Effects of Growth Hormone Administration on Cardiovascular Risk in Cured Acromegalics With Growth Hormone Deficiency
Condition: Acromegaly; Growth Hormone Deficiency; Pituitary Disease
MeSH terms: Dwarfism, Pituitary; Acromegaly; Pituitary Diseases; Endocrine System Diseases
Study type: Interventional

Summary: 
      The purpose of the study is to evaluate the effects of growth hormone (GH) replacement in men
      and women with a history of acromegaly and who are now growth hormone deficient. We will
      compare them to persons with a history of acromegaly who have normal GH levels.

      Acromegaly results when an area in the brain, called the pituitary, produces too much growth
      hormone. When an individual is cured of acromegaly, the growth hormone levels may be normal
      or low (that is GH deficiency). Growth hormone deficiency means the body no longer produces
      as much growth hormone because the pituitary/hypothalamic region was damaged by a tumor or by
      treatment received.

      We will study the effects of growth hormone replacement on the health of the heart and blood
      vessels of GH deficient persons by looking to see if this therapy:

        1. has effects on cardiovascular risk markers (special blood tests which indicate how
           healthy your heart and arteries are)

        2. affects the stiffness of the arteries

        3. affects your heart rate and the capacity of your heart to respond to changes in body
           position

        4. has different effects depending on whether you are taking estrogen / testosterone.

      We will assess these measures of health on one occasion in persons with cured acromegaly and
      normal GH levels and in persons with cured acromegaly who have GH deficiency and a
      contraindication to receiving GH. GH deficient individuals with no contraindication to
      receiving GH, will participate in the study for 12 months. Individuals with normal GH levels,
      or who are GH deficient and have a contraindication to receiving GH, will be asked to return
      for one more visit (without any interventions).
    

Detailed description: 
      The aim of the study is to evaluate the effects of physiologic growth hormone (GH)
      replacement on cardiovascular risk markers, cardiac autonomic function, arterial
      distensibility, body composition, and quality of life in men and women with GH deficiency
      following treatment of acromegaly. We hypothesize that this population will represent a newly
      identified group of patients for whom GH replacement will be of benefit.

      Treatment modalities in acromegaly include transsphenoidal surgery and radiation therapy,
      which can both result in hypopituitarism. A significant subset of cured acromegalics
      therefore develop pituitary hormone deficiencies. Although replacement of adrenal, thyroid
      and gonadal hormones is routine practice, clinicians do not replace GH in this subgroup, even
      in profoundly GH deficient subjects, as there are no randomized studies proving benefit in
      this population. With the accumulation of evidence on the beneficial effects of GH
      replacement, this therapy is becoming standard of care in all subjects with GH deficiency
      (GHD), except in this acromegaly subgroup where GH has been traditionally withheld. The GHD
      syndrome is manifested by an increase in cardiovascular risk, which is potentially reversible
      with GH therapy. Cardiovascular disease is the leading cause of death in acromegalics.
      Although cure of acromegaly is associated with a reduction in mortality attributable to GH
      excess, GHD may be a contributing factor to cardiovascular morbidity and mortality in this
      group of patients, as it is in patients with other pituitary tumors. It is therefore crucial
      to determine how cured acromegalics with hypopituitarism are affected by the GHD syndrome,
      and it is essential to study how this particular population responds to GH therapy. Because
      these patients typically have large macroadenomas and are treated with surgery and radiation
      therapy, long-term management of hypopituitarism is critical. As with all endocrine
      disorders, the goal of therapy is normal hormone replacement, not taking patients from a
      state of hormone excess to one of permanent hormone deficiency.

      Cardiovascular status in acromegaly

      Acromegaly is associated with a 2-3 fold increase in mortality compared to the general
      population. GH excess has been recognized to have multiple effects on the heart and
      cardiovascular system. GH excess affects cardiovascular health indirectly by increasing the
      prevalence of cardiovascular risk factors including hypertension, insulin resistance/type 2
      diabetes, and dyslipidemia. In addition, endothelial dysfunction is more prevalent in
      acromegaly than in normal controls. Impaired endothelium-dependent vasodilatation with
      exaggerated sympathetic-mediated vasoconstrictor response has been recently described in
      acromegalic patients. Although flow-mediated dilatation has been shown to improve in cured
      acromegalics, it has not been shown to return to normal. Reports on the prevalence of
      increased carotid intima-media thickness (IMT) are conflicting. Some studies have documented
      an increase in IMT in active acromegaly and some have not.

      A specific acromegaly-related cardiomyopathy -- independent of hypertension, diabetes and
      dyslipidemia -- has been extensively described. Impairment in ejection fraction after
      physical activity is observed in up to 73% of patients, which may lead to exercise
      intolerance in some of them.

      Morphological and functional cardiac changes are reversed with normalizing GH/IGF-I levels.
      Although ventricular hypertrophy has been shown to regress, it is unclear what proportion of
      patients recover a normal ventricular mass. Several echocardiographic studies have shown that
      with control of disease activity diastolic filling is improved, but the effect on ejection
      fraction and exercise tolerance is variable. Data on reversibility of cardiovascular disease
      in acromegaly are heterogeneous due to evolving definitions of cure for acromegaly, often
      short duration of studies, varying duration of disease activity, differences in gender and
      gonadal status, as well as possible distinct effects of somatostatin analogs on the heart and
      vessels. Dysrhythmias are also more common in acromegaly than in controls. Some studies have
      shown that permanent myocardial scarring may occur.

      In our proposed study population sequelae of previous GH excess may coexist with
      manifestations of GH deficiency.

      Cardiovascular status in GHD

      Cardiovascular morbidity and mortality in adults with GHD has been shown to be increased in a
      number of retrospective studies. Increased arterial IMT, increased prevalence of
      atherosclerotic plaques and endothelial dysfunction have been reported in GH deficient adults
      both in childhood and adulthood onset forms.

      The GHD syndrome is characterized by a cluster of factors that are associated with increased
      cardiovascular risk, such as central adiposity, increased visceral fat, insulin resistance,
      dyslipoproteinemia and decreased plasma fibrinolytic activity. GH administration has
      beneficial 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. GHD is also associated with cardiac autonomic dysfunction that may
      contribute to cardiovascular mortality and improves with GH replacement therapy. Of
      particular importance regarding patients with acromegaly, it has been shown that twelve
      months of GH replacement improves left ventricular mass and cardiac performance in young
      adults with GHD. Therefore, hypopituitary patients with a history of acromegaly who are now
      GH deficient may be particularly good candidates to benefit from physiologic GH replacement.

      Adipose tissue has receptors for GH, which has lipolytic activity. A decrease in central fat
      as assessed by waist-to-hip ratio have been reported in some studies, but not in others.
      Consequences of increased abdominal adiposity include increased risk of cardiovascular
      disease, type 2 diabetes and cerebrovascular disease. Long-term GH treatment decreases total
      body fat including visceral fat. Lean body mass and muscle function are improved with GH
      therapy in adults with GHD. GH increases lean body mass and decreases adipose tissue mass
      when given to adults with GHD or the elderly. Administration of GH causes insulin resistance
      acutely but long-term therapy may restore glucose sensitivity through its effects on body
      composition.

      GH treatment increases lipoprotein (a) (Lp (a)) levels but its effects on other lipoproteins
      are still controversial. Some studies have reported decreases in low-density lipoprotein
      cholesterol (LDL) with or without increases in high-density lipoprotein cholesterol (HDL)
      with GH administration, while others have not. Key factors likely involved in the discrepant
      findings include heterogeneity of patients studied in terms of age of onset of the GHD
      (childhood versus adulthood), gender, severity of GHD and methodological issues such as dose
      and duration of GH administration. In addition, many of the studies have no control period.
      There is a decrease in the hepatic expression of LDL receptors in GHD, which is reversed by
      GH therapy. This phenomenon could be linked to the exaggerated postprandial increase in
      triglycerides-rich particles observed in GHD, which is also normalized by the administration
      of GH.

      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. 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.

      These distal markers reflect the consequences of elevated proinflammatory cytokines such as
      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. Other emerging inflammatory markers include
      intercellular adhesion molecule-1 (ICAM-1), P-selectin and CD 40 ligand (CD40L), which is
      thought to reflect platelet activation and may promote atheromatous plaque destabilization.
      Myeloperoxidase was recently shown to predict the early risk of myocardial infarction and the
      risk of major adverse cardiac events in the following six months. And lately placental growth
      factor (PlGF) has been found to be an independent marker of adverse outcome in patients with
      acute coronary syndromes. The effect of the GH-IGF-I axis on these markers is unknown.

      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. In addition to inflammatory markers,
      thrombogenic cardiovascular risk markers such as fibrinogen, tissue-type plasminogen
      activator (tPA) and plasminogen activator-inhibitor 1 (PAI-1) are thought to be surrogate
      markers of vascular health. It will be critical to determine whether physiologic GH
      replacement has beneficial effects in patients with a history of acromegaly, and to define
      the influence of GH and gonadal status on these risk factors.

      Quality of life has been shown to be poorer in GH deficient females treated for acromegaly
      than in females with other causes of GHD. Short-term GH replacement caused a non-significant
      improvement in quality of life scores in subjects with GHD following cure of acromegaly, but
      the effects of longer GH treatment duration have not been published in this specific
      subgroup. Our study will provide more data on the quality of life of subjects following cure
      of acromegaly (GH deficient versus GH sufficient) and on the effects of GH therapy in the GH
      deficient group.

      Data on body composition and cardiovascular risk markers in patients with cured acromegaly
      are rare. No studies have yet been published comparing these endpoints in GH sufficient and
      GH deficient subjects with a history of acromegaly. Our hypothesis is that GH sufficient
      subjects have a more favorable profile than GH deficient subjects. Several studies have shown
      a normalization of mortality rates in subjects with cured acromegaly compared to subjects
      with active acromegaly. However it has not been demonstrated that this improvement was
      mediated by a normalization of the cardiovascular risk factors. Collecting cross-sectional
      data in this patient population may contribute to answer this question.
    

Intervention name(s): Recombinant human growth hormone; Saline
Intervention type(s): Drug; Drug
Intervention description(s): Starting dose based on age, sex, and estrogen status and ranged from 3-6 mcg/kg/day. GH doses were adjusted based on IGF-1 levels to target the mid-normal range for age.; To maintain study-subject blinding, doses were sham adjusted.
Other intervention name(s): Genotropin; Pfizer, Inc.; Placebo
Intervention MeSH terms: Hormones
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Acromegaly; Growth Hormone Deficiency; Cardiovascular Risk; Pituitary; Hypothalamic