Vol. 16 Supplement 1
Growth Hormone Discovery and Structure
Mat Buchman, BS, Stephen Bell, BA, BS, John J. Kopchick, PhD
The purpose of this review is to describe and document the discovery of growth hormone (GH) and various activities associated with it. Crucial to this discourse will be a chronicle of results related to the structure of GH. Many individuals were instrumental in the early and current work. Throughout the review we present glimpses into their scientific lives as it affects the evolution of GH’s story. We realize that we have not presented a comprehensive review of GH’s history and its current and future status, and apologize for the omission of many individuals who contributed to this story.
Ref: Ped. Endocrinol. Rev. 2018;16(Suppl1):2-10
The Era of Cadaveric Pituitary Extracted Human Growth Hormone (1958 – 1985): Biological and Clinical Aspects
Zvi Laron, MD, PhD (hc)
The first patient treated with cadaveric pituitary GH (hGH) was reported in 1958. Subsequently, collection of cadaveric pituitaries started in many countries and several centers extracted the hormone using one of two methods:
a. Acetone preservation and extraction with hot glacial acetic acid (Rabin method)
b. Collection in distilled water, freezing and extraction on columns yielding several pituitary hormones including hGH (Wilhelmi method).
The purified extracts of hGH were found to have metabolic and growth stimulating activity but the limited amounts permitted the treatment only of children with GH deficiency (GHD). The purified hormone also permitted the development of specific radioimmunoassays enabling the study of the physiological and pharmacological actions of GH.
In 1985 a number of patients treated years before with Wilhelmi hGH were diagnosed with Creutzfeld–Jacob–Disease (CJD). This led to the arrest of hGH production and the use of the then recently developed biosynthetic recombinant hGH.
Ref: Ped. Endocrinol. Rev. 2018;16(Suppl1):11-16
Gene Sequence and Production of Recombinant MetGH/hGH
John S. Parks, MD, PhD
Recombinant human growth hormones were the products of a revolution in biotechnology that took place in the San Francisco Bay area of California in the 1970’s. A combination of Herb Boyer’s restriction enzymes with Stanley Cohen’s bacterial plasmids provided the power to select and amplify virtually any gene. The complementary personalities and talents of Herb Boyer and Robert Swanson led to formation of Genentech and with it the development of a product that overcame the limitations of scarcity and the risks of slow virus contamination inherent in extracted pituitary growth hormone. The extra amino acid in metGH was dropped and other manufacturers joined in the effort to explore indications for rhGH beyond the replacement of a missing hormone. After more than thirty years of availability and careful study, we still have much to learn about the safe and effective use of rhGH.
Ref: Ped. Endocrinol. Rev. 2018;16(Suppl1):17-27
Standardization of Growth Hormone and Insulin-like Growth Factor-I Measurement
Noriyuki Katsumata, MD, PhD
Determination of serum levels of GH and IGF-I is crucial for the diagnosis and treatment of GH deficiency and disorders related to GH excess such as acromegaly and pituitary gigantism. However, significant discrepancies in measured GH values among the methods were observed around the world. In Japan, the Study Committee for GH and Its Related Factors of The Foundation for Growth Science standardized GH values measured with various commercially available GH assay kits by creating formulas to adjust them to their averages. The committee also established reference values for IGF-I in Japanese subjects at all ages from childhood to adulthood. Internationally, collaborators have been working on the harmonization of GH measurements.
Ref: Ped. Endocrinol. Rev. 2018;16(Suppl1):28-32
Regulatory Role for Growth Hormone in Statural Growth: IGF-Dependent and IGF-Independent Effects on Growth Plate Chondrogenesis and Longitudinal Bone Growth
Francesco De Luca, MD
It was initially thought that the growth-promoting effects of GH were exclusively mediated by liver-derived Insulin-like Growth Factor-I (IGF-I). Subsequent studies demonstrated that GH promotes IGF-I synthesis and activity in other organs and in the growth plate.
GH has also IGF-I-independent growth-promoting effects. In Igf1 null mice, high circulating GH levels may be responsible for normal chondrocyte proliferation. Furthermore, tibial growth is reduced more in Ghr null mice than in Igf1 null mice, while the body of mice lacking both Ghr and Igf1 is smaller than that of mice lacking Igf1 or Ghr. The increased IGF-II expression in the growth plate in Igf1 null mice suggests that the IGF-I-independent effects of GH may be mediated by IGF-II. The effects of Igf1 receptor (Igf1r) gene deletion in chondrocytes indicate that GH may promote growth directly at the growth plate even when the local effects of IGF-I and IGF-II are abrogated.
Ref: Ped. Endocrinol. Rev. 2018;16(Suppl1):33-38
Genetic Mutations in the GH/IGF Axis
Sabina Domené, PhD, Horacio M. Domené, PhD
The GH/IGF axis plays an important role in the control of pre and postnatal growth. At least 48 monogenic defects have been described affecting the production, secretion, and action of GH and IGFs.
Molecular defects of the GH/IGF axis resulting in short stature were arbitrarily classified into 4 groups: 1. Combined pituitary hormone deficiency (CPHD) (a. syndromic CPHD and b. non-syndromic CPHD), 2. Isolated GH deficiency (IGHD), 3. GH insensitivity, and 4. IGF-I insensitivity.
Genetic diagnosis is obtained in about 30-40% of children with growth retardation, severe IGHD, CPHD, apparent GH or IGF-I insensitivity, and small for gestational age. Increased accessibility to next generation sequencing (NGS) techniques resulted in a significant number of likely pathogenic variants in genes previously associated with short stature as well as in completely novel genes. Functional in vitro assays and in vivo animal models are required to determine the real contribution of these findings.
Ref: Ped. Endocrinol. Rev. 2018;16(Suppl1):39-62
Pediatric Growth Hormone Deficiency (GHD) in the Recombinant Human GH (rhGH) Era
Michael B Ranke, MD, PhD
During the phase of using hGH extracted from pituitaries (pit hGH) – 1958-1985 – fundamental experience related to the diagnosis and treatment was accumulated. However, since recombinant hGH (rhGH) had become available diagnosis and treatment of GHD were conducted world-wide in a more standardized way. Treatment with rhGH was also accompanied by documentations in large international pharmaco-epidemiological surveys, which provided new insight. Despite of this development the treatment of children and adolescents with GHD raises still issues related to the most effective and efficacious as well as safe use of rhGH. This brief review attempts to discuss a few aspects related to these topics as they have developed during the rhGH era.
Ref: Ped. Endocrinol. Rev. 2018;16(Suppl1):63-69
Adult Growth Hormone Deficiency: from Transition to Senescence
Jens OL Jørgensen, MD, DMSci, Kasper Hermansen, MD, Kirstine Stochholm, MD, PhD, DMSci, Anders Juul, MD, PhD, DMSci
The acute metabolic actions of hGH were discovered in GH-deficient adults (GHDA) 60 years ago and placebo controlled trials of prolonged rhGH replacement therapy appeared 30 years after. Untreated GHDA causes excess morbidity and mortality from cardiovascular disease and the clinical features include fatigue, reduced aerobic exercise capacity, abdominal obesity, reduced lean body mass, osteopenia, and elevated levels of circulating cardiovascular risk biomarkers. Several of these abnormalities normalize with GH replacement. Frequent side effects are fluid retention and insulin resistance, which are reversible and dose-dependent. The dose requirement declines with age and is higher in women. Continuation of GH replacement into adulthood is indicated in some patients with childhood-onset disease so the diagnosis must be reassessed. Observational data show that mortality in GH replaced patients is reduced compared to untreated patients. Thus, GH replacement in GHDA has proven beneficial and safe.
Ref: Ped. Endocrinol. Rev. 2018;16(Suppl1):70-79
Growth Hormone Therapy for Turner Syndrome
Christopher Blunden, MD, Nat Nasomyont, MD, Philippe Backeljauw, MD
Growth failure is nearly universal in individuals with Turner syndrome (TS). It is a consequence of haploinsufficiency of the short stature homeobox gene located on the short arm of the X chromosome (SHOX). Without treatment, individuals with TS are expected to be on average 20 cm shorter than unaffected adult females. Short stature is cited by patients as one of their biggest burdens and may have an adverse impact on psychosocial well-being, pubertal timing, and ability to complete a variety of daily living activities. The routine use of recombinant human growth hormone (rhGH) treatment has increased height outcomes. Clinical evidence has strongly supported the efficacy and safety of this treatment. In this article we review the rationale for rhGH treatment in TS, the factors that affect treatment response, safety and monitoring considerations, and potential changes in the way rhGH may be utilized in TS care in the future.
Ref: Ped. Endocrinol. Rev. 2018;16(Suppl1):80-90
Growth Hormone Treatment for Prader-Willi Syndrome
Maïthé Tauber, MD, Gwenaelle Diene, MD, Catherine Molinas, CRA
The European Marketing Authorization for recombinant human growth hormone (rhGH) in children with Prader-Willi syndrome was the first indication for metabolic and body composition effects in children. In the US it is indicated for short stature associated with PWS. Recombinant hGH is the first treatment for the PWS population and radically changed the care of these children by facilitating access to physicians who prescribe rhGH, mainly paediatric endocrinologists, and manage the organization of multidisciplinary care. Recombinant hGH treatment improved linear growth, body composition, and socialization not only in children but also in young adults. The pathophysiology of combined hormonal deficiencies including GH is starting to be unravelled. We now have to focus on co-morbidities that are not modified by rhGH treatment, such as feeding disorders and behaviour problems, to truly change the life of patients. The transition of care from adolescents to young adults also remains a challenge.
Ref: Ped. Endocrinol. Rev. 2018;16(Suppl1):91-99
Growth Hormone Treatment for Patients with Noonan Syndrome
Ximena Gaete, MD, Fernando Rodríguez, PhD, Fernando Cassorla, MD
Noonan syndrome (NS) is a genetic disorder, which can present clinically with a variable phenotype. Proportional post natal short stature is a common manifestation of NS, with the majority of affected patients having an adult height below the third percentile. Some investigators have reported minor abnormalities in GH secretion and/or action, suggesting that recombinant growth hormone (rhGH) therapy may be useful for the treatment of their short stature. Our review of the literature regarding rhGH therapy in children with NS indicates that this therapy improves height velocity, but relatively few controlled clinical trials reporting adult height are available. rhGH treatment does not appear to be associated with adverse effects in these patients, but data on the possible development of malignancy during treatment are somewhat limited. Therefore, we believe that there is a need for large controlled clinical trials in patients with this condition, in order to accurately assess the effects of rhGH therapy over adult height.
Ref: Ped. Endocrinol. Rev. 2018;16(Suppl1):100-104
Growth Hormone Treatment for Short Children Born Small for Gestational Age
Adriane de Andre Cardoso-Demartini, MD, PhD, Alexsandra C. Malaquias, MD, PhD, Margaret Cristina da Silva Boguszewski, MD, PhD
Despite the difficulty to define born small for gestational age (SGA), being SGA has been associated with a higher risk of short stature, early-onset and rapid progression of puberty, neurocognitive dysfunctions, alterations in body composition, bone density, glucose and lipid metabolism and increased risk for cardiovascular diseases later in life. The majority of children born SGA experience spontaneous catch-up growth during the first years of life. For those who remain with short stature, treatment with recombinant human growth hormone (rhGH) may be initiated, preferably after 2-4 years of age. Response to treatment is variable. However, the benefits of rhGH go beyond increase in stature as the therapy may also improve body composition. In this review we will cover the indication and effects of GH therapy in short children born SGA.
Ref: Ped. Endocrinol. Rev. 2018;16(Suppl1):105-112
Growth Hormone Treatment for Idiopathic Short Stature
Wayne S. Cutfield, BHB, MB, ChB, MD, Benjamin B. Albert, BHB, MB ChB, PhD
ISS is the commonest cause of short stature and poor growth and is arbitrarily defined as a height < -2 SDS without an identified cause. ISS consists largely of normal children with the remainder unrecognised conditions, mainly syndromes and genetic (monogenic and polygenic) causes. Growth response to rhGH is widely variable reflecting the heterogeneity of ISS. Further identification of genetic causes of ISS will better characterise treatment response.
rhGH during childhood has been shown in RCTs to improve adult height by approximately 4 cm which is less than seen in other treated growth disorders. Factors that influence response include; younger age, longer birth length, lower height compared to mid-parental height, delayed bone age and larger rhGH dose.
The evidence that short stature is associated with psychological well-being and quality of life is minimal and that rhGH could improve this is scant. Further research in this area is urgently required.
Ref: Ped. Endocrinol. Rev. 2018;16(Suppl1):113-122
Growth Hormone Treatment for Achondroplasia
Tohru Yorifuji, MD, PhD, Shinji Higuchi, MD, Rie Kawakita, MD
Achondroplasia (ACH) is the most common form of skeletal dysplasia causing rhizomelic, short-limb short stature. Short- and long-term clinical trials have been conducted with rhGH, with similar results across these studies. At supraphysiological dose of GH, height gain of 1-1.5 SDS on the population curve was observed during the first 1-3 years, which was then followed by a smaller increase in growth rate persisting for 5-6 years. These studies led to the approval of rhGH for ACH in Japan where rhGH has been used for 20 years at 0.05 mg/kg/day. Although the available data are still limited, compared to untreated controls, total gain in adult height has been greater in males than in females, reported at 3.5-8.0 cm and 2.8-4.2 cm, respectively. Serious adverse events have been rare although some were potentially life-threatening and need careful monitoring. These results should serve as a comparator for novel emerging treatments for ACH.
Ref: Ped. Endocrinol. Rev. 2018;16(Suppl1):123-128
Psychosocial Aspects of Short Stature and rhGH Treatment: Implicit Trends over 60+ Years
Melissa Gardner, MA, Teresa Scerbak, BS, David E. Sandberg, PhD
Between 1958 and today, advances in research and the clinical management of short stature with GH have occurred. Initially, limited supply of pituitary-derived hGH led to strict criteria for diagnosing GH deficiency and tightly controlled treatment protocols. With the advent of biosynthetic GH, the supply has increased, the number of indications for treatment has grown, and the focus of intervention changed from hormone replacement to treatment of short stature. Improved psychosocial adaptation is an underlying, albeit largely unspoken and inadequately researched, target of treatment. Complicating the ability to make a definitive statement on the effects of rhGH on psychosocial adaptation is the rigor of the psychological outcomes literature. A high risk of bias present in the majority of rhGH treatment studies on psychological outcomes substantially weakens confidence in their results. Studies that convincingly demonstrate, through rigorous research design and methodology, that the benefits of rhGH exceed the risks and burdens are needed.
Ref: Ped. Endocrinol. Rev. 2018;16(Suppl1):129-141
rhGH Abuse for Sports Performance
Alan D. Rogol, MD, PhD
Doping is at least as old as the ancient Olympics. Substances taken to improve athletic performance ranged from stimulants to hallucinogenic plant substances, but more recently include anabolic agents. Recombinant human growth hormone, rhGH, is one agent with a relatively short history of use, but few data to unequivocally show that it actually improves performance.
However, rhGH has therapeutic use for those GH deficient and the concept of a therapeutic use exemption for those with documented deficiency is outlined along with doping control methods.
The athlete’s biological passport, a document with all of the analytical data from an athlete, helps in doping control because any one individual will vary for any analyte over a more narrow range than that for a “normal” control population.
Ref: Ped. Endocrinol. Rev. 2018;16(Suppl1):142-149
Monitoring rhGH Safety: rhGH Registries, SAGhE and Future Needs
Bradley S. Miller, MD, PhD, Ron G. Rosenfeld, MD
The safety of growth hormone (GH) therapy in children has been studied extensively. The identification of Creutzfeldt-Jacob disease in individuals who received pituitary-derived GH led to heightened surveillance for safety issues related to recombinant human GH (rhGH). An excellent safety profile of rhGH has been demonstrated in large Phase IV registries comprising > 600,000 patient-years of rhGH exposure and long-term safety cohorts of adults treated with GH as children. Increased mortality risk has been reported but eliminated when corrected for small size at birth. Increased risk of mortality from cerebrovascular disease has been reported but interpretation of these events remains difficult due to the lack of appropriate control groups and a lack of replication of these findings in other studies. The advent of new long-acting growth hormone (LAGH) products provides an opportunity for the development of cohorts of individuals receiving LAGH replacement therapy for continued long-term safety studies.
Ref: Ped. Endocrinol. Rev. 2018;16(Suppl1):150-161
Long-Acting Growth Hormone Preparations in the Treatment of Children
Rayhan A Lal, MD, Andrew R. Hoffman, MD
Human growth hormone (hGH), which had been in use since 1958, was supplanted by recombinant human growth hormone (rhGH) in 1985 for those with growth hormone deficiency (GHD). Adherence to daily subcutaneous growth hormone is challenging for patients. Thus, several companies have pursued the creation of long acting rhGH. These agents can be divided broadly into depot formulations, PEGylated formulations, pro-drug formulations, non-covalent albumin binding GH and GH fusion proteins. Nutropin Depot is the only long acting rhGH ever approved by the U.S. Food and Drug Administration, and it was removed from the market in 2004. Of the approximately seventeen candidate drugs, only a handful remain under active clinical investigation or are commercially available.
Ref: Ped. Endocrinol. Rev. 2018;16(Suppl1):162-167