DEVELOPMENT OF THE ENDOCRINE SYSTEM Prof. Dr. Olcay Evliyaoğlu

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

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

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

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

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

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

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

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.

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

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

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

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)

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

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

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.

Development of pituitary gland

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

GH GH-BHBP Extracellular part of GH rec

Growth hormone Encoded by GH-1 gene. Locolized on 17q 22-24 chromosome.

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

GHRH Protein with 44 aminoacids Vazoactive intestinal polypeptide/ glukagon family

GH secretion

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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Thyroid hormone synthesis Organification İyodine + thyroglobulin MIT DIT

Thyroid hormone synthesis Conjugation MIT + DIT T3 DIT +DIT T4 Thyroid peroksidase(TPO)

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

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

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

Actions of thyroid hormones

Regulation of thyroid hormones

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

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

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

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

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

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

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

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

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