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Felipe F Casanueva

The diagnosis of GH deficiency, either in children or in adults, can be a cumbersome task (1, 2). For someone unfamiliar with the field, it might seem a strange assertion, considering the amount of new knowledge and the insight arising from worldwide research on GH regulation. When dealing with patients grouped by aetiology, the task is easier and the GH provocative tests are clear-cut. But, clinicians do not deal with groups and we must make individual diagnoses and treatments, and this is where the problem resides. When studying a patient with suspected GH deficiency, there are two categories in which it is easy to classify him, i.e. healthy or with clear-cut GH deficiency, categories in which biochemical tests match clinical suspicion very well. There is a third and larger category, however, in which neither clinical data nor biochemical tests are of definitive help, and one becomes aware that most of

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Felipe F. Casanueva, William L. Gordon, and Henry G. Friesen

Abstract. The use of the rat as an animal model in studies of pituitary tumours has been hampered by the great individual variation and the necessity of killing the animal to assess the development and progression of tumour growth. A study was designed to determine whether computed tomography (CT) could be used to monitor the growth of pituitary tumours in female Sprague-Dawley rats. Animals were injected with oestradiol valerate 2 mg/3 weeks sc, an amount known to lead to development of pituitary tumours (from 45 to 378 mg pituitary weight). Control rats were treated with vehicle alone.

Anaesthetized rats injected with contrast were studied by computerized axial tomography and the single CT scans (coronal cuts) were correlated with direct anatomical measurements obtained after pituitary dissection. All pituitaries weighing more than 54 mg were detected by the CT scanner. A good correlation between measurements made after anatomical dissection was found in the two main axes of the coronal cuts.

In conclusion, CT scanning can be used for assessment of pituitary tumour size in the rat. This technique should be especially helpful in studies where individual evaluation and/or repeated measurements over time are necessary.

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Ignacio Bernabeu, Jose Cameselle-Teijeiro, Felipe F Casanueva, and Monica Marazuela

We report on a patient with active acromegaly and Gilbert's syndrome who developed severe hepatic dysfunction during pegvisomant (PEGv) monotherapy. She was partially resistant to all previous therapies, including long-acting somatostatin analogs and cabergoline. Five months after starting PEGv therapy, with an already normalized IGF1, she developed cholestatic liver dysfunction with jaundice. Liver or biliary diseases including biliary sludge, cholelithiasis or liver steatosis were excluded. A liver biopsy was in keeping with drug-induced liver injury. The discontinuation of PEGv was followed by full clinical and biochemical recovery in 6 weeks. PEGv therapy was not resumed. Apart from a minimal increase of bilirubin levels, no liver function test abnormalities were found during the 4-year follow-up period after the PEGv was discontinued. Drug-induced liver injury is the most serious systemic adverse event resulting from PEGv therapy. Since patients with mild and asymptomatic liver disease could be at a higher risk of PEGv-induced hepatotoxicity, frequent monitoring of hepatic enzymes should be required in these cases.

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R. Betti, F. F. Casanueva, S. G. Cella, and E. E. Müller

Abstract. In unanaesthetized dogs iv administration of the cholinesterase inhibitor eserine (0.5 mg) induced a clear-cut rise in plasma canine growth hormone (cGH) levels. Diphenhydramine and meclastine, two antagonists of histamine (H) H1 receptors completely suppressed the GH-releasing effect of eserine, while cimetidine, an H2 receptor antagonist, only blunted and delayed it. Two long-lasting serotonin (5-HT) receptor antagonists, metergoline and pizotifen, partially or completely suppressed, respectively, GH release evoked by eserine, whereas fenfluramine, a releaser of neuronal stores of 5-HT and hence a functional activator of 5-HT neurotransmission, was ineffective in this context. Pimozide, a long-acting dopamine receptor antagonist, abolished the effect of eserine, whereas domperidone, which has the same pharmacological properties but does not cross the blood brain barrier, failed to do so. Finally, phentolamine, an antagonist of α-adrenoceptors, and propranolol, a β-adrenergic antagonist, were completely ineffective in preventing the rise in plasma cGH levels induced by eserine, as was naloxone, an antagonist of opiate receptors. All these data demonstrate that, although cholinergic mechanisms are involved in the mechanism(s) underlying cGH release, the final common pathway for GH secretion is not cholinergic. Preservation of dopaminergic and H1 neurotransmission, probably within the blood barrier, is needed to allow the neuroendocrine transduction of cholinergic inputs, whereas the role of 5-HT neurotransmission remains uncertain.

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Felipe F. Casanueva, Roberto Betti, Silvano G. Cella, Eugenio E. Müller, and Paolo Mantegazza

Abstract. In unanaesthetized dogs iv administration of the cholinesterase inhibitor eserine (0.5 mg) or the cholinergic muscarinic receptor agonist oxotremorine (0.25 mg) induced a clear-cut rise in plasma canine growth hormone (cGH) levels. Complete suppression of the GH-releasing effect of eserine and oxotremorine was induced by blockade of cholinergic muscarinic receptors by atropine (80 or 20 μg/kg, 30 min before) but not by scopolamine-N-butyl bromide (0.8 mg/dog, 30 min before), an anticholinergic drug which does not cross the blood brain barrier (BBB). In contrast, activation of cholinergic nicotinic receptors by nicotine (6 mg) failed to alter resting cGH concentrations, and pre-treatment with the nicotinic receptor blocker mecamylamine (5 mg, 30 min before) did not counteract the GH-releasing effect of eserine. Other cholinomimetic drugs, e.g. pilocarpine, 4-aminopyridine, carbachol and bethanechol failed to induce a rise in plasma cGH concentrations. These data indicate that: 1) cholinergic muscarinic but not nicotinic receptors located in the central nervous system (CNS) inside the BBB play a facilitatory role in tonic cGH release; 2) pharmacologically distinct muscarinic receptors may exist in the CNS.

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Jaime Pineda, Pedro Martul, Felipe F Casanueva, Carlos Dieguez, Itxaso Rica, and Liliane Loridan

Pineda J, Martul P, Casanueva FF, Dieguez C, Rica I, Loridan L. Oral dexamethasone administration: new pharmacological test for the assessment of growth hormone secretion. Eur J Endocrinol 1994;131:598–601. ISSN 0804–4643

Acute intravenous (iv) dexamethasone administration has been described recently as a new test for the diagnosis of growth hormone (GH) deficiency. In the present study, a new protocol of dexamethasone administration was evaluated. Twelve normal adults and 18 normal prepubertal children were studied. The dexamethasone iv test was performed in six adults at a dose of 4 mg and 12 children at a dose of 2 mg/m2. Blood samples were collected 15 min before, at time zero and every 15 or 30 min during 5 h, resulting in a total of 16 samples. In the remaining six adults and six children, 8 and 4 mg, respectively, of dexamethasone were administered orally at the subject's home, and blood sampling started 90 min later when they arrived at the hospital. Plasma GH was measured by radioimmunassay. The dexamethasone-induced GH response (mean ± sem, μg/1) to the iv or oral protocol did not differ in either the adults (iv 8.2 ± 2.1; oral 8.0 ± 1.6) or the children (iv 14.9 ± 1.3; oral 13.6 ± 1.8). It is concluded that the simpler protocol of acute oral dexamethasone administration hereby presented can be a safe and suitable test of GH secretion.

J Pineda, Sección de Endocrinologia Pediátrica, Hospital de Cruces, 48903 Baracaldo (Vizcaya), Spain

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F Cordido, P Alvarez-Castro, ML Isidro, FF Casanueva, and C Dieguez

OBJECTIVE: It has been gradually realized that GH may have important physiological functions in adult humans. The biochemical diagnosis of adult GHD is established by provocative testing of GH secretion. The insulin-tolerance test (ITT) is the best validated. The ITT has been challenged because of its low degree of reproducibility and lack of normal range, and is contra-indicated in common clinical situations. Furthermore, in severely obese subjects the response to the ITT frequently overlaps with those found in non-obese adult patients with GHD. DESIGN: The aim of the present study was to evaluate the diagnostic capability of four different stimuli of GH secretion: ITT, GHRH, GHRH plus acipimox (GHRH+Ac), and GHRH plus GHRP-6 (GHRH+GHRP-6), in two pathophysiological situations: hypopituitarism and obesity, and normal subjects. METHODS: Eight adults with hypopituitarism (four female, four male) aged 41-62 Years (48.8+/-1.4 Years), ten obese normal patients (five female, five male) aged 38-62 Years (48.1+/-2.5 Years), with a body mass index of 34.2+/-1.2 kg/m(2), and ten normal subjects (five female, five male) aged 33-62 Years (48.1+/-2.8 Years) were studied. Four tests were performed on each patient or normal subject: An ITT (0.1 U/kg, 0.15 U/kg for obese, i.v., 0 min), GHRH (100 microg, i.v., 0 min), GHRH (100 microg, i.v., 0 min) preceded by acipimox (250 mg, orally, at -270 min and -60 min) (GHRH+Ac); and GHRH (100 microg, i.v., 0 min) plus GHRP-6 (100 microg, i.v., 0 min) (GHRH+GHRP-6). Serum GH was measured by radioimmunoassay. Statistical analyses were performed by Wilcoxon rank sum and by Mann-Whitney tests. RESULTS: After the ITT the mean peak GH secretion was 1.5+/-0.3 microg/l for hypopituitary, 10.1+/-1.7 microg/l (P<0.05 vs hypopituitary) for obese and 17.8+/-2.0 microg/l (P<0.05 vs hypopituitary) for normal. GHRH-induced GH secretion was 2+/-0.7 microg/l for hypopituitary, 3.9+/-1.2 microg/l (P=NS vs hypopituitary) for obese and 22.2+/-3.8 microg/l (P<0.05 vs hypopituitary) for normal. After GHRH+Ac, mean peak GH secretion was 3.3+/-1.4 microg/l for hypopituitary, 14.2+/-2.7 microg/l (P<0.05 vs hypopituitary) for obese and 35.1+/-5.2 microg/l (P<0.05 vs hypopituitary) for normal. GHRH+GHRP-6 induced mean peak GH secretion of 4.1+/-0.9 microg/l for hypopituitary, 38.5+/-6.5 microg/l (P<0.05 vs hypopituitary) for obese and 68.1+/-5.5 microg/l (P<0.05 vs hypopituitary) for normal subjects. Individually considered, after ITT, GHRH or GHRH+Ac, the maximal response in hypopituitary patients was lower than the minimal response in normal but higher than the minimal response in obese subjects. In contrast, after GHRH+GHRP-6 the maximal response in hypopituitary patients was lower than the minimal response in normal and obese subjects. CONCLUSIONS: This study suggests that, in this group of patients, although both acipimox and GHRP-6 partially reverse the functional hyposomamotropism of obesity after GHRH, but are unable to reverse the organic hyposomatotropism of hypopituitarism, the combined test GHRH+GHRP-6 most accurately distinguishes both situations, without the side effects of ITT.

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M Doknic, S Pekic, M Zarkovic, M Medic-Stojanoska, C Dieguez, F Casanueva, and V Popovic

OBJECTIVE: It has recently been shown that increased body weight is associated with prolactinomas and that weight loss occurs with normalization of prolactin levels. On the other hand, decreased dopaminergic tone in humans is well correlated with obesity. The objective of this study was to correlate changes in prolactin levels with leptin and body mass index (BMI) in patients with prolactinomas treated with the long-acting dopamine agonist bromocriptine (BC). METHODS: Eleven female and twelve male patients, aged 36.7+/-2.6 years with BMI in males of 30.4+/-1.7 kg/m(2) and in females of 24.4+/-1.2 kg/m(2), were evaluated after 1 and 6 months and 11 patients were further evaluated after 2 years of BC therapy. Plasma prolactin is presented as the mean of four samples taken daily. Serum leptin was determined in the pooled serum from three samples taken at 15-min intervals at 0800 h after an overnight fast. Multivariate linear regression and repeated measures analysis of covariance were used. RESULTS: In males, pretreatment prolactin levels were 71 362+/-29 912 mU/l while leptin levels were 14.9+/-1.8 microg/l. In females, pretreatment prolactin levels were 11 395+/-5839 mU/l and leptin levels were 16.7+/-2.5 microg/l. The sexual dimorphism of serum leptin levels at initial presentation was preserved after adjusting for BMI and prolactin-induced hypogonadism. After 1 month of therapy, prolactin levels significantly decreased (males: 17 618+/-8736 mU/l, females: 3686+/-2231; P<0.05), BMI did not change (males: 30.2+/-1.7 kg/m(2), females: 24.1+/-1.2 kg/m(2); P>0.05), while serum leptin levels decreased (males: 12.5+/-1.5 microg/l, females: 13.6+/-2.1 microg/l; P<0.05). After 6 months of treatment, prolactin further decreased (males: 3456+/-2101 mU/l, females: 677+/-360 mU/l; P<0.05) as did BMI (males: 28.6+/-1.6 kg/m(2), females 23.1+/-1.0 kg/m(2); P<0.05). The difference was more pronounced in male patients. Leptin levels were 12.8+/-2.8 microg/l in males and 12.9+/-1.8 microg/l in females (P<0.05). After 2 years of BC treatment, prolactin levels were near normal (males: 665+/-439 mU/l, females 447+/-130 mU/l; P<0.05) and BMI remained 26.5+/-1.9 kg/m(2) for males and 23.6+/-0.8 kg/m(2) for females (P<0.05). Leptin levels were 9.5+/-2.2 microg/l in males and 18.7+/-3.1 microg/l in females (P<0.05). There was a gradual increase in the gender difference in serum leptin levels over time. Changes in serum leptin levels significantly correlated with changes in BMI (r=0.844, P<0.001) but did not correlate with changes in plasma prolactin levels after 1 month (r=0.166), 6 months (r=0.313) and 2 years (r=0.234, P>0.05). CONCLUSION: The long-acting dopamine agonist BC, by increasing dopaminergic tone, may influence body weight and likely body composition by mechanisms in addition to reducing hyperprolactinemia in patients with prolactinomas.

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LM Seoane, SA Tovar, D Perez, F Mallo, M Lopez, R Senaris, FF Casanueva, and C Dieguez

BACKGROUND/AIMS: Orexins (OXs) are a newly described family of hypothalamic neuropeptides. Based on the distribution of OX neurons and their receptors in the brain, it has been postulated that they could play a role in the regulation of neuroendocrine function. GH secretion is markedly influenced by nutritional status and body weight. To investigate the role OX-A plays in the neuroregulation of GH secretion we have studied its effect on spontaneous GH secretion as well as GH responses to GHRH and ghrelin in freely moving rats. Finally, we also assessed the effect of OX-A on in vitro GH secretion. METHODS: We administered OX-A (10 microg, i.c.v.) or vehicle (10 microl, i.c.v.) to freely moving rats. Spontaneous GH secretion was assessed over 6 h with blood samples taken every 15 min. RESULTS: Administration of OX-A led to a decrease in spontaneous GH secretion in comparison with vehicle-treated rats, as assessed by mean GH levels (means+/-s.e.m. 4.2+/-1.7 ng/ml vs 9.4+/-2.2 ng/ml; P<0.05), mean GH amplitude (3.6+/-0.5 ng/ml vs 20.8+/-5.6 ng/ml; P<0.01) and area under the curve (848+/-379 ng/ml per 4 h vs 1957+/-458 ng/ml per 4 h; P<0.05). In contrast, OX-A failed to modify in vivo GH responses to GHRH (10 microg/kg, i.v.) although it markedly blunted GH responses to ghrelin (40 microg/kg, i.v.) (mean peak GH levels: 331+/-71 ng/ml, vehicle, vs 43+/-11 ng/ml in OX-A-treated rats; P<0.01). Finally, OX-A infusion (10(-7), 10(-8) or 10(-9) M) failed to modify in vitro basal GH secretion or GH responses to GHRH, ghrelin and KCl. CONCLUSIONS: These data indicate that OX-A plays an inhibitory role in GH secretion and may act as a bridge among the regulatory signals that are involved in the control of growth, nutritional status and sleep regulation.

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Maria Koltowska-Häggström, Anders F Mattsson, John P Monson, Paul Kind, Xavier Badia, Felipe F Casanueva, Jan Busschbach, Hans P F Koppeschaar, and Gudmundur Johannsson

Objective: To determine whether impaired quality of life (QoL) in adults with GH deficiency (GHD) is reversible with long-term GH therapy and whether the responses in QoL dimensions differ from each other.

Methods: QoL was measured by the Quality of Life–Assessment for Growth Hormone Deficiency in Adults (QoL-AGHDA) in general population samples in England & Wales, The Netherlands, Spain and Sweden (n = 892, 1038, 868 and 1682 respectively) and compared with corresponding patients’ data from KIMS (Pfizer International Metabolic Database) (n = 758, 247, 197 and 484 respectively) for 4–6 years a follow-up. The subsets of patients from England and Wales, and Sweden with longitudinal data for 5 years’ follow-up were also analysed. The change of the total QoL-AGHDA scores and responses within dimensions were evaluated. Subanalyses were performed to identify any specificity in response pattern for gender, age, disease-onset and aetiology.

Results: Irrespective of the degree of impairment, overall QoL improved dramatically in the first 12 months, with steady progress thereafter towards the country-specific population mean. Problems with memory and tiredness were the most serious burden for untreated patients, followed by tenseness, self-confidence and problems with socialising. With treatment, these improved in the reverse order, normalising for the latter three.

Conclusions: Long-term GH replacement results in sustained improvements towards the normative country-specific values in overall QoL and in most impaired dimensions. The lasting improvement and almost identical pattern of response in each patient subgroup and independent of the level of QoL impairment support the hypothesis that GHD may cause these patients’ psychological problems.