Regulación del crecimiento Endocrinología Dr. Pablo Alvarez A ME-2012

Generalidades: Crecimiento Período prenatal Período postnatal Primera infancia Período de crecimiento estable Pubertad y adolescencia

Secreción circadiana de GH

Regulation of the hypothalamic-pituitary-growth hormone (GH) axis Regulation of the hypothalamic-pituitary-growth hormone (GH) axis. GH secretion by the pituitary is stimulated by GH-releasing hormone (GHRH) and is inhibited by somatostatin (SRIF). Negative feedback control of GH secretion is exerted at the pituitary level by insulin-like growth factor I (IGF-I) and by free fatty acids (FFA). GH itself exerts a short-loop negative feedback by the activation of SRIF neurons in the hypothalamic periventricular nucleus. These SRIF neurons directly synapse on arcuate GHRH neurons and project to the median eminence. Neuropeptide Y (NPY) neurons in the arcuate nucleus also indirectly modulate GH secretion by integrating peripheral GH, leptin, and ghrelin signals and projecting to periventricular SRIF neurons. Ghrelin is secreted from the stomach and is a putative natural ligand for the GH secretagogue receptor that stimulates GH secretion at both the hypothalamic and pituitary levels. On the basis of indirect pharmacologic data, it appears that release of GHRH is stimulated by galanin, γ-aminobutyric acid (GABA), and α2-adrenergic and dopaminergic stimuli and inhibited by somatostatin. Secretion of somatostatin is inhibited by acetylcholine (muscarinic receptors) and 5-HT (type 1D receptors), and increased by β2-adrenergic stimuli and corticotropin- releasing hormone (CRH). ACh, Acetylcholine; CNS, central nervous system; DA, dopamine.

Efecto de secretagogos en la secreción de GH Effect of GH secretagogues on GH, ACTH, and PRL secretion in healthy subjects. Mean (+ SEM) curve responses after administration of ghrelin (1.0 μg/kg), hexarelin (1.0 μg/kg), GHRH (1.0 μg/kg), or placebo. ACTH, adrenocorticotropic hormone; GH, growth hormone; GHRH, growth hormone–releasing hormone; HEX, hexarelin; PRL, prolactin; SEM, standard error of the mean. (Adapted from Arvat E, Maccario M, Di Vito L, et al. Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: comparison and interactions with hexarelin, a nonnatural peptidyl GHS, and GH-releasing hormone. J Clin Endocrinol Metab 2001;86:1169-1174.)

Effect of fasting on growth hormone secretion patterns in a healthy male subject. (From Hartman ML, Veldhuis JD, Johnson ML, et al. Augmented growth hormone [GH] secretory burst frequency and amplitude mediate enhanced GH secretion during a two-day fast in normal men. J Clin Endocrinol Metab 1992;74:757-765.)

Lifetime pattern of GH secretion Lifetime pattern of GH secretion. GH levels are higher in children than in adults, with a peak period during puberty. GH secretion declines with aging.

Secreción de GH en un adulto Interval Young Adult (μg/24h) Fasting Obesity Middle Age 24-hr secretion 540 ± 44 2171 ± 333 77 ± 20 196 ± 65 Secretory bursts 12 ± 1 32 ± 2 3 ± 0.5 10 ± 1 GH burst 45 ± 4 64 ± 9 24 ± 5 10 ± 6 Williams Textbook of Endocrinology, 11th Edition

♀ ♂ RITMO CIRCADIANO EN LA SECRECIÓN DE GH Pulsatile release of growth hormone (GH). The circadian rhythm of GH release is shown in normal human females (top) and males (bottom). Most GH release occurs at night during sleep. (Modified, with permission, from Müller EE et al. Neuroendocrine Control of Growth Hormone Secretion. Physiol Rev. 1999;79:511.) ♂

Ganong, 2010

Receptor GH Growth hormone receptors. A, Model of GH activation of JAK2 tyrosine kinase. GH binding to two GH receptors increases the affinity to each receptor for JAK2. The two receptor-associated JAK2 molecules are in close proximity, so that each JAK2 can phosphorylate the activating tyrosine of the other JAK2 molecule (blue arrows), thereby activating it. Activated JAK2 then phosphorylates itself (red arrow) and the cytoplasmic domain of the GH receptor (purple arrows) on tyrosines. These phosphotyrosines within the GH receptor and JAK2 form binding sites for signaling proteins. B, Regulation of GH receptor-JAK2 signaling. SH2 enhances GH receptor signaling by increasing the activity of JAK2. GH-induced expression of SOCS proteins inhibits further GHR signaling by decreasing the activity of JAK2. Tyrosine phosphatases, such as SHP-2, might also contribute to inhibiting GH receptor signaling by dephosphorylating tyrosines in the GH receptor and/or JAK2. C, GH receptors signaling pathways. Some of the signaling pathways initiated by GH activation of JAK2 are shown. JAK2 phosphorylates SHC, leading to activation of MAPK (blue arrows). JAK2 also phosphorylates STAT transcription factors. MAPK and STATs are important for GH regulation of gene transcription (purple arrows). JAK2 phosphorylates IRS proteins, which are thought to lead to activation of PI3′-kinase (PI3K: red arrows). GH activation of PI3′ kinase via IRS protein might be important for GH stimulation of glucose transport. GH, growth hormone; GHR, growth hormone receptor; IRS, insulin receptor substrates; JAK2, Janus kinase 2; MAPK, mitogen-activated protein kinase; P, phosphate; PI3′K, phosphatidylinositol 3-kinase; SHP-2, src homology 2 domain-containing protein tyrosine phosphatase 2; SOCS, suppressor of cytokine signaling. STAT, signal transducers and activators of transcription. (From Herrington J, Carter-Su C. Signaling pathway activated by the growth hormone receptor. Trends Endocrinol Metab 2001;12:252- 257.)

Biological actions of GH Biological actions of GH. The effects on linear growth, organ size, and lean body mass are at least partly mediated by insulin-like growth factors (IGFs) (somatomedins) produced in the liver and in the GH target tissues as well. IGFBP, insulin-like growth factor- binding protein.

Complementary regulation of GH and insulin secretion coordinates availability of nutrients with anabolism and either caloric storage or mobilization. Note that both hormones are increased by protein and that both stimulate protein synthesis.

Efectos de la GH

Efectos de la GH

Efecto en síntesis proteica

Crecimiento a lo largo de la vida

Tasa de crecimiento de algunos sistemas corporales

Ghrelina

Efectos periféricos

Figure 7-22 Regulation of the hypothalamic-pituitary-growth hormone (GH) axis. GH secretion by the pituitary is stimulated by GH-releasing hormone (GHRH) and is inhibited by somatostatin (SRIF). Negative feedback control of GH secretion is exerted at the pituitary level by insulin-like growth factor I (IGF-I) and by free fatty acids (FFA). GH itself exerts a short-loop negative feedback by the activation of SRIF neurons in the hypothalamic periventricular nucleus. These SRIF neurons directly synapse on arcuate GHRH neurons and project to the median eminence. Neuropeptide Y (NPY) neurons in the arcuate nucleus also indirectly modulate GH secretion by integrating peripheral GH, leptin, and ghrelin signals and projecting to periventricular SRIF neurons. Ghrelin is secreted from the stomach and is a putative natural ligand for the GH secretagogue receptor that stimulates GH secretion at both the hypothalamic and pituitary levels. On the basis of indirect pharmacologic data, it appears that release of GHRH is stimulated by galanin, γ-aminobutyric acid (GABA), and α2-adrenergic and dopaminergic stimuli and inhibited by somatostatin. Secretion of somatostatin is inhibited by acetylcholine (muscarinic receptors) and 5-HT (type 1D receptors), and increased by β2-adrenergic stimuli and corticotropin-releasing hormone (CRH). ACh, Acetylcholine; CNS, central nervous system; DA, dopamine.

Factores de Crecimiento semejantes a Insulina

The normal GH-IGF axis (A) and the GH-IGF axis showing four potential biochemical defects capable of causing GH insensitivity (B): (1) abnormalities of the GH receptor and/or binding protein; (2) abnormal signal transduction, resulting from a defect in the intracellular domain of the GH receptor or postreceptor; (3) defect of IGF synthesis; (4) defect of IGF secretion. (From Rosenfeld RG, Rosenbloom AL, Guevara-Aguirre J. Growth hormone [GH] resistance due to primary GH receptor deficiency. Endocr Rev 1994;15:369-390.)

Estructura

Características de la insulina y los IGF

Sistema insulina/IGF

Relación entre IGF-1 y Crecimiento

Schematic representation of intracellular signaling pathways of the IGF-I receptor. Upon binding IGF-I, the IGF-receptor undergoes autophosphorylation at multiple tyrosine residues. The intrinsic kinase activity of the receptor also phosphorylates IRS-1 at multiple tyrosine residues. Various SH domain–containing proteins, including PI 3-kinase, Syp, Fyn, and Nck, associate with specific phosphotyrosine-containing motifs within IRS-1. These docking proteins recruit diverse other intracellular substrates, which then activate a cascade of protein kinases including Raf-1 and one or more related kinases, MAP kinases (or MEKs), the MAP kinases, and others. These protein kinases, in turn, activate various other elements, including nuclear transcription factors. Alterations in expression of various IGF-I–responsive genes result in longer-term effects of IGF-I, including growth and differentiation. This model of signal transduction cascades also shows a potential mechanism for inhibition of apoptosis. (From Le Roith D, Bondy C, Yakar S, et al. The somatomedin hypothesis: 2001. Endocrine Rev 2001;22:53-74.)

IGF-1 en Músculo Esquelético

Efectos del IGF-1 Endocr. Rev. 2009 30:494-535

Otras hormonas involucradas en el crecimiento Tiroideas Esteroides sexuales Glucocorticoides Insulina

Importacia relativa de otras hormonas implicadas en el crecimiento según la edad

Hormonas implicadas en el crecimiento óseo

Curva de crecimiento * *Enfermedad entre los 5 y 7 años

Factores de crecimiento Que favorece el crecimiento celular Mitogénico o proliferativo Pro-sobrevida Modulador de la diferenciación Quimiotáctico Pro-motilidad, pro-migración, pro- metastático.