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

18 Years
65 Years
Not Enrolling
Growth Hormone Deficiency

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Trial Information

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

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

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

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

- 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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Outcome Measure:

Gender specific effects on cardiovascular risk markers

Outcome Time Frame:

baseline, 1, 3, 6, 7, 9, and 12 months

Safety Issue:


Principal Investigator

Anne Klibanski, M.D

Investigator Role:

Principal Investigator

Investigator Affiliation:

Massachusetts General Hospital


United States: Institutional Review Board

Study ID:




Start Date:

January 2002

Completion Date:

November 2006

Related Keywords:

  • Growth Hormone Deficiency
  • Growth Hormone
  • Cardiovascular risk
  • Pituitary
  • Hypothalamic
  • GH Deficiency
  • Pituitary Tumor
  • Pituitary Disease
  • Dwarfism, Pituitary
  • Endocrine System Diseases



Massachusetts General Hospital Boston, Massachusetts  02114-2617