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In the hypophysectomized albino rat which is protected from contact with steroids in the ration and environment the uterus and vagina are highly atrophic but are sensitive indicators of activity of substances which promote their growth. Both the pituitary growth hormone and certain steroids have the common property of inducing growth of these tissues. The vaginal epithelium consists of 2 layers of cells which differ profoundly in their growth in response to steroids, depending on the molecular structure of these compounds. The differential response to modifications of chemical structures of steroids permits evaluation of the importance of the intramolecular components for the process of growth. The number and site of functional groups, the geometry of the molecule and the state of oxidation are of high importance in determining physiologic activity of steroids in the androstane series; these features are less specific in the estrane series. Side groups at positions C(3) and C(17) are of importance in the promotion of growth by steroids in the androstane series, but these active centers are not equivalent in their physiological influence. As a generalization, hydrogenation of the oxygen function at C(17) (but not at C(3)) and dehydrogenation at critical areas of the ring structure increase the quantitative efficacy of steroids in promoting growth. The position of double bonds and the state of oxidation at both C(3) and C(17) determine the qualitative type of growth-cellular pattern, which a compound in the androstane series induces in the vaginal epithelium.
The influence of pituitary adrenocorticotropic hormone (ACTH) and growth hormone (somatotropin, STH), singly and in combination, has been studied in normal, young adult rats, with respect to antibody formation against Fraction IA of Pasteurella pestis. When ACTH was administered during the period of immunization, in a daily dose just sufficient to prevent body weight increase relative to the non-treated, immunized controls, serum antibody levels against the specific antigen employed were significantly depressed. The administration of STH alone resulted in a marked increase in body weight. The increase in antibody level was not significant at the 5 per cent level when compared with the control values. The same dosage of STH given simultaneously with ACTH maintained body weight at a level slightly above that of the controls, and resulted in an effective counteraction of the antibody depression produced by the latter hormone.
The influence of highly purified pituitary adrenocorticotropic (ACTH) and growth (somatotropic, STH) hormones on resistance of normal, young adult rats infected with Pasteurella pestis organisms (EV 76) has been studied. The daily dosage of ACTH was 0.1 mg. (25 I.U per mg.) and that of STH was 1.0 mg. When these hormones were administered for 3 days prior to infection (1 LD(50)) and for 4 days thereafter, ACTH treatment resulted in a significant depression of resistance (p = < 0.001). The simultaneous administration of STH not only resulted in a definite counteraction of the depression (p = < 0.001), but resistance was increased to a level significantly above that of the non-hormone treated controls (p = < 0.001). Treatment with STH alone also showed a significantly higher protection when compared to the same controls (p = < 0.05). The results of experiments in which the challenge dose was 1 LD(50) suggested that greater alterations in resistance, whether it be a depression or enhancement, could be obtained by continuing hormone treatment after challenge instead of discontinuing on the day prior to challenge. When animals were treated with a relatively high daily dose (1.0 mg.) of ACTH and challenged with only (1/4) of an LD(50) of organisms, the majority of animals died within 4 to 7 days, whereas either the ACTH treatment or the bacterial dose alone resulted in no deaths. If the hormones were administered for 2 weeks prior to challenge with a high, toxic dose of organisms (4 LD(50)), and discontinued thereafter, there were significant differences in mortality in the various groups during the first 24 hours post challenge. The ACTH treated group showed a marked drop in resistance (p = < 0.001). STH, when given alone, exercised a significant protection (p = < 0.02), and in combination with ACTH, effectively counteracted the depression of resistance to acute, toxic deaths induced by the latter hormone (p = < 0.001). In this particular experiment, practically all animals died within 4 to 5 days, owing to the high challenge dose; the few survivors were in the group that had been pretreated with growth hormone. The maximal loss in body weight following an LD(50) challenge dose occurred by the 3rd day post challenge in all groups except in the ACTH-treated animals. At this time the LD(50) control group had lost an average of 14 gm. per rat, the STH group only 3 gm. per rat, whereas the group receiving both hormones lost an average of 7.5 gm. per rat. The ACTH-treated animals showed the greatest weight loss on the 4th day. Thus, under the conditions of the experiment, the beneficial effect of STH on the maintenance of body weight was demonstrated during the period of acute infection. The peak incidence of death in controls or hormone-treated animals following infection with 1 LD(50) of living organisms occurred on the 4th to 5th day post challenge; the earliest deaths occurred on the 3rd day, while the latest occurred on the 7th day. The peak incidence of death after the 4 LD(50) challenge dose occurred earlier, falling on the 2nd to 3rd day. Death was always accompanied by the characteristic gross pathology which results from infection with Pasteurella pestis organisms, particularly in the animals which succumbed after the 3rd day. Bacterial cultures usually revealed the presence of numerous Pasteurella pestis organisms in the spleen and heart blood at the time of death.
Cortisone acetate, hydrocortisone, and hydrocortisone acetate depress the resistance of mice to pneumococcal and influenza viral infections, although hydrocortisone acetate is somewhat less effective than the free alcohol, when given subcutaneously. Pituitary adrenocorticotropin, even in highly purified form and in oil and beeswax, does not significantly alter the resistance of mice to these experimental infections, even when given in doses which may cause profound eosinopenia, lymphopenia, and weight loss, and which are at the limit of tolerance of the animals. Corticosterone depresses resistance to pneumococcal infections significantly, but fails to alter resistance to influenza viral infections. The findings suggest that murine adrenals may produce one of the known adrenal steroids such as corticosterone along with another steroid, or may produce a steroid other than cortisone, hydrocortisone, or corticosterone. When resistance is decreased by adrenal steroids, survival time is invariably shortened, and the effect of the steroid hormones is frequently demonstrable within the 1st day after infection with pneumococci, making it unlikely that the depression of resistance that is seen is primarily due to depression of antibody formation. A single dose of 5 mg. of cortisone may cause depression of resistance and may decrease the survival time for 3 to 6 days afterward. Growth hormone (somatotropic hormone) in highly purified form, and in the doses used, did not overcome the weight loss induced by cortisone, but the animals treated with growth hormone and cortisone regained their lost weight more rapidly than those receiving cortisone alone. Growth hormone alone caused a slight increase in the rate of gain in weight over controls. Growth hormone alone did not increase resistance to infection, and did not increase the survival time, in mice infected with either pneumococci or influenza virus. Growth hormone in various dosages failed to overcome the effect of cortisone in depressing resistance to these infections. Cortisone, hydrocortisone, corticosterone, and corticotropin did not alter significantly the titers of influenza virus attained in the murine lungs during the first 2 days after infection, but cortisone and hydrocortisone markedly delayed the rate at which virus titers declined during the subsequent 6 days. Corticosterone and corticotropin delayed the rate at which the titers declined but slightly, and growth hormone had no apparent effect, as compared with controls. Growth hormone did not overcome the effect of cortisone and hydrocortisone on viral titers. No detectable antibody was found as late as 6 days after infection, in controls or in hormone-treated animals.
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