risk of the need for BPH-related surgery. A comparison of finasteride and dutasteride is shown in Table 3. In recognition of data from the Medical Therapy of Prostatic Symptoms study,6 an additional indication for finasteride is: “in combination with the α-blocker doxazosin, to reduce the risk of symptomatic progression of BPH.â€
[h=3]Finasteride[/h]Soon after the guevedoces’ story became known, and the implications of 5AR deficiency became clear, Merck began an ambitious development program in the research laboratories at Rahway, New Jersey. Following synthesis of many potential 4-aza steroid molecules that would inhibit 5AR, a drug known as MK-906 was selected as the best therapeutic molecule. After successful testing in experimental animals, where the drug was found to sharply reduce DHT levels and prostate volume, 27 MK-906 (later finasteride) went into human trials in 1986. A few years later, reports of phase I testing were reported by Stoner,28Gormley and colleagues,29 Rittmaster and colleagues,30 and others. As expected, men treated with finasteride developed a marked suppression of DHT, no change or slight elevation in serum testosterone, and no change in all other serum components studied. In 1992, the phase III studies, demonstrating safety and efficacy over 1 year of treatment in men with symptomatic BPH, were published in the New England Journal of Medicine,5concomitant with FDA approval.