Growth hormone deficiency
Growth hormone regulation
Growth hormone: regulation, synthesis and secretion
Growth hormone (GH), also referred to as recombinant human GH (rhGH) in its human form, is a pleiotropic hormone that regulates somatic (bodily) growth, nutritional status, reproduction, physical activity and immunity.1 Pituitary GH is produced by somatotropic cells in the anterior pituitary gland.2
Growth hormone regulation
The main regulatory factors for GH include GH releasing hormone (GHRH), somatostatin (SRIF) and insulin-like growth factor (IGF-1).2 Figure 1 shows how these regulatory factors interact, and indicates other stimulators and inhibitors involved in GH pathways.
Figure 1. The neuroendocrine (GHRH/Somatostatin-GH-IGF) axis and hormonal regulators (Adapted).1 The hypothalamic stimulator growth hormone regulating factor (GHRF) and the inhibitor somatostatin mainly control growth hormone (GH) synthesis and secretion by the pituitary somatotrophs. GH stimulates the secretion of insulin-like growth factor-1 (IGF-1), which acts in autocrine, paracrine and endocrine forms in somatic tissues to control various physiological processes. GH and IGF-1 are thought to regulate GH levels through long- and short-loop feedback; GH, GHRH and somatostatin self-regulate their levels via ultra-short-loop feedback. ANP, atrial natriuretic peptide; CRH, corticotropin-releasing hormone; FGF, fibroblast growth factor; GH, growth hormone; GHRH, GH releasing hormone; GnRH, gonadotropin-releasing hormone; IGF, insulin-like growth factor; LH, luteinising hormone; NPY, neuropeptide Y; PACAP, pituitary adenylate cyclase-activating polypeptide; SDF1/CXCL12, chemokine derived factor 1; SS, somatostatin; TH, thyroid hormones; TRH, thyrotropin-releasing hormone.
Growth hormone synthesis and secretion
The modulation of processes involved in the secretion of GH from the pituitary gland begins with activation of G-protein-coupled receptors (GPCRs) in cells in the anterior pituitary.2
Figure 2 shows some of the factors and pathways involved in GH regulation and how this causes adult-acquired GHD.
Figure 2. Causes of acquired adult growth hormone deficiency (Adapted).3 Differentiated pituitary GH production, determined largely by POU1F1, is induced by GHRH and ghrelin, and suppressed by somatostatin through somatotroph receptor signalling. GH binds the preformed GHR dimer. Internal dimer rotation results in JAK2 phosphorylation (P) and signalling by JAK2-dependent and JAK2-independent pathways. GH targets include IGF-1, cell proliferation factors, glucose metabolism and cytoskeletal proteins. GHR signalling may be abrogated by suppressors of cytokine signalling proteins and by phosphatases. GH production may be suppressed by multiple conditions. CNS, central nervous system; GHR, growth hormone receptor; GHRH, growth hormone releasing hormone; IGF-1, insulin-like growth factor 1; IRS, insulin receptor substrate; JAK2, Janus kinase 2; P, phosphorylation.
Growth hormone deficiency overview
Growth hormone deficiency (GHD) is caused by insufficient secretion of GH from the anterior pituitary gland.4 When less GH is available to somatic tissues, particularly the liver, this affects other hormonal regulators and the short-/long-term feedback loops, including the production of IGFs.3 This further suppresses GH production by tissues, in turn causing decreased expression of IGF-1 genes, decreased cell proliferation and reduced glucose metabolism.3
GHD stems from hereditary (congenital) causes, acquired causes or can have no diagnosable cause (idiopathic).2,5
Epidemiology of growth hormone deficiency
The estimated prevalence of GHD in adults is 2–3 in 10,000 people, with males tending to be diagnosed more frequently.6,7 The estimated prevalence of isolated GHD, meaning GHD occurring in isolation without other pituitary hormone deficits, is 1 in 4,000–10,000 live births.5 GHD is hereditary in 3–30% of patients.5
Growth hormone deficiency development and symptoms
GHD development
Growth hormone deficiency (GHD) results in growth delay, maturation delays, including delayed lengthening of bones in the extremities, which is inappropriate in relation to the child’s chronological age, and short stature.4 Short stature is sometimes defined as a height bellow the third percentile of the normal distribution of height.4
Common GHD symptoms in children
In children, the main symptom of GHD is the slowing or termination of growth around two or three years of age, usually resulting in a severe short stature of more than 3 standard deviations (SD) below the mean.8 However, the age of onset can differ from between the first few months following birth to the first few months of adolescence.9 Children with GHD onset at a later age show less severe slowing of growth or short stature.9 Other symptoms that have been associated with GHD in children include:9
- The presence of symptoms of a mass lesion in the hypothalamic region, such as headaches and visual deterioration
- Increased subcutaneous fat, especially at the trunk
- A face that looks younger than the child’s age, with a prominent forehead or depressed mid-facial development
- Delayed dentition
See Figure 3 for an overview of common symptoms in children.
Figure 3. Clinical features of growth hormone deficiency in children. (Created with information from9,10).
Common GHD symptoms in adults
In adults, GHD is commonly characterised by the following symptoms:11
- Increased visceral adiposity
- Decreased lean body mass
- Decreased bone mineral density
- Decreased exercise capacity
- Dyslipidaemia
- Insulin resistance
- Increased cardiometabolic and fracture risk
- Impaired quality of life
Diagnosis of GHD
Diagnosis in children
Growth hormone deficiency (GHD) in children may be suspected and ought to be investigated when any of the following is observed:8
- Severe short stature more than 3 standard deviations (SD) below the mean
- Height more than 1.5 SD below the mid-parental height
- Height more than 2 SD below the mean and a height velocity over 1 year that is more than 1 SD below the mean for chronological age, or a decrease in height SD of more than 0.5 over 1 year in children over 2 years of age
- If short stature is absent, a height velocity more than 2 SD below the mean over 1 year or more than 1.5 SD sustained over 2 years; this may occur in GHD, presenting in infancy or in organic acquired GHD
- Signs indicative of an intracranial lesion
- Signs of multiple pituitary hormone deficiencies (MPHD)
- Neonatal symptoms and signs of GHD
Although there is no agreed diagnostic gold standard for GHD, in clinical practice, diagnosis is made using a variety of assessments, including auxological, biochemistry and imaging tests; in particular, growth hormone provocation tests.12 Serum insulin-like growth factor-1 (IGF-1) has been considered a predictive biomarker for GH.13 Clonidine, arginine and, in some cases, L-dopa are used to stimulate secretion of GH from the pituitary gland, allowing sampling of GH levels in the blood.13 Provocative GH tests are the standard of care, although some of these assessments have low sensitivity and specificity for GH.14
Some studies suggest that IGF-1 should not be used alone for screening of GHD, and GH-stimulation tests could be complementary.13-15 While provocative blood tests are the most commonly used test type in EU5 countries, genetic tests are used more frequently used with paediatric patients (41%) than in adults (16%).16 The development of new diagnostic modalities, such as predictive biomarkers, may aid in improving GHD test sensitivity and specificity.14
Many children with idiopathic GHD (iGHD) are GH sufficient when they are retested following completion of growth, suggesting that there may be some limitations with current diagnostic measures in children.12 Therefore, some caution should be taken when interpreting the results of such tests.12 During the transition from paediatric to adult care in GHD, patients with isolated GHD need to be revaluated for GHD, as GH levels may normalise.17
The following tests are not advised in children and adolescents who are treated with GH:18
- Routine cardiac testing
- Dual X-ray absorptiometry (DXA) scanning
- Measurement of lipid profiles
Diagnosis in adults
Adults with GHD do not have short stature. Biochemical diagnosis is needed to confirm acquired GHD in these adults.3 Testing for GHD in adults should only be conducted if pituitary dysfunction is evident or suspected.3 A parasellar mass lesion, or history of a hypothalamic-pituitary insult, such as surgery, can be counted as evidence of pituitary dysfunction in adults.3 Provocative testing is commonly used in clinical practice, but should be avoided in patients with non-specific symptoms, such as weakness or obesity.3 Patients with three or more documented pituitary-axis deficiencies consistently have GHD, and provocative testing may be unnecessary in these cases.3
For potential adult GHD that has persisted since adolescence, diagnostic evaluation for GHD is conducted following testing and replacement treatment for pituitary hormone deficits.11 GH-stimulation tests follow consideration of the individual clinical context and clinical history that indicate reasonable suspicion of GHD.11
GHD disease burden and quality of life
Quality of life and treatment burden
Children and adults with short stature due to growth hormone deficiency (GHD) report a lower quality of life (QoL) in comparison to those with normal stature and, if left untreated, this can adversely affect QoL.19,20 Treatment for GHD can improve QoL.20 For example, a sample in children from five European countries found that those treated for GHD who achieved normal height reported a higher QoL in comparison with those who were untreated and of short stature.21
Early identification of GHD and treatment can improve patient QoL and disease burden10
In children and adolescents, the burden of GHD is associated with the following factors:10
- Poor appetite
- Poor strength and muscle development
- Low energy levels
- Reduced endurance
- Poor sleep and fatigue
- Impaired attention and concentration
- Bullying, being treated differently, poor confidence and feeling sad or angry
More people with GHD have comorbidities compared with people without GHD, creating further treatment burden for patients with GHD and significant costs to healthcare services.22 For example, in the US, endocrine conditions affect >68% of patients with GHD compared with ≤10% of controls, while metabolic conditions affect >93% of patients with GHD compared with ≤39% of controls.22
Some treatments for GHD may cause paediatric patients to experience pain, bruising, burning, stinging or soreness.23 Parents or caregivers of children with GHD may feel worry, guilt or frustration.23
Early identification of GHD alongside treatment could help patients experience fewer factors that impact their QoL10
Economic burden
GHD imposes an economic burden. The total cost of a complete multi-year course of GH treatment in Italy is estimated at €100,000 per patient, primarily paid for by the national health service.24 In addition, wastage of unadministered drugs can account for up to 15% of consumption.24 In the UK, the average annual cost of treatment is £3,350 per patient, although it is dependent on the dose.25
Given the continual pressure on healthcare systems, increasing prescriptions of low-cost biosimilars may be essential for healthcare sustainability in Europe, as well as in other countries.26 By providing greater competition into the product marketplace, biosimilars induce a reduction in overall biologic costs, therefore, improving budgetary redistribution and patient access to medicines.27 Increased accessibility and improved education for both healthcare professionals and patients are necessary to increase the availability of biosimilar prescriptions with the aim of improving sustainability.26 New biosimilars for growth hormone, such as somatropin, are being developed to reduce the increasing costs of GH therapy.28 However, a longitudinal observational study in the UK found that patient preference was a more important factor in prescribing decisions than the cost of growth hormone products in both primary and secondary care.29 In particular, the main drivers in treatment product selection were the ease of use and the number of steps in dose preparation.29
In people with GHD, poor adherence to, or lack of treatment with, somatropin is associated with increased costs. For example, in a US study, mean annual all-cause healthcare costs were 4.6 times greater ($42,309 vs $9,146) for Medicaid patients with GHD than non-GHD controls.22 For Medicaid patients with GHD, inpatient costs were the largest proportion ($22,385 vs $3,494 for controls), while outpatient costs were a greater proportion for commercial patients ($13,083 vs $4,057 for controls).22 Regarding indirect costs, financial burden associated with GHD is mainly driven by productivity losses associated with reduced QoL.20,30 Therefore, leaving GHD untreated creates significant economic burden for healthcare systems.
References
- Vélez and Unniappan, 2021. A comparative update on the neuroendocrine regulation of growth hormone in vertebrates. https://www.doi.org/10.3389/fendo.2020.614981
- Kato, 2002. Regulation of human growth hormone secretion and its disorders. https://www.doi.org/10.2169/internalmedicine.41.7
- Melmed, 2019. Pathogenesis and diagnosis of growth hormone deficiency in adults. https://www.doi.org/10.1056/NEJMra1817346
- Ranke, 2021. Short and long-term effects of growth hormone in children and adolescents with GH deficiency. https://www.doi.org/10.3389/fendo.2021.720419
- Hage, 2021. Advances in differential diagnosis and management of growth hormone deficiency in children. https://www.doi.org/10.1038/s41574-021-00539-5
- Stochholm and Christiansen. Humana Press, 2011. The epidemiology of growth hormone deficiency. https://www.doi.org/10.1007/978-1-60761-317-6_8
- Feldt-Rasmussen and Klose, 2022. Adult growth hormone deficiency - clinical management. https://pubmed.ncbi.nlm.nih.gov/28402617/
- Murray, 2016. Controversies in the diagnosis and management of growth hormone deficiency in childhood and adolescence. https://www.doi.org/10.1136/archdischild-2014-307228
- Shalet, 1998. The diagnosis of growth hormone deficiency in children and adults. https://www.doi.org/10.1210/edrv.19.2.0329
- Brod, 2017. Understanding burden of illness for child growth hormone deficiency. https://www.doi.org/10.1007/s11136-017-1529-1
- Tritos and Biller, 2021. Current concepts of the diagnosis of adult growth hormone deficiency. https://www.doi.org/10.1007/s11154-020-09594-1
- Chinoy and Murray, 2016. Diagnosis of growth hormone deficiency in the paediatric and transitional age. https://www.doi.org/10.1016/j.beem.2016.11.002
- Iwayama, 2021. Insulin-like growth factor-1 level is a poor diagnostic indicator of growth hormone deficiency. https://www.doi.org/10.1038/s41598-021-95632-0
- Kamoun, 2021. Provocative growth hormone testing in children: How did we get here and where do we go now? https://www.doi.org/10.1515/jpem-2021-0045
- Yuen, 2019. American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for management of growth hormone deficiency in adults and patients transitioning from pediatric to adult care. https://www.doi.org/10.4158/gl-2019-0405
- Bradshaw, 2019. Paediatric and adult GHD tests for diagnosis in Europe PRO159. https://www.doi.org/10.1016/j.jval.2019.09.2488
- Tavares and Collett-Solberg, 2021. Growth hormone deficiency and the transition from pediatric to adult care. https://www.doi.org/10.1016/j.jped.2021.02.007
- Grimberg, 2016. Guidelines for growth hormone and insulin-like growth factor-I treatment in children and adolescents: Growth hormone deficiency, idiopathic short stature, and primary insulin-like growth factor-I deficiency. https://www.doi.org/10.1159/000452150
- Backeljauw, 2021. Impact of short stature on quality of life: A systematic literature review. https://www.doi.org/10.1016/j.ghir.2021.101392
- Loftus, 2019. Targeted literature review of the humanistic and economic burden of adult growth hormone deficiency. https://www.doi.org/10.1080/03007995.2018.1546682
- Silva, 2018. Children's psychosocial functioning and parents' quality of life in paediatric short stature: The mediating role of caregiving stress. https://www.doi.org/10.1002/cpp.2146
- Smith, 2022. PMON64 Economic burden of growth hormone deficiency in a US adult population. https://www.doi.org/10.1210/jendso/bvac150.1162
- Brod, 2017. Understanding treatment burden for children treated for growth hormone deficiency. https://www.doi.org/10.1007/s40271-017-0237-9
- Orso, 2022. Pediatric growth hormone treatment in Italy: A systematic review of epidemiology, quality of life, treatment adherence, and economic impact. https://www.doi.org/10.1371/journal.pone.0264403
- National Institute for Health and Care Excellence (NICE), 2003. Human growth hormone (somatropin) in adults with growth hormone deficiency. https://www.nice.org.uk/guidance/ta64/chapter/1-Guidance
- Godman, 2022. Biosimilars are essential for sustainable healthcare systems; however, key challenges remain as seen with long-acting insulin analogues. https://www.doi.org/10.7324/japs.2022.120306
- de Mora, 2019. Biosimilars: A value proposition. https://www.doi.org/10.1007/s40259-019-00360-7
- Toffoletto, 2016. Comparative pharmacokinetic and pharmacodynamic evaluation between a new biosimilar and reference recombinant human growth hormone. https://www.doi.org/10.1016/j.ghir.2016.09.003
- Chapman, 2017. What drives the prescribing of growth hormone preparations in England? Prices versus patient preferences. https://www.doi.org/10.1136/bmjopen-2016-013730
- Kaplowitz, 2021. Economic burden of growth hormone deficiency in a US pediatric population. https://www.doi.org/10.18553/jmcp.2021.21030
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