Pathophysiology of acromegaly.

This review discusses the pathophysiology of acromegaly. Acromegaly has been classified in this paper into distinct entities based on etiology, ultrastructural features of the pituitary, and cytogenesis. This classification has been proposed based on clinical signs, immunoperoxidase techniques, transmission electromicroscopy and immunoelectron microscopy. Pituitary causes of acromegaly include densely granulated adenomas, sparsely granulated adenomas, mixed growth hormone and prolactin cell adenomas, acidophil stem cell adenomas, mammosomatotroph cell adenomas, and pleurihormonal adenomas. GH cell hyperplasia and GH cell carcinoma are also discussed. Extrapituitary causes of acromegaly include eutopic GH cell adenoma in the sphenoid sinus or parapharyngeal region and excess GHRF secretion which may be eutopic or ectopic. The pathological, clinical, and biochemical evidence in favor of a pituitary or hypothalamic etiology of acromegaly has been reviewed. Finally, a multistage theory of GH cell tumorigenesis has been proposed as a model in an attempt to unify the genetic, environmental and biochemical factors implicated in the pathogenesis of acromegaly.

Sustained pulsatile insulin secretion from adenomatous human beta-cells. Synchronous cycling of insulin, C-peptide, and proinsulin.

The endocrine pancreas secretes insulin in a pulsatile fashion. This rhythm is generated at a site within the pancreas, although its precise location has not been determined. With an in vitro system, we tested the possibility that beta-cells might generate spontaneous pulsatile insulin secretion in the absence of any external influence. Human insulinoma tissue from five patients was perifused for 7-10 h with RPMI-1640 medium and constant concentrations of glucose (5.5 mM). Insulin, C-peptide, and proinsulin were measured in the effluent collected at 3.3-min intervals. All three peptides demonstrated pulsatility of secretion in a similar, synchronous fashion that was sustained throughout each study. The Clifton cycle detection program demonstrated cycling in all five tumors, with an average period for all tumors of 28, 29, and 26 min for insulin, C-peptide, and proinsulin, respectively. Spectral analysis confirmed the regularity and consistency of the hormonal secretory patterns. Mean hormone concentrations secreted by different tumors varied, but insulin and C-peptide were secreted in a nearly 1:1 ratio. This study demonstrates 1) that beta-cells are able to generate spontaneous pulsatile insulin secretory activity, which is independent of innervation or the presence of other islet cells, and 2) proinsulin secretion from the beta-cell also has an inherent pulsatility. The synchrony observed in the cycles of proinsulin and its peptide products confirms their common secretory pathway in the beta-cell. We conclude that the beta-cell may be the originator of insulin cycling.

Human mixed somatotrophic and lactotrophic pituitary adenomas.

Six patients with acromegaly at examination were found to have pituitary adenomas composed of cells that secreted GH and PRL. This was demonstrated by the elevated serum hormone concentrations, by immunoperoxidase staining of 5 specimens, and by electron microscopic examination of 4. Ultrastructural characteristics, described in detail, suggest that these adenomas were mixed adenomas consisting of 2 well-defined, distinct cell types, each secreting one hormone. By immunoperoxidase staining some cells were found to contain immunoreactive growth hormone, other cells immunoreactive prolactin. No cells were detected exhibiting immunostaining for both growth hormone and prolactin. Eelctron microscopy, consistent with the results of immunostaining, revealed the presence of two distinct cell types, distinguishable from each other by their characteristic fine structural features. No intermediate forms were noted. Thus there was no evidence to suggest that one cell type might transform to the other. Present findings seem to indicate that mixed adenomas secreting growth hormone as well as prolactin and consisting of somatotrophs as well as lactotrophs do occur in the human pituitary gland. Although all the results obtained so far suggest that these tumors are composed of two distinct cell types and thus can be interpreted as representing real mixed adenomas, further work is required to establish whether or not they derive from one common progenitor.

Pituitary hyperthyroidism. Case report and review of the literature.

A 58 year old woman with an enlarged sella turcica was found to have hyperthyroidism with a supranormal concentration of serum thyrotropin. Transsphenoidal microsurgery resulted in the removal of a chromophobe adenoma comprised mainly of thyrotropes. Postoperatively, serum thyrotropin, thyroxine and triiodothyronine levels fell within normal limits, and the patient maintained normal thyroid and pituitary function.

Regression of pituitary tumors, a possible effect of bromergocryptine.

With the advent of the prolactin radioimmunoassay and more sensitive methods of roentgenologic examination, prolactin-secreting pituitary tumors are now being diagnosed with much greater frequency. Definitive treatment has been considered to involve transphenoidal hypophysectomy. The symptoms of hyperprolactinemia including amenorrhea, galactorrhea and infertility can usually be controlled without difficulty by bromergocryptine therapy, but little is known regarding continued tumor growth. Bromergocryptine and other ergot alkaloids have been shown to decrease the production of prolactin and to inhibit the rate of pituitary tumor growth in animal studies. In man, evidence for a similar effect is not as clear. The present study demonstrates tumor regression associated with bromergocryptine therapy in two patients.

Localization of prolactin in chromophobe pituitary adenomas: study of human necropsy material by immunoperoxidase technique.

In order to identify prolactin-producing tumours in human pituitary glands, 45 chromophobe adenomas, obtained from unselected necropsies, have been studied by various staining procedures including the immunoperoxidase technique for the demonstration of prolactin. The presence of immunoreactive prolactin was revealed in the cytoplasm of the tumour cells in six cases (13%), indicating that the occurrence of prolactin-producing adenomas is not rare. No correlations were established between tumours and clinical history. Two adenomas were detected in female and four in male patients. The age of the patients at necropsy ranged from 28 to 75 years. Three adenomas were associated with disseminated carcinoma, two with fatal liver disease, and one with diabetes mellitus, atherosclerosis, and pyelonephritis. Manifest endocrine symptoms were not disclosed, and endocrine investigations, including measurements of blood prolactin levels, were not undertaken. Thus, direct evidence is lacking as to whether or not these tumours were actively secreting prolactin. In the non-tumorous parts of the anterior lobes the number of prolactin cells was decreased in two cases, suggesting that prolactin released from the adenoma cells suppressed prolactin production in the non-tumorous pituitary. However, the number of prolactin cells of the non-tumorous adenohypophysis seemed to be unchanged in two and increased in another two cases. The present findings conclusively proved the existence of the prolactin-producing adenomas as a distinct entity. These tumours do not stain with acid or basic dyes, they are PAS or thionin negative, and do not contain immunoreactive growth hormone. Thus, by conventional staining procedures they are indistinguishable from other chromophobe adenoma types. Herlant's erythrosin and Brookes' carmoisine methods, claimed spedifically to stain prolactin cells, failed to provide reliable results, hence their use cannot be recommended in tumour identification. Immunoperoxidase staining of prolactin is the only technique which conclusively reveals the presence of immunoreactive prolactin in the cytoplasm of the tumour cells and permits diagnosis. It is proposed that this technique be introduced in pituitary morphological studies. Its application may lead to a better understanding of problems related to prolactin-producing tumours and their secretory activity.

Effects of caloric restriction and exercise on insulin receptors in obesity: association with changes in membrane lipids.

We have studied the effects of supervised caloric restriction and exercise on mononuclear leukocyte lipid composition, membrane fluidity, and insulin receptors in ten nondiabetic obese adults, (175 +/- 9.3% of ideal body weight) and ten normal adult subjects. In a second study, we examined the effects of caloric restriction alone using a very low calorie liquid diet in the treatment of another ten obese adults. In both groups of obese adults, fasting insulin levels were elevated and fell to normal levels following treatment. Insulin binding to monocytes, which was reduced in obese subjects, increased toward normal after short-term treatment; this was due to the restoration of total insulin binding capacity to levels one half of that seen in the normal adult group. Obese subjects undergoing either treatment had elevated membrane cholesterol/phospholipid ratios prior to treatment (0.499 +/- 0.050 and 0.446 +/- 0.011 v 0.400 +/- 0.025 mol/mol in normal adults P less than 0.005 by ANOVA). Prior to treatment, for all subjects there was a significant inverse correlation between insulin tracer binding and membrane cholesterol/phospholipid ratios (r = .484, n = 34, P less than 0.005). This relationship did not change significantly in obese subjects in either treatment group. Cell membrane microviscosity was determined by fluorescence polarization (FP) using DPH (2 X 10(-6) mol/L). Prior to weight loss, obese subjects had significantly higher FP values than controls (0.304 +/- 0.006 and 0.319 v 0.259 +/- 0.009, P less than 0.005, by ANOVA) indicating greater microviscosity.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of peptides on reduced response of rats to electric footshock after acute administration of morphine.

Acute treatment of rats with morphine (10 mg/kg) resulted in a marked reduction of motor response to inescapable electric footshock (EFS). Nalorphine (2mg/kg) antagonized this action of morphine. Pretreatment with synthetic ACTH 1-24 (10 IU) 60 min prior to testing also inhibited this morphine-induced reduction, whereas other ACTH-like peptides, lacking corticotrophic activity, were ineffective. ACTH 1-24 had no effect on the response of adrenalectomized rats to EFS after morphine. In intact rats dexamethasone pretreatment 4 hr prior to testing also antagonized the action of morphine on EFS. Taken together these findings suggest that ACTH 1-24 interferes with the antinociceptive action of morphine and that the integrity of the adrenal is essential for demonstration of this antagonism.

Pituitary adenomas associated with elevated blood follicle-stimulating hormone levels: a histologic, immunocytologic, and electron microscopic study of two cases.

The histologic, immunocytologic, and electron microscopic features of pituitary adenomas surgically removed from two men with elevated levels of blood follicle-stimulating hormone (FSH) are described. In both cases, the high blood FSH levels were reduced after surgery. By light microscopy, the tumors corresponded to chromophobic adenomas, and the immunoperoxidase technique revealed the presence of immunoreactive FSH (beta-subunit) in the cytoplasm of the adenoma cells. By electron microscopy, the adenoma cells differed considerably from nontumorous FSH cells. They were smaller and angular and contained numerous microtubules as well as spherical secretory granules measuring 100 to 250 nm in diameter and often lining up along the cell membranes. The present findings are consistent with the view that FSH-producing adenomas may originate in the human pituitary.

Effect of starvation on pituitary growth hormone cells and blood growth hormone and prolactin levels in the rat.

Growth hormone (GH) cells of rats were studied on days, 2, 4 and 7 of starvation. Immunoperoxidase staining for light microscopy confirmed the presence of GH in the pituitaries of all groups of animals. Electron microscopy revealed crinophagy in the cytoplasm of GH cells on days 4 and 7. By ultrastructural morphometry, volume density and the diameter of secretory granules in the cytoplasm of GH cells remained unchanged. Blood GH determinations showed a significant decrease on day 4 of the starvation period. On day 7 most of the values were in the range of the controls. Blood prolactin levels fell significantly on day 7. It appears that the pituitary is capable of secreting GH even in rats completely deprived of exogenous nutrients.

Prolactin cells in the human pituitary. A quantitative immunocytochemical analysis.

Sixty adult human pituitary glands taken at autopsy were stained for prolactin using the immunoperoxidase technique, and percentages of prolactin-bearing cells were assessed. There was no difference between the percentages of prolactin cells seen in the adenohypophyses of adult men and nulliparous women; they averaged 16.9%, with an average of from 8.6% to 31.3%. Percentages did not vary with age, and were higher in women in the perinatal period. In multiparous women percentages were increased, which indicates that prolactin cell hyperplasia of pregnancy does not completely reverse. No regression of prolactin cells was evident in the nontumorous portion of glands that harbored prolactinomas; however, percentages were elevated in glands with non-prolactin-producing adenomas. Quantitative adenohypophysial cell classification provides a basis for defining hyperplasia and abnormal distribution of cells that result from various pathologic conditions, drug therapies, and changes in the hormonal environment.

Cushing's syndrome and autoimmunity.

Is Cushing's syndrome ever caused by adrenal stimulating autoantibodies? Specific antiadrenal antibodies were found in the serum of three of seven patients with Cushing's syndrome. The immunologic techniques that showed positive results were complement fixation, tanned RBC hemagglutination, and immunofluorescence. Lymphocytic infiltration of the adrenal was present in two cases, in one of which nodular hyperplasia seemed to be of primary adrenal origin with autoimmunity as a possible cause. However, in cases with clear-cut pituitary origin, the lymphocytic adrenalitis and circulating adrenal antibodies are likely secondary to antigen leaking from damaged tissue.

Acidophil stem cell adenoma of the human pituitary.

Among 87 pituitary adenomas, four neoplasms had a superficial resemblance to undifferentiated cell adenomas and some fine structural features of both sparsely granulated adenomatous growth hormone and prolactin cells. Misplaced exocytosis, fibrous bodies, and multiple centrioles were sometimes revealed within the same cell and usually were accompanied by oncocytic transformation, mitochondrial alterations, and abnormal centriologenesis. The patients had normal or low blood growth hormone levels and elevated or normal prolactin values. All the tumors that were tested contained immunoreactive growth hormone and prolactin, irrespective of the blood hormone levels. The four tumors could represent a hitherto unclassified adenoma type and derive from the common, committed precursor of the two acidophils. The term acidophil stem cell adenoma is proposed to designate this entity.

Staining of human pituitary glands with lead hematoxylin in comparison with other histochemical procedures, including the immunoenzyme technique.

Human pituitary glands and pituitary adenomas, obtained by surgery or at autopsy, have been stained with lead hematoxylin and the results were compared with those of other histochemical procedures, including the immunoperoxidase technique. Lead hematoxylin positivity was found in the cytoplasm of melanocorticotroph, thyrotroph as well as gonadotroph cells, indicating that lead hematoxylin has no selective affinity for melanocorticotroph cells. Lead hematoxylin positive cells also stained with the PAS technique. Lead hematoxylin positivity was not revealed in growth hormone cells or in prolactin cells. Basophilic adenomas, composed of melanocorticotroph cells and associated with Cushing's disease or with Nelson's syndrome or unaccompanied by hormonal hypersecretion, showed intense lead hematoxylin positivity. Thus, no correlation was evident between lead hematoxylin positivity and secretory activity. Acidophilic or chromophobic adenomas consisting of growth hormone cells, prolactin cells, stem cells, undifferentiated cells or oncocytes, however, were negative. It can be concluded that the lead hematoxylin staining techniques a reliable, easy and reproducible histochemical method, and its use can be recommended in studies related to adenohypophysial cytology.