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Objective: We aimed to investigate the efficacy of pegvisomant in patients with acromegaly resistant to long-term (^24-month), high-dose treatment with octreotide-LAR (40 mg/month) or lanreotide (120 mg/month). Design:This was an open, prospective study. Subjects and Methods: We studied 16 patients with acromegaly (nine women; aged 28 -61 years). The main outcome measures were IGF-I levels, blood pressure, glucose tolerance and safety (liver function and tumor size). Pegvisomant was given at doses of 10-40 mg s.c. daily. Dose titration was performed every month by IGF-I assay. Results: Three patients spontaneously stopped pegvisomant treatment after 6-9 months because of poor compliance; from the measurement of serum pegvisomant, another patient was found not to inject herself properly. After 6 months, IGF-I levels decreased by 63^19% (767.8^152.9 vs 299.8^162.9 mg/l, P , 0.0001, t-test); serum IGF-I levels normalized in 57%. After 12 months, IGF-I levels normalized in nine (75%) patients and were reduced by over 50% in another three (25%). The mean tumor volume remained stable during the study (1198^1234 vs 1196^1351 mm 3 , P ¼ 0.37): it did not change (^25% vs basal) in nine patients, increased by 39.4% and 40.8% in two and decreased by 30.8 -46.5% in four. The total/high-density lipoprotein (HDL):cholesterol ratio (from 4.4^1.0 to 3.7^0.6, P¼0.0012), glucose levels (from 5.6^1.2 to 4.4^1.4 mmol/l, P ¼ 0.026), insulin levels (from 12.4^6.7 to 8.1^3.0 mUl/l, P ¼ 0.0023) and homeostasis model assessment (HOMA) index (from 3.4^2.1 to 1.9^1.0, P ¼ 0.0017) decreased. Conclusions: Treatment for 12 months with pegvisomant normalized IGF-I levels, and improved cardiovascular risk parameters and insulin sensitivity in patients with acromegaly resistant to long-term, high-dose treatment with somatostatin analogs. The tolerance of treatment was good.

In order to determine the mechanism by which glucocorticosteroids decrease the serum concentration of thyrotropin (TSH), we studied eight normal subjects before and after they received 16 mg of dexamethasone daily for 2 1/2 days. Serum levels of TSH and prolactin (PRL) were measured in the basal state and in response to the intravenous administration of 200 mug thyrotropin-releasing hormone (TRH); T4, free T4 (fT4), T3, and free T3 (fT3) were measured before TRH injection. Metabolic clearance rates of TSH corrected for body surface area (MCR-TSH/m2) were determined by the method of constant infusion to equilibrium; the production rates of TSH (PR-TSH/m2) were calculated. Dexamethasone produced a decrease in basal TSH from 2.2 to 0.8 muU/ml (P less than 0.02), a statistically insignificant elevation in MCR-TSH/m2 from 25.8 to 34.1 ml/min/m2, and a decrease in PR-TSH/m2 from 79 to 30 mU/day/m2 (P less than 0.01). Peak TSH response to TRH decreased from 16.4 to 5.8 muU/ml (P less than 0.005), as did TSH reserve from 1.58 to 0.54 mU - min/ml (P less than 0.005). Repetitive TRH testing alone did not account for these changes. Basal PRL, peak PRL after TRH, and PRL reserve did not change significantly after dexamethasone administration. Although Basal T4 and fT4 did not change significantly, dexamethasone did decrease T3 from 106 to 61 ng/dl (P less than 0.001) and fT3 from 174 to 76 pg/dl (P less than 0.05). Dexamethasone produced similar changes in patients with various thyroid disorders. In addition, when plasma cortisol was lowered by metyrapone administration in 25 euthyroid patients, the serum TSH concentration rose from 1.6 to 3.1 muU/ml (P less than 0.001). These data indicate that dexamethasone a) suppresses TSH secretion without increasing fT3 and fT4 and b) blunts the TSH, but not the PRL response, to TRH. Hence, one effect of the administration of dexamethasone in high dose is a direct suppression of pituitary TSH secretion. Furthermore, physiologic levesl of circulating cortisol also have a suppressive effect on serum TSH.