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Spontaneously transformed human fetal pituitary cells were isolated from first-passage cultures after 3 to 6 months of long-term maintenance in growth medium containing 15% fetal calf serum. The cells, when injected into nude mice, developed into large tumors in 1 to 2 weeks. Attempts to detect growth hormone, prolactin, follicle-stimulating hormone, luteinizing hormone, or thyroid-stimulating hormone from nude mouse plasma and tumor homogenate by radioimmunoassay were unsuccessful. These hormones could not be demonstrated in tumor cell cytoplasm by immunocytochemistry. Two human fetal pituitary (HFP) cell strains (HFP-T2, HFP-F4) from tissue culture examined at the electron microscopic level were undifferentiated by ultrastructural criteria. However, tumor cells in the nude mice showed signs of fine structural differentiation with well-developed rough endoplasmic reticulum profiles, secretory granules, and intercellular junctions. The tumor cells lost the features of morphological differentiation when returned to tissue culture. These changes could be repeated by alternate passage in nude mouse and tissue culture.

We investigated the pathogenesis of adrenal necrosis using animal models of the disease (induced by administration of acrylonitrile, cysteamine, or pyrazole) and human cases. Results of electron-microscopic and histochemical time-response studies with rat models revealed an early, retrograde embolization of medullary cells and cell fragments in the cortical capillaries that showed prominent endothelial injury. The experimental adrenal lesions were prevented by surgical removal of the medulla one month before administration of adrenocorticolytic chemicals, or by the administration of the alpha-adrenergic antagonist phenoxybenzamine hydrochloride. Histochemical staining for medullary (argyrophil) granules in human cases of adrenal necrosis demonstrated tissue fragments that stained positively for silver in vascular cortical spaces in nine of ten autopsy specimens and in all four surgical cases we reviewed. Thus, catecholamines released from the adrenal medulla and from the retrograde medullary emboli in the cortex may have a role in the pathogenesis of adrenocortical necrosis.

A cell suspension containing more than 90% lactotrophs can be prepared from enzymically dispersed adenohypophyses obtained from male rats pretreated with estradiol. The lactotrophs are separated from the mixed cell population by centrifugation on a discontinuous density gradient prepared from a commercial preparation of colloidal silica (Percoll, Pharmacia). The method allows isopycnic separation of these delicate cells under very mild conditions; normal ionic strength and normal pH were maintained throughout the gradient, centrifugal acceleration did not exceed 1600 X g, and all procedures were done at room temperature. Histological verification that at least 90% of the cells were lactotrophs was done using specific immunoperoxidase staining. The functional capability of the lactotrophs was established by measuring the dose--response to the dopamine agonist bromocriptine and to thyrotropin-releasing hormone (TRH). Bromocriptine decreased spontaneous release in a dose-related way over the concentration range of 10(-10) to 10(-8) M. TRH, which causes an in vivo release of prolactin (PRL) in estrogen-primed rats, produced a dose-related increase in the release of PRL over the concentration range of 3 X 10(-10) to 3 X 10(-8) M after the high spontaneous release had been previously reduced by bromocriptine (3 X 10(-8) M).

We studied 107 adenomas, found incidentally at autopsy in 100 pituitaries, by histologic and immunohistochemical techniques to elucidate their cellular composition and hormone content. No adenohypophyseal hormones were found in 54 (50%) of the adenomas, whereas prolactin was shown in 45 (42%). Of the remaining tumors, two contained prolactin and growth hormone, four contained adrenocorticotropic hormone, one contained thyroid-stimulating hormone, and one contained luteinizing hormone. These findings are consistent with the view that all adenohypophyseal cell types can give rise to neoplasms. No correlation was found between clinical history, autopsy findings, or cause of death and the presence or type of adenoma. The adenomas caused neither local symptoms nor endocrine abnormalities. The prevalence of various adenoma types differed between autopsy specimens and surgical material.

Ultrastructural morphometry was applied to 24 surgically removed human sparsely granulated prolactin cell adenomas in an attempt to correlate the measurements with blood prolactin levels, size of tumour, and age and sex of patient. No correlation was apparent. However, further evaluation revealed that correlation existed between size of tumour and blood prolactin levels, indicating that tumour mass, and not subcellular morphology, was related to the amount of prolactin released.

Light microscopic and immunocytologic investigation revealed focal or diffuse pituitary gonadotroph hyperplasia in 3/27 male and 3/39 female Sprague-Dawley rats over 2 years of age. Three male and 2 female rats exhibited proliferation of morphologically abnormal gonadotrophs which were described as nodules, and 4 male and 5 female rats possessed gonadotroph adenomas which contained both immunoreactive beta-LH and beta-FSH. On plastic sections at the ultrastructural level, a further female rat was found to possess focal gonadotroph hyperplasia, 2 male and 2 female rats, gonadotroph nodules and 2 male and 2 female rats gonadotroph adenomas. While extensive gonadotroph and thyrotroph hyperplasia was observed in the nontumorous portion of the 2 pituitaries harboring thyrotroph adenoma, widespread gonadrotroph hyperplasia was noted in only 2 of 13 pituitaries with gonadotroph adenoma. Gonadotroph adenomas appeared to develop from discrete foci of morphologically altered gonadotrophs. These foci probably then progressed to form nodules and subsequently adenomas. Gonadotrophs within the nodules were often similar in morphology to adenomatous gonadotrophs whereas the earlier, smaller lesions were pleomorphic or more commonly trabecular in appearance. Serum LH levels were measured in some animals. As a group, rats displaying changes in gonadotroph morphology had a higher mean serum LH level than those without these changes, however, the values ranging from 23-249 ng/ml were well within the normal serum LH levels reported in aging rats. Gonadotroph adenomas in human patients have only recently been identified with accuracy and are relatively uncommon. As in the case of rats, they do not appear to arise from a pre-existing end organ hypofunction or pre-existing gonadotroph hyperplasia. A suitable animal model, in the form of spontaneously occurring gonadotroph adenomas in aging rats, might be useful in establishing the etiology, biochemical properties and appropriate therapy for these tumors.

Intrasellar and transplanted pituitaries removed from the same rats were studied using light microscopy, immunocytology, electron microscopy and ultrastructural morphometry following treatment with bromocryptine and/or estrone acetate. Ectopic lactotrophs of rats treated with bromocryptine showed an increase in storage granule size and number, which was not observed in the lactotrophs of corresponding intrasellar pituitaries. In lactotrophs of intrasellar and ectopic pituitaries, treatment with estrone acetate caused a decrease of storage granule size, while rough endoplasmic reticulum (RER) and Golgi region volume density increased. When rats were treated with a combination of bromocryptine and estrone acetate, intrasellar lactotrophs exhibited increased volume density and diameter size in forming granules as well as increased RER volume density. In ectopic lactotrophs, combined treatment led to a decrease in RER, volume densities of Golgi region and forming granules, as well as increased storage granule size. It can be concluded that ectopic lactotrophs were more sensitive to the inhibiting effects of bromocryptine treatment than intrasellar lactotrophs. Intrasellar lactotrophs were more susceptible to estrone acetate than bromocryptine treatment. As a result, the increased responsiveness of ectopic lactotrophs to estrone acetate was less conspicuous.

The effect of bromocriptine (BEC) treatment on spontaneous, sparsely granulated, prolactin-producing pituitary adenomas was studied in aging female Long-Evans rats of at least 23 months of age. Rats treated with BEC for 1-44 days showed a marked decrease in serum prolactin (PRL) concentrations at the end of the treatment period (9.1-34 ng/ml) when compared to the serum PRL levels of age-matched control animals (94.6-233 ng/ml). No significant differences in serum PRL levels (ng/ml; mean +/- SEM) were noted in rats withdrawn for 14 days from BEC treatment (132.9 +/- 18.8) when compared to age-matched controls (181.5 +/- 70.9). The mean pituitary weight (mg) was significantly reduced in the rats treated for 44 days with BEC (23.4 +/- 1.4) compared to untreated controls (43.4 +/- 8.3). At the time of sacrifice, PRL-producing adenomas were found in 16 of 33 control rats, 5 of 10 rats treated for 1 day with BEC, 5 of 20 rats treated with BEC for 44 days, and 12 of 28 rats in the animals withdrawn from BEC treatment for 14 days. Morphometric analysis of sparsely granulated PRL-containing adenomas revealed that, although the nuclear area was reduced after 1 day of BEC treatment, the cytoplasmic area was reduced only after 44 days. Forming granule diameters were significantly increased after 44 days of BEC treatment and markedly decreased in the withdrawal group. Storage granule diameters were increased in both the 1-day and 44-day groups and were decreased in rats withdrawn from BEC for 14 days. Rough endoplasmic reticulum, forming granule, storage granule, and lysosome volume densities were increased after 1 day of BEC treatment. The Golgi region volume density decreased only after 44 days of BEC treatment. We conclude that aging female Long-Evans rats harboring PRL-producing pituitary adenomas can respond to BEC administration with a decrease in serum PRL levels and morphologic changes in adenoma cells. However, the structural alterations in PRL cells of the rat adenomas are less conspicuous than those of human tumors. In the rat, like in human patients, a direct toxic effect of BEC on PRL-producing adenoma cells has not been demonstrated.

The hypothesis that cytokines mediate neutrophil emigration induced by endotoxin (LPS) was studied by examining the potency, the kinetics of neutrophil emigration, and the tachyphylaxis of intradermal sites with IL-1, TNF-alpha and LPS. Human rIL-1 alpha and IL-1 beta, synthetic lipid A, and LPS were several orders of magnitude more potent than human rTNF. The kinetic profiles of neutrophil emigration induced by IL-1 alpha, TNF, and LPS were characterized by minimal emigration in the first 30 min, followed by rapid and transient emigration. After the injection of LPS, the onset and the time at which the rate of emigration was maximal consistently appeared 30 min later than IL-alpha or TNF, suggesting that neutrophil emigration in response to LPS was mediated by a locally generated cytokine. IL-1 and TNF were then examined as potential secondary mediators of LPS-induced emigration by comparing the patterns of tachyphylaxis between LPS and IL-1 alpha or TNF; i.e., the magnitude of neutrophil emigration into inflammatory sites was compared with sites injected 6 h previously (desensitizing injections) with a cytokine or with LPS. Tachyphylaxis was dose dependent with each and also between the IL-1 species; therefore, when tachyphylaxis between the cytokines and LPS was examined, relatively higher doses were selected for the desensitizing injections than for the test injections. With this approach, desensitizing injections of IL-1 alpha diminished the neutrophil accumulation after LPS, and LPS also desensitized sites to IL-1 alpha. However, tachyphylaxis was not observed between TNF and LPS, or between TNF and IL-1 alpha. These data suggest that IL-1, but not TNF, is a potential mediator of LPS-induced neutrophil emigration.

A well-developed 23-year-old man, complaining of blurred vision but with no endocrine symptoms, was found to have a large pituitary adenoma spreading outside the sella. Endocrine investigations disclosed growth hormone deficiency, hyperprolactinemia (responsive to thyrotropin-releasing hormone), and very high blood alpha-subunit (72 ng/ml) level. Histology showed a chromophobic, slightly acidophilic pituitary adenoma with focal fibrosis and calcification. The immunoperoxidase technique revealed prolactin and alpha-subunit in the cytoplasm of a single-cell type, at the light and electron microscopic level, indicating that monomorphous, plurihormonal adenomas exist in the human pituitary. Immunostaining with antibodies raised against beta-thyroid stimulating hormone, beta-follicle stimulating hormone and alpha-endorphin were observed in scattered cells. Those cells that contained immunoreactive alpha-endorphin did not appear to contain alpha-subunit. The ultrastructural features of adenoma cells showed no resemblance to any known cells in nontumorous or tumorous pituitaries. It can be postulated that adenohypophysial cells, after neoplastic transformation, may have the ability to secrete a number of biochemically unrelated hormones, suggesting that during embryologic development they pass through a common progenitor cell stage, capable of plurihormonal activity.

Old female Long-Evans rats with elevated serum prolactin levels were used to study the effect of bromocriptine on the stimulated mammary glands by histology, electron microscopy, and morphometry. Untreated rats were divided into normoprolactinemic (below 30 ng prolactin/ml serum) and hyperprolactinemic control groups (above 30 ng/ml). Treated groups were injected subcutaneously with 1 mg/kg of bromocriptine once daily for 1 day, 30 days and 44 days. One group was treated with bromocriptine for 30 days, and then the drug was withdrawn for an additional 14 days. The light and electron microscopic features of breasts of hyperprolactinemic control, 1 day treatment and withdrawal groups resembled those of postpartum lactating breasts. A unique feature was the presence of large membrane-bound bodies, possibly lysosomes. The breasts of normoprolactinemic control, 30 and 44-day treatment groups were similar by histology and ultrastructure to involuted breasts after cessation of lactation. However, many large lysosome-like bodies and microvilli were found in the alveolar cells which remained tightly apposed. Hyperprolactinemic control rats showed breast stimulation which could be correlated with serum prolactin levels. Serum prolactin concentrations fell within 1 day of bromocriptine treatment, whereas breast tissue responded only after a longer interval. Pituitary weights could be correlated with serum prolactin levels. Withdrawal of bromocriptine resulted in an elevation of serum prolactin levels and breasts returned to the stimulated stage. It can be concluded that bromocriptine reversibly suppresses the stimulation of mammary glands in hyperprolactinemic rats.

Dispersed rat lactotrophs were treated with bromocriptine (10(-10) M) for either 30 min or 3 h to investigate its effect on cell morphology using light and electron microscopy and ultrastructural morphometry. After 30 min, lactotrophs treated with bromocriptine exhibited an increase in storage granule size (p less than 0.05). Crinophagy was also evident and a significant increase in lysosome volume density was observed (p less than 0.001). However, no significant change in prolactin content in the media was detected until 3 h of incubation in bromocriptine (p less than 0.05). At this time a nonsignificant decrease in Golgi region volume density was also observed.

Intrasellar and ectopic lactotrophs and somatotrophs of intact and hypophysectomized rats were studied by histology, immunohistochemistry, electron microscopy and ultrastructural morphometry after 2 weeks of TRH treatment. Both ectopic lactotrophs and somatotrophs of hypophysectomized rats showed subcellular changes indicative of stimulation following TRH treatment. Ultrastructural morphometry revealed that in these ectopic lactotrophs, nuclear volume density decreased, while that of Golgi region and forming granules increased. Similar but less striking morphometric findings were noted in somatotrophs of this group and the intrasellar lactotrophs of treated nongrafted rats. Intrasellar somatotrophs showed increased nuclear volume density and reduced Golgi region volume density, following TRH administration. Ectopic lactotrophs and somatotrophs of intact animals were least responsive to treatment. These results indicate that both ectopic lactotrophs and somatotrophs of hypophysectomized rats are more sensitive to the stimulatory effects of TRH than those of intact animals.

Previous studies showed a rapid decrease of somatostatin concentration in the gut and an increase in serum gastrin levels after a single dose of the duodenal ulcerogen cysteamine. An attempt was made to identify morphologic changes that would correlate with these functional changes. Rats were killed 1, 4, 8, or 24 hr after a single dose of cysteamine and sections of gastric mucosa and pancreas were processed for electron and light microscopy. Subtle ultrastructural alterations were seen in D cells of the stomach (e.g., dilation of mitochondrial cristae and endoplasmic reticulum, and apparent increase in electron density of secretory granules) after cysteamine administration. The number of somatostatin-positive cells visualized by the immunoperoxidase technique using light microscopy was decreased in 1-4 hr but returned to normal by 24 hr. The alterations observed in the G cells after cysteamine administration are consistent with release of gastrin from mature granules and increased synthesis of the hormone. The lack of major morphologic changes in the D cells suggests that cysteamine affects somatostatin without causing cell necrosis or alteration in lysosome formation. The effect of the drug may thus be mediated at the biochemical level without marked morphologic alterations.

The effect of chronic administration of CRF on rat pituitary morphology was studied. Experimental animals received CRF (10 micrograms/day) over a period of 52 days by means of sc osmotic pumps changed at 10- to 14-day intervals. The average 0800 h plasma corticosterone levels in the treated animals were significantly greater than control values [7.52 +/- 0.99 (+/- SE) vs. 1.14 +/- 0.5 micrograms/dl; P less than 0.001]. The CRF-treated animals also had a significantly greater adrenal weight (16.44 +/- 1.38 vs. 12.24 +/- 0.85 mg; P less than 0.05) and lower thymus weight (164 +/- 12 vs. 248 +/- 27 mg; P less than 0.005). There was a marked increase in the number of ACTH-producing cells in the anterior pituitaries of the rats that received CRF (13.3 +/- 0.8% vs. 4.5 +/- 0.3% ACTH-producing cells; P less than 0.001), as determined by immunocytochemical methods. Corticotrophs of rats treated with CRF manifested a significant increase in nuclear area (24.0 +/- 0.7 vs. 21.4 +/- 0.4 micron 2; P less than 0.001) and an increased diameter of forming and storage granules (191.1 +/- 1.1 vs. 158.6 +/- 3.5 nm and 196.1 +/- 1.2 vs. 170.1 +/- 3.7 nm, respectively; P less than 0.001). There was no demonstrable increase in ACTH cell area. These data indicate that long term administration of CRF is capable of increasing the number of pituitary corticotrophs. It also supports the view that the corticotroph hyperplasia occurring after adrenalectomy, in unusual cases of ectopic CRF production, and in rare instances of Cushing's disease is a proliferative response to CRF.

Inflammation constitutes the body's principal mode of defense against infection and other harmful agents. Neutrophil leukocytes are the primary effector cells in this process. The role of protein synthesis in neutrophil emigration into acute inflammatory lesions was examined. Local intradermal injections of actinomycin D, cycloheximide or puromycin could inhibit in a dose- and time-dependent manner neutrophil emigration induced by interleukin-1, tumor necrosis factor alpha or endotoxin, but not by the leukocyte chemoattractants C5a des arg (zymosan-activated plasma), n-formyl-methionyl-leucyl-phenylalanine or leukotriene B4. Maximal inhibition, measured at the time of peak emigration, was greater than 90%. The onset of neutrophil emigration induced by the cytokines or by endotoxin was delayed by 30 to 60 minutes in comparison to the leukocyte chemoattractants. These results demonstrate at least two mechanisms of neutrophil emigration: one with a slower onset and dependence on local RNA transcription and translation and the other rapid in onset and independent of protein synthesis.

In female Long-Evans rats, development of prolactin cell adenomas is preceded by hyperplasia of prolactin cells, suggesting that factors affecting the endocrine function of prolactin cells might have an important role in the genesis of prolactin-producing pituitary tumors.

Gonadotroph adenomas resected from the pituitaries of 8 males and 8 females were studied by transmission electron microscopy and morphometry in order to establish whether they exhibit sexual dimorphism. Random photographs were taken and the following parameters compared: (1) cellular volume, (2) nuclear volume, (3) cytoplasmic to nuclear ratio, (4) volume density of endoplasmic reticulum, (5) volume density of Golgi bodies, (6) volume density of mitochondria, (7) volume density of secretory granules, (8) volume density of lysosomes, (9) diameter of secretory granules, (10) surface to volume ratio of secretory granules, (11) surface to volume ratio of Golgi bodies, (12) surface to volume ratio of nuclei, (13) surface to volume ratio of cells. The results showed that gonadotroph adenomas of males differed significantly from those of females in cell size, cell shape, and electron microscopic features of Golgi apparatus. It remains to be established whether differences in the morphology of non-neoplastic gonadotrophs of males and females can explain the development of morphologically distinct adenoma cells between the sexes.

Fifty-five adenomas were identified and characterized in the anterior pituitaries of 27 male and 39 female SD rats, over 24 months of age, by histology, ultrastructural morphology, and immunocytochemistry. Adenomas were found in 85% of male and 79% of female rats; all known adenohypophysial hormones were represented in various tumors. Prolactin (PRL)-containing adenomas were the most common (47.2%); luteinizing hormone-(LH)-containing adenomas (16.3%), immunonegative adenomas (12.7%), PRL- and growth hormone (GH)-containing adenomas (10.9%), thyroid-stimulating hormone (TSH)-containing adenomas (3.6%), adrenocorticotropin hormone (ACTH)-containing adenomas (3.6%), and GH-containing adenomas (1.8%) were also identified. Unexpected combinations were observed in 3 tumors (5.4%); a GH-LH-containing adenoma, a PRL-ACTH-containing adenoma, and a PRL-LH-TSH-containing adenoma were noted. One intermediate lobe adenoma and 1 metastatic plasmacytoma were diagnosed. It can be concluded that spontaneous pituitary adenomas in aging SD rats are potential models of the human disease because of diversity of hormone content and morphologic appearance.

With the use of electron microscopic morphology and immunochemistry, 5 tumors were studied: a spontaneous prolactin-producing adenoma (LEP rats); an estrogen-induced intrasellar tumor (R-Amsterdam rats); and 3 transplanted tumors, MtT.W10 and MtT.W5 (WF rats) and MtT.F4 (F344 rats). All tumors were derived from rat adenohypophysis and are known to secrete prolactin, growth hormone, or adrenocorticotropic hormone. The spontaneous tumor consisted of a uniform population of cells containing only immunoreactive prolactin. In the estrogen-induced tumor, prolactin and growth hormone were localized in separate cell types with the use of the immunoperoxidase technique. In the MtT.W10 tumor, both immunoreactive prolactin and growth hormone were observed in the same cell and in separate cell types. In the MtT.F4 and MtT.W5 tumors, one cell type was identified that was characterized by lack of morphologic differentiation, reduced secretory granule number, and inconclusive immunopositivity.

In pituitary lactotrophs of female Sprague-Dawley rats given cysteamine (300 mg/kg, per os/day) for 7 days, forming granules were increased in number and contained many separate electron-dense structures suggesting crinophagy. Compared to control values, cysteamine treatment caused no change in blood prolactin (PRL) levels, measured by radioimmunoassay (RIA). 17 beta-Estradiol (50 micrograms, sc/day) for 7 days, induced lactotroph hyperplasia and increased blood PRL levels which were unaffected by simultaneous cysteamine administration. The ultrastructural changes did not reflect those due to bromocriptine suppression of secretory activity, and supported the concept that cysteamine altered lactotroph morphology by an unknown mechanism. In pituitary gonadotrophs following cysteamine treatment, increased electron lucency of luminal contents of dilated rough endoplasmic reticulum was noted; however, blood luteinizing hormone (LH) levels did not differ from those of control values. In ovariectomized rats, cysteamine suppressed castration cell formation and reduced blood LH levels, suggesting an interference with the cell's ability to respond to GnRH stimulation. The morphologic effects of cysteamine appeared to be selective to lactotrophs and gonadotrophs, and were not secondary to vascular impairment, as capillary endothelial cells were undamaged.

Thirty-six rats of both sexes in two groups were treated with aminoglutethimide (AG), a steroid synthesis inhibitor, for 1 and 8 weeks respectively. The anterior pituitaries were investigated by light and electron microscopy, the techniques used including immunocytochemical and morphometric methods. Corticotrophs were identified by the avidinbiotin-peroxidase complex technique at the light and electron microscopic levels. AG administration resulted in hyperplasia of ACTH-containing cells. The increase in the volume density of corticotrophs was prevented by simultaneous medication with 3 mg corticosterone in male rats, whereas in female rats a larger dose of corticosterone was required to suppress pituitary corticotroph hyperplasia. Electron microscopy revealed that in AG-treated rats, corticotrophs were larger and contained more secretory granules than those in controls, the mean secretory granule diameter increasing from 100 nm to 165 nm. Under AG stimulation, corticotrophs showed considerable variations in structural features probably reflecting differences in their functional state. It was apparent that only one ACTH-producing cell type existed in the pars distalis of the rat adenohypophysis, although this cell type may undergo substantial morphologic alterations due to changes in endocrine activity. Gonadotrophs and thyrotrophs showed morphologic signs of stimulation and exhibited hyperplasia following AG treatment indicating that the effect of the drug was not restricted to corticotrophs.

Fifteen sparsely granulated prolactin-producing adenomas and 10 nontumourous adenohypophyses, removed by surgical hypophysectomy, have been studied using morphometry at the electron microscopic level. Compared to non-tumourous prolactin cells, sparsely granulated adenomatous prolactin cells showed a significant decrease in diameter and volume density of secretory granules and an increased volume density of rough-surfaced endoplasmic reticulum and Golgi apparatus. The volume density of mitochondria remained unchanged. These results indicate that the cells of the adenoma are in a highly active functional state. It appears that the equilibrium between hormone synthesis, storage and release is altered in adenomatous prolactin cells.

A single dose of acrylonitrile can produce fatal adrenal apoplexy within approximately 2 h. Our previous studies also indicate that multiple injections of the chemical cause acute hemorrhagic and occasional nonperforating duodenal ulcers. Other authors have reported increase in gut and lung neoplasia after chronic exposure. The present study was designed to elucidate the subacute and chronic actions of acrylonitrile on the adrenals, stomach and duodenum by correlating biochemical, functional and morphologic investigations, as well as to gain insight into the mechanisms of action of acrylonitrile. Rats were exposed to 0, 0.0001% (1 ppm), 0.002%, 0.01%, 0.05% or 0.2% acrylonitrile in drinking water, or to the same amount of the chemical given through daily gavage, for 7, 21 or 60 days. Acrylonitrile caused a time- and dose-dependent decrease in plasma corticosterone levels; aldosterone was affected only by the 'high' dose and prolonged time of exposure. Young rats were more susceptible than adults to this action of acrylonitrile. The adrenal cortex, especially the zona fasciculata, was atrophic in rats that had ingested the nitrile through drinking water. At 0.05% and 0.2%, it also caused decreased food intake and body weight gain. The adrenals were enlarged with a hyperplastic zona fasciculata after daily doses of a bolus of acrylonitrile. Ingestion of the chemical did not interfere with compensatory enlargement of the adrenal gland following unilateral adrenalectomy. On the other hand, the ACTH-induced elevation of corticosterone plasma concentration was significantly attenuated by acrylonitrile in drinking water. Electron microscopy of the adrenal glands revealed no consistent changes in the steroid-producing cells. We thus postulate that accelerated turnover of circulating corticoids and/or interference with the secretion or action of ACTH may primarily be responsible for the decreased plasma levels of corticosterone and aldosterone in rats that ingest acrylonitrile. The mucosa in the stomach at the junction of the forestomach and glandular region of animals that had ingested acrylonitrile was hyperplastic. The corpus also showed regional mucosal hyperplasia with the appearance of 'cobble-stoning'. These changes were preceded and associated with an elevated concentration of non-protein sulfhydryls mostly in the mucosa of the glandular stomach. A similar, less prominent elevation also occurred in the proximal duodenum. These alterations may resemble the preneoplastic combination of elevated glutathione and focal hyperplasia described in the liver with hepatocarcinogens.(ABSTRACT TRUNCATED AT 400 WORDS)

Following 2 weeks of administration of 2-bromo-alpha-ergocryptine, a marked decrease was observed in prolactin immunoreactivity of the grafted pituitaries, whereas no reduction was noted in the intrasellar pituitaries. No evidence of crinophagy was revealed by electron microscopy in prolactin cells of 2-bromo-alpha-ergocryptine-treated rats.

The effect of bromocriptine (BEC), a dopaminergic agonist, on nontumorous pituitary prolactin (PRL) cells of aging female Long-Evans rats, was studied histologically, immunocytologically, electron-microscopically, and morphometrically. Rats were arbitrarily divided into two control groups, one with normal (less than 20 ng/ml) and one with elevated serum PRL concentrations, and into four BEC-treated groups, all of which had increased serum PRL levels prior to commencement of BEC administration. In hyperprolactinemic control rats, compared with normoprolactinemic control rats, pituitary weight and percentage of pituitary PRL cells were increased. The morphologic features of PRL cells in these two groups did not differ markedly, which suggested that hyperprolactinemia was due to increased PRL-cell number and not increased PRL-cell function. Compared with age-matched hyperprolactinemic control rats, hyperprolactinemic rats treated with BEC showed a reversible decrease in serum PRL levels, pituitary weight as well as percentage of pituitary PRL cells, and by ultrastructural morphometry an increase in the volume density of lysosomes. BEC caused no striking changes in nuclear and cytoplasmic areas, volume densities of RER, Golgi regions, mitochondria, lipid droplets, and size and volume densities of forming and storage granules. Since spontaneously hyperplastic PRL cells show less conspicuous morphologic changes following BEC treatment than PRL cells rendered hyperplastic by estrogen administration or pituitary transplantation, it is suggested that PRL cells with no increased endocrine function respond less markedly to dopaminergic suppression than endocrinologically hyperactive PRL cells. It can be concluded that BEC suppresses spontaneous proliferation of PRL cells which occurs with aging.

In order to assess the value of the Grimelius silver method in adenohypophysial cell identification and adenoma diagnosis, 22 nontumorous adenohypophyses and 50 pituitary adenomas were investigated. Grimelius positivity was localized, as documented by mirror sections, predominantly in PAS and led hematoxylin positive cells; but a few negative cells contained argyrophil granules as well. The immunoperoxidase method revealed Grimelius positivity primarily in corticotrophs, thyrotrophs and gonadotrophs, and occasionally in somatotrophs and lactotrophs. Argyrophilia was readily demonstrated in 11 out of 13 corticotroph cell adenomas, in 1 out of 1 thyrotroph cell adenoma, in 5 of 11 null cell adenomas and in 4 out of 5 oncocytomas. No argyrophilia was detected in 5 growth hormone cell adenomas and 5 prolactin cell adenomas. One our of 5 mixed, growth hormone cell-prolactin cell adenomas, and 1 out of 5 acidophil stem cell adenomas showed Grimelius positivity. By electron microscopy, silver grains were localized in the secretory granules. It can be concluded that no specific hormonal products account for argyrophilia.

The effects of cysteamine (CSH) on hypothalamic concentrations of neuropeptides were reviewed and correlated with available information on changes in pituitary hormone content and circulating pituitary hormone levels. In our study, we found notable changes in the morphology of lactotropes from female Long-Evans rats treated for 7 days with CSH (300 mg/(kg X day) per os). Forming granules increased in number, and crinophagy, which is the augmented incorporation of these granules into lysosomes, was evident. Storage granules were reduced in number. These changes were not suppressed by simultaneous administration of 17 beta-estradiol (50 micrograms/day s.c.) for 7 days. CSH administration failed to prevent estrogen-induced lactotrope hyperplasia. Serum prolactin levels were unaffected by CSH treatment. The morphological changes in the adenohypophysis did not resemble those observed when rats were treated with bromocriptine. The rough endoplasmic reticulum luminal density was reduced in gonadotropes from intact CSH-treated rats after 1 wk. CSH treatment suppressed the development of castration cells and significantly reduced serum luteinizing hormone levels in ovariectomized rats. The morphological effects of CSH appeared to be confined to lactotropes and gonadotropes.