Hormonal Control of Growth

Dr. M. Alzaharna (2014) Growth of an individual or an organ involves: – Increase both in cell number and cell size – Differentiation of cells to perform highly specialized functions – and tissue remodeling that may require apoptosis as well as new cell formation Most of these processes depend on locally produced growth factors that operate through paracrine or autocrine mechanisms Many continue to operate throughout life providing not only cell renewal, but also for adaptations to meet changing physiological demands

Dr. M. Alzaharna (2014) Growth Hormone Growth hormone, which is also called somatotropin (STH), is the single most important hormone required for normal growth Attainment of adult size is absolutely dependent on GH; in its absence growth is severely limited

Dr. M. Alzaharna (2014) Synthesis, secretion, and metabolism Although the anterior pituitary gland produces at least six hormones, more than one-third of its cells synthesize and secrete GH 90% of the GH produced by somatotropes is comprised of 191 amino acids and has a molecular weight of ~ 22,000 The remaining 10% has a molecular weight of 20,000 and comprised of 176 amino acids Both forms are products of the same gene Both forms of hormone are secreted and have similar growth-promoting activity, although metabolic effects of the 20K form are reduced

Dr. M. Alzaharna (2014) Synthesis, secretion, and metabolism About half the GH in blood circulates bound to a protein that has the same amino acid sequence as the extracellular domain of the GH receptor GH that crosses the glomerular membrane is reabsorbed and destroyed in the kidney, which is the major site of GH degradation GH also is degraded in its various target cells following uptake by receptor mediated endocytosis

Dr. M. Alzaharna (2014) Mode of action Like other peptide and protein hormones GH binds to its receptor on the surface of target cells GH produces its effects in various cells by stimulating the transcription of specific genes

Dr. M. Alzaharna (2014) Effects on skeletal growth – The ultimate height attained by an individual is determined by the length of the skeleton and, in particular, the vertebral column and long bones of the legs The somatomedin hypothesis – GH may not act directly to promote growth but, instead, stimulates the liver to produce an intermediate, blood borne substance (somatomedin) that activates chondrogenesis and perhaps other GH-dependent growth processes in other tissues Physiological actions of growth hormone

Dr. M. Alzaharna (2014) Physiological actions of growth hormone Somatomedin was found to consist of two closely related substances that also produce the insulin-like activity – These substances now are called insulin-like growth factors, or IGF-I and IGF-II – IGF-I is more important mediator of the actions of GH – Children whose growth is more rapid than average have higher than average concentrations of IGF-I ⁻It is now apparent that GH stimulates secretion of IGFs, which act locally in an autocrine or paracrine manner to stimulate: ⁻cell division, chondrocyte maturation, secretion of extracellular matrix proteins, and bone growth

Dr. M. Alzaharna (2014) Effects of GH/IGF-I on body composition – The bodies of growth hormone-deficient animals and human subjects have a relatively high proportion of fat, compared to water and protein, in their bodies – Most internal organs grow in proportion to body size, except liver and spleen, which may be disproportionally enlarged by prolonged treatment with GH – When human subjects or experimental animals are given GH repeatedly for several days, there is net retention of nitrogen, reflecting increased protein synthesis Physiological actions of growth hormone

Dr. M. Alzaharna (2014) Regulation of GH secretion In humans, GH secretion is pulsatile Frequent bursts of secretion occur throughout the day, with the largest being associated with the early hours of sleep In addition, stressful changes in the internal and external environment can produce brief episodes of hormone secretion Effects of age – GH secretion, though most active during the adolescent growth spurt, persists throughout life, long after growth has stopped

Dr. M. Alzaharna (2014) Regulation of GH secretion In addition to spontaneous pulses, secretory episodes are induced by such metabolic signals as: – a rapid fall in blood glucose concentration – or an increase in certain amino acids Traumatic and psychogenic stresses are also powerful inducers of GH secretion in humans – whether increased secretion of GH is beneficial for coping with stress is not established Three hormones are involved in regulation and somatotropes express receptors for all three hormones: – GH-releasing hormone (GHRH) – Somatostatin – And ghrelin

Dr. M. Alzaharna (2014) Regulation of GH secretion Growth hormone releasing hormone provides the primary drive for GH synthesis and secretion Somatostatin reduces or blocks secretion of GH in response to GHRH, but has little or no influence on GH synthesis – constant secretion of somatostatin restrains secretion of GH – Periodic interruptions in secretion produces a rebound release of GH PVN: periventricular nuclei; ARC: arcuate nuclei; SST: somatostatin; GHRH growth hormone releasing hormone; IGF-I insulin-like growth factor-I; (+) stimulation. (─) inhibition

Dr. M. Alzaharna (2014) Regulation of GH secretion Ghrelin increases responses of somatotropes to GHRH – stimulation of GH secretion by ghrelin requires costimulation by GHRH Negative feedback control sets the overall level of GH secretion by regulating the amounts of GH secreted in each pulse

Dr. M. Alzaharna (2014) Role of Thyroid Hormones Growth is stunted in children suffering from deficiency of thyroid hormones Treatment of hypothyroid children with thyroid hormone results in rapid “catch up” growth and accelerated The effects of thyroid hormones on growth are closely entwined with GH T3 and T4 have little, if any, growth- promoting effect in the absence of GH Thyroid hormones affect synthesis of human GH indirectly by increasing the expression GHRH receptors by somatotropes

Dr. M. Alzaharna (2014) Role of Insulin insulin may serve as a growth-promoting hormone during the fetal period Infants born of diabetic mothers often are larger than normal, especially when the diabetes is poorly controlled Because glucose readily crosses the placenta, high concentrations of glucose in maternal blood increase fetal blood glucose and stimulate the fetal pancreas to secrete insulin Structurally, insulin is closely related to IGF -I and IGF-II and when present in adequate concentrations can activate IGF-I receptors

Dr. M. Alzaharna (2014) Role of Gonadal Hormones Awakening of the gonads at the onset of sexual maturation is accompanied by a dramatic acceleration of growth At the same time that gonadal steroids promote linear growth, they accelerate closure of the epiphyses and therefore limit the final height that can be attained Most, and possibly all, of the increase in height stimulated by estrogens or androgens at puberty is due to increased secretion of GH

Dr. M. Alzaharna (2014) Role of Glucocorticoids Glucocorticoids are required for synthesis of GH and have complex effects on GH secretion When given acutely, they may enhance GH gene transcription and increase responsiveness of somatotropes to GHRH However, GH secretion is reduced by excessive glucocorticoids, probably as a result of increased somatostatin production Impairment of growth is seen in children treated chronically with high doses of glucocorticoids to control asthma or inflammatory disorders Consistent with their catabolic effects in muscle and lymphoid tissues, glucocorticoids also antagonize the actions of GH