Developing long-acting growth hormone formulations. Pippa Cawley, Ian Wilkinson and Richard J. Ross. Academic Unit of Diabetes, Endocrinology and ...
Clinical Endocrinology (2013) 79, 305–309
doi: 10.1111/cen.12240
REVIEW ARTICLE
Developing long-acting growth hormone formulations Pippa Cawley, Ian Wilkinson and Richard J. Ross Academic Unit of Diabetes, Endocrinology and Reproduction, University of Sheffield, Sheffield, UK
Summary Daily recombinant growth hormone (GH) restores normal growth and body composition in GH-deficient children and adults; however, daily injections are inconvenient and can be distressing for some children. On top of this compliance is a problem in up to 75% of children. Developing long-acting GH formulations has proved challenging, and questions remain regarding safety and efficacy. In this review, we focus on the rationale for generating long-acting GH agonists and the technologies being developed to deliver prolonged exposure to GH. (Received 23 April 2013; returned for revision 30 April 2013; finally revised 7 May 2013; accepted 7 May 2013)
Physiology of growth hormone secretion and growth GH secretion from the anterior pituitary results from a dynamic equilibrium between hypothalamic somatostatin and GHRH generating pulsatile GH secretion with low GH levels between pulses. GH pulses occur approximately every three hours with the majority of GH released at night during sleep. GH secretion increases during puberty and declines with age. GH secretion and sensitivity to GH are influenced by age, nutrition, illness and body composition. GH sensitivity, with respect to IGF-I generation, falls during fasting and illness with high GH, low IGF-I levels and growth failure. In contrast, GH sensitivity increases with age and obesity where GH levels are reduced and IGF-I levels maintained. Normal growth and body composition requires both the direct actions of GH and those indirectly mediated by GH-stimulated IGF-I. Differences in growth are determined by many factors, some GH dependant but many as yet undefined. With respect to the nongenetic GH factors that influence growth, there is evidence that the pattern of growth hormone secretion is important. In healthy individuals, GH
Correspondence: Richard Ross, Academic Unit of Diabetes, Endocrinology and Reproduction, University of Sheffield, The Medical School, Sheffield S10 2RX, UK. Tel.: +44 (0) 114 27 12386; E-mail: r.j.ross@ sheffield.ac.uk © 2013 John Wiley & Sons Ltd
pulse amplitude is the most important predictor of growth and IGF-I levels,1 and from animal models, low trough concentrations in between pulses are not required for growth stimulation provided that high-amplitude pulses are present.2 In the treatment of GH-deficient children, the frequency of GH pulses is more important than the total dose, and the same overall dose given daily promotes better growth than when given on alternate days or thrice weekly. Interestingly, in rats, varying the daily dose from week to week resulted in better growth than the same daily dose given over the same time period.3 From treatment studies, there is no evidence that administering more frequent pulses than a single daily injection generates better growth, and the evidence from short-term and long-term (6 months) comparison of pulsatile versus continuous infusions of GH suggests that they are both equally effective in IGF-I generation in GH-deficient patients.4–7 There has been discussion that a long-acting GH, by providing a more constant exposure to GH, may put patients at risk of low-grade acromegaly, but, to date, there has been no evidence of this in the published studies of long-acting GH formulations or continuous GH infusions. The present evidence suggests that daily injections of GH can promote growth similar to endogenous pulsatile GH secretion, that continuous exposure to GH does not result in downregulation and that continuous exposure to GH has the potential to promote IGF-I levels and growth similar to that seen with daily injections.
Compliance with daily GH injections Compliance with daily GH treatment has long been recognized as a problem. Prior to the introduction of pen devices, it was estimated that
