Sources of androgen

Posted by admin on June 21st, 2010 No Comments

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Molecular biology of androgen axis

Testosterone is the major circulating androgen, with 90% produced by the testes. More than half of testosterone is bound to sex-binding globulin and 40% is bound to albumin. Only 3% of testosterone remains unbound, and this is the functionally active form of the hormone. After passive diffusion through the cell membrane into the cytoplasm, testosterone undergoes conversion to dihydrotestosterone (DHT) through the action of the enzyme 5α-reductase. Although the relative potencies of testosterone and DHT are similar (as defined by the ability to cause half-maximal response in a prostate regrowth model), if the conversion of testosterone to dihydrotestosterone is blocked by the 5α-reductase inhibitor finasteride, 13-fold more testosterone is required for the same effect. Both testosterone and DHT exert their biologic effects by binding to the androgen receptor in the cytoplasm, promoting the association of androgen receptor co-regulators. The complex then translocates to the nucleus and binds to androgen response elements in the promoter regions of target genes.

Molecular biology of androgen axis

Androgen deprivation is one of the most effective therapies against any solid tumor; unfortunately, with time, almost all prostate cancers will become androgen refractory.

All current forms of ADT function by either lowering levels of circulating androgens or blocking the binding of androgen to the androgen receptor.

Almost all androgen-refractory prostate cancer remains sensitive to androgen; therefore, ADT should continue in hormone-refractory disease.

Androgens produced by the adrenal gland, androstenedione and dehydroepiandrosterone, are stimulated by adrenocorticotropic hormone (ACTH) released by the pituitary gland in response to corticotropin-releasing factor. Adrenal androgens do negatively feed back on ACTH secretion; cortisol acts as the feedback signal. Adrenal androgens are relatively weak compared with testosterone and DHT and are almost entirely bound to albumin ( Table: Major Circulating Androgens ). Adrenal androgens remain normal in men who have undergone orchiectomy, and adrenal androgens are insufficient to maintain prostatic epithelium in such men.

Table: Major Circulating Androgens

Source	Androgen	Amount Produced per Day (mg)	Relative Potency	Relative Potency/Amount Produced
Testes	Testosterone	6.6	100	15.2
Testes and peripheral tissues	Dihydrotestosterone	0.3	160-190	533-633
Adrenal	Androstenedione	1.4	39	27.9
Adrenal	Dehydroepiandrosterone	29	15	0.5

Drug Interactions in the Treatment of ED, LUTS and BPH: 5-Alpha-Reductase Inhibitors Pharmacodynamics The deficiency of 5-alpha-reductase was discovered more than 30 years ago. At this time, the role of 5-alpha-reductase inhibitors was hypothesized to be beneficial for the treatment of androgen-related diseases. Dihydrotestosterone (DHT) is the main prostatic androgen and is approximately twice as potent as ...
Mechanisms of androgen axis blockade There are four therapeutic approaches for androgen axis blockade in current clinical use: ablation of androgen sources, inhibition of androgen synthesis, antiandrogens, and inhibition of luteinizing hormone–releasing hormone (LHRH) or luteinizing hormone (LH) release ( Table: Therapeutic Approaches to Androgen Deprivation ...
Prostatitis Syndromes. Part 1 The related syndromes of prostatitis remain a frustrating clinical entity both for clinicians, especially primary care physicians, and for their patients. The primary problem facing physicians is differentiating between bacterial and non-bacterial prostatitis. Although non-bacterial prostatitis appears to be far more ...
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Trimethoprim-sulfamethoxazole in the treatment of chronic prostatitis. Part 2 Treatment Antibiotic therapy with appropriate agents, even in well documented infections, rarely proved successful in the past because the diffusion of most antibacterial drugs from plasma into prostatic fluid provided too low a concentration to be effective. Of many drugs tested ...

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