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New approaches to the management of growth hormone disorders

New approaches to the management of growth hormone disorders
  • Endocrinology and metabolism

Resource type

Publication

Improving the management of growth-hormone disorders

Paediatric and adult endocrinologists, and specialist researchers, attended this symposium on new approaches to the management of growth-hormone disorders. The symposium was developed jointly by TOPEC (Omnia-Prova Education Collaborative) and EXCEMED.

Attendees had ample opportunity to exchange views and discuss critical issues with experts in the field. In particular, attendees considered how to put into practice strategies for integrating change.

Lectures covered molecular regulators of growth, clinical implications of the growth and metabolism interface, and treatment with growth hormones. In addition, a panel discussion considered the safety of growth hormones and attendees were able to discuss clinical cases. The focus of this educational activity was to increase knowledge of both diagnostic and management issues for patients with growth disorders, potential problems associated with adherence, safety of treatments and emerging therapies.

This newsletter highlights important subjects that were discussed at this symposium, the learning objectives of which were to:

  • Enhance diagnostic and therapeutic approaches with the use of approved guidelines
  • Manage growth hormone therapy in different conditions and comorbidities
  • Use specific tools for achieving better treatment adherence
  • Improve the use of growth hormone therapy in the light of pharmacogenomics evidence and the long-term effects of such treatments

 

Importance of growth hormone disorders

Disorders involving growth and growth hormone are common world-wide problems that affect patients throughout their life. These disorders potentially lead to short stature and metabolic abnormalities.

In particular diagnosis and management present substantial challenges for healthcare professionals who manage patients with these disorders.

The treatment of children with growth retardation in puberty may also present challenges for healthcare professionals. It is important that doctors and associated healthcare professionals keep up-to-date with the latest developments and guidelines, to ensure that patients receive the best possible care. 

 

Molecular basis of growth failure

Professor Ron G Rosenfeld, MD (Oregon Health & Science University, President, STAT5, LLC, Portland, OR, USA) discussed the expanding network of molecular regulators of growth

Sophisticated genetic investigations have recently increased our knowledge concerning the molecular basis of mammalian growth.

Professor Rosenfeld emphasised that growth in humans is a natural but extremely complex event.

Our knowledge of the many cellular pathways involved in growth regulation has been greatly enhanced by advances in genetic analysis. Hundreds of genes have been found to contribute to either tall or short stature.

Genetic investigations have been performed using numerous techniques including genome-wide studies, candidate gene studies, copy number variation analysis and whole exome sequencing.

New growth defects are been identified that were not originally explainable by classical growth hormone deficiency. New discoveries contributed to the explanation of the variability observed in growth hormone insensitivity (Table 1). This has been possible thanks to research adopting a candidate gene approach.

The candidate gene approach evaluates genes that have been shown to be relevant to the patient’s phenotype. Subsequently, functional studies (which demonstrate the relevance of such mutations and illustrate familial tendencies) are essential to prove a correlation between the phenotype and genotype in the patient and then in the wider family.

Table 1: Molecular basis for variability in growth-hormone insufficiency (GHI)

table 1

However, the candidate gene approach has the following limitations:

  • Only ‘known’ genes are investigated
  • Sequencing may be limited to exons
  • In the absence of family genotype:phenotype correlations, molecular abnormality can be problematic to interpret
  • Data are difficult to interpret in absence of well-conducted functional studies

 

Professor Rosenfeld summarised recent data on molecular defects affecting the growth hormone insulin-like growth factor I (IGF-1) signaling. He described a methodological approach for investigating potential genetic defects in children with growth disorders.

It is essential that doctors should be familiar with the advanced genetic tests including array-CGH (microarray-based comparative genomic hybridization), and both exome and whole genome sequencing.

 

Therapeutic strategies for growth disorders

Dr Nelly Mauras MD (Endocrinology, Diabetes & Metabolism, Nemours Children’s Clinic, Jacksonville, F), USA) reviewed new insights into growth during puberty and potential treatment strategies 

Aromatase inhibitors are potential therapies for treating pubertal males with growth disorders.

Dr Mauras reminded the delegates that significant challenges exist for the optimisation of treatments for children with growth retardation in puberty.

Puberty plays a key role in the physiological achievement of adult height; height deficits are often not corrected by treatment with growth-promoting agents alone, since sex hormones may significantly limit growth potential.

According to some studies, in children treated with growth hormone for growth hormone deficiency, small for gestational age or short stature homeobox-containing gene deficiency, addition of a gonadotropin-releasing hormone (GnRH) analogue showed a substantial height gain (5–10 cm). Such patients, indeed, may potentially benefit from delaying bone maturation and retarding puberty onset.

Aromatase inhibitors

Estrogen blockers, such as aromatase inhibitors (e.g. anastrozole, letrozole and exemestane), have been evaluated in clinical trials as potential therapeutic agents to delay epiphyseal fusion, as either monotherapy or combined with testosterone or growth hormone.

Results indicate that predicted height increases versus placebo and the safety profile is excellent with these agents. However, data on adult height are still missing.

Studies are ongoing to assess aromatase inhibitors either alone (anastrozole or letrozole) or in combination with growth hormone in adolescent boys with idiopathic short stature.

Preliminary data showed that combination treatment appeared to give more anabolic enhancing fat-free mass (FFM) accrual versus either therapy alone. Conversely, data about height gain are largely expected. Dr Mauras commented that there is a need for similar trials in adult patients.

However, aromatase inhibitors are not currently approved by the FDA in children and further studies are needed to address this issue.

 

Human growth hormone – multiple functions

Professor Jens S Christiansen MD (Aarhus University Hospital, Denmark) highlighted the clinical implications of the growth and metabolism interphase 

Recombinant human growth hormone therapy is effective in improving all of the signs and symptoms associated with growth hormone deficiency.

Professor Christiansen reminded delegates that growth hormone has numerous actions in humans, in addition to stimulating growth.

Many body functions and physiological processes are affected by the action of growth hormones, including muscle strength, exercise capacity, bone metabolism, cortisol metabolism, thyroid hormone, cardiac output, total body water and muscle:fat ratio. This is due to the growth hormone receptor being found on virtually all tissues in the body.

Growth hormone deficiency

The clinical consequences of growth hormone deficiency in adults include higher fat mass and lower muscle mass, reduced energy expenditure, reduced lipid oxidation, insulin resistance, dyslipidaemia, higher risk for cardiovascular diseases and osteoporosis, chronic fatigue syndrome, and poor health-related quality-of-life (HRQoL). (Figure 1)

Figure 1: Consequences of growth-hormone deficiency in adults

fig 1

Growth hormone replacement therapy normalises these physiological parameters. In particular, such treatment has a substantial effect on improving HRQoL and well-being.

Growth hormone secretion in normal humans

In normal human subjects, the rate of growth-hormone secretion is markedly stimulated by a number of events, including:

  • Hypoglycemia
  • Intracellular deprivation of glucose as a result of deoxyglucose administration
  • During a rapid fall in the concentration of blood sugar (even in the absence of hypoglycemia)
  • Prolonged fasting
  • Muscular exercise

 

Professor Christiansen explained that growth-hormone secretion also decreases with age, with a peak around 20 years. Furthermore, its actions on skeletal growth and muscle-tissue formation occur from birth to ~20–25 years of age, whereas the metabolic effects are evident throughout life.

 

Growth-hormone dose optimisation

Dr Pinchas Cohen MD (USC Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA) reviewed growth-hormone dosing and monitoring in 2015

Individualised treatment should be the goal of every healthcare professional managing patients with growth-hormone disorders.

Dr Cohen pointed out that growth-hormone therapy can be optimised with careful dose selection and IGF-I based dosing.

The individual’s response to growth-hormone therapy is influenced by the degree of both growth hormone and IGF-1 deficiency.

A variety of growth hormone doses are used in different countries due to perceived differences in efficacy (dose response between dose and growth response), safety profiles (theoretical risks with higher doses), and cost (proportional to dose).

Growth hormone dosing optimisation

In order to achieve a good outcome and minimise potential long-term side effects, patients receiving recombinant human growth hormone must be carefully monitored.

There are a number of paradigms for growth hormone optimisation, including:

  • Prediction model-based dosing
  • Auxology-based dose adjustment
  • Genomics-based dose selection
  • Growth phase-based dosing (catch-up, puberty)
  • IGF-I-based dose adjustment
  • Combinations of the above

 

IGF-I-based dose adjustment has a number of advantages over other paradigms, including being easy to apply to clinical practice, helping to identify poor compliance and related issues, protecting from theoretical concerns of high IGF-I levels, and allowing individualisation based on disease state.

In a study of recombinant growth hormone treatment using IGF-I titration, patients receiving the IGF-I-based dose adjustment achieved a higher height velocity, a greater height gain, and a reduced risk for IGF-I levels (over 2 standard variations), compared with the other paradigms tested.

Dr Cohen cautioned that an IGF-1 level of 2 standard variations may not be appropriate for all patients, and 1 standard deviation should be evaluated. Thus the target for growth-hormone deficiency could be lowered, especially in high-risk patients.

Currently, data on adult height in patients receiving IGF-I-based recombinant human growth-hormone are lacking. There remains an urgent need to address this problem.

Some concerns have been raised about mortality risks (mainly from stroke) following growth-hormone treatment in children. However, data relating to such concerns need to be validated and carefully interpreted: subsequent studies did not confirm any increased risk from cardiovascular disease. 

Regulation of humanin by growth hormone

Growth hormone may regulate other molecules such as humanin (the first mitochondrial peptide), which is related to longevity, improves insulin sensitivity, protects from chemotherapy toxicity, prevents atherosclerosis and has anti-Alzheimer’s disease effects.

Growth hormone has been shown to negatively regulate circulating levels of humanin in mice and man, and this may be a useful novel marker. However, further studies are needed. 

 

Long-acting hormone formulations improve compliance

Professor Andrew R Hoffman MD (Department of Medicine, Stanford University, Stanford, CA, USA) described the use of long-acting growth hormone therapy to potentially improve compliance

Compliance – Drugs don’t work in patients who don’t take them [C Everett Koop, MD. Former Surgeon General]

Professor Hoffman explained that numerous long-acting growth-hormone formulations are being developed for treating children and adults with growth-hormone deficiency. He added that other innovative treatments for growth disorders will be evaluated in the near future.

In a number of growth disorders, daily administration of human recombinant growth hormone has proven to be effective when patients show good compliance. However, poor compliance is a major cause of inadequate response (see Call-out box), with the burden of daily injections being the main reason.

There is a need to demonstrate that weekly or monthly formulations are comparable with daily therapies, with respect to safety and efficacy.

Growth hormone formulations to potentially achieve long-lasting effects

A number of formulations including pegylation, hybrid molecules, carrier-linked growth hormones and depot formulations have been evaluated.

The attributes of an ideal long-acting growth hormone formulation are summarised in table 2.

Table 2: Most important attributes of a long-acting growth hormone formulation

fig 2

Although less-frequent administration of a long-acting growth hormone should improve adherence, there are certain unanswered questions:

  • Is intermittent secretion necessary for robust action?
  • Would long-acting growth hormone increase IGF-1 or would tachyphylaxis or down-regulation of growth hormone receptors occur?
  • Would constant levels produce acromegaly or a new set of induced proteins?
  • What injection schedule is needed to improve compliance (weekly, biweekly, monthly)?

 

LB03002 (LG Life Sciences/Biopartners), a depot formulation of growth hormone, was shown to be similarly effective to daily formulations in promoting growth in adults and children, when administered once weekly. 

In contrast, studies with pegylated growth hormones have been discontinued due to safety issues.

Growth-hormone fusion proteins (recombinant proteins that add amino acid head or tails to the growth hormone molecule) are engineered to give increased circulating half-lives, due to the unique properties of the growth hormone-adjuncts.

Another strategy is to link growth hormone to growth hormone-binding protein, however no clinical data are available both for this approach, or indeed for growth hormone fusion proteins.

Professor Hoffman pointed out that the optimal dosing intervals for efficacy or adherence have not been confirmed for these long-acting formulations.

In particular, their long-term safety is unknown. Studies are urgently required to address this need, he added.

Terms of use

This is a copyrighted resource for the sole purpose of education. Resource may be used for classroom training only and must remain as is, including the branding and EXCEMED logo. It is backed by a publishing license, signed by the author.

Workshop
San Diego, United States
Mar 4, 2015
Target audience
Specialists in pediatric, Endocrinologists, researchers
by Excemed
Endocrinology and metabolism