Cyclical Cushing's disease and its successful control under sodium valproate

Several subgroups of Cushing's disease were recently described (anterior or intermediate lobe origin, hyper-or hypo-pulsatility of cortisol, presence or absence of response after GRH or TRH, cyclical Cushing's disease). We present here a detailed case report on a patient suffering from Cushing's disease whose endocrine functions were extensively investigated. Treatment with bromocriptine, as well as subsequent transsphenoidal surgery, were followed by rapid but transient reversal of symptoms. When clinical manifestations reoccurred, daily measurements of free urinary cortisol revealed a cyclic pattern of cortisol hyperexcretion. A study of ultradian rhythm revealed hyperpulsatility of cortisol secretion. More interestingly, a treatment with sodium valproate, a drug known to inhibit CRH production, was followed by a rapid and longstanding normalization of clinical and biological data for 2 years. Based on these data, and on information from the literature, the present case of Cushing's disease exhibits characteristics suggesting a possible hypothalamic origin.     

Cushing's disease and marked hyperprolactinemia in a patient with a pituitary macroadenoma: effectiveness of bromocriptine treatment

The case of a young boy bearing a pituitary PRL secreting adenoma (20-30,000 ng/ml) with the unusual association of clinical and endocrinological features of Cushing's disease successfully treated with bromocriptine is described. Brain computed tomography evidenced a huge pituitary adenoma leading to visual field defects and raised intracranial pressure. Due to the very large size of the tumor, which rendered the complete neurosurgical removal unlikely, medical treatment with bromocriptine (10 mg/day) was started. Follow-up for more than six months demonstrated an impressive reduction of tumor size, the lowering of prolactin levels into the normal range, the normalization of visual field, and the regression of both clinical and biochemical signs of hypercortisolism.     

Sodium valproate and cyproheptadine may independently induce a remission in the same patient with Cushing's disease

A patient with Cushing's disease was unsuccessfully treated by pituitary surgery and external pituitary irradiation. One year later sodium valproate treatment induced a remission and finally hypocorticism developed. After drug withdrawal hypercoticism recurred. Treatment with cyproheptadine again induced hypocorticism necessitating corticosteroid substitution therapy. Biochemical characteristics of this patient included responsiveness to bromocriptine and cyproheptadine in acute tests. The study demonstrates that sodium valproate and cyproheptadine may both be effective independently in the treatment of the same patient with Cushing's disease. It is proposed that the disease is due to an ACTH producing tumour of pituitary intermediate lobe origin.     

Adrenocorticotropin-producing pituitary carcinoma with metastasis to the liver in a patient with Cushing's disease

A 61-year-old woman who had a nonfunctioning pituitary tumor removed was later found to have a pituitary carcinoma with metastasis to the liver that produced adrenocorticotropic hormone (ACTH), causing Cushing's disease. Despite the second removal of the pituitary tumor, Cushing's disease persisted. Endocrinologic examination demonstrated marked elevation of plasma ACTH, beta-endorphin, and serum cortisol concentrations, which were not suppressed by low- or high-dose dexamethasone administration. A computed tomographic scan of the abdomen revealed a solitary hypodense area in the liver consistent with a metastatic lesion. Immediately after resection of the liver tumor, plasma ACTH concentrations fell to normal range. Such a decline in ACTH secretion was not observed even after the pituitary tumor was removed. Histologic characteristics of both the pituitary and liver tumors were similar. The immunohistochemical study using anti-ACTH antibody showed similar ACTH-positive cells in the pituitary and liver tumors. Based on these findings, the patient was diagnosed as having liver metastasis of ACTH-secreting pituitary carcinoma. This is the first case report in which a metastatic liver tumor of a pituitary carcinoma caused ACTH.     

Cushing's disease in a patient with a 'nonfunctioning' pituitary tumor. Spontaneous development and remission

A 40-year-old woman had visual loss and a large nonfunctioning pituitary tumor. After partial surgical resection and radiation treatment, clinical and biochemical evidence of Cushing's disease developed. The pituitary source of her adrenocorticotropic hormone hypersecretion was documented on selective venous sampling. After 18 months of medical therapy with metyrapone and aminoglutethimide, the patient experienced a spontaneous remission of her hypercortisolism. A "nonfunctioning" pituitary tumor has a hypersecretory potential.     

Secretion pattern of pro-opiomelanocortin-derived peptides by a pituitary adenoma from a patient with Cushing's disease

Fragments of the pituitary adenoma of a patient with Cushing's disease were maintained in defined culture medium. Immunoreactive (IR) ACTH, IR alpha-MSH, IR beta-lipotropin (beta-LPH), IR beta-endorphin, and IR gamma-MSHs secreted from the adenoma were studied with gel permeation chromatography and the respective RIAs. The adenoma secreted roughly equimolar quantities of IR beta-LPH plus IR beta-endorphin, IR gamma 3-MSHs, and IR ACTHs. It also secreted IR alpha-MSH as well as IR gamma 1-MSH, although in a much lower concentration than the above four peptides. The secreted gamma 3-MSH-like peptides were found to be glycosylated. The secretion pattern suggests that this particular adenoma processes the pro-opiomelanocortin molecule in pathways which encompass those of both the pars distalis and the pars intermedia.     

Chemical characterization of adrenocorticotropin and a novel peptide biosynthesized from a pituitary adenoma of a patient with Cushing's disease

ACTH and another unidentified peptide have been biosynthesized in vitro and purified from a pituitary adenoma of a patient with Cushing's disease. The new peptide had an apparent molecular weightof 4000 daltons and was more acidic than ACTH as analyzed by sodium dodecyl sulfate/urea and acidic (pH 4.5) polyacrylamide gel electrophoreses, respectively. Sequence studies revealed the presence of [35S]methionine at position 3 of the new peptide. High performance liquid chromatographic analysis of [35S]methionine-labeled tryptic fragments of the peptide revealed that this peptide contained gamma MSH- (1-7) within its sequence. Our observations raise the possibility that this peptide contains at its N-terminus gamma MSH, a putative peptide proposed by Nakanishi et al.     

Corticotropin-releasing hormone- and adrenocorticotropin-producing pituitary carcinoma with metastases to the liver and lung in a patient with Cushing's disease.

A 53-yr-old man with Cushing's disease was found to have a pituitary carcinoma with metastases to the liver and lung which produced both CRH and ACTH simultaneously. Despite removal of the pituitary tumor, his Cushing's disease worsened. Endocrinological examination then demonstrated elevated plasma CRH and markedly elevated plasma ACTH, beta-lipotropin, and cortisol concentrations, increased urinary 17-hydroxycorticosteroid and 17-ketosteroid excretion, and no suppression of serum cortisol after low or high dose dexamethasone administration. Urinary 17-hydroxycorticosteroid excretion increased in response to metyrapone, and lysine vasopressin elicited a striking increase in plasma ACTH. A computed tomographic scan of abdomen revealed multiple hypodense areas in the liver and bilateral adrenal hyperplasia. Postmortem histological examination revealed a necrotic hemorrhagic pituitary carcinoma with metastases to the liver, lung, and olfactory bulb. Immunohistochemical staining, gel filtration, and Northern blot analysis of liver and lung metastases revealed evidence of the production of both CRH and ACTH in these metastases. We concluded that the patient's pituitary carcinoma produced both CRH and ACTH.     

Sustained remission of Cushing's disease with mitotane and pituitary irradiation

Low doses of mitotane were given orally to 36 patients with Cushing's disease, concurrently with or after pituitary cobalt irradiation. Clinical and biochemical remission occurred in 29. The response to treatment occurred early in 17 patients and late in 12. The different pattern of response to mitotane was not related to the dose given or to its serum level. Early biochemical indicators of adrenal suppression with mitotane were a sharp decrease in adrenal response to the infusion of ACTH and in plasma levels of dehydroepiandrosterone sulfate. Although mitotane was given together with pituitary irradiation, initial remission was due mainly to the adrenal effect of mitotane. Plasma ACTH levels were still elevated when cortisol had returned to normal. In seventeen of the 29 patients who responded to treatment drug therapy has been discontinued, and they remain in remission of Cushing's syndrome. Side-effects have been dose dependent, with anorexia, nausea, decreased memory, and gynecomastia in men being the commonest.     

Treatment of Cushing's disease with reserpine and pituitary irradiation.

Eighteen patients with Cushing's disease were treated with reserpine and pituitary irradiation. Complete remission was obtained in 9 out of 18 patients after reserpine treatment of 1-2 mg per day for a mean period of 20.4 months, and pituitary irradiation with a mean of 5,865 rads. In another 9 patients, reserpine 0.8-2 mg per day for a mean period of 22.5 months, and pituitary irradiation with a mean of 6,650 rads, were employed. Of these 9 patients, an additional subtotal adrenalectomy was carried out in 6 patients who are now in complete remission. Because of severe psychic symptoms resulted from the original disease in 2 of the remaining 3 patients, subtotal adrenalectomy was performed first and pituitary irradiation and reserpine treatment followed. Remission was eventually obtained in these 2 cases. One patient refused the operation, and thus had little clinical remission. All of the 17 cases in remission were followed up for periods of 6 months to 10 yr. During this time, only one case which had responded to reserpine and pituitary irradiation relapsed, but regained remission following resumption of therapy. Another died of cerebral glioblastoma 4 yr after remission of the disease. It was noteworthy that endocrinologic data including: plasma levels of ACTH and 11-OHCS, suppressibility by dexamethasone, responses of plasma GH to arginine and to insulin loads, and diurnal rhythm of plasma 11-OHCS were nearly normal in a considerable number of the cases in remission. Effectiveness of the combined therapy with reserpine and pituitary irradiation for treating Cushing's disease may support a working hypothesis that reserpine acts through some as yet unknown mechanism to correct a presumed central nervous disorder, while suitable pituitary irradiation probably corrects the pituitary dysfunction directly.     

Successful treatment of a patient with refractory adult Still's disease by tacrolimus

Adult Still's disease (ASD) is a systemic rheumatic disease characterized by high spiking fever, erythema, polyarthritis, and increased levels of C-reactive protein, ferritin, and interleukin (IL)-18. Recently, biological agents targeting proinflammatory cytokines such as tumor necrosis factor (TNF) α, IL-1, and IL-6 have been described as effective treatments for refractory ASD. Herein, we present a patient with ASD, who was successfully treated by tacrolimus concomitant with corticosteroid, while infliximab and etanercept were not effective. Tacrolimus may be one of the drugs for the ASD patients refractory to the conventional treatments including TNF inhibitors.     

Development of Cushing's disease in a patient with anorexia nervosa

A young woman developed clinical features of anorexia nervosa with a maximal loss of ideal body weight of 54 per cent at the age of 16 yr. A partial recovery from the anorectic symptoms was encountered six years later. At the age of 27 yr pituitary Cushing's disease was diagnosed and corticotroph cell pituitary adenoma subsequently removed by transsphenoidal surgery. Within two years after the operation the clinical and biochemical signs of hypercortisolism had disappeared but some of the anorectic features reappeared. Without neglecting the likelihood of a simple coincidence, the possibility of a common pathogenetic mechanism for anorexia nervosa and Cushing's disease, either affecting the function of the hypothalamic serotonergic pathways or concentration of glucocorticoid receptors, is discussed.     

Development of Nelson's syndrome in a patient with recurrent Cushing's disease. Analysis of secretory behavior of the pituitary tumor

A markedly cushingoid 32-year-old man presented to Queens Hospital Center with headache, hyperpigmentation, and visual field loss. Twelve years earlier, he had undergone subtotal adrenalectomy for Cushing's disease, but symptoms of hypercortisolemia promptly recurred. Workup revealed the presence of a large, expanding intrasellar mass, plasma ACTH levels between 3,000 and 10,000 pg/ml, and markedly elevated cortisol levels. The secretion of ACTH (mainly ACTH 1-39-like peptide) by the pituitary tumor showed neither diurnal periodicity nor response to a variety of pharmacologic agents known to affect ACTH secretion. The patient demonstrates a rarely observed presentation of Nelson's syndrome, with aggressive adrenotropic pituitary tumor growth even in the presence of chronic hypercortisolemia.     

Reversible pituitary dysfunction in a patient with Cushing's syndrome discovered as adrenal incidentaloma

We report a 45-year-old woman with Cushing's syndrome showing reversible pituitary dysfunction. Left adrenal tumor was incidentally discovered by a screening examination of abdominal computed tomography. Although this patient lacked typical Cushingoid features except hypertension and leg edema, endocrine examinations revealed moderate suppression of plasma ACTH (~6.3 pg/ml) with relatively high levels of serum cortisol (~22.9 microg/dl) without normal circadian rhythm. Plasma ACTH failed to respond to either CRH or metyrapone, and dexamethasone failed to suppress her daily steroid production. Surgical removal of left adrenocortical adenoma and 6-month replacement of hydrocortisone have ameliorated both ACTH and cortisol responses to CRH loading test. Postoperative responses of TSH and GH to TRH and GRH, respectively, were two fold higher than the preoperative levels. In contrast, basal and TRH-induced levels of serum PRL were decreased after surgery although both the basal and stimulated PRL levels were markedly high before surgery. In addition, gonadotropin response to GnRH examined in the same ovarian cycle was decreased in accordance with an increase in serum estradiol and progesterone levels after surgery. Improvement of hypercortisolemia even in a moderate case of Cushing's syndrome not only ameliorates hypertension, obesity and glucose intolerance, but also restores the accompanying dysfunctions of anterior pituitary, suggesting the clinical importance of early discovery and treatment of functioning adrenocortical incidentalomas.