Growth Hormone Administration and Its Effects on Cardiovascular Risk Factors in Growth Hormone Deficient Women
Condition: Growth Hormone Deficiency
MeSH terms: Dwarfism, Pituitary
Study type: Interventional

Summary: 
      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.
    

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
    

Intervention name(s): Somatropin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Stratified based on age and estrogen status from 3 to 6 mcg/kg/day; Dosage based on age and estrogen status ranging from 3 to 6 mcg/kg/day
Other intervention name(s): Genotropin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Growth Hormone; Cardiovascular risk; Pituitary; Hypothalamic; GH Deficiency; Pituitary Tumor; Pituitary Disease