The progestational activity of different gestagens used for human contraception in the beagle bitch

Abstract

In long-term studies chlormadinone acetate (CMA) and cyproterone acetate (CPA) have much more pronounced mammotropic effects in dogs than norethisterone acetate (NA) or levonorgestrel (LN). To evaluate gestagenic potency of these compounds in dogs as a potential determinant of these substance differences, a quantitative canine gestagen bioassay was developed. Ovariectomized adult beagles were sequentially treated with 30 μg estradiol (E 2)/d s.c. for 15 days and gestagen (s.c., p.o.) + 3 μ g E 2/ d s.c. days 16–29. This regimen was found optimal for endometrial gestagen effects. According to their s.c. transformatory potency in day 29 endometrial biopsies, the compounds could be ranked as follows; progesterone (P) <NA<LN=CMA=CPA. The corresponding threshold doses (TD s.c.) were 3.0–10.0, 1.0, 0.1–0.3, 0.1–0.3 and 0.3 mg/d. A different rank was found after p.o. administration: NA<P (s.c.) <LN<CMA=CPA. The corresponding TD p.o. were ≧ 30.0, 3.0–10.0, 1.0, 0.1 and 0.1 mg/d. Related to p, LN and NA have a much lower gestagenic potency in dogs than in humans. The opposite is true for CMA and CPA. The low oral activity of NA and LN in dogs points to an important first liver passage metabolism of both compounds in this species. Serum determinations substantiate the very low or high oral. bioavailability in case of LN, NA and CPA. Clinically, by the oral route of administration, there is no doubt of the fact that CMA is markedly less potent than NA which itself is less potent than LN whereas in the dogs, CMA is unequivocally the most potent of the progestagens under consideration. This implies that the dogs are overdosed with several human multiples when CMA is administered and probably underdosed with NA, at least on a comparative basis. Our data are consistent with the view that the ability or inability of gestagens to induce mammary tumours in chronic toxicity studies might reflect a dog-specific high or low gestagenicity.