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Controversies Regarding the Effects of Growth Hormone on the Heart

      Growth hormone (GH) profoundly affects the developing and adult myocardium. Adult patients with GH deficiency (GHD) and GH excess (acromegaly) provide important models in which to understand the effects of GH in adult cardiac physiology. An increasing body of clinical and experimental evidence illustrates the specific physiological abnormalities that are likely associated with the excess cardiovascular mortality observed in both acromegaly and GHD. Because human GH replacement is now available to treat adults with GHD, new questions emerge about the long-term cardiovascular effects of replacement therapy. In multiple trials, GH therapy for congestive heart failure has been proved ineffective in the absence of preexisting GHD. Case reports suggest that, in the setting of GHD, GH therapy can exert a potent beneficial effect on congestive heart failure. Long-term studies addressing cardiovascular morbidity and mortality are needed to assess the role of GH therapy for GHD.

      Abbreviations:

      GH (growth hormone), GHD (growth hormone deficiency), IGFBP (insulin-like growth factor binding protein), IGF-1 (insulin-like growth hormone 1), NO (nitric oxide), r-hGH (recombinant human growth hormone)
      Growth hormone deficiency (GHD) was described initially in children with short stature. For 30 years, treatment of GHD was limited to the goal of increasing linear growth. Fourteen years ago, a recombinant human growth hormone (r-hGH) became available, which has allowed treatment of adult patients with GHD with the goal of improving their quality of life and potentially decreasing cardiovascular mortality. The earliest clues that growth hormone (GH) therapy may benefit the heart came from research conducted in 1988 that showed that young adults treated with 1 week of supraphysiological doses of r-hGH had improved cardiac contractility on serial echocardiography.
      • Thuesen L
      • Christiansen JS
      • Sorensen KE
      • Jorgensen JO
      • Orskov H
      • Henningsen P
      Increased myocardial contractility following growth hormone administration in normal man: an echocardio-graphic study.
      Since then, many experimental and clinical studies have illustrated the important role of GH in cardiac development as well as the deleterious cardiac effects of both GH excess (acromegaly) and GHD. We summarize some of the most important experimental and clinical evidence regarding the interaction between GH and cardiovascular disease and underscore the need to assess patients with GHD for potential therapeutic intervention.

      BACKGROUND

      Growth hormone is secreted by the somatotroph cells of the anterior pituitary gland.
      • Duello TM
      • Halmi NS
      Ultrastructural-immunocytochemical localization of growth hormone and prolactin in human pituitaries.
      As a single-chain peptide of 191 amino acids, GH is central to the endocrine control of growth. Direct effects of GH can be seen in numerous tissue types and organs.
      • Isaksson OG
      • Eden S
      • Jansson JO
      Mode of action of pituitary growth hormone on target cells.
      The actions of GH include stimulation of skeletal and muscle growth, promotion of cellular uptake of amino acids, and regulation of lipolysis. Many actions of GH are mediated by insulin-like growth factor 1 (IGF-1), which is synthesized in the liver, kidneys, and many tissues. Insulin-like growth factor 1 has both endocrine and autocrine/paracrine actions. It is protein-bound and therefore has a longer half-life than GH. Tissue growth is promoted by IGF-1 acting in concert with GH and other circulating growth factors.
      • Delafontaine P
      Insulin-like growth factor I and its binding proteins in the cardiovascular system.
      Both GH and IGF-1 have anabolic actions that appear complementary.
      Growth hormone and IGF-1 are known to play an important role in cardiac development and as modulators of myocardial structure and function in the adult heart.
      • Colao A
      • Marzullo P
      • Di Somma C
      • Lombardi G
      Growth hormone and the heart.
      Traditionally, the myocardium has been considered a terminally differentiated tissue with myocardial cells unable to proliferate. Recent work by Anversa and Nadal-Ginard
      • Anversa P
      • Nadal-Ginard B
      Myocyte renewal and ventricular remodelling.
      suggested that cardiac cells can divide after cardiac infarction, but as yet the role of GH in this circumstance is not well defined. Somewhat better understood is the myocardial response to stress, such as pressure and volume overload, with remodeling, hypertrophy, and reexpression of fetal cytoskeletal and myofibrillar proteins.
      • Reiss K
      • Meggs LG
      • Li P
      • Olivetti G
      • Capasso JM
      • Anversa P
      Upregulation of IGF1, IGF1-receptor, and late growth related genes in ventricular myocytes acutely after infarction in rats.
      Insulin-like growth hormone 1 immunoreactivity has been found in the inner layers of the left ventricle, where tension and wall stress are known to be high. Also, the onset of IGF-1 expression is known to precede or parallel the development of left ventricular hypertropy, and IGF-1 messenger RNA levels normalize as the hypertrophic response is established.
      • Donohue TJ
      • Dworkin LD
      • Lango MN
      • et al.
      Induction of myocardial insulin-like growth factor-I gene expression in left ventricular hypertrophy.
      • Wahlander H
      • Isgaard J
      • Jennische E
      • Friberg P
      Left ventricular insulin-like growth factor I increases in early renal hypertension.

      EXPERIMENTAL DATA

      Animal models have provided strong evidence that gene expression of the cardiac IGF system is regulated in a coordinated way in response to various pathologic stimuli.
      • Guron G
      • Friberg P
      • Wickman A
      • Brantsing C
      • Gabrielsson B
      • Isgaard J
      Cardiac insulin-like growth factor I and growth hormone receptor expression in renal hypertension.
      Increased levels of IGF-1 messenger RNA and increased numbers of IGF receptors are found in both ventricles in pressure and volume overload, in experimental infarction, and in cardiac hypertrophy.
      • Donohue TJ
      • Dworkin LD
      • Lango MN
      • et al.
      Induction of myocardial insulin-like growth factor-I gene expression in left ventricular hypertrophy.
      • Komuro I
      • Yazaki Y
      Control of cardiac gene expression by mechanical stress.
      Although most actions of IGF-1 are mediated through the type 1 IGF receptor, its activity is precisely mediated by a family of at least 6 structurally related IGF-binding proteins (IGFBPs 1-6) present in the circulation and in extravascular tissues. The IGFBPs are believed to inhibit or augment IGF action and provide a flexible means of modulating the action of IGF activity by regulating its bioavailability to target tissues.
      • Bach LA
      The insulin-like growth factor system: basic and clinical aspects.
      In porcine models of microinfarction, there were considerable alterations of the gene expression of IGFBPs 3, 5, and 6, suggesting a role in angiogenesis and repair processes postinfarction.
      • Kluge A
      • Zimmermann R
      • Weihrauch D
      • et al.
      Coordinate expression of the insulin-like growth factor system after micro-embolisation in porcine heart.
      Postischemic heart failure is associated with a higher expression of IGFBPs 3, 4, 5, and 6 in the infarct and the peri-infarct zone in the left ventricle, starting from the time of infarction and persisting at 6 months. This upregulation was found not only in the inflammatory cells, which migrated into the damaged tissue, but also in the fibroblasts and the vascular endothelial cells. These findings strongly suggest that the IGF system plays an important role in the long-term response of the heart to ischemic injury and subsequent remodeling and tissue repair.
      • Kluge A
      • Zimmermann R
      • Weihrauch D
      • et al.
      Coordinate expression of the insulin-like growth factor system after micro-embolisation in porcine heart.
      • Dean R
      • Edmondson SR
      • Burrell LM
      • Bach LA
      Localization of the insulin-like growth factor system in a rat model of heart failure induced by myocardial infarction.

      CARDIAC EFFECTS OF ACROMEGALY

      Acromegaly has long been appreciated as being detrimental to the heart. Acromegaly is associated with cardiomegaly, hypertension, glucose intolerance, and a specific acromegalic cardiomyopathy. Clinically, left ventricular hypertrophy is the hallmark cardiac lesion found in acromegaly. Histologically, biopsy and autopsy findings have shown interstitial fibrosis that is progressive and, over time, impairs both the systolic and the diastolic function of the heart.
      • Courville CB
      • Mason VR
      Heart in acromegaly.
      • Hejtmancik MR
      • Bradfield Jr, JY
      • Herrmann GR
      Acromegaly and the heart: a clinical and pathologic study.
      • Lie JT
      Pathology of the heart in acromegaly: anatomic findings in 27 autopsied patients.
      Extracellular collagen is increased and coexists with myofibrillar derangement, areas of myocyte necrosis, and lymphomononuclear infiltration, thus resembling a pattern of myocarditis.
      • Hejtmancik MR
      • Bradfield Jr, JY
      • Herrmann GR
      Acromegaly and the heart: a clinical and pathologic study.
      • Lie JT
      Pathology of the heart in acromegaly: anatomic findings in 27 autopsied patients.
      • Hayward RP
      • Emanuel RW
      • Nabarro JD
      Acromegalic heart disease: influence of treatment of the acromegaly on the heart.
      Acromegalic heart disease can be asymptomatic for many years before onset of clinical signs and manifestation of symptoms of cardiac dysfunction. Although a long duration of disease is associated with greater hypertrophy and a greater cardiac mass index,
      • Colao A
      • Merola B
      • Ferone D
      • Lombardi G
      Acromegaly.
      even patients with new onset of disease are known to have higher heart rates and increased systolic outputs consistent with a hyperkinetic syndrome.
      • Thuesen L
      • Christensen SE
      • Weeke J
      • Orskov H
      • Henningsen P
      A hyperkinetic heart in uncomplicated active acromegaly: explanation of hypertension in acromegalic patients?.

      CARDIAC EFFECTS OF GHD

      In the 1990s, when r-hGH became available, a substantial amount of work furthered the understanding of the cardiac effects of growth deficiency and the benefits of replacement therapy. This work was prompted by the recognition that mortality is excessive in patients with GHD. Epidemiological data suggest that adults with hypopituitarism who take pituitary hormones but not GH have reduced life expectancies compared with normal controls. A greater than 2-fold increase in mortality due to cardiovascular disease has been shown.
      • Rosen T
      • Bengtsson BA
      Premature mortality due to cardiovascular disease in hypopituitarism.
      • Bulow B
      • Hagmar L
      • Mikoczy Z
      • Nordstrom CH
      • Erfurth EM
      Increased cerebrovascular mortality in patients with hypopituitarism.
      • Erfurth EM
      • Hagmar L
      Cardiovascular mortality among pituitary insufficient patients [letter].
      It is postulated that the negative effect of GHD is due to the direct effects of GH and IGF-1, to the unfavorable effect of altered lipid profiles, to an increase in the incidence of atherosclerosis, and to endothelial dysfunction.
      • Beshyah SA
      • Johnston DG
      Cardiovascular disease and risk factors in adults with hypopituitarism.
      Carotid intima-media thickness is known to increase substantially in the setting of GHD and to revert to normal levels after 6 months of GH replacement.
      • Markussis V
      • Beshyah SA
      • Fisher C
      • Sharp P
      • Nicolaides AN
      • Johnston DG
      Detection of premature atherosclerosis by high-resolution ultrasonography in symptom-free hypopituitary adults.
      • Capaldo B
      • Patti L
      • Oliviero U
      • et al.
      Increased arterial intima-media thickness in childhood-onset growth hormone deficiency.
      This thickening resolves with only modest or minimal changes in the lipid profile.
      • Pfeifer M
      • Verhovec R
      • Zizek B
      • Prezelj J
      • Poredos P
      • Clayton RN
      Growth hormone (GH) treatment reverses early atherosclerotic changes in GH-deficient adults.
      • Carroll PV
      • Christ ER
      • Bengtsson BA
      • Growth Hormone Research Society Scientific Committee
      • et al.
      Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review.
      These data suggest that GHD is associated with accelerated formation of atheroma as a cause for the increased cardiovascular and cerebrovascular mortality that have been observed.
      Several echocardiographic studies have shown that patients with GHD have decreased left ventricular wall thickness, decreased left ventricular mass index, decreased fractional shortening, and reduced ejection fractions compared with age-, sex-, and height-matched controls.
      • Merola B
      • Cittadini A
      • Colao A
      • et al.
      Cardiac structural and functional abnormalities in adult patients with growth hormone deficiency.
      • Longobardi S
      • Cuocolo A
      • Merola B
      • et al.
      Left ventricular function in young adults with childhood and adulthood onset growth hormone deficiency.
      • Amato G
      • Carella C
      • Fazio S
      • et al.
      Body composition, bone metabolism, and heart structure and function in growth hormone (GH)-deficient adults before and after GH replacement therapy at low doses.
      Valcavi et al
      • Valcavi R
      • Gaddi O
      • Zini M
      • Iavicoli M
      • Mellino U
      • Portioli I
      Cardiac performance and mass in adults with hypopituitarism: effects of one year of growth hormone treatment.
      reported diastolic dysfunction measured by Doppler echocardiography. Johannsson et al
      • Johannsson G
      • Bengtsson BA
      • Andersson B
      • Isgaard J
      • Caidahl K
      Long-term cardiovascular effects of growth hormone treatment in GH-deficient adults: preliminary data in a small group of patients.
      measured baseline exercise capacity in 7 patients with GHD and found that exercise capacity was significantly reduced compared with age-, sex-, and height-matched controls. As a consequence, investigations were designed to evaluate the effects of GH replacement in relation to observed cardiac abnormalities. In 1991, Cuneo et al
      • Cuneo RC
      • Salomon F
      • Wiles CM
      • Hesp R
      • Sonksen PH
      Growth hormone treatment in growth hormone-deficient adults, II: effects on exercise performance.
      showed that GH treatment improved maximal exercise capacity by 20% with no change in physical activity in patients with GHD. In 1993, Amato et al
      • Amato G
      • Carella C
      • Fazio S
      • et al.
      Body composition, bone metabolism, and heart structure and function in growth hormone (GH)-deficient adults before and after GH replacement therapy at low doses.
      observed that 6 months of low-dose GH therapy improved baseline abnormalities of ventricular mass, systolic function, and fractional shortening in 8 patients. These changes disappeared 6 months after withdrawal of GH therapy. In 1995, Valcavi et al
      • Valcavi R
      • Gaddi O
      • Zini M
      • Iavicoli M
      • Mellino U
      • Portioli I
      Cardiac performance and mass in adults with hypopituitarism: effects of one year of growth hormone treatment.
      treated 20 patients with GH for 1 year; their echocardiograms indicated that cardiac function improved, cardiac mass increased, and diastolic abnormalities, noted before treatment, improved to normal. In 1996, 7 patients with GHD were treated with GH by Johannsson et al.
      • Johannsson G
      • Bengtsson BA
      • Andersson B
      • Isgaard J
      • Caidahl K
      Long-term cardiovascular effects of growth hormone treatment in GH-deficient adults: preliminary data in a small group of patients.
      They noted improved age-adjusted exercise tolerance and improved stroke volume and cardiac index. Also, they noted an increased left ventricular mass index but attributed this change to the dosing of GH.
      Beneficial cardiovascular effects of GH replacement in adults with GHD may result not only from cardiac anabolic effects but also as a result of peripheral effects. Caidahl et al
      • Caidahl K
      • Eden S
      • Bengtsson BA
      Cardiovascular and renal effects of growth hormone.
      reported reductions in peripheral vascular resistance in adults with GHD treated with r-hGH. This effect may relate to the stimulatory effect of GH (via IGF-1) on the synthesis of nitric oxide (NO), thereby causing peripheral vasodilation. In a double-blind placebo-controlled trial, Boger et al
      • Boger RH
      • Skamira C
      • Bode-Boger SM
      • Brabant G
      • von zur Muhlen A
      • Frolich JC
      Nitric oxide may mediate the hemodynamic effects of recombinant growth hormone in patients with acquired growth hormone deficiency: a double-blind placebo-controlled study.
      showed that NO production is impaired in adult patients with untreated GHD. Treatment with r-hGH resulted in normalized NO production. We hypothesize that improved NO formation may be 1 explanation for the improved cardiovascular performance of patients with acquired hypopituitarism during GH treatment. Nitric oxide recently has been shown to modulate cardiac cytoskeletal functions by altering myofilament responsiveness of calcium in the myocyte itself.
      • Badorff C
      • Dimmeler S
      NO balance: regulation of the cytoskeleton in congestive heart failure by nitric oxide [editorial].
      These observations may provide an alternative explanation for the increased cardiovascular performance observed after GHD is corrected.

      CARDIAC EFFECTS OF GH TREATMENT OF EXPERIMENTAL HEART FAILURE

      Given the profound effect of both acromegaly and GHD on the myocardium, GH could be beneficial in the treatment of heart failure. This was observed by 2 groups of investigators in animal models of experimental heart failure. In the first study, 6 weeks after rats underwent coronary artery ligation, treatment with GH or placebo was initiated. The GH-treated rats revealed increased contractility compared with controls.
      • Yang R
      • Bunting S
      • Gillett N
      • Clark R
      • Jin H
      Growth hormone improves cardiac performance in experimental heart failure.
      A second group of investigators performed coronary ligations in rat models, followed on day 2 by treatment with IGF-1 or placebo. The treated rats were found to have hypertrophied ventricles and an increased ejection fraction compared with controls, suggesting that IGF-1 could benefit the severely dysfunctional heart.
      • Duerr RL
      • Huang S
      • Miraliakbar HR
      • Clark R
      • Chien KR
      • Ross Jr, J
      Insulin-like growth factor-1 enhances ventricular hypertrophy and function during the onset of experimental cardiac failure.

      GH THERAPY AND HEART FAILURE IN HUMANS

      To date, only 3 randomized, double-blind, placebo-controlled trials of GH have been conducted in patients with congestive heart failure. In 1998, Osterziel et al
      • Osterziel KJ
      • Strohm O
      • Schuler J
      • et al.
      Randomised, double-blind, placebo-controlled trial of human recombinant growth hormone in patients with chronic heart failure due to dilated cardiomyopathy.
      described 50 patients with dilated cardiomyopathy who were randomized to receive either GH or placebo in addition to their usual medications for heart failure. Patients were treated for at least 12 weeks. All patients had detailed assessment of left ventricular function by magnetic resonance imaging, hemodynamic assessment by right heart catheterization, and 6-minute walking tests at baseline and at the end of the study. Osterziel et al
      • Osterziel KJ
      • Strohm O
      • Schuler J
      • et al.
      Randomised, double-blind, placebo-controlled trial of human recombinant growth hormone in patients with chronic heart failure due to dilated cardiomyopathy.
      reported a significant increase in left ventricular mass after GH therapy but were unable to show a change in New York Heart Association functional class, ejection fraction, or distance achieved on a 6-minute walk test.
      The second trial, published by Isgaard et al
      • Isgaard J
      • Bergh CH
      • Caidahl K
      • Lomsky M
      • Hjalmarson A
      • Bengtsson BA
      A placebo-controlled study of growth hormone in patients with congestive heart failure.
      in 1998, revealed similar results. This group treated 22 patients with both ischemic and nonischemic cardiomyopathies with either GH or placebo for 3 months. Patients were assessed by radionuclide angiography, echocardiography, and exercise testing. These investigators found no significant differences in systolic or diastolic cardiac function. Also, no significant differences were found in exercise capacity or functional status.
      A third study, published by Smit et al,
      • Smit JW
      • Janssen YJ
      • Lamb HJ
      • et al.
      Six months of recombinant human GH therapy in patients with ischemic cardiac failure does not influence left ventricular function and mass.
      drew similar conclusions. This group treated 10 patients with either GH or placebo for 6 months. Primary end points were changes in left ventricular function or mass. Patients underwent magnetic resonance imaging and rest and exercise single-photon emission tomography; no changes were seen in left ventricular ejection fraction, left ventricular mass, left ventricular end-systolic dimensions, or end-diastolic dimensions.

      PREVIOUS CASES OF GHD AND REVERSIBLE CARDIOMYOPATHY

      The issue of treating heart failure in patients with known GHD raises new questions. No placebo-controlled trials have been done involving GH replacement therapy in groups of patients with congestive heart failure and GHD. To date, only 4 cases have been published.
      The first patient, reported by Cuneo et al
      • Cuneo RC
      • Wilmshurst P
      • Lowy C
      • McGauley G
      • Sonksen PH
      Cardiac failure responding to growth hormone [letter].
      in 1989, was a 53-year-old man with a history of hypertension who underwent transsphenoidal hypophysectomy in November 1986 for Cushing disease. Congestive heart failure developed in 1987. Echocardiography revealed a dilated diffusely hypokinetic ventricle and a mural thrombus. Coronary angiography revealed nonsignificant disease with a 50% single-vessel lesion. The patient was treated with digoxin, captopril, and diuretics with no notable improvement. A transplantation assessment was considered. In view of the patient's wasted state and panhypopituitarism, GH therapy was initiated. Within days, the patient improved subjectively. Assessment with right heart catheterization after 3 months of therapy revealed a significantly improved cardiac output (2.0 L/min at baseline and 4.1 L/min at 12 weeks), decreased right atrial pressure, and decreased pulmonary pressure (60/31 mm Hg at baseline and 23/5 mm Hg at 12 weeks). Treadmill exercise tolerance was also significantly increased compared with baseline.
      A second case of cardiomyopathy in the setting of GHD was reported in 1992 by Frustaci et al.
      • Frustaci A
      • Perrone GA
      • Gentiloni N
      • Russo MA
      Reversible dilated cardiomyopathy due to growth hormone deficiency.
      The patient, a 49-year-old woman, presented with heart failure and was found to have dilated cardiomyopathy. This occurred against a background of postpartum hypopituitarism (Sheehan syndrome), which developed after a postpartum hemorrhage 20 years previously. Echocardiography revealed a severely dilated heart with right and left ventricular dysfunction. Her ejection fraction was estimated to be 15%, and she had 2/4 mitral regurgitation and 4/4 tricuspid regurgitation. The patient received r-hGH therapy for 3 months. Repeated echocardiography revealed an improved ejection fraction of 49%, a decreased left ventricular enddiastolic pressure (25-15 mm Hg), and substantially improved mitral and tricuspid regurgitation. Cardiac biopsies were performed before and after GH therapy, and specimens were analyzed by electron microscopy. The most striking finding was of a cytosol, which was unusually poor in contractile elements but recovered normal myofibril content after GH replacement therapy. Hemodynamic studies revealed normalized cardiac output (3.3-6.5 L/min) and cardiac index (1.9-3.6 L · min−1 · m−2). These hemodynamic improvements were accompanied by substantial symptomatic improvement at 2 to 3 weeks.
      The third reported case involved a 48-year-old woman with panhypopituitarism secondary to pituitary adenoma and subsequent transsphenoidal resection.
      • Fazio S
      • Biondi B
      • Sabatini D
      • et al.
      Long-term growth hormone deficiency as a cause of cardiomyopathy and its reversibility with specific replacement therapy.
      This patient had pituitary resection and radiation in 1977; in 1983 she developed fatigue and dyspnea. She was diagnosed as having dilated cardiomyopathy and empty sella syndrome/panhypopituitarism. Digoxin, diuretics, and angiotensinconverting enzyme inhibitors were initiated, which resulted in some clinical improvement, but the patient had substantial weakness and exertional dyspnea. In 1994, she was admitted to a hospital with exacerbation of heart failure. Hormonal analysis confirmed that all hormones except GH were replaced correctly. Echocardiography revealed a dilated left ventricle with an ejection fraction of 35%. The patient was treated with GH replacement for 3 months; her echocardiographic abnormalities improved to near normal, and her exercise tolerance increased. Three months after GH therapy was discontinued, echocardiography revealed pretreatment values with decreased physical performance parameters that confirmed the patient's subjective symptoms of fatigue and exertional dyspnea.
      The fourth reported case involved a man with anthracycline cardiomyopathy who survived Ewing sarcoma at 12 years of age.

      Meyers DE, Maddicks-Law J, Seaton DM, Galbraith AJ, Cuneo RC. The role of growth hormone replacement in a growth hormone deficient patient with underlying anthracycline cardiomyopathy and severe congestive heart failure. J Heart Lung Transplant. In press.

      He was treated with amputation and 2 years of combination chemotherapy containing anthracyclines. The patient's history was also notable for a pituitary macroadenoma that required pituitary clearance when he was 37 years of age, resulting in panhypopituitarism that required pituitary replacement therapy. He presented at 39 years of age with decompensated congestive heart failure and required inotropic support; however, he stabilized and had clinical and echocardiographic improvement while taking a combination of diuretics, angiotensin-converting enzyme inhibitors, and β-blockers. The patient did well for 18 months with this therapy, but then his condition deteriorated; he re-presented with heart failure, again required temporary inotropic support, and was considered for transplantation. Transplantation listing was complicated by the patient's pulmonary pressure levels, which were so elevated that heart transplantation was contraindicated. The patient was tested for GHD and was found to have a low IGF-1 level. Replacement therapy with r-hGH as a bridge to transplantation was initiated with dramatic improvement in the patient's clinical situation in the absence of other medication changes. Serial echocardiography revealed improved mitral and tricuspid regurgitation and improved right ventricular function. Left ventricular function was primarily unchanged. Serial hemodynamic studies revealed decreased pulmonary pressures in the absence of a change in right atrial filling pressures, cardiac wedge pressures, or cardiac index, suggesting the improvement was largely due to vasodilatation in the pulmonary vascular bed and improved valvular regurgitation. The patient improved to the point of walking 5 km; he achieved good results on cardiopulmonary exercise testing, indicating that transplantation could be deferred safely.
      This case showed that considerable improvement was achieved with replacement GH therapy, even in the setting of preexisting structural heart disease. These observations suggest that GHD is an important factor in the pathogenesis of heart failure, even when underlying structural heart disease is present.

      CONTROVERSIES REGARDING GH REPLACEMENT THERAPY

      There is considerable debate in endocrinology literature regarding the utility and need for GH replacement in the GH-deficient adult.
      • Cook DM
      Shouldn't adults with growth hormone deficiency be offered growth hormone replacement therapy?.
      • Isley WL
      Growth hormone therapy for adults: not ready for prime time?.
      Among patients with hypopituitarism, there are different degrees of GHD (partial vs total); those with the most severe deficiencies would likely benefit most from therapy. In a recent editorial addressing the issues of GH replacement, Frohman
      • Frohman LA
      Controversy about treatment of growth hormone-deficient adults: a commentary [editorial].
      states that there is no doubt that a syndrome of GHD exists that includes truncal and visceral obesity, decreased lean body mass, osteopenia, glucose intolerance associated with insulin resistance, a lipid profile consistent with atherosclerotic risk, decreased exercise tolerance, altered cardiac structure and function, and a diminished quality of life. That diagnosis remains challenging because the insulin-induced hypoglycemia diagnostic test (long considered the gold standard) is not considered safe in the older or unstable patient. Serum IGF-1 levels, although helpful, can be normal in as many as one third of patients with GHD. Frohman
      • Frohman LA
      Controversy about treatment of growth hormone-deficient adults: a commentary [editorial].
      has suggested that the decision to institute GH replacement therapy needs to be individualized on the basis of patients' metabolic profile, clinical status, and perceived quality of life. Once therapy is initiated, questions remain about the degree of replacement necessary and the duration of replacement therapy required. Questions of long-term safety are frequently raised in relation to GH replacement therapy, especially about oncogenesis, but there is no convincing evidence that patients treated with GH replacement have an increased tumor rate.
      • Bengtsson BA
      • Johannsson G
      • Shalet SM
      • Simpson H
      • Sonken PH
      Treatment of growth hormone deficiency in adults.
      Nevertheless, significant associations remain between excess GH and an increased incidence of colon and other cancers if acromegaly remains uncontrolled for prolonged periods.
      • Orme SM
      • McNally RJ
      • Cartwright RA
      • Belchetz PE
      • United Kingdom Acromegaly Study Group
      Mortality and cancer incidence in acromegaly: a retrospective cohort study.
      The central issues of GH replacement are whether the addition of GH replacement therapy will alter the decreased life expectancy rates and reduce the excess cardiovascular death rates in patients with GHD. To date, no clinical trials have been designed to address these issues, despite the fact that many investigators have expressed a need for such studies.

      CONCLUSION

      Growth hormone profoundly affects the adult myocardium, as illustrated by the adverse effects of both acromegaly and GHD. Growth hormone deficiency provides an important and well-documented model in which to understand the effects of this deficiency in human cardiac physiology. The clinical trials of GH replacement in adults with ischemic and dilated cardiomyopathies have reported no benefit; however, the possibility that GH replacement in adults with GHD will prove to be beneficial in reducing cardiovascular morbidity and mortality remains tantalizing. No placebocontrolled trials involving GH replacement therapy have been conducted in groups of patients with congestive heart failure and GHD. However, the cases reported suggest that, in the setting of established GHD and cardiac dysfunction of any etiology, the addition of GH replacement should be strongly considered as an adjunct to standard heart failure therapy. In addition, given the excess mortality in adults with established GHD, the utility of routine screening of these patients for left ventricular dysfunction and the benefit of replacement therapy should be investigated further.

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