DEVELOPMENT OF THE ENDOCRINE SYSTEM

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 thealpha 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 develpmentEmbryology • 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

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 22-24 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 30-50 % 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

40. Thyroid gland development 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

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

43. Uptake I uptake actively with Na-iodine pump Thyroidhormonesynthesis

44. Thyroidhormonesynthesis • Organification • İyodine+ thyroglobulin MIT DIT

45. Thyroidhormonesynthesis • Conjugation • MIT + DIT T3 • DIT +DIT T4 Thyroid peroksidase(TPO)

46. TİROKSİN (T4) (fenol halkası) (tirozil halkası) I I COOH 5’ 6’ 5 6 a 1’ 1 O CH2 CH b HO 4’ 4 NH2 3’ 3 2’ 2 I I Tip I-II monodeyiodinaz Tip III monodeyiodinaz 5’ - monodeyidinasyon 5 - monodeyidinasyon I I R R R R O O I I I I T3 rT3

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

48. Effects of thyroid hormones • Growth • O2 usage • Heat production • Nerve functions • Lipids • Proteins • Nucleic acids • Vitamins • Inorganic ions • Other hormones Effectmetabolism

49. Actions of thyroid hormones

50. Regulation of thyroid hormones