Lanreotide 60 mg, a new long-acting formulation: effectiveness in the chronic treatment of acromegaly.

Lanreotide (LAN) 60 mg (LAN60), a new long-acting formulation of LAN alleged to suppress GH/IGF-I hypersecretion for 28 d in acromegalic patients, was administered in a prospective open multicenter study to 92 patients with active acromegaly (61 women and 31 men, aged 20-79 yr). LAN60 was given as adjuvant treatment (AT) in 62 patients; the other 30 patients [primary treatment (PT)] were de novo (n = 20) or previously treated only by pharmacotherapy (n = 10). After wash-out from previous treatments, LAN60 was started im every 28 d for 3 injections; the dose was then individually tailored, aiming at lowering GH to less than 2.5 micro g/liter and IGF-I to the normal range. After a median follow-up of 24 months (range, 6-48 months), IGF-I normalized in 65% of patients, decreasing from 199 +/- 8% (expressed as a percentage of the upper limit of normal range; mean +/- SE) to 87 +/- 4% (P < 0.0001). GH fell to less than 2.5 microg/liter in 63% of patients and to less than 1 microg/liter in 25%, decreasing from 20 +/- 3 to 3 +/- 0.4 microg/liter (P < 0.0001). A progressive increase in the rate of IGF-I normalization was observed (from 49% at 1 yr to 77% at 3 yr). The rate of GH/IGF-I normalization was 72% at 36 months by Kaplan-Meier analysis. No tachyphylaxis was observed throughout the study. Shortening the interval between injections to 21 d improved GH/IGF-I suppression. PT and AT patients achieved similar final GH/IGF-I levels and rates of normalization. Tumor shrank in 39% of assessable patients and in 50% of PT. Plasma glucose levels did not change, and high density lipoprotein cholesterol increased (by 19.3 +/- 5.1%; P = 0.0215). Gallstones appeared or worsened in 13% of patients. LAN60 is a new, very effective and long-lasting formulation for the treatment of acromegaly. The persistence of a powerful suppression of GH/IGF-I levels, the progressive increase in the rate of IGF-I normalization, and the similarity in the efficacy achieved in PT and AT patients point to a role for LAN60 in the primary treatment of acromegaly.

Characterization of the intracellular mechanisms mediating somatostatin and lanreotide inhibition of DNA synthesis and growth hormone release from dispersed human GH-secreting pituitary adenoma cells in vitro.

OBJECTIVE: Somatostatin is an endogenous inhibitor of hormone secretion and cell proliferation. Treatment with somatostatin analogues in humans causes a reduction in size and secretory activity of endocrine tumours, including GH-secreting pituitary adenomas. This study was aimed to characterize the intracellular mechanisms mediating the in vitro antiproliferative and antisecretory effects of somatostatin and its analogue lanreotide, on primary cultures of GH-secreting pituitary adenoma cells. DESIGN: Thirteen GH-secreting pituitary adenoma postsurgical specimens were analysed for somatostatin receptor (SSTR) mRNA expression and a subset of them was analysed in vitro for the effect of somatostatin on cell proliferation, assessed by means of [3H]-thymidine uptake, and GH release, using an immunoradiometric assay. Moreover, the intracellular signalling involved in such effects has been studied. RESULTS: All the adenomas analysed expressed at least one somatostatin receptor subtype mRNA. SSTR2 mRNA was identified in 77% of the adenomas, SSTR1 and SSTR3 in 69% and SSTR5 in 60%. Somatostatin and lanreotide inhibited cell proliferation in phorbol ester (PMA)-stimulated conditions (10/13 adenomas), as well as after fetal calf serum (3/3 adenomas) or IGF-I stimulation (2/2 adenomas). Conversely, GHRH or forskolin treatments did not significantly affect DNA synthesis in adenoma cells in the presence or absence of somatostatin (2/2 and 4/4 adenomas, respectively). Vanadate pretreatment reversed somatostatin inhibition of PMA-induced DNA synthesis suggesting an involvement of tyrosine phosphatase in this effect (2/2 adenomas); this was confirmed by the direct induction of tyrosine phosphatase activity in two adenomas after somatostatin treatment. Somatostatin and also lanreotide caused significant inhibition of phorbol ester, forskolin, GHRH and KCl-dependent increase of GH secretion in the culture medium. Moreover, voltage-sensitive calcium channel activity induced by 40 mm KCl depolarization in microfluorimetric analysis, was significantly reduced (5/5 adenomas). CONCLUSIONS: These data show that somatostatin and lanreotide inhibit human GH-secreting pituitary adenoma cell proliferation and hormone release in vitro, and suggest that the activation of tyrosine phosphatases may represent intracellular signals mediating the antiproliferative effects and that the inhibition of the voltage-dependent calcium channels and adenylyl cyclase activities may control GH secretion.

In vitro effect of human recombinant leptin and expression of leptin receptors on growth hormone-secreting human pituitary adenomas.

OBJECTIVE AND STUDY DESIGN: Leptin is a circulating hormone secreted by adipose tissue and a few other tissues. It has recently been demonstrated that leptin and leptin receptors are expressed in normal and adenomatous pituitary cells. The aim of this study was to investigate the effect of recombinant human leptin on GH release from adenomatous GH-secreting cells in culture. Specimens were obtained from 10 patients with acromegaly who had undergone selective transsphenoidal adenomectomy. Cells (2 x 10(5)/well) preincubated for 24 h with leptin (10(-10)-10(-8) m) or control medium were exposed to GHRH for 2 h. The GH released into the medium was measured before and after GHRH incubation. The expression of leptin receptor isoforms was evaluated by reverse-transcriptase polymerase chain reaction (RT-PCR) in cells obtained from five adenomas. RESULTS: After the first incubation, there was a slight dose-dependent leptin-induced decrease in GH released into the medium. A significant increase in GH release after GHRH was noted from cells previously exposed to leptin in comparison with cells incubated with medium alone. Expression of leptin receptors was found in two out of five GH-secreting adenomas evaluated. CONCLUSIONS: Our data confirm that some, but not all, GH-secreting adenomas express leptin receptors. Leptin seems to exert both a slight inhibitory effect on spontaneous GH secretion and a stimulatory effect on GHRH-stimulated GH secretion from GH-secreting adenomatous tissue.