Antibodies Against Hypothalamus and Pituitary Gland in Childhood-Onset Brain Tumors and Pituitary Dysfunction.

Purpose: To detect the presence of antipituitary (APA) and antihypothalamus antibodies (AHA) in subjects treated for brain cancers, and to evaluate their potential association with pituitary dysfunction. Methods: We evaluated 63 patients with craniopharyngioma, glioma, and germinoma treated with surgery and/or radiotherapy and/or chemotherapy at a median age of 13 years. Forty-one had multiple pituitary hormone deficiencies (MPHD), six had a single pituitary defect. GH was the most common defect (65.1%), followed by AVP (61.9%), TSH (57.1%), ACTH (49.2%), and gonadotropin (38.1%). APA and AHA were evaluated by simple indirect immunofluorescence method indirect immunofluorescence in patients and in 50 healthy controls. Results: Circulating APA and/or AHA were found in 31 subjects (49.2%) and in none of the healthy controls. In particular, 25 subjects out of 31 were APA (80.6%), 26 were AHA (83.90%), and 20 were both APA and AHA (64.5%). Nine patients APA and/or AHA have craniopharyngioma (29%), seven (22.6%) have glioma, and 15 (48.4%) have germinoma. Patients with craniopharyngioma were positive for at least one antibody in 39.1% compared to 33.3% of patients with glioma and to 78.9% of those with germinoma with an analogous distribution for APA and AHA between the three tumors. The presence of APA or AHA and of both APA and AHA was significantly increased in patients with germinoma. The presence of APA (P = 0.001) and their titers (P = 0.001) was significantly associated with the type of tumor in the following order: germinomas, craniopharyngiomas, and gliomas; an analogous distribution was observed for the presence of AHA (P = 0.002) and their titers (P = 0.012). In addition, we found a significant association between radiotherapy and APA (P = 0.03). Conclusions: Brain tumors especially germinoma are associated with the development of hypothalamic-pituitary antibodies and pituitary defects. The correct interpretation of APA/AHA antibodies is essential to avoid a misdiagnosis of an autoimmune infundibulo-neurohypophysitis or pituitary hypophysitis in patients with germinoma.

Surgical-pharmacological interactions in the treatment of acromegaly.

INTRODUCTION: Acromegaly requires a multimodal treatment approach that includes surgery by an expert pituitary neurosurgeon, pharmacological treatment with one or more of the available drugs and radiation therapy. These treatment alternatives are not mutually exclusive but rather complement each other when properly indicated in the individual patient. In this review, we summarize and analyze the available data concerning the choice of the surgical approach (microscopy vs. endoscopy) and the interactions between medical treatment with somatostatin analogs and pituitary surgery. AREAS COVERED: Technical aspects, complications and outcome of transsphenoidal surgery (TSS); Advantages and disadvantages of the microscopic and endoscopic approaches; Safety and efficacy of somatostatin analogs (SSA); Primary pharmacological therapy versus primary TSS; Benefits of the preoperative treatment with SSA; and the effect of surgical tumor debulking in the therapeutic response to SSA. EXPERT COMMENTARY: Continuing efforts at improving surgical techniques and at generating more efficacious pharmacological therapies for acromegaly are likely to improve the outcome of these patients. However, an integral approach of the patient aimed not only at achieving biochemical criteria of cure but also at treating the individual comorbidities is mandatory to improve the quality of life of these patients and to reduce their mortality rate.

Nutritional and endocrinologic evaluation of patients with craniopharyngioma.

BACKGROUND & AIMS: Lesions of hypothalamus or adjacent brain structures by the craniopharyngioma (CP) and/or its treatment, as well as changes in orexigenic and anorexigenic hormones, are possible pathogenic factors for the obesity observed in CP patients. This study assessed anthropometric measurements, food intake, and biochemical markers of CP patients. METHODS: Weight, height, skinfold thicknesses, circumferences, body composition, food intake evaluation, basal glucose, lipids, insulin, ghrelin, PYY, and HOMA-IR calculation were obtained from CP children (n = 10, 4F, aged 12 ± 4.2yr) and CP adults (n = 27,13F aged 42 ± 13 yr) and from 32 gender and age matched controls. RESULTS: Overweight/obesity was observed in 51.4% of the patients at the diagnosis and increased to 86.5% at the time of the study. Obesity was more frequent in patients with grade 2 hypothalamic involvement. Most anthropometric measurements were similar in patients and controls. Caloric intake was lower in CP adults, without difference between children. Lipid intake was higher in CP patients. Carbohydrate and protein intakes were lower in CP children, with no difference between adult groups. There were no differences in micronutrients intake as well as in insulin and PYY levels, and HOMA-IR between patients and controls. HDL-c was lower in CP adults and ghrelin higher in CP children. CONCLUSIONS: There is a high rate of overweight/obesity in CP patients at the diagnosis and throughout the follow-up period. Obesity was associated with degree of hypothalamic involvement but not with caloric intake. Obesity and a lipid rich diet may have contributed to the dyslipidemia observed in CP patients.

Delayed ghrelin suppression following oral glucose tolerance test in children and adolescents with hypothalamic injury secondary to craniopharyngioma compared with obese controls.

Ghrelin, released from the stomach, acts at the hypothalamus and is associated with initiation of food intake. We hypothesised that patients with craniopharyngioma and hypothalamic obesity (CRHO) would have ghrelin abnormalities. Fifteen CRHO patients and 15 BMI-matched controls underwent oral glucose tolerance test with dynamic ghrelin measurement. From 0-30 minutes, ghrelin (pg/ml) decreased less (43.4 ? 38.8 vs. 70.8 ? 35.8, p < 0.05) and insulin (pmol/l) increased more (1 669.2 ? 861.7 vs. 1 049.1 ? 560.4, p = 0.04) in CRHO compared with controls, respectively. Insulin area-under-the-curve was a weak negative predictor of the 0?30 minutes ghrelin decrease (r(2) = 0.29, p = 0.02). Delayed ghrelin suppression may contribute to obesity in CRHO.

Hypothalamic involvement predicts cardiovascular risk in adults with childhood onset craniopharyngioma on long-term GH therapy.

CONTEXT: Craniopharyngioma patients without GH therapy are at an increased cardiovascular disease (CVD) risk and particularly concerning women. No previous study on long-term GH therapy in adults with childhood onset (CO) craniopharyngioma was identified. OBJECTIVE: To investigate CVD risk in adults with CO craniopharyngioma on complete hormone replacement, including long-term GH therapy, and to investigate the impact of disease-related factors on CVD risk. DESIGN AND PARTICIPANTS: In a cross-sectional study of operated CO craniopharyngiomas (1958-2000) from a defined area of Sweden (2.5 million), we enrolled 42 patients (20 women) with a median age of 28 years (range 17-57) and assessed CVD risk of 20 (4-40) years after first operation. Comparisons were made with matched controls and between patients with tumor growth into the third ventricle (TGTV) versus non-TGTV. GH therapy was 10-12 years in women and men. Results In comparison with controls, both male and female patients had increased body mass index, fat mass, insulin, and leptin levels. Overall, while not significantly increased in male patients, 55-60% of female patients had a medium-high CVD risk, compared with 10-20% in controls. An increased CVD risk (all P<0.05) and higher levels of fat mass and insulin were recorded in the TGTV group versus the non-TGTV group. Late puberty induction and lack of androgens were shown in female patients. CONCLUSIONS: Adult patients with CO craniopharyngioma, especially those with TGTV, have persistently increased CVD risk. Conventional hormone substitution, including GH, is insufficient to normalize CVD risk, suggesting an important role for irreversible hypothalamic dysfunction.

Curcumin (diferuloylmethane) inhibits cell proliferation, induces apoptosis, and decreases hormone levels and secretion in pituitary tumor cells.

Prolactinomas are the most prevalent functional pituitary adenomas. Dopamine D2 receptor (D2R) agonists, such as bromocriptine are the first line of therapy; however, drug intolerance/resistance to D2R agonists exists. Apart from D2R agonists, there is no established medical therapy for prolactinomas; therefore, identifying novel therapeutics is warranted. Curcumin, a commonly used food additive in South Asian cooking, inhibits proliferation of several tumor cell lines; however, its effect on pituitary tumor cell proliferation has not been determined. Our objectives were to: 1) determine whether curcumin inhibits proliferation of pituitary tumor cell lines; 2) identify the signaling intermediaries that mediate the effect of curcumin; 3) examine whether curcumin inhibited pituitary hormone production and release; and 4) examine whether curcumin could enhance the growth-inhibitory effect of bromocriptine. Using rat lactotroph cell lines, GH3 and MMQ cells, we report that curcumin had a robust dose and time-dependent inhibitory effect on GH3 and MMQ cell proliferation. Inhibitory effects of curcumin persisted, even on removal of curcumin, and curcumin also blocked colony formation ability of pituitary tumor cells. The growth-inhibitory effect of curcumin was accompanied by decreased expression of cyclin D3 and ser 780 phosphorylation of retinoblastoma protein. In addition, curcumin also induced apoptosis in both GH3 and MMQ cells. Furthermore, curcumin suppresses intracellular levels and release of both prolactin and GH. Finally, we show that low concentrations of curcumin enhanced the growth-inhibitory effect of bromocriptine on MMQ cell proliferation. Taken together we demonstrate that curcumin inhibits pituitary tumor cell proliferation, induces apoptosis, and decreases hormone production and release, and thus, we propose developing curcumin as a novel therapeutic tool in the management of prolactinomas.

Fasting and postprandial hyperghrelinemia in Prader-Willi syndrome is partially explained by hypoinsulinemia, and is not due to peptide YY3-36 deficiency or seen in hypothalamic obesity due to craniopharyngioma.

The cause of the unique elevation in fasting plasma levels of the orexigenic gastric hormone ghrelin in many patients with Prader-Willi syndrome (PWS) is unclear. We measured fasting and postprandial plasma ghrelin in nonobese (n = 16 fasting and n = 8 postprandial) and obese non-PWS adults (n = 16 and 9), adults with genetically confirmed PWS (n = 26 and 10), and patients with hypothalamic obesity from craniopharyngioma tumors (n = 9 and 6). We show that 1) plasma ghrelin levels decline normally after food consumption in PWS, but there is still fasting and postprandial hyperghrelinemia relative to the patient's obesity (2.0-fold higher fasting ghrelin, 1.8-fold higher postprandial ghrelin, adjusting for percentage of body fat); 2) the fasting and postprandial hyperghrelinemia in PWS appears to be at least partially, but possibly not solely, explained by the concurrent relative hypoinsulinemia and preserved insulin sensitivity for the patient's obesity (residual 1.3- to 1.6-fold higher fasting ghrelin, 1.2- to 1.5-fold higher postprandial ghrelin in PWS, adjusting for insulin levels or homeostasis model assessment of insulin resistance); 3) hyperghrelinemia and hypoinsulinemia are not found in craniopharyngioma patients with hypothalamic obesity, and indeed, these patients have relative hyperinsulinemia for their obesity; and 4) there is no deficiency of the anorexigenic intestinal hormone peptide YY(3-36) in PWS contributing to their hyperghrelinemia.

Evaluation of the optimum dose of growth hormone (GH) for restoring bone mass in adult-onset GH deficiency: results from two 12-month randomized studies.

OBJECTIVE: To establish the optimum GH dose for restoring bone mineral density (BMD) in adult-onset GH deficiency (GHDA). DESIGN: Two separate randomized, controlled clinical trials. PATIENTS: Fifty-eight adults aged 45.1 (20-64) years with severe GHDA were followed in two 12-month studies. In the first study, patients were randomized to placebo or GH 1.7 IU/m2/day and in the second study GH 0.5 IU/m2/day or 1.0 IU/m2/day. MEASUREMENTS: BMD of the spine, hip, forearm and whole body was measured at 0 and 12 months. Alkaline phosphatase (AP) and collagen markers serum C-terminal propeptide of type I collagen (PICP), type I collagen telopeptide (ICTP) and N-terminal propeptide of type III collagen (PIIINP) were measured at baseline and every 3 months. RESULTS: Biochemical markers of skeletal and soft tissue collagen increased significantly and remained elevated throughout the study period. BMD changes depended on site, dose and gender. In placebo-treated patients, spinal BMD declined by 2.5%. At the low and medium doses, BMD increased by 2.4 and 3.1%, respectively, while a nonsignificant 0.2% decrease was seen with high dose. Forearm BMD decreased by 4.9% (P < 0.05) with high-dose treatment but remained unchanged at lower doses. Males showed larger gains in BMD, but the dose-response relationship was similar in males and females. CONCLUSION: A GH dose of 0.5-1.0 IU/m2/day (4-9 micro g/kg/day) stimulated bone remodelling and increased BMD over 12 months in patients with severe GHDA, irrespective of gender. A higher dose (1.7 IU/m2/day congruent with 15 micro g/kg/day) was associated with initial declines in forearm and whole-body BMD.

Effect of risperidone on prolactinoma growth in a psychotic woman.

OBJECTIVE: The case of a psychotic woman is described in which risperidone use was found to correspond with an increase in the size of a prolactinoma and prevented the return of serum prolactin level to baseline. METHODS: Although the patient had been treated with a high dose of bromocriptine, her prolactin level remained elevated, causing persistent galactorrhea. The patient later was treated with olanzapine and carbamazepine successfully. RESULTS: This case report highlights the role of risperidone on prolactin and discusses alternative methods of treating psychosis when the etiology is unclear, especially in younger patients. CONCLUSIONS: The authors recommend that additional studies regarding the relationship between the growth of prolactinoma and atypical antipsychotics would be worthwhile.

Establishment of reference values for endocrine tests. II: Hyperprolactinemia.

BACKGROUND: In patients with hyperprolactinemia, the thyrotropin-releasing hormone (TRH) stimulation test is widely applied to distinguish prolactinoma from other causes of hyperprolactinemia. In the present study, we established reference values for the plasma concentration of prolactin (PRL) and its response to TRH. METHODS: Basal PRL and the PRL response to 400 micrograms TRH i.v. was determined in 50 subjects recruited from the general population, equally distributed according to sex and age between 20 and 69 years. PRL was determined by a fluoroimmunometric assay. Reference values are given as the observed range. RESULTS: Plasma concentrations of PRL were 4.0-25 micrograms/l (median: 10.0 micrograms/l) in women and 0.5-19.0 micrograms/l (median: 8.5 micrograms/l) in men (p = 0.11). The peak PRL concentration after stimulation with TRH was slightly higher in women (median: 51 micrograms/l) than in men (median: 41 micrograms/l; p = 0.04) and was reached at t = 20 min in all subjects. The relative increase in plasma PRL (median: 440%) did not show a statistically significant effect of age or sex. In 12 subjects (24%), the relative increase in plasma PRL was lower than 250%, which has traditionally been considered the minimum cutoff for a normal response. There were no effects of smoking and alcohol, but regular ingestion of liquorice was associated with lower basal (p = 0.03) and lower stimulated (p = 0.05) plasma concentrations of PRL. CONCLUSIONS: The present study provides reference values for basal and TRH-stimulated plasma concentrations of PRL.

[Influence of radiotherapy and chemotherapy on the function of malignant tumor patients and regulation function of acupuncture].

The observation on the indexes of cortisol, estradiol, estriol and testosterone showed that incretory function of malignant tumor patients had different extent of pathologic changes, after radiotherapy and chemotherapy, making the change strengthened. Acupuncture can regularize this disorder of incretory function of patients treated with radiotherapy and chemotherapy to some extent.

Immunoreactive dynorphin A-like material in extracted human hypothalamic-hypophysial plasma.

Immunoreactive dynorphin A-like material (ir-dyn A) in human plasma was measured by a validated radioimmunoassay. In peripheral plasma extracts mean concentrations between 20 and 40 fmol/ml were determined in volunteers and in patients with pituitary adenomas. In this latter group superimposable levels were detected three days before and during transsphenoidal microsurgery. Interestingly, ir-dyn A levels evaluated in extracts of hypothalamic-hypophysial plasma obtained during surgery, just after tumor removal, were 4-5 times higher than in peripheral plasma. Reverse-phase high performance liquid chromatography (rp-HPLC) of extracts of peripheral plasma samples revealed two immunoreactive peaks. The major form had the same retention time of dyn A-(1-32); whereas a second, more lipophilic, peak eluted later and was not further characterized. In contrast, rp-HPLC analysis of extracts of plasma collected from the suprapituitary region displayed only one peak eluting in the position of synthetic dyn A-(1-17). The presence of dyn-related peptides in hypothalamic-hypophysial plasma supports the hypothesis that they may play a part in the regulation of hypothalamic and/or pituitary functions in humans.

Prolactinoma: avaliaçäo da eficácia dos métodos complementares para seu diagnóstico e da terapia com bromocriptina / Prolactinoma: effectiveness of the diagnostic methods and bromocriptine therapy

Os objetivos do presente trabalho foram de analisar os aspectos clínicos, radiológicos e laboratoriais do prolactinoma diagnosticado em 15 mulheres e correlacioná-los com a terapia com bromocriptina (BRC). Todas pacientes tinham PRL 50ng/ml sendo sete com microprolactinoma (Grupo I) e oito com macroprolactinoma (Grupo II). A queixa mais freqüente foi distúrbio menstrual (100 por cento) sendo a galactorréia presente em 60 por cento. Os sintomas e sinais independeram dos níveis de PRL. Estes foram superiores a 200ng/ml em cinco das pacientes do Grupo I e em apenas dois do Grupo II. A tomografia computadorizada foi efetiva para o diagnóstico dos tumores e o teste do TRH mostrou-se bastante sensível e até mesmo precedeu, em alguns casos, as alteraçöes radiológicas encontradas posteriormente. A BRC mostrou-se efetiva no tratamento tanto dos micro quanto dos macroprolactinomas, havendo melhora clínica, radiológica e laboratorial após seu uso.

A patient with a prolactinoma associated with an aldosterone producing adrenal adenoma: differences in dopaminergic regulation of PRL and aldosterone secretion.

A patient with a rare combination of prolactinoma and aldosterone producing adrenal adenoma (APA) was reported in relation to studies concerning dopaminergic regulation of PRL and aldosterone secretion. The patient is a 38-year-old female with plasma PRL and aldosterone concentrations (PAC) of 563 ng/ml and 54 ng/dl, respectively. A bolus of 10 mg of metoclopramide significantly increased plasma PRL in 6 normal subjects and in 4 patients with APA, whereas the responses were blunted in 7 patients with prolactinoma and in our patient. The response of aldosterone to metoclopramide was less than that of PRL, but similar in all studied subjects, indicating that the dopaminergic inhibition of aldosterone secretion is less than that of PRL in normal subjects and did not change in patients with APA or prolactinoma. Oral administration of 2.5 mg of bromocriptine suppressed plasma PRL significantly in all the subjects studied, but did not produce any consistent changes in PAC. Discrepancies in the response of PRL and aldosterone to metoclopramide and to bromocriptine suggest a difference in the dopaminergic regulation of PRL and aldosterone secretion in both normal subjects and patients with prolactinoma and APA. It is unlikely that reduced dopaminergic inhibition is the basis for hypersecretion of PRL and aldosterone in our patient.

Salmon calcitonin induces pituitary tumor in rats.

Calcitonin is widely used in the treatment of post-menopausal osteoporosis. The present study was designed to investigate the effects of salmon calcitonin (SCT) on the incidence of the pituitary tumors in Sprague-Dawley (SD) rats. Subcutaneous injections of SCT at a dose of 160 IU/kg/day for 6 months reduced body weight and induced one pituitary hyperplasia and three pituitary adenomas in 4 of 5 animals, while 5 controls did not show any changes. Prolactin-positive cells were located at the periphery of the affected pituitaries adjacent to the prolactin-negative adenomas. In addition, serum concentrations of prolactin and TSH were lower than in the controls, although serum calcium or LH levels were not significantly different from the controls. Among 7 animals treated with SCT for 6 months followed by no medication for another 6 months, 5 adenomas were detected, one of which had invasive growth toward the adjacent tissue, whereas only one adenoma was found in 9 controls. These results suggest that SCT administration at a high dose may induce the formation of pituitary adenoma, or may accelerate the development of spontaneous pituitary adenomas, some of which show frequent mitotic figures and invasive growth into the surrounding tissue, possibly resulting in malignant transformation. This indicates the need for caution in considering whether calcitonin injections into patients with osteoporosis as well as Paget's disease may induce such pituitary tumors.

Hypogonadism of male prolactinomas: relation to pulsatile secretion of LH.

In order to investigate whether a hypothalamic disorder cause hypogonadism in male prolactinomas, LH pulsatile secretion was studied in 13 male patients. Serum PRL levels ranged from 186 to 45,000 ng ml-1 before treatment, and all the tumors were macroadenomas. Reduced LH secretion was revealed in 5 of 13 patients, and FSH was reduced in 1 of 13. Serum testosterone (T) levels were lower than the normal limit in all the patients. HCG tests in 3 patients showed good responses, but the peak values of T were lower than those of normal men. LH pulsatilities were examined in 5 hyperprolactinemic patients before treatment, in 4 hyperprolactinemic patients after operation, and in 8 normoprolactinemic patients after operation and/or bromocriptine treatment. There was no significant difference of the mean LH values, the frequencies of LH pulses, and amplitudes among the hyperprolactinemic patients before operation (n = 5), the normoprolactinemic patients after operation (n = 8), and normal men (n = 7). From these results, it was evident that the hypothalamus and pituitary function of male prolactinomas were well preserved, in spite of higher serum PRL levels and larger tumor size than those reported in females. It is suggested that the main cause of hypogonadism in these patients is due to testicular dysfunction resulting from excessive serum PRL.

Selenium concentrations in serum of patients with cerebral and extracerebral tumors.

The concentrations of serum selenium were measured by atomic absorption spectrophotometry in 139 patients with tumors in cranium cavity. The data from patients were compared with those from a reference group of 294 healthy adult individuals. The serum concentrations of selenium is significantly decreased (p less than 0.001) in patients with malignant tumors. The authors discuss the possibilities for treatment of malignant tumours of central nervous system with selenium.

Plasma pituitary hormone responses to the synthetic enkephalin analog (FK 33-824) in normal subjects and patients with pituitary diseases.

D-Ala, Mephe, Met, enkephalin (Sandoz FK 33-824) is a stable long acting analog of methionine-enkephalin. FK 33-824 (0.5 or 1.0 mg), elicited plasma GH and PRL responses in normal subjects. In 23 patients with pituitary dwarfism, the response of plasma GH was markedly impaired, while PRL responded to a variable degree. In patients with acromegaly, there was little or no increase in GH and PRL after FK 33-824. Plasma GH increased to a variable degree after FK 33-824 in patients with hyperprolactinemia, with little change in plasma PRL. FK 33-824 decreased plasma cortisol in normal subjects and patients with pituitary disease. These results show that patients with acromegaly and hyperprolactinemia due to pituitary adenomas and patients with pituitary dwarfism do not respond well to FK 33-824, presumably because of hypothalamic or pituitary derangement.