Cniiwaity Scliool of ;CLedici?ie OKE PLATE (EIGHT FIGCRES) Ovulatioii in the rabbit \\as first observed and described by Walton and Hammond ( ' 2 3 ) . Snbsec~aeiitly other investigators have repcated these obser~-ations, but, as far as we know, no other descriptions have been pnblished. TVe wished to investigate ovulation further, and to accurate17 record OUT observations by making moving pictures of Ihe actual process. Thc Baldwin-Patten moving picture apparatus ( Patten and IZramcr, '33) was used.

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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.

Allen, 1932]. As regards the second method, two chief types of assay are in use, namely the determination of the power of the hypophysis to cause (a) ovulation in the cestrous rabbit, and (b) growth of the immature rat or mouse ovary. The second of these has been most commonly used, but the first is the more definite and the more quantitative. The two methods give very different results, and the first will not be discussed here. Using the rabbit ovulation tests, Wolfe [1931] found that the potency of the anterior lobe of sows decreased at the onset of cestrus, and further decreased during pregnancy, but no attempt was made at a quantitative assay in correlation with definite stages of pregnancy.Fee and Parkes [1929], and Smith and White [1931] have shown that the removal of the pituitary by decerebration, less than 1 hour after mating, inhibits the ovulation which would otherwise take place 10-12 hours later. If, however, the time elapsing between mating and hypophysectomy exceeds 1 hour, ovulation follows in normal sequence. From these experiments it seemed likely that very rapid functional changes must take place in the anterior lobe of rabbits in the first few hours after mating, and that an accurate knowledge of those changes would be of importance. It was decided therefore to obtain and assay PH. LXXXIII.

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