DEVELOPMENT OF THE ENDOCRINE SYSTEM

Prof. Dr. Oya Ercan

 

Steroid hormones: are not storedrate 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: Mutation in the alpha subunit of G protein.

• Testotoxicosis: Mutation of LH receptor ( transmembrane domain - interaction with G protein.)

Syndromes 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.

All hormones are under some type of feedback control:

by cations (Ca-PTH)by metabolism (glucose-insulin)by other hormonesby osmolality or extracellular fluid volume

(vasopressin)

Direct Negative Feedback

• Metabolite

• Cortisol --> ACTH

• Thyroid hormones --> TSH

Indirect Negative Feedback

• Cortisol --> CRF (corticotropin releasing factor)

• Thyroid hormones --> TRH

Short Feedback

• TSH --> TRH

• ACTH --> CRH

Positive Feedback

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

 

Fetal Zone• CYP17 (p450c17) --> DHEA --> placental estrone,

estradiol --> DHEAS --> placental estriol

• Sulfotransferase

Transitional Zone• CYP17 + 3β HSD --> cortisol 

Outer Definitive Zone• 3β HSD --> mineralocorticoids

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.

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.

Biological Effects

• In adipose tissue, IGF’s have the same metabolic actions as insulin but are 1/16th 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 1/16th as potent as insulin in producing hypoglycemia.

Endocrine,paracrine,autocrine actions. Growth promoting effects through IGF

receptors;metabolic effects through insulin receptors.

• 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?).

IGFBPs

IGFBP-1 = 27500 dalton

GH, IGF-1→upregulate IGFBP3

↘downregulate IGFBP1

• 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.

• 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.

 

FETAL ZONE

• CYP 17 (p450c17) DHEA , DHEAS• Sulfotransferase Placenta Placenta estrone estriol estradiol