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IT IS GENERALLY RECOGNIZED that the response of an organism to estrogenic treatment is influenced not only by the quality and quantity of the substance used but also by the sensitivity or threshold to the hormone. Coward and Burn (I), Marrian and Parkes (2), and D'Amour and Gustavson (3) postulate that differences in the extent of the vaginal reaction to equal doses of estrogen are attributable toindividual differences in sensitivity. The importance of age in the degree of response to estrogenic treatment is apparent from the observation (4) that the menstrual thresh-old to ovarian follicular hormone is high in immature rhesus monkeys and from the observation (5) that the responsiveness of the perineum in adult baboons is more marked than in prepuberal animals Wiesner (6) states that, due to the absence of reactivity to estrogen, cornification of the vagina and enlargement of the uterus are not detectable within the first few days of postnatal life

ESTROGEN and progesterone administered in the proper sequence have been found to be more effective than estrogen alone in inducing sexual receptivity in the guinea pig (i). Since this was the only species in which this action of estrogen and progesterone had been observed, it seemed desirable to ascertain if these hormones acting synergistically are not also effective in inducing heat in another species such as the rat. The rat was chosen because the occurrence of mating in 'constant estrous animals' which ordinarily do not mate, ovulate, or form corpora lutea has been reported following the injec'tion of Iuteini2;ing hormone (2, 3). The induced mating was associated with ovulation and corpus luteum formation and suggested a relationship between the appearance of the corpora lutea and mating, similar to that postulated for the guinea pig. The possibility has been investigated and data, which indi' cate that in this respect the rat is similar to the guinea pig, are given below.

THE CONSISTENT induction of mating behavior in the spayed females of severalspecies is dependent upon the injection of estrogen and progesterone in proper sequence (guinea pig, Dempsey, Hertz and Young, 1936; rat, Boling and Blandau, 1939; mouse, Ring, 1944). It is assumed that this is the estrus-mechanism operating in normal females, at least in these species, the progesterone being secreted by luteinizing granulosa cells in the preovulatory follicle. For a review of the literature in this connection see Young (1941).If the normal induction of estrus depends upon the synergistic action of follicular estrogen and progesterone, it is necessary to explain the mechanism by which heat (usually low grade) irregularly follows injections into spayed animals of relatively large amountsof estrogen alone. One possible interpretation is that injected estrogen stimulates the production and release of progesterone or a progesterone-like steroid from an extra-ovarian source.

Castrated adult male rats administered both estradiol benzoate (E) and fluoxymesterone (F) exhibited frequent mounts, intromissions and ejaculations. Male castrates administered only E mounted often but rarely intromitted or ejaculated, whereas those administered only F behaved like oil-injected controls, showing a rapid reduction in the frequency of all mating responses. These results suggest that male rats can achieve intromissions and ejaculations without direct androgenic stimulation of the neural substrate controlling copulation; only androgenic stimulation of the penis is required for the occurrence of these behaviors. (Endocrinology95: 912, 1974)

baton rougeFollowingestrone priming, the ovariectomized golden hamster responds to injections of progesterone in adequate doses by exhibiting psychic estrus as do also certain other common laboratory rodents, a fact first established by Frank and Fraps (1945) and subsequently verified by Kent and Liberman (1947) while studying vaginal smears associated with induced mating. While the threshold dose of progesterone necessary to effect psychic estrus when administered via a subcutaneous route has not been established, Frank and Fraps observed no mating among animals subjected to subcutaneous injection of 0.02 mg. of progesterone 24 to 48 hours after estrogen priming, but found that 0.05 mg. of progesterone was as effective in inducing mating as was 10 times this quantity. The purpose of the present paper is to report that doses of progesterone too small to effect psychic estrus when administered subcutaneously to ovariectomized, estrogenprimed females may be entirely adequate in inducing typical mating responses when introduced directly into the ventricles of the brain.

Male and female rats respond differently to estrogen treatment in terms of the elicitation of mating responses. It was hypothesized that this differential behavioral response may reflect a differential accumulation and/or retention of estrogen in those neural cells which mediate behavior. To test this hypothesis, male, female and neonatally androgen-treated female rats, gonadectomized in adulthood, were administered tritiated estradiol iv and were sacrificed 5, 30 or 60 min later. Radioactivity levels were assessed in the following samples: brain-hypothalamus, preoptic-diagonal band region and cortex; pituitary, muscle and uterus. All tissues exhibited an accumulation of radioactivity. Except for pituitary, all tissue showed decreasing radioactivity with time after treatment. Except for cortex, males exhibited lower radioactivity levels than females. Males, however, weighed more than females at the time of treatment. Therefore, similar procedures were followed in a second experiment in which males and females were equated for body weight. In these animals no male-female differences in radioactivity were found. It was concluded that males and females do not differentially accumulate and retain estrogen. (Endocrinology85: 373, 1969)

ESTROGEN followed after a suitable interval by a small amount of progesterone is more effective than estrogen alone in inducing mating responses in the spayed female guinea pig (Dempsey, Hertz and Young, 1936) and in the spayed female rat (Boling and Blandau, 1939). Heat could be induced consistently in the spayed females of these species only when the two hormones were injected in proper sequence. The estrous behavior following estrogen-progesterone administration more closely resembled normal estrus in character and duration than did that following the injection of estrogen alone. These investigators therefore concluded that in the normal female guinea pig and rat sexual receptivity is the result of a conditioning action of follicular estrogen followed by the action of progesterone secreted by the preovulatory follicle. The literature supporting this view has been extensively reviewed by Young (1941).

MANY EXPERIMENTS have been reported on the effectiveness of hormone administration by other than the parenteral route. It is quite generally agreed that the oral route is least effective1 while percutaneous application is often nearly as effective as subcutaneous injection. In a previous report2on the oral effectiveness of progesterone and pregneninolone in the spayed female guinea pig it was shown that 20times the subcutaneous dose was required to elicit behavioral mating responses. Using the mating response characteristic of the guinea pig and rat as a criterion,3,4it was practicable to compare the two species in their sensitivity to various sex hormones when administered orally, percutaneously or subcutaneously. Materials and methods. Spayed female guinea pigs and rats are properly conditioned if given 10 R.u. estradiol benzpatej subcutaneously in oil. The animals can be brought into heat if they receive subcutaneously 0.05 mg. (guinea pig) or 0.4 mg. (rat) progesteronef 48 or 72, hours later.