Ignite Creation Date:
2024-05-05 @ 11:56 AM
Last Modification Date:
2024-10-26 @ 9:16 AM
Study NCT ID:
NCT00182091
Status:
COMPLETED
Last Update Posted:
2020-09-02
First Post:
2005-09-14
Brief Title:
Effects of Growth Hormone Administration on Cardiovascular Risk in Cured Acromegalics With Growth Hormone Deficiency
Sponsor:
Massachusetts General Hospital
Organization:
Massachusetts General Hospital
Study Overview
Official Title:
Effects of Physiologic Growth Hormone Administration on Cardiovascular Risk in Subjects With Growth Hormone Deficiency Following Cure of Acromegaly
Status:
COMPLETED
Status Verified Date:
2020-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 pituitaryhypothalamic 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
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 pituitaryhypothalamic 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 resistancetype 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 GHIGF-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
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 resistancetype 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 GHIGF-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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None