1. DEVELOPMENT OF THE ENDOCRINE SYSTEM Prof. Dr. Oya Ercan

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: Mutation in the alpha subunit of G protein. Testotoxicosis: Mutation of LH receptor ( transmembrane domain - interaction with G protein.)

5. Syndromes 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. All hormones are under some type of feedback control: by cations (Ca-PTH) by metabolism (glucose-insulin) by other hormones by osmolality or extracellular fluid volume (vasopressin)

11. Direct Negative Feedback Metabolite Cortisol --> ACTH Thyroid hormones --> TSH

12. Indirect Negative Feedback Cortisol --> CRF (corticotropin releasing factor) Thyroid hormones --> TRH

13. Short Feedback TSH --> TRH ACTH --> CRH

14. Positive Feedback Hypophysogonadal (only example) : Estrogen --> LH, FSH

15. Fetal Zone CYP17 (p450c17) --> DHEA --> placental estrone, estradiol --> DHEAS --> placental estriol Sulfotransferase Transitional Zone CYP17 + 3β HSD --> cortisol Outer Definitive Zone 3β HSD --> mineralocorticoids

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- ketosteroid reductase activity: cortisone --> cortisol Cortisol: an important stimulus for preparing the fetus for extrauterine survival.

17. Insulin-like Growth Factors (Somatomedins) They mediate growth promoting action of GH. GH is the primary regulator of their plasma level. They all have insulin-like activity. They are mitogenic for chondrocytes,osteoblasts and a variety of cells derived from extraskeletal tissues. They are transported in plasma bound to carrier proteins → their half life is extended.

18. Biological Effects In adipose tissue, IGF’s have the same metabolic actions as insulin but are 1/16 th as potent. They stimulate chondrocyte DNA,RNA,protein,collagen and proteoglycan synthesis. They act primarily on the skeletal tissues but also stimulate a wide variety of extraskeletal tissues to grow and differentiate.They induce hypoglycemia; on a molar basis IGF-1 is about 1/16 th as potent as insulin in producing hypoglycemia. Endocrine,paracrine,autocrine actions. Growth promoting effects through IGF receptors;metabolic effects through insulin receptors.

19. IGF-1 is lowest at birth and rises progressively throughout childhood.After puberty,plasma IGF level falls to normal adult values. The major regulator of IGF-1 level in serum after birth is GH. Nutritional status is also very important (Malnutrition→IGF↓). There is a decline of about 30% during sleep (sleep associated secretion of GH?).

20. IGFBPs IGFBP-1 = 27500 dalton GH, IGF-1→upregulate IGFBP 3 ↘ downregulate IGFBP 1

21. The morning IGFBP-1(peak levels during the night and a nadir during the day) levels are age-dependent. During childhood,a significant inverse relation is found between IGFBP-1 concentration and chronological age. This pattern is the opposite of that found for total IGF-1 and for IGFBP-3.IGFBP-1 may act as a transport protein for IGF-1 and IGF-2 from the circulation to their target cells.

22. IGFBP-3 in the circulation have been proposed to assure a constant supply of IGFs from a storage pool.Furthermore,BP-3 prevents the insulin-like action of IGFs and protects against hypoglycemia. The levels of circulation IGFBP-3 in healthy subjects show an age-dependent pattern similar to that reported for IGF-1. IGFBP-3 level is equimolar with the total IGF-1 plus IGF-2 concentration suggesting that all IGFBP-3 in circulation is saturated with IGF-3. The levels are decreased in GH deficiency.

31. FETAL ZONE CYP 17 (p450c17) DHEA, DHEAS Sulfotransferase Placenta Placenta estrone estriol estradiol