Lesley H. Rees

DIAGNOSIS AND MANAGEMENT OF ACTH‐DEPENDENT CUSHING'S SYNDROME: COMPARISON OF THE FEATURES IN ECTOPIC AND PITUITARY ACTH PRODUCTION

The clinical features, diagnosis and management of 16 consecutive patients with ectopic ACTH production are described and biochemical data are compared with those of 48 consecutive patients with pituitary‐dependent Cushings disease. In 10 cases the ectopic ACTH secreting tumour was completely occult to routine clinical and radiological investigation, and no basal or dynamic investigation of adrenal‐pituitary function was able clearly to differentiate these patients from those with Cushings disease. High dose dexamethasone suppression testing assessed by plasma cortisol was usually helpful but unexpected responses were seen in both diagnostic groups; the metyrapone test yielded no useful information and should now be abandoned. Hypokalaemia was seen in all patients with ectopic ACTH production but in only 10% of those with Cushings disease who were not on diuretics at presentation. Successful diagnosis and tumour localization was most frequently achieved by a combination of CT scanning of the chest and abdomen and venous catheter sampling for ACTH. All patients in whom the ectopic ACTH‐secreting tumour was obvious at presentation died of their primary tumour within 8 months, whereas seven of the 10 patients with occult tumours at presentation are alive 1·5–16·5 years later, and appear cured. Occult ectopic ACTH secretion may be impossible to distinguish from pituitary Cushings disease. Multiple and repeated investigations are often required to make this differential diagnosis, essential for appropriate therapy.

SHORT AND LONG-TERM RESPONSES TO METYRAPONE IN THE MEDICAL MANAGEMENT OF 91 PATIENTS WITH CUSHING'S SYNDROME

Summary. objective To analyse the clinical and biochemical effects of metyrapone in the treatment of Cushings syndrome.

Long-term treatment of acromegaly with bromocriptine.

Seventy-three patients with active acromegaly were treated for three to 25 months with bromocriptine 10-60 mg/day. Seventy-one patients showed symptomatic and objective clinical improvement. This included reduction in excessive sweating, hand and foot size, and the number of headaches; improved facial appearance; and increased energy and libido. Abnormal visual fields became normal in two patients, one of whom had concomitant radiotherapy. Mean circulating growth hormone levels, obtained by averaging serial samples through the day, fell by more than 7 microng/l or became undetectable in 58 patients (79%) but did not reach normal values: only 15 patients had mean levels on treatment of 5 microng/l or less. Twenty-three patients were diabetic before treatment, and glucose tolerance became normal in 15 and improved in a further five. Provided the drug was started slowly side effects were minor when compared with the considerable clinical benefit obtained.

Possible placental origin of ACTH in normal human pregnancy

IT is well known that the free fraction of plasma cortisol is increased in pregnancy1, but it has not been established whether this is a result of maternal pituitary or placental adrenocorticotrophic hormone (ACTH) secretion. Maternal plasma ACTH levels in human pregnancy have been variously reported as elevated2, or depressed3; but there is no information on the relationship between ACTH levels and the stage of gestation. We now report that maternal ACTH levels increase progressively throughout pregnancy, that urinary free cortisol levels are raised and show resistance to suppression by dexamethasone and we present evidence suggesting that ACTH may be produced by the placenta.

Circadian variation of GH-independent IGF-binding protein in diabetes mellitus and its relationship to insulin. A new role for insulin?

Evidence is accumulating that a non‐GH dependent insulin‐like growth factor‐binding protein (IGF‐BP) is not only a carrier protein but also has an active role in the growth process.

THE OPIOID CONTROL OF LH AND FSH RELEASE: EFFECTS OF A MET‐ENKEPHALIN ANALOGUE AND NALOXONE

The effect of a long‐acting analogue of met‐enkephalin (DAMME) and naloxone on gonadotrophin secretion has been investigated in man. In menopausal women DAMME induced a progressive fall in LH to approximately 60% of basal levels at 3 h, which was blocked by naloxone; there was a smaller fall in FSH that did not attain statistical significance. However, the LHRH‐induced rise in LH and FSH in young male volunteers was unaffected by pretreatment with a high‐dose DAMME infusion. Naloxone infusion in young male and female normal subjects produced a significant rise in both LH and FSH. Long‐term infusion of naloxone appeared to increase the rate, and possibly the amplitude, of LH pulsatility. These results suggest that met‐enkephalin‐like opioid peptides exert a tonic inhibitory control of LH release in both menopausal and young subjects of both sexes. This control is most likely to be at the level of the hypothalamus, and involves modulation of pulsatile LHRH release.

CORTICOTROPHIN RELEASING FACTOR: RESPONSES IN NORMAL SUBJECTS AND PATIENTS WITH DISORDERS OF THE HYPOTHALAMUS AND PITUITARY

Synthetic CRF‐41 has been given to 43 patients with hypothalamic, pituitary or adrenal diseases and contrasted with the responses in 20 normal subjects. In the normal subjects the mean increment in serum cortisol (± SE) was 276 ± 38 nmol/l; the increments showed a significant negative correlation with the basal serum cortisol levels (r= ‐0·56; P<0·02). The mean peak serum cortisol was 662 ± 34 nmol/1 and the mean peak corticosterone was 28·6 ± 3·8 nmol/1. There was a significant positive correlation between the peak serum corticosterone and cortisol concentrations (r= 0·84; P<0·0001). Dexamethasone pretreatment abolished the rise in cortisol in response to CRF‐41. The peak serum cortisol following CRF‐41 was not significantly different between the normal subjects and those patients with pituitary disease who had normal cortisol responses to insulin‐induced hypoglycaemia. However, in individual patients the peak cortisol levels induced by hypoglycaemia were greater than, but significantly correlated with, those induced by 100 μg of CRF‐41. Seven patients were ACTH deficient in response to hypoglycaemia, and of these six responded normally to CRF‐41. Only one of these patients had a lesion clearly originating in the hypothalamus; four had pituitary tumours with suprasellar extensions and the remaining patient had idiopathic GH and ACTH deficiency. Our data suggest that these patients have a functional defect of ACTH secretion due to the failure of CRF to reach the corticotroph. Of the four patients with pituitary‐dependent Cushings disease who were on no treatment at the time of testing, three showed an exaggerated and one a normal response to CRF‐41. These normal or enhanced responses of hypercortisolaemic patients with Cushings syndrome contrast with the complete inhibition of the responses to CRF‐41 in normal subjects given dexamethasone. In the treated patients with Cushings syndrome

ANTERIOR AND POSTERIOR PITUITARY FUNCTION IN BRAIN-STEM-DEAD DONORS: A POSSIBLE ROLE FOR HORMONAL REPLACEMENT THERAPY

Blood samples were obtained, at the time of organ donation, from 31 consecutive brain-stem-dead (BSD) donors referred to one transplant coordinator during a 9-month period. Twenty-four cases (77%) had clinical diabetes insipidus (DI), which was poorly controlled with marked dehydration in a majority of cases (serum osmolality range 268-357; median 302 mOSM/kg). Serum triiodothyronine (T3) was subnormal in 25 (81%); all had normal or high serum reverse T3; and the serum free thyroxine (T4) index was subnormal in 9 (29%), and TSH was subnormal in 7 (23%). In no case were T4 and TSH both subnormal and results were typical of the sick euthyroid syndrome rather than TSH deficiency. Of 21 cases not receiving corticosteroids, 5 (24%) had a serum cortisol above 550 nmol/L (20 micrograms/dl), excluding ACTH deficiency, and only 1 had undetectable cortisol levels. Those with severe hypotension did not have significantly lower serum cortisol (mean 354 vs. 416; P greater than 0.5). Levels of prolactin, growth hormone, gonadotrophins, and gonadal steroids were variable, but only a minority were frankly deficient in these hormones. BSD donors frequently have DI, which is often managed poorly by nonspecialists and requires appropriate replacement therapy. In contrast most patients are not totally deficient in anterior pituitary hormones. Routine hormonal therapy with cortisol and T3 cannot, therefore, be justified on endocrinological grounds. Widespread introduction of such treatment should only follow controlled trials that clearly demonstrate clinically significant improvement in the transplanted organ function, without detriment to the donor.

ECTOPIC HORMONE PRODUCTION BY NON‐ENDOCRINE TUMOURS

The recognition that certain clinical syndromes are due to secretion of hormones by ‘non endocrine’ tumours, has been among the major developments in endocrinology in the last decade and has forged a new link with oncology. The phenomenon has general clinical and biochemical implications. Clinicians now recognize that the accompanying metabolic derangements may be more malign than the neoplams itself, may significantly affect prognosis, and they use the measurement of plasma hormone levels and related substances for diagnosis and management. From the biochemical point of view, the study of ectopic hormone secretion provides new insight into the state of tissue differentiation. It serves as an excellent model for the broader field of inappropriate tumour products, since the structure of most hormones is known and because recent technical advances have improved methods for their purification and assay.

GH FEEDBACK OCCURS THROUGH MODULATION OF HYPOTHALAMIC SOMATOSTATIN UNDER CHOLINERGIC CONTROL: STUDIES WITH PYRIDOSTIGMINE AND GHRH

We have studied the effect of increased cholinergic tone on the GH response to growth hormone‐releasing hormone (GHRH) and on GH feedback, using pyridostigmine, an acetylcholinesterase inhibitor. In six healthy male adult volunteers 120 mg oral pyridostigmine increased basal GH secretion compared to placebo and augmented the GH response to 100 μg i.v. GHRH (1‐29) NH2; the effect was more than the additive effect of pyridostigmine and GHRH when each was given alone. Pretreatment with 2 IU methionyl‐hGH given i.v. abolished the serum GH response to GHRH given 3 h later, demonstrating a negative feedback loop of GH on the response to GHRH; this inhibited response to GHRH was restored in subjects given pyridostigmine as well as methionyl‐hGH. The data demonstrate that enhanced cholinergic tone releases GH, augments the serum GH response to GHRH and unblocks the negative feedback effect of methionyl‐hGH pretreatment on the GH response to GHRH. These results suggest that GH negative feedback effects on its own secretion occur predominantly through increased hypothalamic somatostatin secretion; this somatostatin secretion is under inhibitory cholinergic control.