Assessment of Cardiovascular Risk Markers in GH Deficient Patients With Nonsecreting Pituitary Adenomas

PROJECT TITLE: Assessment of Cardiovascular Risk in Patients with Growth Hormone Deficiency Following Transsphenoidal Surgery for Nonsecreting Pituitary Adenomas.

BACKGROUND Recently, an awareness of the risks of hypopituitarism in adults has been raised by epidemiological studies demonstrating its association with increased mortality, likely from cardiovascular (CV) causes. In particular, untreated growth hormone deficiency has been implicated as a possible cause of this increased mortality. A 2004 clinical review of growth hormone deficiency in adults highlights the plausibility of this argument by citing studies potentially linking GHD to the following: elevated CRP, LDL and coagulation factor levels, increased abdominal obesity, increased insulin resistance, increased prevalence of structural and functional heart disease and increased rates of endothelial cell and large artery dysfunction. Furthermore, therapy for GH deficiency has been shown to lower total and LDL cholesterol and reduce visceral fat mass, reduce signs of early atherosclerosis and perhaps decrease overall risk of myocardial infarction. While these studies suggest that GHD is an important cardiovascular risk factor, we believe the data are imperfect since some of the studies chose comparison groups too dissimilar (allowing for the possibility of unrecognized confounding). Previous studies have assessed cardiovascular risk in patients with hypopituitarism in comparison to the general population or much younger GH replaced subjects or GHD patients before and after GH therapy. In contrast, we plan to compare cardiovascular risk among adult patients rendered growth hormone deficient following surgery for a non secreting pituitary adenoma versus patients who have undergone the same surgery but who remain growth hormone sufficient. We plan to test for growth hormone deficiency using the Arginine/GHRH stimulation test in 80 subjects. We will divide the patients into two groups: growth hormone deficient and growth hormone sufficient. Once we have recruited enough patients in each group (thirty), we will compare known CV risk markers and endothelial function in carefully matched patients from each group. This approach will allow us to compare similar patients (i.e. all will have undergone surgery, some in each group will have undergone radiation) whose primary difference will be the GH status. In addition, from each group we will identify patients with additional pituitary deficiencies in the hope of comparing patients with either isolated GHD or patients with multiple endocrinopathies to similar matched controls.

At least two other novel aspects of our study include the use of magnetic resonance spectroscopy to measure intramyocellular and intrahepatic lipids and venous endothelial cell biopsy to assess endothelial function. Regarding the first modality, elevated levels of intramyocellular and intrahepatic lipids have been associated with insulin resistance in other populations. It is our hypothesis that subtle abnormalities in these lipid stores may correlate with insulin resistance in patients with apparent occult GH deficiency. With regard to endothelial function, previous work has linked GHD with endothelial cell dysfunction but typically through indirect measures including serum markers and arterial flow mediated dilatation. However, a technique has been recently developed to safely sample venous endothelial cells which in turn will enable us to assess directly at the level of endothelial cells, oxidative stress, cell activation and nitric oxide synthesis. It is our belief that this new method will help confirm the contention that GHD alters the basic function of endothelial cells.

STUDY DESIGN This study will assess the level of cardiovascular risk in two patient populations: those patients who are GHD following transsphenoidal surgery for nonsecreting pituitary adenomas and those patients who are not GHD following similar surgery. The primary outcome will be serum markers of cardiovascular risk including lipids, CRP, IL6 and homocysteine.

Experimental Protocol: