The Effects of Growth Hormone Treatment Discontinuation in Adults on Metabolic Profile, Body Composition and Quality Of Life

1. BACKGROUND

Growth hormone deficiency (GHD) in adults is caused by decreased secretion of growth hormone (GH) from the pituitary gland (1, 2). This condition is usually caused by a tumour, surgery and/or radiotherapy involving the pituitary gland (3). Adults with GHD present with a constellation of several non-specific features including low mood, poor general well-being, reduced bone mineral density (BMD), increased body fat, increased cholesterol level and reduced exercise capacity (3, 4, 5). Treatment with recombinant human growth hormone (GH) injection has been proven, in short-term studies, to improve the wide spectrum of health issues associated with GHD (6).

In the UK, the National Institute for Health and Care Excellence (NICE) recommends treating adult patients with GHD with GH until peak bone and muscle mass have been achieved (estimated to be at around the age of 25 years) (7) . For adults over 25 years old, the prescribing of GH treatment is based on the NICE criteria which requires patients to: a) have severe GHD, defined as peak GH response of less than 9 mU/litre during a GH stimulation test; b) have a perceived impairment of quality of life (QoL), as demonstrated by a score of at least 11 in the 'Quality of Life - Adult Growth Hormone Deficiency Assessment' (QoL-AGHDA) questionnaire; c) be receiving appropriate treatment for any other pituitary hormone deficiencies. The UK population of adult patients with GHD receiving GH is quite unique and homogenous as they all have severe GHD and poor quality of life (QoL) prior to commencing the treatment (4). The UK is the only country in the world that offers GH to adult patients with GHD only after poor QoL scores have been confirmed by using the QoL-AGHDA questionnaire (1, 4, 6).

In the UK, provided that a 7-point improvement (or higher) on the 25-point QoL-AGHDA scale is demonstrated during the first 9 months of GH therapy, adult patients with GHD can continue with their GH treatment long-term (7). However, it remains uncertain if the beneficial effects of GH therapy are sustained throughout adult life, as robust evidence on the risks and benefits of long-term GH treatment is limited. Furthermore, the evidence of improved QoL in adult patients with GHD having GH treatment over placebo has not been established (6). Anecdotally, clinicians report encountering patients who question the merit of continuing with long-term GH treatment. Paradoxically, the same patients are apparently reluctant to stop GH therapy due to fears of return of symptoms and uncertainty about the short-term and long-term effects of treatment discontinuation. Consequently, and in the absence of clear evidence and definitive guidance, replacement therapy with GH continues indefinitely in many adults.

To date, the optimal duration of GH replacement therapy in adults and the consequences of treatment withdrawal have not been established. There are only few, mainly short-term, follow-up studies which, however, provide conflicting results. Overall, the beneficial effects of GH treatment appear to occur during the first year of therapy with only a few studies reporting sustained benefits up to 5 years (5, 8-10). It is well established that GH secretion decreases with advancing age and that low GH levels are even associated with increased longevity and decreased morbidity (11, 12). Currently, many adults with GHD are receiving GH indefinitely without knowing if continuing or discontinuing long-term treatment has sustained beneficial or even adverse effects (13, 14). Similarly, reliable data on the impact of discontinuing long-term GH therapy in adults is practically not available. 2. RATIONALE