Disease control of acromegaly does not prevent excess mortality in the long term: results of a nationwide survey in Italy.

OBJECTIVE: This study aimed to assess the long-term outcome of patients with acromegaly. DESIGN: This is a multicenter, retrospective, observational study which extends the mean observation period of a previously reported cohort of Italian patients with acromegaly to 15 years of follow-up. METHODS: Only patients from the centers that provided information on the life status of at least 95% of their original cohorts were included. Life status information was collected either from clinical records or from the municipal registry offices. Standardized mortality ratios (SMRs) were computed comparing data with those of the general Italian population. RESULTS: A total of 811 patients were included. There were 153 deaths, with 90 expected and an SMR of 1.7 (95% CI 1.4-2.0, p < 0.001). Death occurred after a median of 15 (women) or 16 (men) years from the diagnosis, without gender differences. Mortality remained elevated in the patients with control of disease (SMR 1.3, 95% CI 1.1-1.6). In the multivariable analysis, only older age and high IGF1 concentrations at last available follow-up visit were predictors of mortality. The oncological causes of death outweighed the cardiovascular ones, bordering on statistical significance with respect to the general population. CONCLUSIONS: Mortality remains significantly high in patients with acromegaly, irrespectively of disease status, as long as the follow-up is sufficiently long with a low rate of patients lost to follow-up. Therapy strategy including radiotherapy does not have an impact on mortality. Oncological causes of death currently outweigh the cardiovascular causes.

Recurrence of hyperprolactinemia following dopamine agonist withdrawal and possible predictive factors of recurrence in prolactinomas.

BACKGROUND: The optimal duration of cabergoline (CAB) treatment of prolactinomas that minimizes recurrences is not well established. 2011 Endocrine Society Guidelines suggested that withdrawal may be safely undertaken after 2 years in patients achieving normoprolactinemia and tumor reduction. MATERIALS: We analyzed 74 patients (mean age = 46.9 ± 14.4, M/F = 19/55, macro/micro = 18/56) bearing a prolactinoma divided in 3 groups: group A (23) treated for 3 years, group B (23) for a period between 3 and 5 years, and group C (28) for a period >5 years. CAB therapy was interrupted according to Endocrine Society Guidelines. Prolactin (PRL) levels were measured 3, 6, 12 and 24 months after withdrawal. Recurrence was defined with PRL levels ≥30 ng/ml. RESULTS: Groups did not differ in pretreatment PRL levels (123.2 ± 112.1, 120.9 ± 123.8, 176.6 ± 154.0), pituitary deficit (4, 17, 17 %), mean CAB weekly dose (0.7 ± 0.4, 0.6 ± 0.3, 0.7 ± 0.4) and PRL levels before withdrawal (17.1 ± 19.6, 11.4 ± 8.8, 13.8 ± 13.5). Recurrence occurred within 12 months in 34 patients (45.9 %), without significant differences among groups. Neuroradiological evaluation showed a significantly higher presence of macroadenoma in group C (13, 17 and 39 %, respectively). Recurrence rate of hyperprolactinemia did not depend on sex, tumor size or CAB dose but it was significantly correlated with PRL levels at diagnosis and before withdrawal (p = 0.03). Finally, patients with pituitary deficit at diagnosis showed a significantly higher recurrence rate (p = 0.03). CONCLUSIONS: The study provides additional evidence that prolonging therapy for more than 3 years does not reduce recurrence rate. In particular, recurrence risk was similar in micro- and macroadenomas, and higher in patients with pituitary deficits at diagnosis.

Analysis of short- and long-term metabolic effects of growth hormone replacement therapy in adult patients with craniopharyngioma and non-functioning pituitary adenoma.

PURPOSE: Adult patients operated for craniopharyngioma develop more frequently GH deficiency (GHD) than patients operated for non-functioning pituitary adenoma (NFPA). The aim of the study was to compare both short- (1 year) and long-term (5 years) effects of rhGH in 38 GHD adult patients (19 operated for Craniopharyngioma (CP) and 19 for NFPA). METHODS: IGF-I levels, body composition (BF%), BMI, lipid profile and glucose homeostasis were evaluated in all patients. Pituitary MRI was performed at baseline and during follow-up, as needed. RESULTS: At baseline no difference between the two groups was observed, apart from a higher prevalence of diabetes insipidus in CP patients (79 vs 21%). After 12 months, IGF-I SDS normalized and BF% significantly decreased only in the NFPA group. During long-term treatment, decrease in BF% and improvement in lipid profile shown by reduction in total- and LDL-cholesterol were present in NFPA group only, while increase in insulin levels and HbA1c and decrease of QUICKI were observed in CP patients only. Accordingly, after long-term therapy, the prevalence of metabolic syndrome (MS) was significantly higher in CP than in NFPA group (37% in CP and in 5% in NFPA group; p < 0.05). CONCLUSION: The present data suggest that CP patients are less sensitive to the positive rhGH effects on lipid profile and BF% and more prone to insulin sensitivity worsening than NFPA patients, resulting in increased prevalence of MS in CP only.

The exon 3-deleted growth hormone receptor: molecular and functional characterization and impact on GH/IGF-I axis in physiological and pathological conditions.

The GH receptor (GHR) plays a key role in the the function of the GH/IGF-I axis and is the major effector of human growth. A common polymorphic variant consisting of genomic exon 3 deletion or retention (d3-GHR and full-length GHR, respectively), described in 2000, has been linked with increased receptor activity due to enhanced signal transduction. Subsequent pharmacogenetic studies have addressed a possible role of GHR polymorphism on the response to recombinant human GH treatment first in short children and then in adults, many of them suggesting that growth response to GH may be influenced, at least in some aspects, by this polymorphism. Similar studies, performed in patients with acromegaly, assumed an influence of the d3- GHR variant in the relationship between GH and IGF-I levels. More recently, some studies have investigated the relation between GHR genotype and treatment with the GHR antagonist pegvisomant, suggesting a better clinical response to therapy related to d3-GHR genotype. This review provides a summary of the main pharmacogenetic studies performed on this current and still open topic.

Spine Bone Texture Assessed by Trabecular Bone Score in Active and Controlled Acromegaly: A Prospective Study.

CONTEXT: Acromegalic patients have an increased vertebral fracture (VFx) risk due to bone quality reduction, independently of bone mineral density (BMD). OBJECTIVE: The aim of the study is to describe bone quality in acromegaly, measured by trabecular bone score (TBS), a noninvasive index for assessing bone microarchitecture. METHODS: We collected data from 18 patients (13 female, age 56.2 ±â€…15 years) newly diagnosed with acromegaly. Thirty-six age- and sex-matched healthy controls were also recruited. Pituitary function, bone and calcium-phosphorous metabolism, and BMD at spine and femur and TBS (by dual-energy x-ray absorptiometry) were assessed in acromegalic patients at diagnosis and 12 months after the achievement of insulin-like growth factor 1 (IGF-1) normalization. RESULTS: At diagnosis, BMD and the VFx prevalence were comparable between patients and controls (28.3 ±â€…5.9 vs 27.6 ±â€…3.7 and 11% vs 8.3%), whereas TBS was significantly lower in acromegalic patients (1.20 ±â€…0.13 vs 1.30 ±â€…0.06; P < .001) and carboxyterminal telopeptide (CTX) and osteocalcin were significantly higher compared to controls (707 ±â€…365.7 vs 371 ±â€…104.1 pg/mL; P = .001 and 31.6 ±â€…15.4 vs 17.0 ±â€…5.7 ng/mL; P = .001, respectively). One year after IGF-1 normalization, a significant reduction of bone turnover indexes was observed in the group of acromegalic patients surgically cured (osteocalcin decrease of 61.2%, CTX decrease of 60.3%) compared to the ones controlled by medical therapy (osteocalcin decrease of 39%, CTX decrease of 40.7%; P = .01 and P = .001, respectively). Despite these findings, no TBS or BMD variations were observed. CONCLUSION: Acromegalic patients have impaired bone quality despite normal density. Achieving normal growth hormone secretion rapidly leads to the normalization of bone turnover.

Dopamine D2 receptor gene polymorphisms and response to cabergoline therapy in patients with prolactin-secreting pituitary adenomas.

Dopamine-agonist cabergoline (CB) reduces prolactin (PRL) secretion and tumor size in 80% of patients with prolactin-secreting adenomas (PRL-omas) by binding type 2 dopamine receptor (DRD2). The mechanisms responsible for resistance to CB remain largely unknown. To assess the association of DRD2 with sensitivity to CB, TaqI-A1/A2, TaqI-B1/B2, HphI-G/T and NcoI-C/T genotypes were determined in a cross-sectional retrospective study, including 203 patients with PRL-oma. DRD2 alleles frequencies did not differ between patients and 212 healthy subjects. Conversely, NcoI-T allele frequency was higher in resistant rather than responsive patients, considering both PRL normalization (56.6 vs 45.3%, P=0.038) and tumor shrinkage (70.4 vs 41.4%, P=0.006). Finally, [TaqI A1-/TaqI B1-/HphI T-/NcoI T-] haplotype was found in 34.5% of patients normalizing PRL with < or =3 mg/week of CB vs 11.3% of resistants (P=0.021). In conclusion, resistance to CB was associated with DRD2 NcoI-T+ allele, consistent with evidence suggesting that this variant may lead to reduction and instability of DRD2 mRNA or protein.

R990G polymorphism of the calcium-sensing receptor and renal calcium excretion in patients with primary hyperparathyroidism.

CONTEXT: Primary hyperparathyroidism (PHPT) shows a great variability in clinical course and severity. Data concerning the association between polymorphic variants of the gene encoding the calcium-sensing receptor (CaSR) and clinical characteristics of PHPT are not conclusive. OBJECTIVE: To evaluate the frequency of three polymorphisms; A986S, R990G, and Q1011E of CaSR in patients with PHPT and to correlate the genotypes with clinical and biochemical parameters. PATIENTS AND METHODS: The study included 94 consecutive unrelated patients referred to our Departments for PHPT diagnosis and management between 2000 and 2005 and 137 age and sex-matched healthy subjects. Patients and controls were genotyped according to standard procedures. Due to the rarity of 990G allele, homozygous and heterozygous subjects were grouped in R/G+G/G set. All PHPT patients were studied for calcium metabolism parameters and renal and bone complications. RESULTS: The proportion of CaSRvariants was similar in PHPT patients and controls. In PHPT patients, only R990G polymorphism was associated with disease parameters; in comparison with R/R, R/G+G/G patients showed lower mean serum parathyroid hormone (PTH) and phosphate levels (139.9 +/- 62.2 vs 199.9 +/- 136.3 pg/ml, P < 0.05 and 0.69 +/- 0.12 vs 0.81 +/- 0.18 mmol/l, P = 0.031 respectively), higher mean 24-h urine calcium concentration and calcium excretion (9.05 +/- 2.05 vs 6.77 +/- 4.31 mmol/24 h, P = 0.012 and 67 +/- 20 vs 51 +/- 26 mumol/l GF, P = 0.039), and increased prevalence of nephrolithiasis (90.0 vs 44.2%, P = 0.007). CONCLUSIONS: The study showed that patients with PHPT, bearing the 990G allele, had lower serum PTH levels and higher urinary calcium excretion in comparison with the other genotype, suggesting an increased sensitivityof the variant receptor to extracellular calcium. Since this variant was associated with increased occurrence of nephrolithiasis, analysis of this polymorphism might help to predict renal complication of the disease.

Analysis of somatostatin receptors 2 and 5 polymorphisms in patients with acromegaly.

OBJECTIVE: The aim of the study was to investigate the possible correlation of single nucleotide polymorphisms in somatostatin receptor (SSTR)2 and SSTR5 genes with the responsiveness to somatostatin analogs in a cohort of acromegalic patients. STUDY DESIGN: Three single nucleotide polymorphisms (a-83 g, c-57 g, and t80c) of SSTR2 and three (t-461c, c325t, and c1004t) of SSTR5 were analyzed in 66 acromegalic patients with different responsiveness to somatostatin analogs and 66 healthy controls. RESULTS: Allele frequencies in patients and controls were similar. No association between SSTR2 genotypes and GH and IGF-I levels was found. When considering SSTR5 variants, patients homozygous or heterozygous for the substitution c1004 (P+) showed basal IGF-I levels significantly lower than patients homozygous for 1004t (P-). Moreover, serum GH levels were lower in patients with P+/T- haplotype (having c1004 allele and no t-461 allele) than in those with P-/T+. No correlation between SSTR2 and SSTR5 genotypes, responsiveness to somatostatin therapy, and mRNA expression in the removed adenomas (n = 10) was found. CONCLUSIONS: These data suggest a role for SSTR5 t-461c and c1004t alleles in influencing GH and IGF-I levels in patients with acromegaly, whereas SSTR2 and SSTR5 variants seem to have a minor role in determining the responsiveness to somatostatin analogs.

Mitogen-activated protein kinase cascade in human normal and tumoral parathyroid cells.

The calcium-sensing receptor (CaR) activation has recently been shown to modulate the ERK1 and ERK2 cascade in different cell lines. The present study investigated this pathway in human normal and tumoral parathyroid cells. In cells from normal parathyroids and almost all hyperplasia increasing extracellular calcium concentrations (Ca(o)(2+)) induced a significant activation of ERK1 and -2, the percent stimulation over basal activity (at 0.5 mM Ca(o)(2+)) being 545 +/- 140 and 800 +/- 205 in normal cells and 290 +/- 71 and 350 +/- 73 in hyperplasia at 1 and 2 mM Ca(o)(2+), respectively. This effect was mediated by CaR because it was mimicked by the receptor agonist gadolinium and neomycin. Basal and Ca(o)(2+)-stimulated ERK1 and -2 activity was nearly abolished by the PKC inhibitor calphostin C, and PKA changes did not affect ERK1 and -2 activity. PI3K blockade by wortmannin, known to prevent G protein betagamma subunit effect on ERK1 and -2, induced a 30% reduction of the Ca(o)(2+)-stimulated ERK1 and -2 activity. Adenomatous cells showed high PKC-dependent ERK1 and -2 activity in resting conditions that was unresponsive to high Ca(o)(2+). A role of MAPK on PTH secretion was suggested by the finding that PD98059, a specific MEK inhibitor, abolished the inhibitory effect of 1.5 mM Ca(o)(2+) on PTH release from normal parathyroid cells. In conclusion, these data first demonstrate that CaR activation, through the PKC pathway and, to a lesser extent, PI3K, increases ERK1 and -2 activity in normal parathyroid cells and this cascade seems to be involved in the modulation of PTH secretion by Ca(o)(2+). Interestingly, this signaling pathway is disrupted in parathyroid tumors.

Effects of hypothalamic neuropeptides on extracellular signal-regulated kinase (ERK1 and ERK2) cascade in human tumoral pituitary cells.

The G protein-coupled receptor (GPCR) activation has been demonstrated to affect the ERK1/2 cascade in different cell lines. We investigated the effects of hypothalamic neuropeptides acting via GPCR on this pathway in GH-secreting (GH-oma) and nonsecreting (NFPA) pituitary adenomas. GHRH increased ERK1/2 activity (236 +/- 80%) in both gsp- and gsp+ GH-omas, this effect being almost completely abolished by protein kinase C (PKC) blockade. Both GnRH and pituitary adenylate-activating peptide caused a similar PKC-dependent activation of ERK1/2 in most NFPA. Increasing cAMP by forskolin caused a protein kinase A-dependent increase of ERK activity (287 +/- 37%) in GH-omas and had no effect in NFPA. ERK cascade blockade in GH-omas did not affect basal and GHRH-stimulated GH release, whereas it totally prevented the 3-fold increase in cyclin D1 protein expression induced by GHRH. In conclusion, this study demonstrated that in pituitary adenomas the activation of GPCR by neurohormones caused a PKC-dependent activation of ERK1/2 cascade that, at least in GH-omas, resulted to be involved in cyclin D1 induction by GHRH. Moreover, a stimulatory effect of the protein kinase A-dependent pathway on ERK1/2 cascade occurred selectively in GH-omas, probably contributing to the mitogenic potential of the cAMP pathway in this cell type.

Relevant cAMP-specific phosphodiesterase isoforms in human pituitary: effect of Gs(alpha) mutations.

Both cAMP production by adenylyl cyclase and cAMP degradation by phosphodiesterases account for intracellular cAMP levels. We previously demonstrated an increased phosphodiesterase activity in GH-secreting adenomas bearing the gsp oncogene. Here we characterize both the activity and the expression of cAMP-specific phosphodiesterase genes in the human pituitary and in gsp+ and gsp- GH-secreting adenomas and analyze the impact of this intracellular feedback mechanism on the levels of cAMP-responsive element-binding protein phosphorylation. Normal pituitary and gsp- GH-secreting adenomas showed similar phosphodiesterase activities, and 7-fold higher levels were observed in gsp+ tumors. In these tumors the increased activity was mainly owing to isobutyl-methyl-xanthine-sensitive phosphodiesterase 4 and to isobutyl-methyl-xanthine-insensitive isoforms. By semiquantitative RT-PCR, all phosphodiesterase 4 transcripts were expressed in the normal and tumoral pituitary. However, the levels of phosphodiesterase 4C and 4D messenger RNAs were significantly higher in gsp+ than in gsp- GH-secreting adenomas and normal pituitary. Expression of the thyroid-specific isobutyl-methyl-xanthine-insensitive phosphodiesterase 8B was absent in the normal pituitary but detectable in almost all GH-secreting adenomas and higher in gsp+ (P < 0.02). Therefore, this study provides a characterization of phosphodiesterase expression in human pituitary and demonstrates a dramatic induction of the cAMP-specific phosphodiesterases 4C and phosphodiesterases 4D and phosphodiesterases 8B in gsp+ GH-secreting adenomas. Similar levels of cAMP-responsive element-binding protein phosphorylation were observed in gsp- and gsp+ GH-secreting adenomas; however, phosphodiesterase blockade caused an increase in cAMP-responsive element-binding protein phosphorylation that was significantly higher in gsp+ than in gsp- adenomas. Because cAMP-responsive element-binding protein represents the principal end point of the cAMP pathway, these results suggest that the enhanced phosphodiesterase activity may have a significant impact on the phenotypic expression of gsp mutations.

Mutation of somatostatin receptor type 5 in an acromegalic patient resistant to somatostatin analog treatment.

Introduction of somatostatin analogs has greatly contributed to improving the prognosis of acromegaly. Although the majority of patients are effectively treated by these agents, resistance occurs in a subset of patients. So far, resistance to somatostatin has never been associated with mutations of the somatostatin receptor subtypes (sst2 and sst5) that inhibit GH secretion. Molecular analysis of genomic DNA from pituitary tumor and peripheral blood obtained from an acromegalic resistant to octreotide showed a somatic activating mutation of Gsalpha (Arg201Cys), no mutation in sst2, and one polymorphism (Pro109Ser) and one germ line mutation (Arg240Trp) in sst5. Wild-type (WT) and mutant sst5 PCR products were cloned and transfected into Chinese hamster ovary K1 cells. In Chinese hamster ovary K1 cells stably expressing mutant sst5, somatostatin-28 was less potent in inhibiting cyclic AMP levels than in WT cells. Proliferation of mutant cells exceeded that of WT by 50%. Moreover, somatostatin reduced cell growth and MAPK activity in WT but not in mutant cells in which the peptide even increased MAPK activity. We suggest that this mutation that abrogates the antiproliferative action of somatostatin and activates mitogenic pathways may be involved in the resistance to somatostatin treatment.

Growth hormone-releasing hexapeptide (GHRP-6) increases intracellular calcium concentrations in cultured cells from human pituitary adenomas of different types.

OBJECTIVE: The GH-releasing peptide GHRP-6, has been found to interact with specific receptors in somatotrophs, causing cytosolic Ca2+ ([Ca2+]i) rise and GH release. Moreover, this peptide has been demonstrated to stimulate the secretion of pituitary hormones other than GH, i.e. ACTH and prolactin, this effect being generally attributed to a central action. In this study we evaluated whether the pituitary action of this peptide is restricted to cell type of somatotroph lineage. METHODS: The effect opf GHRP-6 on [Ca2+]i was tested in cell preparations obtained from a series of human pituitary adenomas (9 GH-secreting adenomas, 7 nonfunctioning adenomas, 3 ACTH-secreting adenomas, 2 TSH-secreting adenomas and 1 prolactinoma) loaded with the Ca2+ indicator fura-2. RESULTS: GHRP-6, at concentrations higher than 1 nmol/l, significantly increased [Ca2+]i in all tumours, with the exception of the 3 ACTH-secreting adenomas in which the peptide was ineffective at any concentration tested (from 1 nmol/l to 1 micromol/l). By contrast, in all ACTH-secreting adenomas, both corticotrophin-releasing hormone and pituitary adenylate cyclase activating peptide caused a marked [Ca2+]i increase. In tumours responsive to GHRP-6, the peptide caused a typical biphasic [Ca2+]i rise due to Ca2+ mobilization from the intracellular stores and Ca2+ influx through voltage-dependent Ca2+ channels. CONCLUSIONS: These data indicate that almost all tumoral pituitary cell types are targets of GHRP-6 action, the only exception being corticotrophs.

Impact of IGF(CA)19 gene polymorphism on the metabolic response to GH therapy in adult GH-deficient patients.

OBJECTIVE: A polymorphism in the promoter region of the IGF1 gene has been linked to serum IGF1 levels, risk of diabetes, and cardiovascular diseases with conflicting results. The aim of this study was to investigate the impact of this polymorphism on the short-term (1 year, n=98) and long-term (5 years, n=50) metabolic response to recombinant human GH (rhGH) in GH-deficient (GHD) adults. DESIGN AND METHODS: Prospective study on GHD adults. Different genotypes were studied by microsatellite method. According to the most frequent 192 bp allele (19 cytosine-adenosine-repeats), subjects were divided into homozygous (19/19), heterozygous (19/X), and noncarriers (X/X). RESULTS: Basal characteristics of patients as well as their response to rhGH in terms of decrease in body fat percentage and increase in IGF1 levels were not different in the three genotype-groups. Conversely, after 1-year rhGH, a significant worsening of insulin sensitivity (i.e. increase in fasting glucose levels and homeostasis model assessment of insulin resistance) and a significant improvement in lipid profile (i.e. reduction in total cholesterol and LDL-cholesterol) were recorded only in homozygous subjects. In the long-term, insulin sensitivity was restored in all the patients, while a significant improvement in lipid profile was observed in homozygous and heterozygous subjects, but not in noncarrier subjects. No difference in rhGH dose among groups was recorded throughout the study. CONCLUSIONS: In GHD adults, the presence of the WT allele in the IGF1 gene promoter may enhance sensitivity to either negative or positive metabolic changes induced by rhGH.

Role of UGT1A1 and ADH gene polymorphisms in pegvisomant-induced liver toxicity in acromegalic patients.

CONTEXT: Hepatotoxicity is one of the most serious adverse effects in acromegalic patients treated with pegvisomant (PEG-V). Recent studies have found an association between this adverse event and the UGT1A1 allele 28 polymorphism associated with Gilbert's syndrome. OBJECTIVE: To determine whether UGT1A1*28 and alcohol dehydrogenase (ADH) polymorphisms influence liver toxicity during PEG-V treatment. DESIGN AND SETTING: Multicenter observational retrospective study conducted in 13 tertiary care endocrinology units in Italy. PATIENTS: A total of 112 patients with active disease resistant to somatostatin analogs (SSTa) and 108 controls were enrolled. INTERVENTIONS: Clinical and biochemical data were recorded by electronic clinical reporting forms. Blood or DNA samples were sent to the coordinating center for genotyping. RESULTS: No differences in genotypes between patients and controls were found. During PEG-V therapy liver function tests (LFT), abnormalities and overt hepatotoxicity developed in 17 and 4.5% of patients respectively. Logistic and linear regression analyses showed an association between LFT abnormalities during the follow-up visit and prior events of LFT abnormalities in medical history (odds ratio=1.25; P=0.04) and the number of concomitant medications, other than SSTa (B=3.9; P=0.03). No correlation between LFT alterations and UGT1A1 allele 28 as well as ADH1C and B polymorphisms was found. CONCLUSIONS: UGT1A1 allele 28 and ADH1C and B polymorphisms do not predict increased risk of hepatotoxicity during PEG-V therapy. Conversely, patients with multi-therapies and with previous episodes of liver disease should be carefully managed, due to the observed association between these conditions and LFT abnormalities during PEG-V therapy.

Growth hormone receptor variants and response to pegvisomant in monotherapy or in combination with somatostatin analogs in acromegalic patients: a multicenter study.

CONTEXT: The influence of full-length GH receptor (GHR) and exon 3-deleted GHR (d3GHR) on responsiveness to pegvisomant (PEG-V) in acromegalic patients is uncertain. OBJECTIVE: The aim of the study was to assess the distribution of GHR genotypes in a large series of patients on PEG-V therapy and their influence on treatment efficacy and adverse effects. DESIGN AND SETTING: A cross-sectional multicenter pharmacogenetic study was conducted in 16 Italian endocrinology centers of major universities and tertiary care hospitals. PATIENTS: The study included 127 acromegalic patients enrolled from 2009 to 2010 not cured by previous surgery, radiotherapy, and long-acting somatostatin (SST) analogs, treated with PEG-V. INTERVENTION AND MAIN OUTCOME MEASURE: Sixty-three of 127 patients received combined PEG-V + SST analog therapy. Clinical and hormonal data at diagnosis and before and during PEG-V therapy were inserted in a database. GHR exon 3 deletion and other polymorphisms were genotyped by the coordinator center. Differences in PEG-V dosage required for IGF-I normalization and occurrence of adverse effects between carriers and noncarriers of GHR variants were evaluated. RESULTS: d3GHR variants were not in Hardy-Weinberg equilibrium (P = 0.008). No association of these variants with PEG-V dose required for IGF-I normalization, adverse effects occurrence, and tumor regrowth was found in patients on PEG-V and on PEG-V + SST analog treatment. Similar data were obtained considering the GHR variant rs6180. CONCLUSIONS: This study did not confirm a better response of d3GHR to PEG-V treatment in acromegaly. Other studies are needed to determine whether deviation from Hardy-Weinberg equilibrium may indicate an association of d3GHR genotype with poor response to usual treatments.

GH response to oral glucose tolerance test: a comparison between patients with acromegaly and other pituitary disorders.

CONTEXT: The cutoff value of nadir GH after an oral glucose tolerance test (OGTT) used to define disease remission in acromegaly is higher than that observed in healthy subjects. However, it is uncertain whether the impaired GH inhibition might be related to subtle abnormalities of GH secretion or to functional and/or anatomical hypothalamic-pituitary disconnection due to tumor per se or treatments. OBJECTIVE: The objective of the study was to evaluate the impact of pituitary disorders other than acromegaly on GH response to OGTT. DESIGN, SUBJECTS, AND METHODS: Thirty-three patients (24 females and nine males, aged 50.1 ± 12.3 yr, 13 operated and two irradiated) with various hypothalamic-pituitary disorders (HPDs), 45 healthy subjects (controls), and 42 cured acromegalic patients matched for sex, age. and body mass index were investigated. All subjects were studied for IGF-I levels and GH levels before and during the OGTT. RESULTS: In HPD patients mean postglucose nadir GH levels were 0.11 ± 0.08 µg/liter without any difference between patients treated with neurosurgery and/or radiotherapy and untreated and between patients with and without pituitary stalk alterations and/or hyperprolactinemia. Mean nadir GH values were similar in HPD patients and controls (0.11 ± 0.08 vs. 0.08 ± 0.08 µg/liter, P = 0.23) and lower than those found in cured acromegalic patients (0.18 ± 0.13 µg/liter, P = 0.02), although there was an overlapping in about half of patients. CONCLUSIONS: Hypothalamic control of glucose-mediated GH suppression is not perturbed in patients with HPD. These data indicate that defective GH suppression to glucose that is found in acromegaly is unlikely to reflect a lack of integrity of hypothalamic function.

Pharmacogenetics of D2 dopamine receptor gene in prolactin-secreting pituitary adenomas.

IMPORTANCE OF THE FIELD: Dopamine-agonists are the treatment of choice of prolactin-secreting pituitary adenomas (PRL-omas). Their actions on D2 dopamine receptor (DRD2) and the clinical outcome may be affected by polymorphisms. AREAS COVERED IN THIS REVIEW: PRL-omas are well-differentiated endocrine tumors expressing DRD2. The dopamine-agonist cabergoline (CB), normalizes prolactin and reduces tumor size in about 80 - 90% of patients. DRD2 polymorphisms correlate with neuropsychiatric disorders, in particular alcoholism and schizophrenia. This review describes the DRD2 polymorphisms, their functional effects, and their impact on susceptibility and response to dopamine-agonists treatment. Searching PubMed database for pertinent articles we found that some DRD2 polymorphisms, particularly TaqIA, TaqIB and NcoI, are associated with different receptor binding in brain areas. One study carried out in patients with PRL-omas found a correlation between NcoI and TaqIA and resistance to CB. In particular, resistant patients had higher prevalence of NcoI-T allele than the responsive patients, while the commonest haplotype (having TaqIA2 allele) was associated with better response. WHAT THE READER WILL GAIN: This review deals with the connection between DRD2 polymorphisms and PRL-oma treatment and suggests hypotheses for further studies. TAKE HOME MESSAGE: Only one study was carried out to analyze the role of DRD2 polymorphisms in PRLomas response to CB. Further studies, including pituitary and hypothalamus in vivo determination of DRD2 binding according to DRD2 genotypes, investigation of possible post-receptorial mechanisms involved, as well as population studies in collaboration with psychiatrists and neurologists, are needed.

Analysis of genetic variants of phosphodiesterase 11A in acromegalic patients.

OBJECTIVES: Aberrant cAMP signaling is involved in the pathogenesis of somatotropinomas. The aim of the study was to screen acromegalic patients for the presence of variants of phosphodiesterase type 11A (PDE11A) gene, which have been recently identified in adrenocortical and testicular tumors. SUBJECTS AND METHODS: We sequenced the PDE11A gene-coding region in 78 acromegalic patients and 110 controls. Immunohistochemistry for PDE11A was performed in a subgroup of adenomas and normal pituitary samples. RESULTS: We found 15 nonsynonymous germline substitutions in 13 acromegalic patients (17%), i.e. 14 missense variants (Y727C in six, R804H in one, R867G in four, and M878V in three) and one truncating mutation (FS41X), with a prevalence only slightly higher than that observed in controls (14%). Immunohistochemistry revealed PDE11A expression higher in somatotropinomas than in normal somatotrophs, without significant difference between tumors with or without PDE11A variants, with the exception of two tumors (one with loss of heterozygosity (LOH) at the PDE11A locus and one with FS41X mutation) showing markedly reduced PDE11A staining. No significant differences in hormonal and clinical parameters between patients with or without PDE11A variants were observed, although patients with PDE11A changes showed a tendency to have a more aggressive tumor compared with patients with wild-type sequence (extrasellar extension in 69 vs 45%). CONCLUSIONS: This study first demonstrated the presence of PDE11A variants in a subset of acromegalic patients, which was only slightly more frequent than in controls. The normal expression of the enzyme in the majority of tumor tissues together with the lack of significant clinical phenotype suggests that these variants might only marginally contribute to the development of somatotropinomas.