Inhibition of 5alpha-reductase blocks prostate effects of testosterone without blocking anabolic effects.

Abstract

We studied the effect of the 5alpha-reductase inhibitor MK-434 on responses to testosterone (T) in orchiectomized (ORX) male Brown Norway (BN) rats aged 13 mo. At 4 wk after ORX or sham surgery, a second surgery was performed to implant pellets delivering 1 mg T/day or placebo pellets. During the second 4 wk of the study, rats received injections of MK-434 (0.75 mg/day) or vehicle injections. Treatment with T elevated serum T to 75% above that for sham animals (P = 0.002) and did not affect serum dihydrotestosterone (DHT) or serum estradiol. T treatment also caused an elevation of prostate T and a marked elevation of prostate DHT. During the second half of the study, ORX rats lost an average of 18.86 +/- 4.62 g body wt. T completely prevented weight loss, and the effect was not inhibited by MK-434 (P < 0.001). ORX produced a nonsignificant trend toward a small (5%) decrease in the mass of the gastrocnemius muscle (P = 0.0819). This trend was also reversed by T, and the effect of T was not blocked by MK-434. T caused a significant 16% decrease in subcutaneous fat that was not blocked by MK-434 (P < 0.05). Finally, T caused a 65% decrease in urine excretion of deoxypyridinoline, a marker of bone resorption, and again the effect was not blocked by MK-434 (P < 0.0001). In contrast, T caused a greater than fivefold increase in prostate mass, and the effect was almost completely blocked by MK-434 (P < 0.0001). This study demonstrates that 5alpha-reductase inhibitors may block the undesirable effects of T on the prostate, without blocking the desirable anabolic effects of T on muscle, bone, and fat.

• Authors: Stephen E Borst, Jun Hak Lee, Christine F Conover
• Journal: American journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 288 Issue 1 Pg. E222-7 (Jan 2005) ISSN: 0193-1849 [Print] United States
• PMID: 15367394 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 17 beta-benzoyl-4-aza-5 alpha-androst-1-ene-3-one
• Androgens
• Dihydrotestosterone
• Testosterone
• Finasteride
• Cholestenone 5 alpha-Reductase

Topics

• Androgens (blood, pharmacology)
• Animals
• Body Composition
• Bone Resorption
• Cholestenone 5 alpha-Reductase (antagonists & inhibitors, metabolism)
• Dihydrotestosterone (metabolism)
• Drug Interactions
• Finasteride (analogs & derivatives, pharmacology)
• Male
• Muscle, Skeletal (drug effects, metabolism)
• Orchiectomy
• Prostate (drug effects, metabolism)
• Rats
• Rats, Inbred BN
• Testosterone (blood, pharmacology)