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

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Brief Title

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

Official Title

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

Brief Summary

      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.
    

Detailed Description

      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.
    


Study Type

Observational


Primary Outcome

Cardiovascular risk markers, specifically lipids, CRP, IL6 and homocysteine

Secondary Outcome

 Total body fat, trunk fat and lean body mass by DEXA, insulin sensitivity, flow mediated dilatation and endothelial cell biopsy, carotid IMT, intramyocellular and intrahepatic lipid content.

Condition

Growth Hormone Deficiency


Study Arms / Comparison Groups

 I
Description:  Adult patients with GH deficiency due to a nonsecreting pituitary tumor

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

60

Start Date

March 2008

Completion Date

March 2010

Primary Completion Date

January 2010

Eligibility Criteria

        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.
      

Gender

All

Ages

18 Years - 75 Years

Accepts Healthy Volunteers

No

Contacts

Pamela U Freda, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00646308

Organization ID

AAAB9681



Study Sponsor

Columbia University

Collaborators

 EMD Serono

Study Sponsor

Pamela U Freda, MD, Principal Investigator, Columbia University College of P & S


Verification Date

April 2011