5-a-Dihydrotestosterone

Tobias, J.H., Gallagher, A. and Chambers, T.J. (1994) 5 a-Dihydrotestosterone partially restores cancellous bone volume in osteopenic ovariectomized rats. The American Journal of Physiology, 267, E853-E859. 

Saw palmetto extract can inhibit the enzyme 5-a-reductase in vitro. This enzyme converts testosterone into dihydrotestosterone (DHT), which in turn contributes to prostatic enlargement. Saw palmetto also appears to have an antiinflammatory effect and can reduce DHT binding to prostatic androgen receptors (antiandrogenic effect). Despite its proposed 5-a-reductase mechanism. 

Y.S. Choe, P.J. Lidstrdm, D.Y. Chi, T.A. Bonasera, M.J. Welch, J.A. Katzenellenbogen, Synthesis of 11-beta-[F-18]fluoro-5-alpha-dihydrotestosterone and 11-beta-[F-18]fluoro-19-nor-5-alpha-dihydrotestosterone—Preparation via halofluorination-reduction, receptorbinding, and tissue distribution, J. Med. Chem. 38 (1995) 816-825. 

All classes of steroid hormones bind to specific cytoplasmic receptors in their respective target tissues, and are then translocated to the nucleus. For example, testosterone, a lipid-soluble substance, enters the cell and is enzymatically reduced to dihydrotestosterone by 5-a reductase. Dihydrotestosterone then becomes bound to a specific androgen receptor site located in the cytoplasm. This complex becomes activated and is then translocated to the nucleus, where it binds to the chromatin acceptor site consisting of DNA and nonhistone chromosomal proteins. This interaction results in the transcription of a specific messenger RNA that is then relocated to the cytoplasm and translated on the cytoplasmic ribosomes, resulting in the synthesis of a new protein that sponsors the androgenic functions (Figure 61.6). 

HYDROXYMETHYLENE-17-a-METHYL-5-a-ANDROSTAN-17-P-OL-3-ONE see PANIOO 2-HYDROXYMETHYLENE-l 7-a-METHYL-DIHYDROTESTOSTERONE see PANIOO 2-(HYDROXYMETHYLENE)-17-a-METHYLDIHYDROTESTOSTERONE see P.ANIOO 2-HYDROXYMETHYLENE-17-a-METHYL-17-P-HYDROXY-3-ANDROSTANONE see PANIOO 4-(l-HYDROXY-2-((l-METHYLETHYL)AMINO)ETHYL)-l, 2-BENZENEDIOL see DM "600... 

In 1965, Neumann and Wiechert [100] published the results of their investigations of some 150 steroids. They studied the androgenic and anabolic activity of steroids substituted in the C-1 and/or the C-2 position. Five parent compounds were chosen 1. 5a-androstan-17]3-ol 2. testosterone 3. 5a-dihydrotestosterone 4. A -5a-androsten-17j8-ol 3-one and 5. A -5a-androsten-17/3-ol. The parent compounds were further classified according to the substitution in the 17-position, i.e., l7j8-hydroxy, 17a-methyl 17j8-hydroxy, or 17/3-acetoxy compounds. 

The exact cause of BPH is not yet known. Probably there is a multifactorial background. Consequently there are several hypotheses. One of them, the dihydrotestosterone (DHT) hypothesis, claims that DHT is formed in the prostate from testosterone by the enzyme 5 a-reductase and is deposited in prostate tissue, causing the proliferation of the prostate. The concentration of DHT was found to be 5 times higher in BPH than normal. Based on these facts, drugs with a selective inhibition of 5 a-reductase are sought. 

Two recently developed classes of drug show promise, and these act by inhibiting the production of testosterone from cholesterol or its metabolism by the enzyme 5-cc-reductase. Attempts to control benign prostatic hyperplasia provided the incentive for the development of 5-a-reductase inhibitors. It has been known for some time that there is a genetic condition that is manifested by a deficiency of this enzyme. Men who have this gene defect have normal external genitalia but only a very small prostate and additionally, they do not develop acne or exhibit the typical male pattern of hair loss. All of these processes are under the control of 5- -reductase, which controls the conversion of testosterone to another steroid, dihydrotestosterone, and it is an imbalance in the ratio of these two steroids that leads to acne, male-pattern baldness, prostatic hyperplasia and probably prostatic cancer. Several... 

A fruit extract has been shown to selectively antagonize and prevent binding to 52% of dihydrotestosterone receptors in the pros-tate. Oral administration of a fruit extract in mice and rats has demonstrated inhibition of up to 90% of the activity of prostate 5-a-reductase (that transforms testosterone into metabolites increasing the size of the... 

Kicman,A.T.,Coutts,S.B.,Walker,CJ.,and Cowan,D.A. (1995) Proposed confirmatory procedure for detecting 5 alpha-dihydrotestosterone doping in male athletes. Clinical Chemistry, 41,1617-1627. 

Coutts, S.B., Kicman, A.T., Hurst, D.T., and Cowan, D.A. (1997) Intramuscular administration of 5 alpha-dihydrotestosterone heptanoate Changes in urinary hormone profile. Clinical Chemistry, 43,2091-2098. 

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. 

The answer is b. (Idardman, p 1453. Katzung, p 705.) Finasteride is a competitive inhibitor of the steroid 5-reductase, causing reduction in plasma and prostate dihydrotestosterone. Males with benign prostatic hypertrophy (BPH) that are treated with finasteride are found to have decreased prostate size. A change in symptoms related to urination occurs in about one-third of patients... 

Fig. 1.1. General mechanism of action of steroid hormones. Steroid hormones cross through the plasmatic membrane without apparent difficulty favored by gradient. Some, which can be considered prohormones, are metabolized and transformed into more active products. This is the case with testosterone, which becomes dihydrotestosterone (DHT) in the target tissues of androgens, through the 5-alfa-reductase enzyme. The hormone binds to the receptor, a soluble protein of the cellular cytosol that, in the absence of hormone, is found associated with other proteins (hsp90 and others) that maintain the receptor in an inactive state. The hormone-receptor bond causes the other proteins to separate and a homodimer to be formed. The homodimer is the activated form of the receptor since it is capable of recognizing the genes that depend on that steroid hormone as well as of activating its expression, which leads to the synthesis of specific proteins...

Plasma prolactin levels are reduced with acute treatment and remain suppressed after 28 days of chronic treatment (Murphy et al. 1998). With acute treatment, no effects are seen on plasma luteinizing hormone or testosterone levels. However, chronic dietary 5% ginseng increases testosterone levels in male rats (Fahim et al. 1982). Chronic ginsenosides do not alter posterior pituitary hormones oxytocin and vasopressin (Zierer 1991). Similarly, human males administered ginseng extract showed an increase in plasma testosterone, dihydrotestosterone, follicle-stimulating hormone, and luteinizing hormone, but a decrease in prolactin (Salvati et al. 1996). 

Pharmacology Finasteride is a competitive and specific inhibitor of steroid 5 -reductase, an intracellular enzyme that converts testosterone into the potent androgen 5 -dihydrotestosterone (DHT). 

---