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

Abstract

The objective of this study was to determine whether 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 17a-methyltestosterone (MT) as a positive control and testosterone (T) as a negative control to validate this model. Synthetic androgens tested were: 7a-methyl-19-nortestosterone (MENT), dimethandrolone-undecanoate (DMAU), and 11b-methyl-19-nortestosterone-17b-dodecylcarbonate (11b-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/d) did not adversely affect BSP retention or serum liver enzymes. MT (10 mg/kg/d) 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/d) 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. 11b-MNTDC at 10 mg/kg/d 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/d. For the androgens that exhibited liver toxicity at 10 mg/kg/d (MT, DMAU, and MENT), a no-observed-effect level of 1 mg/kg/d was established. Overall ranking of the synthetic androgens from most to least hepatotoxic on the basis of percent BSP retention was: MT & DMAU . MENT . 11b-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.

Development of Dimethandrolone 17 -Undecanoate (DMAU) as an Oral Male Hormonal Contraceptive: Induction of Infertility and Recovery of Fertility in Adult Male Rabbits

“…As DMAU at 10.0 mg/kg/d had been shown previously to affect liver function in the rabbit within 14 days of treatment (Hild et al, 2010), serum samples obtained prior to dosing on days 0, 15, 30, 60, and 90 were analyzed for ALT, AST, GGT, and SDH using established methods. By day 15, serum levels of all 4 liver enzymes were significantly elevated (Table 3), confirming the results of our previous study (Hild et al, 2010). However, serum levels of AST, ALT, and SDH decreased by day 60, but only the level of serum ALT remained significantly higher than that observed prior to treatment (day 0).…”

“…Serum liver enzymes (AST, ALT, GGT, and SDH) were analyzed by Ani Lytics Inc (Gaithersburg, Maryland) as described previously (Hild et al, 2010).…”

Single, escalating dose pharmacokinetics, safety and food effects of a new oral androgen dimethandrolone undecanoate in man: a prototype oral male hormonal contraceptive

“…Several preclinical studies with DMAU administered in an oral aqueous vehicle suspension in rats and rabbits showed that DMA suppresses gonadotropins, maintains androgenic effects, and inhibits spermatogenesis to induce reversible infertility in rodents (Attardi, et al , 2010; Hild, et al , 2010; Hild, et al , 2007). Unpublished toxicology studies administering oral doses of DMAU up to 125mg/Kg in rats, rabbits and monkeys did not reveal toxicological effects of DMAU/DMA even at these high doses (unpublished data form Bioqual Inc., Rockville, MD).…”

Acute Hepatitis and Fevers in an Amateur Body-Builder: A New Complication of Synthetic Androgen Abuse?

“…Injury is related to the dosing (16) and type of the synthetic androgen use with 17-alkylated androgens (methyltestosterone, methandrostenolone, oxandrolone, and stanazol) being responsible for liver damage (1,2,10,11,16). In addition, the accessory use of other potentially hepatotoxic agents in such risktaking individuals, such as tamoxifen in our subject, may compound the injury and complicate the identification of the chief offending agent.…”