Growth hormone (GH), also known as somatotropin, is a peptide hormone that is synthesized and secret
Growth hormone (GH), also known as somatotropin, is a peptide hormone that is synthesized and secreted by the somatotrophs of the anterior pituitary gland. The main action of GH is to stimulate linear growth in children; however, it also fosters a healthy body composition by increasing muscle and reducing fat mass, maintains normal blood glucose levels, and promotes a favorable lipid profile. This article provides an overview of the normal pathophysiology of GH production and action. We discuss the history of GH therapy and the development of the current formulation of recombinant human GH given as daily subcutaneous injections. This paper reviews two of the longest standing FDA-approved indications for GH treatment, GH deficiency and Turner syndrome. We will highlight the pathogenesis of these disorders, including presentations, presumed mechanism(s) for the associated short stature, and diagnostic criteria, with a review of stimulation test benefits and pitfalls. This review also includes current recommendations for GH therapy to help maximize final height in these children, as well as data demonstrating the efficacy and safety of GH treatment in these populations.
Growth hormone (GH), also known as somatotropin, is a peptide hormone that is synthesized and secreted by the somatotrophs of the anterior pituitary gland. 1 The main effect of GH is to promote linear growth in children. Its secretion is pulsatile and primarily controlled by GH-releasing hormone (GHRH) (stimulatory), by somatostatin (inhibitory), and, to a lesser degree, by ghrelin (stimulatory). 2 A complex feedback system involving insulin-like growth factor-1 (IGF-1), leptin, ghrelin, free fatty acids, and the central nervous system regulates GH secretion. 3 , 4 When released, GH binds to its receptor in the liver and cartilage, leading to production of IGF-1, which through endocrine and paracrine/autocrine mechanisms, then stimulates linear bone growth. 5 GH acts at the epiphysis (growth plate) to increase linear growth by promoting differentiation of prechondrocytes and expansion of osteoblasts. 6 , 7 Both GH and IGF-1 are needed to stimulate normal linear growth; however, the exact cellular targets for the direct effects of GH remain ill-defined in complex tissues such as the growth plate. The contribution of the direct and indirect actions of GH is controversial. 8 It is known that, when GH binds to its receptor, it causes dimerization of the receptor, which leads to interaction of the receptor with janus kinase 2 (JAK2) and subsequent tyrosine phosphorylation of JAK2 and the GH receptor itself, followed by changes in the phosphorylation of the signal transducer activator of transcription (STAT) pathway which then stimulates target gene transcription. In the liver, GH receptor activation leads to an increased production of IGF binding protein-3 (IGFBP-3) and acid-labile subunit (ALS) which bind IGF-1 in a ternary complex thereby increasing its half-life 9 ( ).
There are 11 US Food and Drug Administration (FDA)- approved conditions to date that have been shown to benefit from rhGH therapy ( ). The dose used varies by age, physiology, indication, response to treatment, and individual practice preferences of the prescribing physician. In addition, the range of doses, at least for pediatric indications, also stems from results of clinical trials in which initial dosage choices were based on the presence of GH deficiency (lower doses) or (presumed) GH resistance (higher doses). Furthermore, dose selection is also sometimes driven by regulations set forth by third-party payers. Review of GH products available in the US reveals that no single brand is approved for all indications. 16 However, since the active medication, somatotropin, is the same in each product, many physicians feel comfortable using any approved product for any appropriate indication. Similarly, in other parts of the world, GH products are often used interchangeably. The drug approval process in Europe via the European Medicines Evaluation Agency (EMEA) is likely to approve new preparations of rhGH for indications approved for “biosimilar” products. It is suggested by Ranke et al that this type of approval, if granted, should be used with caution as safety and efficacy may be different between medication brands even though the active medication is similar. 17 Ultimately, the informed physician and often the insurance company will influence the choice of the GH product selected for each patient.
GH has two known isoforms, weighing 22 kD and 20 kD; their structures are shown below ( ). The first available rhGH, protropin, was a polypeptide hormone produced by inclusion body recombinant DNA technology. Protropin had 192 amino acids and a molecular weight of 22 kDa. This molecule contained the identical sequence of 191 amino acids found in native pituitary hormone with the addition of a methionine (met-GH) on the N-terminus, initially required to facilitate the biosynthetic process using E. coli. Use of met-GH was associated with the development of antibodies, although typically not of a growth-neutralizing variety. 15 All current forms of rhGH used in practice today have the identical 191 amino-acid sequence found in native pituitary hormone. 16 There are no clinically relevant antibody reactions to current rhGH as it mimics the human GH structure.
Multiple advances in the treatment of GHD have been made in the more than 50 years since treatment began in 1958. 11 Initially, human pituitary GH, derived from pituitary glands of recently deceased humans, was used only for severely GH-deficient children. Limited supply of the hormone and transmission of Creuzfeldt-Jacob Disease in some patients after treatment led to discontinued use of human cadaveric GH in 1985. 12 The structure of GH was determined in 1972 and this led to research and development of synthetic GH. In 1979, Goeddel et al expressed the gene for human GH in Escherichia coli allowing the bacteria to produce human GH in large quantities. 13 In 1985, Genentech became the first company to make recombinant human GH (rhGH), also known as somatotropin. 14
GHD normally presents with short stature, poor height velocity, relative weight preservation, and delayed bone age. In infancy, affected children may also manifest hypoglycemia, prolonged jaundice with or without giant cell hepatitis, and microphallus in males. The estimated incidence of GHD ranges from 1:4000 to 1:10,000. Causes of GHD can be divided into two main categories: congenital and acquired. Congenital causes can be further subdivided into genetic defects18 or anatomical abnormalities (eg, hypothalamic- pituitary stalk transection, optic nerve hypoplasia, and cranial anomalies including holoprosencephaly).19 Acquired etiologies of GHD include suprasellar tumors (most commonly, craniopharyngioma), inflammatory processes, infections of the central nervous system, head trauma,20 post-surgical, post-radiation,21,22 and psychosocial deprivation.23 Although there are many known causes of GHD, most cases appear to have an idiopathic basis. Clinically it is important to rule out all other causes of GHD before referring to the etiology of the condition as idiopathic. GHD is most often a secondary phenomenon resulting from a hypothalamic abnormality (ie, low concentrations of GHRH or an inability of GHRH to reach the pituitary) or, less frequently, from a primary disorder of the pituitary gland leading to reduced secretion of GH. GH secretion from the pituitary gland is dependent on the sleep-wake cycle and, therefore, measurement of random serum levels of GH is not clinically useful. Thus, if the diagnosis of GHD is suspected based on poor height velocity, typically the serum concentrations of the GH surrogates, IGF-1 and IGFBP-3, are measured to screen for GHD.5,24 If these levels are found to be low (especially IGF-1), then a GH stimulation test is commonly performed. In most countries, diagnostic criteria for GHD are based on a combination of auxological data and peak GH responses to two GH provocative tests. Criteria for starting treatment are listed in .25
Over the years, multiple medications, capitalizing on either the known pharmacological regulation of endogenous GH secretion or on the physiology of glucose counter- regulation in response to hypoglycemia, have been used to provoke GH secretion, including l-dopa, insulin, glucagon, clonidine, arginine, and GHRH (no longer available).26 Each has possible side effects and reasons for use. The first of these was the insulin tolerance test (ITT) that stimulated GH by inducing hypoglycemia. The advantage of the ITT is that it allows for simultaneous assessment of the ACTH-cortisol axis which should also respond to hypoglycemia, but the risk of severe hypoglycemia during the test is significant. 27 Many pediatric endocrinologists do not use ITT for this reason. The glucagon stimulation test increases GH secretion by causing an initial rise in the plasma glucose level to ~150 mg/dL, which, in turn, simulates the body to produce insulin to decrease the plasma glucose back to normal, with a frequent nadir of ~60 mg/dL. This physiologically controlled reduction in plasma glucose concentration from slightly above normal to low normal will stimulate GH secretion in non-GH-deficient individuals. There is still a risk of mild hypoglycemia, but severe episodes are far less frequent than occur with the ITT. Clonidine stimulates GH secretion by mimicking the normal α-adrenergic regulation of GH release from the pituitary, but has the risk of inducing hypotension. Since there are risks to performing all of these tests, they should always be performed under the direct supervision of a pediatric endocrinologist and trained nursing staff. An abnormal response to stimulation testing to all agents (except GHRH) is defined arbitrarily as a peak GH level < 10 ng/mL. This definition is controversial because many patients (~75%) with apparent idiopathic isolated GHD diagnosed in childhood will have normal GH responses when retested off GH treatment as adolescents during the transition period or as adults.28 Due to the limitations of the stimulation testing, two failed GH stimulation tests are often required to make a diagnosis of GHD. This is part of the diagnostic criteria for GHD in many countries, as well as a requirement of insurance companies prior to granting authorization for GH treatment.
Diagnosis in GHD is based on both clinical and biochemical parameters as described above. Historically, GH preparations were injected intramuscularly to allow complete absorption while limiting antibody formation. However, once it was shown that subcutaneous (SC) injections were equally effective, less painful, and without side effects,29 this became the preferred route of administration. The recommended frequency of GH injections has also changed over the years. Originally, pituitary GH was given 2 days per week, but then it was discovered that dividing the weekly dose into 3 injections yielded better growth rates.30 It was ultimately discovered that daily injections led to even better growth rates31 which has been confirmed by many studies.32– 34 Serum levels of GH reach a supraphysiological maximum 2 to 6 hours after a SC injection and then fall by about 12 hours.35 Injections in the evening have been shown to result in a more physiological pattern of glucose and protein metabolites than if GH is given in the morning.36 Therefore, rhGH is currently used as a once-daily SC injection, typically given late in the evening in an attempt to mimic the normal sleep-entrained (nychtemeral) secretory pattern of endogenous GH.35
The physiological prepubertal production rate of GH is 0.02 mg/kg/day (0.06 IU/kg/day) which increases two to four times during puberty. The goal of treatment is to mimic these levels while minimizing side effects. There is a wide range of recommended dosing of GH internationally for the treatment of GHD. GH dose ranges between 0.5 to 0.7 IU/kg/week (0.17 to 0.23 mg/kg/week) in most countries. 25 The highest doses are used in the US and range from 0.17 to 0.35 mg/kg/week, while the smallest doses are used in Japan (0.5 IU/kg/week).25 Data from a study by Tanaka using an international survey showed a range of initial GH treatment doses by country ( ).
Because of higher secretion of both GH and IGF-1 during normal puberty, the concept of higher replacement doses during puberty has surfaced. Some studies suggest that patients with GHD may achieve greater pubertal growth if treated with higher doses than are typically recommended for prepubertal children to mimic normal pubertal physiology.37–39 The results of these small-scale studies were sufficient to engender FDA approval for use of higher doses of GH during puberty in children with GHD (up to 0.7 mg/kg/week). Monitoring with serum IGF-1 levels specific for age, gender, and Tanner stage must be used to determine the safe and optimal GH dose in puberty.40 Currently, many endocrinologists continue treatment through puberty with close monitoring of height velocity, bone age, serum IGF-1 levels, and pubertal progression to ensure the maximal effect of treatment. In most countries, GH therapy is continued until height velocity decreases to <2.5 cm/year and/or until the bone age is advanced to between 13 to 15 years for girls and 15.5 to 16 years for boys.25 It is now recommended that most patients with childhood-onset GHD be retested for GHD (except perhaps those with prior clear-cut, permanent GH deficiency, ie, those with multiple pituitary hormone deficiencies and/or an abnormal head MRI) after they have reached final height. Newer data suggest that patients with idiopathic isolated GHD should be retested when they start puberty to determine if they are still GH-deficient. If they pass the repeat GH stimulation testing at the beginning of puberty, then they may be able to reach final adult height even if GH treatment is discontinued.41
The transition period between adolescence and adulthood is a unique time to reassess the need for GH treatment. In the past, use of GH in children with GHD was continued until epiphyseal fusion occurred; however, there are newer data to suggest that GH has important benefits on bone mineralization, lean body mass,42–44 and cardiac risk factors, ie, abnormal lipid profile and excess visceral adiposity.45,46 Based on these metabolic benefits, it is suggested that adults may also benefit from GH treatment. For adults with persistent GHD, the effective dose is one-sixth to one-third less than that needed for growing children and adolescents. In order to establish which adults may benefit from continued GH therapy, it is important to determine who is most likely to have persistent GHD. Over 90% of those patients with multiple pituitary hormone deficiencies and/or clear-cut evidence of organic pituitary disease will have persistent GHD as adults. On the contrary, 67% up to 75% patients with idiopathic isolated GHD in childhood will pass repeat GH testing during the transition phase.28,47 The exact reason for the discrepancy is uncertain, but may result from variations in testing protocols, the lack of reproducibility of GH provocative testing, variation in GH assay methods, failure to use sex-steroid priming, and the effects of nutrition. 48 Thus, it is recommended that most patients with isolated GHD be retested, while those with well-delineated organic causes need not be.
As stated above, the major goal of GH treatment is to provide the short child with improvement in height velocity in order to attain a final height within the range that is expected for his or her family and, if possible, within the normal range of the general population. We will first discuss the efficacy of treatment as it pertains to GHD. Later we will review the safety of use of rhGH in children, as it is imperative to understand and minimize the risk of any potential undesirable effects.
Multiple studies have assessed the efficacy of rhGH use in children with GHD. Evaluation of patients with GHD shows that multiple factors affect final height: number of injections per week, duration of treatment, age at diagnosis, and, most of all, genetic height potential. The data from the Kabi International Growth Study (KIGS) show that children with GHD can attain improvement in final height with GH treatment increasing +1.6 standard deviation (SD) from baseline and falling within range for family height genetics.49 The Swedish analysis of KIGS data showed that subjects with severe GHD (defined as peak GH < 3.3 ng/mL) were shorter than those with partial GHD, even when corrected for mid-parental height, but there was no significant difference between final height in each group.50 Data from the National Cooperative Growth Study (NCGS), in which approximately 20,000 children receiving rhGH have been tracked, show that 40% had idiopathic GHD, while 13.8% had organic GHD. For subjects who were treated for 7 consecutive years, the mean height SD score increased by 2.5 SD in isolated GHD and by 2.0 SD in organic GHD.51 To help determine the optimum GH treatment strategy for children with GHD (and TS), mathematical models have been developed based on clinical data from a large number of subjects. These prediction models are based on known clinical data, including birth status, genetic potential, laboratory data, and GH treatment schedule. The model explains about 61% of the variability in the growth response to GH. It was noted that a better response is seen in those subjects with the following features: lower peak GH level, younger age at the onset of treatment, larger gap between the subject’s height and mid- parental target, higher GH dose, and higher body weight and/or birth weight.51,52 Further model analysis is being developed to optimize GH treatment in children with GHD.