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Following the prolonged administration of synthetic oestrogens to rats it has been shown that changes occur which are associated with a decreased function of the anterior pituitary gland [Noble, 1938a, 1938b, 1939]. When crystals or tablets of active substances were implanted into the subcutaneous tissues it was found that although they produced the typical changes the amount absorbed was very great over a prolonged period. Since inhibition of body-growth, lactation, and gonadotrophic hormone secretion of the anterior pituitary gland is readily produced by oestrogens, it was thought to be of importance to determine quantitatively the amount of oestrogen necessary to produce these effects. The relatively high oestrogenic activity of diethylstilboestrol when administered orally [Dodds, Lawson, and Noble, 1938; Parkes, Dodds, and Noble, 1938; Emmens, 1939], and its comparatively high solubility in aqueous solution, suggested that the oral administration of aqueous solutions could be adopted. By the substitution of
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The numerous publications on the action of androgens on the female animal have shown that quite different types of effects may be produced by closely related substances of the male sex-hormone group. In some cases, however, the type of response has been found to vary with the substance under different experimental conditions. These findings would suggest that some of the effects ascribed to the various androgens may in reality be the resultant of a direct action and an indirect one through interaction with other hormones. In the following observations an attempt has been made to investigate fully the action of testosterone propionate in the female rat. The changes produced in ovariectomized adult rats have been compared with those after hypophysectomy, and the response of the immature hypophysectomized rat has been determined before and after ovarian stimulation by gonadotrophic hormones. As will be shown, testosterone propionate may under some conditions produce
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In a preliminary report [Noble, 1938 a] it was shown that the subcutaneous implantation of crystals of synthetic oestrogenic substances was followed by an inhibition of body-growth for a prolonged period in adult rats, a decreased rate of growth in young animals, and a loss of gonadotrophic hormone from the anterior pituitary gland associated with atrophy of the reproductive organs. These changes could be produced by a substance such as diethylstilboestrol, the molecular structure of which had but little resemblance to the naturally occurring oestrogens. Up to the present time no qualitative differences in the effects of oestrogens on the various parts of the body have been demonstrated. Since a large series of synthetic oestrogenic substances which had been prepared in this laboratory were available for experimental study, it has been possible to compare the effects of representative active substances from different chemical groups with closely related substances of little
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SUMMARY
The progestational activity of 17α-methyldeoxycorticosterone acetate in the immature rabbit was investigated. The substance was found to exhibit high luteoid activity, equalling that of progesterone.
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The role played by the thyroid gland in the initiation and maintenance of the increase in oxygen consumption observed in homeothermic animals on exposure to low environmental temperatures has been the subject of much investigation and controversy. Cold-induced elevation of oxygen consumption has been confirmed for a wide variety of species [Benedict & MacLeod, 1929; Kayser, 1929; Chevillard, 1933; Kleiber & Dougherty, 1934; Collip & Billingsley, 1936; Ring, 1936, 1938, 1939, 1942], and it is also generally accepted that cold exposure induces histological evidence of activity within the thyroid gland [Cramer, 1916; Mills, 1918; Ludford & Cramer, 1928; Kenyon, 1933; Starr & Roskelley, 1940], and an increase in its fixation and turn-over of radio-iodine [Leblond, Gross, Peacock & Evans, 1944]. These observations, plus the finding that thyroidectomized rats are unable to tolerate refrigeration of the order of 0° to +5° C. for more than a few days [Korenchevsky, 1926; Ring,
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Evans, Meyer, and Simpson [1933] reported that in male hypophysectomized rats an extract of pregnant mare serum was capable of causing regeneration of atrophied testes and resumption of spermatogenesis and fertility. The accessory organs grew to normal size. Histologically the testes of the injected animals appeared normal. Similar results have been achieved with extracts of human pregnancy urine by Smith and Leonard [1934] and Evans, Pencharz, and Simpson [1934]. In the present experiments the relative efficiency of these two types of gonadotrophic extract have been compared in their ability to maintain and restore the reproductive system of hypophysectomized male rats.
Methods
Male albino rats of the Wistar Institute strain, 2½ to 3 months old, weighing 150 to 190 g. were hypophysectomized by a modified Selye technique [Collip, Selye, and Thomson, 1933]. Criteria of complete hypophysectomy were body-weight curve, adrenal weight, and examination of sella turcica at autopsy. In doubtful cases
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In a preceding paper [Liu and Noble, 1939] it has been shown that in male hypophysectomized rats, extracts of both pregnant mare serum and pregnancy urine were capable of exerting a marked effect on the testes as well as on the accessory sex organs. In the present experiments it was attempted to determine how far the results obtained on the male were comparable with those on the female hypophysectomized rats under similar experimental conditions.
Methods
The experimental procedure was the same as previously reported [1939]. Vaginal smears were made daily to determine the oestrogenic activity. In mating experiments, normal males were placed with the hypophysectomized females at 2 weeks after the commencement of treatment.
Results
Hypophysectomized controls. As shown in Table I, the rate of atrophy of ovaries and uteri of hypophysectomized rats was gradual up to 6 weeks after operation. After that time very little further decline in weight
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SUMMARY
1. The inhibiting action of extracts of Lithospermum ruderale (lithosperm) when mixed with various hormones has been described.
2. Pituitary gonadotrophin, prolactin (luteotrophin), thyrotrophin and pregnant mares' serum gonadotrophin (PMS) are readily inactivated. Chorionic gonadotrophin is less readily affected, and pituitary growth hormone and ACTH are unaffected by the concentration of lithosperm which inactivates the other hormones. Insulin and posterior pituitary hormones are equally unaffected.
3. PMS 'inactivated' by lithosperm is still capable of causing marked interstitial cell stimulation of the ovary of the intact rat with resulting oestrogen production. Hypophysectomy abolishes this reaction.
4. Various factors influencing the in vitro inactivation have been described, so that a standard method could be developed for testing fractions obtained in purifying lithosperm extracts.
5. Some preliminary extraction methods are discussed.
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Although it is now established that deprivation of vitamin E may lead to disturbances of structure and function of many tissues other than those primarily concerned in the reproductive cycle, it is not surprising, when the striking nature of the testicular degeneration and the curious character of the typical resorption in the female are borne in mind, that there has been a tendency to concentrate attention on the question whether the vitamin plays an essential part in the reproductive cycle.
The most direct approach has been made by investigating whether the vitamin itself exerts a gonadotrophic action. Up to the present the evidence has been inconclusive. The most striking claim is that of Szarka [1929], who stated that oral or parenteral administration of vitamin E concentrates produces oestrus in immature female rats. Later, Verzár [1931] recorded that injection of similar materials produced hypertrophy of the uterus in similar animals, but