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Presentation on theme: "DEVELOPMENT OF THE ENDOCRINE SYSTEM"— Presentation transcript:

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


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)
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 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 +DIT T4 Thyroid peroksidase(TPO)

46 TİROKSİN (T4) I I I I (fenol halkası) (tirozil halkası) COOH HO O CH2
5’ 6’ 5 6 HO 4’ b 1’ O 4 a 1 CH2 CH 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 Effect metabolism

49 Actions of thyroid hormones

50 Regulation of thyroid hormones

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

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

53 Iodine needs in different times of age
Age and stages of life Daily idoine recommendation(g) 6 < 30 6-12 months 40 1< years in iodine deficient regions 90 1-10 years 60-100 Adoles and adults 100 Pregnant and lactating women 150

54 Daily iodine excretion gives intake
İYOT KLİRENSİ TSH (+) dolaşım Follikül hücresi ATPaz bağımlı Na-I simporter I I2 %20 I Pasif reabsorbsiyon %80 + GFR Daily iodine excretion gives intake İdrarla iyot atılımı

55 Iodine induced hyperthyoridism (Jodbasedow effect)
Nodular thyroid disease with otonomy and with out antibodies Iodine induced hyperthyoridism (Jodbasedow effect) 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 There is a U type relation between Iodine intake
and thyroid disease Thyroid disease risk ­


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