Metabolic features and changes in glucose-induced serum glucagon-like peptide-1 levels in children with hypothalamic obesity.

Background Hypothalamic damage may alter glucagon-like peptide-1 (GLP-1) secretion and be involved in the pathogenesis of obesity. We aim to evaluate the metabolic features and the dynamic changes of GLP-1 levels during an oral glucose tolerance test (OGTT) in children with hypothalamic obesity (HO) compared with simple obesity controls. Methods Subjects included eight patients (six females, aged 9-16 years) with hypothalamo-pituitary tumors who later developed obesity and eight controls with simple obesity matched for age, body mass index (BMI), gender and puberty. We assessed the metabolic syndrome features, fat mass, severity of hyperphagia using a standardized questionnaire, and measured glucose, insulin and GLP-1 levels during a standard 75 g OGTT. Results Age, gender distribution, pubertal status and BMI-Z scores were not significantly different. Subjects with HO had higher fasting triglycerides (TG) than controls (128 vs. 94 mg/dL; p=0.05). Four HO subjects and three controls met the criteria for the metabolic syndrome. Fasting and 120 min post-glucose load GLP-1 levels were significantly higher in HO patients than in controls (21.9 vs. 19.7 pg/mL; p=0.025, 22.1 vs. 17.7 pg/mL; p=0.012). Patients with HO had significantly higher hyperphagia scores than in simple obese controls (13 vs. 2.5; p=0.012). Conclusions Patients with HO appear to have more metabolic complications and hyperphagia than controls with simple obesity. Impaired satiety may play an important role in HO. Fasting and glucose-induced serum GLP-1 concentrations seem to be altered in HO patients and could be a part of the pathogenesis of HO.

[A rare case of diencephalic cachexia in an adult female with cranio-pharyngioma]. / Redkii sluchai razvitiia diéntsefal'noi kakheksii u vzrosloi zhenshchiny s kraniofaringiomoi.

Diencephalic cachexia (DС) is progressive weight loss despite a normal caloric intake and a satisfactory state of health, which is caused by hypothalamic lesions. This is a rare (about 100 cases were reported) and potentially fatal disorder of unknown pathogenesis. At present, there is no effective pharmacological therapy for the disorder. Cachexia may regress only if the tumor reduces in size, therefore the timely diagnosis and treatment are of vital importance for the patient. DС is typical of early childhood, and only a few cases have been reported in adults. We present a rare case of DС in a 24-year-old female with papillary craniopharyngioma.

The role of leptin in diencephalic syndrome.

Diencephalic syndrome is a rare condition associated with central nervous system tumors. The most common presentation is secondary failure to thrive with proper caloric intake and no statural impairment. Despite the importance of this syndrome, little is known of its pathophysiology. Some reports have documented changes in human growth hormone and insulin levels at the onset, whereas others have described endocrine disorders of hypothalamic insufficiency resulting from surgery of the tumor. It has been suggested that the hormonal changes described, such as increased human growth hormone and ghrelin or decreased insulin and leptin levels, are related to a patient's BMI. These findings support the role of these 4 hormones as indicators of the patient's nutritional status but not as mediators or potential therapeutic targets of the disease. We report the case of an infant who initially presented with tumor progression and, after chemotherapy, progressive weight gain and reduced tumor size. Because he presented no hormonal deficiencies or obesity after therapy, we were able to analyze his hormonal status uninfluenced by effects of metabolic treatment or excess weight. Although ghrelin and leptin levels have been related to nutritional status, our patient's leptin levels fell when tumor size decreased and weight increased: an extraordinary finding because leptin concentration is expected to increase with weight gain. This paradoxical response suggests that leptin may be dysregulated in diencephalic syndrome or that the diencephalic astrocytoma may have had an effect on leptin secretion.

Presentation and evolution of organic central precocious puberty according to the type of CNS lesion.

OBJECTIVE: To evaluate the influence of the type and treatment of CNS lesion causing central precocious puberty (CPP) on the presentation, hypothalamic-pituitary function and final height. PATIENTS: One hundred patients with CPP caused by central nervous system (CNS) lesion. RESULTS: The CPP was the presenting symptom of the lesion in 25 (10 boys) and occurred in 75 patients (23 boys) previously treated for lesions. These were optic glioma or astrocytoma (n = 45), hydrocephalus (n = 22), hypothalamic hamartoma (n = 15), suprasellar arachnoid cyst (n = 10) and others (n = 8). The percentages of patients with increased height, bone age advance, testicular volume, LH/FSH peaks ratio after gonadotrophin-releasing hormone (GnRH) test and plasma testosterone concentration in boys and oestradiol in girls varied from one aetiology to another. The boys with hamartoma were significantly taller and had greater bone age advance, LH peak and testosterone than boys with optic glioma. The girls with hamartoma and suprasellar arachnoid cyst were significantly younger and had greater LH peak than girls in the other groups. All patients treated for optic glioma had hypothalamic-pituitary deficiencies, including GH (100%), thyrotrophin (71.4%), corticotrophin (12.5%) and pubertal (34.3%) deficiencies. Sixty percent of those with suprasellar cysts lacked GH. Final height was below -2 SD in 15/59 (25%) patients, including 5/11 not treated with GnRH analogue, 3/5 not treated with GH despite GH deficiency, and 2 with hydrocephalus as a result of meningomyelocele. CONCLUSIONS: The type of CNS lesion influences the presentation of CPP. This is probably caused by differences in the mechanisms inducing puberty and to the hypothalamic-pituitary deficiencies associated with the CPP as a result of a lesion and/or its treatment.

Is there a role for ghrelin and peptide-YY in the pathogenesis of obesity in adults with acquired structural hypothalamic damage?

CONTEXT: Obesity is a common sequel to hypothalamic tumors and their treatment, but the underlying mechanisms are not fully established. OBJECTIVE: Our objective was to evaluate the role of ghrelin and peptide-YY (PYY) in human hypothalamic obesity. SETTING: The study took place at a University Medical Center. PARTICIPANTS: Subjects included 14 adult patients (six male, eight female) with tumors of the hypothalamic region and 15 healthy controls (six male and nine female) matched for age, body mass index, and percentage of body fat. INTERVENTIONS: Plasma ghrelin and total PYY were measured using RIAs after an overnight fast and 15, 30, 60, 120, and 180 min after a mixed meal. MAIN OUTCOME MEASURES: We assessed ghrelin, PYY, and appetite ratings. RESULTS: The fall in ghrelin levels after the test meal was similar in the two groups. There was no statistically significant change postprandially in circulating PYY in the patients with hypothalamic damage. Fasting leptin levels and postprandial insulin responses were also similar in the two groups. Patients with hypothalamic damage reported higher hunger ratings at 3 h after the meal (P = 0.01) and a stronger desire to eat at 2 h (P = 0.01) and 3 h (P = 0.02) compared with the control group. CONCLUSIONS: Adult patients with structural hypothalamic damage show impaired satiety, but the changes observed in circulating ghrelin and PYY concentrations in response to a test meal do not indicate a central role for these gut hormones in the control of appetite and the pathogenesis of obesity in these patients.

[Variants of the course of early noncomplicated postoperative period following excision of hypothalamo-hypophysial region tumors in children]. / Osnovnye varianty techeniia rannego neoslozhnennogo posleoperatsionnogo perioda posle udaleniia opukholei gipotalamo-gipofizarnoi oblasti u detei.

A study of non-specific and specific reactions in neurosurgical patients as conducted in the early postoperative period revealed three main variations of an early postoperative clinical course, i.e. with a normal stress-reaction, with a normal stress-reaction concomitant with diabetes insi pidus, and with a lower reactivity to surgical intervention. The treatment algorithms were appropriately amended (the preventive component was added) with due respect to the above circumstances.

Central precocious puberty: clinical and laboratory features.

OBJECTIVE: To determine whether the initial presentation of patients with central precocious puberty (CPP) varies according to the aetiology, whether this permits the differentiation between idiopathic and organic forms, and whether the body mass index (BMI) and plasma leptin concentrations are linked to gonadotrophin secretion. DESIGN: The clinical and laboratory features of 256 patients (26 boys and 230 girls) with CPP were studied separately in boys and girls. We compared patients with idiopathic CPP (seven boys and 186 girls) to those with organic CPP, whose pubertal development revealed a central nervous system (CNS) lesion (five boys and 11 girls), and to patients with organic CPP associated with a previously treated CNS lesion (14 boys and 33 girls). RESULTS: Boys with organic CPP, having revealed or treated CNS lesions, started their puberty earlier (3.0 +/- 1.0 years and 6.7 +/- 0.5 years) than boys with idiopathic CPP (8.5 +/- 0.2 years, P < 0.01 and < 0.05). Boys with organic CPP associated with a treated CNS lesion had lower luteinizing hormone (LH)/follicle stimulating hormone (FSH) peaks ratio after stimulation with gonadotrophin releasing hormone (GnRH) (1.6 +/- 0.5) than did boys with idiopathic CPP (2.2 +/- 0.3, P < 0.05). Girls with organic CPP revealing a CNS lesion started their puberty earlier (3.6 +/- 0.9 years) than girls with idiopathic CPP (6.6 +/- 0.1 years, P < 0.0 l) and had higher LH (P < 0.01) and FSH peaks (< 0.05). Girls with organic CPP associated with a treated CNS lesion had higher BMI (1.8 +/- 0.2 z-score) than did girls with idiopathic CPP (1.3 +/- 0.1 zs, P < 0.05), higher leptin concentrations (11.7 +/- 1.8 microg/l vs. 7.7 +/- 0.5 microg/l, P < 0.0 l), LH peak (P < 0.01), FSH peak (P < 0.05) and LH/FSH peaks ratio (1 +/- 0.1 vs. 0.8 +/- 0.1, P < 0.05). Only 12.4% of the girls with idiopathic CPP had BMI-zs < 0, and their plasma leptins were positively correlated with BMI (P < 0.0001). CONCLUSIONS: The features of central precocious puberty vary according to the aetiology, but it is impossible to exclude a central nervous system lesion in a given patient with central precocious puberty without performing central nervous system imaging. This imaging remains necessary in all cases of central precocious puberty. Most of the girls with idiopathic central precocious puberty had increased BMI, but we found no correlation between plasma leptin concentrations and gonadotrophin secretion.

Evidence for decreased growth hormone in patients with hypothalamic hamartoma due to Pallister-Hall syndrome.

Pallister-Hall syndrome (PHS) is characterized by hypothalamic hamartoma, bifid epiglottis, and central or postaxial polydactyly. Familial transmission is autosomal dominant; isolated cases also occur. To screen for hypothalamic-pituitary dysfunction in PHS, we studied a 12 year-old boy (patient #1), and 14 additional patients (patients #2-14: 7M, 7F; ages 4-72 yr). We performed serial sampling of GH, LH/FSH, TSH, and cortisol from 20.00-08 00 h. At 08.00 h, we measured IGF-I, peak responses of LH and FSH after GnRH, and cortisol after ACTH. We found that 6/7 children, including patient #1, and 6/8 adults had low or absent spontaneous GH secretion and/or low levels of IGF-I. Patient #1 also had accelerated pubertal development, but no other patient had abnormalities of the pituitary-gonadal axis, and none of the 14 patients had an abnormal thyroid or adrenal axis. We conclude that decreased pituitary GH secretion is common in PHS, and may exist in the absence of other forms of endocrine dysfunction.

Endocrinology teaching rounds: primary amenorrhea in a 17-year-old woman.

This endocrinology teaching rounds documents the evaluation of a 17.7-year-old woman with primary amenorrhea. The normal timing of developmental milestones for young women from adrenarche and pubarche through pubertal maturation and growth is reviewed, as are etiologies for amenorrhea. The differential diagnosis of the problem is developed from the patient's initial visit to diagnosis and treatment. The highlights of the management of this young woman after a diagnosis of craniopharyngioma are also discussed. This clinical case emphasizes the importance of understanding normal developmental landmarks and of detecting aberrant physiology-associated amenorrhea even when screening laboratory tests appear normal so that defects in normal development can be addressed earlier in life.

Twenty-four hour rhythm of melatonin in patients with a history of pineal and/or hypothalamo-neurohypophyseal germinoma.

Melatonin deficiency after a pinealectomy has been investigated in animals; however, in humans, this status can be assessed solely by investigating patients with a tumor originating in the pineal gland. This study analyzes secretion of melatonin and pituitary hormones in 14 patients with germinoma originating in the pineal or the hypothalamic-neurohypophyseal region. Thirteen patients had been successfully treated prior to this study. One patient was included in this study before the initiation of treatments. Plasma sampling was performed every 2 hr for 24 hr and melatonin concentrations were measured by radioimmunoassay. Melatonin secretion was nearly absent in the patients with pineal germinoma regardless of treatment option, even in the patient who had been untreated. In contrast, melatonin secretion and its circadian rhythms were not affected in patients with a hypothalamo-neurohypophyseal germinoma. The circadian rhythms of growth hormone and adrenocorticotropic hormone were not dysregulated in patients with the melatonin deficiency. We conclude that germinoma cells originating the pineal gland impair the production of melatonin by pineocytes and consequently induce a permanent melatonin deficiency in those patients. Since melatonin exerts multiple physiological functions, once a clinical concept of "melatonin deficiency syndrome" is established, melatonin replacement therapy could be investigated in patients who have a pineal germinoma or who have undergone a neurosurgical pinealectomy.

An association of hypothalamic hamartoma, central precocious puberty and juvenile granulosa cell tumour in early childhood.

A case of central precocious puberty from infancy due to a hypothalamic hamartoma and associated with an ovarian juvenile granulosa cell tumour is presented. Central precocious puberty was diagnosed by gonadotropin stimulation tests and LHRH agonist therapy was successful. A MR scan, but not a CT scan, demonstrated the hypothalamic hamartoma. The possible influence of early LH stimulation for the development of the granulosa cell tumour is discussed.

Serum leptin levels following hypothalamic surgery.

To study a potential alteration of hypothalamic centers involved in the negative feedback action of leptin on body weight, serum leptin levels were measured in relation to BMI in 18 patients following surgery for a hypothalamic craniopharyngioma (Ctx), and were compared to levels found in 21 patients operated for a pituitary adenoma (Ptx) or in healthy control subjects. All subjects with Ptx received rhGH replacement therapy (0.5 to 2 IU/m2/d), and serum leptin levels were followed in 3 months intervals over 24 months. Serum leptin levels in patients with Ptx were comparable to controls, whereas 7 of the 18 patients with Ctx had higher than expected concentrations for their BMI. GH treatment in Ptx subjects did not alter serum leptin levels. In 5 Ctx patients where preoperative samples were available, weight gain in parallel to an increase in serum leptin levels was observed but only minimal changes in 4 others. Our data support the role of leptin as an important marker of body weight. The rapid increase in serum leptin levels observed in some Ctx subjects suggests that early postoperative measurement of serum leptin levels may help to identify patients at risk of weight gain following hypothalamic destruction.

Adrenal failure due to metastasis both to the hypothalamic-pituitary area and the adrenals.

A 61-year-old white male was admitted to our hospital with a big-cell bronchogenic carcinoma whose first clinical manifestation was diabetes insipidus (DI) secondary to metastasis to the hypothalamic-pituitary area (MHP). In three months, and progressively, he developed anterior pituitary failure, as well as primary adrenal insufficiency (PAI) due to metastasis in both adrenals. Panhypopituitarism or PAI due to both MHP and adrenals has been rarely reported in the literature. A thorough examination of the oncologic patient led us to diagnose hormone insufficiency properly. The absence of reported cases might be due to the fact that the symptoms resulting from hormone insufficiency are veiled by the severe condition of the patients suffering from disseminated cancer.

Hypernatremic myopathy.

We describe a 21-year-old man presenting with proximal muscle weakness associated with hypernatremia. His manifestations other than muscle weakness included dry skin, loss of axillary and pubic hair, decreased libido and loss of thirst sensation. His serum sodium level was elevated to 169-171 mEq./l but all other electrolytes were normal. In addition, serum CK was elevated and an EMG study showed myogenic changes. Endocrinological studies revealed hypothalamic hypopituitarism, while MRI revealed a suprasellar mass. A partial correction of hypernatremia led to an immediate recovery of the muscle weakness as well as a normalization of both the serum CK level and EMG findings, suggesting a direct association between the muscle weakness and hypernatremia. The phosphocreatine/inorganic phosphorus (PCr/Pi) ratios in the resting calf muscle, obtained using 31P magnetic resonance spectroscopy (MRS), were very low during the state of muscle weakness, while they returned to nearly normal values after clinical improvement, suggesting that the muscle weakness in hypernatremic state was caused by a depletion of the intramuscular energy stores, probably due to an overworking Na-K pump to correct the intracellular electrolyte imbalance.

Hypothalamic hamartomas and precocious puberty.

Ten children, five boys and five girls with true precocious puberty at an early age were found to have hypothalamic hamartomas on brain imaging. Very early onset of puberty, varying from a few weeks to three years of age, and rapid progression were characteristic. Accelerated growth velocity and markedly advanced bone age were evident in all. Gonadotropin and gonadal hormone levels were elevated above the prepubertal range. Six children had associated developmental delay or hyperactivity.

Low bone mineral density in adults with previous hypothalamic-pituitary tumors: correlations with serum growth hormone responses to GH-releasing hormone, insulin-like growth factor I, and IGF binding protein 3.

The adverse consequences of growth hormone (GH) deficiency (GHD) on bone growth in children is well described. Whether adult GHD is associated with bone loss is unknown. We evaluated 14 patients with hypothalamic-pituitary tumors (HPT) acquired during adulthood (5 men, 9 women; mean age = 48.1 +/- 4.6 years; mean BMI = 28.8 +/- 1.7) and 14 age-, sex-, and weight-matched controls. Nine HPT patients were receiving gonadal steroid replacement therapy for a mean of 11 years. All subjects had basal IGF-I and IGFBP-3 levels prior to testing with GH-releasing hormone [1 microgram/kg IV bolus; responses expressed as maximum percentage increase above baseline (PERGH)]. Bone mineral density (BMD) of the spine, hip, and total body were measured by dual-energy X-ray absorptiometry. Mean BMD Z-scores of the HPT patients were significantly lower in the femoral neck, Ward's triangle, and trochanter than in controls (all P < 0.05). Mean total body BMD (g/cm2) was also lower in the patient group (1.04 +/- 0.03 versus 1.13 +/- 0.03, P < 0.05). For the subgroup of HPT patients receiving conventional gonadal steroids, mean BMD Z-scores of the lumbar spine also were significantly lower than controls (-1.84 +/- 0.43 versus -0.57 +/- 0.46, P < 0.05). PERGH and IGF-I were correlated with Z-scores of the femoral neck (r = 0.47, P < 0.01; r = 0.45, P < 0.01) and Ward's triangle (r = 0.47, P < 0.01; r = 0.41, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Hypothalamic hamartoma: the role of surgery.

A hypothalamic hamartoma associated with true precocious puberty in a 7-month-old girl is hereby reported. Hormonal studies disclosed elevated serum levels of luteinizing hormone (LH) and follicle stimulating hormone, both of which responded well to LH-releasing hormone stimulation. Following a subtotal removal of the tumor, the clinical manifestations of precocious puberty as well as associated endocrinological abnormalities returned to normal. The role of surgery for this lesion, which appears to be safe when a planned microsurgical course is employed, is discussed.

Radioimmunoassay of growth hormone-releasing hormone (GHRH) with a polyclonal antibody against synthetic GHRH(1-29)-Gly4-Cys-NH2: method and clinical studies.

A radioimmunoassay (RIA) for growth hormone-releasing hormone (GHRH) using a polyclonal antibody against synthetic GHRH(1-29)-Gly4-Cys-NH2 has been developed. The antiserum (RBM105) showed full cross-reactivity with GHRH-(1-44)NH2, GHRH-(1-40)OH, GHRH-(1-37)OH and GHRH-(3-44)NH2, and probably recognized the region of Ala4 to Lys12 of GHRH. Since the sensitivity of the GHRH RIA was 1.5 pg/tube, the lowest detectable plasma level was 5 ng/l when an extract of 0.3 ml of plasma per tube was used. On gelfiltration chromatography, the GHRH immunoreactivity of normal plasma was eluted in the same position as synthetic GHRH. The plasma GHRH concentration in healthy subjects was 20.5 +/- 6.5 ng/l (mean +/- SD), and in patients with hypothalamic disorders was 17.4 +/- 2.0 ng/l. In contrast, the plasma GHRH level in hemodialysis-dependent, chronic renal failure (CRF-HD) patients (38.7 +/- 13.1 ng/l) was significantly higher than normal. The acromegalic patients were 24.3 +/- 11.9 ng/l, except for one patient with ectopic GHRH syndrome (990 ng/l): his plasma GHRH level reached 7,100 ng/l during operation, and then decreased logarithmically to 70 ng/l after 6 h. Somatostatin at concentrations of 10 and 1,000 nmol/l significantly suppressed (GHRH release) from primary culture cells of the GHRH-producing tumor from 17.3 +/- 0.92 ng/2 x 10(5) cells to 9.98 +/- 3.61 and 4.32 +/- 1.01 ng/2 x 10(5) cells, respectively after 48 h. These data indicate that this GHRH RIA is useful for determining the plasma GHRH concentration in normal and diseased states and also for in vitro studies of GHRH release.

[Hypothalamic glioma with diencephalic syndrome and following precocious puberty--a case report].

A 1-year 11-month-old girl was admitted for losing her weight and gait disturbance. At 4 months of age, she began to become emaciated inspite of normal food intake. Physical and neurological examinations were normal except for a marked lack of subcutaneous fat, irritability and nystagmus. CT scans demonstrated a large tumor occupied in the third ventricle and marked dilatation of the lateral ventricles. Endocrinological studies revealed high levels of plasma growth hormone (GH) in contrast with normal levels of somatomedin-C. The basal value of GH returned to normal with a subnormal response to insulin subsequently after VP-shunt. Then, a pilocytic astrocytoma was partially resected with transcallosal approach. Postoperative course was uneventful and her growth rate returned to normal range. CT scans after radiation therapy of 49 Gy showed marked decrease in size of the tumor. At 3 years and 6 months of age, enlargement of her breast was pointed out although MRI indicated no enlargement of the tumor. Basal value of LH, FSH, E 1 and E 2 elevated and LHRH test showed over-response of LH and FSH. Other hypothalamic-pituitary functions were partially preserved. Case of precocious puberty following diencephalic syndrome associated to the hypothalamic and/or optochiasmatic glioma is quite rare in the previous literature. Mechanisms of diencephalic syndrome and following puberty are unclear. However, endocrinological and radiological findings observed in the present case suggest that hormonal disfunction might be due to the failure of inhibition on GH and LHRH secretion mechanism in the anterior hypothalamus.