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

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 CH25’ 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 ­