development of the endocrine system prof. dr. olcay evliyaoğlu
TRANSCRIPT
DEVELOPMENT OF THE ENDOCRINE
SYSTEMProf. 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 develpmentEmbryology
Mesoderm........adrenal cortex
Ectoderm.........adrenal medulla
5-6 wk fetal adrenal cortexOuter 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 --> cortisolCortisol: 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 hormoneEncoded by GH-1 gene.
Locolized on 17q 22-24 chromosome.
GH secretionUnder control of 2 hypothalamic hormones
Growth hormone releasing hormone(GHRH)Somatotropin release-inhibiting factor (SRIF,
somatostatin)
GHRHProtein 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 proteinSingle transmembrans helix Intracellular part
GH
IGF’s (somatomedins)Similliar to proinsulineEffect 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)t ½Transport to target tissue. Modulate the relation with IGF rec6 different IGFBP are cloned IGFBP-3, 90 % related to GH
IGF-1 recStructure resembles insulin rec (2 alpha,2beta
subunits)
GH increaseGHRH
Arginin,leucine
Alpha adrenergic agonists (alpha 2 adrenergic)
Beta adrenergic antagonists
Dopamine, acetylcholine
Hypoglycemia
Sleeping
Exercise
GH decreaseHypergylcemia
Obesity
İncrease in free FA
Glucocortikoid excess
Hypothyroidism
Incresed adrenergic tonus
Psychosocial deprivition
Is derived from primitive pharynx-precursor of T4 producing cellsAnd 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
Thyroid gland development
EmbryogenesisAfter 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
Tiroid kolloidi
tiroglobulin
Proteinsentezi
Çekirdek DNA/RNA sentezi
Damar
G proteini
Thyroid hormone biosynthesis
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 T3DIT +DIT T4
Thyroid peroksidase(TPO)
TİROKSİN (T4)TİROKSİN (T4)
I
HO
I
1’
2’3’
4’
5’ 6’
O
I
I
1
23
4
5 6
CH2 CH
COOH
NH2
(fenol halkası) (tirozil halkası)
I
R O
I
I
R
I
R O
I
I
R
5’ - monodeyidinasyon 5 - monodeyidinasyonTip I-II monodeyiodinaz
Tip III monodeyiodinaz
T3T3 rT3rT3
Serum thyroid hormone concentrations
TT3 TBGTBGTBGTBGTT4TT4TT4TT4 rT3/T4rT3/T4rT3/T4rT3/T4
Effects of thyroid hormones Growth
O2 usage
Heat production
Nerve functions
Lipids
Proteins
Nucleic acids
Vitamins
Inorganic ions
Other hormones
Effect metabolismEffect metabolism
Actions of thyroid hormones
Regulation of thyroid hormones
Regulation of thyroid hormones
CAMP Iodine uptake
İodothyrosine synthesis
Tg synthesis
Glucose oxidation
Colloid pinositosis
Hormone secretion
Thyroid growth
ATP
Adenilate cyclaseTSH
G Protein
Regulation of thyroid hormones
Iodine intakeIodine intake
Physiologic limits
Thyroid membrane iyodine uptake
Pharmachologic doses
TPO activity
Iodine organification (Wolf Chaikoff effect)
TSH induced CAMP stimulation inhibitted
• Tg synthesis• Hormone secretion• Thyroid growth
-- --
Iodine needs in different times of age
Age and stages of lifeDaily idoine
recommendation(g)
6 < 30
6-12 months 40
1< years in iodine deficient regions
90
1-10 years 60-100Adoles and adults 100
Pregnant and lactating women 150
İYOT KLİRENSİ
dolaşım
I2I2
II
%20
%80Pasif reabsorbsiyon
İdrarla iyot atılımı
GFR++
II
ATPaz bağımlı Na-I simporter
TSH (+)Follikül hücresi
Daily iodine excretion gives intakeDaily iodine excretion gives intake
Iodine induced hyperthyoridism(Jodbasedow effect)
Iodine induced hyperthyoridism(Jodbasedow effect)
Nodular thyroid disease with otonomy and with out antibodies
Diffuse goitre with thyroid stimulating antibodies
Jodbasedow effect only in thyroids independent from TSH
Iodine deficiencyIodine deficiency
Iodine deficiency disorders (IDD) global heath problem
World’s most common endocrine disorder
Most frequent reseason for goitre and hypothyroidism
IDDIDD
Goitre
Hypothyroxinemia
Neurodevelopmental disorders
Cretinism
Decreased fertility
Still birth
Increased perinatal mortality
IDD indicatorsIDD indicators
Decreased urinary iodine concentration
Increased serum hTg concentration
Increased newborn and cord blood TSH concentration
Thyroid disease risk Thyroid disease risk
There is a U type relation between Iodine intake
and thyroid disease