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M Arosio

Publications and source records attributed to M Arosio.

18 recordsLinked to original sources
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

Mutations in the alpha subunit of the stimulatory regulatory protein of adenylyl cyclase (Gs) in human GH-secreting pituitary adenomas. Biochemical, clinical, and morphological aspects.

Very recently a subset of human GH-secreting pituitary adenomas carrying a somatic mutation in the alpha subunit of the stimulatory regulatory protein of adenylyl cyclase (Gs) was identified. In all these tumors (Group 2; about 30% of all the GH secreting tumors studied) the alpha s cDNAs contained mutations; in 8 tumors mutations replaced Arginine 201 with either Cystein or Histidine while in the remaining tumors Glutamine 227 was replaced by either Arginine or Leucine. No mutations were observed in the remaining adenomas (Group 1). The two mutations caused a constitutive activation of adenylyl cyclase and a turn on of cAMP synthesis by inhibiting GTPase activity. The transformed phenotype was reflected in adenomatous cells with high rate of cAMP production and in vitro GH secretion. No difference in age, sex, clinical features, duration of the disease and cure rate were observed between the patients without (Group 1) or with alpha s mutation (Group 2), while higher serum GH levels and smaller tumor size were present in Group 2 patients. Moreover, hypersecretory activity in Group 2 tumors was also apparent at electron microscopy; cells of Group 2 tumors were densely granulated and showed prominent rough endoplasmic reticulum and Golgi complex. With respect to Group 1, Group 2 patients were less responsive to GH-releasing hormone (GHRH), while they were more sensitive to somastostatin. The former finding is in agreement with the hypothesis that the oncogenic proteins mimic the effects of extracellular growth factors, so removing the requirement for GHRH; the latter might explain the low rate of tumor growth as due to the counteracting role of endogenous inhibitory factors.

Adenoma↗
PubMed1991

In vivo detection of somatostatin receptors in patients with functionless pituitary adenomas by means of a radioiodinated analog of somatostatin ([123I]SDZ 204-090).

The recent availability of a Tyr3-substituted octreotide (SDZ 204-090) for radioiodination has allowed somatostatin (SRIH) receptor binding to be studied in vivo, and receptor-positive tumors of different origins to be visualized with a gamma-camera. This prompted us to investigate whether this compound could be used for external imaging of functionless pituitary adenomas displaying SRIH receptors. Eight patients with functionless pituitary adenomas, three patients with acromegaly, and three with macroprolactinoma were injected iv with 123I-labeled Tyr3-octreotide and then scanned with a gamma-camera. Positive scans were obtained in the three acromegalics and in two of the eight patients with functionless pituitary tumors. The patients with macroprolactinoma had negative scans. The diagnosis of functionless pituitary adenomas was confirmed by light and electron microscopic examination as well as immunocytochemical studies. In vitro binding of [125I]Tyr11-SRIH to cell membranes was evaluated in four functionless and three GH-secreting adenomas removed from seven of the patients. All of the GH-secreting as well as one of the four functionless adenomas had high affinity SRIH-binding sites, without differences in number or affinity, whereas SRIH-binding sites were not detected in the others. Positive scans were observed only in patients bearing tumors with high affinity SRIH-binding sites. In conclusion, [123I]Tyr3-octreotide appears to be a promising tool for singling out, in vivo, patients with functionless pituitary tumors displaying SRIH receptors who might potentially benefit from octreotide treatment.

Adenoma↗
PubMed1991

Size heterogeneity of circulating growth hormone in acromegaly. "Big-big" GH forms are associated with inappropriately low IGF-I levels.

UNLABELLED: Circulating GH consists of several molecular size species with different biological activity. A reduced sensitivity of some monoclonal antibodies towards high-molecular weight GH variants has been reported. The aim of the present work was to evaluate the molecular size species of circulating GH using Sephadex G-100 gel filtration chromatography in acromegalic patients and in normal subjects employing both RIA and an immunoradiometric assay for all GH determinations. In 6 normal subjects, studied under GHRH stimulation, little GH was 69.8 +/- 6% (mean +/- SD), big GH (44 kD) 26.4 +/- 6% and big-big GH (greater than 80 kD) 2.8 +/- 4%, in IRMA, with a good correspondence with RIA results (70.8 +/- 8, 27.0 +/- 4, and 3.2 +/- 2%, respectively). In 13 untreated acromegalic patients, studied in basal conditions, the little form constituted 76.2 +/- 7%, the big form 18.3 +/- 4%, which is significantly lower than in normals (p less than 0.05), and the big-big form 5.5 +/- 7%. Similar results were obtained with RIA. A clear elevation of big-big GH (21% for both in IRMA, and 15.7 and 27.8% in RIA) was found in 2 patients with IGF-I levels lower than expected on the basis of mean GH concentrations. The study was extended to an additional acromegalic patient, previously operated and irradiated on, characterized by discrepant serum GH levels in RIA (4.6 micrograms/l), and in IRMA (1.4 micrograms/l), and by normal IGF-I levels. Serum GH showed a lack of parallelism to standard GH in RIA, but not in IRMA. RIA immunoreactivity was almost completely composed (92%) of a high molecular weight GH form (greater than 90 kD), not recognized by IRMA. All IRMA immunoreactivity eluted with a Kav corresponding to 19-50 kD. IN CONCLUSION: a. the three main molecular size isomers of serum GH are similarly recognized by IRMA and RIA methods in normal subjects. b. in acromegaly, both quantitative and qualitative modifications of the GH chromatographic profile may be present. In particular, increased amounts of big-big forms, whether or not recognized by monoclonal antibodies, have been observed. Their lower bioactivity, suggested by the normal or lower than expected IGF-I levels, can account for the discrepancy between serum GH levels and the clinical picture or IGF-I levels sometimes observed in acromegaly.

Acromegaly↗
PubMed1990

Acromegaly and thymic hyperplasia: a case report.

Growth hormone overproduction is characterized by increased size of visceral organs as well as growth of bone and soft tissues. We describe a case of a 23-year-old female acromegalic patient, who had been previously unsuccessfully operated upon by transsphenoidal pituitary surgery and then irradiated. In November 1987 a routine X-ray chest examination revealed a mediastinal mass, subsequently confirmed by CT scan. The patient underwent surgical removal of the mass: macroscopical aspect, histological sections and immunocytochemistry showed typical thymic structures without any evidence of neurosecretory activity. No GH-positive cells were found and only small amounts of immunoreactive GHRH like material (9.2 ng/g wet wg) were detected in the tumor extract. Before surgery plasma GHRH levels were not elevated (26 pg/ml); serum GH and IGF-I levels were 27.4 +/- 4.9 micrograms/l and 191 nmol/l, respectively, and remained unchanged after surgery. These data ruled out a GHRH and/or GH ectopic production, confirming the primitive pituitary origin of acromegaly in this patient. It is likely that thymic hyperplasia may be explained by longstanding overproduction of GH and the young age of the patient.

Acromegaly↗
PubMed1990

Clinical, biochemical, and morphological correlates in patients bearing growth hormone-secreting pituitary tumors with or without constitutively active adenylyl cyclase.

Somatic mutations in the alpha-chain (alpha s) of the stimulatory regulatory protein of adenylyl cyclase (Gs) causing constitutive activation of the enzyme have been identified in a subset of human GH-secreting pituitary adenomas. This study reports on the differences between acromegalic patients bearing tumors without (group 1; n = 51) or with (group 2; n = 29) this alteration. No difference in age, sex, clinical features, duration of the disease, or cure rate was observed between the two groups. By contrast, group 2 patients had higher basal GH levels than group 1. Moreover, a significant difference in sellar morphology was found; group 2 patients more frequently showed sellas of normal size (grade I) than group 1. Hypersecretory activity of group 2 tumors was also apparent at electron microscopy; contrary to those of group 1, cells of group 2 tumors were densely granulated and showed prominent rough endoplasmic reticulum and Golgi complex. With respect to group 1, group 2 patients were less responsive to GH-releasing hormone, while they were more sensitive to somatostatin- and dopamine-induced GH inhibition. These results suggest that patients with constitutively active adenylyl cyclase have hyperactive tumors; the sensitivity of these tumors to inhibitory agents (somatostatin and dopamine), possibly counteracting the expression of activating mutations, might explain the low rate of tumor growth.

Acromegaly↗
PubMed1990

Effects of propranolol on GH responsiveness to repeated GH-releasing hormone stimulations in normal subjects.

The influence of beta-adrenergic blockade by oral propranolol on the variability of GH responses to GHRH and on GH responsiveness to repeated GHRH administrations was investigated. Eight normal volunteers underwent three tests on three separate occasions. Each test consisted of two administrations of 80 micrograms GHRH at 2-h intervals without other medication (test 1) or combined with oral administration of 80 mg propranolol 90 min before the first (test 2) or the second GHRH injection (test 3). In test 1 GH levels increased significantly after the first, but not the second GHRH bolus (net incremental area under the curve [nAUC], mean +/- SD: 1453 +/- 974 and 178 +/- 309 micrograms.l-1.(120 min)-1, respectively). In test 2 basal GH secretion was not influenced by propranolol administration, whereas the GH response to the first GHRH injection was significantly greater than in test 1 (2327 +/- 1814 micrograms.l-1.(120 min)-1; p less than 0.05). However, individual subjects showed the same variability of GH response as in test 1. The GH response to the second GHRH bolus remained negligible. In test 3 administration of propranolol 90 min before the second GHRH bolus led to a clear GH increase (690 +/- 1002 micrograms.l-1.(120 min)-1), not significantly different from the GH response to the first bolus (1796 +/- 1375 micrograms.l-1.(120 min)-1). However, only 4 subjects showed a marked restoration of the GH responsiveness to the second GHRH administration. In conclusion, oral administration of propranolol is able to increase GH responsiveness to GHRH without changing the great individual variability. The response to a repeated GHRH stimulation is only partially restored by propranolol.

Administration, Oral↗
PubMed1988

Growth hormone and prolactin secretion in acromegaly: correlations between hormonal dynamics and immunocytochemical findings.

A morphological study was carried out on pituitary adenomas removed from 13 normoprolactinemic and 9 hyperprolactinemic acromegalic patients whose hormonal dynamics had been carefully investigated. Double immunocytochemical labeling with the protein-A-gold electron microscopic technique was used to detect the presence of GH and PRL in the adenomas. Two morphological patterns were found; 11 adenomas contained cells positive only for GH, and 11 contained a variable proportion (from 10-98%) of cells positive for PRL. The great majority of cells positive for PRL also were positive for GH and so were actually mammosomatotrophic cells. Among the normoprolactinemic patients, no cells containing PRL were found in the tumors from 8 patients, and 10-26% of the cells of the tumors of the other 5 patients contained PRL. Two thirds of the hyperprolactinemic patients had tumors containing mammosomatotrophs (18-80%) with or without the concomitant presence of mammotrophs (0-18%). A positive correlation was found between the serum PRL levels and the percentage of mammosomatotrophs. No significant differences in GH secretory responses to TRH, dopamine, GHRH, and SRIH were found between patients having tumors with or without cells positive for PRL. We conclude that 1) the frequency of mammosomatotrophs in adenomas from acromegalic patients is higher than that previously estimated using different immunocytochemical methods; and 2) serum GH responses to TRH and dopamine are not strictly related to the presence of mammosomatotrophs and/or mammotrophs within the tumor.

Acromegaly↗
PubMed1987

Lack of desensitization of adenomatous somatotrophs to growth-hormone releasing hormone in acromegaly.

The study was undertaken to investigate whether GHRH causes desensitization in GH-secreting adenomas in analogy to the normal situation. For this purpose, GH secretion after repeated GHRH administration to acromegalic patients in vivo and cultured adenomatous somatotrophs in vitro was studied. Six acromegalic patients and 6 normal subjects received 3 consecutive 50 micrograms GHRH rapid iv injections at 2-h intervals. Blood samples were drawn at 0, 15, 30, 60, and 120 min after each dose. The acromegalic patients had variable responses to the first injection and in each patient the second and third injections elicited serum GH responses that were quite similar to those after the first one. The GH increment, evaluated as net incremental area under the curve (mean +/- SE; nanograms per ml/120 min) was 2660 +/- 1501 after the first injection, 2176 +/- 1378 after the second injection, and 1978 +/- 1191 after the third injection; P = NS. On the contrary, in normal subjects a marked elevation of GH was observed only after the first injection (net incremental area under the curve, mean +/- SE after the first injection: 710 +/- 154; after the second injection: 6 +/- 39 and after the third injection: 108 +/- 28, P less than 0.01 vs. the first dose). The effect of in vitro GHRH pretreatment on the subsequent response to GHRH was evaluated in monlayer cultures from 12 GH-secreting adenomas. At 10(-8) M, GHRH significantly stimulated GH release from 8 adenomas. The GHRH pretreatment that was effective in inducing desensitization in cultured rat anterior pituitary cells, i.e. preexposure of the cultured cells to 10(-8) M GHRH for 4 h at 37 C, did not abolish the GH response to the subsequent challenge with GHRH (mean percent stimulation: 150 +/- 14% in untreated cells vs. 153 +/- 30% in pretreated cells; P = NS). Only in one adenoma, did GHRH-promoted desensitization occur. No modification was found in GHRH unresponsive adenomas. In the adenomas, not only the efficacy but also the potency of GHRH on GH release after GHRH pretreatment was of the same order of magnitude as in untreated cells. No desensitization to GHRH action occurred when the pretreatment time was prolonged up to 8 h and the GHRH concentration in the preincubation medium was increased to 10(-7) M.(ABSTRACT TRUNCATED AT 400 WORDS)

Acromegaly↗
PubMed1986

Morphological studies on mixed growth hormone (GH)- and prolactin (PRL)-secreting human pituitary adenomas. Coexistence of GH and PRL in the same secretory granule.

A morphological study was carried out on five mixed GH- and PRL-secreting pituitary adenomas, surgically removed from acromegalic patients with hyperprolactinemia, in order to verify whether the two hormones were contained in the same cell or in different cells. Double labeling with the protein A-gold immunotechnique was used to visualize the ultrastructural localization of the two hormones on ultrathin sections of the tumors. By means of this high resolution technique we found in all adenomas the presence of numerous (from 50-80% of the whole cell population) mammosomatotrophs, i.e. cells containing simultaneously PRL and GH. The occurrence of cells producing only GH (in four tumors) or only PRL (in one tumor) was also observed. In mixed cells GH and PRL were segregated in the same mixed granule. In one tumor granules positive only for GH together with mixed granules were found in the same cell. Immunofluorescence studies, at the light microscopic level, allowed us to clearly identify mammosomatotrophs only in two tumors. Double labeling using the gold immunotechnique appears therefore to be the most suitable experimental approach to detect the existence of mixed cells in plurihormonal adenomas. Our results support the idea that the frequency of mixed adenomas with mixed cells may be higher than that believed previously. The simultaneous presence of two hormones in the same secretory granule could explain why, in patients having mixed tumors, factors able to stimulate or inhibit the release of one hormone can also stimulate or inhibit the secretion of the other.

Adenoma↗
PubMed1985

Radionuclide assessment of right-ventricular involvement in inferior acute myocardial infarction: clinical correlations and in-hospital follow-up.

We studied 33 patients (28 males, 5 females) with first inferior acute myocardial infarction (AMI) and 12 normal volunteers. They underwent first-pass (FP) and equilibrium-gated radionuclide angiography (EGRA) within 4 days of the onset of symptoms. The parameters [ejection fraction (EF), peak ejection rate (PER), peak filling rate (PFR)] of the time-activity curve (TAC) of both ventricles [left ventricle (LV), right ventricle (RV)] were computed. The regional wall motion (RWM) was evaluated by parametric images (amplitude and phase). In 43% of the patients with AMI, we found a depressed RVEF, while the LVEF was decreased in only 33%. The sensitivity of diastolic parameters was shown to be clearly superior to that of the systolic parameters (RVPFR, 78%; LVPFR, 79%). The abnormalities of the overall performance of both ventricles were significantly correlated with those of the RWM. The abnormal RVEF allowed us to assess the necrotic involvement of the RV, while a depressed RVPFR suggested an impaired RV compliance mostly on an ischemic basis. Congestive heart failure (CHF) and shock syndrome were significantly correlated with depressed RV parameters, while the LVEF, despite RWM abnormalities, was in the normal range. EGRA with computation of the TAC parameters of both ventricles appeared to be useful for in-hospital prognostic evaluation, therapeutic planning and clinical follow-up of patients with inferior myocardial infarction.

Adult↗
PubMed1985

Human pancreatic growth hormone-releasing factor (hpGRF-44) in acromegaly before and after adenomectomy. Modifications induced by somatostatin (GHRIH) infusion.

The influence of human pancreatic growth hormone-releasing factor (hpGRF-44) on GH secretion was investigated in 15 patients with active acromegaly. Following the administration of hpGRF-44 (1 microgram/kg, iv) mean (+/- SE) serum GH level increased from 22.4 +/- 6.3 ng/ml to 42.9 +/- 8.2. ng/ml (peak, p less than 0.01). The pattern and the magnitude of the GH rises were widely variable and it was possible to identify three types of responses: in fact in 2 cases a very large serum GH rise, eight folds over baseline, was observed, in 7 patients a clear GH stimulation, two-three fold over baseline was noticed and in 6 patients no significant GH modifications were seen. No correlation was found between the response to hpGRF-44 and the existence of abnormal GH responses to dopamine infusion, TRH and dopamine-sulpiride test. In 5 acromegalic patients hpGRF-44 was injected again after transsphenoidal adenomectomy. The magnitude of serum GH response decreased in one hyperresponsive patient, increased in 2 previously unresponsive cases and did not change in the remaining cases. In 6 GH responsive patients hpGRF-44 was injected at 120 min during a 4 hour infusion of somatostatin (GHRIH, 3.33 micrograms/min). GHRIH infusion significantly suppressed GH levels in all the patients and blunted the hpGRF-44 stimulated GH increase. The different patterns of GH response to hpGRF-44 in acromegalic patients suggest a different sensitivity of the adenomatous somatotrophs and a possible contribution by normal GH-secreting cells to hpGRF-44 induced GH response.

Acromegaly↗
PubMed1985

Glycoprotein hormone alpha-subunit response to growth hormone (GH)-releasing hormone in patients with active acromegaly. Evidence for alpha-subunit and GH coexistence in the same tumoral cell.

Basal serum concentrations of glycoprotein hormone alpha-subunit and its response to GH-releasing hormone (GHRH) were studied in 22 acromegalic patients and in normal subjects. Four out of 22 patients had a basal alpha-subunit concentration (1.2-3.5 ng/ml) clearly above the upper limit of the normal range. GHRH injection (1 microgram/kg body weight, bolus dose iv) produced a clear alpha-subunit response [mean % increase: 120 +/- 37 (SD)] in the 4 patients with elevated basal alpha-subunit levels. No increase in serum glycoprotein hormones (TSH, LH, and FSH) occurred. Selective adenomectomy in 2 patients resulted in normalization of both serum GH and alpha-subunit levels, as well as disappearance of the abnormal alpha-subunit response to GHRH. In in vitro studies, only these 2 adenomas secreted alpha-subunit in large amounts (534 and 388 ng/mg protein . 30 min) and was it further stimulated by GHRH (% increase: 83 and 126). Morphological studies done with protein A-gold particle immunotechnique demonstrated that in these adenomas the great majority of the cells contained secretory granules positive for both GH and alpha-subunit. We conclude that: 1) alpha-subunit hypersecretion is present in some acromegalic patients (about 20%), 2) GHRH stimulates alpha-subunit release both in vivo and in vitro only in patients with elevated basal alpha-subunit levels, and 3) in these patients alpha-subunit derives from a common adenomatous cell secreting both alpha-subunit and GH molecules.

Acromegaly↗
PubMed1978

Comparison of placebo and bromocriptine in the treatment of patients with normoprolactinaemic amenorrhoea.

Fourteen women with normoprolactinaemic amenorrhoea were treated with bromocriptine (2.5 mg twice daily) for a period ranging from 4 to 17 weeks, while a matched group fo 19 amenorrhoeic women were treated with a placebo (one tablet twice daily) for 4 to 12 weeks. About half of the patients in both groups had at least one episode of vaginal bleeding during treatment. There was no clear difference in the menstrual and ovulatory pattern between placebo and bromocriptine groups.

Amenorrhea↗
PubMedDate not supplied

[Treatment of acromegaly with octreotide, a synthetic analog of somatostatin with extended action].

Octreotide, an analog of somatostatin, is a valid tool for the cure of acromegalic disease. This compound has a prolonged half-life and is more selective than native somatostatin in suppressing growth hormone (GH) secretion. Octreotide, 100 micrograms tid sc, decreases GH levels and improves clinical symptoms in about 85% of acromegalic patients, lowering GH to below 5 ng/ml in 45% and to below 2 ng/ml in 17-21%. Octreotide normalizes somatomedin-C (IGF-I) levels in 36-50% of patients. The increase of dosage up to 1500 micrograms/day does not appear useful in poor responsive patients. No adverse effects on other endocrine functions submitted to hypothalamus-pituitary control have been observed. A slight shrinkage of the pituitary tumor is observed in 30-50% of cases. Octreotide therapy is well tolerated and side effects are usually mild. However the possibility of colelithiasis, liver damage and diabetes mellitus in patients with glucose intolerance must be taken into account. In conclusion octreotide is a useful complement to therapeutic means now used for the treatment of acromegaly.

Acromegaly↗