CONTEXT Cortistatin binds all somatostatin receptor subtypes but also has particular central actions; moreover, a specific cortistatin receptor has also been discovered. OBJECTIVE We compared the endocrine effects of cortistatin-17 with those of somatostatin-14 in patients with acromegaly (ACRO) or prolactinoma (PRLOMA). Normal subjects (NS) were studied as control group. DESIGN All subjects underwent the following tests: 1) saline, 2) somatostatin-14 (2.0 microg/kg.h iv, 0-120 min) and 3) cortistatin-17 (2.0 microg/kg.h iv, 0-120 min) infusion. RESULTS Cortistatin-17 and somatostatin-14 inhibited GH secretion to the same extent in ACRO (P < 0.05) and NS (P < 0.01). Cortistatin-17 and somatostatin-14 inhibited PRL secretion in PRLOMA (P < 0.05), to some extent in ACRO (P value not significant), but not in NS. Insulin secretion was inhibited by both cortistatin-17 and somatostatin-14 to the same extent in all groups (P < 0.05). CONCLUSIONS Cortistatin-17 and somatostatin-14 display the same effects on GH, PRL, and insulin secretion in patients with ACRO or PRLOMA.

The aim of the present multicentric, open-label, non-comparative study was to evaluate the role of octreotide long-acting repeatable (LAR) as primary therapy for the treatment of GH-secreting pituitary macroadenomas. The patients received octreotide LAR 20 mg every 4 weeks for 12 weeks; afterwards the dose was confirmed or adjusted at 30 mg every 4 weeks, for the remaining 12 weeks, for responder or non-responder patients, respectively. Responder patients continued the study until 48 weeks. Twenty-one naïve active acromegalic patients were enrolled. In all patients, GH profile, IGF-I levels and magnetic resonance imaging (MRI) were evaluated at baseline and during treatment. The ability of octreotide LAR to decrease mean GH <2.5 μg/l and/or normalize IGF-I levels, adjusted for age and gender, was defined respectively as total or partial success. Total success was achieved in 5/21 (23.8%), 6/20 (30%) and 4/14 (28.6%) patients after 12, 24 and 48 weeks; partial success in 7/21 (33.3%), 9/20 (45%) and 9/14 (64%) patients at 12, 24 and 48 weeks according to GH levels, while according to IGF-I levels in 7/21 (33.3%), 7/20 (35%) and 5/14 (35.7%) patients at 12, 24 and 48 week. Tumor size was notably decreased after treatment with octreotide LAR: in 16 macroadenoma patients completing the study, the tumor sizes were 1609±1288, 818±616 (49.1±23.7%) and 688±567 mm 3 (54.6±24.4%) at baseline, 24 and 48 weeks. This study shows that oc-treotide LAR is effective in suppressing GH/IGF-I secretion and inducing tumor shrinkage in GH-secreting macroadenomas in a 48-week treatment. Octreotide LAR could be used as primary therapy in patients harbouring large pituitary tumors, who are less likely to be cured by neurosurgery.

Introduction: acromegalic therapeutic goals are directed at removing the tumor, preventing tumor re-growth and reducing long-term morbidity and mortality. In this scenario, the acromegalic patient needs a variety of health resources (diagnostic tests, surgery, radiotherapy, specialist visits and drugs) for his/her cure, in order to decrease/stop the progression of the disease and to cure the co-morbid diseases. Lack of epidemiological data has suggested performing an Italian retrospective study aiming to assess the health resource consumption that is caused by acromegalic cure and the relative co-morbidities, in order to estimate the amount of the direct costs of acromegalic patients. Method: a retrospective study was performed on a total of 134 patients (142 patients selected, 76 in Genoa and 66 in Turin) for a period of about 7 yr preceding the enrolment date. Only direct costs were evaluated by performing an analysis on the perspective of Italian Healthcare Service (SSN). Results: the mean total direct costs for acromegaly cure ranged from 7.968,41 to 12.533,02 €/yr ( p <0,01; Mann Whitney Test), respectively, for Responders and Non-Responders. The cost driver was drug (SS analogs) for acromegalic cure. The co-morbidity conditions associated to acromegalic Non-Responder patients are clearly higher than those with well-controlled disease. Conclusion: the study supports the hypothesis that controlled patients drove a saving for SSN in comparison to poor control patients that use more health resources.

Ghrelin, a peptide predominantly produced by the stomach, has been discovered as natural ligand of the growth hormone secretagogue receptor (GHS-R) type 1a. More recently, ghrelin attracted enormous interest as new orexigenic factor. However, ghrelin exerts several other neuroendocrine, metabolic and also non-endocrine actions (e.g. cardiovascular activities) that are explained by the widespread distribution of ghrelin and GHS-R expression. The existence of GHS-R subtypes and evidence that neuroendocrine but not all other ghrelin actions are dependent on acylation in serine 3 add further complexity to the system whose major physiological role remains to be definitely clarified. What we are learning from the studies about the control of ghrelin secretion is that it is mostly under metabolic control; the most important impact of ghrelin would, in turn, be metabolic. However, a recent study states that the ghrelin knockout (KO) mouse is not anorectic dwarf and this evidence clearly depicts a remarkable difference from the leptin KO mouse. Nevertheless, the original and fascinating ghrelin story as well as its potential pathophysiological implications in endocrinology and internal medicine are not definitely canceled by this evidence. Besides potential clinical implications for natural or synthetic ghrelin analogues acting as agonists or antagonists, open questions that are waiting for an answer are: how many are the ghrelin receptors? Is ghrelin the or a GHS ligand, i.e. are there other natural GHS-R ligands? Is there a functional balance between acylated and unacylated ghrelin forms that would play different actions? Within the next years these questions will find the appropriate answer and we'll know about the ghrelin system something more precise; this knowledge will more appropriately clarify the potential clinical perspectives.

GH hypersecretory states include organic and functional causes. Among functional GH hypersecretory states, enhanced somatotroph secretion physiologically occurs at birth associated with reduced IGF-I levels reflecting the still immature sensitivity of liver to circulating GH levels; this may also occur in women exposed to oral extrogens. Pathophysiological conditions of GH hypersecretion are generally associated with congenital or acquired/functional conditions of peripheral GH insensitivity. Genetic alterations of the GH receptor lead to the so called Laron's syndrome. On the other hand, a relevant number of clinical conditions (malnutrition, malabsorption, anorexia nervosa, liver cirrhosis, renal failure, Type 1 diabetes mellitus) are associated with acquired GH insensitivity and a more or less pronounced GH hypersecretion. Both organic and acquired conditions of GH insensitivity show low IGF-I synthesis and release and therefore lack the negative IGF-I feedback action on somatotroph function. GH hypersecretion may be associated with renal failure; however, in this case, the alteration in the metabolic clearance rate of GH would also have a role; moreover, IGF-I levels are generally normal in this condition. Hyperthyroidism is another condition connoted by elevated GH levels that reflects a true GH hypersecretory state and is, in fact, associated with high-normal IGF-I levels; this peculiar condition is likely to be reflecting the stimulatory effect of thyroid hormones on both GH and IGF-I secretion and is promptly reversed by treatment-induced euthyroidism. Apart from these "functional" hypersecretory state, the classic organic GH hypersecretory state is represented by acromegaly or giantism. In these conditions GH hypersecretion is generally sustained by a pituitary adenoma hypersecreting GH alone or together with another pituitary hormone, mostly PRL; less frequently GH hypersecretion may be due to ectopic GHRH hypersection. Exaggerated GH secretion elicits exaggerated IGF-I synthesis and secretion that is, in turn, responsible for the large majority of endocrine signs and symptoms. In the appropriate clinical context of acromegalic features, evidence of concomitant marked GH and IGF-I hypersecretion at baseline demonstrates active acromegaly or giantism and indicates the need for magnetic resonance imaging in order to verify the presence of a pituitary tumor. However, as random measurement of basal GH levels is not reliable for definite diagnosis of acromegaly, it is considered mandatory to rely on the lack of GH suppression below 1 microg/l during oral glucose tolerance test (OGTT) coupled with elevated IGF-I levels. The same criteria are assumed, at present, to define true cure of the disease after (or under) treatment. There is consensus about the assumption that concomitant normalization or persistent abnormality of both OGTT-induced GH nadir and IGF-I levels define a successfully or a poorly controlled disease status, respectively. On the other hand, acromegalic patients with GH nadir above 1 microg/l or IGF-I levels persistently elevated are inadequately controlled and their disease should not be considered inactive. It has been clearly demonstrated that an extended exposure to GH and IGF-I excess level, even if slight, has a very harmful effect on patients; therefore early diagnosis of acromegaly and appropriate definition of its cure are of fundamental extreme in order to plan a prompt and appropriate therapeutic intervention(s) guaranteed also by the continuous improvement in the therapeutic tools available to treat this systemic disease.