Journal of Andrology
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Published-Ahead-of-Print April 8, 2010, DOI:10.2164/jandrol.109.009365

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Effects of Synthetic Androgens on Liver Function Using the Rabbit as a Model

Sheri Ann Hild *, Barbara J Attardi , Sailaja Koduri , Bruce A Till , and Jerry R Reel

* To whom correspondence should be addressed. E-mail: shild{at}comcast.net.

The objective of this study was to determine if the rabbit was a suitable model to test new synthetic androgens for potential liver toxicity within a short dosing interval. Adult male rabbits were dosed orally daily on days 0-13 with 17 {alpha}-methyltestosterone (MT), as a positive control, and testosterone (T), as a negative control, to validate this model. Synthetic androgens tested were: 7 {alpha}-methyl-19-nortestosterone (MENT), dimethandrolone-undecanoate (DMAU), and 11{beta}-methyl-19-nortestosterone-17{beta}-dodecylcarbonate (11{beta}-MNTDC). Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase (GGT), and sorbitol dehydrogenase (SDH), as well as clearance of intravenous injected bromsulfonphthalein (BSP) from serum on days 0, 7 and 14, were determined. As expected, T (10 mg/kg/day) did not adversely affect BSP retention or serum liver enzymes. MT (10 mg/kg/day) increased BSP retention, and AST, ALT, GGT, and SDH levels indicating that this model could detect androgens known to be hepatotoxic. DMAU and MENT (10 mg/kg/day), increased BSP retention, and all 4 serum liver enzymes as well, but the effects were less than those observed with MT at the same dose. All parameters returned to baseline 2 weeks after cessation of dosing. 11{beta}-MNTDC at 10 mg/kg/day did not have an effect on BSP retention or liver enzymes, but a slight increase in serum GGT levels was observed in rabbits treated with 25 mg/kg/day. For the androgens that exhibited liver toxicity at 10 mg/kg/day (MT, DMAU, and MENT), a no observed effect level (NOEL) of 1 mg/kg/day was established. Overall ranking of the synthetic androgens from most to least hepatotoxic based on %BSP retention was: MT >> DMAU > MENT > 11{beta}-MNTDC. Hence, the rabbit appears to be a promising model for detection of potential liver toxicity by synthetic androgens using BSP clearance and serum liver enzyme levels as early indicators of injury.


Key words: Androgen • Andropause • Contraception • Hormone • hepatotoxicity




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B. J. Attardi, J. A. Engbring, D. Gropp, and S. A. Hild
Development of Dimethandrolone 17{beta}-Undecanoate (DMAU) as an Oral Male Hormonal Contraceptive: Induction of Infertility and Recovery of Fertility in Adult Male Rabbits
J Androl, September 1, 2011; 32(5): 530 - 540.
[Abstract] [Full Text] [PDF]


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