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Twenty-eight patients underwent transsphenoidal pituitary surgery for Cushing's disease. Selective surgical procedures were performed in 26. In 19 patients pituitary adenoma was confirmed histologically and 5 had clumps or clusters of ACTH-staining cells. At follow-up after 22.3 (range 5-56) months 21 (75%) patients remained in clinical and biochemical remission. The 24-h urinary free cortisol performed between 1 and 4 weeks postoperatively while patients took replacement doses of dexamethasone (0.5 to 0.75 mg per day) was found to predict outcome. All patients with suppressed urinary free cortisol excretion have remained in remission, 3 with levels in the normal range have suffered late relapse after initial remission, and 4 with elevated urinary free cortisol excretion were regarded as having failed to remit. Furthermore, all patients with unsuccessful outcomes had no pituitary adenoma and 3 had features consistent with corticotrope nodular hyperplasia at histological examination compared to only 2 and 1, respectively, of patients still in remission. We conclude that 24-h urinary free cortisol performed at 1 to 4 weeks postoperatively whilst on low-dose dexamethasone and the histological findings may predict outcome following transsphenoidal pituitary surgery in Cushing's disease.

Cushing's syndrome was diagnosed in a 14 year old girl and, 5 years later, in her nephew (sister's son) also when he was 14 years of age. Administration of tetracosactid (Synacthen) did not stimulate adrenocortical function in either patient, nor did dexamethasone suppress the elevated urinary steroids in the girl, and only partially suppressed them in the boy. Both patients were adrenalectomized and made an uneventful recovery. The surgical specimens were identical both on gross inspection and histologically, showing the typ ical morphological features of pigmented multinodular adrenocortical dysplasia. We believe that this lesion represents an inherited adrenocortical maldevelopment (rather than true neoplasia) leading to an autonomous adrenocortical hyperfunction which typically manifests itself clinically during adrenarche (i.e. functional adrenocortical maturation) at the beginning of puberty. Family Cushing's syndrome, caused by pigmented multinodular adrenocortical dysplasia, represents a disease entity.

Cushing's syndrome was found in 2 of 4 siblings all of which also had other malformations. After bilateral adrenalectomy no hyperpigmentation was noted. Morphologically the adrenals of both siblings with Cushing's syndrome showed the typical lesions of the so-called microadenomatosis or primary adrenocortical nodular dysplasia with foci of eosinophilic giant cells. This is a new form of Cushing's syndrome due to an inborn error of the adrenals and no hypothalamic-pituitary dysfunction.

A case is presented of a 43-year-old Caucasian female with Cushing's syndrome, malignant hypertension and renal insufficiency. Plasma cortisol values were elevated (19.5 microgram/100 ml at 0800 h and 18.5 microgram/100 ml at 2200 h) with loss of diurnal variation and failure of suppression with low and high dose dexamethasone. 17-ketogenic steroid excretion remained unchanged after metyrapone administration. Adrenal vein plasma cortisol values showed prominent left-sided gradient. Gross, histologic and electron-microscopic examination of the left adrenal gland revealed changes of nodular adrenal hyperplasia. The presence of a suppressed right adrenal gland was confirmed post-operatively by a five day ACTH infusion. This case may represent a previously unreported variant of Cushing's syndrome due to unilateral nodular adrenal hyperplasia.

The fifth case of Cushing's syndrome with bilateral adrenocortical tumours is described. By the hormonal dynamic studies both tumours have been shown to be autonomous in the secretion of cortisol. Histopathologically, both tumours were identified as benign adrenocortical adenomas without nodules, and the right one was a so-called black adenoma. A high concentration of cortisol was obtained from both tumour tissue extracts. The differential diagnosis of Cushing's syndrome due to bilateral adrenocortical adenomas from primary adrenocortical nodular dysplasia is briefly discussed.

Pituitary adenomas were found in 21 (84%) of 25 dogs with spontaneous pituitary-dependent hyperadrenocorticism. Six dogs had pars intermedia adenomas, whereas 15 had tumours of the pars distalis. Diffuse corticotroph cell hyperplasia was found in 1 of the 4 pituitaries without adenoma; in 2 dogs with pituitary adenoma, coexisting hyperplasia of the surrounding corticotrophs was also present. Immunocytochemical staining of the pituitaries revealed positive staining for ACTH, beta-lipotrophin, and beta-endorphin in the majority of both pars distalis and pars intermedia adenomas. The most frequent and intense staining was found with anti-beta-endorphin. In most part intermedia tumours, many cells stained strongly for alpha-MSH; double immunostaining of one pars intermedia adenoma for ACTH and alpha-MSH showed that some tumour cells stained only for ACTH or alpha-MSH whereas others contained both peptides. Only occasional cells stained for alpha-MSH in pars distalis adenomas.

Cushing's syndrome has been demonstrated in four of seven siblings with clinical manifestations appearing around puberty in three of the four siblings. The only other associated findings in these cases were short stature and disturbed carbohydrate metabolism. Adenomatous hyperplasia of the adrenal glands was demonstrated in 3 of the patients, and a virilizing adrenal carcinoma in the fourth sibling. The pathogenesis of the adrenocortical disorders in these siblings is discussed.

A 55 year old woman with an unusual form of Cushing's disease was studied. During several periods (periods lasting up to 84 days) evidence of cortisol hypersecretion with cycles occurring every 6 days was found. Suppression of plasma cortisol through orally administered dexamethasone (up to 32 mg per day) could not be achieved either during periods of cyclic cortisol hypersecretion or during apparent remission with normal cortisol secretion. Marked suppression of plasma ACTH was measured in response to an iv infusion of 50 mg cortisol over a period of 55 min whereas a similar test with 2 mg dexamethasone (iv bolus) did not suppress ACTH secretion. Transsphenoidal exploration of the sella revealed a tumour surrounding the anterior pituitary. Examination of the pituitary showed a few tiny tumour structures embedded in normal tissue which could not be removed, when the tumour was resected selectively under preservation of normal appearing tissue. Post-operatively, clinical and chemical remission (normal response to 1 mg dexamethasone) was observed for about 4 months. Thereafter, cortisol hypersecretion occurred again necessitating bilateral adrenalectomy. Our results are compatible with the assumption that normal hypothalamic-pituitary-adrenal suppressibility with cortisol, but not with dexamethasone, was caused by the loss of feedback receptors for dexamethasone in the presence of cortisol receptors in the cells which secrete ACTH or CRF. The combination of cyclic hypercortisolism with dexamethasone non-suppressible Cushing's syndrome has not been reported before and thus represents a new variant of Cushing's syndrome.