Search

THE ABDOMINAL fibroids which are produced in the guinea pig by estrogens (Lipschutz and Iglesias, 1938) may easily be prevented by the administration of certain cortical steroids such as desoxycorticosterone and dehydrocorticosterone (work of Lipschutz, Nunez, Vargas and Zanartu; see review by Lipschutz, 1944). Since 28 different steroids have been extracted from the adrenal cortex (Reichstein and Shoppee, 1944) of which 6 or 7 have cortical activity, the question arose as to the role of these steroids in the system of anti-tumoral auto-defense by the maintenance of the steroid balance, in accordance, 0 with the concept of Lipschiitz (1943). We proposed to attack this problem by removing the adrenal glands from guinea pigs which were to be treated afterward with fibromatogenic quantities of estrogen. But in order to study the question experimentally, it was necessary to replace the adrenal cortex with a steroid possessing cortical activity but lacking any antifibromatogenic action.

The guinea pig is unusual in that its postnatal growth appears to be independent of GH even though its pituitary gland produces a GH molecule. The effects of fasting on the GH secretory pattern and the GH responses to insulin, GH-releasing factor (GRF), and somatostatin (SS) during fasting have now been studied by automatic microsampling of blood in chronically cannulated normal guinea pigs. Withdrawal of food in both male and female guinea pigs changed the GH secretory pattern dramatically. The normal episodic GH secretory pattern [large GH peaks occurring at 3.6 +/- 0.4-h intervals over a low (approximately 0.5-1.5 ng/ml) baseline secretion] was altered to a pattern of more continuous GH output, characterized by a 10-fold elevated baseline secretion (5-15 ng/ml) with no large secretory episodes or troughs. Glucose injections (three injections of 600 mg, iv, at hourly intervals) in fasted guinea pigs lowered their elevated blood GH levels significantly (from 9.1 +/- 1.1 to 6.5 +/- 0.9 ng/ml). Insulin injections (1, 2, or 6 U, iv) inhibited spontaneous GH pulses in normally fed animals, but had little effect on the high continuous GH tone during fasting. The elevated GH secretion in fasted animals could be inhibited by continuous infusion of SS or a single iv injection of a long-acting SS analog. The secretion of GH during fasting could be further increased, either by injections of GRF (two injections of 2 micrograms, iv, 90 min apart), producing peak levels of 102 +/- 16 and 68 +/- 21 ng/ml (above a baseline output of 8.8 +/- 2.2 ng/ml), or by a continuous iv infusion of GRF (12 micrograms/h). Because the GH secretory pattern in the guinea pig is so sensitive to nutrition and insulin, this species may provide an interesting model in which to study selectively the metabolic, as opposed to growth-promoting, actions and regulation of GH.

GH binding proteins (GHBPs) are present in the blood of several species and by complexing with circulating GH may alter its clearance and distribution. The actions of human GHBP (hGHBP) have hitherto been studied indirectly via their effects on the clearance of hGH. In the present experiments, recombinant preparations of hGHBP and a shorter variant lacking exon 3 (delta 3hGHBP) were tested in vivo, either alone or after preincubation with recombinant hGH, recombinant 20K methionyl-hGH, or rat GH. Multiple serial blood sampling was performed in conscious chronically cannulated guinea pigs and both GHBP and GH variants monitored in the same samples by specific RIAs, unaffected by endogenous activities in this species. hGHBP, delta 3hGHBP, hGH, and 20K met-hGH (10-40 micrograms) were all cleared rapidly when injected alone (t1/2 = 11-20 min). However, when the same amounts of hGHBP and hGH were incubated together for 60 min and then injected, the clearance of both proteins was greatly prolonged (t1/2 hGHBP = 75-94 min, hGH = 80-137 min). Similar results were obtained for hGH complexed with delta 3hGHBP, and over a range of GH:GHBP ratios from 0.3:1 to 4:1. The effect was specific for 22K hGH; neither rat GH nor 20K met-hGH altered hGHBP clearance, nor were their clearances slowed by preincubation with hGHBP. Rapid complex formation also could be demonstrated in vivo. Injections of hGH 30 min after delta 3hGHBP, or vice versa, altered the established plasma disappearance curve of hGHBP, and hGH clearance was slowed in parallel. During a continuous infusion of hGH to steady state, injections of delta 3hGHBP increased plateau hGH concentrations by forming a delta 3hGHBP/hGH complex in the circulation. These experiments show that the conscious chronically cannulated guinea pig provides a useful model in which the in vivo interaction between hGHBP and hGH can be studied dynamically. The results imply that the location, extent, and rate of complex formation between GHBP and GH may be an important determinant of the passage of GH between the intra- and extravascular compartments, which could affect the pattern of tissue exposure to GH.

To further examine whether nongonadal restraint of gonadotropin secretion during prepubertal development plays a major role in the timing of puberty in the guinea pig, as it does in the monkey and other primates, two experiments were performed. In the first, neonatal male and female guinea pigs were either bilaterally gonadectomized or sham gonadectomized on day 2 of age, or left intact. Circulating LH concentrations were measured in blood samples collected by cardiac puncture every 4 days beginning on day 2 of age and continuing until the animals were 98 days of age. In the second experiment, the time course of the LH response to ovariectomy was examined in juvenile female guinea pigs that were castrated on day 10 of age and were either isolated from or allowed to remain with their mothers for the duration of the study. To place into perspective the time course of the LH response to prepubertal gonadectomy, the effect of castration on LH secretion in adult animals was also examined. Serum LH concentrations were determined by a RIA that employed GDN-15 as the first antibody. Orchidectomy on day 2 of age resulted in an immediate and progressive rise in serum LH concentrations, which plateaued by 30 days of age at levels indistinguishable from those of adult castrates. In contrast, ovariectomy on day 2 of age failed to elicit an immediate rise in serum LH. Instead, circulating LH concentrations in neonatally castrated female guinea pigs were not significantly different from those in intact controls until day 14 of age, at which time serum LH rose progressively to plateau by 30 days of age at levels comparable to those in adult castrates. The time courses of LH secretion after ovariectomy of 10-day-old guinea pigs that were either isolated from or allowed to remain with their mothers were not significantly different and were similar to that observed after ovariectomy at 2 days of age. For reasons presented in detail in Discussion, the foregoing findings fail to support the view that nongonadal restraint of gonadotropin secretion during prepubertal development plays a major role in the timing of sexual maturation in the guinea pig. This laboratory rodent, therefore, may be viewed as a poor paradigm for study of the neuroendocrine basis of puberty in primates.

Studies of placental inner-ring deiodination of T4 were carried out in pregnant guinea pigs, by in situ placental perfusion. When [131I]T4 and [125I]rT3 were administered to the mother, the ratio of fetal side to maternal side [131I]rT3 was more than 10 times greater than the corresponding ratio for [125I]rT3. When radiolabeled T4 was supplied to the fetal side of the placenta in perfusion fluid, and the perfusate recycled through the placental circuit, there was a progressive increase in labeled rT3 concentration in the perfusate. These results indicate that the guinea pig placenta actively deiodinates both maternal and fetal T4 in the inner ring in vivo. We found evidence of very little outer ring deiodination of either T4 or rT3. The quantitative contribution of placental deiodination of maternal T4 to circulating rT3 in the fetus appears to be small; however, placental deiodination of fetal T4 (about 0.5 nmol/kg fetal BW X day) could contribute significantly to fetal rT3 levels. Our observations are consistent with the hypothesis that placental inner-ring deiodination of T4 plays a part in the regulation of fetal iodothyronine metabolism.

Subcutaneous administration of bovine (b) TSH (up to 10 IU) to 8-week-old male guinea pigs was followed by a transient elevation in serum thyroid hormone levels (T4 and T3) and an increase in thyroid weight (approximately 25-40%), which returned to control levels by 3 days. Total thyroid TSH receptor content was assessed by the binding of receptor-purified [125I]bTSH to 15,000 X g fractions of thyroid homogenate. The TSH receptor content paralleled the increase in thyroid weight, with no detectable change in the TSH-binding capacity per mg tissue. Intraperitoneal minipump infusions of bTSH (1 IU/day) over 6 days produced marked and persistent increases in thyroid hormone levels and thyroid weight (greater than 300%) and a similar increase in TSH receptor content. There was no change in the single site equilibrium association constant for bTSH [1.1 X 10(9) M-1 +/- (SE) 9.6 X 10(7) M-1] and no alteration in the binding capacity per mg tissue (67.2 +/- 6.4 pg/mg). Investigation of the in vitro adenylate cyclase response to bTSH (10 mU/ml) and the production of immunoassayable cAMP showed no difference between thyroid tissue obtained from bTSH-treated animals and that obtained from untreated control animals. These observations demonstrated that TSH exerted a positive regulatory effect on its receptor and, under the in vivo conditions used, failed to induce TSH receptor loss or physiologically important desensitization. Such data may explain how TSH receptor antibodies are able to act as TSH agonists and maintain increased thyroid hormone output in human disease.

The administration of 1.6 μg 17β-estradiol benzoate (EB) 60 h before an injection of 0.5 mg progesterone induced optimal lordosis responses in ovariectomized guinea pigs. To determine whether the presence of estrogen in neural tissue throughout the 60-h period was necessary for the display of lordosis, various antiestrogens (i.e. MER-25, CI-628, enclomiphene, or zuclomiphene) were administered during the late portion of the 60-h period. Dose-dependent inhibition of lordosis resulted when these antiestrogens were injected at 40 and 47 h after EB injection. On the other hand, injection of supplemental EB late in the priming period enhanced the display of lordosis. A correlation between behavioral antiestrogenicity and in vitro competition for cytoplasmic hypothalamic-preoptic area (H-POA) estrogen receptors was observed for all of the antiestrogens tested except MER-25. The rank order of behavioral antiestrogenic activity was: CI-628 > MER-25 = enclomiphene > zuclomiphene. The relative binding affinities of...

Specific binding sites for [3H]progesterone ([3H]P) and for the synthetic progestagen [3H]R-5020 (17α,21-dimethyl-19-nor-pregna-4,9-diene-3,20-dione) are found in the cytosol and nuclear fractions of the fetal uterus of the guinea pig. P, R-5020, and 5α-dihydroprogesterone compete for binding with [3H]P and [3H]R-5020. Estradiol (E2), estrone, testosterone, and cortisol do not compete. In the cytosol fraction, the dissociation constant (Kd) at 4 C is 3.3 ± 1.7 (sd) × 10−9m for [3H]P, and the concentration of sites (n) is 180 ± 28 fmol/mg protein. Two components are found in sucrose density gradients at 6–7S and 4S. Few if any [3H]P-specific sites can be detected in uterine cytosol until 37–42 days of gestation. By 50–52 days, the concentration of sites is 35.4 ± 6.34 fmol/mg protein. These sites increase at the end of gestation to 85.6 ± 15.7 fmol/mg protein. Similar specific binding sites are found in the fetal ovaries, and at the end of gestation reach concentrations of 25.6 ± 8.6 fmol/mg protein. In an...

Immunocytochemical localization of neuron-specific enolase (NSE) in thyroid C cells was investigated in various mammalian species. In bovine thyroid glands most of the C cells were weakly immunoreactive to anti-NSE antiserum. In other mammalian species, including dogs, guinea pigs, rabbits, cats, pigs, rats, hamsters, mice, and monkeys, some C cells or only a few C cells were weakly immunoreactive to the antiserum. It seems that normal C cells contain NSE in small amounts only or are devoid of NSE. After chronically induced hypercalcemia, C cells revealed hypertrophic and hyperplastic features. Whereas immunoreactive calcitonin was markedly decreased, marked increase of immunoreactive NSE was observed in C cells of both dogs and guinea pigs; almost all C cells were filled with reaction product for NSE. After administration of ethylenethiourea for a period of 3-8 months, C cells revealed a marked decrease of secretory granules and appearance of vesicular inclusions of various sizes, which were immunoreactive to the calcitonin antiserum, indicating a disturbance of calcitonin synthesis. No immunoreactivity for NSE was observed in C cells from dogs and guinea pigs so treated. In rabbits showing hypocalcemic tetany, calcitonin immunoreactivity was very intense and NSE immunoreactivity was faint to negative in the C cells. Thus, the level of NSE in C cells was clearly connected with the functional activity of the cells.

Cytoplasmic fractions obtained from lungs of several animal species at different stages of development were examined for dexamethasone receptors. Specific dexamethasone binding was measured by a charcoal assay and by sucrose density gradient centrifugation. Dexamethasone receptors were demonstrated in the lungs of rabbit fetuses between the 21st day of gestation and birth, rat fetuses during the last 3 days of pregnancy, guinea pig fetuses at 35–45 days of gestation and human fetuses at the 9th to 17th gestational weeks. The dexamethasone receptors present in all the species examined sediment near 7S on linear 10–30% sucrose gradients. In human fetal lung cytosol the concentration of binding sites increased about 3-fold between the 9th and the 17th week of gestation. Lower but significant levels of the dexamethasone binding component were found in lungs of mature rabbits but it could not be detected in lungs of adult rats, mice, hamsters or guinea pigs. More detailed studies in the rat showed that the rec...

An assay was developed for the measurement of progestin receptors in purified cell nuclei of the central nervous system after progesterone injection. The affinity of the nuclear progestin receptor in the hypothalamus-preoptic area-septum of female guinea pigs for [3H]17α,21-dimethyl-19-nor-pregna-4,9- diene-3,20-dione (Kd ≧ 0.16 nm) is similar to that previously reported for the cytosol receptor in this tissue. Although all brain areas studied (hypothalamus, preoptic area-septum, midbrain, and cerebral cortex) accumulated some nuclear progestin receptor after progesterone injection, the hypothalamus had the highest concentration. Guinea pigs primed with a large dose (10 μg) of estradiol benzoate accumulated more nuclear progestin receptor after an injection of progesterone than animals primed with a low dose (1.6 μg) of estradiol benzoate. This is consistent with our previous finding that estradiol benzoate induces cytoplasmic progestin receptors in a dose-dependent manner. By 2–4 h after progesterone inj...

Antisera generated in guinea pigs against partially purified PRL receptors derived from rabbit mammary glands were tested for their effect on PRL binding and the biological effects of PRL in vitro and in vivo. Several dilutions of either normal guinea pig serum or anti-PRL receptor serum were incubated in vitro with homogenates of rat ovaries. Although specific binding of PRL was inhibited as much as 90% by the anti-serum, normal guinea pig serum had little effect. There was no inhibition of binding of LH and FSH to ovaries by these antisera. When these antisera were administered to normal cycling rats, the most pronounced effect was an increase in the number of corpora lutea, presumably due to the prevention of the luteolytic effect of PRL. When one of these antisera was given to adult rats immediately after parturition, weight gain of their pups decreased significantly, possibly reflecting a decrease of milk yield. Thus, passive immunization of animals with anti-PRL receptor sera modifies the actions of PRL on some of its target tissues.

The levels of two steroid-binding proteins, progesterone-binding globulin (PBG) (1) and corticosteroid-binding globulin (CBG), present in the plasma of pregnant guinea pigs were determined just before and after parturition. Both PBG (3.37 ± 2.1 μm) and CBG (10.1 ± 1.7 μm) were present in high levels just before parturition and were found to decrease with a half-life of 2 days after delivery. PBG and CBG were also found in the milk whey of lactating guinea pigs but at much lower levels (26.5 ± 12 and 375 ± 18 nm, respectively, on day 1 post partum). The whey content of each protein declined with a halflife of 3 days. The whey steroid-binding proteins were indistinguishable from their plasma counterparts on the basis of ion exchange and gel filtration chromatographies, sucrose gradient centrifugation, susceptibility to heat denaturation, and hormone binding specificity. (Endocrinology 106: 1747, 1980)

Guinea pig ovaries obtained from pregnant and non-pregnant animals, incubated in the presence of a NADPH-generating system, converted [3H]-dehydroepiandrosterone and [14C]testosterone to estradiol. Under the same conditions, no radioactive estrogen could be identified in adrenal and placental incubations. The rate of formation of estradiol from dehydroepiandrosterone was linear during the 30-min incubation. The initial rates of formation for estradiol were 415 X 10(-13) and 10.4 X 10(-13) mol/min/g tissue for the ovaries from pregnant and non-pregnant guinea pigs, respectively. The formation of estrone was shown only in the pregnant animal, and the initial rate of formation was 36.0 X 10(-13) mol/min/g tissue. These in vitro studies suggest that the major site of estrogen formation in both pregnant and non-pregnant guinea pigs is the ovary.

Beginning at the first or second day of life, dosages of 500 µg. of testosterone propionate per 100 gm. body weight were administered daily to intact and castrated guinea pigs. There was no statistically significant evidence that the intromission and ejaculation responses developed precociously in these animals, when compared with intact guinea pigs receiving sesame oil. These results differ from those obtained with the rat in which precocious sexual development has been produced by testosterone propionate treatment. It was concluded from the accumulated evidence that the guinea pig and rat do not respond similarly to testosterone propionate during post-natal development and maturity.

PREVIOUS INVESTIGATORS have shown that prolonged inanition in the experimental animal is accompanied by morphological alterations in the thyroid gland, characterized by atrophy, involution and degeneration (1, 2). Myers (3) and Stefko (4) have described similar changes in man in undemutrition. More recently Rabinovitch (5) has described the thyroid of guinea pigs fed an inadequate diet resulting in the loss of 20 to 30% of their weight in 9 to 11 days. In such animals there was almost complete cessation of proliferative activity, the acinar epithelium was flattened and the colloid was hard and dense. There is some evidence (6, 7) that certain of the vitamin deficiencies may result in structural changes in the thyroid similar to those which have been described in inanition. The present investigation, in which the observations of Rabinovitch have been confirmed, is concerned chiefly with two aspects of the problem

SEVERAL INVESTIGATORS (1-3) have recently shown by direct evidence that progesterone, the corpus luteum hormone, has the capacity to induce androgenic reactions in the rat. Previously, evidence indicative of the androgenicity of progesterone had been suggested by several investigators. Hill (4-5) showed that ovaries of mice, when transplanted to the ears of castrate mice, apparently produced an androgenic substance. This work was confirmed by Deansely (6) in the rat. Papanicolaou (7, 8) also showed that ovaries in normal guinea pigs had an androgenic action when stimulated with the APL factor of pregnancy urine. Several other workers have also shown that ovaries, transplanted into a large series of castrate male rats or guinea pigs, had an androgenic effect in an occasional animal (9, 10, 11). Since the only direct evidence for the androgenicity of progesterone had been obtained in the rat, it was thought of interest to determine directly if this property could also be shown with the guinea pig as the exp...

S35-labeled thiocyanate was administered to guinea pigs which had been previously treated with thyrotropin. The TSH pretreated animals exhibited T/S gradients of radioactivity which were twice as great as those of the control animals. Paper chromatography of the thyroid homogenates revealed that sulfate-S35 was the chief sulfur product of thiocyante-S35 metabolism. Thyrotropin produced an increase in the intrathyroidal concentration of sulfate-S35 as compared with the concentration in the controls receiving only labeled thiocyanate. Pretreatment with thiourea abolished the TSH response but augmented the concentration of thiocyanate-S35 within the thyroid gland. These results suggest that TSH enhanced the intrathyroidal metabolism of thiocyanate- S35.

The brains and pituitaries of guinea pigs injected with I131-labeled triiodothyronine showed an active concentration of radioactive material identifiable as triiodothyronine. In the brain the labeled hormone was found by autoradiographic procedures to be primarily in the nuclear areas, with the greatest accumulations occurring in the neurosecretory regions. The anterior pituitary lobe was consistently more active in concentrating the injected material than was the posterior lobe. When T131-labeled thyroxine was injected, the brain and both pituitary lobes were able to concentrate only very small amounts of the labeled hormone, the anterior lobe appearing to concentrate the hormone as readily as the posterior lobe.

In order to localize 5-hydroxytryptamine (5-HT) stores in the islet of Langerhans of guinea pig pancreas, a cytochemical procedure for the ultrastructural differentiation between catecholamines and indoleamines was used. Islet tissue of animals receiving reserpine was similarly analyzed. The results obtained with the cytochemical reactions were correlated with those of pancreatic amine assays performed before and after reserpine administration. Dense reactive granules were observed in β cells of normal guinea pigs with the cytochemical procedures. These granules correspond to those normally observed in β cells and known to store insulin. After reserpine administration, the reactivity of the granules disappeared and simultaneously a marked decrease in pancreatic 5-HT content was observed. The possible participation of insulin was discarded in view of results drawn from in vitro experiments. Light and electron microscopic observations also suggested that the granular population of β cells, reflecting their ...

One injection of 5 U of ACTH stimulated net synthesis of guinea pig adrenal DNA, RNA and protein, and significantly increased gland weight within 24 hr. The sensitivity of adrenal growth response to ACTH was proportionately greater in desamethasone-suppressed animals than in normals. In both groups, however, the adrenal growth response to a second injection of ACTH was inhibited by effects of the first injection. This diminished sensitivity to ACTH of nucleic acid and protein synthesis, observed as steroidogenic response increased, could be overcome by further treatment with ACTH. The effect of ACTH upon adrenal growth is therefore biphasic. The period of decreased sensitivity of adrenocortical growth response is of longer duration than the stimulatory effect of ACTH, since further response is limited for at least another 24 hr. (Endocrinology 83: 956, 1968)

Initial rates of cortisol 2α- and 6β-hydroxylation were determined in liver whole homogenates from 2 guinea pig genotypes differing in their ability to hydroxylate cortisol (high and low producers). Under optimal conditions (pH, TPNH and tissue concentration) the subcellular distribution, developmental pattern and effect of substrate concentration have been studied. No significant difference was found between the 2 types in regard to the subcellular distribution of the enzymatic activities, which were primarily concentrated in the microsomal fraction. The developmental pattern of the cortisol 2α- and 6β-hydroxylase specific activities (on a unit wet tissue weight basis) of adrenal and liver homogenates from males and females of the 2 strains was determined at a substrate concentration of 10 μm. In the high producers there was an increase in the adrenal 2α- and 6β- hydroxylase specific activities after birth up to approximately 100 days of age. The much lower adrenal activities in the low producers increas...

The mode of inheritance of the ability to form hydroxylated derivatives of cortisol (polar corticosteroids) in the guinea pig, with special emphasis given to 2α-hydroxycortisol, was studied. Two homozygous strains of short-haired English type guinea pigs differing greatly in this trait were crossed. The F1 generation exhibited polar corticosteroid excretion intermediate between that found in the parents but no significant difference in the excretion of cortisol. The F2 generation could be categorized (bringing the distribution of the F1 progeny into account) into 3 classes: low, medium and high hydroxycortisol excretors having a frequency consistent with the 1:2:1 genotypic ratio. Mating of a high excretor from the F2 generation with homozygous low excretors resulted in progeny of medium excretors. The fact that the ability to form hydroxycortisol derivatives is genetically determined suggests that the determination of urinary levels (or production rates) of these compounds may be useful in assessing the ...

Biologic assay of anterior pituitaries of intact adult female guinea pigs by the HCG-augmentation assay revealed a concentration of 13–15 μg-equivalents of NIH-FSHSl/ mg dry weight, values similar to those previously observed in female rats and mice. However, in contrast to male rats and mice, which exhibit pituitary FSH concentrations 10 times higher than those of females, male guinea pig pituitary FSH concentration was identical with that of the female. LH was virtually nonexistent in guinea pig pituitaries, concentrations of 0.2–0.4 μg-equivalents of NIH-LH-Sl/mg dry weight having been observed in both males and females. These LH values are approximately 10 times lower than those previously reported for rats and mice. Gonadectomy failed to increase male or female guinea pig anterior pituitary LH concentration and failed to elevate serum LH to levels detectable by the ovarian ascorbic acid depletion assay. These responses of guinea pig pituitary LH to gonadectomy are similar to those of mice, but differ...

RECENTLY a number of observations have indicated a relationshipof ascorbic acid to the endocrine control of reproduction. Experimentalresults have shown an effect of hormone preparations on ascorbicacid content of tissues and blood plasma, and converselyascorbic acid has been reported to influence the response of animals tocertain gonadotropic preparations. Mosonyi (1936, 1937) observed a 30 to 40 per cent decrease in theascorbic acid content of the livers and adrenals of guinea pigs afterthe administration of estrogens to females or androgens to males.Nespor (1937) found that there was first a rise and later a fall in theascorbic acid content of the testes of young guinea pigs on the scorbuticdiet after giving gonadotropic hormone. The simultaneous loss byother tissues indicated to him a utilization of ascorbic acid in thetestes at the expense of other tissues.

LEWIS AND TURNER (I) have reviewed the evidence for the noiveffectiveness of ovarian hormones in stimulating mammary gland hyperplasia in the hypophysectomized animal. The results of a number of such experiments, reported since 1935, have been uniformly negative. It has been shown that the mammary gland can be developed in hypophysectomizied animals with injections of anterior pituitary from pregnant animals or from animals given preliminary treatment with estrone (I-6). Guinea pigs, rabbits, rats and mice have been employed in such studies. Many experiments had shown that estrogen will grow the mammary ducts in most species, whereas a combination of estrogen and progestin is required to cause complete lobulealveolar proliferation (see Turner, 7, for review). When it was established, in this laboratory, that the ovarian hormones act on the AP causing development there of a mammary growth factor (I, 2), it seemed probable that the mammogenic growth complex consisted

THE adrenal hypertrophy which follows the injection of estrogen is well documented. However, recovery of adrenal size and function following estrogen induced stress and the factors which modify the recovery phase have received little attention. Lynch (1952) observed that the adrenal continued to hypertrophy, in rats, for 3 weeks after discontinuing estradiol benzoate and that adrenal weight did not return to normal until 9 weeks after the cessation of treatment. The influence of nutrition on the recovery phase was not studied. Nevertheless, nutritional studies warrant consideration for chronic inanition alone serves as a stress in rats (Quimby, 1948), guinea pigs (D’Angelo et al., 1948) and mice (Boutwell et al., 1948). Furthermore, a high protein diet may increase the response of the pituitary-adrenal system to stress (Ingle et al., 1947; Leathern, 1947; Hay et al. 1948; Moya et al., 1948; Henriques et al., 1949) and an adequate amount of protein is required for a maximal adrenal response to stress (Cons...

Spectral values of iodinated compounds in the thyroid were followed by means of I131 and I127 tests in rats and guinea pigs. The rate of biogenesis of thyroid hormones was found to be slowed down in guinea pigs so that 12 hr after I131 administration there was a predominance of MIT over DIT, while 2 minutes after I131 administration to rats DIT predominated over MIT. The following ratio of molecular representation was found chemically (I127): I’:T3:T4:MIT:DIT 1.00:1.20:2.42:7.61:10.44 in rats and 1.00: 1.39:3.70:6.11:6.28 in guinea pigs. In the chemical (I127) analysis, an unidentified compound (F) appeared at the front of the chromatograms, representing 4.04% in rats and 11.77 % in guinea pigs. In a further observation, the chemical analysis yielded a larger amount of T4, T3 and substance F than of MIT and DIT, while the I131 test showed only the presence of I’, MIT and DIT following the administration of MTU. These results led to the expression of a hypothesis on the existence of a heterogeneity and of ...

IN A SERIES of papers published since 1922, Carl Moore and his coworkers (1, 2, 3, 4) have presented abundant evidence to show that exposure of the testes of the rat, guinea pig, and sheep to temperatures above that of the scrotum results in degeneration of the germinal epithelium and a consequent failure of spermatogenesis. This work was confirmed by Fukui (5) who exposed the scrota of rabbits to midsummer sunlight and found selective destruction of the germinal epithelium. He also applied continuous streams of hot water (44°–49°C.) to the scrota of dogs, cats, guinea pigs, rats and goats and found degenerative changes in the germinal epithelium i n every case. Young (4) studied the order of sperm cell degeneration in guinea pig testes after water heated to 46° or 47° C. had been run over the scrotum for 15 or for 30 minutes. He found that degeneration of the germinal epithelium begins immediately after treatment and continues until the end of ia days.

During the course of a study of the histogenesis of the estrogeninduced tumors of guinea pigs (Nadel, 1949), the influence of ascorbic acid upon the development of this type of tumor was investigated. An unexpected finding, compatible with acute scurvy (Meyer and McCormick, 1928), developed when stilbestrol pellets were implanted into guinea pigs kept on a diet partially deficient in ascorbic acid. A study of the possible interrelationship between ascorbic acid and stilbestrol metabolism was undertaken. This paper deals with effects of stilbestrol implants on adrenal ascorbic acid concentration and adrenal weights of female guinea pigs maintained at different levels of ascorbic acid deficiency. Stock virgin female guinea pigs raised at the National Institutes of Health Breeding Farm were used in all the experiments. A stock diet of commercial Purina rabbit chow and fresh cabbage was supplemented with carrots once a week. Animals were transferred from this stock diet to the scorbutogenic diet described below.

In vivo studies in castrate guinea pigs demonstrated longer retention of progesterone- 3H in uterus than in heart or diaphragm. Estrogen pretreatment for 2 days increased the progesterone-3H uptake 7-fold in uterus but not in the other organs. Analysis of the estrogenprimed uterus revealed that 88% of the total radioactivity was progesterone-3H 1 hr after injection. The uterine uptake of progesterone-H3 was blocked by progesterone but not by cortisol, estradiol or testosterone treatment, The distribution of tritium in blood, heart and diaphragm was not influenced by any of the 4 steroids. These in vivo observations suggest that progesterone binding to estrogen-primed uterus is specific and of limited capacity. (Endocrinology 86: 1059

Rats, mice and guinea pigs were daily injected with sublethal doses of nicotine for 6.5–9 months. Formalin-induced fluorescence and iodate reaction were used to demonstrate the noradrenaline-containing adrenomedullary cells, chromaffin reaction to demonstrate both catechol amines. The medullary volume and the volume of the noradrenaline-containing tissue were determined plani metrically. In the rat, treatment with nicotine did not affect the adrenal weight but caused an 110% increase of the medullaiy volume. This increase was mainly due to a 470% increase in the volume of the noradrenaline-containing adrenomedullary parenchyma. No changes in the adrenal weight, the medullary volume or the distributions of the histochemical reactions were detected in the adrenals of the guinea pig and the mouse.

SEVERAL WORKERS have shown that ovaries transplanted into a large series of castrate males (rats and guinea pigs) have an androgenic effect in an occasional animal (i, i, 3). Hill (4, 5) has transplanted the ovaries of mice to the ear where they are subjected to a temperature several degrees lower than are abdominal ovaries. In this position, the ovaries apparently produce an androgenic substance. This work has been confirmed by Deansely (6) n i the rat. Hill noted an extensive luteinisation of the transplanted ovaries and Deansely has suggested that there may be a relation between thecal luteinisation and the masculinising action of the graft. Desclin (7), however, disagrees with this hypothesis. Papanicolaou (8, 9) has shown that ovaries in normal guinea pigs have an androgenic action when stimulated with the APL factor of pregnancy urine. He believes that this androgenic substance i s produced by the hypertrophied interstitial tissue of the ovaries.

The correction of menstrual disorders by the use of various products of glandular origin has been tried by hundreds of workers since Knauer (1), in 1896, first demonstrated the effect of ovarian transplants on the endometrium. That the placenta might be a gland of internal secretion producing large amounts of sex hormone was first suggested by Halban (2) in 1905, but proof of this hypothesis was not forthcoming until seven years later when Iscovesco (3) demonstrated, in placental tissues, large quantities of a lipoid principle capable of producing growth and vascularity in the resting tubular tract of the rabbit. The presence of this principle, which we now know to be estrin, was soon corroborated by Aschner (4), Fellner (5), and Frank (6). Ercoli (7), in 1915, secured similar results in guinea pigs and suggested that clinical application be made of this property of placental extracts. In 1926 Zondek and Aschheim (8) succeeded in isolating a second principle from the placenta, an anterior pituitary-like g...

It has been known since the work of such investigators as Allan and Wiles (1932) using the cat and Pencharz and Long (1933) using the rat that pregnancy can continue in gravid animals after hypophysectomy. This observation has been confirmed in many different species such as guinea pigs, mice, dogs, rabbits, and monkeys. It is now well-established, of course, that pregnancy is able to continue because the placenta takes over in part the functions of the pituitary gland and ovary. In the lower mammals investigated, the placental hormone chiefly responsible for maintaining pregnancy seems to be a luteotrophin, since ovariectomy in animals such as the rat results in abortion or resorption of the foetuses in hypophysectomized pregnant animals although pregnancy continues undisturbed if the ovaries are left intact. In certain species including the primates, the placenta is able also to take over the function of the ovaries

BISCHOFF, H. W., AND W. R. LYONS. Immunologic investigation of hypophyseal tnammotropic prepara′tions. To appear in this Journal. Mammotropic (lactogenic) preparations made from beef or sheep pituitaries were found to be an′tigenically indistinguishable as far as could be determined by the technics employed for active and passive anaphylaxis, Dale and Arthus reactions, precipitin and complement fixation tests. As little as 12 micro′grams of beef or sheep mammotropin sufficed to produce anaphylaxis in sensitized guinea pigs, whereas normal guinea pigs receiving 20 milligrams showed no bad effects. Severe skin reactions were produced in rabbits sensitized to either beef or sheep mammotropin when they were injected intradermally with 1.0 mg. of either beef or sheep mammotropin. The mammotropic preparations were free from serum proteins and whether made from beef or sheep pituitaries they produced in rabbits, precipitins or complement fixing antibodies capable of reacting equally well to like concentrations o...

THE remarkable loosening of the pelvic ligaments which occurs both at the symphysis pubis and iliosacral junctions in the pregnant guinea pig has been observed and described by numerous investigators. These separations become so extensive, as pregnancy progresses, that a condition is attained in which the two halves of the pelvis can be freely and independently manipulated thus making possible an increase in the diameter of the birth canal. Hisaw (1926) found that pronounced relaxation of the pelvis could be induced experimentally by injecting blood serum of pregnant rabbits or guinea pigs into normal virgin guinea pigs during estrus or into castrated female guinea pigs that had been conditioned with estrogen. The pelvic ligaments usually showed marked relaxation within 8 to 12 hours after one injection of the serum. The relaxative substance was found also in the blood of pregnant sows, dogs, cats and mares, in extracts of the placentae of rabbits (Hisaw, 1927, 1929) and corpora lutea of the sow (Hisaw, F...

IN A PREVIOUS PUBLICATION (1) it was shown that undernutrition of the guineapig resulted in marked structural changes in the thyroid, characterized by atrophy and flattening of the acinar epithelium and retention of colloid suggesting a resting, inactivegland. Refeeding resulted in a rapid gain in body weight and return of thyroid structure to normal. The thyroid of the undernourished animals was markedly sensitive to stimulation by the thyrotropic principle of the anterior hypophsis. Evidence was presented which indicated that the structural changes observed in the thyroid of the undernourished animalswere due to impairment of the thyrotropic function of the anterior pituitary. The changes occurring in the ovaries of these animals are described in the present communication. For this study mature, female guinea pigs, weighing approximately 300 gm., were selected. Details of the care and feeding of these animals have been described (1). Animals eating a full diet were killed while gaining weight, to serve ...

Loeb (1) has shown that oral or intraperitoneal administration of potassium iodide to guinea pigs does not prevent the compensatory hypertrophy which occurs after extirpation of the greater part of the thyroid gland. Gray and Loeb (9), Rabinovitch (2), McCordock (7), and Silberberg (3) have subsequently observed that the administration of potassium iodide orally or by intraperitoneal injections to normal guinea pigs for a certain length of time results in a very pronounced increase in the mitotic proliferation of the thyroid epithelium. It also leads to a slight increase in the size of the epithelium, to a slight softening of the colloid and to a marked increase in the number of phagocytes within the colloid. Marine (4) on the other hand maintains that the intraperitoneal injection of KI to guinea pigs previously subjected to partial thyroideetomy always prevents the onset of compensatory hypertrophy. Des Ligneris (5) had previously found that feeding KI in dogs causes an increase in the amount and hardne...

INTRODUCTION THE antiluteinizing potency of progesterone known through the work of Dempsey, Selye and others has been tested in experiments with intrasplenic ovarian grafts in castrated female guinea-pigs (Mardones et al., 1951). When estrogen is administered appearance of hemorrhagic follicles in the graft is prevented and large corpora lutea are produced; when progesterone is given simultaneously with estrogen, corpora lutea fail to appear. Evidence has been given that the quantity of progesterone necessary for complete prevention of estrogen-induced corpora lutea is probably smaller than that which is produced by the normal ovary in the luteal phase. Since these results have been obtained in experiments with the continuous administration of progesterone (absorbed from pellets) they do not definitely prove that the antiluteinizing faculty of progesterone interferes in the autoregulatory mechanism on which the sequence of the ovarian phases depends; but these results would not be contrary to the concept ...

A considerable amount of progress has been made since the original studies on the lactogenic hormone of the anterior pituitary by Strieker and Greuter (1), Corner (2), and Nelson and Pfiffner (3, 4), toward an understanding of the physiology of milk secretion. These and other confirmatory studies were made on animals with intact hypophyses and thoroughly demonstrated the relation of the anterior lobe to the initiation of lactation. The ablation of the pituitary in lactating animals demonstrated the necessity of that gland for the maintenance of milk secretion. See Nelson (5) for a review of these studies. It was reasonable to suppose that the administration of lactogenic hormone to hypophysectomized animals would result in the initiation of lactation. However, the results of such studies have been conflicting. Lyons, Chaikoff and Reichert (6) and McPhail (7, 8) reported the initiation of lactation in hypophysectomized dogs, ferrets, and cats while Selye, Collip and Thomson (9) were unable to do so in the ...

Steinach (1) has reported that rats, a species highly insusceptible to tuberculosis, were rendered susceptible, by adrenalectomy, to bovine tubercle bacilli. We have administered adrenal products to tuberculous patients who suffered greatly with malaise and lack of vigor—some with toxemia, others without, and noted an improvement in their vigor, a lessening of their fatigue and an apparent beneficial effect on the tuberculous process. These latter effects induced us to carry out a series of experiments on guinea pigs to test whether adrenal products would exert any effect upon tuberculosis either in the susceptibility to infection or in the character of the lesion. Whole adrenal gland, eschatin, and a material made according to the method of Swingle and Pfiffner (2) were employed.

LESSIONS THAT ARE PROPERLY PLACED in the hypothalamus of female guinea pigs may be followed by sterility due to an abolition of mating activities. This sterile condition may or may not be associated with changes in the reproductive organs (1, 2). The majority of the animals show normal ovarian cyclic changes following the operation which indicates that in these the loss of mating activity is not due to a disturbance of hypophysial function. Moreover, properly timed injections of ovap ian hormones, of hypophysial extracts and of mixtures of ovarian hormones and hypophysial extracts fail to induce estrous behavior in these animals, although they do so in normal animals (3). On the basis of these experiments it has been concluded that, although the genital changes that may follow hypothalamic lesions are due to a disturbance of hypophysial function, the loss of mating activity is due to a destruction of a part of the central nervous system that is essential for the integration of this complex behavioral pattern.

Study of collagen composition and in vivo and in vitro collagen biosynthesis and maturation in 10-day-old carrageenan-induced granulomas from female guinea pigs demonstrated that old animals have decreased amounts of neutral salt and acid soluble collagen, decreased in vitro biosynthesis and turnover, and lower ratios of proline to hydroxyproline (P: OH-P) in all collagen fractions. At any age the P:OH-P ratios appeared to reflect the rate of synthesis and turnover of collagen in the tissue studied, the more soluble, more immature, less polymerized forms having higher ratios. Estradiol administration to old animals reversed the values toward those found in young animals. In both young and old, estradiol decreased total collagen content of skin and granuloma while increasing bone mass, bone collagen, and calcium content. In the granuloma, estrogen reduced the amount and content of soluble collagen, almost eliminating the acid soluble; P:OH-P ratios in all fractions were increased and proline content of the...

There pituitary-thyroid system following the extensive changes induced in these glands by the administration of anti-thyroid agents. Morphologic alterations are known to persist in the thyroid of various species long after goitrogen withdrawal (Astwood, Sullivan, Bissell, and Tyslowitz, 1943; Mackenzie and Mackenzie, 1944; Engle and Aranov, 1946; Webster, 1949) but the status of thyroid and pituitary function under these conditions has received scant attention. There are certain indications that restoration of the normal pituitary-thyroid balance after thyroid inhibition may be characterized by an initial period of temporarily enhanced function. D’Angelo, Paschkis, Cantarow, Siegel, and Rivero Fontan (1951) have demonstrated in guinea pigs treated for prolonged periods with propylthiouracil (PTU), that depressed thryoid uptakes of I131 quickly rebound above the normal range after goitrogen withdrawal and that increased radioactivity in such glands reflects not only increased tissue mass but also augmented...

PREVIOUS observations indicate that exposure to ionizing radiation is capable of altering the endocrine integration essential for cyclic reproductive phenomena in the female. The evidence consists largely of observed abnormalities in the estrous rhythm of guinea pigs (Genther, 1931), rats (Freed et al., 1948; Leitch et al., 1949), and mice (Bischoff et al, 1944). Other indications of endocrine disturbances in reproduction are suggested by the reports of Mandel (1935) that precocious sexual maturity occurs in young rats following exposure to x-rays and of Schmidt (1937) that decreased estrogen excretion during estrus occurs in guinea pigs after local irradiation of the ovaiy. The present study was undertaken to determine whether total body irradiation is capable to modifying the growth of endometrial tissue in the rabbit, and, if possible, to establish whether such modifications could be attributable to changes in the level of endogenous hormone or to changes in the sensitivity of the target tissue to horm...

Propylthiouracil (PTU)-induced goitrogenesis was selectively impaired in male guinea pigs by anterior hypothalamic lesions. These lesions also reduced or abolished the PTU-induced enlargement of the adenohypophysis and the increase of thyrotrophin (TSH) stores therein, without causing gonad atrophy. Afore posterior lesions affected TSH secretion less and did cause gonad atrophy. The findings are interpreted to mean that neither the synthesis nor the release of TSH can reach maximal levels in the absence of the neural structures which were damaged. IN HATS, appropriate hypothalamic lesions have been found to impair, but not abolish, thyrotrophin (TSH) secretion (1–5). In dogs, on the other hand, similar lesions seem to eliminate TSH secretion, or at least its release phase, since they reduce both thyroid size and I131 uptake to hypophysectomy-like levels (6). This apparent species difference in the extentto which TSH secretion may be decreased by hypothalamic damage suggests that further comparative studie...

DESOXYCORTICOSTERONE has been shown to be capable of producing a progestational type of endometrium in immature rabbits that were pretreated with estrone (1-5). Hoffman (6) reported that this hormone could induce an estrous type of endometrium in spayed rabbits and that with continued injections the endometrium would become of a progestational type. However, Hohlweg (2) did not obtain this initial estrogenic action and a progestational effect in rabbits was obtained only after the animals had been primed with estrone. The mating response in spayed guinea pigs can be elicited with desoxycorticosterone (3). In the experiments reported here, efforts were made to determine the possible role of the animals own adrenal glands in the progestational activity of desoxycorticosterone acetate. It has been shown that progesterone can be recovered from the adrenal cortex (7), but any action of this gland in the intermediary metabolism of the steroids is unknown.

Observations on the histology of the pancreatic islands of animals in hyperpituitary or hypopituitary states are rare in contrast to the abundance of physiological data. Anselmino and his co-workers (1, 2, 3) have described an increase in number and size and a new formation of islands in rats after 6 to 7 injections of an anterior lobe extract. Aron (4) has induced a premature appearance of islands in foetal guinea pigs injected in utero with an anterior lobe preparation. Kojima (5) discovered an accumulation of granules in the island cells of rats after posterior lobe feeding but none after anterior lobe feeding. Reports of negative or doubtful findings predominate, such as those of Putnam et al (6) and Evans et al (7) who found pancreases much larger than normal but no increase or histological differences in islet tissue of dogs made acromegalic by long-continued injections of anterior lobe extracts. Lucke (8) also observed no histological changes in islands of rats whose carbohydrate metabolism had bee...

INTRODUCTION Arelationship between vitamin C and functioning of the adrenal cortex has been recognized but some phases of the nature of the interaction are still in question. Reports of this relationship have been given by Lockwood and Hartman (1933), Lockwood et al (1936), Kuchel and Mitchell (1936), Lauber and Rosenfeld (1938), Broch (1939), Giroud and Martinet (1940), Hartman (1941), Prina (1946), Tuba, Hunter and Osborne (1946), Dean and Morse (1948), Vogt (1948), and Stepto, Pirani, and Consolazio (1950). To study a phase of this relationship, guinea pigs were fed a diet deficient in vitamin C, some of which received cortisone and the others did not. MATERIALS AND METHODS In this study, 20 male guinea pigs, each weighing approximately 280 grams, were used. All animals were given the same basal diet: hulled oats, 75 lbs.; soy bean meal, 25 lbs.; Lederle fortified supplement