Biomedical subjects

Anna Spada

Publications and source records attributed to Anna Spada.

At least 19 recordsLinked to original sources

PubMed2006

HESX1 expression in human normal pituitaries and pituitary adenomas.

Hesx1 is a paired-like homeobox gene first expressed during mouse embryogenesis in the anterior midline visceral endoderm. As gastrulation proceeds, Hesx1 is expressed in the ventral prosencephalon and, subsequently, at E9.0 appears in the ventral diencephalon and in the thickened layer of oral ectoderm that give rise to Rathke's pouch, the primordium of the anterior pituitary gland. Hesx1 continues to be expressed in the developing anterior pituitary until E11.5 when its transcripts disappear in a spatiotemporal sequence corresponding to progressive pituitary cell differentiation, becoming undetectable by E15.5. In the present study, we investigated whether HESX1 is expressed during adult life in human normal pituitaries and in different types of human pituitary adenomas. We analysed, using quantitative RT-PCR method, three normal pituitaries, seven GH-, two TSH-, two PRL-, one ACTH-secreting adenomas, and seven nonfunctioning pituitary tumors. HESX1 mRNA was found to be expressed in normal pituitaries and in all the pituitary tumors that we have analysed. These results suggest that in humans HESX1 is not turned-off during the adult life as it occurs in mice. Thus, HESX1 in humans might play a role in the maintenance of the anterior pituitary cell types and function, as well as in the differentiation of pituitary adenomas, whose pathogenetic mechanisms remain to be further investigated. This is the first study on HESX1 expression in humans during adult life.

Adenoma↗

PubMed2006

Mutations in the Gs alpha gene causing hormone resistance.

G-protein-coupled receptors (GPCRs) and G proteins mediate the effects of a number of hormones of relevance to endocrinology. Genes encoding these molecules may be targets of loss- or gain-of-function mutations, resulting in endocrine disorders. The only mutational change of G proteins so far unequivocally associated with endocrine disorders occurs in the Gsalpha gene (GNAS1, guanine nucleotide binding protein alpha stimulating activity polypeptide 1), which activates cyclic AMP (cAMP)-dependent pathways. Heterozygous loss-of-function mutations of GNAS1 in the active maternal allele cause resistance to hormones acting through Gsalpha-coupled GPCRs, whereas somatic gain-of-function mutations cause proliferation of endocrine cells recognizing cAMP as mitogen. This review will focus on inactivating mutations leading to hormone resistance syndromes, i.e., pseudohypoparathyroidism types Ia and Ib.

Chromogranins↗

PubMed2006

Mechanisms of disease: Mutations of G proteins and G-protein-coupled receptors in endocrine diseases.

G proteins and G-protein-coupled receptors (GPCRs) mediate the effects of a number of hormones. Genes that encode these molecules are subject to loss-of function or gain-of-function mutations that result in endocrine disorders. Loss-of-function mutations prevent signaling in response to the corresponding agonist and cause resistance to hormone actions, which mimics hormone deficiency. Gain-of-function mutations lead to constitutive, agonist-independent activation of signaling, which mimics hormone excess. Disease-causing mutations of GPCRs have been identified in patients with various disorders of the pituitary-thyroid, pituitary-gonadal and pituitary-adrenal axes, and in those with abnormalities in food intake, growth, water balance and mineral-ion turnover. The only mutational changes in G proteins unequivocally associated with endocrine disorders occur in GNAS (guanine nucleotide-binding protein G-stimulatory subunit alpha, or G(s)alpha). Heterozygous loss-of-function mutations of GNAS in the active, maternal allele cause resistance to hormones that act through G(s)alpha-coupled GPCRs, whereas somatic gain-of-function mutations cause proliferation of endocrine cells that recognize cyclic AMP as a mitogen. The study of mutations in G proteins and GPCRs has already had major implications for understanding the molecular basis of rare endocrine diseases, as well as susceptibility to multifactorial disorders that are associated with polymorphisms in these genes.

Adrenal Glands↗

PubMed2006

Effect of recombinant hGH (rhGH) replacement on gonadal function in male patients with organic adult-onset GH deficiency.

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.

Adult↗

PubMed2006

Resistance to growth hormone releasing hormone and gonadotropins in Albright's hereditary osteodystrophy.

Heterozygous inactivating mutations in the Gs alpha gene cause Albright's hereditary osteo-dystrophy (AHO). Consistent with the observation that only maternally inherited mutations lead to resistance to hormone action (pseudohypoparathyroidism type Ia [PHP-Ia), recent studies have provided evidence for a predominant maternal origin of Gs alpha transcripts in endocrine organs, such as thyroid, gonad and pituitary. Accordingly, patients with PHP-Ia display variable degrees of resistance to parathyroid hormone (PTH), thyroid stimulating hormone (TSH), gonadotropins and growth hormone (GH) releasing hormone (GHRH). Although the incidence and the clinical and biochemical characteristics of PTH and TSH resistance have been widely investigated and described, the cause and significance of the reproductive dysfunction in AHO is still poorly understood. The clinical finding of alterations of GH secretion in these patients was described for the first time only 2 years ago. The present report briefly reviews the literature focusing on the actual knowledge about these last two subjects.

Female↗

PubMed2006

DAX1 and X-linked adrenal hypoplasia congenita: clinical and molecular analysis in five patients.

OBJECTIVE: Mutations in the gene coding for the orphan nuclear receptor DAX1 cause X-linked adrenal hypoplasia congenita (AHC). Affected boys usually present with primary adrenal failure in early infancy or childhood. Impaired sexual development due to hypogonadotropic hypogonadism becomes manifest at the time of puberty. Moreover, evidence from Dax1 knockout mice and a limited number of patients with AHC, suggests that mutations in DAX1 may directly cause abnormalities in spermatogenesis. The aim of this study was to characterize clinically and genetically five patients with AHC. DESIGN: DNA sequencing analysis, endocrine testing, testicular ultrasound and semen analysis with 1-year follow-up after gonadotropin treatment. METHODS: We report on five men with classic AHC manifestations. Genomic DNA was extracted from patients' peripheral blood leukocytes and the coding region, splice sites, and promoter (-240 bp) region of DAX1 were directly sequenced. RESULTS: Three known and two novel mutations were detected in the DAX1 coding sequence in these patients. Semen analysis was performed in four of the five patients and showed azoospermia. Twelve-month treatment with gonadotropins did not restore fertility in these patients. All patients showed a normal testicular Doppler ultrasound, in contrast with that observed in Dax1-deficient mice, which display abnormalities in the rete testis. CONCLUSIONS: These cases further expand the number of DAX1 mutations reported in the literature, as well as our clinical knowledge of this rare disease.

Adolescent↗

PubMed2006

Non-functioning pituitary adenoma database: a useful resource to improve the clinical management of pituitary tumors.

OBJECTIVE: The long-term outcome of non-functioning pituitary adenoma (NFPA) patients is not clearly established, probably due to the low annual incidence and prolonged natural history of these rare tumors. The aim of this study was to evaluate clinical data at presentation and long-term post-surgery and radiotherapy outcome in a cohort of patients with NFPA. DESIGN AND METHODS: A computerized database was developed using Access 2000 software (Microsoft Corporation, 1999). Retrospective registration of 295 NFPA patients was performed in seven Endocrinological Centers of North West Italy. Data were analyzed by STATA software. RESULTS: The main presenting symptoms were visual defects (67.8%) and headache (41.4%) and the most frequent pituitary deficit was hypogonadism (43.3%), since almost all tumors were macroadenomas (96.5%). Surgery was the first choice treatment (98% of patients) and total debulking was achieved in 35.5%. Radiotherapy was performed as adjuvant therapy after surgery in 41% of patients. At the follow-up, recurrence occurred in 19.2% of patients without post-surgical residual tumor after 7.5 +/- 2.6 years, regrowth in 58.4% of patients with post-surgical remnant after 5.3 +/- 4.0 years and residue enlargement in 18.4% of patients post-surgically treated with radiotherapy after 8.1 +/- 7.3 years. CONCLUSIONS: Our database indicates that the goal of a definitive surgical cure has been achieved during the last decade in a low percentage of patients with NFPA. This tumor database may help to reduce the delay between symptom onset and diagnosis, to assess prognostic parameters for the follow-up of patients with different risk of recurrence and to define the efficacy and safety of different treatments and their association with mortality/morbidity.

Adenoma↗

PubMed2005

Comparison between six-year therapy with long-acting somatostatin analogs and successful surgery in acromegaly: effects on cardiovascular risk factors.

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.

Acromegaly↗

PubMed2005

Expression of the antiapoptotic gene seladin-1 and octreotide-induced apoptosis in growth hormone-secreting and nonfunctioning pituitary adenomas.

CONTEXT: Seladin-1 (from selective Alzheimer's disease indicator-1) is a recently discovered gene that has been found to be down-regulated in brain regions affected by Alzheimer's disease. Seladin-1 effectively protects neurons against beta-amyloid-mediated toxicity and prevents apoptosis via inhibition of the activation of caspase-3, a key mediator of the apoptotic cascade. Although seladin-1 is expressed in the pituitary gland, no study addressed the expression or the function of this gene in pituitary adenomas. OBJECTIVE: The aim of the present study was to determine the expression level of the seladin-1 gene in pituitary tumors, i.e. GH-secreting and nonfunctioning pituitary adenomas (NFPA), and to determine whether differential expression might be associated with different somatostatin (sst)-induced apoptosis. RESULTS: We found by quantitative real-time RT-PCR that the expression level of seladin-1 was significantly higher in NFPA (n = 21) than in GH-secreting adenomas (n = 30; mean +/- se, 25.69 +/- 6.39 vs. 8.02 +/- 2.68 pg/microg total RNA; P = 0.006). Although the amount of activated caspase-3 did not differ between the two groups of tumors, in primary cell cultures, octreotide was able to increase apoptosis, evaluated by the level of cleaved cytokeratin 18 and the presence of apoptotic nuclei, in GH-secreting adenomas, but not in NFPA. This different response was not attributable to differences in the amount of transcript of sst receptors 2 and 5, which was similar in the two groups of tumors. CONCLUSIONS: Our results suggest that differential seladin-1 expression in pituitary adenomas may be associated with a different apoptotic response to sst analogs.

Adenoma↗

PubMed2005

Expression of the two alternatively spliced PRKAR1A RNAs in human endocrine glands.

Heterozygous loss of function mutations in human PKAR1A gene (PRKAR1A) have been identified in patients with Carney complex (CNC), an autosomal dominant familial multiple neoplasia syndrome displaying different endocrine tumors, including adrenocortical tumors, GH-secreting pituitary tumors and thyroid adenomas. Although PRKAR1A is encoded by a single gene, it is transcribed from at least two different promoters, adjacent to different first non-coding exons (1a and 1b), giving rise to alternately spliced transcripts coding for identical proteins. The separate regulation of the two distinct promoters and the presence of multiple alternatively spliced first exons suggest a complex mechanism of PRKAR1A expression regulation. In order to investigate the relative expression of the two mRNA transcripts (1a and 1b) in human adult endocrine tissues involved in the determination of CNC phenotype, we selected 17 pituitary, 20 adrenal and seven thyroid tissues from tumoral and peri-tumoral lesion samples. Expression of the two transcripts was evaluated by semi-quantitative RT-PCR and real-time RT-PCR. This study first reports that human pituitary and thyroid tissues show a similar expression of the two transcripts, whereas in adrenal tissues transcript 1b is the most abundant one.

Adrenal Gland Neoplasms↗

PubMed2005

Pathogenesis of prolactinomas.

In recent years the demonstration that human pituitary adenomas are monoclonal in origin provides further evidence that pituitary neoplasia arise from the replication of a single mutated cell in which growth advantage results from either activation of proto-oncogenes or inactivation of tumor suppressor genes. However, with the exception of one RAS mutation identified in a single unusually aggressive prolactinoma resistant to dopaminergic inhibition that resulted to be lethal, no mutational changes have been so far detected in prolactinomas. In the absence of genetic changes, modifications in the level of expression of oncogenes or tumor suppressor genes have been detected in these tumors, although it is unknown whether these changes have a causative role or are a secondary event. Indeed, our knowledge on the molecular events involved in lactotroph proliferation is even more limited in comparison to the other tumor types, since these tumors are very infrequently surgically removed and therefore available for molecular biology studies. In this respect, it is worth noting that the molecular and biological abnormalities so far described in prolactinomas mainly concern aggressive and atypical tumors and likely do not apply to the typical prolactinomas, that are characterized by good response to medical treatment and a very low growth rate.

Cell Cycle↗

PubMed2005

Somatic mutational analysis of DAX1 in testes from men with idiopathic azoospermia.

Mutations in the orphan nuclear receptor DAX1 (NR0B1) cause X-linked adrenal hypoplasia congenital (AHC), a disorder characterized by primary adrenal failure, hypogonadotropic hypogonadism. and azoospermia. We tested the hypothesis that DAX1 somatic mutations in human testis may cause azoospermia. DAX1 sequencing analysis in 15 testicular biopsy samples from men with idiopathic nonobstructive azoospermia did not reveal mutations in the coding region of the gene. We conclude that somatic abnormalities in DAX1 are absent or uncommon in these patients.

Adult↗

PubMed2005

Ghrelin and adiponectin in patients with Cushing's disease before and after successful transsphenoidal surgery.

BACKGROUND: Ghrelin, an endogenous ligand of the GH secretagogue receptor that exerts orexigenic activity, is negatively correlated with body mass index (BMI) and insulin resistance. Conversely, low levels of adiponectin (ApN), a circulating adipocytokine with antidiabetic, antiatherogenic and anti-inflammatory properties, have been found in several insulin-resistant conditions. Although Cushing's syndrome causes several metabolic and hormonal changes leading to insulin resistance and central obesity, few data concerning the impact of glucocorticoid excess on ghrelin and ApN levels are so far available. DESIGN: We evaluated ghrelin and ApN levels in 14 women (age +/- SE 39.5 +/- 3.9 years, BMI +/- SE 25.8 +/- 1.4 kg/m2) with Cushing's disease (CD) at baseline and after successful transsphenoidal surgery (TSS) and in 14 age- and BMI-matched healthy women. RESULTS: Despite similar levels of fasting glucose, insulin, homeostatic model assessment-estimated insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) values, patients with CD had ghrelin levels lower than controls (117.8 +/- 21.5 vs. 269.6 +/- 51.4 pmol/l, P < 0.01), and ghrelin levels did not correlate with ACTH, cortisol, androgen and GH levels. Patients and controls showed similar ApN levels (11.1 +/- 1.6 vs. 11.5 +/- 2.0 mg/l), which correlated negatively with insulin, HOMA-IR and BMI and positively with QUICKI and high density lipoprotein (HDL)-cholesterol only in controls. At 10.2 +/- 0.7 months after successful TSS, patients showed a significant increase in ghrelin levels compared to pretreatment values (342.5 +/- 25.6 vs. 117.8 +/- 21.5 pmol/l, P < 0.005) along with significant modifications in BMI, insulin, HOMA-IR and HDL-cholesterol and no change in ApN levels. In two patients tested on days 2-4 after TSS, no modification in ghrelin and ApN levels was observed, despite a dramatic reduction in cortisol levels. CONCLUSION: Cortisol excess did not directly affect ghrelin and ApN levels in patients with CD. The observation that ghrelin levels were low during the active phase of CD and increased after recovery suggests that glucocorticoids may influence ghrelin levels indirectly by modulating adiposity and metabolic signals over the long term.

Acute Disease↗

PubMed2004

Proliferation of transformed somatotroph cells related to low or absent expression of protein kinase a regulatory subunit 1A protein.

The two regulatory subunits (R1 and R2) of protein kinase A (PKA) are differentially expressed in cancer cell lines and exert diverse roles in growth control. Recently, mutations of the PKA regulatory subunit 1A gene (PRKAR1A) have been identified in patients with Carney complex. The aim of this study was to evaluate the expression of the PKA regulatory subunits R1A, R2A, and R2B in a series of 30 pituitary adenomas and the effects of subunit activation on cell proliferation. In these tumors, neither mutation of PRKAR1A nor loss of heterozygosity was identified. By real-time PCR, mRNA of the three subunits was detected in all of the tumors, R1A being the most represented in the majority of samples. By contrast, immunohistochemistry documented low or absent R1A levels in all tumors, whereas R2A and R2B were highly expressed, thus resulting in an unbalanced R1/R2 ratio. The low levels of R1A were, at least in part, due to proteasome-mediated degradation. The effect of the R1/R2 ratio on proliferation was assessed in GH3 cells, which showed a similar unbalanced pattern of R subunits expression, and in growth hormone-secreting adenomas. The R2-selective cAMP analog 8-Cl cAMP and R1A RNA silencing, stimulated cell proliferation and increased Cyclin D1 expression, respectively, in human and rat adenomatous somatotrophs. These data show that a low R1/R2 ratio promoted proliferation of transformed somatotrophs and are consistent with the Carney complex model in which R1A inactivating mutations further unbalance this ratio in favor of R2 subunits. These results suggest that low expression of R1A protein may favor cAMP-dependent proliferation of transformed somatotrophs.

Adenoma↗

PubMed2004

Long-term evaluation of postoperative acromegalic patients in remission with previous and newly proposed criteria.

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.

Acromegaly↗

PubMed2004

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. 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.

Adiponectin↗

PubMed2004

Parental origin of Gsalpha mutations in the McCune-Albright syndrome and in isolated endocrine tumors.

Activating mutations of the Gsalpha gene are detected in different endocrine tumors, such as GH-secreting adenomas and toxic thyroid adenomas, and in hyperfunctioning glands from patients with McCune-Albright syndrome (MAS). There is increasing evidence that the Gsalpha gene is subjected to imprinting control and that Gsalpha imprinting plays a key role in the pathogenesis of different human diseases. The aim of this study was to investigate the presence of a parent specificity of Gsalpha mutations in 10 patients affected with MAS and 12 isolated tumors (10 GH-secreting adenomas, one toxic thyroid adenoma, and one hyperfunctioning adrenal adenoma). The parental origin of Gsalpha mutations was assessed by evaluating NESP55 and exon 1A transcripts, which are monoallelically expressed from the maternal and paternal alleles, respectively. By this approach, we demonstrated that in isolated GH-secreting adenomas, as well as in MAS patients with acromegaly, Gsalpha mutations were on the maternal allele. By contrast, the involvement of other endocrine organs in MAS patients was not associated with a particular parent specificity, as precocious puberty and hyperthyroidism were present in patients with mutations on either the maternal or the paternal allele. Moreover, isolated hyperfunctioning thyroid and adrenal adenomas displayed the mutation on the maternal and paternal alleles, respectively. These data confirm the importance of Gsalpha imprinting in the pituitary gland and point out the high degree of tissue specificity of this phenomenon.

Adenoma↗

PubMed2004

Biallelic expression of the Gsalpha gene in human bone and adipose tissue.

Mutations of the Gsalpha gene inherited from the mother lead to pseudohypoparathyroidism (PHP) type Ia (PHP Ia), in which Albright's hereditary osteodistrophy is associated to resistance to the action of different hormones, whereas the same mutations inherited from the father lead to isolated Albright's hereditary osteodistrophy [pseudo-PHP (PPHP)]. Accordingly, it has been suggested that Gsalpha is under tissue-specific imprinting control, and recent studies provided evidence for a predominant maternal origin of Gsalpha transcripts in different endocrine organs involved in the PHP Ia phenotype. To establish whether Gsalpha is imprinted also in tissues that are site of alteration both in PHP Ia and PPHP, we selected 20 bone and 10 adipose tissue samples, which were heterozygous for a known polymorphism in exon 5. Expression from both parental alleles was evaluated by RT-PCR and enzymatic digestion of the resulting fragments. By this approach, the great majority of the samples analyzed showed an equal expression of the two alleles. Our results provide evidence for the absence of Gsalpha imprinting in human bone and fat and suggest that the clinical finding of osteodystrophy and obesity in PHP Ia and PPHP patients despite the presence of a normal Gsalpha allele is likely due to Gsalpha haploinsufficiency in these tissues.

Adipose Tissue↗