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Objective: A common polymorphic variant of GH receptor (exon 3 deletion, d3GHR) has been linked with increased response to recombinant human GH (rhGH) in some patients with or without GH deficiency (GHD). The aim of the study was to investigate the impact of the GHR genotype on the phenotype of GHD adults and on the metabolic effect of rhGH therapy., Design: Prospective study of GHD patients evaluated before and during short- (1 year, n=100) and long-term (5 years, n=50) rhGH therapy., Methods: Effects of rhGH on IGF1 levels, body composition (body fat percentage, BF%), body mass index, lipid profile, and glucose homeostasis (fasting insulin and glucose, insulin sensitivity indexes) were evaluated according to the presence or the absence of the d3GHR variant., Results: The different genotype did not influence basal phenotype of GHD. Short-term rhGH determined normalization of IGF1 levels, decrease in BF%, and worsening of insulin sensitivity, independently from the presence of the d3GHR allele. A significant increase in high-density lipoprotein cholesterol occurred in the d3GHR group. Normalization of IGF1 levels and decrease in BF% were maintained after 5 years. Insulin sensitivity restored to basal values, though in d3GHR patients fasting glucose remained significantly higher than at baseline. After both 1 and 5 years, percentage of subjects with impaired glucose tolerance, similar in the two groups at baseline, decreased in fl/fl while doubled in d3GHR patients. In this last group, a long-term significant reduction in total and low-density lipoprotein cholesterol was also observed., Conclusion: The functional difference of d3GHR may influence some metabolic effects of rhGH on GHD adults.

Autoimmune hypophysitis (AH) is an inflammatory disease that can present either as empty sella or as pituitary mass. A 16-years-old girl was admitted at our Unit for primary amenorrhea. A pituitary MRI performed 2 years before for severe headache demonstrated a large sellar and suprasellar lesion. As a craniopharyngioma was suspected, the consultant neurosurgeon suggested the removal of the lesion. Two months later, a preoperative MRI showed the disappearance of the lesion and a residual empty sella, figure consistent with AH. When the patient came at our observation, basal and dynamic testing documented a state of hypopituitarism, high titers of antipituitary antibodies and a partial empty sella at MRI. Hormonal replacement therapy was started, obtaining a good clinical and biochemical control. Four years later, severe headache and a MRI suggestive of pituitary adenoma recurred. A relapse of the autoimmune phenomenon seemed the most feasible hypothesis. A MRI performed 3 months later did not show any pituitary lesion and empty sella was again described. This patient represents one of the few reported cases of recurrent hypophysitis and demonstrates that both pituitary enlargement and empty-sella can be seen in the same patient at different times of his history.

The aim of this study was to evaluate GH/IGF-I axis and other pituitary functions in adult patients with coeliac disease. For this purpose, twenty-eight adult coeliac patients [20M, 8F:19-74 years; body mass index (BMI): 18.5-28 kg/m (2)] were recruited. Basal thyroid, adrenal and gonadal function, serum IGF-I and PRL, and routine parameters were evaluated. Dynamic GH secretion was carried out by GHRH plus arginine test. In 20 patients, antipituitary antibodies (APA) were also evaluated. Seven out of 28 patients, independently from disease onset and the gluten-free diet (GFD), showed an impaired GH secretion (25%). All were males, 2 with severe growth hormone deficiency (GHD) and 5 with partial GHD. In patients with GHD, as compared to coeliac patients with normal GH secretion, HOMA (2.1+/-1.2 vs. 0.9+/-0.4) and QUICKI (0.35+/-0.03 vs. 0.39+/-0.02) levels were significantly higher and lower, respectively, while IGF-I levels were slightly lower (17.7+/-3.7 vs. 24.7+/-6.3, p=NS). APA were negative in all 20 patients studied. In conclusion, a significant number of adult coeliac patients show an impaired GH secretion, this alteration being predominant in males and independent from disease onset and diet regimen. Given the absence of APAs, the cause of this pituitary dysfunction remains unclear even if a previous autoimmune involvement in some cases cannot be excluded., (Georg Thieme Verlag KG Stuttgart New York.)

Central hypothyroidism (CH) is a rare cause of hypothyroidism characterized by a defect of thyroid hormone production due to an insufficient TSH stimulation. CH can be congenital in the case of genetic defects or acquired in the case of lesions affecting either pituitary or hypothalamus. Diagnosis is usually made on a biochemical basis showing defective thyroid hormone circulating levels associated to inappropriately low TSH levels. Treatment of CH takes advantage of thyroid hormone replacement even though treatment cannot be tuned as easily as in primary hypothyroidism because the evaluation of circulating TSH has a very limited value in central defects. Interestingly, GH deficiency may mask subclinical forms of CH that reach a biochemical evidence only after institution of GH replacement therapy.

Objective: Recombinant hGH (rhGH) therapy may unmask central hypoadrenalism in adults with organic GH deficiency (GHD), likely by normalizing 11beta-hydroxysteroid dehydrogenase type 1 isoenzyme (11betaHSD1) activity and reducing cortisone to cortisol conversion. The aim of the present study was to evaluate the hypothalamic-pituitary-adrenal (HPA) axis in children with idiopathic isolated GHD and normal pituitary magnetic resonance imaging (MRI) both before and during rhGH therapy., Design and Patients: This was a single-centre study of 10 consecutive children [five males and five females, mean age: 12.2 +/- 1.0 year]. Evaluation was performed at baseline and on rhGH (mean duration: 10.9 +/- 2.9 months, mean dose: 0.030 +/- 0.002 mg/kg bw/day)., Measurements: HPA function was assessed by serum cortisol levels before and after appropriate provocative stimuli, that is, 1 microg ACTH test (N = 5 patients) or insulin tolerance test (ITT, N = 5 patients), evaluating all children with the same stimulation test both before and during rhGH therapy. Central hypoadrenalism was excluded by the presence of either a peak of > 500 nmol/l or a rise in cortisol levels of > 200 nmol/l, after both tests., Results: On rhGH therapy, serum IGF-I levels normalized, while serum cortisol and ACTH levels did not significantly differ from those recorded at baseline. The mean serum cortisol peak after both provocative tests was not significantly different on rhGH therapy and at baseline (498 +/- 41 vs. 580 +/- 35 nmol/l, respectively, P = 0.06), the mean cortisol rise being 280 +/- 45 and 270 +/- 36 nmol/l on rhGH and at baseline, respectively., Conclusions: According to the diagnostic criteria, no child became hypoadrenal on rhGH, contrary to what observed in patients with organic GHD, further supporting the view that only in patients with organic multiple pituitary hormone deficiency GHD masks the presence of a hidden central hypoadrenalism.

Objective: Previous evidence indicated that, in adults with organic hypopituitarism, GH deficiency (GHD) may mask the presence of other pituitary deficits, in particular central hypothyroidism and hypoadrenalism. Little and conflicting information is available about the relationship between GHD, rhGH therapy and gonadal function in males. The aim of the present study was to investigate the hypothalamic-pituitary-gonadal axis (HPG) in male adults with organic GHD and normal HPG axis., Patients: Twelve male adults (mean age 48 +/- 7 years) with organic GHD and normal HPG axis., Measurements: Serum levels of testosterone, LH and FSH (basal and after GnRH stimulation test), SHBG and IGF-I and percentage body fat (BF%) were evaluated before and during rhGH (mean dose 0.24 +/- 0.02 mg/day for 13 +/- 1 months) treatment., Results: Serum IGF-I levels normalized during rhGH treatment and BF% significantly decreased. Serum testosterone levels significantly decreased (from 18.1 +/- 1.7 to 14.2 +/- 1.6 nmol/l, P = 0.01), with a parallel and significant decrease of serum SHBG (from 31.1 +/- 3.6 to 24.3 +/- 2.3 nmol/l, P < 0.05). Thus, calculated free testosterone (cFT) did not change (from 0.39 +/- 0.17 to 0.33 +/- 0.14 nmol/l, P = ns). Finally, no difference was found in basal and GnRH stimulated gonadotrophins levels., Conclusions: In conclusion, the condition of GHD does not seem to mask central hypogonadism, in contrast to what is observed for central hypothyroidism and hypoadrenalism. However, the significant decrease in serum testosterone levels, strictly related to SHBG decrease, suggests that evaluation of the HPG axis during rhGH treatment cannot be based on the measurement of total testosterone levels, but should mainly rely on calculation of cFT and a careful clinical evaluation, in order to avoid unnecessary replacement therapy.

Context: The effects of chronic therapy with long-acting somatostatin analogs (SSTa) on metabolic and cardiovascular parameters have been partially elucidated in acromegalic patients., Objective: The objective of this study was to compare the long-term effects of SSTa treatment and successful surgery on GH/IGF-I secretion and cardiovascular risk parameters in acromegaly. DESIGN, PATIENTS, AND INTERVENTION: This was a retrospective study of 36 acromegalic patients treated with SSTa and evaluated after a median of 66 months and of 33 sex-, age-, and body mass index-matched cured patients evaluated after a similar period of remission, all from the Institute of Endocrine Sciences (Milan, Italy)., Main Outcome Measures: The main outcome measures were fasting and post-oral load glucose homeostasis, hemoglobin A(1c), insulin sensitivity and secretion by several indexes, lipid profile, and blood pressure., Results: Fasting and areas under the glucose response curve rose in patients controlled (n = 29) and not controlled (n = 7) by SSTa, becoming higher than those in cured subjects. A 1% hemoglobin A(1c) increase was observed in all nondiabetic SSTa patients, but not in cured subjects. Basal insulin secretion and resistance, evaluated by homeostasis model assessment, decreased in all SSTa patients, whereas oral glucose tolerance test-derived insulin secretion and resistance, evaluated by insulinogenic index and oral glucose tolerance test-derived insulin secretion, improved only in SSTa-treated controlled patients. Triglycerides did not change during SSTa, whereas high-density lipoprotein cholesterol increased in SSTa-treated controlled patients. At the last visit, the contemporary presence of at least three cardiovascular risk factors was more frequent in patients treated with SSTa than in cured subjects., Conclusions: SSTa therapy induces long-lasting disease control and improvement of insulin sensitivity and high-density lipoprotein cholesterol levels in responsive patients. The progressive glucose homeostasis alterations, observed independently from the degree of cure, suggest the need for glucose homeostasis and peripheral vascular complications monitoring during chronic SSTa treatment.

Criteria to define remission of acromegaly have changed over years. Since 2000, criteria for cure are normal IGF-I levels and a nadir GH after oral glucose tolerance test (OGTT) of less than 1 microg/liter, although recent studies have suggested to lower this cutoff value. This study reevaluated long-term disease activity of acromegalic patients, who were previously considered in remission, using these criteria. The study included 70 of 146 patients operated on between 1984 and 1996 who were considered cured based on normal IGF-I levels, GH values less than 2.5 microg/liter, and/or disappearance of abnormal GH response to TRH/GnRH. Among these 70 patients, 16 were lost to follow-up, three died, and 11 (one of whom had disease recurrence) only gave a phone interview. Forty patients participated in the study and were reevaluated for IGF-I levels and post-OGTT GH nadir after 14.3 +/- 4.2 (mean +/- sd) yr from surgery. In all patients, normal IGF-I levels and a post-OGTT GH nadir of less than 1 microg/liter were found. In particular, 19 patients had a GH nadir of less than 0.19 microg/liter, i.e. the upper limit (mean + 2 sd) found in 30 controls, whereas 21 patients had a nadir between 0.19 and 0.77 microg/liter. No significant differences in hormonal parameters and comorbidities between the two subgroups were observed. These data showed that lowering the post-OGTT GH cutoff value within the normal range does not seem to better discriminate patients with different disease activity or long-term recurrence risk.

The aim of the study was to evaluate the hypothalamus-pituitary-adrenal (HPA) axis in patients (nine males, three females; mean age +/- sem 51 +/- 2 yr) with adult-onset GH deficiency (GHD) due to surgically treated pituitary tumors with preserved HPA function and without evidence of tumor recurrence before and during recombinant human (rh) GH replacement therapy (duration 31 +/- 6 months). HPA function was assessed by urinary free cortisol and morning serum cortisol levels as well as cortisol responses to 1 mug ACTH test (n = 7 patients) or insulin tolerance test (n = 5 patients) before and during rhGH therapy, the cut-off for the diagnosis of hypoadrenalism being a cortisol peak less than 18 microg/dl (<500 nmol/liter) after stimulatory tests. Serum cortisol and urinary free cortisol levels were significantly lower on therapy than before [7.6 +/- 0.8 vs. 11.5 +/- 0.9 microg/dl (208 +/- 22 vs. 317 +/- 24 nmol/liter), P < 0.01, and 19.6 +/- 2.5 vs. 32.2 +/- 3.2 microg per 24 h (54 +/- 7 vs. 89 +/- 9 nmol per 24 h), P < 0.05, respectively], whereas no change in cortisol-binding globulin levels was observed. Cortisol peak after either ACTH test or insulin tolerance test was lower on rhGH therapy than before [15.9 +/- 1.5 vs. 20.2 +/- 1.1 microg/dl (437 +/- 43 vs. 557 +/- 31), P = 0.01, and 13.1 +/- 2.6 vs. 20.4 +/- 1.4 microg/dl (362 +/- 71 vs. 564 +/- 37 nmol/liter), P = 0.03, respectively]. Accordingly, central hypoadrenalism was detected in nine of 11 patients. In conclusion, low GH and IGF-I levels, likely enhancing the conversion of cortisone to cortisol, may mask a condition of central hypoadrenalism. Therefore, the reassessment of HPA function in GHD patients during rhGH therapy is mandatory.

The mechanisms involved in the preprandial rise and postprandial fall of circulating ghrelin levels are as yet unknown. Many hormonal and metabolic responses to nutrient intake begin during the cephalic or preabsorptive phase and are mostly mediated by the autonomous nervous system. The aim of the present study was to investigate the effects of the cephalic phase on ghrelin response to feeding in human subjects. The modified sham feeding (MSF), a well established technique in which nutrients are smelled, chewed, and tasted, but not swallowed, was used. Sixteen healthy volunteers (seven men and nine women; mean age +/- sd: 31 +/- 8 yr; body mass index, 22 +/- 3 kg/m(2)) were studied after overnight fasting. Seven of them received a standardized mixed meal, and nine underwent MSF. Blood samples for ghrelin, insulin, and glucose were taken at time -30, 0, 15, 30, 45, 60, 120 min during both tests. Pancreatic polypeptide determinations were evaluated at all times as markers of vagal activity only during MSF. Ghrelin levels significantly increased from time -30 to 0 min before the two tests, then significantly decreased: after the real feeding from 933 +/- 479 pg/ml (277 +/- 142 pmol/liter) to 455 +/- 185 pg/ml (135 +/- 55 pmol/liter; P < 0.05), and after the sham feeding from 917 +/- 313 pg/ml (272 +/- 93 pmol/liter) to 519 +/- 261 pg/ml (154 +/- 77 pmol/liter; P < 0.05). There were no significant differences between the patterns of the responses as evaluated by ANOVA (P = 0.863). As expected after MSF, plasma pancreatic polypeptide concentrations promptly increased from 58 +/- 29 pg/ml (14 +/- 7 pmol/liter) to 113 +/- 38 pg/ml (27 +/- 9 pmol/liter) at 15 min (P < 0.01). Both insulin and glucose levels increased during the actual mixed meal, whereas they were not significantly modified by MSF. In conclusion, circulating ghrelin concentrations are decreased by sham feeding as they are by real feeding in humans. These findings underline the importance of the cephalic response to nutrient intake, i.e. the role of vagal activity, in the control of ghrelin secretion.

Objective: To evaluate circulating levels of ghrelin and adiponectin (ApN) in GH-deficient (GHD) adults before and after short- and long-term recombinant human GH (rhGH) administration., Patients and Methods: Twenty-three patients were studied. Seventeen subjects (Group A, 12 men, five women) were evaluated at baseline and after 1 year rhGH therapy (dose mean +/- SD: 0.3 +/- 0.1 mg/day) with the assessment of serum IGF-I, ghrelin, ApN, leptin, insulin and glucose levels, percentage of body fat (BF%), HOMA-IR and QUICKI. Seventeen age-, sex- and body mass index (BMI)-matched healthy subjects were recruited for comparisons. Six patients (Group B, three men, three women) underwent IGF-I generation test (rhGH 0.025 mg/kg/day for 7 days), blood sampled at baseline and on day 8 for determination of IGF-I, ghrelin and ApN levels., Results: Group A: at baseline GHD patients showed low IGF-I levels and BF% significantly higher than controls (31.4 +/- 2.5 vs. 26.4 +/- 1.3, P < 0.05). Glucose, insulin, leptin, tryglicerides, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels, as well as HOMA-IR and QUICKI values were similar in the two series, while total cholesterol levels were higher in GHD. In GHD, ghrelin levels were significantly lower than in controls (193.9 +/- 27.1 vs. 298.1 +/- 32.5 pmol/l, respectively, P = 0.02), while ApN levels were similar (10.2 +/- 1.1 and 9 +/- 1 mg/l, respectively, P = ns). After 1 year of rhGH therapy, BF%, BMI, serum total and LDL cholesterol significantly decreased, serum leptin levels showed a trend to decrease, while HOMA-IR and QUICKI did not change. Ghrelin and ApN levels significantly increased from 193.9 +/- 27.1 to 232.4 +/- 26.3 pmol/l (P < 0.01) and from 8.6 +/- 0.8 to 10.3 +/- 1.1 mg/l (P < 0.05), respectively. In group B, the expected increase in IGF-I levels was associated with a significant decrease in ghrelin levels, while ApN did not change., Conclusion: GHD patients showed serum ghrelin lower than controls, probably due to the higher BF%. No difference in ApN was observed. Ghrelin and ApN increments induced by long-term treatment may be related to the significant BMI and BF% reduction that is the predominant metabolic effect of rhGH therapy. Conversely, the decrease in ghrelin levels observed after short-term rhGH administration may be consistent with an inhibitory feedback of GH and/or IGF-I on ghrelin release.

Since the effects of recombinant human growth hormone (rhGH) replacement therapy on glucose metabolism are still a matter of debate, the aim of the present study was to evaluate the impact of long-term rhGH treatment on insulin sensitivity. Simple indices of insulin resistance (IR) and insulin sensitivity (IS), based on fasting glucose and insulin, such as the homeostasis model assessment of insulin resistance (HOMA-IR) and the quantitative insulin check index (QUICKI), were used to estimate the degree of IR and IS in 20 normoglycemic patients (11 men and 9 women; mean age, 44 +/- 14 years) with severe adult-onset GH deficiency (GHD). Measurements were determined at baseline and after 1 and 5 years of continuous rhGH therapy. Basal values were compared to those obtained in 20 healthy sex- and age-matched controls. Starting rhGH dose ranged from 3 to 8 microg/kg/d in keeping with sex and age, then doses were titrated according to insulin-like growth factor-I (IGF-I) levels. At baseline all patients had low IGF-I levels (10 +/- 5.4 nmol/L), high body mas index (BMI; 27.5 +/- 4 kg/m(2)), and elevated body fat percentage (BF%; 31.8 +/- 9.6). Fasting glucose and insulin levels, as well as HOMA-IR and QUICKI, did not differ significantly from those recorded in the control group. After 1 year of rhGH replacement therapy, normalization in IGF-I levels and a significant reduction in BF% were observed (P <.001), and these effects were maintained after 5 years of treatment. Fasting glucose increased from 79 +/- 10 to 87 +/- 13, and 87 +/- 12 mg/dL (P <.05) after 1 and 5 years of therapy, respectively. Fasting insulin significantly increased after 1 year, without further modifications in the long-term follow-up. HOMA-IR significantly increased from 2.1 +/- 1.7 to 2.5 +/- 1.7 (P <.05) after 1 year, then decreased to 2.3 +/- 1.5 (P = not significant [NS] v basal) after 5 years. A specular decrease in QUICKI from 0.37 +/- 0.05 to 0.34 +/- 0.03 (P <.01) occurred after 1 year, with a trend to increase (0.35 +/- 0.04; P = NS v basal) after 5 years. No patient developed impaired fasting glucose. In conclusion, rhGH therapy determined an increase in fasting glucose and insulin levels, causing in the short-term period a worsening of IS. The sustained reduction in BF%, without further deterioration of IS, suggests that long-term beneficial effects on body composition may overcome the negative influence of GH on glucose metabolism.

Objective: Recombinant hGH treatment may alter thyroid hormone metabolism and we have recently reported that 50% of patients with GH deficiency (GHD) due to organic lesions, previously not treated with thyroxine, developed hypothyroidism during treatment with recombinant human GH (rhGH). These results prompted us to evaluate the impact of rhGH treatment on thyroid function in children with GHD., Design: Open study of GH treatment up to 12 months. Investigations were performed at baseline, and after 6 and 12 months of GH therapy. MEASUREMENT AND STUDY SUBJECTS: Serum TSH, FT4, FT3, AbTg and AbTPO, IGF-I, height and weight, were evaluated in 20 euthyroid children (group A) with idiopathic isolated GHD and in six children (group B) with multiple pituitary hormone deficiencies (MPHD) due to organic lesions. Among the latter, four already had central hypothyroidism and were on adequate LT4 replacement therapy, while two were euthyroid at the beginning of the study., Results: Serum IGF-I levels normalized in all patients. In both groups, a significant reduction in FT4 levels (P < 0.01) occurred during rhGH therapy. No patient in group A had FT4 values into the hypothyroid range, while in four of six patients in group B, fell FT4 levels into the hypothyroid range during rhGH. In particular, the two euthyroid children developed central hypothyroidism during rhGH treatment, and their height velocities did not normalize until the achievement of euthyroidism through appropriate LT4 substitution. No variation in serum FT3 and TSH levels was recorded in either groups., Conclusion: Contrary to that observed in patients with MPHD, rhGH replacement therapy does not induce central hypothyroidism in children with idiopathic isolated GHD, further supporting the view that in children with MPHD, as in adults, GHD masks the presence of central hypothyroidism. Slow growth (in spite of adequate rhGH substitution and normal IGF-I levels) is an important clinical marker of central hypothyroidism, therefore a strict monitoring of thyroid function is mandatory in treated children with MPHD.

The effect on thyroid function of GH administration to 66 adult patients with severe GH deficiency was studied. Seventeen patients were euthyroid, and 49 had central hypothyroidism and were adequately treated with L-T(4). Forty patients were assigned to a low recombinant human GH (rhGH) regimen (3 microg/kg body wt.d for 3 months followed by 6 microg/kg body wt.d for another 3 months) and 26 to a higher one (6 microg/kg body wt.d for 3 months followed by 12 microg/kg body wt.d for another 3 months). Serum IGF-I, TSH, free T(4) (FT(4)), free T(3) (FT(3)), reverse T(3), T(4)-binding globulin, and antithyroid autoantibody (TgAb and TPOAb) were measured in basal condition and after 3 and 6 months of therapy. Normalization of IGF-I levels was obtained after 6-month rhGH treatment in 67% of patients, independently from the dose, whereas a significant reduction in FT(4) and reverse T(3) levels was recorded (P < 0.01), without variations in all the other parameters studied, including serum TSH, FT(3), and T(4)-binding globulin circulating levels. Antithyroid autoantibodies were detected in 11 of 66 patients (16.6%). Eight of 17 (47%) euthyroid subjects and 9 of 49 (18.3%) central hypothyroid patients, despite adequate substitution at baseline, showed FT(4) levels under the normal range at the end of the study. Altogether, 17 of 66 patients (25.7%) worsened their thyroid function. This study shows that GH deficiency masks in a consistent number of adult patients a state of central hypothyroidism. Therefore, during rhGH treatment, a careful monitoring of thyroid function is mandatory to start or adjust L-T(4) substitutive therapy.