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In a collection of 108 surgically removed, light and electron microscopically studied pituitary tumors, 19 adenomas (17.6%) could be found of which oncocytic tumor cells constituted more than 50%. These showed histologically, in conformity with the criteria of oncocytes, a fairly broad cytoplasm with finely granular or, in part, finely vacuolar structures and distinct cell membranes. The nuclei were predominantly round and moderately rich in chromatin but also in part, pyknotic. In paraffin-embedded sections the tumors could not be distinguished with certainty from chromophobe or moderately granulated acidophil adenomas. In plastic-embedded sections they could be identified by the typical filmy and finely granular feature of the cytoplasm which was distinctly different from conglomerations of secretory granules. Ultrastructurally they were characterized by many densely packed mitochondria. These were, in part, hydropically swollen. Furthermore, 5 tumors exhibited increased hormone-synthesizing organelles, 2 of which induced an acromegaly.

98 biopsies of the paraadenomatous adenohypophysis in acromegaly, galactorrhea combined acromegaly, isolated galactorrhea, hypothalamic-hypophysial Cushing's disease, Nelson's syndrome, and in nonfunctional adenomas were studied by light microscopic methods in order to find evidence for a possible hyperplasiogenic origin of the different types of adenomas. It was hoped that the numerical relations and structures of hypophysial cells might provide significant information. Nodular ACTH cell-hyperplasia was found frequently apart from ACTH cell-tumors in Cushing's disease and Nelson's syndrome and on this basis we suggest that the adenomas in both diseases arise from hyperplasia. During their further development these adenomas seem to become autonomous, since the number of paraadenomatous ACTH cells decreased in bigger tumors.

The gonadotrophic cells of the male rat adenohypophysis were investigated by light and electron microscopy after castration, after administration of the antiandrogen cyproterone, and after treatment with the steroidogenesis inhibitor amino-glutethimide. The numbers of FSH and ICSH gonadotrophs were generally higher in the three test groups than in normal controls and their structures were of the same kind. Examination of the ultrastructure revealed an increase and dilatation of the rough endoplasmic reticulum, enlargement of the ring-shaped Golgi complexes, and a moderate decrease in the content of secretory granules. The dilatation of the ergastoplasm resulted in some cases in signet-ring cells corresponding to the castration cells seen by light microscopy. No qualitative differences in pituitary gonadotrophs were found to result from surgical or so-called chemical castration, but there were quantitative differences. The ultrastructural and histological features after castration were more evident. Many degenerating gonadotrophs were present. FSH cells could be differentiated from ICSH cells in nearly all cases.

Summary The corticotrophic cells of the anterior pituitary glands of male rats were investigated by light and electron microscope after administration of Carbenoxolonesodium, which acts like mineralocorticoids, after treatment with the steroidogenesis-inhibitors Metyrapone and Amino-glutethimide and after injections of Methylprednisolone. Carbenoxolone was administered by stomach tube for 12 weeks, the others were injected intraperitoneally for 3 weeks. After withdrawl of Carbenoxolone, no structural or numerical changes of the corticotrophs could be observed. Metyrapone and Amino-glutethimide caused identical alterations. The corticotrophs were much more numerous and showed a more distinctive stellate form. The rough endoplasmic reticulum increased and contained more ribosomes. The Golgi complexes were ring-shaped and enlarged. The content of secretory granules remained nearly unchanged. The nuclei showed a moderate pleomorphism. These findings indicate an increased synthesis of ACTH. After Methylprednisolone was administered, a considerable reduction of the number of corticotrophic cells and a moderate decrease of the ergastoplasm in the single cell were observed thus a low level of ACTH-production can be supposed.

Surgical specimens of 15 normal and 106 para-adenomous anterior pituitaries were studied immunocytochemically and in part electron microscopically for the presence of hyperplasia. GH cell hyperplasia was found in 13% of all normal pituitaries, in 6% of the cases with Prolactin secreting adenomas and in 9% of the cases with ACTH secreting adenomas. Prolactin cell hyperplasia occured in nearly equal percentages (17–23%) in normal pituitaries and in areas adjacent to GH-, Prolactin-or ACTH-secreting adenomas or adjacent to inactive adenomas. Previous findings of relatively more frequent Prolactin cell hyperplasia occuring together with Prolactin producing adenomas have to be revised. Prolactin cell hyperplasia as a primary source of hyperprolactinemia is very rare and almost always occurs in conjunction with oncocytic adenomas. ACTH cell hyperplasia was found in 13% of the normal pituitaries, in 14% of the cases with Prolactin secreting adenomas, in 58% of the cases with ACTH producing adenomas and in 40% of the pituitaries with GH secreting adenomas. We have no explanation for the latter result. ACTH cell hyperplasia may be the primary cause of Cushing's disease (18% of all Cushing cases). Hyperplasia of TSH cells in normal pituitaries was rare (7%) and with the exception of Prolactin producing adenomas (22%) was not found near adenomas. Clinical-pathological correlations are discussed.

The pituitary and adrenal glands are a functional endocrine unit affected by local or organ-limited senile amyloid syndromes. These occur as interstitial (pituitary only) or intracellular (pituitary and adrenal) varieties. The pituitary and right adrenal glands of each of 108 consecutive autopsy cases of individuals aged 85 years and over were investigated for the prevalence, distribution and immunostaining characteristics of local amyloid. Intracellular amyloid was detected in 77 (71%) pituitaries and 73 (68%) adrenals. Interstitial amyloid was found in 86 pituitaries (80%). Immunohistochemical studies, investigating different amyloid fibril proteins, amyloid P component, ubiquitin, intermediate filaments and pituitary hormones, failed to demonstrate any similarities, and a common origin is unlikely. Statistical analyses demonstrated significant correlations between the occurrences of all three local amyloids. The clinical and histopathological significance of local pituitary and adrenal amyloid remains obscure. The results suggested that the pathogenesis of the local senile amyloidoses of the pituitary and adrenals may be influenced by a common, still uncharacterized variable. It is not clear whether this variable also contributes to the pathogenesis of other senile amyloid syndromes, such as those associated with Alzheimers' disease.

Eleven pituitary adenomas in patients with acromegaly were examined with special reference to their secretory activity. The adenomas with high secretion of growth hormone were histologically characterized by well-developed vascularization, sparsely acidophilic granulation of the cytoplasm, and pleomorphism of the nuclei. Ultrastructural findings were a well-developed rough-surfaced endoplasmatic reticulum, a large, double Golgi-complex, relatively densely packed cytoplasmatic organellas, more immature than mature secretory granules, and only a few products of granule-degradation. Two adenomas showed signs of high activity histologically only but this was not confirmed by ultrastructural examination. The two were recurrent adenomas; therefore we suppose that pleomorphism of the nuclei in association with an increased number of mitoses must be interpreted as sign of increased rate of tumor growth and not of secretory activity. Comparison of the morphological degree of secretory activity with the preoperative plasma level of growth hormone yielded a good degree of correlation in 9 of 10 cases.

5 cases with Cushing's syndrome had typical hormone levels indicating hyperadrenocorticism due to a hypothalamic-hypophyseal disturbance, which was treated by transnasal transsphenoidal hypophysectomy. The anterior pituitary glands of all cases were studied under light and electron microscopes. Compared with normal controls an elevated number of corticotrophic cells were present. Many of them were enlarged and sparsely granulated and large Golgi complexes, elevated amounts of ribosomes, and many immature secretory granules were found in the ultrastructure, indicating a high degree of secretory activity. In 3 cases multiple hyperplasias of corticotrophic cells were found. These consisted of relatively small cells with many secretory granules and pleomorphic and moderately hyperchromatic nuclei which were regarded as signs of proliferation. In one case the transition of hyperplasias into a mucoid cell adenoma was demonstrated. The cells of this adenoma reacted histochemically like normal ACTH cells. The ultrastrncture was characterized by multipolar outlines, large Golgi complexes, many secretory granules, many ribosomes, small accumulations of fine filaments, and pleomorphism of the nuclei with cytoplasmic invaginations. The morphology of this adenoma was almost identical with the structure of corticotrophic adenomas developed after bilateral adrenalectomy (Nelson's adenoma). Moreover in 4 cases cells with Crooke's hyalinization were found. The causes of their presence are discussed.

A collection of 108 surgically removed pituitary adenomas was studied by histologic, immunohistochemical and electron microscopical methods. It included 7 predominantly chromophobe adenomas of patients whose clinical symptoms consisted of a pure galactorrhea. Ultrastructurally, 4 of these adenomas contained little endoplasmic reticulum so that an endocrine activity of the tumors could not be assumed. These cases represented inactive adenomas which probably led to a disturbance of the secretion of prolactin-inhibiting factor by suprasellar extension resulting in stimulation of the non-tumorous adenohypophysis and secondary hyperprolactinemia.

A case of a feminizing adrenocortical tumor associated with Cushing's syndrome in a 29 year old male is presented. The ultrastructural features are compared with adrenal tumors secreting aldosterone, glucocorticoids or androgens. As in adrenal carcinomas, this tumor demonstrates nuclear pleomorphism with enlarged nucleoli and nuclear pseudoinclusions. The cytoplasmic organelles show some parallels between feminizing and androgensecreting adrenal tumors. Different types of mitochondria occur with varying amounts of smooth endoplasmic reticulum. Numerous microbodies are present.

The aim of this study was to investigate the qualitative and quantitative changes of ACTH-cells in the rat after application of a specific and a non-specific stimulus. A CRF-analog (lysin-vasopressin) and a prostaglandin (prostaglandin E1) were used. 40 rats were injected lysin-vasopressin or prostaglandin E1, respectively, for 4 weeks. The pituitary glands were investigated by means of light microscopy, electron microscopy and morphometry. Activation of the ACTH-cells could be observed after use of both substances, the effect of lysin-vasopressin being more intense than that of prostaglandin E1. Enlargement of the nucleus, the cytoplasm and the organelles involved in hormone-production and -transport were found and verified by morphometry. Additionally an increase in number of the cells could be demonstrated. Prostaglandin influenced not only ACTH-cells, but also other cells of the anterior pituitary.

Male Wistar rats were partially hypophysectomized and sacrificed at intervals of from 2 days to 1 year following the operation. The resected material was examined under the light microscope and the residual pituitary under the light and electron microscope. Neither regeneration nor an anatomical restoration of the adenohypophysis occurred even one year after partial hypophysectomy. An increased number of small chromophobe stem cells and juvenile chromophil cells were found in the residual pituitary. The amount of mitoses were not significantly increased.

A 54 year old woman suffered from acromegaly due to a pancreatic islet cell tumour producing GHRH. The tumour was demonstrated on CT scan. The diagnosis was established from elevated plasma levels of GHRH, GH and prolactin, and by the lack of signs of a pituitary adenoma in trans-sphenoidal surgery. Acromegaly was cured by tumour removal. Light microscopically, the tumour showed a medullary and microlobular pattern. The cells were large and often cuspidal. Small granules were found in semi-thin sections. Small aggregations of amyloid fibres were seen, mostly around capillaries. Immunocytochemistry revealed GHRH, NSE, neurotensin, serotonin, VIP and PP. S 100 was positive only in nerve fibres. Staining for GH, ACTH, calcitonin, a-HCG,ß-HCG, insulin, glucagon, gastrin, substance P, bombesin and somatostatin was negative. Ultrastructure showed oval partly lobulated nuclei with small nucleoli, moderate amounts of rough endoplasmic reticulum, many free ribosomes, some large Golgi fields and small numbers of secretory granules measuring 150 nm or, in a few cells, 650 nm.

Light and electron microscopic examination of adrenal cortices from 4 cases with classical laboratory and clinical features of Cushing's syndrome was performed. Pathologic examination revealed diffuse adrenal cortical hyperplasia and nodular configuration. The cells were predominantly compact in type. Ultrastructural alterations consisted in swelling of the very numerous mitochondria with a rather empty appearance. The prominent agranular endoplasmic reticulum shows various degrees of dilatation. The lipid vaculoes are reduced in number. There is a close structural relationship between lipid vacuoles and mitochondria with fusion of membranes and discontinuity of membranes in some occasions. The cells with numerous lipid vaculoes resemble normal cells of the outer zona fasciculata. In the second case there was an association of Cushing's syndrome with an increased production of aldosterone and androgens. Ultrastructural changes in this case were thick walled intra-mitochondrial tubules and whorled membranous structures of the agranular endoplasmic reticulum. These are considered as morphological equivalents to altered hormonal function of the adrenal cortex.

Carbenoxolone-sodium in a dose of 8 to 50 mg each day was administrated by a stomach tube to Wistar rats for 9 to 14 weeks. The zona glomerulosa of the adrenal glands showed a dose-dependent decrease in width and a more distinct delineation from the zona fasciculata. The ultrastructural findings were a reduction of smooth endoplasmic reticulum and mitochondria, a decrease in size of the Golgi complex and a flattening of the cell membranes. After withdrawl of Carbenoxolone we could observe the ultrastructural equivalent of increased hormone production with a tendency for the normal cell structure to be restored. The ultrastructural changes induced by Carbenoxolone are interpreted as an inhibition of aldosterone production. Our findings and the plasma renin and aldosterone activity support the hypothesis that Carbenoxolone directly affects the zona glomerulosa by its mineralocorticoid-like activity.

The morphology of three cases of parathyroid carcinoma is described, including the electron microscope findings in two of these cases. The clinical and morphologic points for the tentative diagnosis of parathyroid carcinoma are discussed. The malignancy of a parathyroid tumour is proved by lymphogenic or hematogenic metastases, by histological evidence of tumour infiltration into the surrounding tissues (including macroscopic adherence and sometimes vocal cord paralysis), and by cytologic evidence of mitoses. Nuclear atypism is often present but is neither a necessary nor an adequate proof of malignancy, because it is also seen in benign adenomas and in hyperplastic parathyroids. The ultrastructure of the carcinoma cells was also characterized by nuclear atypism and mitoses. In one carcinoma, the contents of cytoplasmic organelles varied in different cells, indicating various endocrine activity of the tumour cells. In another parathyroid carcinoma with low endocrine activity, copious cytoplasmic organelles and many secretory granules were found. There seem to be three possible causes of non-functioning parathyroid carcinomas: 1. lack of hormone synthesis, 2. impairment of cellular hormone secretion, 3. synthesis of a pathologic protein with defective endocrine activity.

Four adenomas and one carcinoma of the adrenal cortex associated with Cushing's syndrome were investigated by light and electron microscope. The structure was compared to their hormonal function. We differentiate predominantly clear cell adenomas, which are characterized by a large number of lipid vacuoles, from compact cell adenomas with well-developed steroid hormone-producing cytoplasmic organelles. The compact cell adenomas are considered the morphologic equivalent of a high functional state, whereas the clear cell adenomas represent a storage phase and can be stimulated by ACTH. Ultrastructurally the adenoma cells with increased granular endoplasmic reticulum and pleomorphic mitochondria showed marked differences from the cells of the fasciculate and reticular zone in normal and hyperplastic adrenal glands. Electron microscopy revealed only differences of degree between adrenal carcinoma and compact cell adenoma. In the carcinoma as well as in the compact cell adenomas pleomorphic nuclei with enlarged and hyperchromatic nucleoli and nuclear inclusions were observed. Histological and ultrastructural features which may be useful in the differential diagnosis of adrenal adenomas and carcinoma are discussed.

Four pituitary tumors of patients adrenalectomized for bilateral adrenal hyperplasia with Cushing's syndrome 4–12 years before, were classified histologically as mucoid cell adenomas. Histochemically the tumor cells reacted like normal ACTH cells. The ultrastructure showed cells with multipolar outlines tending to surround other cells, large Golgi complexes, many immature secretory granules, a lot of mature granules with perigranular membranes and 200–600mµ in diameter, scattered particles of endoplasmic reticulum, a great abundance of ribosomes, pleomorphic mitochondria, a few small accumulations of fine filaments, and moderate pleomorphism of the nuclei with distinct nucleoli and sporadically cytoplasmic invaginations. It can be assumed that these adenomas developed from hyperplasias of ACTH cells. In all cases elevated levels of ACTH had been found in the plasma.

The atrophic adrenal cortex associated with corticosteroid-producing tumours was investigated by electron microscopy in 5 cases. The well-preserved zona glomerulosa was easily distinguished from lipid-rich glomerular cell complexes of the outer zona fasciculata in epoxy sections. Little difference from normal ultrastructure was observed in the cells of the zona glomerulosa. The zona fasciculata-reticularis, however, showed marked changes in the ultrastructure. The mitochondria are diminished, with reduced internal structures. Almost no agranular endoplasmic reticulum is evident. The fasciculata cells contain huge membranebound lipid vacuoles. Comparable ultrastructural changes in animals have been described after hypophysectomy or after treatment with glucocorticoid hormones. The electron microscope findings are considered to be the result of the suppression of ACTH secretion and probably of a direct inhibition of protein synthesis in adrenocortical cells by the elevated steroid hormone levels produced by the adrenal tumours.