15 General introduction 1 The endocrine regulation of growth and body composition Insulin like growth factors (IGFs), insulin and growth hormone (GH) have been established to play an important role in regulating growth in the fetal as well as the postnatal phase. IGF-II mainly stimulates growth in the embryonic and early fetal period. IGF-I, on the other hand, is the major growth stimulating factor in late gestation and the postnatal period. (11) Hence, IGF-I is a key factor in the endocrine regulation of growth in preterm infants. IGF-I is a small polypeptide with a wide range of function. It is mainly synthesized in the liver and stimulates cell division, growth, and motility, as well as glucose uptake, and protein synthesis. In addition, IGF I inhibits apoptosis and has an antiinflammatory and anti-oxidative effect. (12-15) In utero, IGF-I is secreted into the blood under control of insulin. After birth, GH gradually takes over this role. Insulin like growth factor binding proteins (IGFBPs) are also important factors which regulate the bioavailability of IGF-I. (11) In addition, thyroid hormones in general stimulate cell differentiation and support tissue accretion by regulating the IGF-I receptor and oxidative metabolism. Glucocorticoids also stimulate cell differentiation and negatively modulate growth in late gestation. Other factors implicated in fetal and postnatal growth are leptin and ghrelin. Both hormones have a possible growth promoting effect, yet their precise roles remain to be elucidated. (16) IGF-I has also been associated with the regulation of body composition. (12) Interestingly, the relationship between IGF-I and body composition has been reported to vary depending on the timing of IGF-I and body composition measurement. For example, in preterm infants higher IGF-I in the first month of life has been associated with an increased fat free mass. Meanwhile, higher IGF-I levels at and after term equivalent age have been associated with a decreased fat free mass.(17) Nevertheless, studies on this are rare in the preterm population and definitive conclusions on the relationship between IGF-I and body composition are yet to be drawn. Nutrition in relation to growth and body composition Nutrients are a substrate for growth and are crucial for the development of the endocrine axes. In particular protein availability has significant impact on hormone levels and hormone sensitivity in fetal as well as neonatal life.(18-20) Protein malnutrition in infants depresses hepatic IGF-I, IGFBP-3 and IGFBP-4 synthesis and enhances hepatic IGFBP-1 and IGFBP-2 synthesis, leading to reduced IGF-I bioavailability and impaired growth. Preterm infants require 3 to 4 grams of protein per kg per day depending on their gestational age and co-morbidities. To optimize nitrogen accretion, the protein
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