Growth hormone is a well-established treatment for a variety of growth disorders including poor growth due to growth hormone deficiency, Turner syndrome, short stature in children born small for gestational age, Prader-Willi syndrome, and chronic renal insufficiency (Fisher and Acerini, 2013). In childhood and adolescence, the aim of growth hormone therapy is to increase height velocity to enable patients to reach a final adult height within their genetically predicted range. Growth hormone is also licensed for use in adults with growth hormone deficiency, a condition associated with reduced quality of life and energy levels, altered body composition, and reduced bone mineral density, among others (National Institute for Health and Care Excellence (NICE), 2003; 2010). Growth hormone treatment therefore often involves regular growth hormone injections for a number of years and, in some cases, for life.
Patient adherence to long-term growth hormone therapy (somatropin) is essential for treatment success. However, this presents a challenge at each stage of the patient treatment journey, from early childhood all the way to adulthood. A retrospective observational study that collected data from primary care physicians on 75 children, found that 23% missed more than two growth hormone injections each week, and most patients missed some injections (Kapoor et al, 2008). Height velocity in those who missed more than two injections a week was significantly reduced (41% lower than in highly adherent patients). Similarly, a New Zealand study involving 177 children found that poor adherence to growth hormone therapy is common (66% of patients missed more than one injection per week) and significantly impairs linear growth (Cutfield et al, 2011).
Both studies were retrospective, with Kapoor et al (2008) obtaining an estimate of adherence based on prescription data, while Cutfield et al (2011) relied on the number of returned empty growth hormone vials. Although these studies sought to estimate adherence objectively, as the measures used were indirect, it is likely that the level of adherence was overestimated (Kapoor et al, 2008; Cutfield et al, 2011). Despite these limitations, the evidence linking poor adherence to suboptimal growth is compelling.
A systematic review of the literature by Fisher and Acerini (2013) concluded that adherence to paediatric growth hormone therapy is indeed suboptimal, but the causes are complex and require multifactorial interventions (Fisher and Acerini, 2013).
In medical therapy, ‘compliance’ usually refers to the willingness and ability of patients to follow instructions from their physician, with the implication that they are passively following doctors’ orders (Osterberg and Blaschke, 2005). Today, the term ‘adherence’ is preferred, as it focuses on a treatment plan developed through a ‘therapeutic alliance or contract between patient and physician’ (Osterberg and Blaschke, 2005). These, terms, as well as others such as ‘persistence’ and ‘concordance’, are often used interchangeably in the literature, despite the fact that they provide different interpretations of the patient/health professional relationship (Vrijens et al, 2012). In this article, the term ‘adherence’ is used to refer to a patient's uptake of medical advice. With respect to informed consent, the Montgomery vs Lanarkshire Health Board (2015) ruling brought to the fore the patient's right to be given all the information they request and require in order to make their own decisions about the treatment they wish to receive. The case also gave recognition to the more active and informed role of patients in treatment decisions (Chan et al, 2017).
The challenge facing nurses working in endocrinology departments to improve adherence with growth hormone treatment has been apparent for some time. An advisory board of senior endocrine nurses (the authors of this article) was convened to help address this challenge.
Why does adherence matter?
Treatment adherence is a key factor influencing the outcomes of long-term growth hormone treatment. Suboptimal adherence has a substantial negative impact on patients (such as poorer health outcomes), the healthcare system (for example unnecessary changes of the drug dose or treatment course), and society (Fisher and Acerini, 2013), and has economic implications if the patient's health deteriorates (NICE, 2009).
In children with growth hormone deficiency, the consequences of suboptimal adherence are relatively easy to identify because under-treatment is likely to result in decreased growth velocity (Fisher and Acerini, 2013). In addition to the clinical implications, there is a potential for wasted resources, and even withdrawal of treatment in the UK as, in childhood treatment, there needs to be a growth velocity above 50% of baseline in the first year of treatment, and then over 2 cm a year until the end of growth, to maintain funding from the patient's clinical commissioning group (NICE, 2010).
As patients approach adolescence (often described as the transition phase), they usually want to develop greater independence both from their families and their endocrinology team. The goal of this phase is to ensure that healthcare is uninterrupted, co-ordinated, and developmentally appropriate before, during and after adolescents transfer to the adult healthcare system (Kaufman and Pinzon, 2007). However, the transition process can be challenging. This is a time when self-injection of growth hormone can help patients feel more in control of their condition, but it can also be more difficult to monitor missed doses, resulting in suboptimal adherence.
There is also a significant risk that patients transitioning from the care of paediatric services into adult services may be caught in a ‘no man's land’ where it is unclear who is responsible for their progress. If these issues are not promptly addressed, some patients may become lost to follow-up for extended periods of time. A seamless transition service is therefore essential.
The consequences of suboptimal adherence in adult patients are not as easy to measure as they are for children. With children, we can point to the increased growth velocity as an obvious benefit of treatment, but for adult patients, the advantages of growth hormone are often more wide-ranging and easy to miss in the short term. This is why adult patients with growth hormone deficiency need to be educated about the long-term benefits of therapy and the consequences of suboptimal adherence.
These physical risks include alterations in body composition (such as truncal obesity), bone metabolism and density, as well as impaired cardiac structure and function during adult life (de Boer et al, 1995; Underwood et al, 2003; van der Klaauw et al, 2006). Evidence suggests that adults with growth hormone deficiency have a significant reduction in bone mineral density at both distal and proximal sites, and a decrease in bone G1a-protein and procollagen III levels compared with healthy controls (Amato et al, 1993). Other studies have documented an increased prevalence of osteopaenia in adult patients, making them vulnerable to sustaining fractures (de Boer et al, 1995; Doga et al, 2005).
It is also suggested that cardiac function could be compromised; clinical studies have found short- and long-term effects on cardiac function in the absence of long-term growth hormone treatment. A reduction in left ventricular mass index and left ventricular systolic function with decreased fractional shortening have been reported (Amato et al, 1993). Reduced exercise capacity, low heart rate, and dilated cardiomyopathy have also been observed (Isgaard, 2004). Gazzaruso et al (2014) found that, in untreated growth hormone deficiency, cardiovascular risk is increased, owing to abnormal lipid profile and impaired glucose metabolism. They also reported that patients with growth hormone deficiency had elevated levels of cardiovascular risk biomarkers.
Adult patients are also at risk of psychological symptoms that vary for each individual, but common themes include tiredness, disturbed sleep, lack of motivation, low confidence and self-esteem, and reduced social interaction (Brod et al, 2014).
Factors that affect adherence to long-term growth hormone treatment
A number of factors that influence treatment adherence have been identified. These can be categorised as: external factors (for example cost, injection training, and duration of treatment); patient-related factors (such as the degree of involvement in decisions, perceived seriousness of the condition, and level of understanding of the treatment and its benefits) (Rosenfeld and Bakker, 2008) and lifestyle and family-related factors (eg, children regularly moving between separate households).
The factors affecting adherence in each population differ. In paediatric patients, adherence may be affected by medication issues (such as inadequate supply and side effects), scheduling issues (social convenience), as well as cognitive issues (such as forgetfulness and lack of understanding of instructions). During adolescence, adherence may also be affected by additional factors such as denial, peer pressure, and reluctance to seek medical advice (Fisher and Acerini, 2013). Understanding these factors and the extent to which they influence adherence may suggest ways in which patient adherence to growth hormone treatment could be improved, for example by running local pilot studies on young people's knowledge on suboptimal adherence, promoting resources (printed materials, websites, and/or forums) and highlighting the benefits of growth hormone, as well as encouraging self-management.
Literature on the factors that affect growth hormone treatment adherence in adults is limited. However, evidence suggests that adults who become growth hormone-deficient as a result of radiotherapy (late effects) or who have had brain surgery can suffer from cognitive deficits and fine motor functioning/manual dexterity issues (Anderson et al, 2001; Ellenberg et al, 2009), which can have a profound effect on their ability to maintain optimal adherence to therapy. It is possible that adult patients experiencing ‘survivorship’ issues (late effects, which manifest as depression and lack of self-motivation) are less likely to adhere to growth hormone treatment. Adult patients are very complex and no single pathway of care will suit every patient. Optimal adherence in adult patients should be achieved through individualised care packages. The additional complexity of multiple hormone deficiencies also needs to be acknowledged, as, very often, patients may have suboptimal adherence to other therapies, not just growth hormone treatment.
The importance of recognising patients as active and informed decision-makers
Enabling patients (or their caregivers, in the case of very young patients) to be active and informed decision-makers in their care has become an important area of interest. Patients have the primary responsibility for managing their health in the context of their wider lives, and this needs to be supported by the way health professionals interact with them. Thus, health professionals play an important role in this process, as they need to create an environment in which patients feel able to participate in and contribute to treatment decisions if they so wish (NICE, 2012).
The deliberative collaboration between clinicians and patients is often called shared decision-making. In this patient-centred, dialogue-driven approach, health professionals empower patients with knowledge about the benefits, adverse reactions and burden of different treatment options, while patients indicate the aspects of treatment that matter to them, as well as their preferred treatment options (Rodriguez-Gutierrez et al, 2016). In this respect, the objective of shared decision-making is not to empower patients to dictate all the aspects of their care, but to facilitate their active participation in growth hormone treatment and enable patients to make informed choices about their healthcare (Acerini et al, 2018). Appropriately personalised shared decision-making (specific to the growth hormone disorder being treated) can support suitable education on a patient's diagnosis, and equip and encourage patients (as well as their families and carers) to better understand and discuss their condition. Subsequently, shared decision-making can help increase patients’ awareness of the benefits of growth hormone treatment, the importance of regular growth hormone dosing, and the consequences of missed injections. Increased knowledge and active participation in decision-making can provide patients with the empowerment necessary for an increased sense of ownership and satisfaction with their treatment that may lead to optimised treatment adherence and better health outcomes—an observation that is supported by a growing body of evidence (Acerini et al, 2018).
Clinicians ought to keep in mind that children's and adolescents’ active participation in treatment decision-making will likely increase as they get older, while that of their parents will play a less prominent role. Thus, it is important for the shared decision-making process to be reviewed and revised, as required, in order for it to remain relevant to the patients’ preferences and treatment goals (Acerini et al, 2018). The development of training sessions and workshops may be necessary in order to ensure that health professionals are prepared with the appropriate skills to implement shared decision-making, and, in turn, ensure its long-term success. For many patients, an open and in-depth discussion with their health professionals about their disease and treatment may initially be difficult; thus, workshops can help train health professionals in approaches to gradually implement shared decision-making into their clinic (Acerini et al, 2018).
How to optimise adherence
During the first advisory board meeting, the advisers worked on identifying and sharing practices that, in their experience, helped optimise adherence with growth hormone treatment. It became clear that the various tools and strategies that the advisers found effective often needed to be adapted and tailored to take account of the needs of patients at different stages of their growth hormone treatment journey. Thus, what works well during a patient's childhood is not necessarily as effective during their adolescence or adulthood (Table 1). It is important to note, however, that support strategies used at different stages are not mutually exclusive, but build on each other from one stage to the next.
| Childhood | Adolescence | Adulthood | |
|---|---|---|---|
| More frequent clinic appointments | ✓ | ✓ | – |
| Home visits | ✓ | ✓ | ✓ |
| Telephone consultations | – | ✓ | ✓ |
| Family doctor involvement | ✓ | ✓ | ✓ |
| Home-care nurses | ✓ | ✓ | ✓ |
| Regular device training sessions | ✓ | ✓ | – |
| Text alerts | – | ✓ | ✓ |
| Smartphone apps | ✓ | ✓ | ✓ |
This tailored support can be refined further in order to address individual needs, for example:
Essential components in the delivery of tailored support include:
The advisers suggested many different strategies and initiatives to help improve patient adherence according to development stage (see Table 2). For children, these include education (of both the patient and carers), a simple reward system, gamification technologies (Radovick et al, 2018), and patient empowerment where possible. For adolescents, further empowerment, and optimal use of transition services, are of particular importance. For adults, there is a focus on regular follow-up (including text or email reminders) and reinforcement of the quality-of-life benefits of growth hormone therapy. It is important for health professionals to ensure that the content and language used for each strategy is appropriate for the age and/or mental capacity of each individual patient. Not all strategies will be suitable for each individual centre and patient, but the four options set out in Box 1 offer guidance for most clinical scenarios. Key strategies to prevent or reverse suboptimal adherence are centred on choice, information, teamwork, and support. The advisers agreed that these recommendations should be implemented following a review of existing services in order to assess how effectively these meet individual patient needs. Endocrine centres have distinct ways of operating that are suited to the size of the patient population that they serve. For example, group support meetings for new starters may be suitable for small centres, but impractical to facilitate in larger centres. Thus, these recommendations ought to be implemented in ways that are appropriate for each centre.
| Childhood | Adolescence | Adulthood |
|---|---|---|
| Educate and support patients’ and families from the outset, providing simple, clear information | Make adolescent patients feel in control of their treatment, making their own decisions | Aim for regular follow-up with adult patients |
| Encourage perseverance by showing patients their progress, and compare with outcomes of suboptimal adherence | Anticipate and prepare for adherence issues before patients reach this stage | Focus on quality-of-life benefits of growth hormone therapy, to ensure patients are aware of the additional role of growth hormone |
| Offer a choice of devices if possible | Adapt advice on devices to the patient's lifestyle | Tailor support to work with patients’ underlying comorbidities |
| Use simple rewards for children such as stickers, inexpensive toys or books | Revisit adolescent patients’ education about their treatment | Offer close support in the initial titration months and manage expectations |
| Make the growth hormone injection part of the child's daily routine | Explore each patient's attitude to growth hormone therapy and to the wider issues they face | Consider text or email reminders for patients |
| Make use of home-care services if available | Help patients fit their growth hormone treatment more easily into their lives | Make use of home-care services if available |
| Provide reassurance and support for patients with needle phobia | Make use of Transition or Young Adult clinics | |
| Use age-appropriate educational materials such as story books, comics and growth hormone-specific apps | Ensure good follow-up for patients on transfer from paediatric to adult services | |
| Aim for continuity of support from childhood to adulthood | Adapt support offered to the changing needs of patients |
| Choice | It is good practice to provide patients and their families with a choice of how their growth hormone therapy will be monitored. For example, by offering more frequent clinic visits, suggesting telephone consultations for those living far from their centres or with busy lifestyles, or arranging home visits with patients causing particular concern |
| Information | Good-quality, accessible information about their treatment and progress should also be available. This can include simple charts or graphics, showing growth tracked over time, so they can see the effects of their treatment |
| Teamwork | A team-based, multidisciplinary approach to delivering endocrine nursing services should be the goal for all centres, to ensure consistent and seamless care, and to reduce the risk of patients ‘falling through the net’ |
| Support | Ensuring there is adequate support at the transition stage between adolescence and adulthood is especially important given the potential vulnerability of these patients. Support can include self-injection education, and advice for school trips and for moving from junior to senior school and onward to further education. ‘Buddy’ systems and other patient support group initiatives can be useful, as well as local or national support groups |
The importance of measuring and monitoring adherence
It is usually more straightforward to monitor adherence in children than in older patients, because their height can be regularly measured, so, if there is an unexplained decrease in growth, then adherence issues may be considered. In adults, measuring adherence is more difficult to assess, as the effects are more subtle and non-specific than those observed in children (Auer et al, 2016). Insulin-like growth factor 1 (IGF-I) is commonly used as a biomarker. However, IGF-I status in adults is complex and does not depend solely on growth hormone status—in fact, there is considerable overlap in IGF-I levels between adults with normal growth hormone status and those with growth hormone deficiency (Mukherjee and Shalet, 2009). Using IGF-I alone as a marker for suboptimal adherence is therefore not advisable. Regular clinic visits are also important, and missed appointments, especially when they happen often, can be a warning sign that adherence may be an issue.
It is often possible to identify patients who struggle with adherence from very early on in the treatment process, and extra effort should be made with these families from the outset. Using a home-care team can help develop good working relationships with patients and carers, and motivate them to take the patients’ growth hormone treatment seriously. Another option is to contact a patient's pharmacy to see if the growth hormone prescriptions are being collected.
When patients reach adolescence, growth and puberty status should be monitored every 6 months. Every effort should be made to prevent patients being lost to follow-up at this important phase of their development. A team approach is particularly important for monitoring patients through transition into adulthood.
Suggested further reading on the role of nurses working in this area is given in Box 2.
Summary
A key step toward improving patient adherence with growth hormone therapy is to review existing endocrine services and adapt or change these in line with the suggested recommendations in order to meet individual patient needs. The mapping of the adherence journey the authors have undertaken showed them that this is an issue relevant to every stage from childhood through the transition to adolescence, and into adulthood. Endocrine nursing services should be designed with patients and carers at the forefront, ensuring they receive up-to-date information on devices, as well as good-quality education and support. Patient autonomy should always be encouraged where possible, beyond a patient's choice in terms of devices and self-injection. Identifying best practices and sharing them with the wider nursing community will help raise standards of care, and ultimately help patients achieve their treatment goals.