5«-Dihydrotestosterone

Fig. 9. Abbreviated steroid biosynthesis where DHEA = dehydroepiandrosterone and DHT = dihydrotestosterone.

A mixture of 1 gram of 2-hydroxymethylene-dihydrotestosterone, 10 cc of pyridine and 2 cc of propionic anhydride was allowed to react at room temperature for 16 hours and then poured into water. The resulting suspension was heated for 1 hour on the steam bath to hydrolyze the excess of propionic anhydride, cooled and extracted with methylene dichloride. The extract was consecutively washed with dilute hydrochloric acid, sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. There was thus obtained the dipropionate of 2-hydroxymethylene-dihydrotestosterone which was treated with hydrogen, in methanol solution. 

Boffa L.C., Scarf S., Marian M.R., Dai40nte G, Allfrey V.G., Benatti U., Morris O. L. Dihydrotestosterone as a selective cellular/nuclear localization vector for anti-gene peptide nucleic acid in prostatic carcinoma cells. Cancer Res. 2000 60 2258-2262. 

DHT Dihydrotestosterone StAR Steroidogenic acute regulatory (protein)... 

Dihydrotestosterone Is Formed From Testosterone in Peripheral Tissues... 

The most significant metabolic product of testosterone is DHT, since in many tissues, including prostate, external genitalia, and some areas of the skin, this is the active form of the hormone. The plasma content of DHT in the adult male is about one-tenth that of testosterone, and approximately 400 ig of DHT is produced daily as compared with about 5 mg of testosterone. About 50-100 ig of DHT are secreted by the testes. The rest is produced peripherally from testosterone in a reaction catalyzed by the NADPH-depen-dent 5oi-reductase (Figure 42-6). Testosterone can thus be considered a prohormone, since it is converted into a much more potent compound (dihydrotestosterone) and since most of this conversion occurs outside the testes. Some estradiol is formed from the peripheral aromatization of testosterone, particularly in males. 

Figure 42-6. Dihydrotestosterone is formed from testosterone through action of the enzyme 5a-reductase.

Valencia A., Collado P., Cales J.M., et al. (1992). Postnatal administration of dihydrotestosterone to the male rat abolishes sexual dimorphism in the accessory olfactory bulb a volumetric study. Dev Brain Res 68, 132-135. 

The testes and adrenal glands produce 90% and 10%, respectively, of circulating testosterone. Testosterone enters prostate cells, where predominantly type II 5a-reductase activates testosterone to dihydrotestosterone, which combines with a cytoplasmic receptor. The complex enters the nucleus and induces changes in protein synthesis which promote glandular tissue growth of the prostate. Thus, 5a-reductase inhibitors (e.g., finasteride and dutas-teride) directly interfere with one of the major etiologic factors of BPH. 

By reducing serum levels of dihydrotestosterone, which is linked to the development of prostate cancer, it has been... 

Sub-type inhibition of the 5a-reductase enzyme Percent of inhibition of serum dihydrotestosterone level Percent of patients with reduction in serum dihyrotestosterone Time to peak onset of reduction in serum dihydrotestosterone level Percent inhibition of intraprostatic d i hy d rotestosterone Half-life... 

The antiandrogens block androgen receptors to inhibit the action of testosterone and dihydrotestosterone in prostate... 

Evidence that BPH could be hormone related came from studies of a population of pseudohermaphrodites in the Dominican Republic. These individuals are genetically male, but do not display normal male genitalia until the onset of puberty. They are therefore raised as females until puberty. Studies revealed that these pseudohermaphrodites are deficient in an isoform of the enzyme steroid 5a-reductase, which is responsible for catalyzing the conversion of testosterone to dihydrotestosterone (DHT). In addition to the overt sexual manifestations of this condition, affected individuals show no incident of male pattern baldness, mild or no acne, and underdevelopment of the prostate. These observations led researchers to postulate that a selective inhibitor of steroid 5a-reductase would be an effective treatment for BPH. 

Figure 8.17 Reaction mechanism of testosterone reduction to dihydrotestosterone (DHT) as catalyzed by the enzyme steroid 5a-reductase.

Note THF = tetrahydrofuran BHT = butylated hydroxytoluene, an antioxidant Camptothecin (CM) = causes inhibition of the DNA enzyme topoisomerase (Top 1) which induces DNA damage and apoptosis DHT = dihydrotestosterone PrEC = normal prostate stromal cells LNCaP, PC-3, DU-145 = neoplastic prostate epithelial cells (See Table 21.1). 

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