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Biomedical subjects

Anna Spada

Publications and source records attributed to Anna Spada.

32 records · Page 2Linked to original sources
PubMed2004

Effect of recombinant human growth hormone (GH) replacement on the hypothalamic-pituitary-adrenal axis in adult GH-deficient patients.

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.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2003

Circulating ghrelin levels in celiac patients.

OBJECTIVE: Ghrelin, the gut-brain peptide, recently identified as the natural endogenous ligand for growth hormone secretagogue receptors, exerts various endocrine and nonendocrine effects, including the control of energy homeostasis and food intake, but its possible relevance in malabsorption syndromes is unknown. Therefore, the aim of this study was to evaluate circulating ghrelin levels in adults with untreated and treated celiac disease (CD) and, for comparison, in healthy subjects. METHODS: Fasting serum ghrelin levels were measured in 30 consecutive patients with newly diagnosed CD, 13 celiac patients successfully treated with a gluten-free diet (GFD), and 30 healthy controls. RESULTS: Ghrelin levels were abnormally high in patients with active CD compared with controls (297 +/- 17.6 vs 218 +/- 15.2 pmol/L, p<0.01) and correlated positively with intestinal mucosal lesion severity (rs=0.444, p<0.02). In the successfully GFD-treated patients, ghrelin values were normal compared with controls (233 +/- 22.0 vs 218 +/- 15.2 pmol/L, ns) and, moreover, correlated negatively with body mass index (r=-0.632, p=0.02), unlike in the untreated patient group (r=-0.263, ns). CONCLUSION: High ghrelin levels characterized our series of adult patients with newly diagnosed CD and correlated significantly with the degree of severity of intestinal mucosal lesions. This is the first evidence of a relationship between ghrelin and inflammatory processes, but the mechanisms involved are still unclear. Furthermore, our findings suggest that an interplay of hormonal, metabolic, and nutritional factors could influence ghrelin secretion under pathophysiological circumstances.

Adolescent↗
PubMed2003

Genetics of pituitary tumors: Focus on G-protein mutations.

In recent years the demonstration that human pituitary adenomas are monoclonal in origin has provided 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. While common oncogenes, such as Ras, are only exceptionally involved, the only mutations identified in a significant proportion of pituitary tumors, and particular in GH-secreting adenomas, occur in the Gsalpha gene (GNAS1) and cause constitutive activation of the cAMP pathway (gsp oncogene). Moreover, pituitary tumors overexpress hypothalamic releasing hormones, growth factors, and their receptors as well as cyclins involved in cell cycle progression. As far as the role of tumor suppressor genes in pituitary tumorigenesis is concerned, reduced expression of these genes seems to frequently occur in pituitary tumors as a consequence of abnormal methylation processes. Although the only mutational change so far identified in pituitary tumors is the gsp oncogene, this oncogene is not associated with a clear phenotype in patients bearing positive tumors. Mechanisms able to counteract the cAMP pathway, such as high sensitivity to somatostatin, and induction of genes with opposite actions, such as phosphodiesterases, CREB end ICER, or instability of mutant Gsalpha, have been proposed to account for the lack of genotype/phenotype relationships.

Animals↗
PubMed2003

An alternate translation initiation site circumvents an amino-terminal DAX1 nonsense mutation leading to a mild form of X-linked adrenal hypoplasia congenita.

Mutations in DAX1 [dosage-sensitive sex reversal-adrenal hypoplasia congenita (AHC) critical region on the X chromosome gene 1; NR0B1] cause X-linked AHC, a disease characterized by primary adrenal failure in infancy or childhood and reproductive abnormalities later in life. Most of these patients have nonsense or frameshift mutations that cause premature truncation of the DAX1 protein, thereby eliminating its transcriptional silencing activity. We evaluated a patient with an unusual form of AHC manifest as late-onset adrenal insufficiency and gonadal failure. DNA sequence analysis revealed a novel amino-terminal DAX1 nonsense mutation (Q37X), predicted to cause a severe truncation of the protein. Using a combination of in vitro translation assays and studies of DAX1 expression and function in transfected cells, we demonstrate that, in contrast to more distal mutations leading to a nonfunctional protein, this mutation is associated with a milder phenotype due to the expression of a partially functional, amino-truncated DAX1 protein generated from an alternate in-frame translation start site (methionine, codon 83). The production of this amino-truncated isoform appears to rescue the classical AHC phenotype, thereby delaying the onset of clinically significant adrenal dysfunction until early adulthood. Thus, this case demonstrates a relatively rare phenomenon by which the clinical severity of an inherited human disease is reduced after alternate translation from a site downstream of a premature stop codon.

Adrenal Hyperplasia, Congenital↗
PubMed2003

Growth hormone-releasing hormone resistance in pseudohypoparathyroidism type ia: new evidence for imprinting of the Gs alpha gene.

Heterozygous inactivating mutations in the Gs alpha gene cause Albright's hereditary osteodystrophy. Consistent with the observation that only maternally inherited mutations lead to resistance to hormone action [pseudohypoparathyroidism type Ia (PHP Ia)], recent studies provided evidence for a predominant maternal origin of Gs alpha transcripts in endocrine organs, such as thyroid, gonad, and pituitary. The aim of this study was to investigate the presence of pituitary resistance to hypothalamic hormones acting via Gs alpha-coupled receptors in patients with PHP Ia. Six of nine patients showed an impaired GH responsiveness to GHRH plus arginine, consistent with a complete GH deficiency (GH peak from 2.6-8.6 microg/liter, normal > 16.5), and partial (GH peak 13.9 and 13.6 microg/liter) and normal responses were found in two and one patient, respectively. Accordingly, IGF-I levels were below and in the low-normal range in seven and two patients. All patients had a normal cortisol response to 1 microg ACTH test, suggesting a normal corticotroph function that was confirmed by a normal ACTH and cortisol response to CRH test in three patients. In conclusion, we report that in addition to PTH and TSH resistance, patients with PHP Ia display variable degrees of GHRH resistance, consistent with Gs alpha imprinting in human pituitary.

Adrenocorticotropic Hormone↗
PubMed2003

Circulating levels of ghrelin in human fetuses.

OBJECTIVE: Ghrelin is a GH secretagog isolated recently from rat stomach and involved in the stimulation of food intake and adiposity in rodents and humans. Moreover, subsequent studies showed that ghrelin is expressed in rat and human placenta, suggesting a possible influence of the peptide on fetal growth. The aim of this study was to evaluate circulating levels of ghrelin in appropriate for gestational age (AGA) or intrauterine growth-restricted (IUGR) fetuses. SUBJECTS AND METHODS: Ghrelin levels between 20 and 39 weeks of gestation were measured in 16 AGA and nine IUGR fetuses in whom blood was collected by cordocentesis performed for prenatal diagnosis of different diseases or during elective cesarean section. In most samples, GH, cortisol and leptin levels were also evaluated. Results are expressed as means+/-S.D. Differences were tested using the Student's t-test with Welch correction. P<0.05 was considered significant. RESULTS: All fetuses showed levels of ghrelin in the umbilical venous blood (100+/-99 pmol/l) that did not correlate with the gestational age or the maternal ghrelin levels. No difference was found between umbilical venous and arterial concentrations, suggesting that fetal tIssues are a source of ghrelin. Ghrelin levels in IUGR fetuses were significantly higher than those found in AGA fetuses (176+/-125 vs 58+/-44 pmol/l; P<0.005). Moreover, in samples obtained at birth, ghrelin concentrations correlated negatively with birth weight (P<0.05). In IUGR fetuses, GH and cortisol concentrations were higher and leptin levels lower than in AGA fetuses, although no significant correlation between these parameters and ghrelin levels was found. CONCLUSION: The presence of ghrelin in the fetal circulation as well as its increase in IUGR fetuses suggest a role of this peptide during intrauterine development.

Adult↗
PubMed2002

Growth factors and human pituitary adenomas.

In recent years the demonstration that human pituitary adenomas are monoclonal provides further evidence of genomic mutations occurring in the progenitor cell that subsequently undergoes clonal expansion. Up to now the only mutations identified in a significant proportion of pituitary tumors, and particular in GH-secreting adenomas, occur in the Gsalpha gene and cause constitutive activation of the cAMP pathway. Subsequent studies revealed that these mutations are associated with several feedback mechanisms that, at least in part, counteract the oncogenic potential of mutant Gsalpha. As far as the promoting agents are concerned, several lines of evidence indicate that in pituitary tumors growth factors or their receptors may be overexpressed at variable levels. The contribution of these defects in human pituitary tumorigenesis remains to be established.

Adenoma↗
PubMed2002

Serum activin A levels in different thyroid disorders.

Activin A belongs to the transforming growth factor-beta superfamily that exerts a wide range of biologic activities on cellular proliferation and differentiation. Although it was suggested that gonadal tissue is the primary site of activin production, several extragonadal sources have subsequently been identified, including human thyrocytes. The goal of the present study was to evaluate serum activin A levels in a series of patients with different thyroid disorders during the active state of the diseases and after recovery. Serum activin A levels were evaluated in 60 healthy subjects (controls), 8 with multinodular nontoxic goiter (MNG), 30 hyperthyroid (15 with Graves' disease (GD), 12 with autonomous hyperfunctioning adenoma (ATA), and 3 with thyrotropin (TSH)-secreting pituitary adenoma, 16 hypothyroid (11 with Hashimoto's thyroiditis and 5 after total thyroidectomy), and 9 patients with resistance to thyroid hormone (RTH) by commercial enzyme-linked immunosorbent assay (ELISA) kit. Patients with GD and ATA showed activin A levels higher than those found in controls and similar to those observed in MNG (GD, 0.74 +/- 0.3 ng/mL; ATA, 0.86 +/- 0.4; and MNG; 1.0 +/- 0.2 vs. controls: 0.39 +/- 0.5, p < 0.001), while in patients with Hashimoto's thyroiditis, total thyroidectomy or RTH activin A levels were similar to those of controls. In conclusion, this study demonstrates that thyroid hyperplasia and hyperfunction result in increased levels of activin A, although the normal levels observed in thyroidectomized patients clearly demonstrate that the thyroid gland is not the predominant source of activin A in normal conditions. Because activin A may exert negative action on thyrocyte proliferation, it is conceivable that activin A hypersecretion in thyroid disorders might represent a counteracting mechanism.

Activins↗
PubMed2002

The gsalpha gene: predominant maternal origin of transcription in human thyroid gland and gonads.

Mutations in the guanine nucleotide binding alpha-subunit 1 gene (GNAS1) cause Albright's hereditary osteodistrophy, and the parent of transmission determines variable phenotypic expression of the disease. This has suggested that GNAS1 may be under tissue-specific imprinting control, although studies so far available have failed to clearly define the pattern of GNAS1 expression in humans. To establish if GNAS1 is imprinted in human endocrine tissues, we selected 14 thyroid, 10 granulosa cell, 13 pituitary (3 normal glands, 7 GH-secreting adenomas, and 3 nonfunctioning adenomas), 3 adrenal, and 11 lymphocyte samples shown to be heterozygous for a known polymorphism in exon 5. RNA from these tissues was analyzed by RT-PCR, and expression from both parental alleles was evaluated by enzymatic digestion and subsequent quantification of the resulting fragments. The parental origin of Gs alpha was assessed by evaluating neuroendocrine secretory protein 55 and extra large alphas-like protein transcripts, which have been shown to be monoallelically and parent-specifically expressed from the maternal and paternal allele, respectively. By this approach, the great majority of thyroid (n = 12), ovarian (n = 7), and pituitary (n = 11) samples showed an almost exclusive or significantly predominant expression of the maternal allele over the paternal one, whereas in lymphocyte and adrenal samples both alleles were equally expressed. Our results provide evidence for a predominant maternal origin of GNAS1 transcripts in different human adult endocrine tissues, particularly thyroid, ovary, and pituitary, and strongly suggest that this mechanism may play a crucial role in the determination of the phenotypic expression of Albright's hereditary osteodistrophy.

Adenoma↗
PubMed2002

Hypogonadotropic hypogonadism as a presenting feature of late-onset X-linked adrenal hypoplasia congenita.

Mutations in the orphan nuclear receptor DAX-1 cause X-linked adrenal hypoplasia congenita. Affected boys usually present with primary adrenal failure in early infancy or childhood. Impaired sexual development because of hypogonadotropic hypogonadism becomes apparent at the time of puberty. We report adult-onset adrenal hypoplasia congenita in a patient who presented with hypogonadism at 28 yr of age. Although he had no clinical evidence of adrenal dysfunction, compensated primary adrenal failure was diagnosed by biochemical testing. Semen analysis showed azoospermia, and he did not achieve fertility after 8 months of treatment with gonadotropins. A novel Y380D DAX-1 missense mutation, which causes partial loss of function in transient gene expression assays, was found in this patient. This case demonstrates that partial loss-of-function mutations in DAX1 can present with hypogonadotropic hypogonadism and covert adrenal failure in adulthood. Further, an important role for DAX-1 in spermatogenesis in humans is confirmed, supporting findings in the Dax1 (Ahch) knockout mouse.

Adrenal Glands↗
PubMed2002

Circulating ghrelin levels in basal conditions and during glucose tolerance test in acromegalic patients.

BACKGROUND: Ghrelin exerts a wide range of metabolic functions. In contrast to the body of information accumulated on the role of ghrelin on energy balance, the possible relevance of the peptide on GH secretion in physiological and pathological conditions has so far been poorly investigated. AIM: The aim of the present study was to evaluate circulating ghrelin levels in acromegalic patients in basal conditions and in response to oral glucose tolerance test (OGTT). PATIENTS: Serum ghrelin, insulin and leptin levels were measured in 31 healthy normal weight subjects as controls, 25 patients with simple obesity and 17 non-diabetic acromegalic patients. Ghrelin and insulin response to OGTT was evaluated in six controls, four obese and six acromegalic patients. RESULTS: The acromegalic patients showed ghrelin levels lower than those observed in normal weight subjects (201+/-20 vs 329+/-32 pmol/l, P<0.05) and similar to those found in obese subjects (165+/-14 pmol/l, P=not significant). Both obese and acromegalic patients had insulin levels significantly higher than controls, while high levels of leptin were detected only in obese subjects. Serum ghrelin levels showed a significant negative correlation with insulin, leptin and body mass index (P<0.05) in normal and obese subjects. No correlation was observed in acromegalic patients, although those with severe insulin resistance showed the lowest ghrelin values (161+/-20 pmol/l). In controls and obese subjects, ghrelin levels showed a significant decrease (25-40%) during OGTT, while no effect was detectable in acromegalic patients. CONCLUSIONS: This study reports that patients with active acromegaly show low levels of circulating ghrelin that are not further reduced by OGTT, this pattern of secretion probably depending on both GH-induced insulin resistance and the putative GH/IGF-I negative feedback control on ghrelin secretion.

Acromegaly↗