Transcript Hormone

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)





t½
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 pouchprecursor 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
 DIT +DIT
Thyroid peroksidase(TPO)
T3
T4
TİROKSİN (T4)
(fenol halkası)
(tirozil halkası)
I
I
5’
HO
6’
1’
b
4’
3’
5
O
a
4
3
2’
I
1
CH2
CH
NH2
2
I
Tip I-II
monodeyiodinaz
5’ - monodeyidinasyon
Tip III
monodeyiodinaz
I
R
COOH
6
I
R
O
I
I
T3
5 - monodeyidinasyon
R
R
O
I
I
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
TSH
CAMP
Adenilate cyclase
ATP
Iodine uptake
İodothyrosine
synthesis
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
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 life
Daily idoine
recommendation(g)
6<
30
6-12 months
40
1< years in iodine deficient
regions
1-10 years
Adoles and adults
Pregnant and lactating women
90
60-100
100
150
İYOT KLİRENSİ
TSH (+)
dolaşım
Follikül hücresi
ATPaz bağımlı
Na-I simporter
I2
I
I
%20
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
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