Brief Communication Lack of change in insulin levels as a biological marker of PAI-1 lowering in GH-deficient adults on r-HGH replacement therapy Matteo Nicola Dario Di Minno a, ⁎, Vittorio Palmieri a , Gaetano Lombardi b , Salvatore Pezzullo a , Ferdinando Cirillo a , Carolina Di Somma b , Domenico Valle c , Giovanni Di Minno a a Dept. of Clinical and Experimental Medicine, Reference Centre for Coagulation Disorders, “Federico II” University, Naples, Italy b Dept. of Endocrinology and Oncology, “Federico II” University, Naples, Italy c Eli Lilly, Florence, Italy article info Article history: Received 23 October 2008 Received in revised form 29 May 2009 Accepted 3 June 2009 Available online 20 August 2009 Keywords: GH-deficient adults IGF-1 insulin PAI-1 t-PA r-HGH treatment Introduction Patients with growth hormone (GH) deficiency (GHD) have decreased life expectancy and increased risk of cardiovascular events [3,22,25]. An impaired fibrinolysis is a major determinant of cardiovascular risk [4,27]. PAI-1, the main physiologic inhibitor of t- PA, regulates the fibrinolytic system. Raised plasma levels of PAI-1 have been documented in ischemic heart disease and in subjects who subsequently develop myocardial infarction [7]. Abnormally high circulating levels of PAI-1 are associated with high risk for stroke and myocardial ischemia [4,27]. Prospectively, raised levels of PAI-1 is a strong determinant of vascular ischemic events [11,18,20,21]. It is also known [see 16,17 for a review], that PAI-1 inhibition rises with the increase in t-PA antigen, so that high levels of either factor reflect an impaired fibrinolysis. This information is based on a series of data: a) concentrations of t-PA antigen above normal ranges are present in subjects with high plasma PAI-1 levels; b) increases in t-PA antigen reflect the inhibitory effect of PAI-1 on t-PA activity; c) there is a negative correlation between t-PA antigen and activity in plasma samples. Prospectively, r-HGH replacement may be associated with improved cardiovascular risk profile in GHD [5,24,28]. Adults with GHD exhibit abnormally elevated levels of PAI-1. PAI-1 levels may decrease in response to recombinant human GH (r-HGH) replace- ment therapy in GHD [10,12,15]. r-HGH replacement may be asso- ciated with hyperinsulinemia that in turn impacts PAI-1 as much as t- PA [6,13,23]. In 60 GHD adults, we have prospectively measured PAI-1, t-PA, insulin, and insulin-like growth factor-1 (IGF-1), at baseline and after 6-mo r-HGH replacement. We have also evaluated whether changes in insulin and/or IGF-1 levels following r-HGH replacement in GHD adults relate to changes in PAI-1 levels. Methods Patients This sub-study was designed as an addendum of a multicenter randomized trial (B9REW-GDED), that involved 56 study centers and included 595 adult patients with GHD of either childhood- or adulthood-onset, randomized to receive r-HGH replacement therapy either at low-dose (LD 3 μg/kg/d for 3 mo and, then, 6 μg/kg/d for 3 mo) or at conventional dose (CD 6 μg/kg/d for 3 mo and, then, 12 μg/ kg/d for 3 mo). Safety and efficacy data from the main study (B9R-EW- GDED) have been reported elsewhere [13]. The observation period was decided to be 6 months (6-mo) according to finding [12] that this is the shortest exposure time to r-HGH to achieve significant changes in fibrinolytic variables. The present report is based on 60 Italian participants who gave their informed consensus to enter the sub-study (57% out of the 105 eligible individuals from all the Italian Centers [1]). Of those, 26 were females, 34 were males; 25 had childhood-onset and 35 an adulthood- onset GHD. No significant differences were found between the 60 participants included in the present report and the whole sample enrolled in the Italian sub-study as to parameters analyzed at baseline and after 6-mo r-HGH treatment period (p always N 0.1). A thorough data collection was achieved for each of the 60 subjects (by a trained staff), including the search for the coexistence of other pituitary hormone deficiencies. Diagnosis of GHD was based on clin- ical evaluation and peak serum GH levels b 3.0 or 9.0 μgL after Thrombosis Research 124 (2009) 711–713 ⁎ Corresponding author. Dept. of Clinical and Experimental Medicine, Via S. Pansini 5, 80131 Naples, Italy. Tel./fax: +39 817462060. E-mail address: dario.diminno@hotmail.it (M.N.D. Di Minno). 0049-3848/$ – see front matter © 2009 Published by Elsevier Ltd. doi:10.1016/j.thromres.2009.06.018 Contents lists available at ScienceDirect Thrombosis Research journal homepage: www.elsevier.com/locate/thromres