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IT HAS BEEN SHOWN that single injections of estradiol benzoate, progesteroneor of combinations of both into normal adult female baboons in the first part of the cycle will cause the turgescent perineum to undergo deturgescence (11, 12, 13). Deturgescenceof the perineum is normally encountered in the second part of the cycle when the corpus luteum develops on the ovary. In castrate animals treated repeatedly with estrogen the perineum becomes turgescent, but when the estrogen is withdrawn the perineum undergoes deturgescence. It was felt that progesterone could cause perineal deturgescence by acting directly on the perineum as this substance is normally present in the second half of the cycle. Gillman and Stein (16) have shown that, even in the presence of enormous quantities of estrogen, the perineum will undergo deturgescence, provided adequate quantities of progesterone are simultaneously administered.

It has been known for many years that emotional states and mental and physical efficiency of women fluctuate very considerably during the menstrual cycle. Ellis (1) has summarized in a masterly fashion the literature relating to this subject. The social implications of these collective observations have not been sufficiently appreciated in regulating the activities of women in industry and in other potentially hazardous occupations. Frank (2) has drawn attention to the severe handicaps experienced by some women in the premenstruum. These may become so grave as to necessitate drastic treatment by temporary or even permanent inactivition of the ovaries. Frank thought that these disturbances were associated with an overproduction of estrogen and its defective excretion. Later Israel (3) tentatively concluded that premenstrual tension was due to defective luteiniziation or relative hyperestrogenemia and he therefore suggested the use of corpus luteum to alleviate this condition. In a recent paper it was shown...

THE PROGESTATIONAL EFFECT of progesterone on the uterus of the castrated rabbit previously treated with estrogen is widely known (1, 2). It is also well known that estrogen can antagonize the progestational response induced by progesterone (3, 4). It is not known, however, that in castrated rabbits progesterone and estrogen combined in suitable concentrations can induce widespread vascular changes both in the myometrium and endometrium, culminating in uterine hemorrhage. Zondek (5, 6) by using prolan A has caused uterine hemorrhage in non-castrated immature rabbits. He believed that “either from estrin or progesterone or from both a new substance is formed in the body in the interval between its production and its utilization and that this transformed substance causes bleeding.” It is the object of this paper to examine the various combinations of estradiol benzoate and progesterone which can evoke the vascular changes in the uterus of castrated rabbits.

THE OBJECT OF THIS PAPER is to record the effects of single injections of varying amounts of estradiol on the behavior of the perineal (sexual) swelling and on the length of themenstrual cycle in the baboon (Papio porcarius) when given on the 8th to ioth day of the menstrual cycle. An assessment is made of the action of exogenous estrogen on the ovary as determined by the reaction of the perineal swelling and by the alteration in the length of the menstrual cycle.Atthe same time the possibility is considered of determining by an indirect approach, the amount of estrogen elaborated by the ovary on a particular day in the first part of the cycle. At the same time the mechanism whereby menstruation is postponed by the administration of estrogen is discussedin the light of the facts presented in this study. Attention is also drawn to the fact that whenever estrogen is used therapeutically in sufficient amounts, among its various effects it will also produce ovarian inhibition.

IT HAS BEEN SHOWN PREVIOUSLY (1) that 3 to I J mg. of progesterone administered to baboons as a single injection in the first part of the cycle rapidly induced perineal deturgescence and rest within 4 to 7 days; without the intervention of bleeding the perineum commenced to swell once more and passed through a normal cycle except that the experimental cycle of which this new one was a part was lengthened. A single injection of as much as 20 mg. of progesterone, however, given under similar circumstances, induced theswollen perineum to return rapidly to rest within 4 to 7 days, but bleeding was precipitated prematurely and the cycle was shortened by more than half its normal length. Moreover, when a single injection of 1 to 5 mg. of estradiol bensoate was given to baboons in the first part of the cycle the turgescent perineum continued to increase in sise for 4 to 11.

Despite the fact that estrogens are extensively used in clinical gynecology, from the literature available it appears that, with one exception (1), there is no information concerning the effect of estrogens on the human ovary. Even when estrogen has been used to postpone the onset of mestruation in normal women (2) it has not been possible to predicate how it was accomplished except that it is commonly stated that this hormone inhibits temporarily the gonadotropic function of the anterior lobe of the pituitary. The understanding of the action of estrogen in the human female is further complicated by the fact that even in laboratory mammals and especially in primates there is still a paucity of data as to how estrogen affects the normal ovary. According to Allen, Hisaw and Gardner (3) estrogens given over long periods of time inhibit the ovary. The ovaries of mice after treatment with 500 i.u. of estrogen weekly for 150 days are usually small (3).

THE PERINEUM of the adult female chacma baboon has been shown to undergo rhythmical alterations in size during the menstrual cycle (1, 2, 3). These flue-tuations have been measured and recorded daily and correlated with the vaginal smear (4). Parkes and Zuckerman (5) were the first to show that the turgescence of the perineum in baboons is due to the presence of estrone. This has been confirmed by Gillman in both adult and prepubertal baboons (6, 7). The factors responsible for perineal deturgescence and menstruation are less definitely known.Allen (8, 9) and Corner (10) have suggested that the withdrawal of estrone is responsible for menstruation. This has been largely supported by Zucker-man (n). Fluhman (12,) maintained on valid evidence that the'estrin privea1 hypothesis of Allen and Corner was inadequate to explain the onset of bleeding.

BLEEDING from the uterus in Primates is usually attributed to withdrawal of estrogen or progesterone or to simultaneous withdrawal of both these hormones. The role of the pituitary in the bleeding mechanism is said to be secondary via the gonadotrophic hormones which regulate the amount of estrogen and progesterone secreted by the ovary. However, Hartman et al. (1930) reported that in the hypophysectomized monkey, estrogen-withdrawal bleeding occurred only after the administration of alkaline extracts of the pituitary. These investigators emphasized that, after treatment with their pituitary extract, bleeding could occur without any observable change in the ovaries or uterus. Accordingly, Hartman et al. postulated as the direct cause of bleeding the presence of a hormone independent of follicle-stimulating or luteinizing principles contained in the pituitary.

IN A PREVIOUS communication (i) we reported on the quantitative inhibition of estradiol benzoate by progesterone in the immature and adult castrate baboon (Papio porcarius). The criteria used for this purpose were based on the perineal deturgescence and the onset of progesterone-withdrawal bleeding. No proportional relationship was found in the antagonism of estradiol benzoate and progesterone such as was said to exist in other animals. Instead we discovered that an adequate or optimal amount of progesterone could antagonize effectively large quantities of estradiol. The antagonism of these hormones has been examined in the mouse (2), in the rat (3), in the rabbit (3, 4, 5), in the monkey (6) and in the Algerian monkey (3). The rabbit has been the animal commonly employed for this purpose, but Robson (2) alone has presented a detailed quantitative analysis of the antagonism between estrogen and progesterone.

A simple dietary technique is described for the production of hepatic necrosis. The liver lesion develops consistently in rats weighing between 30 and 200 gm. at the commencement of the experiment. The time of onset of necrosis, however, is a function of the age of the rat.

IN A PREVIOUS study (I) it was shown that progesterone when repeatedly given in the first part of the cycle of a normal adult female baboon the turgescent perineum underwent deturgescence very rapidly and returned to its resting state. This resting condition could be maintained over a period the length of which was determined only by the administration of the progesterone. Further it was shown that if the total quantity of the hormone exceeded 15 mg. bleeding invariably occurred after withdrawal, the exact time of the onset of bleeding being determined purely by the quantity of progesterone used. If the total amount of progesterone happened to be less than 15 mg. then, after its induced resting state, the turgescent perineum rose rapidly without any microscopic evidence of bleeding. This experimentally affected cycle was invariably a prolonged one. The conclusion was arrived at that in a normal adult baboon deturgescence is a positive phenomenon initiated by progesterone or an allied substance.

THE MENSTRUAL CYCLE of the baboon has been under investigation for the past 10 years in our department. During these studies dailymeasurements of the fluctuations in the perineum of the normal female baboon have proved a reliable indicator in experimental work involving the female sex hormones because it is demonstratively sensitive to estrogens as well as to progesterone. By this simple method of external measurement uncomplicated by operative procedures the qualitative effects of both these hormones in prepubertal, castrate, and normal animals have been followed day by day. Having in our hands this simple external indicator we have recently concentrated our efforts on the quantitative balance between estrogens and progesterone. By varying the amounts of estrogen and progesterone any gradation of change in the cycle between one that is normal and one that has been upset is accessible to mensurable expression. Clinically it is of the utmost importance to understand this quantitative balance between the es...

THE DISTRIBUTION of lipoids in the endometrium at different phases in the human menstrual cycle was first described by Aschheim (1). He drew attention to the appearance of fat in the base of the uterine gland cells in 80% of endometria in the late second half of the cycle. Unfortunately Aschheim's findings were seriously questioned by Froboese (3) who was of the opinion that the intracellular fat in the glands was due to degenerative changes which immediately precede menstruation. On this account Aschheim's original observations failed to emerge from their academic obscurity; certainly no attempt had been made to apply these facts to clinical problems. Gillman (4, 5) in refuting Froboese's contention that basal fat was due to cell degeneration, affirmed instead that the fat was related to progesterone metabolism. Gillman (5) found that throughout the first half and indeed in the first week of the second half of the cycle, with few exceptions, the gland cells contained no Sharlach stainable fat.

THE QUANTITATIVE INHIBITION of estrogen by progesterone has been estimated exclusively by means of histological examination of the endometrium in primates. In the baboon, however, it is possible to determine the quantitive inhibition of the two ovarian hormones by means of the sexual skin and the time of the onset of bleeding after the last injection of the combined hormones. When estradiol benzoate is administered to a prepubertal or castrate baboon the perineum swells or turgesces, and with effective doses it reaches its maximum size in 7 to 10 days. When the hormone is withheld the perineum returns to its resting level about the 10th day, and between the 10th to 16th days after withdrawal of the estrogen bleeding supervenes (2, 3).

Complete removal of the pancreas from normal baboons, as in other mammals, leads to the development of the classical features of diabetes, including hyper glycaemia, ketonaemia and ketonuria, polydipsia, and polyuria. Investigation of the diabetic state in experi mental baboons revealed that the severity of the ketosis could not be correlated with the degree of hyperlipaemia or with the hyperglycaemia, and that the extent of the hyperglycaemia did not influence the hyperlipaemia (Gillman et al., 1958a). On the basis of experiments conducted in dogs, cats, and rats, it is generally believed that the fundamental disorder of carbohydrate meta bolism in diabetic animals is alleviated by hypophysec tomy, or by adrenalectomy, and that the administration of pituitary extracts and of adrenocortical hormones will once again restore the diabetic picture in depan creatized-hypophysectomized and in depancreatized adrenalectomized animals respectively (Houssay and Biasotti, 1931 ; and Long and Lukens, 1936). Reinvestigation of the role of the hypophysis and of the adrenal in depancreatized baboons not receiving insulin will show that the severity of the diabetes, as assessed by the hyperglycaemia and glycosuria, is not immediately alleviated by hypophysectomy although the clinical condition of the baboon is improved. It will also become apparent from the data presented below, taken in conjunction with previously reported experi ments (Gillman et al.9 1958a), that each aspect of the disorder of lipid metabolism is dependent upon a parti cular pattern of endocrine function. It is suggested that analysis of the various lipid fractions in the blood as well as of the blood sugar and blood ketones in each human diabetic may afford a useful guide to the relative participation of the endocrine glands in maintaining the disorder of metabolism.

ALTHOUGH the estrogen bleeding threshold has been established for monkeys (I, 2), no data are available concerning the minimum amount of estrogen required to produce an effect in the genital system identical with that induced by endogenous estrogen elaborated by the monkey's own ovaries during the first part of the cycle. We are not entitled to claim that the minimum amount of estrogen necessary to cause bleeding is identical with that secreted by the animal from the time of menstruation up to ovulation, even though there is a marked similarity in the histological appearances presented by these two types of endometrium at the height of estrogen effectiveness. With ordinary histological techniques the structure of two specimens of endometrium may appear to be the same, and yet with more sensitive histochemical procedures a very distinct difference may become manifest. This has been clearly shown in the human endometrium (3, 4, 5).

REVERSAL of the albumin/globulin ratio is commonly encountered in Africans in different parts of the continent of Africa. This reversal is ascribed in large measure to malnutrition and/or infection. Whatever the cause, the mechanism for this reversal still remains obscure.

Both acute necrosis and fibrosis of the liver of dietary origin in rats can be followed by complete restitution of structure in an appropriate dietary setting.

DEPANCREATIZED baboons, deprived of insulin for 4 days, develop a lipaemia and a fatty liver, which may contain 34 per cent of fat when estimated on a wet-weight basis1,2. The lipaemia in diabetic rats has generally been attributed to mobilization of fat from the depots. In the baboon, the severity of the lipaemia and the degree of fat accumulation in the liver, particularly in young animals with poorly developed fat depots, suggested that the fat was not mobilized only from the depots, and this warranted a re-investigation of the origin of the fat in the liver and in the plasma. In this communication it is proposed to report on the incorporation of 2-14C sodium pyruvate into the glyceride glycerol in a normal baboon and in depancreatized baboons either receiving insulin or deprived of insulin.

Le carcinome hepatocellulaire du type trabeculaire a paru dans 2 rats sur 5, 745 jours apres l'implantation de boulettes de progesterone cristallin et de propionate de testosterone, pesant 8 a 10 mg chacune. Un de ces rats a developpe un carcinome provenant de l'epithelium d'une bronchiole respiratoire. L'absence d'une cholangiofibrosite antecedente, d'une necrose ou d'une cirrhose hors de l'endroit de la tumeur du foie chez les rats soumis aux epreuves experimentales, peut necessiter un nouvel examen de la signification des lesions hepatiques comme facteur predisposant au cancer chez l'homme.

The role of the thyroid gland in modifying the incidence of hyperplasia and tumor formation of estrogen-induced pituitary tumors was invesigated in experiments using a total of 184 adult albino rats of Wistar strain. Single pellets of estradiol benzoate were implanted subcutaneously in 173 of these rats. Thiourea and thiouracil were fed at a 0.5% level in the stock ration. Thyroxin was injected subcutaneously 3 times a week in doses of 20 mcg. A steady enlargement of the pituitary gland was induced by estradiol benzoate in normal adult rats. In some rats pituitary enlargement can be detected by the 50th day and the gland may have increased 40-fold in weight between the 100th and 150th day. Thyroxin administration accelerates development of pituitary tumors and leads to premature death of the rats. In rats bearing an estrogen pellet but fed thiourea or thiouracil the pituitary gland showed only mild hyperplasia. Although only 2 of 6 throidectomized rats treated with estrogen survived beyond the 100th day evidence suggests that thyroidectomy also prevented the pituitary gland enlargement and that even partial thyroidectomy appeared to counteract the estrogens effect. Pituitary enlargement was also effectively inhibited by dietary restrictions as well as feeding of antithyroid drugs. It is concluded that depression of thyroid function inhibits pituitary hyperplasia and tumor formation in estrogen-treated rats while thyroxin produces the reverse effect.

SEVERE nuclear vacuolation has been observed in the liver cells of human diabetics1–3, of infants suffering from malnutrition2 and of patients suffering from various diseases2–5, but has not been reported in experimental diabetes, whether produced by pancreatectomy or by alloxan in laboratory animals. The factors promoting nuclear vacuolation still await investigation.

Die Entstehung von Reticulosarkom bei Ratten nach mehrmaliger Injektion von Trypanblau kann unterdruckt werden durch Entkraftung, Verabreichung anti-thyreoidaler Mittel und durch alle andern Faktoren, welche den Stoffwechsel herabsetzen.

CYTOSIDEROSIS is a diffuse metabolic disorder characterized by the deposition of large quantities of iron pigment, at first mainly in the liver and later in other organs and tissues of the body1,2. It occurs consistently in adult pellagrins, although it is commonly seen also in other members of the African population not suffering overtly from acute episodes of malnutrition3.

THE human corpus luteum of pregnancy is cystic up to the fourth month of pregnancy. The fluid content of the luteal follicle may be as much as 1.5 c.c.

OVER several years we have accumulated extensive material of serially sectioned ovaries and uteri of Elephantulus myurus jamesoni. From an examination of the ovaries it is now possible to identify accurately the physiological state of the animal in respect of its menstrual or reproductive cycle.

IT has been repeatedly shown1 that the administration of progesterone in amounts of 15–20 mgm. to normal adult baboons in the first part of the cycle (eighth-tenth day) will cause the turgescent perineum to undergo deturgescence, and premature bleeding supervenes within 5–8 days of the last injection. Any quantity of progesterone more than 3 mgm. and less than 15 mgm. will only cause perineal deturgescence.