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DEVELOPMENT OF THE ENDOCRINE SYSTEM Prof. Dr. Olcay Evliyaoğlu.

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Presentation on theme: "DEVELOPMENT OF THE ENDOCRINE SYSTEM Prof. Dr. Olcay Evliyaoğlu."— Presentation transcript:

1 DEVELOPMENT OF THE ENDOCRINE SYSTEM Prof. Dr. Olcay Evliyaoğlu

2 Steroid hormones:  are not stored  rate of synthesis = rate of secretion

3 Adrenal, gonadal steroids:  Synthesis is controlled by trophic hormones. Stimulating hormone > receptor > activation of adenylate cyclase > cAMP increases

4  McCune Albright Syndrome: Activating mutation in the alpha subunit of G protein.  Testotoxicosis: Activating mutation of LH receptor ( transmembrane domain - interaction with G protein.)

5 Disorders of hormone resistance  Insulin resistance  Testicular feminization  Certain types of dwarfism  Diabeted insipidus (nephrogenic)  Pseudohypoparathyroidism

6 Hormone ↑ --> receptor number decreases  “down regulation” or “desensitization”  obesity - insulin  precocious puberty - GnRH analogues

7 Hormone ↑ --> receptor number increases  “up regulation”  estrogen - FSH ↑ ---> LH receptors increase

8 Distinguishing characteristic of endocrine systems: feedback control & hormone production.

9  The paradigm for feedback control is the interaction of the pituitary gland with the thyroid, adrenals and gonads.  Hormones produced in peripheral endocrine organs feedback on the hypothalamic-pituitary system > regulate the production of the trophic hormones that control peripheral endocrine glands.

10 Negative Feedback  Metabolite  Cortisol --> ACTH/ CRH  Thyroid hormones --> TSH /TRH

11 Short Feedback  TSH --> TRH  ACTH --> CRH

12 Positive Feedback  Hypophysogonadal (only example) : Estrogen --> LH, FSH

13 Adrenal gland develpment Embryology Mesoderm adrenal cortex Ectoderm adrenal medulla 5-6 wk fetal adrenal cortex  Outer definitive zone (glucokortikoids and mineralocorticoids)  Inner fetal zone (androgenic precursors)

14 At birth AG is 0,5 % of total BW Glomerulosa 15 % Fasiculata 75 % Reticularis 10 %

15 Fetal zone disappears around 1 years of age Glomerularis and fasiculata development is completed in 3 years. Reticularis development is completed in 15 years

16 Fetal cortisol --> cortisone (Midgestation: cortisone (x4-5 cortisol))  Cortisone: relatively inactive glucocorticoid; it protects the anabolic milieu of the fetus: cortisol can retard placental and fetal growth.  As term approaches; liver, lung express 11-beta hydroxy steroid dehydrogenase I activity: cortisone --> cortisol  Cortisol: an important stimulus for preparing the fetus for extrauterine survival.

17 Development of pituitary gland

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19 Growth hormone  The most produced hormone in the pituitary.  Single chain alpha-helical nonglukolized polypeptide.  Consists of 191 aminoacids and two intramolecular disulfide bounding.  22kDa molecüler weight  75%  20kDa  10-25%  N-asetile ve desamine forms veya oligomers

20  GH  GH-BHBP  Extracellular part of GH rec

21 Growth hormone  Encoded by GH-1 gene.  Locolized on 17q chromosome.

22 GH secretion  Under control of 2 hypothalamic hormones  Growth hormone releasing hormone(GHRH)  Somatotropin release-inhibiting factor (SRIF, somatostatin)

23 GHRH  Protein with 44 aminoacids  Vazoactive intestinal polypeptide/ glukagon family

24 GH secretion

25 Human growth hormone (hGH)  Nonpulsatile GH secretion in infants.  During childhood 24 hour integrated GH secretion increase progressively.  In puberty GH secretion amplitude increase to peak levels ( effect of gonadal steroids on GHRH).  GH secretion decrease with age but secreted life long.

26 GH-releasing peptides (GHRP)or secretagogues (GHS)  Ligands that increase GH produced by humans  Do not use GHRH or SRIF receptors  GHS-R  G-protein associated rec protein kinase C  hypothalamus, pituitary somatotrophs

27  Ghrelin  Endogen ligand for GHS-R.  Increase GH secretion in rats (intracellular Ca increase).  Physiologic mediator of nutrition

28 GH effect  Bound to GH-binding protein (GHBP) (at least 50 %)  GHBP, is the extra cellular component of GH-R

29  GH-R member of cytokine rec family  620 aa protein  On plasma membrane.  Extracellular part is transport protein  Single transmembrans helix  Intracellular part

30  GH  IGF’s (somatomedins)  Similliar to proinsuline  Effect on extrauterine growth via IGF-1ile (70aa polypeptide)

31 Disorders associated with low IGF-1 levels  GH deficiency  Hypothyroidism  Malnutrition  Chronic diseases

32  Fetal IGF-1 is correlated with gestastional age  Newborn IGF-1 levels are % of adult values  Increase through out childhood and reach adult levels in puberty  Gonadal steroids increase IGF-1 production.  In puberty levels are 2-3 fold higher than adult values  Increase osteoblastic activity and collagen synthesis stimulate long bone growth

33  IGF’ s are bound to IGF binding proteins (IGFBP)  t ½  Transport to target tissue.  Modulate the relation with IGF rec  6 different IGFBP are cloned  IGFBP-3, 90 % related to GH

34  IGF-1 rec  Structure resembles insulin rec (2 alpha,2beta subunits)

35 GH increase  GHRH  Arginin,leucine  Alpha adrenergic agonists (alpha 2 adrenergic)  Beta adrenergic antagonists  Dopamine, acetylcholine  Hypoglycemia  Sleeping  Exercise

36 GH decrease  Hypergylcemia  Obesity  İncrease in free FA  Glucocortikoid excess  Hypothyroidism  Incresed adrenergic tonus  Psychosocial deprivition

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40 Is derived from primitive pharynx-precursor of T4 producing cells And fourth pharengeal pouch- precursor of calcitonin(C) cells For development and descent of thyroid several transcription factors such asTITF1/NKX2, FOXE1 and PAX 8 are needed to work on time and coordinated Thyroid gland development

41 Embryogenesis  After 1st month it is visable.  At ıntrauterin 8 wk Tg synthesis begins shows thyroid activity  10. wk iodine trapping  12. wk colloid formation begins and withTSH sec from pituitary T4 synthesis begins  This synthesis increase progresively with hypothalamic maturation after 18 wk of gestation

42 Tiroid kolloidi tiroglobulin Protein sentezi Çekirdek DNA/RNA sentezi Damar G proteini Thyroid hormone biosynthesis

43 Thyroid hormone synthesis  Uptake  I uptake actively with Na-iodine pump

44 Thyroid hormone synthesis  Organification  İyodine + thyroglobulin MIT DIT

45 Thyroid hormone synthesis  Conjugation  MIT + DIT T3  DIT +DITT4 Thyroid peroksidase(TPO)

46 TİROKSİN (T4) I HO I 1’ 2’ 3’ 4’ 5’6’ O I I CH 2 CH COOH NH 2 (fenol halkası)(tirozil halkası) b a I R O I I R I R O I I R 5’ - monodeyidinasyon5 - monodeyidinasyon Tip I-II monodeyiodinaz Tip III monodeyiodinaz T3 rT3

47 Serum thyroid hormone concentrations  TT3¯ TBG¯ TT4¯ rT3/T4­

48 Effects of thyroid hormones  Growth  O2 usage  Heat production  Nerve functions  Lipids  Proteins  Nucleic acids  Vitamins  Inorganic ions  Other hormones Effect metabolism

49 Actions of thyroid hormones

50 Regulation of thyroid hormones

51 CAMP Iodine uptake­ İodothyrosine synthesis Tg synthesis Glucose oxidation Colloid pinositosis Hormone secretion Thyroid growth ATP Adenilate cyclase TSH G Protein

52 Regulation of thyroid hormones Iodine intake Physiologic limits Thyroid membrane iyodine uptake ­ Pharmachologic doses TPO activity¯ Iodine organification (Wolf Chaikoff effect) TSH induced CAMP stimulation inhibitted •Tg synthesis •Hormone secretion •Thyroid growth

53 Iodine needs in different times of age Age and stages of life Daily idoine recommendation(  g) 6 < months40 1< years in iodine deficient regions years Adoles and adults100 Pregnant and lactating women150

54 İYOT KLİRENSİ dolaşım I2I2 I2I2 I I %20 %80 Pasif reabsorbsiyon İdrarla iyot atılımı GFR + + I I ATPaz bağımlı Na-I simporter TSH (+) Follikül hücresi Daily iodine excretion gives intake

55 Iodine induced hyperthyoridism (Jodbasedow effect) Iodine induced hyperthyoridism (Jodbasedow effect) Nodular thyroid disease with otonomy and with out antibodies Diffuse goitre with thyroid stimulating antibodies Jodbasedow effect only in thyroids independent from TSH

56 Iodine deficiency  Iodine deficiency disorders (IDD) global heath problem  World’s most common endocrine disorder  Most frequent reseason for goitre and hypothyroidism

57 IDD Goitre Hypothyroxinemia Neurodevelopmental disorders Cretinism Decreased fertility Still birth Increased perinatal mortality

58 IDD indicators Decreased urinary iodine concentration Increased serum hTg concentration Increased newborn and cord blood TSH concentration

59 Thyroid disease risk  There is a U type relation between Iodine intake and thyroid disease


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