DISCOVERIES 2018, Jan-Mar, 6(1): e82 DOI: 10.15190/d.2018.2 Growth Hormone Deficiency Diagnosis Focused REVIEW An update on the diagnosis of growth hormone deficiency Georgiana Roxana Gabreanu * ‘ Carol Davila University of Medicine and Pharmacy, Bucharest, Romania * Corresponding author: Georgiana Roxana Gabreanu, MD, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; Email: [email protected] Submitted: March 21, 2018; Revised: April 02, 2018; Accepted: April 11, 2018; Published: April 12, 2018; Citation: Gabreanu GR. An update on the diagnosis of growth hormone deficiency. Discoveries 2018, January-March; 6(1); e82. DOI:10.15190/d.2018.2 ABSTRACT extreme or morbid obesity. In addition, Growth hormone deficiency (GHD) is an endocrine administration of macimorelin with drugs that disorder, which may be either isolated or associated prolong QT interval and CYP3A4 inducers should with other pituitary hormone deficiencies. In be avoided. Genetic screening could obviously bring children, short stature is a useful clinical marker for a great insight in the GHD pathology. However, it GHD. In contrast, symptomatology is not always so remains an open question if it would be also cost obvious in adults, and the existing methods of effective to include it in the routine evaluation of the testing might be inaccurate and imprecise, especially patients with GHD. Although major progresses have in the lack of a suggestive clinical profile. Since the been made in this area, genetic testing continues to quality of life of patients diagnosed with GHD could be difficult to access, mostly because of its high also be significantly affected, in both children and costs, especially in the low-income and middle- adults, a correct and accurate diagnosis is therefore income countries. tremendously important to select those patients that can benefit from the GH treatment. In general, the Keywords: endocrine diseases are challenging in terms of Growth hormone deficiency, Insulin-like Growth diagnosis, the simple measurement of the basal level Factor-1, IGF- Binding protein 3, insuline tolerance of hormones is not sufficient for distinguishing test (ITT), GHRH-arginine stimulation test, Glucagon between the physiological and pathological stimulation test, macimorelin, genetic testing. conditions. Traditionally, several stimulation tests Abbreviations: have been considered by professional clinical guidelines, such as insulin tolerance test (ITT), Growth hormone (GH), Growth hormone deficiency (GHD), insulin tolerance test (ITT), Insulin-like Growth GHRH-arginine stimulation test and the glucagon Factor-1 (IGF-1), GH releasing hormone (GHRH), IGF stimulation test, and all of them have both binding protein 3 (IGFBP3), Acid Labile Subunit (ALS), advantages and limitations. More recently GH releasing hormone and arginine (GHRH-arginine), (December 2017), FDA approved a growth hormone GHRH plus growth hormone-releasing peptide (GHRP), secretagogue receptor agonist, macimorelin, for the glucagon stimulation test (GST), growth hormone secretagogue receptor (GHSR). diagnosis of adults with GHD. The obvious advantage for macimorelin is the simple oral administration and the high level of agreement with 1. Introduction the insulin tolerance test for those patients with organic disease and low levels of insulin-like growth Growth hormone is a polypeptide secreted by the factor (IGF-I). However, the safety profile and the somatotropic cells of the anterior pituitary, and the diagnostic value was not yet established for the process is regulated by complex mediators and pediatric population and for those adults with mechanisms. Some of the key regulatory factors www.discoveriesjournals.org/discoveries 1 Growth Hormone Deficiency Diagnosis are GH releasing hormone (GHRH), somatostatin, Society. The adult patients that are recommended by GH releasing peptide and insulin-like growth factor the authors to be tested for growth hormone (IGF-I) (Figure 1). The deficiency of growth deficiency are those who experienced surgical hormone is an endocrine disorder that may be interventions or irradiation due to several brain isolated or associated with other pituitary hormone tumors or any other pathology that could affect the deficiencies1. hypothalamus or the pituitary gland, and Growth hormone deficiency occurs in both subsequently would lead to acquired GHD. Finally, children and adults. As the Endocrine Society although rare, idiopathic GHD could also occur in indicates, childhood-onset GHD may be triggered by adults2. organic causes, or it can be idiopathic, with an While in children short stature is a useful unknown cause2. Patients with childhood-onset clinical marker for GHD, symptomatology is not GHD are recommended to be retested as adults, always so obvious in adults, consisting of since cases of reconversion to a normal GH response nonspecific clinical signs, such as reduced muscle were described, especially in the idiopathic GHD mass with fatigue and poor exercise capacity, (the cause is unknown)2,3. However, it is not glucose intolerance, atherosclerosis and 2,4 necessary to reassess those patients with mutations osteoporosis . The Endocrine Society or irreversible lesions, as they do not revert to recommends testing only for patients with a normal GH responses2. Thus, a proportion of the probability to be diagnosed with GHD based on adults with GHD diagnose is represented by those medical history and clinical symptomatology. with prior childhood-onset GHD. Another Otherwise, the existing methods of testing might be proportion of adults with GHD is represented by inaccurate and imprecise2. Therefore, those patients those with acquired deficiency during adulthood. A lacking a suggestive clinical profile (especially the clinical practice guideline on adult growth hormone idiopathic GHD ones) are recommended to be tested deficiency was established in 2011 by the Endocrine with two stimulation tests for the final diagnosis, Figure 1. Regulation of Growth Hormone Secretion www.discoveriesjournals.org/discoveries 2 Growth Hormone Deficiency Diagnosis since they show a high rate of false-positive in hepatic function7. The Growth Hormone Research response to a single GH stimulation test2. Society strongly recommends in a consensus In addition, the quality of life of patients statement on the diagnosis of children with diagnosed with growth hormone deficiency could be idiopathic short stature (2008) that IGF1 levels significantly affected, in both children and adults. A should be measured as part of the evaluation of very interesting report based on interviews with children with low height velocity8. According to the adult patients diagnosed with GHD highlights a Endocrine Society’s clinical guideline, the low level mixture of feelings. Some of the patients feel of IGF-I after discontinuation of GH treatment for at “embarrassed” of their body image, they have a least 1 month is sufficient to confirm the diagnostic sense of ”failure”, and they sometimes end up in of GHD in those children with irreversible lesions or depression, stress and anxiety. The social life could documented genetic mutations, and no additional be also affected, and this is sometimes due to the stimulation tests are required2. Low levels of IGF1 lack of energy and persistent fatigue to meet friends and IGFBP3 have been shown to have high or to continue certain projects. Also, irregular specificity for GHD, especially for young children, sleeping patterns worsen the fatigue in some of the and even higher when combined with height patients, others experience memory loss or they velocity in the pediatric population. However, “struggle” to focus or concentrate on daily tasks, normal values cannot exclude GHD and should be such as reading “a paragraph in a magazine confirmed with other tests, since the sensitivity is article”5. A correct and accurate diagnosis is relatively low7. therefore tremendously important to select those Differences of IGF1 levels may arise between patients that can benefit from the GH treatment. various immunoassays, thus it is recommended to use the same type of IGF assay throughout the entire 2. Growth Hormone and Insulin-like Growth follow-up of a patient, to minimize the bias9. Factor-1 (IGF-1)) In 2011, an international consensus on behalf of the Growth Hormone Research Society, the IGF society, Majority of endocrine diseases are challenging in the Pituitary Society and the IFCC was published terms of diagnosis and the simple measurement of regarding the standardization and evaluation of the basal level of hormones is not sufficient for growth hormone and insulin-like growth factor distinguishing between the physiological and assays. In order to improve assay comparison, it pathological conditions6. The growth hormone is is recommended to use an international standard for secreted from the anterior pituitary in approximately each hormone assay, to implement internal quality 10 pulses per day, which means that a single control programs and to participate in an accredited measurement of GH could not be of diagnostic proficiency testing/external quality assessment value, since the level of GH is only detectable about program10. 90 minutes per day in basal conditions7. Thus, Auernhammer et al. highlight in a recent paper the 3. Stimulation tests for growth hormone remarkable role of the functional diagnosis in deficiency (GHD) diagnosis endocrinology, which is represented by stimulation tests when the evaluation of the growth hormone Conventional