FROM DIABETES INSIPIDUS TO SELLAR XANTHOGRANULOMA - A "YELLOW BRICK ROAD" DEMANDING TEAM-WORK.

Xanthogranulomas are inflammatory lesions exceptionally rarely occurring in the sellar region. Sellar xanthogranulomas (SXG) result from secondary hemorrhage, infarction, inflammation or necrosis upon existing craniopharyngioma (CP), Rathkès cleft cyst (RCC) or pituitary adenoma (PA), or represent a stage in xanthomatous hypophysitis evolution. "Pure SXG" are independent of a preexisting lesion. A 70 year old male patient, laryngeal cancer survivor, presented with central diabetes insipidus (CDI). MRI revealed an intra-suprasellar mass of uncertain origin. Transsphenoidal surgery resulted in an efficient lesion resection with maximal pituitary sparing. Pathological report has confirmed SXG without conclusive identification of preexisting sellar lesion. Age at presentation and gender were atypical for SXG. The most frequent presenting signs of SXG were absent. Most SXG are initially misdiagnosed as CP, RCC or PA. Preoperative clinical and radiological uncertainty may impact operative planning. Differentiating from CP is crucial, due to divergent operative target goals and prognosis. Intraoperative frozen section analysis could guide surgical extensiveness. Close collaboration must include endocrinologist, neuroradiologist, neurosurgeon and pathologist. Quantity and quality of provided tissue are essential for avoiding bias in pathohistological analysis of cystic or heterogenous lesions. Awareness is needed of new pathological entities in the sellar-parasellar region. SXG should be considered in differential diagnosis of CDI-causing sellar lesions.

Chronic cognitive sequelae after traumatic brain injury are not related to growth hormone deficiency in adults.

OBJECTIVE: The objective of the study was to asses the possible influence of hypothalamo-pituitary deficiencies, and growth hormone (GH) deficiency in particular, on cognition in adult patients with traumatic brain injury (TBI). TBI is a recently identified risk factor for cognitive deficits and hypopituitarism. Even the patients with favorable outcome after TBI may present with persistent bodily, psychosocial, and cognitive impairments, resembling patients with untreated partial or complete pituitary insufficiency. DESIGN: We performed retrospective and cross-sectional study of endocrine and cognitive function in TBI in 61 patients (aged 37.7 +/- 1.7 years) of both sexes (44 m,17 f), at least 1 year after TBI (3.9 +/- 0.6 years). Serum insulin-like growth factor 1 (IGF-I), thyroxin, thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (in men), prolactin, and cortisol were measured, and GH secretion was assessed by growth hormone releasing hormone (GHRH) + growth hormone releasing peptide-6 (GHRP-6) test. Cognitive function was assessed by using a standard neuropsychological battery. RESULTS: GH deficiency (GHD) and GH insufficiency (GHI) were found in 20 patients (32.8%). After adjustment for confounders [age, body mass index (BMI), education level, time elapsed from TBI], there were no significant differences in results of neuropsychological tests between patients with TBI with GHD, GHI, and normal GH secretion. There were no correlations of neuropsychological variables with stimulated peak GH secretion or IGF-I level. CONCLUSIONS: GHD persists long after the TBI, independently of trauma severity and age at traumatic event. GH secretion is more sensitive to TBI than other pituitary hormones. No evidence is found for an association of cognitive function impairment and somatotropic axis impairment in adult patients tested more than 1 year after the TBI.

ACTH and cortisol responses to ghrelin and desmopressin in patients with Cushing's disease and adrenal enlargement.

BACKGROUND: Overexpression of ghrelin and vasopressin (V3) receptors demonstrated on corticotrophe adenomas accounts for exaggerated ACTH and cortisol responses to ghrelin and desmopressin (DDAVP) in patients with Cushing's disease (CD). AIM: In this study we have compared ACTH and cortisol responsiveness to DDAVP and ghrelin in CD patients with and without adrenal enlargement. SUBJECTS AND METHODS: Ghrelin and DDAVP tests were performed in 15 patients with CD (7 with and 8 without signs of adrenal enlargement) with CRH test in 8 patients. In 7 age and sex-matched healthy subjects, ghrelin test was performed. Plasma ACTH and serum cortisol concentrations were measured after ghrelin, DDAVP and CRH. Growth hormone was measured after stimulation with ghrelin. RESULTS: Significantly higher baseline and peak ACTH and cortisol concentrations after ghrelin were observed in all patients with CD compared to healthy control subjects. Patients with CD and adrenal enlargement had significantly lower baseline and peak ACTH concentrations after stimulation with ghrelin compared to CD patients without adrenal enlargement, while cortisol levels at baseline and after ghrelin administration were similar. Three out of seven patients with CD and adrenal enlargement did not respond to DDAVP while they responded well to CRH and ghrelin. CONCLUSION: Patients with CD and adrenal enlargement pose special diagnostic problems. They may have lower baseline ACTH levels and may not respond to DDAVP while they respond to ghrelin and CRH. Despite increased endogenous cortisol levels in CD, cortisol responses to ghrelin and CRH are preserved in patients with CD and adrenal enlargement.

Cytogenetic findings in Serbian patients with Turner's syndrome stigmata.

Cytogenetic findings are reported for 31 female patients with Turner's syndrome. Chromosome studies were made from lymphocyte cultures. Non-mosaicism 45,X was demonstrated in 15 of these patients, whereas only three were apparently mosaic. Eight patients showed non-mosaic and four patients showed mosaic structural aberrations of the X-chromosome. One non-mosaic case displayed a karyotype containing a small marker chromosome. Conventional cytogenetics was supplemented by fluorescence in situ hybridization (FISH) with an X-specific probe to identify the chromosomal origin of the ring and a 1q12-specific DNA probe to identify de novo balanced translocation (1;9) in one patient. To our knowledge, this is the first finding of karyotype 45,X,t(1;9)(cen;cen)/46,X,r(X),t(1;9)(cen;cen) in Turner's syndrome. The same X-specific probe was also used to identify a derivative chromosome in one patient.

Glucose metabolism during ghrelin infusion in patients with anorexia nervosa.

Anorexia nervosa (AN) is an eating disorder characterized by self-induced starvation due to fear of adiposity. Ghrelin, gastric peptide with potent orexigenic, adipogenic, GH-releasing and metabolic properties, is elevated in AN. We have previously shown that intervention with exogenous ghrelin is not effective in terms of inducing neuroendocrine and appetite responses in AN. In this arm of the same study protocol we investigated glucose metabolism responses to 5 h i.v. infusion of active ghrelin in a) 9 severely malnourished AN patients, b) 6 AN patients who partially recovered body weight (PRAN), c) 10 constitutionally thin female subjects with regular menstrual cycles. At baseline, no significant differences were observed in blood glucose, insulin, c-peptide, adiponectin, and homeostasis model assessment index values, between the studied groups. During ghrelin infusions, blood glucose levels significantly increased in all groups although significantly less in low-weight AN; insulin levels were not significantly affected, while c-peptide levels were significantly suppressed only in the constitutionally thin and PRAN subjects. In addition to our previous findings of impaired neuroendocrine and appetite responses in patients with AN, we conclude that metabolic responses to ghrelin are attenuated in these patients, which tend to recover with weight gain.

Ghrelin has partial or no effect on appetite, growth hormone, prolactin, and cortisol release in patients with anorexia nervosa.

CONTEXT: Anorexia nervosa (AN) is an eating disorder characterized by self-induced starvation. Gastric hormone ghrelin, potent orexigen, and natural GH secretagogue are increased in AN. Although exogenous ghrelin stimulates appetite, GH, prolactin, and cortisol release in humans, its effects have not been studied, during infusions, in AN patients. OBJECTIVE: The objective of the study was to determine the effects of ghrelin on appetite, sleepiness, and neuroendocrine responses in AN patients. DESIGN: This was an acute interventional study. SETTING: The study was based at a hospital. Investigated SUBJECTS: Twenty-five young women, including nine patients diagnosed with AN with very low body weight, six AN patients who partially recovered their body weight but were still amenorrheic, and 10 constitutionally thin female subjects, without history of eating disorder, weight loss, with regular menstrual cycles, were included in the study. INTERVENTION: Each patient received 300-min iv infusion of ghrelin 5 pmol/kg.min and was asked to complete Visual Analog Scale questionnaires hourly. MAIN OUTCOME MEASURES: Visual Analog Scale scores for appetite and sleepiness, GH, prolactin, and cortisol responses were measured. RESULTS: At baseline, AN patients had significantly higher ghrelin, GH, and cortisol levels and significantly lower leptin than constitutionally thin subjects. GH responses to ghrelin infusion were blunted in patients with AN. Ghrelin administration did not significantly affect appetite but tended to increase sleepiness in AN patients. CONCLUSIONS: Ghrelin is unlikely to be effective as a single appetite stimulatory treatment for patients with AN. Our results suggest that AN patients are less sensitive to ghrelin in terms of GH response and appetite than healthy controls. Ghrelin effects on sleep need further studies.

Ghrelin test for the assessment of GH status in successfully treated patients with acromegaly.

OBJECTIVE: Posttreatment assessment of disease activity and definition of cure of acromegaly, using measurement of GH secretion, remains problematic. Furthermore, with our efforts to achieve tight biochemical control of the disease it is foreseeable that a proportion of patients may be rendered GH deficient, thus requiring testing for GH deficiency. The aim of our study was to evaluate residual GH secretion in cured patients with acromegaly. DESIGN AND METHODS: At baseline, circulating GH, IGF-I, IGFBP-3, leptin and lipid (cholesterol and tri-glycerides) levels were measured in 33 acromegalic patients nine years after treatment with surgery of whom 6 were additionally irradiated. Two tests were performed: the GH suppression test--oral glucose tolerance test (OGTT) and the GH provocation test--ghrelin test (1 microg/kg i.v. bolus) and the results were compared with 11 age- and sex-matched control subjects. RESULTS: According to the consensus criteria (normal IGF-I levels and post-OGTT GH nadir <1 microg/l), 21 treated acromegalic patients were cured, 6 had discordant IGF-I and GH nadir values during OGTT, while 6 had persistent acromegaly. After the GH provocative test with ghrelin (cut-off for severe GH deficiency is GH <3 microg/l), we detected 9 severely GH deficient patients (GHD) among 21 cured acromegalic patients. Mean GH peak (+/-s.e.m.) response to the ghrelin test in GHD acromegalics was significantly lower compared with acromegalics with sufficient GH secretory capacity and control subjects (1.2 +/- 0.2 microg/l vs 20.1 +/- 2.4 microg/l vs 31.1 +/- 2.5 microg/l respectively, P<0.0001). Mean IGF-I and IGFBP-3 levels were not different between GHD and GH-sufficient cured acromegalics. Leptin levels and body mass index (BMI) were significantly higher in GHD male acromegalics compared with GH-sufficient male acromegalics. GHD female acromegalics tended to have higher BMIs while leptin levels were not different. CONCLUSIONS: The assessment of residual GH secretory capacity by the GH provocation test is necessary in the long-term follow-up of successfully treated acromegalics since a large proportion of these patients are rendered GH deficient.

Diabetes mellitus and cognitive functioning in a Serbian sample.

INTRODUCTION: Diabetes is associated with cognitive impairments, particularly in executive functioning and memory. AIM: The aim was to describe cognitive functioning in Type 1 (T1DM) and Type 2 (T2DM) diabetes compared to healthy controls in a Serbian sample. METHOD: We studied 15 patients with adult onset T1DM (age range 19-60 years), 37 patients with T2DM (age range 50-77 years), and 32 healthy controls (28-78 years). All participants underwent comprehensive neuropsychological assessment. RESULTS: T2DM subjects exhibited poorer performance than healthy controls in global cognitive performance, as well as verbal learning and memory. After correcting for multiple comparisons, follow-up examination of individual tests showed significantly poorer performance only on Trail Making Test Part B (TMT-B). Effect sizes for T2DM versus healthy controls ranged from medium to large for several cognitive variables, while comparisons between T1DM and the other two groups tended to yield much smaller effects. CONCLUSION: T2DM is associated with poorer cognition, particularly in executive functions, learning/memory, and global cognition. Lack of group differences may be due to use of an adult onset T1DM sample, relatively young age of our T2DM sample, or characteristics of healthy control subjects in our Serbian sample.

Blocked growth hormone-releasing peptide (GHRP-6)-induced GH secretion and absence of the synergic action of GHRP-6 plus GH-releasing hormone in patients with hypothalamopituitary disconnection: evidence that GHRP-6 main action is exerted at the hypothalamic level.

GH-releasing peptide (GHRP-6; His-D Trp-Ala-Trp-D Phe-Lys-NH2) is a synthetic compound that releases GH in a specific and dose-related manner through mechanisms and a point of action that are mostly unknown but different from those of GHRH. In man, GHRP-6 is more efficacious than GHRH, and a striking synergistic action on GH release is observed when GHRP-6 and GHRH are administered simultaneously. Based on such a synergistic action, it has been hypothesized that GHRP-6 acts through a double mechanism by actions exerted both at the pituitary and hypothalamic levels. The aim of the present study was 2-fold: 1) to further characterize the mechanism of action and synergistic effects of GHRP-6; and 2) to study its action in patients with hypothalamopituitary disconnection. Twelve patients with different neuroendocrine pathologies leading to a state of hypothalamopituitary disconnection (functional stalk section) and 11 age- and sex-matched normal controls were studied. Each subject underwent 3 tests on separate occasions, being challenged with GHRH (100 micrograms, i.v.), GHRP-6 (90 micrograms, i.v.), or GHRH plus GHRP-6. GH was analyzed as the area under the curve (mean +/- SE, micrograms per L/120 min). In normal subjects GH secretion was 483.7 +/- 99.2 after GHRH, 1434.8 +/- 393.0 after GHRP-6, and 3771.5 +/- 399.6 after GHRH plus GHRP-6; the level of GH secreted after GHRH plus GHRP-6 treatment was significantly (P < 0.05) higher than after the arithmetic sum of GH levels after both compounds administered separately. In the group of patients with hypothalamopituitary disconnection, the level of GH secreted after GHRH was similar to that in controls (423.4 +/- 62.8); however, a complete blockade was observed after GHRP-6 (97.3 +/- 7.9), significantly (P < 0.05) lower than after GHRH as well as lower than the GHRP-6-induced GH release in control subjects (P < 0.01). After GHRH plus GHRP-6, the patients with hypothalamopituitary disconnection showed severely reduced secretion (745.3 +/- 67.6; P < 0.01 vs. controls), a value that was not significantly different from the arithmetic addition of levels produced by both compounds administered separately.(ABSTRACT TRUNCATED AT 400 WORDS)

Serum leptin and insulin concentrations in patients with insulinoma before and after surgery.

Inferential studies suggest that circulating insulin concentrations positively regulate leptin secretion by adipocytes. In humans, however, insulin requires prolonged periods of time, and relatively artificial set-ups before a relationship with leptin can be observed. In the present work, serum leptin concentrations were measured in five patients with insulinoma before and one month after surgery and in five control subjects matched by sex and body mass index (BMI). The control subjects presented a mean serum leptin concentration of 6.7+/-1.5 microg/l and a BMI of 24.9+/-1.1. The mean serum leptin concentration in patients with insulinoma was 11.8+/-3.1 microg/l (P < 0.05 vs controls), with a BMI of 26.3+/-1.9. After surgery, there was a non-significant reduction in BMI (25.8+/-1.7), and a clear reduction in serum leptin concentration (5.6+/-2.4 microg/l, P < 0.05 vs pre surgical values and no difference vs control subjects). The fasting area under the curve (AUC) of insulin concentration (in mU/l per 120 min) before surgery was 14421+/-4981 and after surgery was 1306-/+171 (P < 0.05). Before surgery, serum leptin concentrations significantly correlated with BMI (r = 0.71) and AUC of insulin (r = 0.82), a correlation that was lost after surgery. In conclusion, serum leptin concentrations are significantly elevated in patients with chronically high insulin levels due to insulinoma. After surgical treatment and normalization of insulin values, leptin levels return to normal.

Pituitary enlargement due to primary hypothyroidism: growth hormone response to GHRH, GHRP-6 and GHRH plus GHRP-6.

GH secretion after growth hormone-releasing hormone (GHRH), growth hormone releasing peptide-6 (GHRP-6) and after combined administration of both peptides was studied in a patient with lactotrope and thyrotrope hyperplasia due to primary hypothyroidism. Pituitary pseudotumor disappeared after thyroid hormone replacement; this was evidenced by magnetic resonance imaging (NMR). There was no difference between areas under the curve (AUCzero-120 min) during GHRH test before and after thyroid hormone replacement (136.5 vs 129.0 micrograms/l min). Maximal GH increases over basal values (delta GH) did not change (1.5 and 1.9 micrograms/l). GH secretion induced by GHRP-6 increased after treatment (AUCzero-120 min 197.2 vs 650.4 micrograms/l min). delta GH increments were 4.0 and 18.3 micrograms/l before and after therapy respectively. When the peptides were administered together a synergistic effect on GH secretion was observed but GH release was much more powerful after pituitary pseudotumor disappearance (AUCzero-120 min 1043.2 vs 2046.7 micrograms/l min). This was accompanied by increased delta GH (22.7 vs 35.5 micrograms/l). The synergic action of peptides normalized in euthyroid condition and after the resolution of pituitary pseudotumor mainly due to improved GH response to GHRP-6. Blunted response of GH to GHRP-6 and GHRP-6 plus GHRH were in part due to known effects of hypothyroidism on GH secretion. Hypothalamopituitary disconnection and/or decrease in the synthesis of an unknown factor in the hypothalamus which mediates the effects of GHRP-6 may have participated in the GH responsiveness of this patient. This case adds to in vivo evidence that GHRP-6 operates through a non-GHRH dependent mechanism.

Evaluation of pituitary GH reserve with GHRP-6.

GH releasing peptides (GHRPs) were developed before the isolation and identification of GH releasing hormone (GHRH) in 1982 yet the clinical era of the GHRPs began in 1988. Since then clinical studies have been greatly extended. We studied the effects of GHRPs on GH release as a function of age, metabolic status and in different neuroendocrine pathologies. The different mechanism of action of GHRPs versus GHRH and the site of action have been addressed. There is a large variability in the stimulatory action of GHRH contrasted with the reproducibility of action of GHRPs. In different metabolic states GH response after GHRH is more impaired than after GHRP-6. On the other hand in different neuroendocrine pathologies GH response after GHRP-6 is more impaired than after GHRH. Each secretagogue provides separate information on GH secretion, necessary not only for linear growth but for general metabolism.

Growth hormone secretagogues in pathological states: diagnostic implications.

The identification and cloning of the receptor for synthetic growth hormone (GH) secretagogues, even before the endogenous ligand has been identified or its precise physiological role established, suggests that there is a novel target of action for this class of drug. In an attempt to select patients who will benefit from GH treatment, GH secretagogues are being evaluated for their usefulness in diagnosing GH deficiency. The effects of GH-releasing peptides (GHRPs) on GH release as a function of age and metabolic status, and in different neuroendocrine pathologies, are described, as are the different mechanisms of action, potency and reproducibility of the response to GHRPs compared with GH-releasing hormone (GHRH). GHRPs offer the advantage over GHRH in natural models of deranged GH secretion in that, in various metabolic states (e.g. obesity, anorexia nervosa and non-insulin-dependent diabetes mellitus), the GH response to GHRH is more impaired than it is to GHRPs. However, in some neuroendocrine pathologies, the reverse is true. Thus, both secretagogues provide separate information on the physiological status of somatotrophs.

[Gastrointestinal gastric tumor (GIST) as a cause of massive hemorrhage from the upper digestive tract].

Gastrointestinal stromal tumors GIST are rare mesenchymal tumors of the gastrointestinal tract characterized by expression of a receptor that activates tyrosine kinase called C- kit. Since malignant GIST has an extremely poor prognosis even after surgical resection. The developement of a tyrosine kinase inhibitor, STI571/imatinib mesylate/Gleevec, Glivec which inhibits the BCR-ABL, PDGF-R alpha, and C-Kit receptors, has changed the management of unresectable malignant GIST and has improved the survival of patients with metastaic disease. We report a 32 year old male patient with subcardiale gastric GIST and massive gastrointestinale bleeding. The patient underwent total gastrectomy, D2 lymphadenestomy, distal pancreatectomy and splenectomy on 02.02. 2004. Histopathology examination of the primary tumor revealed a strong C-Kit expression and CD 34 +++, Ki67 20 and so called "Pure GIST" was approved Liver metastasis was detected on ultrasound and CT 12 months later and segmentectomy S7 was performed on 23.03.2005. Postoperative course was uneventfull. HP examination--malignant 35 x 30 mm sarcoma like tumor of mesenchymal origin. The patient received adjuvant imatinib-mesylate Gleevec Novartis Pharma Basel 400 mg a day. The initial complete response to treatment continued to 24 monts postoperatively Imatinib is a recent and very promising tretemenextirpation remains the only curative treatment of malignant GIST as evideneced by our patient.

Plasma ghrelin levels of gastrectomized and vagotomized patients are not affected by glucose administration.

BACKGROUND: Ghrelin is a brain-gut peptide with GH-releasing and appetite-inducing activities, secreted mainly by the stomach. Circulating ghrelin concentrations fall rapidly after nutrient ingestion as well as after oral and intravenous glucose challenge. A number of gut hormones including ghrelin require an intact vagal system, which has been hypothesized to have a major role in initiating the postprandial fall in ghrelin levels. AIM: We aimed to investigate the effect of oral glucose challenge on ghrelin secretion in gastrectomized (GASTRX) and vagotomized patients. DESIGN: Interventional study. PATIENTS: Six GASTRX-vagotomized patients and 11 healthy sex- and body mass index (BMI)-matched subjects. METHODS: An oral glucose tolerance test (OGTT) was performed in all subjects. At baseline, circulating plasma total ghrelin, serum glucose, insulin and GH levels were measured. Serum glucose, insulin, GH and plasma ghrelin levels were determined every 30 min for 2 h. RESULTS: Plasma ghrelin levels at baseline were reduced by 55% in GASTRX-vagotomized patients compared to the control group (P < 0.01). In control subjects, plasma ghrelin levels decreased significantly during the OGTT whereas in GASTRX-vagotomized patients no reduction was registered (26.4 +/- 2.8% vs. 5.5 +/- 3.4%). The OGTT revealed a significantly greater increase in circulating glucose levels and serum insulin levels while GH response was not different in GASTRX-vagotomized patients compared to control subjects. CONCLUSIONS: Our data show that circulating ghrelin levels in GASTRX and vagotomized patients were not suppressed after oral glucose administration, unlike control subjects, suggesting that this effect could be due, at least in part, to the lack of contribution of the vagal nervous system to the regulation of ghrelin.

Absence of desensitization by hexarelin to subsequent GH releasing hormone-mediated GH secretion in patients with anorexia nervosa.

OBJECTIVE: Both the basal levels and the neuroregulation of GH secretion are perturbed in patients with anorexia nervosa. It is unknown if these alterations are due to severe undernutrition or if they reflect basic neurotransmitter alterations of the patient's neural pathways. On the other hand, prior administration of the GH secretagogue hexarelin in normal subjects blocks the GH-releasing capability of GH releasing hormone (GHRH) administered 2 hours later. In the present work a sequential test was performed using the administration of hexarelin as first stimulus followed 120 minutes later by GHRH. The two aims of the study were: (a) to evaluate the interaction of GHRH and hexarelin, and (b) to further understand the alterations in GH neuroregulation in patients with anorexia nervosa. DESIGN: The GH stimuli used were hexarelin (1 micrograms/kg i.v.), a GH stimulus whose main action is hypothalamic, followed 120 minutes later by GHRH (1 micrograms/kg i.v.) as a pituitary stimulus. Each woman was tested once. PATIENTS: Thirty-two woman matched for age participated in the study: six normal-weight women as controls, 14 women with anorexia nervosa, seven women with secondary amenorrhoea due to voluntary weight loss for aesthetic reasons, and five normal-weight women after 72 hours of a controlled hypocaloric diet (800 cal/day). MEASUREMENTS: Plasma GH levels were measured by time-resolved fluoroimmunosasay, each value shown is the mean +/- SE in mU/l. RESULTS: The administration of hexarelin to the normal-weight women induced a clear-cut GH secretion (expressed as mean +/- SE of GH peak in mU/l of 77.5 +/- 21.8, but blocked the GH-releasing capability of GHRH administered 120 minutes later (6.6 +/- 2.8, P < 0.05). In contrast, the women with anorexia nervosa showed a normal GH response after the two stimuli: hexarelin 64.8 +/- 9.2. GHRH 71.1 +/- 14.2. The absence of heterologous desensitization was specific to anorexia nervosa, because the women with amenorrhoea due to voluntary weight loss but with a normal energy intake showed a pattern similar to the controls (GH after hexarelin 60.3 +/- 9.5 and to GHRH 120 minutes later 6.2 +/- 1.0 (P < 0.05)). Similarly, the women after the short-term hypocaloric diet showed a hexarelin-mediated GH secretion of 99.6 +/- 17.8, which blunted the subsequent administration of GHRH (GH mean peak of 9.9 +/- 2.9, P < 0.05 vs hexarelin). CONCLUSIONS: In the normal subjects, the administration of hexarelin induced clear-cut GH secretion, but inhibited the action of GHRH when administered 120 min later, while this heterologous desensitization was not observed in the patients with anorexia nervosa. This sequentially delayed test may be of some value in the clinical setting for assessing the status of patients with anorexia nervosa.

Case report of hypopituitarism with suspected syndrome of inappropriate VP secretion (SIADH) due to a large aneurysm of the internal carotid in the sellar region.

Hypopituitarism and hyponatremia, especially when severe, are infrequent findings particularly when the cause of hypopituitarism at presentation is unknown and untreated. Interestingly, hyponatremia is usually seen in elderly patients with hypopituitarism due to various causes. We present a case with unrecognized and untreated hypopituitarism due to a large aneurysm of the internal carotid artery in the sellar region causing the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

GH response to growth hormone releasing hormone and hypoglycaemia is unaltered by high endogenous plasma calcitonin levels in patients with medullary thyroid carcinoma.

OBJECTIVE: As it has previously been reported that calcitonin suppresses stimulated growth hormone release, we have studied the serum growth hormone response to growth hormone releasing hormone and insulin-induced hypoglycaemia in patients with high calcitonin levels due to medullary carcinoma of the thyroid. DESIGN: Growth hormone releasing hormone (100 micrograms i.v.) and insulin (0.15 units/kg i.v.) were given and the growth hormone responses in the patients with medullary carcinoma of the thyroid and normal healthy controls were compared. PATIENTS: Eight with histologically confirmed medullary thyroid carcinoma, two females and six males, aged 21-77 years, were studied and compared with seven healthy age and sex matched controls. MEASUREMENTS: Growth hormone and calcitonin were measured. RESULTS: No significant difference was found between the growth hormone responses observed in patients with medullary carcinoma when compared with normal controls either after GHRH or during insulin-induced hypoglycaemia. CONCLUSION: We conclude that calcitonin does not alter the pituitary response to GHRH in medullary thyroid carcinoma and is unlikely to play an important role in regulating growth hormone secretion because calcitonin did not modify the release of growth hormone after insulin-induced hypoglycaemia.

Growth hormone secretion elicited by GHRH, GHRP-6 or GHRH plus GHRP-6 in patients with microprolactinoma and macroprolactinoma before and after bromocriptine therapy.

OBJECTIVE: Growth hormone-releasing peptides (GHRPs) are potent GH releasers which act at both pituitary and hypothalamic levels through specific G-protein coupled receptors, recently cloned. A synergistic effect from the simultaneous administration of GHRH + GHRP-6 on GH release is observed in normal subjects, while it is absent in patients with hypothalamo-pituitary disconnection. We studied the effects of GHRH, GHRP-6 and both secretagogues on GH release in patients harbouring pituitary tumours that may be reduced in size by medical treatment. DESIGN: Analysis of peak GH response to GHRH, GHRP-6 and GHRH plus GHRP-6 in patients with micro- and macroprolactinomas. Integrated GH response over 2 hours calculated as AUG-GH mU/l x 120 min. Analysis of delta PRL above the basal level in response to the same GH releasers. PATIENTS: Eleven patients with macroprolactinomas aged 41.2 +/- 4.8 years (range 24-75), nine patients with microprolactinomas aged 31.5 +/- 3.4 (range 22-53) and 13 healthy subjects aged 42.1 +/- 4.7 years (range 22-64) were studied. Prolactinoma patients were then treated with bromocriptine (15-20 mg orally) for 6-24 months. Tests were repeated when there was evidence of tumour shrinkage and normalized plasma prolactin concentrations. RESULTS: Peak GH response before treatment in macroprolactinoma patients was 4.9 +/- 0.9 mu/l after GHRH, 8 +/- 4 mU/l after GHRP-6 and 18 +/- 5 mU/l after GHRH + GHRP-6. Synergism was absent. AUC were 390 +/- 90; 500 +/- 100 and 1100 +/- 300 mU/l x 120 min respectively. These values were all significantly different (P < 0.05) from normal subjects and patients with microprolactinomas with peak GH 16.8 +/- 0.9 mU/l after GHRH; 43 +/- 6 mU/l after GHRP-6 and 130 +/- 10 mU/l after GHRH + GHRP-6. AUC-GH was 1200 +/- 400 after GHRH, 2200 +/- 400 after GHRP-6 and 9000 +/- 1000 mU/l x 120 min after GHRH + GHRP-6. As in normal subjects, synergism was preserved in patients with microprolactinoma (P > 0.05). After treatment with bromocriptine peak GH in patients with macroprolactinoma was 8 +/- 4 mU/l after GHRH, 22 +/- 5 mU/l after GHRP-6 and 70 +/- 20 mU/l after GHRH + GHRP-6. AUC-GH was 800 +/- 300, 1100 +/- 300 and 3500 +/- 800 mU/l x 120 min, respectively. The response of GH after GHRP-6 and GHRH + GHRP-6 improved significantly (P < 0.05) in treated patients with macroprolactinoma. There was no significant change in GH response in microprolactinoma patients after treatment with bromocriptine. Peak GH after GHRH was 30 +/- 20 mU/l, after GHRP-6 it was 75 +/- 8 mU/l and after GHRH + GHRP-6 it was 200 +/- 30 mU/l. AUC-GH was 1500 +/- 700 after GHRH, 4500 +/- 500 after GHRP-6 and 15,100 +/- 600 mU/l x 120 min. Delta prolactin after GHRP-6 did not change before and after bromocriptine treatment in patients with macroprolactinoma or microprolactinoma. CONCLUSION: GH release after GHRP-6 or GHRH + GHRP-6 is fully preserved in patients with microprolactinomas and does not differ before and after treatment with bromocriptine. Patients with macroprolactinoma have blunted responses of GH after GHRH and GHRP-6 and synergism is severely compromised. GH responsiveness to and synergistic interaction between GHRH and GHRP-6 recovers after shrinkage of macroprolactinoma with bromocriptine. Prolactin release stimulated by intravenous administration of GHRP-6 in healthy subjects was not seen in patients with micro- or macroprolactinomas.

Gonadotropin response to clomiphene and plasma leptin levels in weight recovered but amenorrhoeic patients with anorexia nervosa.

Anorexia nervosa (AN) is a state of leptin and gonadotropin deficiency. Leptin levels are decreased in normal weight women with hypothalamic amenorrhea and leptin may be a sensitive marker of overall nutritional status. The aim of the study is to provide additional information on plasma leptin levels and on gonadotropin responses after clomiphene testing in patients with AN who recovered weight but were still amenorrheic. We evaluated 17 patients with AN, female age 20+/-1.2 yr who reached goal weight [body mass index (BMI) 14.9+/-0.5 to 19.3+/-0.4 kg/m2]. At diagnosis serum leptin levels were 2.2+/-0.1 microg/l while after behavioural therapy and hypercaloric diet for 6-12 months serum leptin levels rose to 6.4+/-1.4 microg/l significantly lower compared with those in the control (no.=10, age 28+/-6.2 yr, BMI 21.1+/-0.3 kg/m2, leptin 9.3+/-0.7 pg/l; p<0.05). None of the patients resumed spontaneous menstrual cycles after weight gain. They were tested with a 10-day administration of clomiphene citrate. All had a significant rise in LH secretion (from 1.7+/-0.3 IU/l to 8.3+/-0.9 IU/l, p<0.01) and serum estradiol levels (from 19.0+/-5.4 to 937.7+/-241.2 pg/ml, p<0.03). Nine out of 17 patients menstruated after clomiphene. Serum leptin levels were not different in those who menstruated from those who did not (6.4+/-1.4 to 6.8+/-1.4 microg/l, p>0.05). Body compositon was studied in 12 additional carefully matched patients with AN who recovered weight. Six of them resumed spontaneous menstrual cycles. Neither BMI, body fat, nor leptin appeared as significant determinants of menstrual status. In conclusion, relative hypoleptinemia persists, independent of fat mass, in weight recovered patients with AN. A normal response to clomiphene in weight-recovered yet still amenorrhoeic patients with AN, offers reassurance that the axis is intact and that the problem lies in the hypothalamus. It is reasonable to believe that nutritional disturbances, fat intake and persisting psychological factors still affect plasma leptin levels and reproductive functions in weight-recovered patients with amenorrhea.