Long-Acting Growth Hormone

Abstract

Human growth hormone (GH) is a 22 kDa protein synthesized and secreted in the anterior pituitary gland. GH synthesis and release is induced by hypothalamic GHreleasing hormone (GHRH) and ghrelin and attenuated by somatostatin and negative feedback by insulin-like growth factor (IGF)-I [1]. The secretion of GH is episodic with several secretory peaks. The majority of spontaneous peaks occur during sleep, but it is also influenced by age, gender, intercurrent and chronic illnesses, and by nutritional status [1, 2]. GH is required for linear growth during childhood and adolescence. GH regulates the production of IGF-I, which is mostly produced in the liver, and, together, GH and IGFI stimulate skeletal growth [1]. GH also has profound metabolic effects throughout life [2]. Through its anabolic, lipolytic, and antinatriuretic effects, it increases muscle mass and bone formation, reduces fat mass, and increases total body water. GH augments metabolic activity, resulting in a rapid and large increase in resting energy expenditure and fat oxidation, and protein synthesis increases [3]. Additionally, the peripheral conversions of thyroxine (T4) to triiodothyronine (T3) and of cortisol to the inactive cortisone rise. Furthermore, GH increases insulin resistance and causes hyperinsulinaemia. The lipolytic effect, and hence the impact upon body composition, is of course most readily appreciated during the initial years of replacement therapy, since a new steady state will be reached [4]. The diagnosis of GH deficiency (GHD) requires demonstration of a blunted response to stimulation tests according to specific diagnostic criteria [5, 6]. Insulininduced hypoglycaemia (insulin tolerance test [ITT]) is the reference golden standard for diagnosing GHD, but the GHRH–arginine test and glucagon test are commonly used, with different cut-offs applied for the different tests. IGF-I is correlated with GH secretion, but because of overlap in IGF-I levels in healthy individuals and patients with GHD, IGF-I is not useful for diagnosing GHD [7]. However, IGFI expressed as ageand gender-adjusted standard deviation score (IGF-I-SDS) is routinely used for monitoring GH dosing. GHD during childhood results in growth retardation, as well as an abnormal body composition, with more body fat than lean body mass, and decreased physical capacity and quality of life. Treatment with GH in children with GHD has been well established for some 20–30 years and has, in several studies, been verified to promote linear growth and improve metabolism [6]. In fact, replacement of GH today extends long into adult life and even into senescence. Nowadays, indications include GHD in both children and adults, children with Prader–Willi Syndrome, Turner Syndrome, and Noonan Syndrome, as well as idiopathic short stature (ISS), children born small for gestational age (SGA), and children with chronic renal insufficiency (CRI). Treatment with GH became possible in the late 1950s following the isolation and purification of GH from human cadaver pituitary glands by Raben [8]. Since only extracts from the human pituitary gland were effective in humans, the availability of GH for clinical use was very limited. Following the introduction of the biosynthetically derived natural sequence (22 kDa GH) in the mid 1980s, there has been no shortage of GH for clinical use. C. Hoybye Department of Endocrinology, Metabolism and Diabetology, Karolinska University Hospital, Stockholm, Sweden