The Use of Dogs for Studies of Toxicity of Contraceptive Hormones

Abstract

Responses to endogenous and exogenous sex steroids in the dog are characteristic for that species, differing in many important aspects from other laboratory animals and man. Long-term administration to dogs of progesterone and synthetic compounds structurally related to this natural gestagen has resulted in precocious development of mammary gland tumours and other changes suggesting stimulation of anterior pituitary activity. Progestogens structurally related to testosterone have not induced similar effects. Results obtained to date indicate a lack of relevance of data obtained in the dog to the prediction of clinical potential of sex steroids for mammary gland carcinogenesis.The scientists responsible for pre-clinical evaluation of the safety of a new drug for use in man are continually placed in a dubious position: of what potential relevance to man are the results of their animal studies? One approach to increasing the predictability of the results of animal toxicity studies for man is by the use of more than one species of animal. The assumption is made that the more animal species affected by a test compound in a given way, the more likely an untested species (in this case man) will respond in a similar manner. The converse is also assumed; namely, that a toxic effect elicited in only one animal species of several tested is less likely to be predictive for man. In prac¬ tice this philosophy is expressed in the standard use in many areas of the world of two types of animals, rodents and non-rodents. The rodents usually selected are the mouse or the rat, and the non-rodent is most often the dog. More recently, however, toxicologists have tended to use subhuman primates in this category presumably because they are phylogenetically closer to man than other experimental species.In the U. S. a unique series of toxicity studies with oestrogens and progesto¬ gens intended or used for contraceptive purposes in man was introduced by the F. D. A. in 1967A. in (Goldenlhal 1969. These were 7-year studies in dogs and 10-year studies in monkeys. The F. D. A. guidelines for the long-term toxicity trials with contraceptive steroids specified that the compounds be administered at 10 and 25 times the human dose in dogs and 10 and 50 times the human dose in monkeys on a body weight basis. Additional groups could be included, of course, at the discretion of each sponsoring firm. Furthermore, the dosing regimen for both dogs and monkeys was required to be the same as that for women. Because of certain characteristic responses to endogenous and exo¬ genous sex steroids the relevance of the studies in dogs was questioned. Some unique responses of the bitch to sex steroids In response to both endogenous and exogenous sex steroids, the female dog responds in several parameters in a manner not observed in other experimental species or in man.

Contraceptive steroids and the mammary gland: Is there a hazard?

“…Initial findings indicated that synthetic progestins derived from 19-nortestosterone stimulate mammary tumor development in the dog only weakly or not at all [1,3,19]. The difference in tumorigenicity of these two classes of progestins has been attributed to differences in progestin activity, as reflected by their transformative potency in the endometrium, the 17c~-hydroxyprogesterone derivatives being much more potent in the dog than are the 19-nortestosterone derivatives [19][20][21].…”

“…The difference in tumorigenicity of these two classes of progestins has been attributed to differences in progestin activity, as reflected by their transformative potency in the endometrium, the 17c~-hydroxyprogesterone derivatives being much more potent in the dog than are the 19-nortestosterone derivatives [19][20][21]. In humans, however, CS derived from 19-nortestosterone have greater progestin activity than do those derived from 17o~-hydroxyprogesterone [21].…”

“…An important question is how the progestin activity of CS on the endometrium, assessed as endometrial transformation in a modified Clauberg test [19,21], is related to their ability to stimulate proliferation in the mammary gland. In one investigation there was a good COlaelation between the magnitude of these two actions [2].…”

“…Growth stimulation by CS of (partly) transformed cells cannot be excluded as another mechanism [99,100]. The finding in toxicity studies of CS in the dog that some of the mammary "nodules" disappeared upon cessation of treatment [19] is suggestive of such an effect. Great effort is still needed to elucidate the mechanism behind these mitogenic effects, and to define the periods of susceptibility as well as the subsequent events that force target cells away from the normal differentiation program.…”

Serum oestrogen, progesterone and prolactin concentrations in cyclic, pregnant and lactating beagle dogs

“…Such understanding is important because animal testing requirements for hor¬ monal contraceptives and for progestagens and oestrogens used over long periods for non-contra¬ ceptive purposes include long-term toxicity studies in the dog. Certain progestagens used for human contraception have led to mammary gland changes in the dog, including enhanced occurrence of mammary gland neoplasia (Goldzieher & Kraemer, 1972; Wazeter, Geil, Berliner & Lamar, 1973;Hill & Dumas, 1974). The fact that the changes in the mammary gland have been found almost exclusively in the dog, rather than in rats, monkeys and man, has led to the assumption that the pro¬ gestagens concerned are progestationally very active in the dog (Hill, Averkin, Brown, Gagne & Segre, 1970;Graf, El Etreby, Richter, Günzel & Neumann, 1975;Haase, Beier, Hartmann & Elger, 1977), or that the canine mammary and/or anterior pituitary gland is very sensitive to progestagens (Neumann & Elger, 1972).…”