Palliative therapy of an ectopic cushing's syndrome due to a metastatic carcinoid tumor

Summary The case of a 39-year-old patient with ectopic Cushing's syndrome due to a metastatic carcinoid tumor is presented. Palliative therapy consisting of 800 mg ketokonazole and 0.3 mg SMS 201-995/die resulted in clinical remission and correction of hypokaelmia and hypercortisoluria. Combined therapy was clearly superior to monotherapy with ketokonazole or SMS 201-995, respectively. Side effects were not observed, the tumor masses remained unchanged throughout the observation period of now 19 months.Abbreviations ACTH adrenocorticotropic hormone - opDDD 1,1 dichloro-2(o-chlorophenyl)-2-(p-chlorophenyl)-ethane - 5-HIAA 5-hydroxyindolaceticacid - VIP vasoactive intestinal pepide - CRH corticotropin releasing hormone     

Virilization due to ovarian androgen hypersecretion in a patient with ectopic adrenocorticotrophic hormone secretion caused by a carcinoid tumour: case report

A 52-year-old woman presented with symptoms of virilization, which had been ongoing for 5 months. At the age of 34 years, she had a large abdominal carcinoid tumour removed. Twelve years later, she presented with Cushing's syndrome due to ectopic adrenocorticotrophic hormone (ACTH) production by carcinoid metastases localized in the right parametrium, fornix posterior and right diaphragm. Debulking laparotomy was performed followed by remission of hypercortisolism. Relapse of hypercortisolism followed 3 years later, and a second debulking laparotomy was performed including resection of the right ovary. In the following year, relapses of hypercortisolism were observed until bilateral adrenalectomy was performed. Laboratory evaluation revealed elevated serum levels of testosterone (23.0 nmol/l), androstenedione and 17-hydroxyprogesterone, and a serum estradiol (E2) level in the premenopausal range. The computerized tomography (CT) of the abdomen showed a large pelvic mass on the left side of the uterus without a recognizable left ovary. Treatment with a GnRH agonist (goserelin, 3.6 mg s.c., monthly) was initiated, resulting in normalization of the androgen levels. One year later, obstruction of the right ureter occurred due to progression of the pelvic metastases, thus a third debulking laparotomy with resection of the pelvic metastases including the left ovary was performed. The microscopic examination of the removed pelvic mass showed malignant carcinoid tissue with focal remnants of atrophic ovarian tissue. Two years after surgery, serum androgen levels are undetectable. We hypothesize that the high levels of ACTH at the site of the left ovary have induced androgen hypersecretion by steroid-producing cells in the ovary of our patient.     

FatalAspergillus fumigatus septicemia in a patient with an ectopic ACTH-producing neuroendocrine pancreatic tumor

The case of a 71-yr-old Caucasian patient who suffered from an adrenocorticotropic hormone (ACTH)-producing tumor and developed a fulminantAspergillus fumigatus septicemia is reported. The patient presented initially with a recent onset of hyperglycemia and had excessive plasma levels of cortisol and ACTH. A computer-assisted tomography scan showed a tumor associated within the head of the pancreas. During his hospital course, he developed a rapid progressive fatalAspergillus fumigatus pneumonia and an upper gastrointestinal bleeding. At necropsy multiple abscesses in the brain, lungs, heart, kidneys, small bowel and mesentery were present as a result of Aspergillus septicemia. A neuroendocrine pancreatic tumor, 8 cm in diameter, was found in the head of the pancreas without any signs of malignancy. The tumor showed immunohistochemical and electron microscopic evidence of ACTH expression, but of no other pituitary or pancreatic hormones. This case demonstrates the fulminant progress of a septicemia based on an immunologically compromised patient because of ectopic Cushing’s syndrome. Early diagnosis of ectopic ACTH syndromes is essential for adequate therapy in order to prevent complications and fatal infections.     

Neuroendocrine control of growth hormone secretion

The secretion of growth hormone (GH) is regulated through a complex neuroendocrine control system, especially by the functional interplay of two hypothalamic hypophysiotropic hormones, GH-releasing hormone (GHRH) and somatostatin (SS), exerting stimulatory and inhibitory influences, respectively, on the somatotrope. The two hypothalamic neurohormones are subject to modulation by a host of neurotransmitters, especially the noradrenergic and cholinergic ones and other hypothalamic neuropeptides, and are the final mediators of metabolic, endocrine, neural, and immune influences for the secretion of GH. Since the identification of the GHRH peptide, recombinant DNA procedures have been used to characterize the corresponding cDNA and to clone GHRH receptor isoforms in rodent and human pituitaries. Parallel to research into the effects of SS and its analogs on endocrine and exocrine secretions, investigations into their mechanism of action have led to the discovery of five separate SS receptor genes encoding a family of G protein-coupled SS receptors, which are widely expressed in the pituitary, brain, and the periphery, and to the synthesis of analogs with subtype specificity. Better understanding of the function of GHRH, SS, and their receptors and, hence, of neural regulation of GH secretion in health and disease has been achieved with the discovery of a new class of fairly specific, orally active, small peptides and their congeners, the GH-releasing peptides, acting on specific, ubiquitous seven-transmembrane domain receptors, whose natural ligands are not yet known.     

Reversible dilated cardiomyopathy due to growth hormone deficiency.

An unusual case of severe dilated cardiomyopathy is described in a woman with postpartum hypopituitary function, which was characterized by marked decrease of cardiac myofibrils (decreased ratio of myofibrillar volume:cell volume) and somatomedin C deficiency. The patient was treated with a daily intramuscular dose of 4 UI of recombinant human growth hormone for 3 months. Clinical and laboratory assessment and follow-up consisted of noninvasive (echocardiograms, Doppler study, and clinical laboratory tests) and invasive procedures (angiography and endomyocardial biopsy). Morphologic study included optical and electron microscopic examinations and morphometric analysis. The patient exhibited a relevant improvement of cardiac function after recombinant human growth hormone administration. The clinical improvement was confirmed by normalization of electrocardiographic voltages, increased myocardial mass, angiography, and optical and electron microscopic examination, which showed a dramatic recovery of myofibrillar content in myocardiocytes. Furthermore, withdrawal of growth hormone was followed by reduction of electrocardiographic voltages and myocardial mass as well as by impairment of left ventricular function. The authors suggest that there are forms of dilated cardiomyopathy that may benefit dramatically by growth hormone administration. These forms should be identified by growth hormone/somatomedin C axis deficiency and by decrease in myofibrillar content at endomyocardial biopsy.     

Oncogenic hypophosphataemia and ectopic corticotrophin secretion due to oat cell carcinoma of the trachea.

A case of oat cell carcinoma causing Cushing''s syndrome and oncogenic hypophosphataemic osteomalacia is reported. The association of the two disorders in one patient is believed to be unique and this is the second reported case of oncogenic osteomalacia caused by oat cell carcinoma.     

Endocrine cells in human laryngeal tumors (ectopic hormone secretion)

Hormone-producing cells (apudocytes) were found immunohistochemically in 3 out of 15 squamous cell carcinomas of the larynx. In one tumor these cells synthesized melatonin and a thyrotropic hormone, in the other insulin, and in the third insulin and somatotropic hormone. The appearance of tumor cells with endocrine function in nonendocrine neoplasias is considered to be not ectopic but the result of malignization at the level of polypotent cells followed by their differentiation into epithelial or endocrine cells.     

A role of thyrotropin-releasing hormone in insulin secretion by isolated rat pancreatic islets

Insulin-secreting pancreatic cells also express thyrotropin-releasing hormone (TRH). Although the physiological role of TRH in this localization is unclear, its participation in glucoregulation has been implied. To test this hypothesis, we blocked the last step of post-translational maturation of the TRH molecule by disulfiram, which is an active inhibitor of peptide -amidation (PAM) within pancreatic islet cells. The treatment of male rats with 200 mg/kg/day of disulfiram during a 5-day period resulted in a low PAM activity, a high insulin content and its basal secretion from pancreatic islets, and the inability to release insulin in response to glucose (16.7 mM) or hypo-osmotic (30%) challenge in vitro. The addition of TRH (1 nM) to the medium during incubation restored the insulin content and both basal and glucose stimulated insulin secretions to control levels. Conclusion: TRH plays an important role in the mechanism of insulin secretion and its response to glucose stimulation.     

Regulation by catecholamines of spontaneous growth hormone secretion in the baboon

To gain an increased understanding of the role of central neurotransmitters in the regulation of spontaneous growth hormone (GH) secretion in the primate, we investigated the effects of peripheral intravenous infusion of the alpha-adrenergic receptor-blocking agent, phentolamine (5.0-mg bolus and 1.5 mg . kg-1 . 12 h-1), and the tyrosine hydroxylase inhibitor, alpha-methyl-p-tyrosine (MPT, 300 mg . kg-1 . 24 h-1), on the pattern of GH secretion in five adolescent male baboons. Serum GH concentrations were measured in blood samples taken at 20-min intervals over 12 h (0530-1730) after an overnight fast. In nontreatment control studies, GH secretion exhibited a predictable rhythmic oscillation with a mean period of 5.7 +/- 0.4 (SE) h. Phentolamine significantly decreased the 12-h mean and integrated GH concentrations compared to control values, but the small peaks of GH, which could be distinguished from base-line concentrations in three of the animals, occurred at the same time as during control studies. Whereas alpha-methyl-p-tyrosine slightly reduced serum levels of GH, it significantly increased the GH pulse frequency in the baboons. A two- to fourfold increase in serum prolactin levels occurred in all animals treated with MPT. These findings suggest that alpha-adrenergic pathways play a stimulatory role in maintaining spontaneous daytime GH secretion in the baboon and that one or more catecholamines are involved in the generation of rhythmic GH release.     

Normal growth hormone secretion is rare after microsurgical normalization of growth hormone levels in acromegaly

The effect of microsurgery on growth hormone (GH) secretion was studied in 34 patients with acromegaly. All patients showed enlarged sella volumes according to encephalography and macroadenomas at surgery. Preoperative GH levels were elevated in all 34 patients and 14 had concomitant hyperprolactinemia. There was a correlation between basal GH levels and sella size. Visual field defects, suprasellar extension, long duration of the disease, hyperprolactinemia and aneuploidy were noted in patients with low as well as high levels of GH preoperatively. The average reduction of GH levels in the total series was 71 +/- 21% (mean +/- SD). A notably similar reduction of GH levels was seen regardless of preoperative GH levels, concomitant hyperprolactinemia, visual field defects, size of the adenoma, invasive growth or increasing experience of the surgeon. Therefore, normal GH levels after surgery were reached mainly in patients with moderate GH increments preoperatively. GH levels were normalized by surgery in 15 patients but only four of these showed normal GH response to TRH and iota-dopa tests. Thus, only four patients (12%) fulfilled these criteria for cure of GH homeostasis.