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The long-term follow-up of 21 patients who had undergone bilateral adrenalectomy for Cushing's disease has revealed eight definite and two suspected cases of pituitary tumors. The average time from adrenalectomy to the diagnosis of the pituitary tumor was 6 1/2 years, with a range of 1 1/2 to 12 years. The incidence of tumors in this study (38%) is higher than that reported by others and may reflect (1) that none of these patients received pituitary irradiation in addition to adrenalectomy, (2) the length of follow-up, and (3) the high index of suspicion and early diagnosis of pituitary tumors in recent years. These data raise the question of whether bilateral adrenalectomy alone is an acceptable form of therapy for Cushing's disease. For patients treated in this way, a life-long commitment should be made to undergo annual reexamination for the possible occurrence of a pituitary neoplasm. (Arch Intern Med138:575-579, 1978)

✓ A case of Nelson's syndrome with an adrenocorticotropic hormone-secreting pituitary chromophobe microadenoma is presented to demonstrate the potential capability of rapid sequential (dynamic) computerized tomography (CT) scanning for the diagnosis of a pituitary microadenoma that was isodense with the adjacent pituitary gland on conventional enhanced CT scanning. The dynamic CT scans showed transient high density in this microadenoma contrasting with the pituitary gland in the early-enhancement phase, and thereafter the contrast density was indistinguishable from that of the pituitary gland in the delayed-enhancement phase. For the detection of pituitary microadenoma, dynamic CT combined with subsequent delayed CT scanning can provide diagnostic and localizing information.

SUMMARY A 26-year-old man with the Nelson's syndrome is described, in whom an abdominal tumour developed, accompanied by recurrent Cushing's syndrome 11 years after total adrenalectomy. Upon removal the tumour was a myelolipoma containing islands of adrenocortical-like elements. On incubation of the tumour with radioactive precursors, its capacity to produce cortisol in vitro was shown. The name adrenocortico-myelolipoma is suggested for this tumour.

Eight patients with pituitary Cushing's syndrome and 2 with Nelson's syndrome were followed from one to ten years after removal of pituitary adenomas. A detailed assessment of the pituitary-adrenal axis was obtained in all patients when last seen, save the first, who had undergone a complete hypophysectomy ten years previously. Long-term observations have shown sustained endocrine cure in 7 of 8 patients with pituitary Cushing's syndrome. One patient with Nelson's syndrome was also cured. There was no operative morbidity or mortality. There were no instances of diabetes insipidus. The long-term results in this study indicate that patients with pituitary Cushing's syndrome have a better than 90% chance of being cured after transsphenoidal removal of the pituitary (micro) adenomas. Current diagnostic and therapeutic concepts in the management of pituitary Cushing's syndrome are discussed in detail.

ACTH-producing pituitary adenomas obtained from two patients with Cushing's disease were maintained in organ culture for 2 weeks. After 4–6 days of incubation, hydrocortisone (0.1, 1, and 5 mg/ ml) was added to the culture medium. Addition of cortisol to the media in concentrations which generally inhibit the ACTH secretion in vivo in patients with Cushing's disease (1 mg/ml) failed to affect the ACTH secretion in vitro. A decrease of ACTH secretion occurred only with 5 mg/ml after 5 days of incubation. A similar effect on growth hormone (GH) release was seen when cortisol (10 mg/ml) was added to cultures from GH-producing pituitary adenoma. No ultrastructural changes were found in cultured cells that could be attributed to the addition of 0.1 mg/ml cortisol in the culture medium. With higher concentrations, (1 mg/ml and 5 mg/ml) minor ultrastructural changes were suspected. Our present findings implicate the hypothalamus as the target area for the feedback control of ACTH in Cushing's disease but could not reveal whether or not the primary lesion (i.e. the tumor) was of pituitary or hypothalamic origin. Our organ culture system appears to be a suitable model for investigating possible ACTH-regulating factors.

Summary We describe two patients with Nelson's syndrome in whom pregnancy progressed normally to spontaneous delivery of normal infants. One patient, who subsequently was found to have a basophil adenoma of the pituitary, developed diabetes insipidus in late pregnancy and the diabetes insipidus regressed spontaneously after delivery.

The effects of cyproheptadine, desmethylcyproheptadine, serotonin, γ-amino-butyric acid (GABA) and sodium valproate were studied on ACTH secretion by cultured non-enzymatically dispersed pituitary tumour cells from three patients with Nelson's syndrome. Cyproheptadine (1–10 μmol/l) and desmethylcyproheptadine (1–10 μmol/l) suppressed ACTH secretion significantly (P

Plasma ACTH determinations were made by radioimmunoassay, every 10 min for 8 hours during sleep in a patient with Nelson's syndrome. The plasma ACTH concentrations were relatively stable, fluctuating in a narrow range. It is strongly suggested that the pituitary tumor itself was secreting ACTH in an autonomous manner and it is concluded that a neuronally initiated program of ACTH secretion, was absent in the present patient with Nelson's syndrome.

A human pituitary adenoma responsible for a case of Nelson's syndrome was maintained in organ culture and the incubation medium was examined with four different RIAs; human corticotropin (ACTH), beta-MSH, lipotropin (LPH), and beta-endorphin (beta-End). All four immunoreactivites (IRs) were present in the medium obtained after 24 h of incubation. Gel exclusion chromatography under denaturing conditions (6 m guanidine HCl) revealed several immunoreactive components. Two components having both human beta-MSH (beta-hMSH) and human LPH (hLPH) IR coeluted with beta-hLPH and gamma-hLPH; a component with beta-hMSH IR but no hLPH IR coeluted with [125I]beta-hMSH; a component with human ACTH (hACTH) IR eluted at the position of hACTH. Sephadex G-50 gel exclusion chromatography revealed that approximately 80% and 20% of human beta-End (beta-hEnd) IR were accounted for by components coeluting with beta-hLPH and beta-hEnd, respectively. These data demonstrate the presence in this incubation medium of materials similar to if not identical with beta-hLPH, gamma-hLPH, hACTH, beta-hMSH, and beta-hEnd; they suggest that all of these peptides may be secreted in the circulation of patients with Nelson's syndrome.

Following total adrenalectomy in Cushing's syndrome associated with adrenal hyperplasia, but not with adrenal adenoma or malignancy, elements of the pituitary may be stimulated to grow rapidly and even aggressively. There is strong evidence to support the idea that there is a pre-existing tumor in many, if not all, of these cases. In some, the tumor may be too small to deform the sella turcica. After adrenalectomy, these patients should be observed carefully and frequently for hyperpigmentation, visual field defects, and sella turcica enlargement.

A 35-yr-old woman with Nelson's syndrome presented with amenorrhea and virilization. Serum testosterone (T) concentration was 605 ng/dl and fell to 33 ng/dl when dexamethasone was administered. The MCR of T fell from 1383 to 991 liters/day and the T production rate decreased by 96%. With administration of synthetic ACTH, T concentration rose to 338 ng/dl. Plasma ACTH concentration paralleled T during repeated suppression testing, suggesting that T secretion was dependent on ACTH hypersecretion. Preoperative and intraoperative ovarian vein catheterization suggested that the predominant source of androgen production was from the right ovarian vein. Laporatomy revealed multiple paraovarian tumors in the right mesosalpinyx and mesovarium. Incubation of tumor slices and ovarian tissue with [3H]pregnenolone and [14C]17-hydroxyprogesterone demonstrated conversion of both precursors to T by the tumor and confirmed that the tumors were the source of androgen excess. The microscopic appearance of the tumors closely resembled the morphology of testicular and paratesticular tumors of men with congenital adrenal hyperplasia and Nelson's syndrome. The analogous dependency of the tumors on ACTH hypersecretion in men with paratesticular tumors and in this woman with paraovarian tumors suggests that the tumors may arise in both males and females from a common steroid-secreting cell of adrenogenital origin.

Up to one-third of subjects who have had bilateral adrenalectomy for treatment of Cushing's disease will develop Nelson's syndrome. To examine the value of pre-operative ACTH assays in predicting outcome, we have studied fifteen cases of Cushing's disease treated by bilateral adrenalectomy and pituitary irradiation. Three patients developed Nelson's syndrome. There was no significant correlation between preoperative ACTH level, either 8 am 'basal' or during metyrapone testing, and ACTH concentration post-treatment. Plasma ACTH concentration in the first year after treatment, however, showed a highly significant correlation with the latest postoperative value (n = 14, r = 0.684, P less than 0.01), even more marked when subjects with duration of follow-up less than 3 years were excluded (n = 11, r = 0.836, P less than 0.002). In nine of fifteen patients, plasma ACTH showed either no change or a definite fall during subsequent follow-up. We conclude that plasma ACTH measurement in the first post-operative year is a good indicator of eventual outcome. The continued fall in plasma ACTH shown in many patients after the first year of treatment suggests an effect of irradiation on the pituitary.

The effect of synthetic MIF (H-Pro-Leu-Gly-NH2) on beta-MSH secretion was studied in five patients with Nelson's syndrome and in one patient with Addison's disease. Two milligrams of the tripetide were injected intravenously (1 mg in an acute injection, followed by a 30-minute-infusion of 1 mg in 20 ml of saline solution). No consistent effect could be observed during the 90-minute period after the beginning of the infusion. In the same patients, LVP stimulation and dexamethasone suppression tests brought about significant changes in the plasma beta-MSH and ACTH levels.

✓ At the start of transsphenoidal microsurgery for removal of various types of pituitary adenomas, 21 patients received a 1-hour intravenous infusion of 5-bromodeoxyuridine (BUdR, 200 mg/sq m) to label tumor cells in the deoxyribonucleic acid (DNA) synthesis phase (S-phase). Excised tumor specimens were fixed in 70% ethanol and stained by the indirect peroxidase method using anti-BUdR monoclonal antibody as the first antibody. The percentage of BUdR-labeled cells, or S-phase fraction, was calculated for each specimen. The S-phase fraction was less than 0.1% in nine cases, 0.1% to 0.5% in seven, and greater than 0.5% in five. Except in two cases of Nelson's syndrome, in which it was greater than 1%, the S-phase fraction did not correlate with any other variable, including patient age, tumor size, or the duration of signs and symptoms. The small S-phase fraction of most of the pituitary adenomas correlates well with the clinical behavior of these tumors, which grow much more slowly than other kinds of brain tumors such as gliomas. However, the S-phase fractions varied by as much as one order of magnitude. The higher S-phase fractions may reflect aggressive and invasive growth. These results indicate that immunohistochemical studies of cell kinetics using BUdR and anti-BUdR monoclonal antibodies may provide information about the biological characteristics of pituitary adenomas which could lead to the design of appropriate treatment regimens (including surgery, radiation therapy, and chemotherapy) for individual patients.

Bilateral paratesticular tumors were observed in a 32-yr-old man 14 yr after he developed a pituitary tumor after adrenalectomy for Cushing's disease (Nelson's syndrome). Plasma ACTH concentrations were markedly elevated (mean, 6350 pg/ml), but urinary free cortisol concentrations were low (27-31 micrograms/24 h). Catheterization revealed a spermatic to peripheral venous gradient for cortisol consistent with secretion of this steroid by the tumor. This was confirmed by decreased cortisol excretion after tumor excision. Serum androgen (testosterone, androstenedione, dihydrotestosterone, and dehydroepiandrosterone-sulfate) and progestin (progesterone and 17-hydroxyprogesterone) concentrations were decreased and did not decline further after tumor removal. These latter observations suggested that the paratesticular tumors did not secrete appreciable testosterone or any of its immediate precursors. Serum gonadotropin levels were also low. Cyproheptadine treatment resulted in a marked lowering of plasma ACTH concentrations (221-320 pg/ml). This was associated with an increase in both plasma LH and testosterone concentrations. These observations are consistent with the hypothesis that ACTH may directly affect LH and testosterone secretion.

Excerpt Since describing a single patient who, following bilateral adrenalectomy for Cushing's syndrome associated with adrenal hyperplasia, subsequently developed an ACTH-producing tumor of the pi...

Tumors of the pituitary of sufficient size to enlarge the sella and, in some instances, to produce ocular symptoms were present either before or after adrenal resection in 12 of 122 patients studied at the Mayo Clinic who had Cushing's syndrome associated with adrenocortical hyperplasia. As a group, these 12 patients presented a high incidence of cutaneous pigmentation and unusual ophthalmologic difficulties. Seven of the tumors were examined histologically; all were composed predominantly of chromophobe cells. One tumor was malignant, with extracranial metastatic lesions, but the other 6 showed no convincing histologic evidence of malignancy. Such tumors were not observed in a group of 34 patients who had Cushing's syndrome associated with adrenocortical tumor. The clinical course of all of 5 patients treated by total adrenalectomy and of 3 of 5 patients treated by subtotal adrenalectomy suggested that adrenal resection not only did not favorably influence the pituitary tumors but actually may h...

Corticotrophin (A.C.T.H.) levels were measured by radioimmunoassay in the cerebrospinal fluid (C.S.F.) of six patients without endocrine disease and three adrenalectomised patients with high plasma-A.C.T.H. levels. A.C.T.H. levels were raised in the C.S.F. when plasma levels were high, the highest C.S.F. values being obtained in a patient with extrasellar extension of an A.C.T.H.-producing pituitary tumour.

In 17 years, 108 patients with Cushing's syndrome were treated at Vanderbilt University. Seventeen had adrenal adenoma, 10 adrenal carcinoma, 17 ectopic ACTH syndrome, and 64 Cushing's disease. Surgery for adrenal adenoma was uniformly successful. Three carcinomas were surgically cured, and two patients had remissions; these two and another patient subsequently responded to o.p′DDD. Four cases were not amenable to therapy. No patient with ectopic ACTH syndrome was cured, but some responded metabolically to metyrapone. In Cushing's disease, pituitary irradiation cured 10 of 51 patients and improved 13 without complications. All six unilateral adrenalectomies and two of five subtotal adrenalectomies were unsuccessful, but bilateral adrenalectomy (19 cases) was always curative. After o,p′DDD treatment serum cortisol levels returned to normal, without mineralocorticoid deficiency, in eight patients. Thus, except in patients with ectopic ACTH syndrome or adrenal carcinoma, appropriate treatment for Cu...

In this case report we demonstrated that treatment with the long-acting D2 receptor agonist cabergoline for 1 year induced normalization of plasma ACTH levels and disappearance of the pituitary tumor in a patient with Nelson's syndrome. A young man underwent bilateral adrenalectomy and subsequent pituitary irradiation for Cushing's disease after unsuccessful neurosurgical treatment. Thereafter, he was given cortisone acetate replacement at the dose of 62.5 mg a day. Fifteen months after pituitary irradiation, he developed Nelson's syndrome, having skin hyperpigmentation, high plasma ACTH levels (376 ng/l) and a pituitary microadenoma (5 mm) documented at magnetic resonance imaging (MRI) of the pituitary region. After 6 months of cabergoline treatment, given at the dose of 1 mg a week, plasma ACTH levels were significantly decreased (from 376 to 113 ng/l) but they were not normalized. Cabergoline dose was then increased up to 2 mg a week. Six months later plasma ACTH levels were normalized (22 ng/l) and MRI demonstrated the disappearance of the pituitary adenoma. In order to investigate on the direct effect played by cabergoline treatment on the remission of Nelson's syndrome, the treatment was withdrawn. Plasma ACTH levels significantly increased (119 ng/l) after 3 months of treatment withdrawal. At the last follow-up, during cabergoline treatment at the dose of 2 mg/week plasma ACTH levels were normalized (40.4 ng/l). This case demonstrated that cabergoline treatment is able to induce the remission of Nelson's syndrome and may be a valid therapeutic alternative in this syndrome. PMID

Summary We report the use of nivazol in a patient with Nelson’s syndrome. Nivazol was highly effective in reducing ACTH secretion but, contrary to reports of its use in other primates, in our patient nivazol did have systemic glucocorticoid effects.

The patient with Nelson's syndrome in this report represents an unusual case in which regular cyclic menstruation was preserved even though a large ACTH-producing pituitary adenoma was present. Despite normal menses and pregnancy, the radiologic findings of an enlarged sella turcica and an enhanced lesion on CAT scan were identified. This case demonstrates that patients with normal menstruation can have significant pituitary disease, and it exemplifies the need for regular follow-up examination to look for radiologic abnormalities in patients who have had adrenalectomy for treatment of Cushing's disease.

• To establish the incidence of Nelson's syndrome in children treated with total bilateral adrenalectomy (TBA) for Cushing's disease, a survey was made of members of The Lawson Wilkins Pediatric Endocrine Society. Thirty-one patients aged 10 months to 16 years had been treated with TBA for Cushing's disease; one had been treated with ortho para prime isomer of dichlorodiphenyldichloroethane alone. Postadrenalectomy hyperpigmentation was reported in 18 patients. Sella enlargement was detected in eight patients (25%) after 1 to 5.5 years (mean, three years) post-TBA. Five of these patients have had documented pituitary adenomas to date. This incidence is higher than the adult figure of 10% to 16%. ( Am J Dis Child 131:1353-1356, 1977)

We investigated the molecular size of circulating immunoreactive ACTH by gel chromatography in patients with ACTH hypersecretion due to various disorders of the hypothalamic-pituitary-adrenal axis. 4 patients with Addison's disease, 2 with Nelson's syndrome, 4 with Cushing's disease, 6 with the ectopic ACTH syndrome (2 bronchial carcinoma, 1 medullary carcinoma, 1 metastatic islett cell carcinoma, 1 benign bronchial carcinoid and 1 patient with occult ectopic Cushing's syndrome) and 1 patient with hypersecretion of ACTH from a clinically nonfunctioning pituitary adenoma were studied. Analysis of the molecular size of immunoreactive ACTH was performed by gel chromatography on a Sephadex G-75 column (superfine, 100×1.5 cm) equilibrated with 1% formic acid. 2 ml fractions were collected and evaporated to dryness. The ACTH content of the recovered samples was determined by RIA. In Addison's disease, Nelson's syndrome and Cushing's disease the plasma showed a single peak of ACTH immunoreactivity at the expected position of 1–39 ACTH. In the ectopic ACTH syndrome the plasma of 4 patients revealed at chromatography at least one other peak eluting between the void volume and 1–39 ACTH suggestive of a high molecular weight form of ACTH whereas plasma of 2 patients showed only a single ACTH peak at the position of labeled 1–39 ACTH. The patient with a clinically non-functioning pituitary adenoma revealed a gel filtration pattern similar to the patients with ectopic ACTH syndrom and secretion of high molecular weight ACTH. We conclude that secretion of high molecular weight forms of ACTH is not a unique feature of the ectopic ACTH syndrome. It may therefore not serve as a marker of the ectopic Cushing's syndrome in the differential diagnosis of the ACTH dependent Cushing's syndrome. Vice versa, lack of high molecular weight ACTH does not exclude an ectopic source of ACTH secretion as cause of Cushing's syndrome.

Large, adrenocorticotrophic hormone-secreting pituitary tumors (Nelson's syndrome) developed in four of 12 patients treated with a bilateral adrenalectomy for Cushing's disease. Two of the patients with Nelson's syndrome suffered spontaneous pituitary tumor infarctions. One patient improved under close observation and subsequent radiation therapy, although she ultimately died from her locally invasive tumor. The condition of the other patient—which had stabilized—appeared to be worsened by surgical intervention. The high incidence of these tumors after bilateral adrenalectomy, their large and aggressive nature, and their apparent propensity to undergo spontaneous infarction supports the position that initial therapy for Cushing's disease should be directed to the pituitary gland. (Arch Intern Med139:340-342, 1979)

Chickens, Eggs, and Seller Explosions In 1958, Nelson and his colleagues described a patient who was discovered to have a sizable, chromophobe pituitary tumor three years after bilateral adrenalectomy for Cushing's disease. 1 The temporal sequence of "Cushing's disease, bilateral adrenalectomy, symptomatic pituitary tumor" has been documented repeatedly since. The Nelson's syndrome literature contains no little admonition to follow the radiographic anatomy of the sella turcica sequentially in those patients deprived of their adrenals for the conquest of Cushing's disease, to take neuroendocrinologic alarm from the appearance of progressive skin hyperpigmentation, and to follow the plasma levels of adrenocorticotropic hormone (ACTH) in such patients. Aggrandizement in any of these measures signals the presence of a functioning pituitary mass. The further caveat has also been issued that prophylactic pituitary irradiation does not eliminate the risk of a new, hazardous pituitary growth in patients who have undergone therapeutic adrenal deprivation. 2,3 Not

Excerpt Pituitary disorders, including acromegaly, Cushing's disease, Nelson's syndrome and chromophobe adenoma, have been treated with 910-Mev alpha particles. By using their special radiobiologic...