Welcome from Tamara L. Wexler MD, PhD
The Goldilocks Principle
Growth hormone follows the Goldilocks Principle: Too much is bad. Too little is bad. The body does best with Just the Right amount. How does one determine what is too little, and when to replace GH? This EndoScan focuses on adult acquired GH deficiency (GHD), and the impact of GH replacement (GHR).
The dangers of excess growth hormone (GH) have been known for well over a century; acromegaly was first described by Pierre Marie in 1886, and the syndrome existed long before that. Untreated acromegaly is associated with sleep apnea, insulin antagonism and resistance, soft tissue and synovial growth, increased bone turnover, and a 2.5- to 3-fold increase in cardiovascular mortality with survival reduced by ~10 years.
However, too little growth hormone is also bad for health. Growth hormone deficiency has negative effects on the cardiovascular system (including reduced left ventrical ejection fraction [LVEF], systolic hypertension, and a different mechanism of insulin resistance), bone, body composition, and quality of life.
The Effects of GH Disequilibrium: Cardiovascular, Bone, and Quality of Life
The Impact of GH on Cardiovascular Health
Growth hormone impacts the cardiovascular system, with both too much GH and too little GH having negative effects on cardiovascular health. GH excess is associated with inflammatory, metabolic, structural and functional cardiac changes, including hypertension (diastolic dysfunction); insulin resistance (antagonism of insulin action combined with impairment of insulin’s promotion of glucose uptake by skeletal muscle); dyslipidemia; endothelial dysfunction; and increased myocyte size with ventricular interstitial fibrosis. A specific acromegaly-related cardiomyopathy has been described, characterized in part by increased left ventricular mass (LVM); this is seen even in younger patients with shorter disease duration, and over time becomes a biventricular concentric myocardial hypertrophy characterized by interstitial fibrosis.
GHD also carries increased cardiovascular risk, with increased visceral adiposity, cardiovascular risk markers, and cardiovascular morbidity. The sequelae may include decreased LVEF and LVM; increased visceral adiposity; increased insulin resistance (here, from decreased glucose storage rate and inhibition of the glycogen synthase pathway); systolic hypertension; dyslipidemia; premature atherosclerosis; and other mechanisms.
The Impact of GH on Bone
Perturbations to GH impact the equilibrium of bone deposition and resorption. GH largely works via IGF-1, which enhances osteoblast differentiation and bone formation. Acromegaly is a high bone turnover state, with increased vertebral fractures (even in the absence of marked bone loss). The most visible signs of acromegaly are often due to bone effects, including calvarial thickening, prominent supraorbital ridges, and bilateral mandibular prognathism; if prior to fusion of the epiphyseal plates, excess growth hormone acts on long bones, leading to the condition termed gigantism.
Growth hormone deficiency leads to low-bone-turnover, low bone mineral density and mineral content, and an increased fracture risk; and osteoporosis, in part reversible with GHR.
The Impact of GH on Quality of Life
Growth hormone disequilibrium has a negative impact on Quality of Life (QoL); specific questionnaires have been developed to capture impaired QoL in patients both with too much GH (AcroQoL, the Acromegaly Quality of Life Questionnaire) and too little GH (QoL-AGHDA, the QoL-Assessment of Growth Hormone Deficiency in Adults).
Happily, many of the negative sequelae of GHD can be addressed, at least in part, by appropriate GH replacement.
The Impact of Growth Hormone Replacement
Growth hormone can be replaced, though there is some debate over when and why to replace it. Growth hormone replacement improves cardiovascular markers and function, body composition (reducing visceral fat while increasing fat-free mass), exercise capacity, bone density and bone mineral content, and quality of life. The strength of the recommendation to replace GH (in defined GHD) does vary; of note, this is based on the value placed on the efficacy of replacement, and not on safety concerns.
This EndoScan focuses on GH replacement in adult GH deficiency, particularly its effects on heart, bone, and quality of life, including in the oft-overlooked group of patients with prior GH excess (treated acromegaly). Growth hormone also has a range of approved uses in children, and is used in non-GHD adults (non-approved indications); these issues will be addressed in a future issue of EndoScan.
We review recent papers discussing the cardiovascular, bone, and QoL impact of growth hormone replacement or treatment. We begin with The Endocrine Society Guidelines for diagnosis and treatment of adult GHD. The criteria for determining what constitutes GHD include not only GH and IGF-1 levels (as discussed below), but the underlying likely cause; idiopathic growth hormone deficiency is extremely rare. Certain underlying co-morbidities—including obesity and CHF—may lead to lower levels of growth hormone (such as by impacting its secretion), but the significance of low serum hormone measurements in these patients is not clear, and whether the situations warrant GHR is controversial. Appropriate threshold levels for GH in overweight/obese individuals are discussed in a study by Dichtel and colleagues.
The study by Cittadini and colleagues focuses on patients with CHF and low peak GH, and the impact of GH on cardiac parameters; this cohort differs from others in that the subjects did not have a known pituitary cause for GHD. The impact of GH replacement on bone is discussed in research by Appelman-Djikstra and colleagues, which follows a well-described GHD cohort for 15 years of GH replacement. Quality of life improvements with GHR are addressed in a large retrospective analysis by Tritos and colleagues, comparing the efficacy and safety of GHR in individuals with GHD following cure of acromegaly versus treatment of non-functioning pituitary adenomas. While patients are often screened for GHD after treatment of pituitary adenomas that are non-functional or that secrete hormones other than GH, this is less often the case after treatment for acromegaly. The population of patients with cured acromegaly has a high rate of GHD, and there is increasing evidence suggesting that these patients should not be overlooked.
The commentaries for the latter three studies (Cittadini et al, Appelman-Djikstra et al and Tritos et al), also draw on other findings in the literature to place the studies in context.
In determining when it is appropriate to replace GH in GHD adults, establishing a clear diagnosis of GHD is essential.
GHD can be determined in several ways. In patients with a known reason for pituitary dysfunction and with ≥3 pituitary deficiencies, an IGF-1 level <2 standard deviations below the reference range (- 2 SDS) is considered clinically diagnostic (though in some cases further dynamic testing may be required for insurance reimbursement.) Otherwise, dynamic testing is done to establish the initial diagnosis.
The most common dynamic test until 2008 was the GHRH-arginine stimulation test. While the insulin tolerance test is oft cited as the gold standard, safety concerns regarding its use (risk of hypoglycemia, requiring close monitoring) made GHRH-arginine stimulation testing a popular option. In July of 2008, the sole manufacturer of recombinant GHRH in the U.S. ceased production, leading to a search for alternate dynamic testing—namely, glucagon stimulation testing (GST). While the mechanism by which GST works is unclear, it has gained favor in GHD diagnosis; in this EndoScan, we review a paper by Dichtel and colleagues recommending GST thresholds by BMI level.
Other diagnostic tests are in development; they rely on ghrelin-mimetic GH secretagogues (GH-releasing peptide-2 and -6, nonpeptide ghrelin mimetics), one of which (macimorelin) has been submitted to the FDA, but as of November of 2014 was not accepted.
In summary, when indicated, the benefits of GHR include reduction of cardiovascular risk and morbidity, as well as improvements in body composition, exercise capacity, bone, and QoL. Appropriate diagnosis of GH deficiency and monitoring of replacement are important aspects to clinical care. These issues are addressed in the following reviews.
Aeterna Zentaris Inc. News Release: FDA Issues Complete Response Letter for Aeterna Zentaris’ Macrilen NDA in Adult Growth Hormone Deficiency. November 6, 2014. http://www.aezsinc.com/en/page.php?p=60&q=637. Accessed April 17, 2015.
Aimaretti G, Corneli G, Razzore P, et al. Comparison between insulin-induced hypoglycemia and growth hormone (GH)-releasing hormone + arginine as provocative tests for the diagnosis of GH deficiency in adults. J Clin Endocrinol Metab. 1998;83(5):1615-1618.
Aimaretti G, Corneli G, Razzore P, et al. Usefulness of IGF-I assay for the diagnosis of GH deficiency in adults. J Endocrinol Invest. 1998;21(8):506-511.
Appelman-Dijkstra NM, Claessen KM, Hamdy NA, Pereira AM, Biermasz NR. Effects of up to 15 years of recombinant human GH (rhGH) replacement on bone metabolism in adults with growth hormone deficiency (GHD): the Leiden Cohort Study. Clin Endocrinol (Oxf). 2014;81(5):727-735.
Arcopinto M, Bobbio E, Bossone E, Perrone-Filardi P, Napoli R, Sacca L, Cittadini A. The GH/IGF-1 axis in chronic heart failure. Endocr Metab Immune Disord Drug Targets. 2013;13(1):76-91.
Biller BM, Samuels MH, Zagar A, et al. Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency. J Clin Endocrinol Metab. 2002;87(5):2067-2079.
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Cittadini A, Marra AM, Arcopinto M, et al. Growth hormone replacement delays the progression of chronic heart failure combined with growth hormone deficiency: an extension of a randomized controlled single-blind study. JACC Heart Fail. 2013;1(4):325-330.
Cook DM, Yuen KC, Biller BM, Kemp SF, Vance ML; American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists medical guidelines for clinical practice for growth hormone use in growth hormone-deficient adults and transition patients - 2009 update. Endocr Pract. 2009;15 Suppl 2:1-29.
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Tritos NA, Johannsson G, Korbonits M, et al. Effects of long-term growth hormone replacement in adults with growth hormone deficiency following cure of acromegaly: a KIMS analysis. J Clin Endocrinol Metab. 2014;99(6):2018-2029.
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Wexler T, Gunnell L, Omer Z, et al. Growth hormone deficiency is associated with decreased quality of life in patients with prior acromegaly. J Clin Endocrinol Metab. 2009 Jul;94(7):2471-2477.
Wexler TL, Durst R, McCarty D, Picard MH, et al. Growth hormone status predicts left ventricular mass in patients after cure of acromegaly. Growth Horm IGF Res. 2010;20(5):333-337.
Yuen KC, Biller BM, Molitch ME, Cook DM. Clinical review: Is lack of recombinant growth hormone (GH)-releasing hormone in the United States a setback or time to consider glucagon testing for adult GH deficiency? J Clin Endocrinol Metab. 2009;94(8):2702-2707.