C24 – Growth PDF

PHYSIOLOGY 24 – Growth 1.​ Growth Growth is the sum of a variety of processes whose common characteristic is the augmentation of the body mass. Therefore, in humans it is also defined as the addition of new tissue from childhood to adult age. Growth is not a homeostatic function; it occurs only...

PHYSIOLOGY 24 – Growth 1.​ Growth Growth is the sum of a variety of processes whose common characteristic is the augmentation of the body mass. Therefore, in humans it is also defined as the addition of new tissue from childhood to adult age. Growth is not a homeostatic function; it occurs only during specific periods of life. The factors determining growth are -​ Heredity -​ Nutrition -​ Environmental influences -​ Endocrine regulation. The individual will grow up in the best way when all these elements act synergically. The cellular mechanisms underlying growth are ​ Hypertrophy ​ Hyperplasia ​ Differentiation ​ Matrix deposition ​ Remodelling 2.​ Endocrine control The primary hormone related to growth is the growth hormone (GH) (30% of the genetic potential for the growth of an individual is represented by this hormone). The secondary hormones related to growth are -​ thyroid hormones, -​ glucocorticoids, -​ sexual hormones. The hormonal regulation of growth changes during life. It is possible to identify 4 main periods during which growth occurs: prenatal, infantile, juvenile, adolescence. Insulin and IGFs (described later) are present in all the periods. GH production starts after birth from infantile period to adolescence as well as TH. Sex hormones contribute to growth only during adolescence. ​ Prenatal period: the velocity of growth is constant (this period is GH free) ​ Infantile period: there is a peak after birth (GH is boosted by the thyroid hormone) ​ Juvenile growth: growth slows ​ Adolescence: there is a peak (GH is boosted by sex hormones)  3.​ Skeletal growth One of the main parameters that indicates an addition of tissues in the body is height. Final height depends on length of spinal cord and long bones lower limbs. Growth of these bones is due to epiphyseal plates: direction of growth is from diaphysis towards epiphysis. The epiphyseal plate features change during development. From birth to puberty: 1.​ Mature chondrocytes produce extracellular matrix 2.​ Mature chondrocyte, hypertrophy and degradation 3.​ Matrix calcification 4.​ Osteoblasts and vessels migration 5.​ Bone 6.​ Osteoblasts proliferation from periosteum and beginning of rearrangement Puberty and post puberty: 1.​ Thinning of the epiphyseal plate 2.​ Ending of duplication ability of progenitor cells 3.​ Chondrocyte’s degeneration 4.​ Fusion of the epiphyseal plate with epiphysis and diaphysis Growth of long bones stops when there are no more germinal layers. However, the growth of skulls and extremities can be reactivated by growth hormone in adulthood (but the long bones cannot elongate anymore). 5.​ GH production and molecular mechanisms of action In the adenohypophysis, there are: -​ Acidophilic Cells that contain the glycoprotein hormones: o​ Somatotropes which produce GROWTH HORMONE o​ Lactotropes which produce PROLACTIN -​ Basophilic Cells that contain the glycoprotein hormones: o​ Thyrotropes which produce THYROID STIMULATING HORMONE o​ Gonadotropes which produce LUTEINIZING HORMONE or FOLLICOLE STIMULATING HORMONE o​ Corticotropes which produce ADRENOCORTICOTHROPIC HORMONE -​ Chromophobes: These are cells that have minimal or no hormonal content. The growth hormone GH is tiny and released from more than 1/3 of cells of adenohypophysis. GH is specie specific, non-human GH is inactive in humans. The half-life of GH is 20 min. GH receptor is a complex receptor composed by two subunits. Once the GH binds the receptor, it dimerizes; the dimerization leads to JAK tyrosine kinase phosphorylation that in turn induce the phosphorylation of TYK2 and of the receptor itself. This induces the activation (phosphorylation) and dimerization of STAT that move into the nucleus leading to bioeffects. 6.​ Insulin GF Growth hormone does not act directly on bone, but it needs intermediates that are called somatomedins. This fact has been demonstrated by the following experiment. An experimental model lacking GH has been administered with GH directly on bone and with GH on plasma. -​ GH administration directly on bone tissues of experimental models didn’t lead to any result while GH administration on bone tissue through plasma leaded to growth. This means that there are plasma factors mediating the effect of GH on bone. These acting factors are the insulin like growth factor (IGF). They are so called since they are similar to insulin in structure. They are also defined somatomedins. Characteristics: -​ FG has an 85% homology with proinsulin but a peptidic chain ≠. -​ There are 2 types, IGF I and IGF II. o​ In blood, IGF II > IGF I -​ Plasmatic concentration parallels the rate of growth and to the GH concentration. -​ IGF production is stimulated by GH -​ There are 6 types of IGF transporters in the blood. -​ 2 types of receptors, with a tyrosine kinase activity. -​ Local IGH interacts w organs to promote growth -​ Plasmatic IGF acts on the hypothalamus in a negative feedback Nevertheless, even if GH does not act directly during growth, its presence is somehow needed to increase the rate of growth. This has been demonstrated considering different results in the treatment of children with GH insensitivity due to a receptor deficiency and children with GH deficiency. -​ The first group was treated with administration of IGF-1, while the second group was treated with administration of both IGF-1 and GH. -​ As shown in the graph blow, the growth velocity of the second group was better than the one of the first group. This is due to the fact that actually GH can act directly on many tissues. The main target organ is the liver that produce IGF-1 that enter the circulation to reach IGFs receptors on other organs. However, in other organs GH leads to specific metabolic effects and in some organs also to the production of local IGFs that act, together with IGFs from the liver, to increase the growth rate. This local autocrine action has a different relevance depending on the tissue that is considered. The local autocrine action can occur also in bones even if the level of GH receptors in this tissue is very low. 7.​ Effects of GH Metabolic effects caused directly by GH are: ​ Protein metabolism (anabolic effect) ​ Lipid metabolism (fatty acids mobilisation) ​ Glucidic metabolism (reduction of carbohydrates usage) ​ Hepatic ketogenesis ​ Hepatic IGFs release Tissutal effects caused by direct and IGFs-mediated action are: ​ Bone growth  ​ Visceral, heart and muscle growth ​ Thickening of skin and connective tissue ​ Potentiation of the trophic effect of hypophysial hormones on glands. 8.​ GH secretion control GH secretion is controlled by the hypothalamus and hypophysis. The hypothalamus produces growth hormone releasing factor (GHRH) that in turn stimulates the hypophysis to release growth hormone GH. The hypothalamus receives negative feedback from IGFs. Moreover, it can be influenced by other factors: stress and availability of lots of aminoamides can increase the production while glucose and fatty acids reduce the release of GH. Also the hypophysis receives negative feedback from IGFs and can be regulated by other hormones. More specifically GH production is inhibited by insulin and high doses of glucocorticoids, while it is enhanced by thyroid hormones, sex hormones and basal doses of glucocorticoids. The fact that glucocorticoids feedback on the pituitary, explains why therapies with administration of cortisol should be stopped slowly. Indeed, cortisol feedbacks on the pituitary causing the adrenal medulla to reduce the production of natural cortisol. An abrupt withdrawal of the therapy would cause cortisol level to drop, leading to dangerous consequences. The graph below shows the effect of insulin-like growth factor-1 administration on GH production The graph below shows the effect insulin administration on GH production 9.​ GH secretion modality There are two modality of GH secretion: ​ Episodic ​ Pulsatile The episodic secretion is due to increase in plasmatic aminoacid level, muscular exercise, surgical operations, high temperature, emotional stresses, reduction of plasmatic glucose and fatty acid level. The pulsatile secretion is responsible for growth. The amount of GH released through pulsatile modality therefore changes during different periods (higher in adolescence). In this graph is represented the variation of pulsatile secretion during the different periods of life related to growth. 10.​Secondary hormones THYROID HORMONE The functions of thyroid hormone are: ​ Differentiation ​ Sustain metabolic rate The releasing of thyroid hormone is mandatory for differentiation. Its deficiency leads to cretinism. This is because without thyroid hormone the differentiation and remodelling of the nervous system is not possible. Amplitude and frequency of pulsatile secretion of GH depends on thyroid glands. Thyroid hormones promote synthesis and cellular response to GH and perform metabolic synergic actions. An increase of thyroid hormones however does not correspond to and increased production of GH, it must have a specific value. Both hyperthyroidism and hyperthyroidism cause a decreased production of GH INSULIN Insulin deficiency during childhood associated to a delay in growth. This is of course due to lack of glucose, that represents “the fuel of energy” needed for growth. Moreover, a lower level of insulin is thought to induce lower levels of IGF1 receptors. The graph below shows the result of an experiment with rats. Rats were pancreatectomized and GH + insulin were administrated as shown in the graph. There is a failure to respond to GH in the period coincident with the decrease in daily insulin. Probably this is because insulin promote IGFs receptors (that are homologous to insulin receptors). GLUCOCORTICOIDS Glucocorticoids keep the trophism of organs. They are permissive for growth since promote: ​ Adequate functionality of organs and tissues ​ Wellness state ​ Hunger Low doses or acute administration of glucocorticoids increase GH gene transcription as well as responsivity to GHRH. Conversely very high levels can lead to decreased growth. Therefor they must have a precise level. The graph below shows changes in body weight of rats administered with cortisone. An increase in cortisone administration corresponds to a decrease in body weight. 11.​Clinical point Insufficient GH production results in: ​ Panhypopituitarism: it is the worst case and consists in the deficiency of all anterior pituitary hormones ​ Selective GH deficiency: there is a deficiency related only to growth hormone ​ Laron Dwarfism: deficiency in GH receptors. It leads to metabolic and growth problems. It is responsive to IGF-1 treatment ​ African Pygmies: normal GH and IGFs binding but there is a defect in post receptor pathways. Tissue resistance to IGF-1 causes short stature. Excessive GH production: ​ Gigantism: excess of GH prior to epiphyseal closure during puberty leads to acceleration of long bone growth. There are different types of results depending on the genetic of the individual ​ Acromegaly: GH hypersecretion occurs after epiphyseal closure leading to overgrowth of extremities and short bones of the face The images below show three examples of dwarfism, gigantism, and acromegaly Cretinism Cretinism is caused by a congenital deficiency of thyroid hormones. Thyroid hormones are needed to improve the central nervous system during post-natal development. They allow increases in mass, “neurological pruning” and development of synapses, and myelination. the absence of the thyroid hormones impairs all these processes resulting in an inadequate brain development leading to neurological and cognitive impairment (in addition to the significant general growth impairment)