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Hormone Action & Synthesis

Dr. Paul Foster - MBChB1 - CEP
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Paul Foster

on 19 October 2015

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Transcript of Hormone Action & Synthesis

Hormone Action & Synthesis
MBChB1 - CEP
Dr. Paul A. Foster
Lecturer in Molecular Endocrinology

Hypothalmo-pituitary axis
Thyroid Gland
Lecture 4: Adrenal Gland
Lecture 5: Endocrinology of
Calcium Homeostasis
Lecture 6: Ovarian & Testicular Function
Lecture 7: The Pancreas
Hypothalamus
Pituitary
Thyroid
Parathyroid
Adrenal
Pancreas
Ovaries
Testis
Lecture Learning Outcomes
- Understand the concept of glands, hormones and target tissues
- Name the three major groups of hormones and outline their synthesis, storage, transport to the target organs and how they react with specific receptors in or on the target organ
- Understand the role of feedback and endocrine axis in endocrine regulation
- Indicate the role of clinical observation in our understanding of hormone actions.
Comparative endocrinology

Actions of hormones similar throughout evolution.
Controlling Molecules
Clinical Endocrinology

Action of hormones as related to pathology
Still controlling molecules - just different examples
Caveman Endocrinologist?
Fredrick Banting

1921 - Discovers insulin
Protein & Peptide Hormones

Most common type of hormone:
Made of chains of amino acids
Hydrophilic!
Preformed and stored in membrane bound vesicles ready for release by exocytosis.

Produced on ribosomes (RER) as large precursor molecule - pre-prohormone

Pre-prohormone prohormone hormone
Pineal Gland
Thymus
Kidney
Digestive tract
The Endocrine System

A system of ductless glands and cells that secrete hormones.

Regulates - Metabolism, homeostasis, and reproduction.
GLANDS
ENDOCRINE GLANDS - release secretions (hormones) into blood directly from cells - ductless glands.

EXOCRINE GLANDS - (not part of the endocrine system) release their secretions outside the body and may be ducted e.g. gut secretions, sweat glands

MIXED GLANDS - e.g. Pancreas produces digestive juice + insulin, glucagon and somatostatin.
Two major regulatory systems of the body
They monitor and maintain a constant internal and external environment
ENDOCRINE
NERVOUS
Chemical component
Many hormones
Few neurotransmitters
Generally rapid
Generally slow
Speed of effect
Generally long-lasting
Generally short-lived
Duration of effect
Localisation of effect
Widespread - in blood
Localised - cell to cell
What is Endocrinology?
A hormone is a substance secreted directly into the blood by specialised cells.

Carried in the blood to receptors on target organs (can be endocrine, autocrine, paracrine)

Hormones are present in only minute concentrations in the blood and bind specific receptors in target cells to influence cellular reactions.
Mechanisms of chemical signalling
An intracrine signal is generated by a chemical acting within the same cell.

Autocrine signals are those in which a chemical acts on the same cell.

A paracrine mechanism is defined as chemical communication between neighbouring cells within a tissue or organ.

A chemical released by a specialized group of cells into the circulation and acting on a distant target tissue defines the ‘classical’ endocrine and neuroendocrine signalling mechanism.
The control of action at a distance
Feedback
- process by which body senses change and responds to it.

Negative Feedback
(most common)
- process by which body senses change and activates mechanism to reduce it.
The final product of an endocrine cascade acts to inhibit the release of hormones higher up the cascade.

Positive Feedback
- process by which body senses change and activates mechanism to amplify it.
Feedback - Control of hormonal release
Protein & Peptide Hormone Synthesis
Pre-pro Thyrotrophin Releasing Hormone (TRH)
BIG Protein (mol. wt. ~ 29,000)
= TRH (mol. wt. ~ 300)
proteolysis
In the corticotroph, pre-pro-opiomelanocortin produces one ACTH
Note: in other cells, proteolysis of POMC releases different hormones
alpha-subunit
beta-subunit
Thyroid stimulating hormone (TSH)
These glycoprotein hormones are related:
All released from anterior pituitary
A common alpha subunit
Beta subunit confers specificity
Luteinising hormone (LH)
Follicle stimulating hormone (FSH)
human Chorionic gonadotropin (hCG)
All made from cholesterol.
Steroid hormones
Hormones of the adrenal cortex and sex hormones
Hydrophobic!
Not stored - synthesised as required, then diffuse out of cell
Steroid hormone synthesis
NUCLEUS
MITOCHONDRIA
hydrolysis of esters
and release of
cholesterol
cholesterol to
pregnenolone
processing of
pregnenolone
S.E.R.
egress by diffusion or facilitated
Note: Movement of cholesterol to mitochondrion regulated by steroid acute regulatory protein (StAR). ACTH regulates StAR activity and processing of cholesterol
Tissue-specific and cell-specific expression of the enzymes necessary for each steroid hormone e.g in adrenal 3 cortical regions :

zona glomerulosa - aldosterone
zona fasciculata - cortisol
zona reticularis - adrenal androgens

e.g.zona glomerulosa contains cells expressing enzymes leading to aldosterone synthesis. Cells here do NOT express the enzymes necessary for cortisol synthesis or sex steroid synthesis.
Secretion & Excretion
Newly synthesized steroid hormones are rapidly secreted from the cell, with little if any storage.

Increases in secretion reflect accelerated rates of synthesis.

Steroid hormones are eliminated by inactivating metabolic transformations and excretion in urine or bile
Tyrosine derivatives bound together.
Contain 4 iodine atoms (T4).
Contain 3 iodine atoms (T3).
Small, non-polar molecules - therefore hydrophobic.
Soluble in plasma membranes
Amines - Thyroid Hormones
Thyroid follicles
How are hormones transported?
Peptide hormones hydrophilic

Steroid & Thyroid hormones
hydrophobic

Steroid & Thyroid hormones require carrier proteins
Increase solubility
Increase half-life
Reservoir in blood
Specific binding proteins e.g.Thyroid binding globulin (TBG) and cortisol binding globulin (CBG).

Non-specific binding proteins e.g. Albumin - loose binding. Aldosterone binds to albumin.
Site of Action of Hormones
Protein/peptide - Cell surface receptors - activate second messenger cascade to cause change in cellular function.

Steroid hormone - Intracellular receptors - cytoplasm or nuclear - Hormone-receptor complex binds to HRE.
CYP11A: Rate limiting step - Pregnenolone
What can go wrong? Endocrine Disorders

Excess:
Often caused by tumours
Or exogenous administration of hormone
Treatment - surgical removal of part of gland

Deficiency:
1° - primary organ inadequate, tropic hormone - feedback
2° – tropic hormone deficient
Autoimmune organ destruction most common cause

Treatment - replacement therapy
Orally absorbed, long half-life eg steroid (corticosteroid), thyroid (thyroxine) hormones.
Injection eg GH, insulin – peptide hormones. Otherwise degraded in GI tract.

NOTE! Failure can occur at any point in chain from synthesis to initiation of response including at receptor level or cascade generation.
Examples of Endocrine Disorders
Growth Hormone
Dwarfism
Gigantism
Excess
Deficient
Antidiuretic Hormone
Diabetes
Insipidus
Hyper-
valemia
Diabetes
Mellitus
Insulin
Coma
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