Published Online
on May 3, 2004

A more recent version of this article appeared on May 25, 2004

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Submitted on February 4, 2004
Revised on February 20, 2004
Accepted on February 23, 2004

Growth Hormone Replacement Decreases Plasma Levels of Matrix Metalloproteinases (2 and 9) and Vascular Endothelial Growth Factor in Growth Hormone-Deficient Individuals

Harpal S. Randeva PhD, FRCP^*, Krzysztof C. Lewandowski MD, MRCP, Jan Komorowski PhD, Robert D. Murray MRCP, Chris J. O’Callaghan PhD, Edward W Hillhouse PhD, FRCP, Henryk Stepien PhD, and Stephen M. Shalet MD, FRCP

From the Molecular Medicine Research Group, Biological Sciences, University of Warwick, UK (H.S.R., K.C.L., E.W.H.); the Department of Endocrinology, The Medical University of Lodz, Poland (J.K., H.S.); the Department of Endocrinology, Christie Hospital, Manchester, UK (R.D.M., S.M.S.); and the Department of Community Health and Epidemiology, Queen’s University, Kingston, Ontario, Canada (C.J.O.).

^* To whom correspondence should be addressed. E-mail: hrandeva{at}bio.warwick.ac.uk.

Background--Matrix metalloproteinases (MMP) are implicated in cardiovascular disease. Growth hormone (GH) deficiency is associated with increased cardiovascular mortality. We assessed whether GH replacement, in GH-deficient adults, has any effect on plasma levels of MMP-2 and MMP-9 and on vascular endothelial growth factor (VEGF), known to activate MMPs.

Methods and Results--The study comprised 66 GH-deficient adults, 37.8±14.7 years of age (37 female). Plasma MMP-2 and MMP-9, VEGF, and insulin-like growth factor-1 (IGF-1) were measured at baseline (V₁), at 12 months (V₂), and at 24 months of GH treatment (V₃). IGF-1 levels rose under GH replacement (mean±SD): V₁, 151.6±91.9 µg/mL; V₂, 270.2±114.8 µg/mL; and V₃, 266.2±109.8 (V₁ versus V₂; P<0.001: V₂ versus V₃; P=0.76). MMP-9 exhibited the most pronounced and sustained decline from 1248.0±651.1 ng/mL at V₁, 949.2±457.7 ng/mL at V₂, and 760.8±386.1 ng/mL at V₃ (P<0.001 at all time points). A similar pattern was detected for VEGF levels: 358.5±209.0 pg/mL at V₁, 310.6±225.7 pg/mL at V₂ (P<0.001), and 283.7±202.7 pg/mL at V₃ (V₂ versus V₃; P=0.005). MMP-2 demonstrated a significant decline initially from V₁ to V₂ (1134.4±217.8 ng/mL versus 1074.5±203.0 ng/mL, respectively; P=0.031), reaching a plateau at V₃ (1072.3±220.2 ng/mL) (V₂ versus V₃; P=0.93). A negative relation existed between MMP-9 versus IGF-1 and MMP-2 versus IGF-1 (P<0.001 and P=0.007, respectively) as well as between VEGF and IGF-1 (P<0.001).

Conclusions--These changes in MMPs and VEGF may contribute to the anticipated reduction in vascular mortality in hypopituitary adults receiving GH replacement.

Key words: atherosclerosis • cardiovascular diseases • growth substances • metalloproteinases • vasculature

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