Growth. Introduction. Page 1. GH and its story lines. the GH receptor. Jack kinase box. Jack kinase box

Transcription

1 Growth Introduction to GH in general, chemistry, anaphylactic shock, GHBP, bioassays, GHRH,, glucostats and catecholamines GH regulates protein, fat and carbohydrate metabolism and is regulated by proteins, FFA, glucose and other factors. GH indirect effects are mediated by liver somatomedins (insulin-like growth factors or IGF) the GH receptor 22 Mechanism of : GHRH,,GH, IGF Pubertal growth spurt in humans, an example of activation of the GH axis Pathologies: dwarfism, gigantism, acromegalia, clinical tests. GH use/abuse GHr Jack kinase box GHr Jack kinase box Introduction GH and its story lines Page 1

2 Introduction GH, GHRH, GH effects Mechanism of Puberty Pathologies GH is a protein similar to Prl / hpl heterogeneity anaphylaxis GH - BP & GH / T evolution bioassay vs RIA regulation The median eminence (M) is the link between the brain and the anterior pituitsry Introduction GH, GHRH, GH effects Mechanism of Puberty Pathologies GH is a protein similar to Prl / hpl heterogeneity anaphylaxis GH - BP & GH / T evolution bioassay vs RIA regulation The median eminence (M) is the link between the brain and the anterior pituitsry Page 2

3 Introduction GH, GHRH, GH effects Mechanism of Puberty chemical stimuli stress centers sleep centers long loop negative feed-back hypothalamus GHRH anterior pituitary GH liver ultra short loop negative feed-back short loop negative feed-back Pathologies somatomedins or IGF tissues GHRH-BP GH - BP & DHT The median eminence (M) is the link between the brain and the anterior pituitary Introduction GH, GHRH, GH effects Mechanism of Puberty Pathologies plasma GH plasma GH glycemia Hours after insulin saline IGF - 1 GH secretion is controlled by hypothalamic neurohormones and by IGF Page 3

4 Introduction GH, GHRH, GH effects plasma GH (ng / ml) male female episodic GH release changes with age Mechanism of time of day juvenile Puberty GH (integrated conc. in ng / ml) plasma GH (ng / ml) early puberty post puberty Pathologies adult aged age in years time in a 24 hours period GH secretion is controlled by hypothalamic neurohormones and by IGF Introduction GH, GHRH, GH effects Mechanism of Puberty Pathologies and GRH short loop feedback / GRH feed-back IGF long loop feedback VMN /glucostat /GH GH pulsatile release / GRH & pulses CAs and steroids GH secretion is under the direct dual control of a stimulatory (GHRH) and an inhibitory () input Page 4

5 Introduction GH, GHRH, GH effects Mechanism of Puberty Pathologies The hypothalamic median eminence (M) is the link between the brain and the endocrine system Introduction GH, GHRH, GH effects Mechanism of Puberty Pathologies Main neurohormones involved in the neuroendocrine control of growth,, GHRH and Ghrelin Page 5

6 Introduction GH, GHRH, GH effects Mechanism of Puberty Pathologies Growth, effect of growth hormone - releasing hormone (GHRH) on plasma GH, placebo vs GHRH Introduction GH, GHRH, GH effects Mechanism of Puberty Pathologies Ocreotide is a long - lasting somatostatin analog used in medicine Page 6

7 Introduction GH, GHRH, GH effects Mechanism of Puberty Pathologies Ocreotide is a long - lasting somatostatin analog used in medicine Introduction GH, GHRH, GH effects Mechanism of Puberty Pathologies Ocreotide is a long - lasting somatostatin analog used in medicine Page 7

8 Introduction GH, GHRH, GH effects Mechanism of Puberty Pathologies LH / FH TH PRL ACTH GH GH, as many anterior pituitary hormones, has a circadian secretion pattern Introduction GH, GHRH, before T4 GH effects Mechanism of after T4 Puberty Pathologies GH secretion is partially dependent of T3, a thyroid hormone Page 8

9 Growth Hormone (GH) effects GH, GHRH, GH effects Mechanism of Puberty Pathologies timulates body growth and is anti-insulinic Decreases fat and increases lean body mass Invoved in cardiac and immune function Involved in mental agility and aging GH current therapeutic use has been based on the above listed effects (eg. short stature children, adult GH deficiency, HIV-associated wasting), but it has also shown some negative effects (eg. death in acute catabolic states, insulin resistance, vascularization of the retina and nephropaties, all debilitating complications of diabetes). A summary of GH effects and of its current therapeutic uses Growth Hormone (GH) effects GH, GHRH, GH effects Mechanism of Puberty Pathologies GH has direct and indirect effects, the latter being mediated by the IGFs Page 9

10 Growth Hormone (GH) effects GH, GHRH, growth plate GH effects Mechanism of Puberty Pathologies GH has direct and indirect effects, the latter being mediated by the IGFs Growth Hormone (GH) effects GH, GHRH, growth plate GH effects Mechanism of Puberty Pathologies mineral balance N growth velocity Na K P GH has direct and indirect effects, the latter being mediated by the IGFs Page 10

11 Growth Hormone (GH) effects GH, GHRH, GH effects Mechanism of Puberty Pathologies lowers blood aminoacid concentrations lowers blood urea nitrogen. Positive N balance increases DNA, RNA, and protein synthesis elevates glycemia by decreasing CH utilization and sensitivity to the insulin-hypoglycemic effect elevates fat oxidation. Lowers respiratory quotient induces growth in general mostly through IGFs stimulates growth and calcification of cartilage GH abuse causes diabetes mellitus by exhaustion of ß-cells overstimulated by high glycemia (metahypophyseal diabetes). Impaired glucose tolerance in acromegaly might be related to this inter GH promotes the use of fat depots as energy source rather than glucose (sparing effect of glucose) Growth Hormone (GH) effects GH, GHRH, GH effects Mechanism of Puberty Pathologies muscle liver adipose aa uptake prot synthesis prot synthesis RNA synthesis glucose uptake glucose uptake gluconeogenesis lipolysis increased muscle mass IGF - I chondrocytes of bone collagen synthesis protein synthesis cell proliferation increased linear growth M / IGF production IGF - II decreased adiposity many organs and tissues protein synthesis RNA synthesis DNA synthesis cell size and number increased tissue growth and increased organ size GH has direct effects on metabolism but its effects on growth are mediated by IGF Page 11

12 Growth Hormone (GH) effects GH, GHRH, GH effects muscle aa uptake prot synthesis glucose uptake glucose glycogen G P Mechanism of Puberty Pathologies liver adipose prot synthesis RNA synthesis gluconeogenesis IGF production lipolysis glucose uptake proteins aa uptake Krebs cycle pyruvate acetyl CoA triglycerides The effect of GH on intermediary metabolism is characterized by a glucose sparing effect Growth Hormone (GH) effects GH, GHRH, GH effects Mechanism of Puberty Pathologies Direct and indirect s of GH on growth and metabolism Page 12

13 Growth Hormone (GH) effects GH, GHRH, GH effects Mechanism of Puberty Pathologies Requirement of insulin for normal growth in response to GH. Rats were pancreatectomized 3 to 7 weeks before the experiment was begun. ach rat was fed 7 g of food per day. The treated group was injected with the indicated amounts of GH daily. Note the failure to respond to GH in the period between 20 and 44 days, coincident with the decrease in daily insulin dose, and the resumption of growth when the daily dose of insulin was restored. GH effect on growth requires the presence of insulin for optimal performance Growth Hormone (GH) effects GH, GHRH, GH effects Mechanism of Puberty Pathologies body weight time in days body length time in days ffects of cortisone on growth in hypophysectomiz ed rats given GH replacement. The growthpromoting response to GH, measured as a change in either body weight or length, decreased progressively as the dose of cortisone was increased from 0.1 to 1.0 mg per day. The decrease in body weight seen when 1.0 mg per day of cortisone was given probably results from net breakdown of muscle mass. GH effect on growth requires the absence of cortisone for optimal performance Page 13

14 GHRH and GH, GHRH, IGF-1 GHRH T GH effects Mechanism of Puberty GH release Pathologies somatotroph Most of the effects of GHRH and of are mediated by AC and PLC GHRH and GH, GHRH, IGF-1 GHRH T GH effects Mechanism of T GHRH Puberty GH release T Pathologies somatotroph Ghrelin Most of the effects of GHRH and of are mediated by AC and PLC Ca Page 14

15 GHRH and GH, GHRH, GH effects Mechanism of Puberty Pathologies CF plasma memb IC F COOH enzyme channel N H 2 GTP GT P G GDP the GHRH peptide: GPCR, AC/cAMP, PLC/IP3, PLA/PG sexual dimorphism (DHT), receptors for the peptide: GPCR, Gi, AC, open K channels, hyperpolariza-tion, lower Ca influx Most of the effects of GHRH and of are mediated by AC and PLC Growth Hormone (GH) GH, GHRH, GH effects Mechanism of Puberty Pathologies The effects of GH are mediated by single transmembrane domain receptors Page 15

16 Growth Hormone (GH) GH, GHRH, GH effects Mechanism of Puberty Pathologies The effects of GH are mediated by single transmembrane domain receptors Growth Hormone (GH) GH, GHRH, GH effects kinase GH Mechanism of Cys residues Puberty Pathologies hydrophobic aminoacids JAK 2 TAT DNA The effects of GH are mediated by single transmembrane domain receptors Page 16

17 Growth Hormone (GH) GH, GHRH, GH effects Mechanism of Puberty Pathologies GH receptors do not have a kinase Dimerization, if GH excess inhibition Ligand binding results in rapid phosphorylation of cell proteins on Tyr Janus (JAK) kinases are cytoplasmic tyrosine kinases which physically associate with box 1 - box 2 domains of the ligand bound receptor leading to auto - phosphorylation on Tyr residues and phosphorylation of transcription factors called signal transducers and activators of transcription or in short TAT Most GH effects are mediated by IGFs The effects of GH are mediated by single transmembrane domain receptors Growth Hormone (GH) GH, GHRH, GH effects Mechanism of Puberty Pathologies The effects of GH are mediated by single transmembrane domain receptors Page 17

18 Growth Hormone (GH) GH, GHRH, GH effects Mechanism of Puberty Pathologies The effects of GH are mediated by single transmembrane domain receptors IGFs and other Growth Factors GH, GHRH, GH effects Mechanism of Puberty Pathologies Cys residues hydrophobic aminoacids NH2 GFs-BP as local storage also? Gi2?? GF IGF II PDGF insulin IGF I TAT COOH kinase Cys rich JAK2 GH Prl cytokines Growth Factor families Insulin GF (>10), FGF (9), IGF (2), NGF (4), PDGF (2), TGF-ß (24) PO The effects of IGFs are mediated by single transmembrane domain receptors Page 18

19 IGFs and other Growth Factors GH, GHRH, GH effects Mechanism of Puberty Pathologies Growth Factor families Insulin GF (>10), FGF (9), IGF (2), NGF (4), PDGF (2), TGF-ß (24) PO The effects of IGFs are mediated by single transmembrane domain receptors IGFs and other Growth Factors GH, GHRH, GH effects Mechanism of Puberty Pathologies Growth Factor families Insulin GF (>10), FGF (9), IGF (2), NGF (4), PDGF (2), TGF-ß (24) PO The effects of IGFs are mediated by single transmembrane domain receptors Page 19

20 IGFs and other growth factors GH, GHRH, GH effects Mechanism of Puberty Pathologies Unlike hormones, GFs are produced by many tissues. They are not produced in specific glands. They are secreted proteins exerting multiple effects on cell growth, metabolism, differentiation, and on growth / development of organisms. Binding proteins control growth factor availability GFs s might be endocrine, paracrine, juxtacrine, autocrine, and intracrine (PDGF) Cytokines, secreted proteins produced by macro-phages, lymphocytes, and blood cell precursors controlling the immune and hematopoietic systems GFs have Tyr-K except TGFß which phosphorilates er / Thr residues, receptor dimerization amplification through multiple kinases & stats (signal transducers and activators of transcription) long-term effects of GFs are dependent on shifts in gene expression The effects of IGFs are mediated by single transmembrane domain receptors IGFs and other growth factors GH, GHRH, GH effects IGF regulates somatic growth in direct relation to GH Plethora of s attributed to GFs, but precise role in growth and development is still partially unresolved. Mechanism of Puberty Pathologies xamples: GF induce wool shedding & is used for shearing sheep FGF induces limb development. xp. in chick embryos NGF induces sympathetic AN. Ab experiment in rat embryo. Target-derived neurotrophic factor hypothesis PDGF is involved in wound healing. Multiple sclerosis TGFß in immune function, inflammation, reproduction. Activins stimulate FH secretion. MIH, involved in sexual differentiation has 30% aa identity with TGFß. timulates wound healing. TGFß excess causes fibrosis The effects of IGFs are mediated by single transmembrane domain receptors Page 20

21 IGFs and other growth factors GH, GHRH, GH effects Mechanism of Puberty Pathologies The effects of IGFs are mediated by single transmembrane domain receptors IGFs and other growth factors GH, GHRH, IGF-1 GH effects Mechanism of Puberty Pathologies Aminoacids in black are in identical position in A and B chains of insulin Page 21

22 IGFs and other growth factors GH, GHRH, GH effects Mechanism of Puberty Pathologies Insulin and IGF-1 receptors are structurally related heterotetrameric glycoproteins IGFs and other growth factors GH, GHRH, GH effects Mechanism of Puberty Pathologies Proinsulin, insulin-like growth factor-i (IGF-I) and insulin-like growth factor-ii (IGF-II). tructures are drawn to emphasize similarities. Amino acid sequences show about 50% identity in the regions corresponding to the A and B chains of all three compounds, and more than 74% identity in the IGFs. The C chain regions have the most variability. Insulin and IGF-1 receptors are structurally related heterotetrameric glycoproteins Page 22

23 Pubertal growth in humans GH, GHRH, GH effects Mechanism of Puberty Pathologies Hormonal regulation of growth at different stages of life. IGFs = insulinlike growth factors; GH = growth hormone; T3 = triiodothyronine. Growth acceleration at puberty is associated with increased GH Pubertal growth in humans GH, GHRH, GH effects Mechanism of Puberty Pathologies A. Typical growth curves for boys and girls. Note that growth is not linear and that it proceeds at the same rate in juvenile boys and girls. At puberty, which begins earlier in girls than in boys, there is a spurt in growth that immediately precedes growth arrest. B. Nonlinearity of growth is more clearly evident when plotted as changes in growth velocity over time. Note that growth, which is very rapid in the newborn, slows during the juvenile period and accelerates at puberty. Growth acceleration at puberty is associated with increased GH Page 23

24 Pubertal growth in humans GH, GHRH, GH effects Mechanism of Puberty Pathologies Growth acceleration at puberty is associated with increased GH Pubertal growth in humans GH, GHRH, 24h mean GH effects Mechanism of height velocity chart GH secretion pulse amplitude Puberty Pathologies pulse frequency Growth acceleration at puberty is associated with increased GH Page 24

25 Pubertal growth in humans GH, GHRH, IGF-1 IGF-1 GH effects Mechanism of GH growth velocity IGF-1 BP3 Puberty Pathologies Growth acceleration at puberty is linked to increased GH, IGF1 and IGF-BP3 Pubertal growth in humans GH, GHRH, IGF-1 GH before testosterone GH effects Mechanism of GH growth velocity GH after testosterone Puberty Pathologies GH secretory episodes are increased in frequency and amplitude by testosterone Page 25

26 Human ndocrine Diseases GH, GHRH, GH effects Mechanism of Puberty Pathologies GH-related human endocrine diseases Human ndocrine Diseases GH, GHRH, GH effects Mechanism of Puberty Pathologies A GH hypersecretion: Harvey Cushing s first acromegalic patient Page 26

27 Human ndocrine Diseases GH, GHRH, GH effects Mechanism of Puberty Pathologies GH hyposecretion leads to dwarfism. Tom Thumb Idiopathic short stature due to low GH, GRH, IGFI Laron dwarfism due to low GH/IGF, GHr, & GH-BP GH bioassay, epiphyseal growth plates, steroids GH hypersecretion before puberty and gigantism GH hypersecretion after puberty and acromegaly bt and milk production or pushing the envelope illegal bt use in athletes. Acromegaly / diabetes ndocrine pathologies related to GH and the IGF axis Human ndocrine Diseases GH, GHRH, GH effects Mechanism of Puberty Pathologies Normal Pathologies ndocrine pathologies related to GH and the IGF axis Page 27

28 Human ndocrine Diseases GH, GHRH, GH effects Mechanism of Puberty Pathologies AP anterior pituitary hypo-- plastic) PP posterior pituitary (ectopic) P pituitary stalk (absent) Normal Deficient A pathology related to a GH deficiency of hypothalamic origin Human ndocrine Diseases GH, GHRH, GH effects Mechanism of Puberty Pathologies Growth Hormone (GH) insensitivity with a phenotype very similar to GH deficiency. This child has Laron s syndrome and lacks GH receptors Growth acceleration at puberty is associated with increased GH Page 28

29 Human ndocrine Diseases GH, GHRH, GH effects Mechanism of Puberty Pathologies erum IGF-1 and IGF-2 in normal, acromegalic and GH deficiency patients Human ndocrine Diseases GH, GHRH, GH effects Mechanism of Puberty Pathologies erum IGF-1 and IGF-2 in normal, in hypopituitary dwarfism and in pygmies Page 29

30 Human ndocrine Diseases GH, GHRH, GH effects Mechanism of Puberty Pathologies Laron s syndrome, a pathology related to a GH receptor deficiency Human ndocrine Diseases GH, GHRH, GH effects Mechanism of Puberty Pathologies Mother & son. At 8-foot-4, Leonid tadnik, 33 years old, is the tallest human being on the planet (2005) Gigantism due to AP hyperfunction after a surgery procedure at age 12 Page 30