Expert Review of Molecular Diagnostics
ISSN: 1473-7159 (Print) 1744-8352 (Online) Journal homepage: http://www.tandfonline.com/loi/iero20
The macimorelin-stimulated growth hormone test for adult growth hormone deficiency diagnosis Vrinda Agrawal & Jose M Garcia To cite this article: Vrinda Agrawal & Jose M Garcia (2014) The macimorelin-stimulated growth hormone test for adult growth hormone deficiency diagnosis, Expert Review of Molecular Diagnostics, 14:6, 647-654, DOI: 10.1586/14737159.2014.915746 To link to this article: http://dx.doi.org/10.1586/14737159.2014.915746
Published online: 16 May 2014.
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iero20 Download by: [Cornell University Library]
Date: 11 October 2016, At: 09:36
Diagnostic Profile
The macimorelin-stimulated growth hormone test for adult growth hormone deficiency diagnosis Expert Rev. Mol. Diagn. 14(6), 647–654 (2014)
Vrinda Agrawal1 and Jose M Garcia*1,2 1 Division of Diabetes, Endocrinology and Metabolism, MCL, Center for Translational Research on Inflammatory Diseases, Michael E DeBakey Veterans Affairs Medical Center, 2002 Holcombe Blvd, Bldg 109, Rm 210, Houston, TX 77030, USA 2 Department of Molecular and Cell Biology and Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA *Author for correspondence: Tel.: +1 713 794 7989 Fax: +1 713 794 7771 [email protected]
Adult growth hormone deficiency (AGHD) causes a reduction in lean body mass, bone mineral density, exercise tolerance and overall quality of life and treatment with growth hormone (GH) improves some of these outcomes. Because symptoms are non-specific and random GH levels are not useful in establishing its diagnosis, provocative tests are often necessary. The insulin tolerance test is the ‘gold standard’ test for diagnosis of AGHD but it is often cumbersome to perform and is contraindicated in certain patients due to the risk of hypoglycemia. Administration of the orally available ghrelin mimetic and GH secretagogue macimorelin increases GH levels acutely via the ghrelin receptor GHSR1-a and it has been shown to have good sensitivity and specificity for diagnosing AGHD. Here we review the evidence of the potential use of macimorelin for this indication. KEYWORDS: AEZS-130 • GH • GHD • ghrelin • GHS
Adult growth hormone deficiency (AGHD) is a condition usually caused by damage to the pituitary gland or the hypothalamus as a result of tumors, surgery, radiation or trauma to these areas [1]. In children, growth hormone deficiency usually presents with severe growth failure, delayed bone age, increased weight/height ratio, an immature face with underdeveloped nasal bridge and frontal bossing, sparse hair growth and delayed puberty [2]. However, in adults, AGHD is often characterized by nonspecific symptoms including fatigue and weakness as well as an increase in fat mass, a reduction in lean body mass, reduced muscle strength and exercise capacity, impaired psychological wellbeing and increased rate of fractures, cardiovascular disease, dyslipidemia and decreased survival [3]. Growth hormone (GH) replacement in this setting reverses the body composition changes, increases exercise capacity, dyslipidemia and bone density and improves quality of life, making the diagnosis of AGHD extremely relevant from a clinical perspective. GH secretion
GH secretion is directly controlled by hypothalamic and peripheral factors acting on informahealthcare.com
10.1586/14737159.2014.915746
GH-secreting cells in the pituitary, known as somatotrophs [4]. Hypothalamic growth hormone-releasing hormone (GHRH) and somatostatin (SRIH) stimulate and inhibit GH secretion, respectively [5] by binding to specific cell-surface receptors on the somatotroph cells (FIGURE 1). GH secretion is also influenced by metabolic and hormonal signals from other glands, including glucocorticoids, thyroid hormones and sex steroids, which may act directly or via hypothalamic connections. Furthermore, GH regulates its own secretion by a feedback mechanism. Other peripheral mediators, such as IGF-I, free fatty acids, glucose and insulin, can act as parts of this feedback mechanism [6]. In addition, GH secretion is influenced by other peptides and neurotransmitters, including the GH secretagogue (GHS) ghrelin. Ghrelin is a 28 amino acid peptide, produced predominantly by the oxyntic cells in the stomach [7]. It is the natural ligand of the GH secretagogue receptor type 1a (GHS-R1a) and it induces a strong GH-releasing activity upon activating this receptor [8]. The GH-releasing effect of ghrelin is mediated primarily by GHRH-secreting neurons at the hypothalamic
2014 Informa UK Ltd
ISSN 1473-7159
647
Diagnostic Profile
Agrawal & Garcia
Hypothalamus
GHS-R1a
Provocative testing for the diagnosis of AGHD
All GH provocative tests are based on the concept that a given acute stimulus provokes GH secretion and that this increase in GH can be detected by sequential serum sampling after the stimulus is given. GHRH (+) An ideal GH provocative test should have Ghrelin (+) several characteristics. These include the Somatostatin (-) GHRHR ability to distinguish growth hormone SSTR deficiency (GHD) patients from normal GHS-R1a Pituitary individuals, test reproducibility and little somatotrophs IGF-1 R or no side effects. In addition, the test should be inexpensive, simple and quick, Ghrelin (+) with the idea that it can be performed in an office setting. Commonly used provocGrowth ative tests have been validated in a study hormone comparing six of them with cutoffs for GHR IGF-1 (-) optimal positive predictive values, sensitivOxyntic Stomach ities and specificities. These results are cells Liver summarized in TABLE 1 [13]. One of the problems in interpreting the results of most GH stimulation tests in adult patients is the presence of obesity. One of the reasons is that obesity per se is IGF-1 a state of relative hyposomatotropism. In Figure 1. Physiology of growth hormone secretion. obesity, spontaneous GH secretion is GHR: Growth hormone receptor; GHRH: Growth hormone-releasing hormone; reduced, GH clearance is enhanced and GHRHR: GHRH receptor; GHS-R1a: Growth hormone secretagogue receptor 1a; stimulated GH secretion is reduced. IGF-I SSTR: Somatostatin receptor. levels are unaffected, and this discordance is secondary to increased hepatic sensitivity level but it also exerts a direct effect on somatotrophs. Ghrelin to GH. Low levels of GH in obesity result in upregulation of and GHRH have synergic activities indicating that they have, GH receptor and GH sensitivity. Body fat distribution may at least in part, different mechanisms of action [9]. also be a determinant of GH concentrations in obese subjects with an inverse correlation between waist-to-hip circumference AGHD diagnosis and plasma GH [14]. Hence, obese individuals can have a falseSince the manifestations of AGHD may be non-specific, the positive result in a provocative test, if BMI-specific cutoffs of diagnosis of this disorder requires biochemical confirmation GH responses are not used. because unlike in children with GH deficiency, there is no unequivocal clinical marker of deficiency in adults. Individu- Insulin tolerance test als with a history of pituitary or hypothalamic disease, This test is well-validated and has long been considered the trauma, radiation or surgery, other pituitary hormone defi- gold standard by clinical practice guidelines for the diagnosis of ciencies or childhood-onset GH deficiency are usually con- AGHD. The test carries a sensitivity of 96% and a specificity sidered at risk for AGHD. In these patients, the presence of of 92% [13]. It is performed by administering 0.1 unit of insulow IGF-I circulating levels and deficiencies of three or more lin per kilogram of body weight and measuring blood glucose other pituitary hormones (panhypopituitarism) are usually and GH before and 15, 30, 60, 90 and 120 min after the sufficient for diagnosis [10]. However, a large number of injection. Insulin tolerance test (ITT)-mediated GH peak of patients with AGHD do not meet these criteria. Random
ISSN: 1473-7159 (Print) 1744-8352 (Online) Journal homepage: http://www.tandfonline.com/loi/iero20
The macimorelin-stimulated growth hormone test for adult growth hormone deficiency diagnosis Vrinda Agrawal & Jose M Garcia To cite this article: Vrinda Agrawal & Jose M Garcia (2014) The macimorelin-stimulated growth hormone test for adult growth hormone deficiency diagnosis, Expert Review of Molecular Diagnostics, 14:6, 647-654, DOI: 10.1586/14737159.2014.915746 To link to this article: http://dx.doi.org/10.1586/14737159.2014.915746
Published online: 16 May 2014.
Submit your article to this journal
Article views: 105
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iero20 Download by: [Cornell University Library]
Date: 11 October 2016, At: 09:36
Diagnostic Profile
The macimorelin-stimulated growth hormone test for adult growth hormone deficiency diagnosis Expert Rev. Mol. Diagn. 14(6), 647–654 (2014)
Vrinda Agrawal1 and Jose M Garcia*1,2 1 Division of Diabetes, Endocrinology and Metabolism, MCL, Center for Translational Research on Inflammatory Diseases, Michael E DeBakey Veterans Affairs Medical Center, 2002 Holcombe Blvd, Bldg 109, Rm 210, Houston, TX 77030, USA 2 Department of Molecular and Cell Biology and Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA *Author for correspondence: Tel.: +1 713 794 7989 Fax: +1 713 794 7771 [email protected]
Adult growth hormone deficiency (AGHD) causes a reduction in lean body mass, bone mineral density, exercise tolerance and overall quality of life and treatment with growth hormone (GH) improves some of these outcomes. Because symptoms are non-specific and random GH levels are not useful in establishing its diagnosis, provocative tests are often necessary. The insulin tolerance test is the ‘gold standard’ test for diagnosis of AGHD but it is often cumbersome to perform and is contraindicated in certain patients due to the risk of hypoglycemia. Administration of the orally available ghrelin mimetic and GH secretagogue macimorelin increases GH levels acutely via the ghrelin receptor GHSR1-a and it has been shown to have good sensitivity and specificity for diagnosing AGHD. Here we review the evidence of the potential use of macimorelin for this indication. KEYWORDS: AEZS-130 • GH • GHD • ghrelin • GHS
Adult growth hormone deficiency (AGHD) is a condition usually caused by damage to the pituitary gland or the hypothalamus as a result of tumors, surgery, radiation or trauma to these areas [1]. In children, growth hormone deficiency usually presents with severe growth failure, delayed bone age, increased weight/height ratio, an immature face with underdeveloped nasal bridge and frontal bossing, sparse hair growth and delayed puberty [2]. However, in adults, AGHD is often characterized by nonspecific symptoms including fatigue and weakness as well as an increase in fat mass, a reduction in lean body mass, reduced muscle strength and exercise capacity, impaired psychological wellbeing and increased rate of fractures, cardiovascular disease, dyslipidemia and decreased survival [3]. Growth hormone (GH) replacement in this setting reverses the body composition changes, increases exercise capacity, dyslipidemia and bone density and improves quality of life, making the diagnosis of AGHD extremely relevant from a clinical perspective. GH secretion
GH secretion is directly controlled by hypothalamic and peripheral factors acting on informahealthcare.com
10.1586/14737159.2014.915746
GH-secreting cells in the pituitary, known as somatotrophs [4]. Hypothalamic growth hormone-releasing hormone (GHRH) and somatostatin (SRIH) stimulate and inhibit GH secretion, respectively [5] by binding to specific cell-surface receptors on the somatotroph cells (FIGURE 1). GH secretion is also influenced by metabolic and hormonal signals from other glands, including glucocorticoids, thyroid hormones and sex steroids, which may act directly or via hypothalamic connections. Furthermore, GH regulates its own secretion by a feedback mechanism. Other peripheral mediators, such as IGF-I, free fatty acids, glucose and insulin, can act as parts of this feedback mechanism [6]. In addition, GH secretion is influenced by other peptides and neurotransmitters, including the GH secretagogue (GHS) ghrelin. Ghrelin is a 28 amino acid peptide, produced predominantly by the oxyntic cells in the stomach [7]. It is the natural ligand of the GH secretagogue receptor type 1a (GHS-R1a) and it induces a strong GH-releasing activity upon activating this receptor [8]. The GH-releasing effect of ghrelin is mediated primarily by GHRH-secreting neurons at the hypothalamic
2014 Informa UK Ltd
ISSN 1473-7159
647
Diagnostic Profile
Agrawal & Garcia
Hypothalamus
GHS-R1a
Provocative testing for the diagnosis of AGHD
All GH provocative tests are based on the concept that a given acute stimulus provokes GH secretion and that this increase in GH can be detected by sequential serum sampling after the stimulus is given. GHRH (+) An ideal GH provocative test should have Ghrelin (+) several characteristics. These include the Somatostatin (-) GHRHR ability to distinguish growth hormone SSTR deficiency (GHD) patients from normal GHS-R1a Pituitary individuals, test reproducibility and little somatotrophs IGF-1 R or no side effects. In addition, the test should be inexpensive, simple and quick, Ghrelin (+) with the idea that it can be performed in an office setting. Commonly used provocGrowth ative tests have been validated in a study hormone comparing six of them with cutoffs for GHR IGF-1 (-) optimal positive predictive values, sensitivOxyntic Stomach ities and specificities. These results are cells Liver summarized in TABLE 1 [13]. One of the problems in interpreting the results of most GH stimulation tests in adult patients is the presence of obesity. One of the reasons is that obesity per se is IGF-1 a state of relative hyposomatotropism. In Figure 1. Physiology of growth hormone secretion. obesity, spontaneous GH secretion is GHR: Growth hormone receptor; GHRH: Growth hormone-releasing hormone; reduced, GH clearance is enhanced and GHRHR: GHRH receptor; GHS-R1a: Growth hormone secretagogue receptor 1a; stimulated GH secretion is reduced. IGF-I SSTR: Somatostatin receptor. levels are unaffected, and this discordance is secondary to increased hepatic sensitivity level but it also exerts a direct effect on somatotrophs. Ghrelin to GH. Low levels of GH in obesity result in upregulation of and GHRH have synergic activities indicating that they have, GH receptor and GH sensitivity. Body fat distribution may at least in part, different mechanisms of action [9]. also be a determinant of GH concentrations in obese subjects with an inverse correlation between waist-to-hip circumference AGHD diagnosis and plasma GH [14]. Hence, obese individuals can have a falseSince the manifestations of AGHD may be non-specific, the positive result in a provocative test, if BMI-specific cutoffs of diagnosis of this disorder requires biochemical confirmation GH responses are not used. because unlike in children with GH deficiency, there is no unequivocal clinical marker of deficiency in adults. Individu- Insulin tolerance test als with a history of pituitary or hypothalamic disease, This test is well-validated and has long been considered the trauma, radiation or surgery, other pituitary hormone defi- gold standard by clinical practice guidelines for the diagnosis of ciencies or childhood-onset GH deficiency are usually con- AGHD. The test carries a sensitivity of 96% and a specificity sidered at risk for AGHD. In these patients, the presence of of 92% [13]. It is performed by administering 0.1 unit of insulow IGF-I circulating levels and deficiencies of three or more lin per kilogram of body weight and measuring blood glucose other pituitary hormones (panhypopituitarism) are usually and GH before and 15, 30, 60, 90 and 120 min after the sufficient for diagnosis [10]. However, a large number of injection. Insulin tolerance test (ITT)-mediated GH peak of patients with AGHD do not meet these criteria. Random
