Effects of Growth Hormone Administration on Cardiovascular Risk in Cured Acromegalics With Growth Hormone Deficiency
Effects of Growth Hormone Administration on Cardiovascular Risk in Cured Acromegalics With Growth Hormone Deficiency
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).
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.
Inclusion Criteria:

 -  Age 18-75

 -  History of acromegaly with biochemical cure documented with a normal oral glucose
 tolerance test (OGTT) and/or a non-elevated IGF-I without concurrent use of
 somatostatin analogs, dopamine agonists or GH receptor antagonists. Subjects will have
 been treated with medication, surgery, radiation, or a combination of these

 -  At the time of enrollment a minimum of 6 months must have elapsed since surgery.

 -  No malignancy on colonoscopy performed since the diagnosis of acromegaly

 -  GHD due to surgical or radiation treatment

 -  GHD will be defined as a peak plasma GH of less than 5 ng/ml in response to an insulin
 tolerance test or a GH-releasing hormone (GHRH) plus arginine stimulation test

 -  GHD will also be diagnosed if IGF-I levels are below 2 standard deviations for the
 age-sex normal range in a patient with at least two other documented anterior
 pituitary hormone deficiencies

 Exclusion Criteria:

 -  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 non-melanoma skin cancer

 -  Hemoglobin <11.0 gm/dl

 -  Uncontrolled hypertension

 -  Hepatic or renal disease (aspartate aminotransferase (AST) or alanine aminotransferase
 (ALT) > 3x upper limit of normal (ULN) or creatinine level >2.5 mg/dl)

 -  Congestive heart failure (New York Heart Association's classification system Class
 II-IV congestive heart failure (CHF) will be excluded)

 -  Unstable cardiovascular disease (coronary artery or cerebrovascular disease) or
 symptoms within one year prior to entry into the study

 -  Initiation or discontinuation of gonadal steroid therapy within 3 months of entry

 -  Diabetes mellitus, impaired fasting glucose, impaired glucose tolerance

 -  Pregnancy or nursing

 -  Active carpal tunnel syndrome

 -  Subjects who have received GH therapy within one year prior to entry into the study

 -  For female subjects age >40 a screening mammogram must have been obtained within one
 year prior to their baseline visit.

 -  Sensitivity to m-cresol