Growth Hormone Administration and Its Effects on Cardiovascular Risk Factors in Growth Hormone Deficient Women

February 12, 2008 updated by: Massachusetts General Hospital

Gender-Specific Effects of Physiologic GH Administration on Cardiovascular Risk Factors in Women With Growth Hormone Deficiency

The purpose of the study is to evaluate the effects of growth hormone replacement on women with growth hormone deficiency. Growth hormone deficiency means the body no longer produces growth hormone due to a tumor or some kind of disease of the brain in an area called the pituitary/hypothalamic region. This is the area of the brain where growth hormone is normally produced. We, the researchers at Massachusetts General Hospital, will establish the effects of growth hormone replacement on cardiovascular parameters (laboratory tests, the flexibility of the arteries, changes in heart rate) in women with growth hormone deficiency. Our goal is to see if this therapy:

  • has effects on women's cardiovascular risk markers (special blood tests which indicate how healthy the heart and arteries are)
  • has effects on women's types and levels of various substances circulating in their blood
  • in women affects the stiffness of their arteries and heart rate variability in parallel with changes in cardiovascular risk markers
  • has different effects depending on whether women are pre or post menopausal.

Participation in this study is expected to last approximately 12 months.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The aim of the study is to evaluate the gender specific effects of physiologic Growth Hormone (GH) replacement in women with GH deficiency on the basis of pituitary/hypothalamic region tumors, radiation, or surgery on cardiovascular risk markers and arterial distensibility. Cardiovascular mortality in growth hormone (GH) deficient adults has been shown to be increased in a number of retrospective studies. Increased arterial intima-media thickness, increased prevalence of atherosclerotic plaques and endothelial dysfunction have been reported in growth hormone deficient adults both in childhood and adulthood onset forms.

The growth hormone deficiency (GHD) syndrome is associated with a cluster of cardiovascular-risk factors such as central adiposity, increased visceral fat, insulin resistance, dyslipoproteinemia and decreased plasma fibrinolytic activity. GH administration has effects on a number of these factors, but it is unknown which mechanisms are implicated in GH action on the process of atherosclerosis. In addition to alterations in atherosclerotic markers, abnormalities in cardiac function and structure have been reported among patients with GHD possibly contributing to the increased cardiovascular mortality. In addition, GHD is associated with cardiac autonomic dysfunction that may also contribute to cardiovascular mortality and improves with GH replacement therapy.

The vast majority of studies have focused primarily on men and the gender-specific effects of GH replacement on cardiovascular risk factors remain unknown. In addition to being of interest in terms of understanding the physiologic effects of GH therapy, there are important therapeutic implications regarding data in women. Cardiovascular disease is the leading cause of mortality in women. Effects of GH replacement on bone density may be less pronounced in women and because specific GH effects on cardiovascular risk factors in women are unknown, many adult women with GHD are untreated.

Long-term GH treatment decreases total body fat including visceral fat. Decreases in central fat as assessed by waist to hip ratio have been reported in some studies, but not in others. Administration of GH causes insulin resistance acutely but long-term therapy may restore glucose sensitivity. GH treatment increases lipoprotein (a) (Lp (a)) levels but its effects on other lipoproteins are still controversial. Some studies have reported decreases in LDL cholesterol with or without increases in HDL cholesterol with GH administration, while others have not. Twelve months of GH replacement improves left ventricular mass and cardiac performance in young adults with GHD. Key factors likely involved in the discrepant findings include heterogeneity of patients studied in terms of age of onset of the GH deficiency (childhood versus adulthood), gender, severity of GHD and methodologic issues such as dose and duration of GH administration. In addition, many of the studies have no control period.

Inflammation plays a central role in the pathophysiology of atherosclerosis. Each atherosclerotic lesion represents a different stage of a chronic inflammatory process in the arterial wall and different markers along the inflammatory cascade have been reported to predict cardiovascular risk [34]. Among those, high-sensitivity testing for C-reactive protein (CRP) is one of the best validated. Several prospective studies support a strong link between levels of CRP and future risk of coronary events. CRP adds considerable value to the total and HDL cholesterol measurement in the prediction of cardiovascular risk. Other distal indicators of inflammation such as serum-amyloid polypeptide A (SAA) likewise predict coronary risk. These distal markers reflect the consequences of elevated proinflammatory cytokines like interleukin-6 (IL-6). GH is known to have important immunomodulatory effects. We therefore hypothesized that the effects of GH on the process of atherosclerosis might be mediated through the cytokine-inflammatory pathway. We have recently investigated the effects of physiologic GH replacement in cardiovascular risk markers in men with GHD. In this study we found that CRP and IL-6 levels decreased in GH treated men compared to controls despite no significant change in serum lipid levels. We also recently have investigated levels of inflammatory markers in women with hypopituitarism compared with healthy controls. We found that women with hypopituitarism have increased levels of IL-6 and CRP suggesting that chronic inflammation may be involved in the pathogenesis of atherosclerosis in this population. It will be critical to determine whether physiologic GH replacement has beneficial effects in women, and whether these effects are influenced by estrogen.

We will investigate the effect of long-term physiologic GH administration on IL-6, CRP, SAA as well as other classic cardiovascular risk factors in women with GHD in a randomized, placebo-controlled study. In addition, we will evaluate structural/function correlates in women by measuring arterial wall distensibility and heart rate variability in parallel with cardiovascular risk markers.

We will establish the gender-specific effects of physiologic GH replacement on cardiovascular risk in women with GHD by investigating whether this therapy:

  1. has gender-specific effects on cardiovascular risk markers
  2. has gender-specific effects on lipid profiles
  3. alters heart rate variability and arterial distensibility in parallel with changes in cardiovascular risk markers
  4. has different effects depending upon gonadal status

Study Type

Interventional

Enrollment (Actual)

63

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Massachusetts General Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • GH deficiency due to pituitary or hypothalamic tumors or disease affecting this area. Subjects will have been treated with medication, surgery, radiation, or a combination of these. GH deficiency will be defined as a peak plasma GH of less than 5 ng/ml in response to insulin tolerance testing or growth hormone releasing hormone (GHRH) plus arginine stimulation test. In subjects with suspected hypothalamic dysfunction the arginine plus L-dopa stimulation test may be used, with a cutoff of 1.7 ng/ml for diagnosis of GH deficiency. Partial GH deficiency will be defined as a GH peak of 5 to 9 ng/ml (inclusive) during insulin tolerance testing or GHRH plus arginine testing.
  • GH deficiency will also be diagnosed if insulin-like growth factor-I (IGF-I) levels are below 2 standard deviations for the age-sex normal range in a patient with at least two documented hormone deficiencies.
  • Subjects must have evidence of a stable pituitary mass (for at least 12 months) if there is a history of a tumor except in the case of ACTH-producing microadenomas, where no follow-up imaging is required after cure.
  • Subjects age 40 and over must have a screening mammogram if they have not already had one within one year prior to their baseline visit

Exclusion Criteria:

  • Active Cushing's disease within 1 year
  • History of acromegaly
  • Untreated thyroid or adrenal insufficiency. Subjects on replacement therapy must be stable for at least 3 months prior to entry into the study.
  • History of malignancy except for skin cancer and except for childhood solid malignancy with documented cure for > 10 years prior to starting the study
  • Hemoglobin <10.0 gm/dl
  • Hepatic or renal disease (SGPT/SGOT > 3x upper limit of normal (ULN) or creatinine levels >2.5 mg/dl)
  • Congestive heart failure (CHF) (New York Heart Association's classification system Class II-IV CHF will be excluded)
  • History of unstable cardiovascular disease (coronary artery or cerebrovascular disease) or symptoms within one year prior to entry into the study
  • Diabetes mellitus
  • Pregnancy or nursing
  • Active carpal tunnel syndrome

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: 2
Drug: Placebo
Dosage based on age and estrogen status ranging from 3 to 6 mcg/kg/day
Active Comparator: 1
Drug: Somatropin
Stratified based on age and estrogen status from 3 to 6 mcg/kg/day
Other Names:
  • Genotropin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Gender specific effects on cardiovascular risk markers
Time Frame: baseline, 1, 3, 6, 7, 9, and 12 months
baseline, 1, 3, 6, 7, 9, and 12 months

Secondary Outcome Measures

Outcome Measure
Time Frame
Heart Rate Variability
Time Frame: baseline, 3, 6, 9, and 12 months
baseline, 3, 6, 9, and 12 months
Quality of Life
Time Frame: baseline, 1, 3, 6, 7, 9, and 12 months
baseline, 1, 3, 6, 7, 9, and 12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Massachusetts General Hospital

Investigators

  • Principal Investigator: Anne Klibanski, M.D, Massachusetts General Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2002

Primary Completion (Actual)

November 1, 2006

Study Completion (Actual)

November 1, 2006

Study Registration Dates

First Submitted

August 24, 2005

First Submitted That Met QC Criteria

August 25, 2005

First Posted (Estimate)

August 26, 2005

Study Record Updates

Last Update Posted (Estimate)

February 18, 2008

Last Update Submitted That Met QC Criteria

February 12, 2008

Last Verified

February 1, 2008

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2001p-001761

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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