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Practical approaches to the management of acromegaly are discussed. The roles of surgery, radiotherapy, and medical treatment with oral dopamine agonists such as bromocriptine or the long-acting somatostatin analogue octreotide given subcutaneously are reviewed. Most cases need surgery, but cure is rare in patients with macroadenomas, although common with microadenomas. Radiotherapy should be considered in surgical failures, but takes several years to be effective. Medical treatment with octreotide is effective in the majority, for whom it represents a major advance, but it needs to be administered subcutaneously and the development of gallstones and gastritis in long-term treatment are problems. Bromocriptine is usually less effective, but occasionally still plays a role in the therapeutic program. Combinations of the different modalities are usually required in the management of acromegalic patients.

Gallbladder stones (GBS) are found in up to 50% of patients receiving octreotide, but the reported prevalence of cholecystolithiasis in patients treated with octreotide is variable and little is known about gallstone incidence, composition, pathogenetic mechanisms, dissolvability, and primary prevention. Octreotide treatment apart, in industrialised societies most GBS are mixed in composition, cholesterol-rich (arbitrarily greater than 70% cholesterol by weight), radiolucent (70%), and, given a patent cystic duct (70%), dissolvable in bile rendered unsaturated in cholesterol by oral ursodeoxycholic (UDCA) +/- chenodeoxycholic (CDCA) acid treatment. They form when (1) GB bile becomes supersaturated with cholesterol (as the molar ratio of cholesterol to phospholipids in biliary vesicles approaches 1:1, the vesicles become unstable); (2) there is an imbalance between pro- and anti-nucleating factors, which favors cholesterol crystal precipitation; and (3) there is stasis within the GB as a result of altered motor function and/or excess mucus that traps the crystals. These changes may be associated with altered (4) biliary bile acid composition (more DCA and less CDCA than normal), and/or (5) phospholipid fatty acid composition (arachidonyl-rich lecithin acting as a substrate for mucosal prostaglandin synthesis which, in turn, may influence both gallbladder motility, and mucus glycoprotein synthesis and secretion). During octreotide treatment, meal-stimulated cholecystokinin (CCK) release is impaired leading to GB hypomotility, but little is known about the effects of octreotide on biliary cholesterol saturation, crystal nucleation time, mucus glycoprotein concentration, bile acid or phospholipid fatty acid composition. Most, but not all, reports suggest that the prevalence of GBS in octreotide-treated patients is considerably greater than that in age-, sex-, and weight-matched controls, but proof (by pre-treatment and on-treatment ultrasound) that the GBS were absent before, but developed during, therapy is not always available. Furthermore, there are few data on analysis of GBS composition in patients developing stones during treatment, although initial reports suggest that octreotide-associated GBS are also radiolucent, cholesterol-rich, and dissolve with oral bile acid treatment. Maximum GBS attenuation values, measured in Hounsfield Units (HU) by localized computerized tomography scanning of the GB, predict stone composition and dissolvability: GBS with scores of less than 100 HU are cholesterol-rich and dissolve well with oral bile acid treatment. However, preliminary results in 11 acromegalic patients treated with 200 to 600 micrograms octreotide/d for 29 to 68 months show that the HU scores range from 23 to 490 (mean +/- SEM, 116 +/- 41), suggesting that at least four of these 11 patients have non-cholesterol stones.(ABSTRACT TRUNCATED AT 400 WORDS)

Infusion of growth-hormone release inhibiting hormone (G.H.-R.I.H.) in four fasting subjects reduced plasma glucagon and insulin concentrations to undetectable levels and this was associated with a highly significant decline in plasma-glucose (28±S.E.M. 3 mg. per 100 ml. in 1 hour, p

Ten normal male subjects were administered clonidine (0.1 and 0.2 mg) or a highly-selective alpha2-adrenoceptor agonist S 3341 (1 and 2 mg) on separate occasions in a double-blind randomise

Cushing's syndrome remains one of the most challenging problems in clinical endocrinology. Cushing's disease is caused in the majority of cases by basophil pituitary microadenomas which may be successfully treated by trans-sphenoidal hypophysectomy. Treatment with metyrapone or o,p'-DDD can always induce a clinical remission but not a cure, and neurotransmitter therapy may be effective in a minority of cases. Pituitary irradiation cures about half of cases in the long-term and may be used for surgical failures. Tumours producing ectopic ACTH are frequently benign, small and occult and may produce a syndrome clinically indistinguishable from Cushing's disease. Biochemical investigations cannot absolutely distinguish pituitary from ectopic sources of ACTH and therefore body CT scanning and percatheter venous sampling are essential diagnostic investigations. Tumour localization may result in resection and complete cure, although even small tumours may have a malignant potential. Adrenal tumours are readily diagnosed by plasma ACTH measurement and adrenal CT scanning. Adrenal adenomas are cured by adrenalectomy. Carcinomas may be treated by a combination of adrenalectomy, radiotherapy and o,p'-DDD, but long-term prognosis is poor.

SummaryPlasma Cortisol levels were elevated in a large proportion of samples from manic patients. Although a correlation was found between clinical ratings of the severity of mania and the degree of elevation of daytime Cortisol levels, some patients with low clinical ratings had elevated Cortisol levels. During treatment with haloperidol, Cortisol levels returned to normal earlier that the clinical state. The underlying mechanisms are discussed.

Human growth hormone releasing hormone (GHRH) was originally extracted from two pancreatic tumours in patients with acromegaly, and is now known to consist of a 44 residue amidated peptide or its C-terminal-shortened derivatives. The sequence of rat GHRH has also been determined; this 43 residue peptide shows approximately 70% homology with human GHRH, and is located mainly in the arcuate nucleus of the hypothalamus. Pulsatile GH release in the rat is principally a consequence of the pulsatile release of hypothalamic GHRH, although this appears to be associated with a transient suppression of somatostatin release. Exogenous GHRH specifically increases circulating GH in many species, and in the long term may increase growth. In normal man, several analogues of GHRH have been shown to be safe, sensitive and specific stimuli to GH release; although there may be a variable prolactin response, this is usually of small magnitude. Continuous infusion of GHRH leads to a decrement in responsiveness, due at least in part to changes in hypothalamic somatostatin. The GH response to GHRH is also modulated by obesity, blood sugar, free fatty acids, and GH itself. Many children with 'GH deficiency' (idiopathic, radiation-induced, or secondary to hypothalamopituitary tumours) respond to intravenous GHRH with an acute rise in serum GH. Early studies also indicate that long-term therapy with subcutaneous GHRH may increase growth velocity in some of these children. It is concluded that analogues of GHRH are useful in the investigation of the hypothalamopituitary axis, and may be important in the therapy of short stature.

We have previously reported that in normal subjects plasma immunoreactive somatostatin levels rise after a mixed meal. The contribution of individual nutrients to this rise, and the molecular nature of the somatostatin immunoreactivity measured, have now been studied. Six normal healthy subjects received, on separate occasions, isocaloric (520 calories,) and isovolumetric (260 ml) quantities of carbohydrate, protein, and fat. The mean fasting plasma somatostatin level was 29 ± 5 pg/ml. After carbohydrate a peak of 48 ± 7 pg/ml was reached at 30 min, and after protein and fat there were more sustained rises with peak levels of 74 ± 8 pg/ml and 80 ± 9 pg/ml, respectively. Sephadex G50 chromatography of extracts of fasting peripheral plasma showed two main peaks of somatostatin immunoreactivity, one coeluting with cyclic somatostatin and a larger peak of approximately 3500 molecular weight (mol wt). Levels of both 1600 and 3500 mol wt somatostatin were increased 60 min after a mixed meal. Approximately 80% of the 3500 mol wt form of somatostatin could be converted to the 1600 mol wt form by treatment with dithiothreitol (an agent which reduces disulphide bonds). It is concluded that: (a) in normal subjects fat and protein are potent stimuli for somatostatin release; (b) somatostatin in normal peripheral plasma exists in multiple forms, and that both 1600 and 3500 mol wt forms of somatostatin immunoreactivity are stimulated by feeding; (c) the 3500 mol wt form could represent a dimer of somatostatin, or a somatostatin molecule linked to a second peptide chain by disulphide bonds.

Summary Hirsuties and virilism may result from excess androgen production from autonomous tumours of the ovary or adrenal cortex, from Cushing's disease or congenital adrenal hyperplasia, but most commonly from the polycystic ovary syndrome or drug administration. Autonomous tumours may usually be differentiated from polycystic ovaries by combined measurement of plasma and urinary androgen levels before and after dexamethasone administration, and visualisation of the ovaries using gynaecography or laparoscopy. Tumours should be removed and a trial of prednisolone therapy considered in patients with polycystic ovaries. For those patients presenting with the polycystic ovary syndrome and infertility, ovulation can usually be induced using clomiphene or gonadotrophins.

The administration of the long-acting dopaminergic agonist bromocriptine to five healthy volunteers inhibited the rise in plasma-aldosterone that normally follows the administration of frusemide. This inhibition was not due to a lowering of plasma-renin activity. It is suggested that dopamine may modulate the normal secretion of aldosterone either directly, or indirectly, possibly by inhibition of prolactin secretion.

The hypothesis that the "down-regulated" gonad is less vulnerable to the effects of cytotoxic chemotherapy for advanced Hodgkin's disease has been investigated. Thirty men and eighteen women were randomly allocated to receive an agonist analogue of gonadotrophin-releasing hormone prior to, and for the duration of, cytotoxic chemotherapy. Buserelin (d-Ser-[TBU]6 LHRH ethylamide) was prescribed in two different dosage schedules to twenty men, and in a single dosage schedule to eight women. A standard gonadotrophin-releasing hormone test (GnRH 100 micrograms) was performed 1 week prior to and on day 1 of each cycle of chemotherapy. In all patients peak luteinizing hormone responses to GnRH were suppressed throughout treatment. The higher of the two dosage schedules used in the men caused more effective suppression of luteinizing hormone, and both regimens led to an initial suppression of peak follicle-stimulating hormone responses to GnRH, which was not maintained. At follow-up assessment up to 3 years from the completion of treatment, all men treated with buserelin were profoundly oligospermic and four of the eight women were amenorrhoeic. All ten male controls were profoundly oligospermic, and six of nine female controls were amenorrhoeic. In the dosages and schedules investigated, buserelin was ineffective in conserving fertility.

The effects of the ergoline derivative, lergotrile mesylate, on the serum levels of PRL, GH, TSH, LH, FSH, cortisol, and blood sugar were studied in six normal males. The effects of lergotrile mesylate on the serum levels of GH and PRL were also studied in eight patients with acromegaly and in two with idiopathic hyperprolactinemia. In the normal subjects, 2 mg oral lergotrile lowered basal PRL levels after 90 min and markedly impaired the PRL response to TRH (200 micrograms iv); the mean peak value +/- SE was 8.3 +/- 1.1 micrograms/liter, compared to the control value of 66.6 /+- 11.3 micrograms/liter. Lergotrile raised serum GH levels in five of the six subjects to peaks of 8-49 micrograms/liter, compared to 2-8 micrograms/liter after placebo. In three subjects, the GH response to lergotrile was attenuated by the prior administration of the dopamine antagonist, metoclopramide (10 mg orally). Lergotrile had no effect on FSH and LH levels under basal conditions or after the gonadotrophin-releasing hormone (GnRH; 100 micrograms iv). Circulating TSH levels were unaltered basally but impaired after TRH. Blood sugar levels were unaltered; serum cortisol was elevated in five of six subjects; there was a brief depression of diastolic blood pressure, but no change in pulse rate. The side effects after lergotrile were variable, with drowsiness as a consistent feature. These actions are similar to those of bromocriptine (an ergot derivative treatment of hyperprolactinemia and acromegaly, to suppress PRL and GH secretion, and in parkinsonism. Therefore, it may be expected that lergotrile could fulfill these clinical uses; however, in the studies comparing the effects of single oral doses of lergotrile (2 mg) and bromocriptine (2.5 mg) on GH and PRL secretion in patients with acromegaly and hyperprolactinemia, lergotrile in the dose used has been found to have an earlier onset and shorter duration of action.

Growth hormone release inhibiting hormone (GHRIH) was administered by constant infusion over 75 minutes to eight acromegalic patients at different doses. 100 to 1,000 mug were equally effective in reducing circulating growth hormone (GH) levels; 25 mug lowered GH levels in only five patients, and at this dose the extent of the fall was smaller than from doses of 100 mug or more. 10 mug was ineffective. Injection of single doses of 500 mug by intravenous, subcutaneous, and intramuscular routes caused only small and transient reductions in GH levels, though the effect was improved by injecting the hormone intramuscularly in 2 ml of 16% gelatin. Injection of a suspension of 4 mg GHRIH in 1 ml of arachis oil lowered growth hormone levels for between three and four hours.In four acromegalic patients an oral 50-g glucose tolerance test was performed during a continuous infusion of either saline or 1,000 mug GHRIH. The "paradoxical" rise in growth hormone seen in these patients during the saline infusion was suppressed by GHRIH. The blood glucose responses were, moreover, modified by GHRIH in that the peak was delayed and occurred at the end of the infusion in each case. A "normal" glucose tolerance curve was converted to a "diabetic" type of response in two patients. This effect could be accounted for by the inhibition of insulin secretion known to occur with large doses of GHRIH.We speculate that acromegaly may be primarily a hypothalmic disease due to deficiency of GHRIH resulting in excessive secretion of growth hormone from the pituitary and adenoma formation due to inappropriate and prolonged stimulation of the pituitary.

Publisher Summary This chapter discusses nature and biological function of the known hypothalamic hormones. The existence of a hypothalamic factor regulating thyroid-stimulating hormone (TSH) secretion from the anterior pituitary was first demonstrated by Greer. Tashjian demonstrated that synthetic thyrotropin-releasing hormone (TRH) caused the release of prolactin from rat pituitary tumor cells in vitro . The availability of synthetic TRH made possible the establishment of radioimmunoassay. Harris showed that localized electrical stimulation of the rat hypothalamus in the region of the median eminence and preoptic suprachiasmatic regions caused ovulation. Gonadotropin-releasing hormone (GnRH) not only stimulates the release of luteinizing hormone and follicle stimulating hormone, but also there is evidence that the synthesis of these two hormones is stimulated by GnRH. The availability of synthetic GnRH led to the development of several radioimmunoassays. The development of section bioassays for the pituitary hormones that are released has greatly improved the feasibility of these assays of releasing hormones.

This chapter reports observations on concentrations of ACTH activity in nonendocrine tumors. It also discusses the plasma ACTH levels in patients with the ectopic ACTH syndrome. The tumors associated with the ectopic ACTH syndrome show a wide range of ACTH levels. The bronchial carcinoids, thymoma, and medullary carcinoma of the thyroid contain higher ACTH concentrations than the ectopic oat cell carcinomas of bronchus with the exception of one oat cell tumor. The significance of ACTH activity in control tumors is not clear. The tissues may adsorb and concentrate circulating ACTH to a greater extent than nontumorous tissue or they may, in some cases, synthesize but not release ACTH at a rate sufficient to cause clinical evidence of metabolic disturbance. Thus, it is known that patients with progressive carcinoma of the bronchus not associated with the ectopic ACTH syndrome have adrenocortical hyperfunction, which is most marked in patients with oat cell carcinomas of the bronchus, and does not appear to be because of emotional stress.

Elevated plasma and urinary corticosteroid levels, a disturbed diurnal rhythm, and adrenocortical resistance to dexamethasone suppression were seen in three patients with severe depression. These abnormalities of pituitary-adrenal function are similar to those observed in Cushing's syndrome, but they disappeared with successful treatment of the depression. Diagnostic confusion could arise in a patient with depression and suspected Cushing's syndrome.

The contributions of changes in the rate of gastric emptying and insulin response to the abnormalities of oral glucose tolerance found in thyroid disease have been studied in 12 thyrotoxic and 9 hypothyroid patients. In thyrotoxicosis, rapid gastric emptying was associated with elevated peak blood-glucose and insulin levels, but there was evidence suggesting some impairment of insulin response. However, in the fasting state, despite normal blood-sugar concentrations plasma-insulin levels were elevated. 2 patients were prediabetic, with diabetic glucose-tolerance curves and markedly impaired insulin release when thyrotoxic; although their glucose tolerance reverted to normal with treatment of the thyrotoxicosis, their insulin responses remained subnormal. In hypothyroidism gastric emptying was prolonged; blood-glucose concentrations were depressed both fasting and after glucose loading, while insulin levels were unchanged. With the exception of hyperinsulinaemia at the end of the glucose-tolerance tests in the hypothyroid patients, all the abnormalities were reversed by treatment.