Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours.

OBJECTIVES: Somatostatin (SST) analogues play an important role in the medical management of somatotroph pituitary adenomas and new agonists have the potential to be effective in a wider group of pituitary and other tumours. The anti-proliferative effect of SST occurs through multiple mechanisms, one of which is cell-cycle arrest, where p27, a cyclin-dependent kinase inhibitor, is an important regulator. We hypothesised that SST may upregulate p27 protein levels and downregulate the MAP kinase pathway in these tumours. METHODS: Human pituitary adenoma cells and rat pituitary cell line (GH3) were cultured and treated in vitro with octreotide and the broad-spectrum SST agonist SOM230 (pasireotide). Immunoblotting for p27 and phospho-ERK (pERK) was performed and proliferation assessed by [3H]-thymidine incorporation. Histological samples from acromegalic patients treated with octreotide before surgery were immunostained for p27 and compared to samples from untreated patients matched for sex, age, tumour size, extension and invasiveness. RESULTS: We detected upregulation of p27 protein levels with SST analogue treatment in vitro in human pituitary adenoma samples. pERK1/2 was inhibited by SST analogues in both the human samples and GH3 cells. SST and its analogues inhibited the proliferation of GH3 cells. p27 immunostaining was stronger in samples from patients with longer preoperative octreotide treatment (more than 6 months) than in samples from patients with shorter treatment periods. CONCLUSIONS: This study demonstrates that SST-mediated growth inhibition is associated with the downregulation of pERK and upregulation of p27. More potent and broader-spectrum SST analogues are likely to play an increasing role in the treatment of tumours, where the MAP kinase pathway is overactivated.

Bone mineral density in acromegaly: the effect of gender, disease activity and gonadal status.

OBJECTIVE: Data on bone mineral density (BMD) in acromegaly are conflicting as most previous studies collectively evaluated eugonadal and hypogonadal patients of both sexes, with or without active disease. We have evaluated BMD in 152 acromegalic patients of both sexes with varying disease activity and gonadal status. DESIGN: Cross-sectional, retrospective. PATIENTS: We studied 152 acromegalic patients (99 women aged 26-72 years, and 53 men aged 21-75 years), 107 with active and 45 with controlled disease. Eighty-five patients had normal gonadal status and 67 were hypogonadal. MEASUREMENTS: In all patients we measured serum GH levels by immunoenzimometric assay, and serum IGF-I levels by radioimmunoassay. BMD was assessed at spine L2-L4 (LS) and at femoral neck (FN) by dual energy X-ray absorptiometry; results are expressed as Z-values. RESULTS: We evaluated the effect of GH excess on bone at different sites in relation to gonadal status, disease activity and gender. At LS, in respect to the reference population, BMD (mean +/- SE) values were higher in eugonadal patients (active: 0.71 +/- 0.29, P < 0.02; controlled: 0.65 +/- 0.28, P < 0.05) and lower in hypogonadal ones (active: -0.64 +/- 0.35, 0.1 < P < 0.05; controlled: -1.05 +/- 0.36, P < 0.01), regardless of disease activity. On the contrary, at FN, BMD was higher than in the reference population, both in eugonadal (1.01 +/- 0.22, P < 0.001) and hypogonadal (0.63 +/- 0.17, P < 0.001) patients only in subjects with active disease, but not in those in which the disease was controlled (eugonadal: 0.31 +/- 0.23, P = ns; hypogonadal 0.04 +/- 0.28, P = ns). We did not observe any difference in BMD values according to gender both at LS (males vs. females -0.02 +/- 0.30 vs. 0.01 +/- 0.24, P = ns) or at FN (0.77 +/- 0.19 vs. 0.63 +/- 0.15, P = ns). CONCLUSIONS: The anabolic effect of GH excess on bone in acromegalic patients is: (i) gender-independent; (ii) evident at the spine only in eugonadal regardless of disease activity; (iii) evident at femoral neck only in the presence of active disease regardless of gonadal status.

Transdermal oestradiol replacement therapy enhances platelet constitutive nitric oxide synthase activity in postmenopausal women with type 2 diabetes mellitus.

OBJECTIVE: To determine whether treatment with transdermal oestrogen replacement therapy (TERT) in postmenopausal women with type 2 diabetes mellitus was able to increase the activity of constitutive nitric oxide synthase (cNOS) in platelets. RESEARCH DESIGN AND METHODS: Eighteen postmenopausal women with type 2 diabetes mellitus (group A) were studied in basal conditions (A1) and on the 10th day of the third month of a sequential opposed TERT (A2) evaluating platelet cNOS activity measured by the conversion of radiolabelled l-arginine to l-citrulline. As a control group (B) 25 normal postmenopausal women underwent the same treatment (B1 and B2 before and during treatment, respectively). RESULTS: Basal values of platelet cNOS activity were superimposable (0.6 +/- 0.1 vs. 0.7 +/- 0.1 fmol/min/109 plts, NS). During TERT, platelet cNOS activity rose in A and B (0.6 +/- 0.1 vs. 1.8 +/- 0.1 fmol/min/109 plts, P < 0.05 and 0.7 +/- 0.1 vs. 2.4 +/- 0.2, P < 0.001, A1 vs. A2 and B1 vs. B2, respectively). However, platelet cNOS activity of A2 did not reach the values of B2 (1.8 +/- 0.1 vs. 2.4 +/- 0.2 fmol/min/109 plts, P < 0.05; A2 vs. B2, respectively). CONCLUSIONS: Sequential opposed transdermal oestrogen replacement therapy was able to increase platelet cNOS activity in postmenopausal women with type 2 diabetes mellitus, suggesting that its use might be positive in preventing cardiovascular pathologies.