T. A. Howlett

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.

Transsphenoidal resection in Cushing's disease: undetectable serum cortisol as the definition of successfuI treatment

OBJECTIVE We tested the hypothesis that in Cushings disease, ACTH secretion from the normal pituitary surrounding an ACTH‐secreting adenoma is inhibited and hence removal of the entire adenoma should result in an undetectable serum cortisol in the immediate post‐operative period.

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.

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.

CRF IN THE DIFFERENTIAL DIAGNOSIS OF CUSHING'S SYNDROME: A COMPARISON WITH THE DEXAMETHASONE SUPPRESSION TEST

Accurate differential diagnosis of the precise cause of Cushings syndrome can be difficult, and conventional tests such as those based on the use of dexamethasone may be misleading. We have therefore studied the cortisol and ACTH responses to ovine corticotrophin‐releasing factor (CRF‐41) in 28 consecutive patients with Cushings syndrome, and compared the diagnostic value of this test with that of the high‐dose dexamethasone suppression test (8 mg/day for 48 h).

Pituitary ACTH dependent Cushing's syndrome due to ectopic production of a bombesin-like peptide by a medullary carcinoma of the thyroid.

A 41‐year‐old man presented with Cushings syndrome and the biochemical features of ectopic ACTH production. Investigation revealed mediastinal metastases from a medullary carcinoma of the thyroid. The peripheral plasma contained grossly elevated levels of bombesin‐like immunoreactivity (irBombesin) as well as calcitonin; blood sampling via a venous catheter confirmed a gradient of irBombesin, but not of ACTH, in the mediastinal vein draining the tumour. On extraction the tumour contained a bombesin‐like peptide, but not vasopressin or corticotrophin releasing factor and only very low levels of ACTH; immunohistochemical studies showed positive immunostaining for bombesin and calcitonin but none for ACTH or CRF. No ACTH was released from dispersed tumour cells in vitro. However an extract of the tumour stimulated ACTH release in vitro from perifused dispersed rat anterior pituitary cells. This is the first reported case of Cushings syndrome due to ectopic production of a bombesin‐like peptide, causing excessive pituitary ACTH secretion.

A BROMOCRIPTINE-RESPONSIVE CORTICOTROPH ADENOMA SECRETING α-MSH IN A PATIENT WITH CUSHING'S DISEASE

Clinical and in‐vitro investigations have been performed on a corticotroph adenoma removed from a patient suffering from Cushings disease. Prior to surgery, the patients Cushings disease had been successfully controlled, clinically and biochemically, by long term administration of bromocriptine. After selective adenomectomy, tumour tissue was investigated by a perfused isolated cell column technique. It was shown that the tumour cells secreted immunoreactive‐ (IR‐) ACTH and IR‐α‐MSH and that the release of both peptides was promptly suppressed by dopamine. Chromatographic analysis of the secreted IR‐α‐MSH revealed a high proportion of acetylated α‐MSH; smaller amounts of desacetyl α‐MSH and diacetyl α‐MSH were present. The relevance of these findings to the proposal that certain corticotroph adenomas are derived from the intermediate lobe of the pituitary is discussed. It is concluded that there is little direct evidence for involvement of the residual zona intermedia of the adult human pituitary in the development of Cushings disease.

The interrelationship of beta endorphin, ACTH and cortisol in depressive illness: a controlled study.

Plasma cortisol, ACTH and beta endorphin were measured before and after dexamethasone in 8 severely depressed patients and 8 age- and sex-matched controls to examine the relationship of ACTH and endogenous opioids to cortisol in depression. Despite having significantly higher plasma levels of cortisol than the controls, the depressed patients did not have correspondingly elevated plasma levels of ACTH. Beta-endorphin levels were also similar in the two groups. All three hormones suppressed to some degree after dexamethasone, but cortisol suppressed less in patients than controls. Our findings suggest that in severe depressive illness abnormalities exist in the hypothalamic-pituitary-adrenal axis peripherally as well as centrally.

‘Dynorphin’ in plasma: enzymatic artifact and authentic immunoreactivity

The potent opioid peptide dynorphin (DYN) is found in posterior pituitary vasopressinergic neurones and in adrenal medullary cells suggesting that secretion into plasma is likely. We have developed a sensitive radioimmunoassay in order to study plasma DYN in man. It transpired that extraction prior to assay was essential since unextracted plasma caused gross and non-parallel inhibition of binding of tracer. Plasma extracted using leached silica glass ( Vycor ) caused inhibition of tracer binding which diluted in parallel to synthetic DYN suggesting the presence of substantial amounts of DYN-like immunoreactivity ( irDYN ) in plasma. Further investigation however demonstrated that this irDYN was artifactual and caused by enzymatic degradation of tracer. Although use of Seppak C18 cartridges resulted in reliable extraction of synthetic porcine DYN from acidified plasma, we have not detected irDYN in any plasma so far studied using this technique. However, extraction of non-acidified plasma using our antibody coupled to Sepharose CNBr-activated 4B followed by gel filtration chromatography demonstrated a single peak of irDYN of molecular size similar to DYN. These data suggested that a small amount of a DYN-like peptide does circulate in human plasma although this is not identical to porcine DYN(1-17). The implication of our results for the measurement of other similar peptides in plasma is discussed.

The effect of ovine corticotrophin-releasing factor on the hormonal response to insulin-induced hypoglycaemia

In order to investigate the role of hypothalamic corticotrophin‐releasing factor (CRF41) in the mediation of the pituitary ACTH response to hypoglycaemia, eight normal adult males were studied on four occasions. Commencing at 0830 h after an overnight fast, each received, in double‐blind, random order, intravenous boluses of: A, normal saline control; B, soluble insulin 0.15U/kg; C, ovine CRF41 (oCRF41) 100 μg; D, soluble insulin 015U/kg followed immediately by oCRF41 100 μg. Adequate hypoglycaemia (blood glucose < 2–2 mmol/1) was achieved in each subject when insulin was given alone or with oCRF41, and there was no difference in the glucose nadir between the 2 days. Peak plasma ACTH was significantly higher after insulin plus oCRF41 than after insulin alone (P<0.05) or oCRF41 alone (P<0.01) and this enhancement of ACTH release was most marked in the first phase of the response at 30 min (P<0.001, b vs d). There was no difference in the peak serum Cortisol response whether oCRF41 and insulin were given alone or together and although the area under the Cortisol curve was greater after insulin plus oCRF41, this difference was explicable simply on the basis of the earlier onset of the Cortisol response to oCRF41.