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G Faglia

Publications and source records attributed to G Faglia.

At least 91 records · Page 5Linked to original sources
PubMed1993

G-proteins and hormonal signalling in human pituitary tumors: genetic mutations and functional alterations.

In the last few years, molecular studies on pituitary adenomas have yielded several lines of evidence supporting a primary pituitary origin for these tumors. In fact, analyses of x-chromosomal inactivation show that the great majority of pituitary tumors are monoclonal in origin, suggesting that one or more mutations are responsible for the selective expansion of a single cell clone. Mutations constitutively activating GTP-binding proteins have been identified in subsets of pituitary adenomas. Single amino acid substitutions replacing Arg 201 with either Cys, His, or Gln 227 with either Arg or Leu of the alpha-subunit of the Gs gene were identified in one third of growth hormone (GH)-secreting adenomas. Both mutations stabilize alpha s in its active conformation by inhibiting GTPase activity, thus mimicking the effect of specific extracellular growth factors, such as growth hormone releasing hormone (GHRH). Since several lines of evidence suggest that cAMP is involved in somatotrope replication, it has been proposed that the alpha s gene can be converted into an oncogene, designated gsp (for Gs protein). Recently, the ras oncogene has been identified in one prolactinoma characterized by unusual invasiveness. Although these data seem to negate a primary role for hypothalamic neurohormones in adenoma formation, it is conceivable that the hormones may exert a role in the sequence of events leading to clonal expansion of a transformed cell. Moreover, alterations in receptor and/or postreceptor events triggered by hypothalamic neurohormones may result in amplification of stimulatory inputs and impairment of inhibitory ones.

Animals↗
PubMed1993

Galanin infusion partially restores the blunted growth hormone responses to repeated growth hormone releasing hormone stimuli in normal adults.

In order to understand the role exerted by the endogenous somatostatinergic tone in the blunting of GH responsiveness to repeated GHRH administration, we evaluated GH responses to the second GHRH bolus during a simultaneous infusion of galanin, which has been reported to inhibit the endogenous somatostatin release. Seven normal adults (3M/4F, age range 19-28 yr), admitted to the study after giving informed consent, were tested on three occasions, with a) two consecutive 1 micrograms/kg iv GHRH boluses administered at 0 min and 120 min, b) one GHRH bolus at 0 min followed by an infusion of 10 micrograms/kg bw galanin (diluted in 40 ml 0.9% NaCl) between 100 min and 140 min and c) two consecutive GHRH boluses (same dose and temporization of administration of test a) associated with a galanin infusion from 100 min to 140 min. GH responses were evaluated as the net incremental area under the curve (GH nAUC/h); all data were expressed as mean +/- SE. GH responses to the first GHRH bolus were similar in the three tests (mean GH nAUC, test A 990 +/- 80, test B: 1006 +/- 112, test C: 1077 +/- 80 ng/ml/h). In test A the second GHRH bolus was unable to sustain GH elevated levels (mean GH nAUC: 32 +/- 12 ng/ml/h vs first GHRH: 990 +/- 80 ng/ml/h, p < 0.0001). Similarly, in test B galanin infusion alone was unable to determine a clear GH rise (mean GH nAUC: -25 +/- 16 vs first GHRH: 1006 +/- 112 ng/ml/h, p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Growth hormone treatment in adults with GH deficiency: effects on new biochemical markers of bone and collagen turnover.

Serum bone Gla protein (BGP) and bone alkaline phosphatase (B-AP), markers of bone formation, carboxyterminal cross-linked telopeptide of type I collagen (ICTP), marker of bone resorption, and aminoterminal propeptide of type III procollagen (PIIINP) levels, index of collagen synthesis, were determined in 8 adults (mean age +/- SE: 29.6 +/- 1.2 yr) with childhood onset GHD before and after 3 and 6 months of recombinant GH treatment (0.5 IU/kg/week). Before treatment, mean BGP (3.8 +/- .5 ng/ml) and B-AP (44.9 +/- 6.9 IU/L) were significantly (P < 0.001 and p < 0.05, respectively) lower than those recorded in normals (5.4 +/- 0.1 ng/ml and 61.8 +/- 1.9 IU/L, respectively), while serum ICTP and PIIINP levels were similar to those found in controls (ICTP: 4.7 +/- 0.8 vs 4.1 +/- 0.3 ng/ml; PIIINP: 3.7 +/- 0.6 vs 3.2 +/- 0.2 ng/ml). BGP and ICTP levels significantly (p < 0.005) increased after 3 (28.4 +/- 5.3 ng/ml and 17.5 +/- 2.8 ng/ml, respectively) and 6 months (25.1 +/- 5.0 ng/ml and 15.0 +/- 1.9 ng/ml, respectively) of recombinant GH treatment. B-AP levels significantly (p < 0.01) increased during the treatment (basal: 44.9 +/- 6.9 IU/L, 3rd month: 173.6 +/- 40 IU/L, 6th month: 194.4 +/- 40 IU/L), while non B-AP levels remained similar to those recorded in basal condition. Serum PIIINP levels significantly (p < 0.0001) rose up after 3 (12.5 +/- 1.4 ng/ml) and 6 months (10.2 +/- 0.8 ng/ml). Serum BGP and ICTP levels were directly (r = 0.85, p < 0.001; r = 0.53, p < 0.01) correlated with serum IGF-I levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Epidemiology and pathogenesis of pituitary adenomas.

Pituitary tumorigenesis is characterized by initiation, implying spontaneous or acquired mutations and promotion, implying that tumour expansion is sustained by intrinsic or extrinsic promoting factors. Pituitary tumours have a doubling time of 100 to 700 days. Seventy per cent of cases occur in 30 to 50-year-old patients, but tumours with highest growth rate (prolactin and ACTH-secreting adenomas) are also encountered in patients < 20 years. Pituitary adenomas occur at a greater frequency in females but there is no vivo evidence for a direct role of sex hormones. Oestrogen can amplify tumour growth factors in pituitary cell lines. One-third of GH-secreting adenomas have elevated cAMP resting levels which appear to be caused by a somatic mutation in the Gs protein associated with the GHRH receptor. This maintains the adenylate cyclase system in a turned-on state. Patients with mutant Gs protein have higher GH levels, reduced GHRH response, elevated TRH response, good suppressibility by SRIH and smaller tumour size compared to other acromegalic patients. Hypothalamic releasing hormones may be able to sustain pituitary tumour development since some acromegalic patients with GHRH-secreting tumours may harbour a pituitary GH-secreting adenoma. A lack of inhibitory factors may also have a promoting role in tumour progression.

Adenoma↗
PubMed1992

The silent corticotropinoma: is clinical diagnosis possible?

Up to now, the diagnosis of silent corticotroph cell pituitary adenomas has been made only on histopathological basis. In this paper we describe 6 women affected with pituitary adenomas, without evident clinical features of hypercortisolism, in whom retrospective data suggested the possibility of clinically diagnosing silent corticotropinomas in vivo. In all patients basal ACTH and cortisol levels were normal, and the low-dose dexamethasone test constantly suppressed serum cortisol and urinary 17-hydroxycorticosteroid levels. The CRH and/or lysine-vasopressin tests, performed in five patients, always induced exaggerated ACTH/cortisol rises. In three cases the response to the opiate agonist loperamide was assessed and no inhibition of ACTH/cortisol levels was found. All patients underwent pituitary surgery. In five cases evidence of corticotropinoma was obtained by immunohistochemistry or immunofluorescence studies; moreover, in one adenoma ACTH was secreted into the culture medium, and in another one CRH and arginine-vasopressin induced a marked intracellular [Ca++] rise. Electron microscopy study of the adenoma, removed from three patients, showed the presence of adenomatous corticotroph cells. Finally, in another woman no hormonal abnormalities were initially observed and she was operated for a "nonfunctioning" pituitary adenoma, but four years later an overt Cushing's disease appeared, suggesting that a silent corticotropinoma subsequently became functional, although the formation of a different adenoma cannot be excluded. In conclusion, the occurrence of ACTH/cortisol hyperresponsiveness to CRH and/or lysine-vasopressin and the lack of suppression of ACTH/cortisol secretion to opioid agonists in patients with apparently "nonfunctioning" pituitary tumors might allow the in vivo recognition of silent corticotropinomas.

17-Hydroxycorticosteroids↗
PubMed1992

Value of serum dehydroepiandrosterone sulfate assay in the evaluation of pituitary-adrenal insufficiency after pituitary adenomectomy.

The value of dehydroepiandrosterone sulfate (DHEA-S), a specific marker of adrenal androgen production, in the assessment of clinical states of hypercortisolism and hypocortisolism has been suggested. Since the way to simply test for ACTH reserve in patients (pts) with pituitary tumors after adenomectomy is not standardized, in this study serum DHEA-S concentration was measured in order to establish whether its determination might be a sensitive index of ACTH deficiency. Serum DHEA-S concentration was evaluated in 29 pts with hypothalamic-pituitary tumors (16 females, 13 males, aged 20-70 yr), 14 of whom had GH-secreting adenomas, 13 nonfunctioning adenomas, 1 prolactinoma and 1 craniopharyngioma. Serum DHEA-S and cortisol (F) levels were determined both before and every day for 8 days after pituitary adenomectomy. Before surgery in all pts mean DHEA-S and F basal values were 3.57 +/- 0.42 mumol/L and 391.8 +/- 29.0 nmol/L, respectively. Eight out of 29 pts showed reduced DHEA-S levels (0.85 +/- 0.19 mumol/L), which remained lower than normal in the postsurgical period; on the contrary, F levels were reduced in only 2 and 3 cases before and after surgery, respectively. In 3 other pts DHEA-S levels were normal before surgery and then were low in the postoperative period, while serum cortisol remained normal in all cases. In most of these patients, the finding of impaired responses to hypothalamic-pituitary-adrenal tests, together with a reduced corticosteroid urinary excretion, confirmed the existence of a secondary hypoadrenalism and the necessity for an adequate replacement therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma↗
PubMed1992

Potential indications for octreotide in endocrinology.

Treatment with Sandostatin is established in acromegaly, thyroid-stimulating hormone (TSH)-producing pituitary, and endocrine-active gastroenteropancreatic tumors. Potential indications include ectopic hormone syndromes, medullary thyroid carcinomas, pituitary resistance to thyroid hormones, tall stature children, diabetes mellitus and diabetic complications, polycystic ovary syndrome, and Graves' ophthalmopathy. Particularly in the ectopic growth hormone-releasing hormone (GHRH) syndrome, Sandostatin is unequivocally effective and, in the ectopic corticotropin syndrome selected cases can be treated successfully with Sandostatin, leading to marked clinical improvement. In many of the above situations, only subgroups show a response to Sandostatin, which may be identified by scintigraphy with labeled Sandostatin. This pertains also to Graves' ophthalmopathy, for which Sandostatin may be particularly promising and where positive and negative Sandostatin scans have been demonstrated. However, for all these potential indications, larger, well-studied series are needed, before definitive conclusions can be drawn.

Acromegaly↗
PubMed1992

Pituitary resistance to thyroid hormones.

Pituitary thyroid hormone resistance (PRTH) refers to a particular form of thyroid hormone refractoriness that is accompanied by peripheral hyperthyroidism, as only the TSH-secreting pituitary cells appear to be resistant to the effects of thyroid hormones. The presence of PRTH is suspected and diagnosed on the basis of the finding of high free thyroid hormone levels along with unsuppressed TSH, clinical signs and symptoms of hyperthyroidism and values of at least one of the parameters evaluating peripheral thyroid hormone action in the hyperthyroid range. However, most patients with PRTH present with clinical signs and symptoms of thyroid dysfunction, particularly goiter and tachycardia, overlapping those recorded in patients with generalized thyroid hormone resistance (GRTH), i.e. refractoriness to thyroid hormones at both pituitary and peripheral tissue level. Moreover, most of them display normal values of other parameters evaluating the peripheral effects of thyroid hormones and bear mutations in the gene encoding for T3 nuclear receptors similar to those found in patients with GRTH. These findings are questioning the existence of PRTH as a separate clinical entity and support the view that the various forms of thyroid hormone resistance may be part of a spectrum of disease with variable expression in different issues.

Adolescent↗
PubMed1992

[Therapeutic use of somatostatin analogues in endocrinology].

The recent availability of the long-acting somatostatin analogue, octreotide, has allowed its therapeutical use in a wide variety of human diseases, including some digestive, neoplastic and autoimmune disorders. This review focuses on the treatment of some endocrine disorders with octreotide. Evidence is accumulating that octreotide treatment is effective in improving the cure rate of pituitary surgery in acromegaly by shrinking the tumour size, and in lowering GH and IGF-I levels in the vaste majority of patients. Octreotide is also effective in ameliorating TSH-induced hyperthyroidism in patients with TSH-secreting adenomas. Moreover, octreotide has proved useful in the management of endocrine tumours of the gastroenteropancreatic tract (vipomas, glucagonomas, gastrinomas, insulinomas, and carcinoids) by reducing hormone levels and in some instances the size of the primary and/or metastatic lesions. Besides the above well-established indications there are some other potential indications (non-secreting pituitary tumours, medullary thyroid carcinoma, ectopic Cushing's syndrome, diabete mellitus, Graves' ophthalmopathy, tall children and polycystic ovary syndrome) that still await further investigation. Side-effects of octreotide, particularly the formation of gallstones, should be carefully monitored.

Acromegaly↗
PubMed1992

Ectopic acromegaly.

Ectopic acromegaly is a rare syndrome (less than 1% of acromegalic patients) caused by ectopic growth hormone-releasing hormone (GHRH) or growth hormone (GH)-producing tumors. Its recognition is clinically important because acromegaly may be a symptom of an aggressive tumor, and different therapeutic approaches are required. Most cases are caused by either extra- or intracranial GHRH-producing tumors, whereas in rare instances the underlying disease is an ectopic GH-secreting tumor. The routine evaluation of circulating GHRH in all acromegalic patients may allow its early recognition, because plasma levels greater than 0.3 ng/mL are virtually diagnostic of a GHRH-producing tumor (frequently a bronchial or pancreatic carcinoid), whereas suppressed levels may suggest an ectopic GH-producing tumor. In addition to classic imaging techniques, whole body scintiscan with labeled octreotide may help in the localization of ectopic tumors. Surgical removal of the ectopic tumor is the therapy of choice, but it is not always feasible because patients often present with widespread metastases. Patients with GHRH-induced acromegaly benefit from the administration of the long-acting somatostatin analog, octreotide, which reduces GH, IGF-I, and GHRH, and may shrink the ectopic tumor, its metastases, and the secondary pituitary enlargement.

Acromegaly↗
PubMed1991

Patterns of gastrin secretion in patients with nonfunctioning pituitary adenomas.

The presence of gastrin in pituitary tissue as well as gastrin hypersecretion by some pituitary adenomas have been documented using different methodological approaches. In the present study, serum gastrin levels were measured in 93 patients with nonfunctioning pituitary adenoma, i.e. a condition lacking a reliable marker of the disease. Elevated gastrin levels (85-2, 180 ng/l; normal range: 15-80 ng/l) were found in 14/93 patients (15%), the highest values being observed in one patient with MEN I syndrome. In all but MEN I hypergastrinemic patient, a severe gastric hypochlorhydria (Basal Acid Output: 0.04 +/- 0.1 mmol H+/h) unresponsive to pentagastrin (Maximum Acid Output: 0.1 +/- 0.2 mmol H+/h) was seen. Secretin injection caused gastrin to increase in the patient with MEN I and in another hypergastrinemic patient. Antiparietal cells autoantibodies were positive in 3/11 patients. No changes in gastrin concentrations were found after administration of several agents usually employed in the evaluation of pituitary function, except a significant gastrin reduction after octreotide injection. In two hypergastrinemic patients who underwent pituitary adenomectomy, the high gastrin levels did not change after surgery. Finally, gastrin was undetectable in the culture media of 15 pituitary adenomas surgically removed from both normo- and hypergastrinemic patients and immunocytological studies of tumor cells did not show any gastrin staining. In conclusion, although in patients with pituitary adenomas serum gastrin evaluation is indicated in order to document the presence of a MEN I syndrome, the present data show that high gastrin levels cannot be taken as a specific marker of nonfunctioning pituitary adenomas unless the peripheral origin of hypergastrinemia is excluded.

Adenoma↗