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The Anterior Pituitary Gland in Tumor-Bearing Rats

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The Anterior Pituitary Gland in Tumor-Bearing Rats THE ANTERIOR PITUITARY GLAND IN TUMOR-BEARING RATS JACOB HEIMAN, M.D. (From the Institute of Cancer Research, Coluinbia University, Francis Carter Wood, Director) Since 1927 a large number of rats with spontaneous neoplasms, trans- planted tumors, and tumors induced by antuitrin-S and theelin have been under observation by the writer (1). Of late the gonads and pituitary gland have been particularly studied with the object of ascertaining whether a rela- tionship exists between the growing tumor and morphologic changes in the glandular organs of the host. Since hormonal assay in laboratory animals is difficult, the attempt has been made to discover, also, whether the physiological activity of a gland is linked with changes in its cellular morphology. The hypophysis, because of its complex structure, lends itself well to this purpose. REVIEWOF THE LITERATURE The literature recording attempts to discover some correlation between the anterior pituitary lobe and tumor growth may be briefly reviewed as it deals with (a) the normal pituitary; (b) changes in the gland in normal ani- mals injected with hormones; (c) changes in the gland in animals with spon- taneous, induced, or transplanted tumors; (d) hypophysectomy and tumor growth; (e) gonadectomy and tumor growth. The Normal Pituitary: There are many detailed reports concerning the gross and minute anatomy of the pituitary in the rat and mouse, giving its size and weight in relation to other organs. Bailey (2) mentions the close resemblance between the structure of the pituitary in man and in laboratory animals, even to the finer details. Hatai (3), in studies on the albino rat, concluded that increase in body weight is accompanied by a proportionate increase in the weight of the pituitary gland, but that this increase is greater in females than in males. Addison and Adams (4) found the female pituitary to be twice as heavy as that of the male. Rasmussen (5) also states that the gland is heavier in the female. He observed that as body weight increased the anterior or glandular lobe showed a greater increase than the posterior lobe or pars nervosa. Andersen (6) gives the weight of the pituitary in the female rat as between 7.7 and 12.3 mg. Olga Fischer (5) measured the gland in rats and found the average transverse diameter in females to be 4.2 mm., and in males 4.0 mm., while the sagittal diameter in females was 2.32 mm. and in males 2.25 mm. Wolfe and Cleveland (8) describe the cyclic histological variations in the anterior pituitary gland of the albino rat. Erdheim (9), as is well known, has demonstrated an increase of acidophilic cells in pregnancy, and Martins and de Mello (10) have recorded an increase of basophilic cells in the an- terior lobe in castrated animals. 423 424 JACOB HEIMAN The percentages of the different cells in the anterior lobe of the pituitary show wide fluctuations, which make the establishment of normal standards difficult. Rasmussen (11) found the following percentages in man: in the male, chromophobes 52 per cent, acidophils 37 per cent, basophils 11 per cent; in the non-pregnant female chromophobes 50 per cent with a coefficient of variation of 14 per cent, eosinophils 44 per cent with a variation of 19 per cent, basophils 7 per cent with a variation of 42 per cent. Wolfe (12) also found fairly large variations in the level of chromophobes. He obtained the following differential count in rats: chromophobes 62 per cent (55 to 73), eosinophils 34 per cent (30 to 40), and basophils 4 per cent (3 to 6). Baso- phils occur in greater number in the young. Severinghaus and his associates (13) have thoroughly reviewed the present knowledge of the pituitary, em- phasizing the uncertainties encountered in studying the normal gland. Changes in the Pituitary in Normal Animals Injected with Hormones: Changes in the pituitary following hormone injection include (I) those pro- duced by gonadotropic hormones and (11) those produced by the administra- tion of the estrogenic hormone. I. Over fifteen years ago Evans and Long (14) studied the effect of intraperitoneal injections of the anterior lobe of the pituitary upon growth and maturity and the estrous cycle in rats, but made no mention of changes in the pituitary gland. In 193 1 B. Zondek (15) reported that injection of anterior pituitary substance in immature animals was followed by changes .in the anterior lobe of the hypophysis which could be considered as a maturation of the gland. Collip, Selye, and Thomson (16) observed that prolonged administration of the gonadotropic hormone caused enlargement of the pitui- tary, but only in females, Wolfe (17), studying the effects of the same sub- stance in immature and mature females, reported that the changes induced consisted in loss of granules in both eosinophils and basophils. As a result of similar experiments Collip, Selye, and Bachman (18) concluded that after repeated injections an anti-gonadotropic substance develops, a view which corresponds with the recent concept of the presence of anti-hormones in the blood. Severinghaus (19) found that injection of the gonadotropic hormone was followed by a depletion of basophilic granules but an increase in the number of basophil cells and a corresponding decrease in chromophobes. Fluhmann (20) observed an increase in weight of the pituitary in female rats, and in the number of basophils and of castration cells. Similar changes were observed by him after injections of gonadotropic substance from the blood of pregnant women, with a decrease in eosinophils and an increase in chronio- phobes. Nelson (2 1) concluded from his experiments with antuitrin-S that in castrates no effect is exerted on the pituitary gland, which would indicate that castration prevents degranulation in the injected animals. Wolfe (22) gave daily injections for 140 days of anterior pituitary-like extract of preg- nancy urine to immature female rats and observed enlargement of the pituitary and a definite morphologic reaction in the anterior lobe. After prolonged in- jections the gland returns to normal size and degranulation of the chromophile cells occurs. A summary of these scattered observations shows the following effects on the pituitary gland of the injection of the gonadotropic hormone. THE ANTERIOR PITUITARY GLAND IN TUMOR-BEARING RATS 425 (1) In immature animals, maturation of the pituitary. (2) In castrated animals, no influence on the pituitary. (3) In normal animals of both sexes, increase in weight and appearance of castration cells. (4) In immature rats, a decrease in eosinophils; enlargement and de- granulation of basophils ; increase in small granular basophilic cells. (5) Depletion of basophilic granules with an increase in the basophil cells and a decrease in the chromophobe cells. (6) In females, increase in weight of the pituitary (8.5 to 26 mg.). (7) With prolonged injections, no effect except possible increase in chromophobes. (8) Increase in basophils and chromophobes; diminution in acidophils. 11. The literature abounds with reports on the influence of estrogenic substance (estrin, theelin, amniotin, synthetic estrogenic hormone, etc.) on the glandular portion of the pituitary. In 1932 Spencer and D’Amour (23) re- ported that no histologic changes were observed in the pituitary following sub- cutaneous injection of 20 rat units of estrin daily for fifty-four days. Moore and Price (24), on the contrary, concluded that the presence of sufficient amounts of gonadal hormones of either sex lowers hypophyseal activity. In 1934, Nelson (25) reported that estrin, injected subcutaneously, diminished the number of basophils in the pituitary, and caused the disappearance of castration cells in previously castrated animals of both sexes. He obtained a greater reaction in the female than in the male rat, with an increase in chromophobe celIs. Andersen (26) reported that in castrated rats amniotin caused a restoration of the atrophied pituitary to the original weight as ob- served in normal animals in estrus. Collip et al (27) found that the ad- ministration of large doses of estrin to female rats led to hypertrophy of the anterior lobe within a few days, an effect which was less marked in males and in castrates. Crooke and Korenchevsky (28) in 1935 found that estrin, in normal males, increased the weight of the pituitary, but caused no histologic changes, while in female and male castrates the normal histology was restored, as noted by Andersen. Still later (1936) McEuen et al (29) reported on some effects of prolonged administration of estrin. In 6 castrated female rats the pituitary was enlarged, and in 3 females adenomata developed. In 5 normal males and one castrate male there was also an increase in size, and another castrate male developed a cystic adenoma. B. Zondek (30) in 1936 concluded that after prolonged administration to mice of follicular hormone (estrin), the function of the anterior lobe is inhibited, rendering inactive the growth and sex hor- mones. The gland becomes enlarged and there is an increase in weight in males, while in females tumors appear. Cramer and Horning (31) in 1936 reported that prolonged application of estrin to mice resulted in functional inactivity, producing a systemic condition resembling that following hypo- physectomy. Morphologically a hyperplasia of the anterior lobe was ob- served with diminished chromophils and an increase in chromophobe cells. In an early report (1934) Burrows (32) described the effect produced by applying estrin to the skin of mice, but did not mention the pituitary. In
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