Clinics in Endocrinology and Metabolism最新文献

Evidence is growing that the somatomedins act by a paracrine and/or autocrine mechanism. The importance of these mechanisms relative to the traditional endocrine actions is not clear, and it is possible that these growth factors act through all three mechanisms. Supporting the possible paracrine/autocrine mechanisms are reports that production of somatomedins or somatomedin-like peptides is widespread throughout the body. Additionally, the somatomedins have biological actions on remarkably diverse cell types, and these responsive cells are found in close proximity to cells known to produce somatomedin. Finally, factors that alter the growth rate of cultured cells produce parallel changes in somatomedin secretion, suggesting that these phenomena are closely linked.

Taken together, the studies reviewed here suggest that although gonadotropins are necessary for follicular growth, they are insufficient by themselves to explain the dynamics of folliculogenesis. Indeed, the role of gonadotropins in follicular maturation must necessarily be permissive: that is LH and FSH initiate a synchronized cascade of follicular events directly mediated by paracrine and autocrine factors.

The cytoplasmic secretory granules of corticotrophs in the anterior pituitary are basophil in trichrome stains and periodic acid-Schiff positive in the histochemical stain for glycoprotein due to their content of the glycosylated 16000 N-terminal fragment of the precursor protein proopiomelanocorticotrophin (POC). The granules show a positive immunocytochemical reaction to antibodies raised against ACTH, β- endorphin and N-terminal fragments of POC. A small subset of corticotrophs contains immunoreactive αMSH in addition. Immunocytochemistry shows the corticotrophs to constitute about 15–20% of the anterior pituitary cells arranged both singly and in clumps. They are distributed in the median wedge and anteriorly, laterally and posteriorly adjacent to the pars nervosa which is often ‘invaded’ by corticotroph basophils. The αMSH subset is prominent in the rudimentary intermediate lobe and is scattered anteriorly in the pituitary of the human fetus. Crooke cell hyalinization is associated with pathologically maintained hypercortisolaemia and with glucosteroid therapy. The hyalinization is demonstrated in ultrastructure to be due to massive accumulation of intermediate cytoplasmic filaments 7–8 nm in diameter that are normally present in only small number. The change is associated with a varying degree of loss of secretory granules.

In untreated Addison's disease there is a marked increase in the number of corticotrophs, many of which are arranged in distended alveoli to form micronodules. The vast majority of cases of pituitary-dependent Cushing's disease and all cases of Nelson's syndrome are associated with a basophil or chromophobe adenoma. These give a positive immunocytochemical reaction with anti-ACTH, β-endorphin and N-terminal POC. In ultrastructure the cells of the chromophobe adenomas are seen to contain sparse secretory granules that are usually smaller than those in the chromophil adenomas. There are only very few reports of pituitary-dependent Cushing's disease found to be due to immunocytochemically confirmed corticotroph hyperplasia with or without a corticotroph adenoma. A few cases have been described in which the adenoma cells show Crooke's hyalinization, associated in one example with secretion of a big ACTH found more typically in ectopic ACTH-secreting tumours. A group of cases due to corticotroph adenoma has been reported whose excessive ACTH secretion is reduced by treatment with the dopamine agonist bromocriptine, in which it is suggested that the tumour cells arise from a subset of corticotrophs of pars intermedia origin. A puzzling finding has been the incidence of immunoreactive corticotroph adenomas that are not associated with any evidence of clinical or biochemical Cushing's disease. These have been noted in surgically resected material as well as in postmortem pituitaries.

The morphological features of the adult human adrenal cortex are described with particular respect to changes induced by alterations in function of the hypothalamo-pituitary axis. The occurrence of nodules in the normal and hyperplastic cortex (Cushing's and Conn's syndromes) is discussed in relation to the diagnostic problems that they still pose. Explanations based on the normal mechanisms of functional zonation in the cortex are provided for the different cell types which comprise cortical neoplasms associated with various syndromes of hypercorticalism (Cushing's, adrenogenital and Conn's syndromes), together with morphological and functional criteria to distinguish adenomas from carcinomas.

The 41-amino acid CRF fulfils all the criteria for a corticotrophin releasing factor, although considerable evidence suggests that other factors, particularly VP, also play a physiologically significant role in controlling ACTH release. Although human CRF has now been identified as a 41-residue peptide, most studies to date have used oCRF-41 in their exploration of the physiology and pathology of the hypothalamic-pituitary-adrenal axis. Low doses of oCRF-41 appear to be safe, and for specific tests of the readily-releasable pool of ACTH and related peptides 100 μg is a practical dose for most purposes. Although serious side-effects have only been noted at doses above 100 μg, it is reasonable to monitor all patients administered CRF-41 with great care, and in particular to be alert to hypotension, especially in patients with corticosteroid deficiency. There is little doubt that, in combination with the standard insulin-tolerance test, the CRF test is a useful means of diagnosing hypothalamic or portal dysfunction in patients with secondary adrenal failure. However, in the diagnosis and differential diagnosis of Cushing's syndrome, the role of the CRF test remains unclear. In normal subjects, a high basal cortisol level usually inhibits the response to CRF, such that a greatly enhanced response is suggestive of pituitary-dependent Cushing's syndrome. In patients with diagnosed ACTH-dependent Cushing's syndrome, an absent response to CRF predisposes towards an ectopic source of ACTH. However, there are exceptions in all directions, and it is uncertain whether the CRF test will prove of greater value than the traditional procedures, such as the dexamethasone suppression test. The differential diagnosis of depression and Cushing's disease may be its greatest value.

In terms of treatment, there are as yet few data on the usefulness of CRF in expediting recovery of the pituitary-adrenal axis following long-term suppression, such as in patients with Cushing's syndrome treated by removal of a unilateral adenoma or trans-sphenoidal microadenomectomy. It is possible that such treatment may eventually be a useful application of CRF, although data are not yet available.

Adrenocortical insufficiency causes difficulty in diagnosis and morbidity out of proportion to its rarity, because of the non-specific, multi-system nature of the clinical features. Most of these are due to cortisol deficiency. Prominent features are well-known ones such as weight loss and asthenia, and hypoglycaemia. Less prominent in recent accounts are those due to failure of cellular sodium export and to vasopressin excess, which are frequent and clinically significant. For this reason, the clinical features of isolated ACTH deficiency, isolated glucocorticoid deficiency and Addison's disease overlap greatly. In addition, cortisol deficiency has secondary endocrine effects, e.g. glucocorticoid-reversible hypothyroidism, hyperprolactinaemia and hypercalcaemia. Further overlap between the various steroid insufficiency syndromes occurs because of the association of various organ-specific autoimmune endocrinopathies with Addison's disease. Over 80% of Addison's disease is of the autoimmune type, though almost any systemic destructive process can cause similar steroid insufficiency.

Demonstration of adrenal insufficiency requires various combinations of tetracosactrin adrenal stimulation tests, and hypoglycaemia or equivalent tests, if the cause is ACTH deficiency but the correct test can only be chosen to suit a firm clinical diagnosis. The treatment of adrenocortical insufficiency is described.