Emanuele Ferrante

Efficacy and tolerability of gamma knife radiosurgery in acromegaly: a 10‐year follow‐up study

Objective  The long‐term efficacy and safety of stereotactic radiosurgery by gamma knife (GK) still remain unknown. The aim of the study was to investigate the long‐term efficacy and tolerability of GK in acromegalic patients.

Different effects of short- and long-term recombinant hGH administration on ghrelin and adiponectin levels in GH-deficient adults.

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.

Recombinant hGH replacement therapy and the hypothalamus–pituitary–thyroid axis in children with GH deficiency: when should we be concerned about the occurrence of central hypothyroidism?

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.

Prevalence of GH deficiency in cured acromegalic patients: impact of different previous treatments

OBJECTIVE Radiotherapy (RT) for pituitary adenomas, including GH-secreting ones, frequently leads to GH deficiency (GHD). Data on the effects of surgery alone (S) on dynamic GH secretion are limited. The aim of the study was to investigate the occurrence of GHD in acromegalic patients treated with different therapeutic options. DESIGN AND METHODS Fifty-six patients in remission from acromegaly, (33 F & 23 M, age: 54+/-13 years, body mass index (BMI): 28.4+/-4.1 kg/m(2), 21 with adequately substituted pituitary deficiencies) treated by S alone (n=33, group 1) or followed by RT (n=23, group 2), were investigated for GHD by GHRH plus arginine testing, using BMI-adjusted cut-offs. Several metabolic and cardiovascular parameters (waist circumference, body fat percentage, blood pressure, fasting and post-oral glucose tolerance test glucose, HbA1c, insulin resistance and lipid profile) were evaluated in all the patients and 28 control subjects with known diagnosis of GHD. RESULTS Serum GH peak after challenge was 8.0+/-9.7 microg/l, without any correlation with post-glucose GH nadir and IGF-1 levels. The GH response indicated severe GHD in 34 patients (61%) and partial GHD in 15 patients (27%). IGF-1 were below the normal range in 14 patients (25%). The frequency of GHD was similar in the two treatment groups (54% in group 1 and 70% in group 2). No significant differences in metabolic parameters were observed between acromegalic patients and controls with GHD. CONCLUSIONS Severe GHD may occur in about 60% of patients treated for acromegaly, even when cured after S alone. Thus, a stimulation test (i.e. GHRH plus arginine) is recommended in all cured acromegalic patients, independently from previous treatment.

Recombinant Human GH Replacement Therapy in Children with Pseudohypoparathyroidism Type Ia: First Study on the Effect on Growth

CONTEXT Since the identification of GH deficiency due to resistance to GHRH in patients with pseudohypoparathyroidism type Ia (PHP-Ia), no study investigated the effects of recombinant human GH (rhGH) therapy on height velocity (HV) in these patients. OBJECTIVES, PATIENTS AND METHODS To address this question, eight prepubertal PHP-Ia children with GH deficiency (seven girls and one boy, aged 5.8-12 yr) underwent a 3- to 8-yr treatment with rhGH. Height and HV were measured before and at 6-month intervals during therapy. Nine sex- and age-matched children with idiopathic GH deficiency were monitored during rhGH therapy for comparison. RESULTS In PHP-Ia children, height sd scores increased from -2.4 ± 0.58 to -1.8 ± 0.47 (P = 0.04) after 12 months, this increase being maintained after the second (-1.6 ± 0.6) and third (-1.15 ± 0.6) year of therapy, similarly to what recorded in children with idiopathic GH deficiency. The HV and HV sd scores after 3 yr maintained a significant increase from 3.5 ± 0.6 to 7.0 ± 0.9 cm/yr (P < 0.0001) and from -2.8 ± 0.8 to +2.2 ± 1.0 (P < 0.0001), respectively. Six patients treated for 4-8 yr had a reduced pubertal spurt and did not improve their near-adult height, with the only exception of one patient in whom estrogen production was blocked by GnRH analogs. CONCLUSIONS We report the first study on the efficacy of rhGH replacement therapy in prepubertal children with PHP-Ia and provide indication that treatment of GH deficiency should be started soon due to the rather limited time window for a potentially effective therapy.

Thyrotropin-secreting pituitary adenomas: Outcome of pituitary surgery and irradiation

OBJECTIVE Our objective was to describe the effects of surgery and radiotherapy on hormonal control and tumor mass in short- and long-term follow-up of TSH-secreting pituitary adenomas (TSHomas). METHODS This was a retrospective multicenter study. RESULTS We collected data of 70 TSHomas (70% macroadenomas). The mean follow-up was 64.4 (range 3-324) months. Overall, 97% of patients were treated with surgery; in 27% of them radiotherapy was associated. After surgery, 75% of patients normalized thyroid function, 58% normalized both pituitary imaging and hormonal profile, 9% developed pituitary deficiencies, and 3% had tumor or hormonal recurrence, all within the first 2 years after surgery. Presurgical medical treatment did not significantly improve surgical outcome (63% vs 57%). Radiotherapy controlled hypersecretion in 37% of patients within 2 years, whereas 32% of patients developed new pituitary deficiencies from 18 to 96 months from treatment. At last follow-up, 80% of patients normalized thyroid function, whereas 20% were currently on medical treatment: 85% with somatostatin analog (SSA) alone and 15% with SSA combined with methimazole. Subjects who achieved disease control had surgery as the only treatment in 80% of cases and surgery combined with irradiation in 20%. CONCLUSIONS Surgery remains the first-choice treatment for TSHoma. If surgery is successful, recurrence is rare. When surgery is unsuccessful or contraindicated, SSA and radiotherapy are effective in controlling hyperthyroidism and tumor growth in the majority of patients. The effects of radiotherapy on TSH secretion and tumor mass are greater within the first years after treatment, whereas pituitary deficiencies may occur several years later.

Influence of the d3GH receptor polymorphism on the metabolic and biochemical phenotype of GH-deficient adults at baseline and during short- and long-term recombinant human GH replacement therapy

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.

GH Replacement Improves Quality of Life and Metabolic Parameters in Cured Acromegalic Patients with Growth Hormone Deficiency

OBJECTIVE Effects of GH replacement in patients with GH deficiency (GHD) after a cure for acromegaly so far have been poorly studied, although its prevalence among acromegalic patients may reach the 60%. The aim of the study was to evaluate whether metabolic parameters and quality of life are improved by GH replacement in patients with prior acromegaly and severe GHD. DESIGN AND METHODS This was a prospective study on 42 GHD subjects [22 men, mean age (sd): 48 ± 10]: 10 acromegalics treated with recombinant human GH (group A), 12 acromegalics who refused treatment (group B), and 20 subjects operated for nonfunctioning pituitary adenoma on recombinant human GH (group C). Serum IGF-I levels, lipid profile, glucose levels (fasting and after an oral glucose tolerance test), glycosylated hemoglobin, insulin resistance (homeostasis model assessment insulin resistance index), anthropometric parameters (body mass index, waist circumference, body composition), and quality of life (Questions on Life Satisfaction-Hypopituitarism Z-scores) were evaluated at baseline and after 12 and 36 months. RESULTS At baseline, group B showed higher IGF sd score than group A and C, as well as better quality of life and higher post-oral glucose tolerance test glucose levels than group A. After 12-months, similarly in group A and C, the IGF-I sd score significantly increased, and body composition and lipid profile improved, without deterioration of glucose tolerance. Quality of life significantly improved too, and the baseline difference between group A and B disappeared. Results were confirmed after 36 months. CONCLUSIONS In GHD acromegalic patients, GH therapy improved body composition, lipid profile, and quality of life as in patients with GHD due to nonfunctioning pituitary adenoma, without negative effects on glucose metabolism. GH replacement therapy should be considered in these patients, as in patients with GHD from other causes.

Effect of growth hormone deficiency and recombinant hGH (rhGH) replacement on the hypothalamic–pituitary–adrenal axis in children with idiopathic isolated GH deficiency

Objective  Recombinant hGH (rhGH) therapy may unmask central hypoadrenalism in adults with organic GH deficiency (GHD), likely by normalizing 11β‐hydroxysteroid dehydrogenase type 1 isoenzyme (11βHSD1) 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.

Growth hormone replacement therapy in growth hormone deficient children and adults: Effects on hemochrome

Several lines of evidence have suggested a role of the GH/IGF-I axis in the regulation of hemochrome. Many studies have been carried out in GH deficient children and adults about this topic, reporting predominantly a positive effect of recombinant human GH (rhGH) on red series, with no action on serum leucocytes and platelets counts. The aim of this study was to assess the impact of GH deficiency (GHD) and of rhGH replacement on blood cells count in 17 pre-pubertal children with idiopathic isolated GHD (11 males and 6 females, aged 9.1 ±0.8 yr) and in 18 patients with adult-onset GHD (12 males and 6 females, aged 47.9±3.0 yr). Evaluation of absolute and SD score (SDS) values of red blood cells, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelets and white blood cells was performed at baseline and after 12 months of rhGH treatment (0.045±0.001 mg/kg bw/day and 4.2±0.5 μg/kg bw/day for children and adults, respectively). At baseline, all patients showed low IGF-I levels. Effectiveness of rhGH therapy was documented by significant increase in height SDS, height velocity and serum IGF-I levels in children. In adults, adequacy of rhGH was demonstrated by significant increase in serum IGF-I and significant decrease in body fat. At baseline, about 25% of patients (4 of 17 children and 4 of 18 adults) showed normochromic normocytic anemia, while the other indices were normal. In 7 of the 8 anemic patients, normal levels of hemoglobin were restored on rhGH, while no change in all the other indices was observed. In conclusion, rhGH therapy at physiological doses has no effect on erythropoiesis in GHD children and adults with normal blood cells count, while in patients with normochromic normocytic anemia rhGH is able to restore normal hemoglobin levels.