Predictors of morbidity and mortality in acromegaly: an Italian survey.

OBJECTIVE: To describe demographic and hormonal characteristics, comorbidities (diabetes mellitus and hypertension), therapeutic procedures and their effectiveness, as well as predictors of morbidity and mortality in a nationwide survey of Italian acromegalic patients. DESIGN: Retrospective multicenter epidemiological study endorsed by the Italian Society of Endocrinology and performed in 24 tertiary referral Italian centers. The mean follow-up time was 120 months. RESULTS: A total of 1512 patients, 41% male, mean age: 45±13 years, mean GH: 31±37 µg/l, IGF1: 744±318 ng/ml, were included. Diabetes mellitus was reported in 16% of cases and hypertension in 33%. Older age and higher IGF1 levels at diagnosis were significant predictors of diabetes and hypertension. At the last follow-up, 65% of patients had a controlled disease, of whom 55% were off medical therapy. Observed deaths were 61, with a standardized mortality ratio of 1.13 95% (confidence interval (CI): 0.87-1.46). Mortality was significantly higher in the patients with persistently active disease (1.93; 95% CI: 1.34-2.70). Main causes of death were vascular diseases and malignancies with similar prevalence. A multivariate analysis showed that older age, higher GH at the last follow-up, higher IGF1 levels at diagnosis, malignancy, and radiotherapy were independent predictors of mortality. CONCLUSIONS: Pretreatment IGF1 levels are important predictors of morbidity and mortality in acromegaly. The full hormonal control of the disease, nowadays reached in the majority of patients with modern management, reduces greatly the disease-related mortality.

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.

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.

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.

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.

Thyrotrophin-Releasing Hormone Raises Cytosolic Free Calcium Concentration in Human Adenomatous Somatotrophs and Corticotrophs; Comparison with in vivo Responsiveness to Thyrotrophin-Releasing Hormone in Patients with Acromegaly or Cushing's Disease.

Abstract The effect of thyrotrophin-releasing hormone (TRH) on intracellular free Ca(2+) concentration, [Ca(2+))i, was investigated with the fluorescent dye fura-2 in cell suspensions obtained from 13 human growth hormone-secreting adenomas and 6 adrenocorticotrophin-secreting adenomas. Preoperatively, 9 out of 13 acromegalic patients showed a positive growth hormone response to TRH administration while none of the 6 patients with Cushing's disease had a plasma adrenocorticotrophin increase after TRH injection. In all the growth hormone-secreting adenomas the addition of TRH (100 nM) caused a significant rise in [Ca(2+)]i (from a resting level of 133+/-40 (+/-SD) to a value of 284+/-119 nM at 100 nM TRH, n = 42; P<0.001). The transient induced by TRH was found to have a dual origin, one due to Ca(2+) mobilization from intracellular stores which was maintained in presence of EGTA (3mM) and verapamil (10 muM) and a plateau phase due to Ca(2+) influx from the extracellular media. Somatostatin (0.1 muM) lowered both resting [Ca(2+)]i and TRH-induced transients. The effect of gonadotrophin-releasing hormone on [Ca(2+)]i was evaluated on cell suspensions obtained from 6 growth hormone-secreting adenomas. Gonadotrophin-releasing hormone (100 nM) caused a marked rise in [Ca(2+)]i (from 179+/-25 to 283+/-15nM) on the cell suspension obtained from the only in vivo responsive adenoma while it was ineffective in the remaining 5. Although TRH was ineffective in modifying plasma adrenocorticotrophin levels in all patients with Cushing's disease, in 5 out of 6 tumors the addition of 100 nM TRH caused a significant rise in [Ca(2+)]i (from 102.5 +/- 36 to 163+/-66 nM, n = 22; P < 0.005). However, the effect of TRH on [Ca(2+)]i was significantly lower than that caused by arginine vasopressin, a physiological stimulator of adrenocorticotrophin release ([Ca(2+)]i values; 145+/-78 nM at 100 nM TRH versus 300+/-140 at 10 nM arginine vasopressin, n = 15; P<0.05). Moreover, the effect of arginine vasopressin on [Ca(2+)]i was detectable at concentrations as low as 0.1 nM while TRH was effective at concentrations higher than 1 nM. By contrast, gonadotrophin-releasing hormone was ineffective in increasing [Ca(2)]i in all the adrenocorticotrophin-secreting adenomas studied. Collectively, these data indicate that sensitivity to TRH is present in almost all the growth hormone- and adrenocorticotrophin-secreting adenomas independently of the responsiveness of the individual patients to the peptide.

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 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.

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.

[Treatment of acromegaly with octreotide, a synthetic analog of somatostatin with extended action]. / Il trattamento dell'acromegalia con octreotide, analogo sintetico della somatostatina a lunga durata d'azione.

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.

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.