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At present, there is growing evidence implicating GH and/or IGF-I in the intricate cascade of events connected with the regulation of heart development and hypertrophy. Moreover, GH excess and/or deficiency have been shown to include in their advanced clinical manifestations almost always an impaired cardiac function, which may reduce life expectancy. This finding is related both to a primitive impairment of heart structure and function and to metabolic changes such as hyperlipidemia, increase of body fat and premature atherosclerosis. Patients with childhood or adulthood-onset GH deficiency have a reduced left ventricular mass and ejection fraction and the indexes of left ventricular systolic function remain markedly depressed during exercise. Conversely, in acromegaly the cardiac enlargement, which is disproportionate to the increase in size of other internal body organs, has been a rather uniform finding. The severity of the acromegalic cardiomyopathy was reported to be correlated better with the disease duration than with circulating GH and/or IGF-I levels. Myocardial hypertrophy with interstitial fibrosis, lymphomononuclear infiltration and areas of monocyte necrosis often results in concentric hypertrophy of both ventricles. The treatment of GH deficiency and excess improved cardiac function. Interestingly, based on the evidence that GH increases cardiac mass, recombinant GH was administered to patients with idiopathic dilated cardiomyopathy. It increased the myocardial mass and reduced the size of the left ventricular chamber, resulting in improvement of hemodynamics, myocardial energy metabolism and clinical status. These promising results open new perspectives for the use of GH in heart failure.

GABAergic drugs affect PRL secretion in both rat and man. Sodium valproate (SV) inhibits GABA transaminase so increasing the endogenous GABAergic tone. The aim of this study was to evaluate the effects of SV at low and high doses on PRL release in healthy subjects and hyperprolactinemic patients. Fifteen patients with prolactinomas, 8 patients with non-tumoral hyperprolactinemia and 10 healthy subjects were studied: in non consecutive days, all subjects received placebo and SV at the dose of 400 and 800 mg po. Serum PRL levels were assessed 30, 15 and 5 min before and every 30 min for 4 hours after administration. SV at the dose of 400 mg induced a significant decrease of serum PRL in healthy subjects (p < 0.05), whereas no effect was noted in both tumoral and non-tumoral hyperprolactinemia. The administration of 800 mg SV induced a significant decrease of PRL levels in healthy subjects and in patients with non-tumoral hyperprolactinemia (p < 0.05). Conversely, in prolactinomas a paradoxical increase of serum PRL concentration (p < 0.05) was observed 120 min after the administration of the drug. These data confirm the inhibitory activity of SV on PRL release in healthy subjects, and suggest the existence of a partial resistance to GABA in non-tumoral hyperprolactinemia. In prolactinomas, the paradoxical PRL increase after high dose of SV suggests the existence of a complete pituitary resistance to GABA. This finding might be explained by the appearance of the stimulatory effect of GABA at hypothalamic level that could have been unmasked by the lack of pituitary GABA effects on adenomatous lactotrophs.

Objective: The balance of evidence suggests that acromegaly is a risk factor for colonic neoplasia. We have evaluated the prevalence of colonic polyps in acromegalics from Southern Italy and characterized the lymphocyte subsets in the colonic lamina propria in order to analyze differences in the colonic immunological environment., Design: All the patients and controls were submitted to pancolonoscopy. Ten per-endoscopic biopsies of the intestinal mucosa surrounding polyps were carried out to evaluate lymphocyte subsets., Patients: Fifty acromegalics and 318 sex- and age-matched controls entered this study. Colonic lamina propria lymphocyte subsets were studied in 34 patients and 34 controls., Results: Colonic polyps were resected in 23 acromegalics (46%) and 42 controls (13.2%; P < 0.0001); hyperplastic polyps were found in 24% and 6.3%, adenomatous polyps in 22 and 6.9%, (P < 0.01), adenocarcinoma in 2 and 1.2% while synchronous polyps occurred in 18% and 2.5% (P < 0.01), respectively. The number of polyps was significantly correlated with age both in acromegalics (r = 0.422, P < 0.005) and in controls (r = 0.865, P < 0.001). However, polyp prevalence was greater in patients aged below 40 yrs (r.r = 1.9) and in patients with two or more skin tags (r.r = 1.2). A significant decrease of CD20, CD19, CD16, gamma/delta, CD4@leu8- and increase of CD3 and CD4+/leu8+ was found in the lamina propria lymphocyte subsets., Conclusions: The results of this study confirm that acromegalics are at increased risk of colonic polyps compared to the healthy population. The increased prevalence of premalignant polyps, namely the adenomatous type, suggests that acromegalics should undergo a careful screening and follow-up by pancolonoscopy. An impairment of mucosal immune surveillance seems to exist in acromegaly although a causal effect in the polyp formation cannot be ruled out.

The aim of the current study was to evaluate the effectiveness of a long-term treatment with sodium valproate in 19 patients with Cushing's disease. Before therapy beginning, the patients were subjected to acute test with 600 mg sodium valproate. Then, they were subjected to a 3-month therapy with sodium valproate at the dose of 600 mg/day before surgery (presurgical study). The 7 patients not surgically cured were subjected again to a 3-month therapy with sodium valproate at the dose of 600 mg/day after surgery (postsurgical study). Circulating ACTH and cortisol and urinary free cortisol levels were evaluated before and monthly after the beginning of the therapy. A decrease of plasma ACTH and serum cortisol levels greater than 50% of baseline was considered as positive response to acute test whereas the normalization of plasma ACTH, serum cortisol and urinary free cortisol levels and the clinical remission were considered as positive response to the long-term treatment. At acute test, 8 patients were considered responders and 11 patients non-responders. In no patient plasma ACTH, serum cortisol and urinary free cortisol were normalized during the long-term treatment. Urinary free cortisol levels significantly decreased (483.2 +/- 33.8 vs 699.4 +/- 67.0 micrograms/24 h), whereas plasma ACTH (302.8 +/- 17.7 vs 183.3 +/- 25.0 ng/l) and serum cortisol (466.5 +/- 23.2 vs 356.7 +/- 19.6 micrograms/l) significantly increased during sodium valproate administration in the 19 patients enrolled in the presurgical study. Plasma ACTH (247.7 +/- 22.3 vs 168.6 +/- 15.0 ng/l), serum cortisol (387.4 +/- 35.8 vs 282.0 +/- 16.0 micrograms/l) and urinary free cortisol (370.9 +/- 70.6 vs 261.3 +/- 37.8 micrograms/24 h) levels significantly increased in the 7 patients enrolled in the postsurgical study. No patient had clinical remission of Cushing's disease. In conclusion, the current study showed that long-term therapy with sodium valproate is not useful in the therapeutic management of Cushing's disease neither as alternative nor as adjunctive therapy to surgery.

Objective: Hexarelin is a synthetic hexapeptide with potent GH-releasing activity in both animals and men. The aim of this study was to investigate the effect of a bolus injection of hexarelin given in the morning during wakefulness and during nocturnal sleep in a group of normal adult men., Design and Subjects: Eight normal men, aged 21-33 years, of normal height and within 10% of ideal body weight were studied. All subjects received in random order saline or hexarelin (2 micrograms/kg) in the morning between 0800 and 0900 h after they had fasted overnight. The same experiments were performed during nocturnal sleep in the same subjects. Saline or hexarelin were injected within 30 minutes after the onset of sleep between 2300 and 2400 h. Sleep was recorded by visual inspection., Measurements: In all four test sessions blood samples were taken 30, 15 minutes and immediately before the injection of saline or hexarelin and then every 15 minutes for 2 hours. GH was measured by an immunoradiometric assay. All values are expressed as peak GH levels or as area under the curve (AUC) calculated by trapezoidal integration., Results: Mean peak GH concentrations after hexarelin during the morning (58.2 +/- 4.7 micrograms/l) (GH micrograms/l l x 2 = mU/l) were not different from those observed during sleep (61.2 +/- 4.3 micrograms/l). The rate of disappearance of GH from plasma was slower during sleep (t1/2 = 64.9 +/- 14.8 min) than during morning hours (t1/2 = 24.9 +/- 1.4 min, P < 0.01). Mean AUC responses to hexarelin during sleep (1466 +/- 145 micrograms.min/l) were significantly higher than during morning hours (903 +/- 94 micrograms.min/l, P < 0.001)., Conclusions: These results show that GH responsiveness to a growth hormone releasing peptide is preserved during the night. This could be exploited for diagnostic and/or therapeutic purposes.

Cabergoline (CAB), a new, potent, and long-lasting PRL-lowering agent, was shown to be effective in tumoral hyperprolactinemia. The aim of this study was to investigate the effectiveness of CAB in patients with prolactinoma proven to be resistant to bromocriptine (BRC) and quinagolide (CV 205-502). Twenty-seven patients (19 macro- and 8 microprolactinomas) were treated with CAB at a weekly dose of 0.5-3 mg for 3-22 months. All patients were previously shown to be resistant to BRC, and 20 of them were resistant to CV 205-502 as well. Basal serum PRL levels before CAB treatment ranged from 108-3500 micrograms/L in macroprolactinomas and from 64-205 micrograms/L in microprolactinomas. Gonadal failure was present in all patients, whereas symptoms of tumor expansion, such as visual field defects and headache, were present in 10 of 27 patients. Eight macroprolactinomas had previously undergone surgery and/or radiotherapy. CAB treatment normalized serum PRL levels in 15 of 19 macroprolactinomas and in all 8 microprolactinomas. In 3 of the remaining 4 patients it caused a notable decrease in prolactinemia (89%, 80.5%, and 68.7% of the baseline). Only 1 patient was withdrawn from CAB therapy after 3 months at the weekly dose of 2 mg due to the absence of any significant clinical, hormonal, or radiological improvement. Gonadal function was restored in 18 of 27 patients, galactorrhea disappeared in 5 of 6 women, and headache improved in 7 of 8 patients. A significant tumor shrinkage was detected by computed tomography and/or magnetic resonance imaging in 9 macroprolactinomas and 4 microprolactinomas. CAB was well tolerated by all patients, except 6 who referred slight and short-lasting nausea, postural hypotension, abdominal pain, dizziness, and sleepiness at the beginning of treatment. In particular, CAB was well tolerated by 19 patients previously shown to be poorly tolerant to BRC and CV 205-502. In conclusion, CAB may represent, at the moment, the only successful therapy for prolactinoma-bearing patients resistant to BRC and CV 205-502, as it normalized PRL levels in 22 of 27 patients, reduced tumor size in 13 of 27 patients, and improved clinical symptoms in 25 of 27 patients in the present study.

Medical treatment of acromegaly with dopamine agonists possesses 2 main advantages: the oral administration and the low costs. In this study, we reported on the results of chronic treatments with quinagolide (CV 205-502), cabergoline (CAB) and long-acting depot preparation of bromocriptine (BRC-LAR) in 34 acromegalics. Patients were divided into three groups on the basis of different treatment: CV 205-502 given to 16 patients at the dose of 0.3-0.6 mg/day for 6 months; CAB given to 11 patients at the dose of 1.0-2.0 mg weekly for 6 months; and BRC-LAR injected into 7 patients at the dose of 100 mg/month for 6-12 months. Basal and oral glucose tolerance test-stimulated serum GH levels, basal and TRH-stimulated PRL levels, plasma insulin-like growth factor I (IGF-I) levels, computed tomography scan, and/or magnetic resonance imaging were assessed before and quarterly during treatments. The chronic administration of CV 205-502, CAB, and BRC-LAR caused a significant decrease of circulating GH, IGF-I, and PRL levels (P < 0.005). Normalization of circulating GH and IGF-I levels was obtained in 7 of 16 (43.8%) patients treated with CV 205-502. Serum GH response to oral glucose tolerance test (oGTT) significantly improved (P < 0.005), and PRL levels were significantly suppressed during treatments. No correlation was found between basal and TRH-stimulated PRL levels and GH suppression during different therapies. Immunohistochemical staining revealed 19 GH-positive and 10 GH + PRL-positive adenomas. A significant association was found between GH/PRL staining and responsiveness to chronic treatments (chi 2 = 7.985, P < 0.005). Three patients had significant adenoma shrinkage. Slight nausea and hypotension which spontaneously disappeared within therapy progression, were referred by 5/16 patients during CV 205-502 and 2/7 during BRC-LAR. The results of this study indicate that CAB and BRC-LAR cannot be considered as useful medical approaches for acromegalics, whereas CV 205-502 normalized circulating GH and IGF-I levels in 47.8% of patients.

At present, there is a growing body of evidence implicating growth hormone (GH) and/or insulin-like growth factor-I (IGF-I) in the intricate cascade of events connected with the regulation of heart development and hypertrophy. In addition, advanced clinical manifestations of abnormal GH levels almost always include impaired cardiac function, which may reduce life expectancy. This finding is related both to a primary impairment of heart structure and function and to metabolic changes such as hyperlipidaemia, increased body fat and premature atherosclerosis. Acromegalic cardiomyopathy is better correlated with disease duration than with GH or IGF-I levels. Myocardial hypertrophy with interstitial fibrosis, lymphomononuclear infiltration and areas of monocyte necrosis often result in increased right and left ventricular mass concentric hypertrophy. Conversely, patients with childhood or adult-onset GH deficiency (GHD) have a reduced left ventricular mass (LVM) and ejection fraction (EF) and the indices of left ventricular systolic function remained markedly depressed during exercise. Cardiac function is reported to improve during octreotide and GH replacement treatment in acromegaly and GHD, respectively. The evidence that GH can increase cardiac mass suggests its use in the treatment of idiopathic dilated cardiomyopathy. In a recent study on such patients, the administration of recombinant GH (rGH) was demonstrated to increase myocardial mass and reduce the size of the left ventricular chamber, resulting in improved haemodynamics, myocardial energy metabolism and clinical status.

The aim of this study was to evaluate the effect of acute human corticotropin (ACTH)-releasing hormone (CRH) administration (100 micrograms, as i.v. bolus) on tumor necrosis factor-alpha (TNF alpha) levels in the inferior petrosal sinuses and in the peripheral blood of 7 patients with Cushing's disease subjected to diagnostic inferior petrosal sinus sampling. Blood samples for ACTH, beta-endorphin (beta-EPH) and TNF alpha were collected from inferior petrosal sinuses and periphery simultaneously. In addition, TNF alpha concentrations were measured after CRH administration (10 nmol/l, 100 nmol/l and 1 mumol/l) in culture medium from primary cultures obtained in 3 of 7 patients. At baseline, plasma ACTH and beta-EPH levels were significantly higher in the inferior petrosal sinus ipsilateral to the ACTH-secreting adenoma than in the contralateral one and in the periphery (p < 0.001) whereas no significant difference was found as far as serum TNF alpha levels were concerned. CRH administration caused a significant increase of ACTH (p < 0.001), beta-EPH (p < 0.01) and TNF alpha (p < 0.01) levels greater in the ipsilateral inferior petrosal sinus than in the contralateral one and in the periphery. In addition, CRH increased ACTH, beta-EPH and TNF alpha levels in the culture medium of three ACTH-secreting tumors at the doses of 100 nmol/l and 1 mumol/l (greater than 300, 200 and 110% of baseline pretreatment incubation levels, respectively). These data suggest that CRH may increase TNF alpha concentrations in the inferior petrosal sinus ipsilateral to the ACTH-secreting adenoma and in the peripheral blood as well. In addition, it stimulated TNF alpha release both in vivo and in vitro. These findings suggest the possibility that an imbalanced intrapituitary TNF alpha production can be detected in ACTH-secreting adenomas.

Patients with acromegaly have significant morbidity and mortality, associated with cardiovascular disease. Acromegaly is often complicated by other diseases such as diabetes mellitus, hypertension, and coronary artery disease, so the existence of acromegalic cardiomyopathy remains uncertain. Cardiac performance was investigated in patients with uncomplicated acromegaly. A subgroup of hypertensive acromegalics was also studied. In addition, the effects of chronic octreotide therapy or surgery on cardiac structure and function in acromegaly were studied. Twenty-six patients and 15 healthy controls underwent gated blood-pool cardiac scintigraphy and echocardiography at rest and during exercise. Echocardiography was repeated after 6 months of octreotide therapy (n = 11). Cardiac scintigraphy was repeated after 12 and 24 months of octreotide therapy (n = 10) or 12 to 24 months after surgery (n = 8). ECG, blood pressure, and heart rate were monitored during cardiac scintigraphy. Left ventricular mass (LVM) was calculated from the findings of the echocardiography. Serum growth hormone (GH) levels and plasma insulin-like growth factor-1 (IGF-1) levels were monitored. LVM index was significantly higher (P < .003) in acromegalics than controls and in hypertensive acromegalics than normotensives, but all other indices of cardiac function were similar. Chronic octreotide decreased GH and IGF-1 levels and improved the structural abnormalities as measured by echocardiography. Chronic octreotide or surgery did not alter cardiac function parameters. Thus, important changes in cardiac structure and function occur in uncomplicated acromegaly, and improvements can be demonstrated after chronic octreotide therapy. Heart disease in acromegaly appears to be secondary to high circulating GH levels.

Background: Higher vasopressin (AVP) levels have been found in the inferior petrosal sinus ipsilateral to the ACTH-secreting adenoma than in the contralateral one, suggesting a potential pathogenetic role of AVP in Cushing's disease., Design: In order to investigate AVP release, plasma ACTH and AVP concentrations were assayed in the inferior petrosal sinuses and in the peripheral blood before and after CRH stimulation., Patients: Twenty patients with Cushing's disease and 12 with other pituitary diseases were subjected to simultaneous and bilateral inferior petrosal sinus sampling for diagnostic purposes. Ten healthy sex and age-matched subjects served as control for peripheral AVP values., Measurements: Plasma ACTH concentrations were measured by RIA using commercial kits. Plasma AVP concentrations were assayed by RIA in acetone extracts of 1-2 ml plasma., Results: Plasma AVP levels in the inferior petrosal sinuses were significantly higher in Cushing's disease than in patients with other pituitary diseases (P < 0.05) and in both groups AVP levels were higher in the inferior petrosal sinuses than in the peripheral blood (P < 0.01). In Cushing's disease, ACTH, but not AVP levels, were higher in the inferior petrosal sinus ipsilateral to the adenoma than in the contralateral one (P < 0.01). Seven patients showed a significant ACTH and AVP increase (greater than 50% of baseline) after CRH stimulation in the inferior petrosal sinus ipsilateral to the adenoma. Conversely, no change was found in AVP levels in the remaining 13 patients. When AVP values were analyzed in relation to surgical cure, higher inferior petrosal sinus levels (P < 0.05) were found in 6 patients with poor outcome: 4 of these patients had significantly decreased plasma AVP concentrations (by 32-43% of baseline) after CRH bolus. Peripheral AVP levels were similar in healthy subjects and patients with Cushing's disease whereas they were significantly reduced in patients with other pituitary diseases (P < 0.002)., Conclusions: The results of this study show that patients with Cushing's disease and poor surgical outcome had the highest AVP levels in our series. CRH administration caused different effects on AVP levels: it increased them in 35% of patients whereas there was no response in the remaining patients. On the basis of these findings, it is hypothesized that AVP might be involved in the persistence of ACTH hypersecretion in a subset of patients poorly responsive to surgery.

The effect of corticotropin (ACTH)-releasing hormone (CRH) administration on alpha-melanocyte-stimulating hormone (alpha-MSH), ACTH and beta-endorphin (beta-EPH) was evaluated in the inferior petrosal sinuses and in the periphery of 30 patients affected with Cushing's disease subjected to simultaneous and bilateral inferior petrosal sinus sampling for diagnostic purposes. Baseline PRL levels, sensitivity to dexamethasone and surgery outcome were compared to alpha-MSH response. CRH bolus did not modify alpha-MSH concentrations either in the inferior petrosal sinuses or in the periphery in the 30 patients considered as a whole. In 7 of 30 patients, however, a greater than 50% increase over baseline alpha-MSH levels (from 50 to 115.5%) was recorded in the inferior petrosal sinus ipsilateral to the adenoma (from 42.9 +/- 1.7 to 76.4 +/- 4.6 ng/l; p < 0.001), whereas no change was found in the contralateral inferior petrosal sinus or in the periphery. Conversely, as expected, ACTH and beta-ELI significantly increased in all the patients after CRH both in the inferior petrosal sinuses and in the periphery (particularly in the inferior petrosal sinus ipsilateral to the adenoma). No difference in sensitivity to dexamethasone (urinary cortisol percent decrease: 66.4 +/- 4.9 vs. 67.8 +/- 3.4) and surgery outcome (chi 2 test: p = 0.7) was found between patients with alpha-MSH response to CRH and patients without such a response. By contrast, baseline PRL levels, although being normal in both groups, were significantly higher in patients with alpha-MSH response to CRH (18.1 +/- 1.6 vs. 10.1 +/- 0.7 micrograms/l; p < 0.001). In conclusion, the results of the present study suggest that in a subset of patients with Cushing's disease (23.3% of our series) alpha-MSH may be released after the administration of CRH together with ACTH and beta-EPH by adenomatous corticotrophs. In this subset of patients, PRL levels may be in the upper normal range.

Octreotide (OCT) administration provides a biochemical cure in most acromegalic patients. This drug, however, causes several side effects and is very expensive. Acute testing has been reported to predict chronic responsiveness to OCT administration. The aim of this retrospective study was to evaluate which test, if any, among acute testing, short-term (1 month) administration, and 111In-pentetreotide (111In-DTPA-Phe-D-OCT) scintigraphy, is best in predicting response to long-term OCT treatment. Sixty-eight patients with active acromegaly were studied. An acute test (100 micrograms sc OCT) was performed as usual: a GH decrease greater than or equal to 50% of baseline was considered a positive response. GH and insulin-like growth factor I (IGF-I) were then assayed after 1 month (300 micrograms daily) and 3 months (150-600 micrograms daily) of OCT administration. GH was considered normalized when decreased less than or equal to 5 micrograms/L. Twenty-six of 68 patients were subjected to 111In-pentetreotide scintigraphy. Linear correlation analysis of the results was performed. Sensitivity, specificity, and positive and negative predictive values of the three tests were also calculated. Thirty-eight of 68 patients (56%) responded to the acute test. Among these 38 patients, 20 experienced normalization of GH and IGF-I levels during long-term therapy, as did 8 patients who did not respond to the acute test. No significant correlation was found between GH percent decrease during acute testing and long-term therapy (r = 0.11). Seven patients who responded to the acute test and 2 who did not respond had adenoma shrinkage during therapy. Conversely, GH and IGF-I decrease after short-term treatment significantly correlated with long-term treatment (r = 0.76 and 0.64, P < 0.01). Of the 26 patients subjected to 111In-pentetreotide scintigraphy, 13 had significant tracer uptake: normalization of GH and IGF-I was obtained in 8 patients. A significant correlation was found between tracer uptake and GH/IGF-I inhibition after 3 months of therapy (r = 0.6; P < 0.05). In the whole population, the positive predictive value of acute testing, short-term OCT administration, and 111In-penetreotide scintigraphy was 53%, 70%, and 73%, respectively, when the GH normalization (< 5 micrograms/L) after 3 months of therapy was considered. Moreover, 111-In-pentetreotide scintigraphy had the highest specificity (100% in patients with baseline GH values below 50 micrograms/L) compared with that of acute testing and short-term OCT administration. The acute test cannot be considered as a valuable index to identify patients' responsiveness to long-term OCT therapy, but it can be useful to test tolerability. By contrast, 1 month of OCT administration or the in vivo imaging of somatostatin receptors by 111-In-pentetreotide might better indicate the patients who might effectively benefit from this treatment.

The effect of somatostatin on thyroid function was studied in 12 patients with growth hormone (GH)-secreting and eight patients with clinically non-functioning adenomas (NFA) and normal pituitary/ thyroid axis; the patients were subjected to the administration of octreotide (OCT), which is a long-acting somatostatin analog. All the patients received an acute test with 100 micrograms of OCT, both short term (1 month) and long term (6 months), with doses ranging from 300 to 600 micrograms/day. Serum thyroxine (T4), triiodothyronine (T3), free T4, free T3, thyroglobulin and basal and thyrotropin (TSH)-releasing hormone (TRH)-stimulated TSH were evaluated before and after 1 and 6 months of therapy. Circulating GH and insulin-like growth-factor I (IGF-I) in acromegalics and GH, IGF-I and alpha-subunit in NFA were assessed at baseline and every month. The acute administration of 100 micrograms of OCT significantly reduced the TSH response to TRH (p < 0.01) in both acromegalics and NFA. In all the patients OCT administration caused a significant decrease of GH, IGF-I and alpha-subunit levels (p < 0.01). In addition, after 1 month of therapy both baseline and TRH-induced TSH secretion were decreased significantly in acromegalics and NFA. After 6 months of therapy, baseline and TRH-induced TSH was still reduced in NFA. Conversely, in acromegalics, baseline TSH levels were increased while TSH response to TRH was inhibited. No change of T4, T3, free T4 and free T3 was observed in NFA, whereas a slight but significant increase of T4 and decrease of T3 was recorded in acromegalics.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied the tumor-seeking agent technetium-99m-labeled pentavalent dimercaptosuccinic acid ([99mTc](V)DMSA) to visualize 21 growth hormone (GH)-, nine prolactin (PRL)-, two mixed GH/PRL-, six adrenocorticotrophin (ACTH)-secreting and 15 clinically non-functioning pituitary adenomas, three craniopharyngiomas and one dysgerminoma of the sella. All non-adenomas and 31 out of 53 adenomas were studied before treatment: 22 after surgery and/or radiotherapy. Eight cases of acromegaly were studied before and after chronic treatment with octreotide, whereas three cases of acromegaly, one of prolactinoma and two of non-functioning adenoma were imaged before and after adenomectomy. As a control group, 27 patients without any clinical evidence of pituitary adenoma were studied: 10 of them were operated on previously and treated with iodine-131 for metastatic thyroid carcinoma, 10 had brain tumors and the remaining seven patients had functional pituitary hypersecretion (four Klinefelter's syndrome, two primary hypothyroidism and one Addison's disease). The scintigraphy was repeated after testosterone in Klinefelter's syndrome, L-thyroxine in primary hypothyroidism and cortisone administration in Addison's disease. Seventeen GH-secreting (81%), seven PRL-secreting (78%), three ACTH-secreting (50%), 15 non-functioning (100%) and one (50%) mixed adenoma significantly concentrated [99mTc](V)DMSA, showing elevated tumor-to-background (T/B) ratios. The T/B ratios were similar in untreated and surgically treated adenomas (11.2 +/- 5.6 vs 11.8 +/- 6.2). Radiotherapy significantly lowered the [99mTc](V)DMSA uptake to 5.1 +/- 2.8 (p < 0.1 vs untreated patients). Non-adenomatous lesions of the sella turcica did not concentrate [99mTc](V)DMSA in the pituitary as well as brain tumors and 8 out of 10 metastatic thyroid cancers. The treatment with octreotide normalized GH and insulin-like growth factor I levels and reduced [99mTc](V)DMSA from 15.7 +/- 4.8 to 13.5 +/- 3.9 (p < 0.05). Conversely, adequate substitutive therapy completely inhibited the uptake of the radiotracer in Klinefelter's syndrome, in primary hypothyroidism and in Addison's disease. The [99mTc](V)DMSA scintigraphy showed an overall sensitivity of 81% (43/53) in detecting pituitary adenomas, which was increased to 95% for lesions greater than 10 mm in size. High-quality images with minimal total body radiation were obtained, enabling a good in vivo characterization of viable adenomatous tissue as well as an accurate monitoring of the effects of different therapeutic regimens.

The growth hormone (GH) inhibitory effect of CV 205-502 was evaluated during acute and 3-month administration, alone or in combination with octreotide, in 12 therapy-resistant acromegalic patients. Although these patients previously had undergone surgery and received chronic therapy with octreotide at 0.3-0.6 mg/day, they still had high GH and insulin-like growth factor I (IGF-I) levels. CV 205-502 (0.15 mg), octreotide (0.1 mg) and placebo were tested acutely. CV 205-502 at the dose of 0.15 mg caused a decrease of GH level (from 34.9 +/- 15.1 to 2.7 +/- 0.3 micrograms/l) in 4/12 (33.3%) and completely inhibited prolactin (PRL) secretion in all the patients. Octreotide caused a decrease of GH level (from 37 +/- 6.7 to 15.9 +/- 3.0 micrograms/l) without any change of PRL level. The GH and PRL levels were not changed during placebo administration. CV 205-502 at the dose of 0.3 mg/day (chronic test) normalized GH and IGF-I levels in five patients (41.6%: the four responders to the acute test and an additional patient who was a poor responder to acute CV 205-502 administration). The remaining seven patients were subjected to CV 205-502 (0.6 mg/day) and octreotide (0.6 mg/day) in combination for 3 months. In 2/7 patients the combined therapy induced a greater inhibition of GH and IGF-I levels than did each drug when administered alone. The drug was well-tolerated by the 12 patients. In conclusion, CV 205-502 is able to normalize GH and IGF-I levels and to improve clinical symptoms in certain acromegalic patients resistant to other therapeutic approaches.(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of this study was to evaluate serum baseline and gonadotropin-releasing hormone (GnRH)-stimulated follicle-stimulating hormone (FSH) and luteinizing hormone (LH) concentrations in the inferior petrosal sinuses and in peripheral blood in nine normoprolactinemic and eight hyperprolactinemic patients who were being subjected to perihypophyseal phlebography for diagnostic purposes or neurosurgical indications. Serum FSH and LH concentrations were significantly higher in both inferior petrosal sinuses than in peripheral blood (p < 0.001 and p < 0.05, respectively) in normoprolactinemic but not in hyperprolactinemic patients. Additionally, in normoprolactinemic patients, the LH response to intravenous bolus GnRH in the inferior petrosal sinuses (evaluated as peak/basal) was significantly greater than in hyperprolactinemic patients (p < 0.01). No difference was found as far as FSH response to GnRH was concerned. In conclusion, these findings suggest that the hypogonadism of hyperprolactinemic patients may depend on the impaired release of LH at the pituitary level.

Background: In the last decade, the treatment of macroprolactinomas has been significantly improved by the introduction in the clinical practice of new drugs with dopamine-agonist properties. In particular, the availability of different forms of bromocriptine (BRC) with long duration of action and slow absorption, suitable for injectable (BRC-LAR) or oral (BRC-SRO) administration, has allowed one to obtain a more constant bromocriptinemia than with standard BRC, thus reducing adverse reactions. Moreover, a selective action on dopamine D2 receptors has been achieved using a new non-ergot derivative: the quinagolide (CV 205-502). The aim of this study was to evaluate the effects of BRC-LAR, BRC-SRO and CV 205-502 in 34 patients with macroprolactinoma. PROTOCOL OF THE STUDY: BRC-LAR was given at the monthly dose of 50-100 mg for 6-24 months to 8 patients whose PRL levels were 150-700 micrograms/l. BRC-SRO was given at the daily dose of 5-20 mg for 1-24 months to 10 patients whose PRL levels were 120-900 micrograms/l. CV 205-502 was given at the daily dose of 0.075-0.6 mg for 6-12 months to 16 patients whose PRL levels were 250-2,050 micrograms/l. CT and/or MRI scans were performed before and during treatment to evaluate tumor shrinkage. Data are presented as Mean +/- SD., Results: Serum PRL levels normalized in 8/8 with BRC-LAR, 7/10 with BRC-SRO and 12/16 patients with CV 205-502. A significant shrinkage of tumor mass was obtained in 7/8 with BRC-LAR, 9/10 with BRC-SRO and 16/16 patients with CV 205-502, with consequent improvement of visual-field defects. Overall, the drugs were rather well tolerated: no patient stopped BRC-LAR or BRC-SRO and only 2 stopped CV 205-502. In particular, nausea, vomiting, headache, hypotension that disappeared spontaneously were observed in 5/8 with BRC-LAR, 4/10 with BRC-SRO and 4/16 with CV 205-502., Conclusions: The medical approach with long-acting BRC preparations and CV 205-502 which selectively binds D2 receptors allows one to obtain rapid normalization of PRL levels and shrinkage of macroprolactinomas in a large series of patients. These drugs are rather well tolerated also by patients proven to be untolerant to standard BRC.

The clinical effects of CV 205-502, a potent and non-ergot-derived dopamine agonist, were investigated in 24 selected patients with hyperprolactinemia previously treated with standard oral bromocriptine, the slow-release oral form of bromocriptine (BRC-SRO) and/or the long-acting injectable form of bromocriptine (BRC-LAR); 14 were chosen because of their resistance to treatment and ten because they were intolerant of the different forms of bromocriptine. A macroprolactinoma was present in seven patients and a microprolactinoma in ten, whereas seven had no radiological images of a pituitary tumor and were classified as having non-tumoral hyperprolactinemia. All the 24 patients were treated with CV 205-502 at a daily dose of 0.075-0.6 mg for 3-12 months. All the patients had gonadal dysfunction and galactorrhea. Basal serum prolactin values ranged from 70 to 1677 ng/ml. CV 205-502 was effective in 11 of the 14 patients resistant bromocriptine, BRC-SRO and BRC-LAR; serum prolactin levels became normal within 6 months and a tumor shrinkage was obtained in five of the seven macroprolactinomas. In general, the drug was effective and well tolerated. Only three patients (two resistant and one intolerant) manifested nausea, vomiting and postural hypotension. In conclusion, this study shows that CV 205-502 is effective in bromocriptine-resistant hyperprolactinemic patients. Furthermore, CV 205-502 has insignificant and tolerable side-effects in patients intolerant of bromocriptine. CV 205-502 can, therefore, be considered a useful and effective drug, and an interesting therapeutic alternative to the ergot-derived dopamine-agonist drugs in use today.

The ability of CRH to cause a paradoxical response of GH in acromegaly is still under debate. In this study, the effect of CRH administration on GH release was evaluated in a large series of patients with active acromegaly, both in vivo, compared to that of TRH and GnRH, and in vitro. The study was organized as follows. In vivo study: 30 acromegalic patients were submitted to TRH, GnRH, and CRH tests on non-consecutive days: blood samples were collected before and 10, 20, 30, 45, 60, 90, and 120 min after bolus. In nine patients the CRH test was repeated after a 3-month therapy with octreotide and at the dose of 300-600 micrograms sc thrice daily. In vitro study: CRH (10 nmol/l, 100 nmol/l, and 1 mumol/l) was tested on pituitary tumor tissue obtained in eight patients during transsphenoidal adenomectomy and immediately placed in sterile Ca2+ and Mg2+ free buffer phosphate. A paradoxical GH response to TRH (evaluated as a GH increase over 50% of basal values) was recorded in 19 patients (63.3%), whereas 7 patients (23.3%) responded to GnRH and 4 others to CRH (13.3%). TRH administration induced a maximal percent GH increase significantly greater than that induced by GnRH and CRH (p < 0.05). Octreotide caused the normalization of GH and insulin-like growth factor-I levels in all the patients, as well as the disappearance of the GH paradoxical response to CRH in 3/4 patients. All four CRH responders and four CRH non-responders, used as controls, were surgically treated and adenomatous tissue was used for the in vitro study.(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of this study was to investigate the effects of a 6-month octreotide treatment on cardiac mass and function by means of Doppler echocardiography in 11 normotensive patients affected with active acromegaly. The GH and insulin-like growth factor-I levels were normalized during octreotide therapy from 34 +/- 6.5 and 767.4 +/- 72.4 micrograms/L to 4.6 +/- 0.9 and 235 +/- 10.3 micrograms/L, respectively (P < 0.001; mean +/- SEM). After the 6-month treatment, we observed a significant decrease in the left ventricular mass index from 138 +/- 11 to 116 +/- 13 g/m2 (P < 0.001) and in the mean wall thickness/internal end-diastolic radius ratio from 0.47 +/- 0.1 to 0.44 +/- 0.1 (P < 0.001). No significant differences were found in systolic function indices, whereas diastolic filling indices improved over the course of the therapy; the isovolumic relaxation time decreased from 115 +/- 6 to 100 +/- 6 ms (P < 0.05), tricuspid late diastolic filling velocities decreased from 41 +/- 3 to 36 +/- 2 cm/s (P < 0.03), and tricuspid deceleration time decreased from 280 +/- 28 to 198 +/- 15 ms (P < 0.005); the ratio of early to late peak velocity of the right ventricular filling significantly increased from 1 +/- 0.01 to 1.3 +/- 0.1 (P < 0.03). A significant correlation was detected between left ventricular mass regression and increase in the early to late peak velocity ratio of the left ventricular filling (r = 0.62; P < 0.05). The results of this study show an improvement in cardiac structural and functional abnormalities during chronic treatment with octreotide, thus supporting the hypothesis of a specific heart disease secondary to high circulating GH levels.

The effects of a chronic treatment with octreotide were evaluated in 19 patients affected with functionless pituitary adenomas. Octreotide caused a significant decrease of GH and IGF-I levels in all the patients and no significant change in thyroid, adrenal and gonadal function. In contrast, during the therapy, the glucose response to an oral glucose tolerance test considerably increased and was delayed, while the insulin response decreased and was delayed. Serum alpha-subunit (alpha-SU) was above normal in 10 of 16 patients in which this evaluation was performed: octreotide caused a significant decrease (p < 0.01) of alpha-SU levels in 6 of these 10 patients. Octreotide did not induce any significant change in visual fields except in 1 patient, who had a great improvement of visual perimetry and a decrease of alpha-SU levels but unmodified CT scan features. In our series of patients, octreotide was ineffective in reducing tumor mass. The efficacy of octreotide might rely on the presence of somatostatin receptors on adenoma-cell membranes. Therefore patients with functionless adenomas to be treated with octreotide might be identified with pituitary scintiscan using the recently available labeled 111In-octreotide.

In our previous studies we had demonstrated that, in children affected with isolated GH deficiency (IGHD), a short-term recombinant growth hormone (rGH) therapy increases the 11-deoxycortisol (S) secretion and induces an IGF-I responsiveness to the ACTH challenge. The aim of the present study was to further investigate the mechanisms by which IGF-I is secreted after ACTH challenge in children affected with IGHD by correlating IGF-I versus cortisol (F) time courses after ACTH administration. Ten children affected with IGHD were subjected to rGH therapy (4 IU/day subcutaneously) for 10 days. The responsiveness of IGF-I, F and S to the ACTH 1-17 test were evaluated before and at the end of the therapy. No IGF-I response to the ACTH test was recorded in the patients before the rGH treatment, whereas after rGH administration ACTH induced a significant IGF-I release (p < 0.001) which started at the 1st hour, reached a peak value between the 5th and 6th hours and disappeared at the 10th hour. In conclusion, our study confirms that a short-term rGH therapy induces an IGF-I responsiveness to ACTH and helps to better define the kinetics and the mechanism of this IGF-I response to ACTH.