Domenico Valle

Occurrence of Pituitary Dysfunction following Traumatic Brain Injury

Traumatic brain injury (TBI) may be associated with impairment of pituitary hormone secretion, which may contribute to long-term physical, cognitive, and psychological disability. We studied the occurrence and risk factors of pituitary dysfunction, including growth hormone deficiency (GHD) in 50 patients (mean age 37.6 +/- 2.4 years; 40 males, age 20-60 years; 10 females, age 23-87 years) with TBI over 5 years. Cranial or facial fractures were documented in 12 patients, and neurosurgery was performed in 14. According to the Glasgow Coma Scale (GCS), 16 patients had suffered from mild, 7 moderate, and 27 severe TBI. Glasgow Outcome Scale (GOS) indicated severe disability in 5, moderate disability in 11, and good recovery in 34 cases. Basal pituitary hormone evaluation, performed once at times variable from 12 to 64 months after TBI, showed hypogonadotrophic hypogonadism in 7 (14%), central hypothyroidism in 5 (10%), low prolactin (PRL) levels in 4 (8%), and high PRL levels in 4 (8%) cases. All subjects had normal corticotrophic and posterior pituitary function. Seven patients showed low insulin-like growth factor-I (IGF-I) levels for age and sex. Results of GHRH plus arginine testing indicated partial GHD in 10 (20%) and severe GHD in 4 (8%) cases. Patients with GHD were older (p <0.05) than patients with normal GH secretion. Magnetic resonance imaging demonstrated pituitary abnormalities in 2 patients; altogether pituitary dysfunction was observed in 27 (54%) patients. Six patients (12%) showed a combination of multiple abnormalities. Occurrence of pituitary dysfunction was 37.5%, 57.1%, and 59.3% in the patients with mild, moderate, and severe TBI, respectively. GCS scores were significantly (p <0.02) lower in patients with pituitary dysfunction compared to those with normal pituitary function (8.3 +/- 0.5 vs. 10.2 +/- 0.6). No relationship was detected between pituitary dysfunction and years since TBI, type of injury, and outcome from TBI. In conclusion, subjects with a history of TBI frequently develop pituitary dysfunction, especially GHD. Therefore, evaluation of pituitary hormone secretion, including GH, should be included in the long-term follow-up of all TBI patients so that adequate hormone replacement therapy may be administered.

Cut-off limits of the GH response to GHRH plus arginine test and IGF-I levels for the diagnosis of GH deficiency in late adolescents and young adults

OBJECTIVEnTo define the appropriate diagnostic cut-off limits for the GH response to GHRH+arginine (ARG) test and IGF-I levels, using receiver operating characteristics (ROC) curve analysis, in late adolescents and young adults.nnnDESIGN AND METHODSnWe studied 152 patients with childhood-onset organic hypothalamic-pituitary disease (85 males, age (mean+/-s.e.m.): 19.2+/-0.2 years) and 201 normal adolescents as controls (96 males, age: 20.7+/-0.2 years). Patients were divided into three subgroups on the basis of the number of the other pituitary hormone deficits, excluding GH deficiency (GHD): subgroup A consisted of 35 panhypopituitary patients (17 males, age: 21.2+/-0.4 years), subgroup B consisted of 18 patients with only one or with no more than two pituitary hormone deficits (7 males, age: 20.2+/-0.9 years); and subgroup C consisted of 99 patients without any known hormonal pituitary deficits (60 males, age: 18.2+/-0.2 years). Both patients and controls were lean (body mass index, BMI<25 kg/m(2)). Patients in subgroup A were assumed to be GHD, whereas in patients belonging to subgroups B and C the presence of GHD had to be verified.nnnRESULTSnFor the GHRH+ARG test, the best pair of highest sensitivity (Se; 100%) and specificity (Sp; 97%) was found choosing a peak GH of 19.0 microg/l. For IGF-I levels, the best pair of highest Se (96.6%) and Sp (74.6%) was found using a cut-off point of 160 microg/l (SDS: -1.3). Assuming 19.0 microg/l to be the cut-off point established for GHRH+ARG test, 72.2% of patients in subgroup B and 39.4% in subgroup C were defined as GHD. In patients belonging to group B and C and with a peak GH response <19 microg/l to the test, IGF-I levels were lower than 160 microg/l (or less than 1.3 SDS) in 68.7 and 41.6% of patients respectively predicting severe GHD in 85.7% of panhypopituitary patients (subgroup A).nnnCONCLUSIONSnIn late adolescent and early adulthood patients, a GH cut-off limit using the GHRH+ARG test lower than 19.0 microg/l is able to discriminate patients with a suspicion of GHD and does not vary from infancy to early adulthood.

Effect of opioid blockade on insulin and growth hormone (GH) secretion in patients with polycystic ovary syndrome: the heterogeneity of impaired GH secretion is related to both obesity and hyperinsulinism

OBJECTIVEnTo investigate the involvement of opioid tone, obesity, and hyperinsulinemia in GH secretion in women with polycystic ovary syndrome (PCOS).nnnDESIGNnControlled clinical study.nnnSETTINGnCatholic University of Sacred Heart School of Medicine in Rome, Italy.nnnPATIENT(S)nTwenty-two patients with PCOS and 14 healthy, normally ovulating volunteers, matched for age and body mass index.nnnINTERVENTION(S)nPatients underwent a GH-releasing hormone (GHRH) test and an oral glucose tolerance test before and after 4-5 weeks of treatment with 50 mg/d of naltrexone.nnnMAIN OUTCOME MEASURE(S)nSerum concentrations of GH, insulin, glucose, steroids, and gonadotropins, as well as the GH area under the curve (AUC-GH) and the insulin area under the curve (AUC-I), were measured before and after naltrexone treatment.nnnRESULT(S)nIn patients with PCOS, the administration of naltrexone increased the GH response to the GHRH test without interfering with the insulin response to the oral glucose tolerance test. However, the GH response to the GHRH test was improved significantly only in lean patients with PCOS, whereas obese patients with PCOS did not show any improvement in GH secretion. In obese control subjects, the treatment reduced plasma basal insulin concentrations and increased the AUC-GH, whereas in lean control subjects, the treatment reduced the GHRH-induced response. In normoinsulinemic patients with PCOS, the GH response to the GHRH test increased significantly after treatment, whereas the AUC-I was not affected. In hyperinsulinemic patients with PCOS, treatment with naltrexone significantly reduced the AUC-I, whereas the AUC-GH increased only in lean hyperinsulinemic patients with PCOS.nnnCONCLUSION(S)nNaltrexone treatment improves GHRH-induced GH secretion in patients with PCOS. However, this GH response is heterogeneously represented in relation to both obesity and hyperinsulinism.

Impact of long-term naltrexone treatment on growth hormone and insulin secretion in hyperandrogenic and normal obese patients

The growth hormone (GH) response to stimulation tests is impaired in obesity. Moreover, obese patients exhibit a paradoxical increase of GH to GH-releasing hormone (GHRH) stimulation after food ingestion; this paradoxical response is reversed by naloxone infusion. On the other hand, beta-endorphin seems to exert profound effects on insulin release. Recent studies also demonstrated an impairment of GH response to several stimuli in polycystic ovary syndrome (PCOS), a condition associated with obesity, hyperinsulinism, and insulin resistance. Chronic inhibition of opioid tone by the opioid antagonist naltrexone (NTX) is able to reduce the insulin response to an oral glucose tolerance test (OGTT) in hyperinsulinemic PCOS patients. Since insulin and GH may reciprocally influence their secretion and the opioid system may have a role in the pathogenesis of hyperinsulinemia and reduced GH secretion, we have explored the involvement of these neuroendocrine mechanisms in essential obesity and in obesity associated with hyperandrogenism by a long-term treatment with an opiate antagonist. We tested seven obese patients affected by PCOS, seven matched women with essential obesity (EO), and five non-obese control subjects. All patients, in the follicular phase, underwent an OGTT (75 g) and basal hormone assay. Two days later, patients were subjected to a GHRH test. The patients then had 4 weeks of treatment with NTX 50 mg/d. Following continuation of the treatment, OGTT and GHRH tests were repeated. Insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) plasma concentrations were also determined in the basal condition before and after NTX treatment. NTX treatment reduced fasting insulin levels in patients with EO (P < .05) and restored a normal GH response to GHRH without affecting IGF-1 and IGFBP-3 levels. In PCOS subjects, NTX reduced the insulin response to a glucose load and failed to modify the blunted GH response to GHRH. Our data suggest a significant difference in opioid system function in PCOS and EO subjects, indicating a particular form of obesity in PCOS. The opiate antagonist treatment in EO may act through the reduction of negative insulin feedback on GH secretion. In PCOS patients, the failure to improve GH secretion in obese hyperandrogenized patients may be related to a high opioidergic tone or to the inhibitory predominance of other neurotransmitters.

Physiological role of the opioid-cholinergic interaction in growth hormone neuroregulation: Effect of sex and food intake

Studies performed in animals and humans have suggested a functional interaction between opioid and cholinergic systems in the control of growth hormone (GH) secretion. Moreover, the sex-dependent modulation of GH secretion in humans is well established. To investigate the role of sex and food intake in the regulation of the reciprocal influences of opioids and acetylcholine in the modulation of GH secretion, we studied the GH response to pyridostigmine (PYR) alone and during a naloxone (NAL) infusion in a group of normal men and women before a meal (at 1:00 PM) and postprandially. In women, the response of GH to PYR alone before the meal was significantly lower than in the men (area under the curve [AUC], mean +/- SEM, 320.18 +/- 87.16 v 1,031.06 +/- 333.21 micrograms/L/90 min, P < .01). Before the meal, NAL completely abolished the response of GH to PYR in men (AUC, 1,031.06 +/- 333.21 v 16.50 +/- 7.50 micrograms/L/90 min, P < .01), whereas infusion of NAL did not significantly modify the GH response to PYR in women. Consumption of the meal significantly decreased PYR-induced GH release in both women (AUC, 21.75 +/- 12.75 v 320.18 +/- 87.16 micrograms/L/90 min, P < .05) and men (AUC, 45.75 +/- 18.75 v 1,031.06 +/- 333.21 micrograms/L/90 min, P < .01). Conversely, food intake did not change the effects of NAL infusion on the GH response to PYR either in women or in men. We conclude that the sex-dependent opioid modulation of PYR-induced GH secretion is observed before a meal but not in the postprandial state. Food intake may be hypothesized to influence the cholinergic regulation of GH secretion and the sex-dependent opioid modulation of central cholinergic tone.

Opioid dysregulation in anorexia nervosa: Naloxone effects on preprandial and postprandial growth hormone response to growth hormone-releasing hormone

Previously, we have shown that in the opposite extremes of nutritional status, obesity and anorexia nervosa (AN), growth hormone (GH) response to growth hormone-releasing hormone (GH-RH) is not inhibited by the ingestion of a normal 800-cal meal consumed at lunch time (1 PM), which is at variance with results in normal subjects. However, in obese patients the postprandial increase in GH response to GH-RH is inhibited by an infusion of naloxone (NAL). In this study we have tested anorectic patients, performing the following tests at 1 PM: GH-RH test (50 micrograms IV) or, in a different day session, NAL (1.6 mg/h, starting 30 minutes before GH-RH) + GH-RH test (50 micrograms IV). The tests were performed in the following three different experimental conditions: (1) short-term fasting studies (lasting from breakfast), (2) long-term fasting studies (from midnight of the day before) and (3) postprandial studies (after a standard meal consumed 1 hour before the test). In AN, the GH response to GH-RH was not influenced by NAL infusion at 1 PM, in both short- and long-term fasting studies (short-term fasting: peak values after GH-RH alone, 26.5 +/- 6.5 ng/mL, during NAL, 28.0 +/- 3.3 ng/mL; long-term fasting: peak values after GH-RH alone, 32.2 +/- 6.8 ng/mL, during NAL, 30.6 +/- 4.0 ng/mL). A partial NAL-inhibitory effect was instead observed in postprandial studies, as evidenced by the calculation of areas under the curve ([AUCs] 1,662.1 +/- 90.0 after GH-RH alone v 1,090.5 +/- 245.4 ng/mL/h during NAL).(ABSTRACT TRUNCATED AT 250 WORDS)

Characteristics of adult patients with growth hormone deficiency who underwent neurosurgery for functioning and non-functioning pituitary adenomas and craniopharyngiomas

The aim of the present study was to evaluate the characteristics of GH deficiency (GHD) in adult patients after neurosurgery for pituitary adenomas and craniopharingiomas. One hundred and one GHD patients, (42 F/59 M), aged 47.58±14.4 yr (mean±SD; range 21–78), body mass index (BMI) 28.6±0.6, with a history of adult-onset hypothalamic-pituitary disease, were recruited for the study. The whole group included: 45 non-functioning pituitary adenomas, 23 craniopharyngiomas, 16 PRLomas, 8 GHomas, 7 ACTHomas and 2 FSHomas; in particular 51 were macroadenomasand 27 microadenomas. At study entry, GHD diagnosis was carried out by assessing GH secretion after GHRH+arginine. All patients were submitted to the study at least 12 months after neurosurgery and, where needed, subjects were replaced with an appropriate treatment. GHD was mild in 3/101 (3%) and severe in 98/101 patients (97%). Other hormone deficiencies associated with GHD were considered: TSH, ACTH, FSH/LH, ADH. The distribution of peak GH among all patients, according to the type of disease before neurosurgery, showed that patients with Cushing disease were characterized by the presence of higher peak GH. According to the number of additional hormone deficits, the distribution of peak GH among all patients was as follows: GHD was isolated in 4/101 subjects (4%; group A), while it was associated with 1 (14/101, 14%; group B), 2 (22/101, 22%; group C), 3 (44/101, 43%; group D) and 4 hormone deficits (17/101, 16%; group E). GHD was severe in all patients in the panhypopituitaric group. Total IGF-I plasma levels in the whole group of GHD patients were 95.2±4.2 μg/l. In all groups of patients IGF-I was lower in subjects with severe GHD than in those with mild GHD (93.6±4.1 vs 148.6±33.6 μg/l, p<0.03). In particular, according to the type of disease presented before neurosurgery, patients with Cushing disease were characterized by the presence of higher IGF-I plasma levels compared to the other. According to the number of additional deficits, the distribution of IGF-I plasma levels was characterized by higher values when GHD was isolated than when it was associated with multiple hormone deficiencies. IGF-I plasma levels were positively associated to peak GH during GHRH+arginine (r=0.4, p<0.0005). We conclude that patients after neurosurgery approach for sellar and parasellar neoplasia, within an appropriate clinical context, and both the presence of additional pituitary hormone deficiency and low levels of IGF-I can be considered a clear GHD condition, and therefore do not require provocative tests evaluating GH secretion.

Pre- and postprandial pyridostigmine and oxiracetam effects on growth hormone secretion in anorexia nervosa

Previous studies have shown that food ingestion is not capable of inhibiting the GHRH-induced GH release in anorexia nervosa, at variance with what is observed in normal subjects. Moreover, a cholinergic alteration has been hypothesized in this disorder. In a group of 24 anorectic patients in a stabilized phase of the illness, we tested, before and after a standard meal, the GH response to GHRH alone and after pre-treatment with pyridostigmine, an inhibitor of acetylcholinesterase, and, on a different day, with oxiracetam, which stimulates the central cholinergic neurones. The GH response to GHRH was significantly increased by both drugs in a fasting state. The postprandial response was not significantly modified by pyridostigmine nor by oxiracetam. Neither of these compounds was able to enhance the postprandial GH paradoxical response to GHRH in anorectic patients. The lack of effect of both groups postprandially also suggests a suppression of somatostatinergic activity.

Influence of chronic Naltrexone treatment on growth hormone and insulin secretion in obese subjects.

OBJECTIVE: Recent studies have demonstrated the restoration of a normal 24u2005h GH profile induced by a reduction of insulinaemia after weight loss, suggesting a reciprocal relationship between plasma insulin and GH concentrations. We aimed to clarify if an opiate-induced reduction in plasma insulin could affect GH secretion in obesity. DESIGN: We have studied the insulin response to an oral glucose tolerance test (OGTT) and the GH response to GHRH before and after prolonged treatment with Naltrexone (NTX). C-peptide, IGF-I, IGFBP-3 plasma levels and the IGF-I/IGFBP-3 molar ratio were also determined. SUBJECTS: Twelve obese women (aged 25–41u2005y; Body mass index (BMI): 31–39u2005kg/m2) and six lean normal women (aged 25–38; BMI: 19.8–23.1u2005kg/m2). MEASUREMENT: GH was determined by the IRMA method; insulin, C-peptide, IGF-I and IGFBP-3 were assayed by the RIA method. For molar comparison between IGF-I and IGFBP-3 we have considered 30.5u2005kDa the molar weight of IGFBP-3. Results are expressed as mean±s.e.m. RESULTS: We observed a significant decrease in basal concentration of both insulin (230.1±34.9 vs 133.2±16.9u2005pmol/L; P<0.005) and C-peptide (3.7±0.3 vs 2.4±0.1u2005µg/L; P<0.02). No modifications in the insulin secretory response to the OGTT were observed. A significant increase of the GHRH-induced GH peak response (7.7±1.4 vs 19.7±3.1u2005µg/L; P<0.01) and GH-AUC (533±151 vs 1415±339u2005µg/L/120u2005min; P<0.01) was found after NTX treatment. A negative correlation was found between basal insulin and GH peak values, both before (r=−0.641, P=0.027) and after NTX (r=−0.714, P=0.013). No modifications were found in IGF-I, IGFBP-3 and IGF-I/IGFBP-3 molar ratio. Moreover, NTX affected neither the insulin response to OGTT or IGF-I, IGFBP-3 and IGF-I/IGFBP-3 molar ratio in a group of six lean controls. Conversely, NTX significantly reduced the GH response to GHRH, when expressed as both peak and AUC values. CONCLUSIONS: The opiate antagonist significantly reduced basal insulin concentrations and augmented the GH response to GHRH in obese subjects. In the absence of modifications in IGF-I and IGFBP-3 plasma levels and their molar ratio, we propose that insulin may exert a negative feedback on GH secretion.

Growth Hormone (GH) Releasing Hormone- and Thyrotropin Releasing Hormone-Induced GH Release in the Acute Phase of Trauma

A great number of metabolic and hormonal derangements have been described in traumatized patients. Plasma concentrations of many substrates, enzymes, and metabolites rise and/or fall, and indices of organ and tissue function change without unequivocal overall patterns. Endocrine variations can mediate a lot of these metabolic pathway dysfunctions; in general two different secretory patterns can be seen in anterior pituitary hormones: an increase of adrenocorticotropic hormone (ACTH), prolactin (PRL), and growth hormone (GH) and a decrease of other hormones [thyroid stimulating hormone (TSH), luteinizing hormone (LH), follicle stimulating hormone (FSH)]. Neurohypophysial hormones can be involved depending on the kind of trauma. Catecholamines, insulin, and glucagon levels also change, and are of fundamental importance in the regulation of intermediate metabolism in such patients.