Assessment of Cardiovascular Risk Markers in Growth Hormone Deficient Patients With Nonsecreting Pituitary Adenomas
Assessment of Cardiovascular Risk Markers in Growth Hormone Deficient Patients With Nonsecreting Pituitary Adenomas
The purpose of this study is to determine if patients with a history of nonsecreting
 pituitary adenomas with untreated GH deﬁcient patients have proﬁles consistent with increased
 cardiovascular risk compared to patients without GH deficiency who have undergone similar
 surgery.
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:

 Subjects for this study will have all undergone transsphenoidal surgery for a nonsecreting
 pituitary adenoma. In addition, there may be some additional subjects, who have also
 undergone transsphenoidal surgery for a nonsecreting pituitary adenoma, recruited by word of
 mouth from the cohort of patients described above. Only patients who are not receiving GH
 therapy will be considered. Of those patients who have received RT, only those at least 5
 years from radiotherapy will be recruited in order to lessen the likelihood of a false
 positive Arginine/GHRH stimulation test which can occur in the early years post RT.

 The remaining respondents will be stratified into two groups based on the presence or absence
 of a history of other hypopituitarism: 1) those with > 1 known pituitary hormone deficiency
 (other than GH) and who are on replacement for these and 2) those with no known pituitary
 hormone deficits. The status of other pituitary hormone replacement therapies will be
 verified prior to the arrival of the subjects for further testing. Patients will need to be
 on stable doses of replacement therapy for at least 3 months prior to the study visit and if
 on hormone replacements they must be on hydrocortisone < 30 mg/day or equivalent and
 physiological doses of thyroid and sex steroid replacements. If possible, patients will be
 asked to provide copies of their most recent endocrine studies if these were not available
 from the chart review to verify the adequacy of their replacement therapy. Any woman known to
 be pregnant or any woman of childbearing age with a positive urinary HCG will not be
 considered for the study (we will screen all woman of childbearing age at the first visit
 prior to initiation of any testing). In addition, any woman actively nursing cannot be
 included in the study (we will ask all women of childbearing age at the first visit). We will
 recruit equal numbers from these two groups, inviting subjects to our Neuroendocrine Unit for
 an initial visit where they will undergo a clinical exam with vital signs, anthropometric
 measurements and skin fold thickness assessments. Subjects will also undergo GH stimulation
 testing with Arginine/GHRH to identify GH deficient (peak GH < 4 µg/L) and nonGH de•cient
 (peak GH > 10 µg/L) groups. Lastly, all subjects will have an endothelial cell biopsy
 performed.

 Thirty matched pairs of patients from the GHD and GH sufficient groups will be contacted
 further for an additional visit to our unit for some or all of the following tests:

 -  Fasting blood sampling for CV risk markers including CRP, homocysteine, lipoproteins,
 IL6 IGFI and IGFBP3 (all subjects, n=30 pairs)

 -  75 gm OGTT; Insulin and glucose (all subjects, n=30 pairs)

 -  DEXA scan to assess body composition and bone density (all subjects, n=30 pairs)

 -  Ultrasound to assess carotid intimal medial thickness and brachial artery flowmediated
 dilatation (subset of subjects, n=10 pairs).

 -  Magnetic resonance spectroscopy assessment of intramyocellular lipids and intrahepatic
 lipids in a subset of each group of the cohort (subset of subjects, n=10 pairs).
 Subjects will be studied within 6 months of their initial GH stimulation test.

 STUDY DRUGS Subjects will undergo an Arginine/GHRH stimulation test. They will receive Rgene
 (Upjohn) a 10% Arginine Hydrochloride solution in water and Geref Diagnostic (Serono).

 STUDY SUBJECTS Subjects for the study will include adult patients who have undergone
 transsphenoidal pituitary surgery for a nonsecreting pituitary adenoma.

 STUDY LOCATION This study will take place out of the Neuroendocrine Unit, Columbia
 University.

 POTENTIAL RISKS Participation in this study will involve minimal standard risks associated
 with blood draws. In addition there is a potential risk from exposure to radiation from DEXA
 scans. However, the amount of radiation exposure from DEXA scanning is only one percent of a
 chest xray and it is in accordance with federal guidelines for this type of research. Given
 the risk posed to a fetus from radiation exposure, pregnant or nursing mothers will be
 excluded from the study. To assess for pregnancy we will chec a urine HCG on all women of
 childbearing age prior to initiating any testing. In addition, women of childbearing age will
 be asked if they actively nursing and if so they will be excluded from the study. Since the
 risk to pregnant or nursing mothers is present only at the time of testing, no additional
 precautions against pregnancy need to be taken in the days following our testing. Ultrasound
 (for IMT and flow mediated dilatation studies) poses minimal risk beyond mild discomfort from
 the gel and probe. MRI also poses minimal risk beyond mild discomfort from the enclosed space
 and noise of the machine as long as there is no metal within the scanner room. The subjects
 will be asked a series of questions by the MRI technicians to ensure that they are safe to
 proceed with MRI. In addition, pregnant woman cannot undergo MRI. The risks of endothelial
 biopsy are thought to include pain, inflammation, infection and clots. In a previous study it
 was found to be safe but patients will be asked to return one week after the biopsy for
 evaluation of the site. If any symptoms arise prior to one week follow up patients will be
 advised to call or proceed to the emergency room.

 The most common adverse reactions from the administration of arginine include nausea,
 vomiting, headache, flushing, numbness, local venous irritation. Systemic allergic reaction
 is rare but patients with highly allergic tendencies will not be included. Pregnant or
 nursing subjects will also be excluded as mentioned above. For GHRH, common side effects
 include transient warmth/flushing of face, injection site pain, redness/swelling at site of
 injection, nausea, headache, vomiting, strange taste in mouth, paleness, tightness in chest.
 A physician will be present throughout the administration of these two drugs.

 POTENTIAL BENEFITS The results of the growth hormone stimulation test will be made available
 to subjects and their doctors. Therefore, if a subject is found to be growth hormone
 deficient, he or she might benefit from growth hormone therapy which has been shown, in some
 studies, to improve body composition, cholesterol levels and other factors associated with an
 increased risk for cardiovascular disease. A decision to initiate therapy, however should
 only occur after a careful discussion between the subject and his or her personal physician
 occurs. There may also be some benefit from DEXA scanning as it might identify previously
 undiagnosed osteoporosis. This condition has effective treatment options. Lastly,
 participation in the study will help further contribute to our understanding of the risk of
 heart disease in growth hormone deficient patients.
Inclusion Criteria:

 -  Adult patients with a history of a nonsecreting pituitary tumor with or without prior
 pituitary surgery.

 Exclusion Criteria:

 -  Current use of GH therapy or within the prior 3 months. Pituitary tumor necessitating
 surgery.