Adult growth hormone deficiency: clinical advances and approaches to improve adherence

ABSTRACT

Introduction: There have been significant clinical advances in the understanding of the diagnosis and benefits of long-term recombinant human growth hormone (rhGH) replacement in adults with GH deficiency (GHD) since its approval in 1996 by the United States Food and Drug Administration.

Areas covered: We searched PubMed, Medline, CINAHL, EMBASE and PsychInfo databases between January 2000 and June 2019 for published studies evaluating adults with GHD. We reviewed the data of the oral macimorelin test compared to the GHRH plus arginine and the insulin tolerance tests that led to its approval by the United States FDA and European Medicines Agency for adult diagnostic testing. We summarize the clinical advances of long-term benefits of rhGH therapy and the potential effects of GH receptor polymorphisms on individual treatment responsiveness. We identify that non-adherence and discontinuation rates are high and recommend strategies to support patients to improve adherence. We also provide an overview of several long-acting GH (LAGH) preparations currently under development and their potential role in improving treatment adherence.

Expert opinion: This article summarizes recent clinical advances in rhGH replacement therapy, the biological and molecular aspects that may influence rhGH action, and offers practical strategies to enhance adherence in adults with GHD.

KEYWORDS:

• Growth hormone
• adult growth hormone deficiency
• advances
• adherence
• long-acting growth hormone

Article highlights

• Since adult growth hormone deficiency (GHD) has been characterized as a clinical entity, the effects of recombinant human GH (rhGH) replacement therapy have been extensively evaluated. Improvements in most, but not all, metabolic and psychological abnormalities associated with this condition have been demonstrated. Recent long-term studies have suggested that most of the beneficial effects of rhGH therapy are sustainable long-term, but not without some drawbacks.

• Diagnosis of adult GHD often requires performing GH stimulation testing. The utilization of the newly approved oral macimorelin test in the United States and Europe will likely increase over time because the test is simple to perform, highly reproducible, well-tolerated and safe. The lower GH cut-point of 2.8 μg/L was selected by the United States Food and Drug Administration as the cut-point; however, the GH cut-point up to 5.1 μg/L may also be considered because it increases the sensitivity of the test while maintaining its specificity to the GH cut-point of 2.8 μg/L.

• Age of the patient is an important determinant for rhGH dose initiation, and maintenance with lower doses is emphasized for older patients.

• Treatment with rhGH therapy has been shown to improve health-related quality of life (QoL) in most adults with GHD, and those with worse baseline QoL generally responded better than those with relatively normal baseline QoL.

• Due to the presence of GH and IGF-I receptors throughout the body, the effects of rhGH therapy on skin, sleep, and coagulation system in adults have been investigated in greater detail in recent years. Decreased sweating and skin sebum content causing dry skin and early skin aging, decreased REM sleep, increased slow-wave sleep which may contribute to impaired memory functions, and impaired coagulation and fibrinolysis have been reported in adults with GHD, and rhGH replacement therapy has been shown to reverse some of the abnormal parameters affecting the skin, sleep pattern, and coagulation system.

• Previous studies have consistently shown that treatment with rhGH may worsen insulin resistance, but recent large observational studies have demonstrated conflicting data. Some studies have suggested that the incidence rate of diabetes mellitus (DM) was persistently increased, while others have shown no increase in the frequency of DM with long-term rhGH therapy. Close monitoring of glucose parameters remains essential during rhGH treatment especially in ‘at risk’ patients (e.g. patients with obesity or glucose intolerance).

• Previous data on cancer risk with long-term rhGH replacement therapy has been inconsistent, with some studies suggesting an increased risk and others demonstrating a neutral effect, or even decreased risk. Therefore, definitive conclusions regarding the risk of cancer induction with rhGH therapy cannot be drawn, but existing data suggest that long-term rhGH therapy is safe.

• Increased mortality has been reported in previous epidemiological studies in patients with hypopituitarism, with GHD being implicated as one of the contributing factors. Some of the recently published large observational studies have shown that rhGH therapy increased mortality rates, whereas others have demonstrated that the overall mortality in the treated patients compared with the general population was significantly reduced. Because of the heterogeneity of patients and selection bias of some results cannot be excluded, firm conclusions at this point cannot be drawn on the effects of long-term rhGH therapy on mortality rates in adults with GHD.

• Previous systematic reviews and meta-analysis in adults with GHD have shown that d3-GHR isoform may exert a weak influence on therapeutic response to rhGH, but data are heterogeneous and inconsistent likely because most studies involved small numbers and were not designed to address the question of GHR genotype–genotype relationships.

• Studies suggest that adults with GHD report low persistence with rhGH therapy and high discontinuation rates, which are mainly associated poor understanding and perceived benefit of treatment. Although many factors can impact adherence to rhGH treatment, non-adherence can be minimized through shared decision-making and a personalized treatment plan at rhGH initiation.

• Long-acting GH preparations represent an advancement over daily rhGH injections because of fewer injections that may offer increased acceptance, tolerability, and therapeutic flexibility to patients that potentially can improve treatment outcomes. However, given the non-physiological profile of LAGH preparations, long-term surveillance are needed to assess for efficacy and safety that will be essential for understanding the impact of prolonged exposure to these compounds.

Declaration of interest

Kevin Yuen has received research grants to Barrow Neurological Institute from Pfizer, Novartis, Aeterna Zentaris, Millendo, Ionis, Corcept, and Crinetics, and has served on advisory boards for Pfizer, Novo Nordisk, Aeterna Zentaris, and Corcept. Sofia Llahana has received unrestricted educational grants and consultation fees from Pfizer, Sandoz, and Bayer. BSM is a consultant for Abbvie, Ascendis, BioMarin, Bluebird Bio, Novo Nordisk, Pfizer, Sandoz, Sanofi Genzyme, and Tolmar and has received research support from Alexion, Abbvie, Amgen, Ascendis, BioMarin, Novo Nordisk, OPKO, Protalix, Sandoz, Sangamo, Sanofi Genzyme, Tolmar and Takeda. Bradley S. Miller. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.