Year 1 Endocrinology Notes – Omair Shariq 2007
Life Cycle and Regulatory Systems -Endocrinology
Contents
SESSION 1: Introduction to the endocrine system
1.1 Define the terms hormone, endocrine gland, neurotransmitter and neurosecretion. ............................................... 5
1.2 Identify the features which distinguish endocrine from paracrine and autocrine systems....................................... 5
1.3 State that most hormones can be classified either as protein (and polypeptide) or steroid hormones, as well as
miscellaneous. ...................................................................................................................................................... 5
1.4 Describe the principal stages of protein/polypeptide hormone synthesis, how they are stored and the mechanism of
their secretion into the circulation. ......................................................................................................................... 6
1.5 Describe the different types of membrane receptor and the intracellular mechanisms of action induced by
hormones. ............................................................................................................................................................ 7
1.6 Explain how steroid hormones are synthesised and released into the circulation. ................................................. 9
1.7 Describe the receptors and mechanisms of action of steroid hormones. ............................................................. 10
1.8 Define the terms negative and positive feedback and explain how any individual hormone system is controlled. . 11
SESSION 1: The hypothalamo-adenohypophysial axis
1.1 Draw a diagram showing how hypothalamic hormones reach their target cells in the adenohypophysis (anterior
pituitary) using the terms hypothalamic nuclei, neurosecretions and hypothalamo-hypophysial portal system. .......... 12
1.2 Identify the six chief adenohypophysial hormones and relate them to the hormones which control them. ............ 13
1.3 Describe the general features of synthesis, storage and release of the adenohypophysial hormones, including the
pre-prohormone and prohormone stages when relevant. ........................................................................................ 13
1.4 Describe the principal physiological actions of corticotrophin (ACTH), thyrotrophin (TSH) and the two
gonadotrophins (LH and FSH). ............................................................................................................................ 14
1.5 Draw a diagram illustrating direct, indirect and short negative feedback loops, using the hypothalamoadenohypophysial-thyroidal axis for your example................................................................................................ 15
1.6 Describe the growth promoting and metabolic actions of somatotrophin. .......................................................... 15
1.7 Draw a labelled diagram illustrating the various controlling influences on somatotrophin release. ...................... 16
1.8 List the various actions of prolactin indicating which one is its principal physiological effect. ............................ 17
1.9 Draw a diagram illustrating how prolactin release is controlled, using the term neuroendocrine reflex arc. .......... 17
1.10 Explain why hyperprolactinaemia is associated with a contraceptive effect on the reproductive system. ............ 18
Summary table of the hypothalamo-adeno-hypophysial axis: ................................................................................. 18
SESSION 2: Hypothalamo-neurohypophysial axis
2.1 Draw a simple labelled diagram identifying the principal features of the neurohypophysial system. .................... 19
2.2 Name the two neurohypophysial hormones and indicate how their chemical structures differ. ............................ 20
2.3 Describe the principal steps involved in the synthesis, storage and release of the neurohypophysial hormones. .... 20
Arginine Vasopressin .................................................................................................................................................. 20
Oxytocin ...................................................................................................................................................................... 20
2.4 Name the receptors for vasopressin and the major intracellular pathway activated through each receptor. ........... 21
2.5 Name target cells for each of the vasopressin receptors. ................................................................................... 21
2.6 List the principal physiological actions of the neurohypophysial hormones. ...................................................... 21
2.7 Relate the actions of the hormones to their receptor types. ............................................................................... 22
2.8 Draw a labelled diagram illustrating the physiological action of vasopressin on renal water reabsorption. ........... 22
2.9 Describe the control systems involved in the production of the neurohypophysial hormones .............................. 22
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2.10 Draw a simple diagram illustrating the neuroendocrine reflex arc for oxytocin. ............................................... 23
SESSION 2: Insulin secretion and intermediary metabolism
2.1 Explain why the blood glucose concentration is closely regulated and list the hormones that control it. ............... 24
2.2 Draw a labelled diagram illustrating the relationship between the different types of cell in the islets of Langerhans.
Describe the endocrine pancreas. ......................................................................................................................... 24
2.3 Give an overview of the principal metabolic pathways for carbohydrates, proteins and fats, and the hormones that
regulate these pathways. ...................................................................................................................................... 25
Hormonal Regulation of Protein metabolism: ........................................................................................................ 26
Hormonal Regulation of Fat metabolism:............................................................................................................... 27
Overview of Carbohydrate, Protein and Fat Metabolism: .......................................................................................... 28
2.4 Describe the structure of a typical islet of Langerhans, identifying the different cellular components and their
principal endocrine secretions. ............................................................................................................................. 28
2.5 Describe the main features of insulin synthesis, storage and secretion. .............................................................. 28
2.6 List and describe the principal actions of insulin.............................................................................................. 29
2.7 Discuss the insulin receptor and its function. ................................................................................................... 30
2.8 Draw a labelled diagram illustrating the factors which regulate the release of insulin. ........................................ 30
2.9 Describe the synthesis, storage and secretion of glucagon. ............................................................................... 31
2.10 List and describe the principal actions of glucagon. ....................................................................................... 31
2.11 Draw a labelled diagram illustrating the factors which regulate the release of glucagon. ................................... 31
2.12 Describe in your own words what the diagnosis of diabetes means to patients (video) ...................................... 32
2.13 Describe the beta-cell sensing mechanism of glucose ..................................................................................... 32
2.14 Describe the endocrine regulation of intermediary metabolism ....................................................................... 32
SESSION 3: Diabetes Mellitus
3.1 List the principal signs and symptoms of diabetes mellitus, and relate them to the underlying pathophysiology. .. 34
3.2 Distinguish between Diabetes Mellitus types 1 and 2. ...................................................................................... 34
3.3 Explain the aetiology of type 1 diabetes mellitus. ............................................................................................ 35
3.4 Define insulin resistance and explain how it is related to diabetes, dyslipidaemia, hypertension and heart disease.35
3.5 Describe the consequences of insulin resistance on glucose, lipid and protein metabolism .................................. 35
3.6 Describe the physiology and risks of obesity. .................................................................................................. 36
3.7 Describe the pathophysiology of type 2 diabetes .............................................................................................. 36
SESSION 3: The thyroid and Iodothyronines
3.1 Describe the anatomy of the thyroid and the structure of the follicles. ............................................................... 37
3.2 List the main hormones produced by the follicular and parafollicular cells of the thyroid. .................................. 37
3.3 Describe using a diagram the features of iodothyronine synthesis, storage and release. ...................................... 37
3.4 Describe the physiological actions of the iodothyronines.................................................................................. 38
3.5 Explain the mechanism(s) of action of the iodothyronines. ............................................................................... 39
3.6 Describe the control mechanisms of iodothyronine production with particular reference to the hypothalamopituitary-thyroidal axis. ....................................................................................................................................... 39
3.7 Describe the principal clinical effects of excess circulating iodothyronines, and name the condition described. ... 40
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3.8 Describe the principal clinical effects associated with a deficiency in circulating iodothyronines, and name the
condition described. ............................................................................................................................................ 41
3.9 Understand the principles of treatment issues in the individual patient. ............................................................. 42
SESSION 4: The adrenals and the corticosteroids
4.1 Describe the anatomy of the adrenal gland, identifying the medulla and the cortical zones. ................................ 43
4.2 List the main hormonal products from the adrenal medulla and the adrenal cortex. ............................................ 43
4.3 Draw simple pathways identifying the main intermediates in the synthesis of the adrenal steroids. ..................... 44
4.4 State that the adrenal steroids exert their main effects via intracellular receptors and genomic mechanisms. ........ 44
4.5 Identify the main mineralocorticoid in humans and describe its principal actions ............................................... 45
4.6 Describe the control mechanisms for meneralocorticoid hormones. .................................................................. 45
4.7 Identify the main glucocorticoid in humans and describe its principal actions. ................................................... 46
4.8 State that cortisol plays an important role in the endocrine response to stress. .................................................... 46
4.9 Describe the principal features of the hypothalamo-pituitary-adrenal axis. ........................................................ 46
4.10 State that adrenal androgen production in women can be clinically important in conditions of overproduction. .. 47
4.11 Describe the effects of excess and deficiency of cortisol................................................................................. 47
4.12 Recognise the necessity for adrenal steroids for survival. ............................................................................... 47
SESSION 5: The gonads
5.1 Describe the stages of gametogenesis and the process of steroidogenesis in male and female gonads. ................. 48
5.2 Draw simple flow charts illustrating the synthesis of progesterone, 17b-oestradiol and testosterone. ................... 50
5.3 Label diagrams illustrating the principal structures of the testes and ovaries. ..................................................... 51
5.4 Describe the principal ovarian and endometrial changes that occur during the menstrual cycle. .......................... 51
5.5 Relate the synthesis of the major gonadal steroids in males and females to the relevant hormones of the
hypothalamo-adenohypophysial axis. ................................................................................................................... 53
5.6 Describe how the cyclic production of ovarian steroids is linked to the endometrial, cervical and other changes of
the menstrual cycle. ............................................................................................................................................ 55
5.7 Describe the actions of the gonadal steroids in males and females. ................................................................... 55
5.8 Identify the principal features of the control systems operating on the production of the gonadal steroids, with
particular reference to negative and positive feedback loops, in males and females. ................................................. 55
5.9 Define the terms primary and secondary amenorrhoea. .................................................................................... 56
5. 10 List the principal causes of infertility with references to endocrine causes. ..................................................... 56
5.11 Name the two major functions of the testes and, with the use of a simple diagram, describe how they are regulated
by the hypothalamo-pituitary axis. ....................................................................................................................... 57
5.12 With the use of diagrams that distinguish between follicular (early, mid, late) and luteal phases of the menstrual
cycle, summarise endocrine regulation of ovarian function. ................................................................................... 57
Summary: .......................................................................................................................................................... 57
SESSION 6: The parathyroids and calcium metabolism:
6.1 List the functions of calcium in the body. ........................................................................................................ 58
6.2 Identify the principal organs involved in calcium metabolism........................................................................... 58
6.3 Identify the bone cells and their functions. ...................................................................................................... 58
6.4 List the principal hormones which regulate blood calcium ion concentration, and their sites of synthesis. ........... 59
6.5 Briefly describe how parathormone, 1,25-dihydroxycholecaciferol and calcitonin are synthesized. ..................... 59
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6.6 Describe the principal effects of parathormone, 1,25-dihydroxycholecaciferol and calcitonin on bone, the kidneys
and the intestinal tract. ........................................................................................................................................ 59
6.7 Describe the mechanisms of action of parathormone, calcitrol and calcitonin. ................................................... 60
6.8 Explain how parathormone, 1,25-dihydroxycholecaciferol and calcitonin production are controlled, identifying the
principal stimulus in each case. ............................................................................................................................ 61
6.9 List the principal causes of hypocalcaemia. ..................................................................................................... 61
6.10 List the principal causes of hypercalcaemia. .................................................................................................. 61
6.11 Distinguish between primary, secondary and tertiary hyperparathyroidism. ..................................................... 62
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Session 1 – Introduction to Endocrinology
Learning objectives
1.
Define the terms hormone, endocrine gland, neurotransmitter and neurosecretion.
2.
Identify the features which distinguish endocrine from paracrine and autocrine systems.
3.
State that most hormones can be classified either as protein (and polypeptide) or steroid hormones, but that a few do not
fall easily into either of these two groups and therefore form a third group.
4.
Describe the principal stages of protein/polypeptide hormone synthesis, how they are stored and the mechanism of their
secretion into the circulation.
5.
Describe the different types of membrane receptor and the intracellular mechanisms of action induced by hormones.
6.
Explain how steroid hormones are synthesised and released into the circulation.
7.
Describe the receptors and mechanisms of action of steroid hormones.
8.
Define the terms negative and positive feedback and explain how any individual hormone system is controlled.
1.1 Define the terms hormone, endocrine gland, neurotransmitter and
neurosecretion.
Hormone: the bioactive messenger molecule secreted by an endocrine gland
into the blood to stimulate its target cells
Endocrine gland: a group of cells which secrete hormones directly into the
blood stream.
Neurotransmitter: A chemical agent that is released from an axon terminal
(on the presynaptic neurone) and diffuses across the synaptic cleft to bind
with a receptor on the surface of the postsynaptic cell. They transmit
excitatory/inhibitory nerve impulses across a synapse.
Neurones in hypothalamus can
release their neurosecretions
either across synapses to
influence other neurones ( act
as neurotransmitters) or into
the blood which carries them
to target cells (act as
hormones)
Neurosecretion: a chemical agent (i.e. hormone) secreted by neurones into an extracellular space (i.e. blood
stream) to have an effect on target cells.
1.2 Identify the features which distinguish endocrine from paracrine and
autocrine systems.
Endocrine: the hormone is secreted directly into the bloodstream to have an effect upon a target cell a distance
from the source (i.e. FSH)
Paracrine: the hormone is released into the immediate area around the source and has an effect on local
neighbouring cells close by (i.e. glucagon)
Autocrine: a local hormone which exerts an effect on its own sites of production. (i.e. oestradiol)
1.3 State that most hormones can be classified either as protein (and
polypeptide) or steroid hormones, as well as miscellaneous.
1) Protein and polypeptide:
 Synthesised from amino acids linked by peptide bonds.
 Consist of less than 10 amino acids.
 Some protein hormones contain carbohydrate residues and are called glycoproteins
2) Steroid hormones:
 Hormones produced from adrenal cortices (corticosteroids) the gonads (androgens, oestrogens and


progestogens) and vitamin D3 metabolites
All derived from cholesterol
Four rings
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3) Miscellaneous:
 Some derived from amino acids (i.e. tyrosine) – includes:



iodinated thyronines of thyroid gland
catecholamines (adrenaline and noradrenalin of the adrenal medulla and dopamine of the
hypothalamus
Some are lipid-soluble, such as prostaglandins and thromboxanes.
1.4 Describe the principal stages of protein/polypeptide hormone synthesis, how
they are stored and the mechanism of their secretion into the circulation.
Overview:

Innitially synthesized on the
ribosomes of the endocrine cells as
larger proteins known as
preprohormones.

Then cleaved to prohormones by
proteolytic enzymes in rough
endoplasmic reticulum.

The prohormone is then packaged
into secretory vesicles by the Golgi
apparatus.

It is cleaved to yield the active
hormone and other peptide chains
found in the prohormone.

Synthesis, Storage and Secretion:
1) Transcription from DNA template
to produce mRNA template.
2) mRNA becomes associated with ribosomes
along the rough ER in cytoplasm.
3) tRNA enter cytoplasm and attach to specific
amino acids (charged tRNA), and they then
migrate to the ribosomes where they link up
with mRNA codons according to complementary base pairing.
4) Amino acids become linked to each other by
Peptide bonding to form the new protein or
polypeptide molecule (translation)
5) Pre-prohormone molecule migrates through
Membrane of the RER and loses signal peptide
sequence.
6) Resulting prohormone reaches Golgi complex and becomes incorporated into membrane-bound vesicle (storage)
7) Granule dissociates from Golgi apparatus and moves through cytoplasm towards cell membrane. Inside the
granule protease enzymes split prohormone into its components.
8) Secretion via exocytosis - associated with excitation of endocrine cell by a stimulus. Triggered by Ca2+ influx.
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1.5 Describe the different types of membrane receptor and the intracellular
mechanisms of action induced by hormones.
Receptor: a protein on the cell membrane or within the cytoplasm or cell nucleus that binds to a specific chemical
messenger (a ligand) and initiates the cellular response to the ligand.



Receptors for peptide hormones and catecholamines are proteins located in the plasma membranes of the
target cells (transmembrane proteins).
 Because protein and polypeptide hormones generally unable to penetrate the cell membranes.
Receptors for steroid and thyroid hormones are proteins located mainly inside the target cells (intracellular
proteins).
 Because steroids are fat-soluble and can penetrate plasma membranes via simple diffusion.
Two main types of transmembrane receptors:
Tyrosine Kinase



Inherent enzyme activity
When appropriate hormone binds to this receptor, conversion of ATP
to ADP catalysed and simultaneous phosphorylation of a specific
cytoplasmic proteins.
Majority of proteins that are phosphorylated contain the amino acid
tyrosine (hence the name tyrosine kinase)
Protein kinase is the name
for any enzyme that
phosphorylates other
proteins by transferring to
them a phosphate group from
ATP. Introduction of the
phosphate group changes the
conformation and/or activity
of the recipient protein,
often itself an enzyme
1. Binding of a messenger to receptor changes
conformation of the receptor so enzyme
portion (located on cytoplasmic side of the
membrane) is activated.
2. Results in autophosphorylation – receptor
phosphorylates own tyrosine groups.
3. Newly created phosphotyrosines serve as
‘docking’ sites for cytoplasmic proteins
with a high affinity.
4. Bound proteins then bind other proteinsleads to cascade of signalling pathways
inside the cell.
G-Protein Linked

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


Bound to the receptor is a protein located on the inner (cytosolic) surface of the plasma membrane and
belonging to the family of proteins known as G proteins (guanine nucleotide binding protein)
Inactive G-protein consists of 3 different subunits (α, β and γ).
When ligand binds to receptor, conformation changes, so α subunit dissociates from the other two.
Subunit can link up with another plasma-membrane protein- either an ion channel or an enzyme (known as
plasma membrane effector proteins).
This permits the release of second messenger molecules such as cAMP, cGMP, DAG and Ca2+ ions
Two most important effector-protein enzymes: adenyl cyclase (cAMP as second messenger) and phospholipase C
(DAG and Ca2+ as second messenger)
Second messengers are non-protein substances that enter the cytoplasm or are enzymatically generated there
as a result of plasma-membrane receptor activation and diffuse throughout the cell to transmit signals.

Cyclic AMP:
1. When the ligand binds to the receptor, the receptor activates its associated G-protein.
2. G-protein becomes able to exchange a GDP (guanosine diphosphate) molecule on its alpha subunit
for a GTP (guanosine triphosphate) molecule.
3. Then the alpha subunit breaks free from the beta and gamma subunits, and the receptor.
4. The enzyme adenylate cyclase is activated by Gα-GTP and synthesizes the second messenger cyclic
adenosine monophosphate (cAMP) from ATP.
5. cAMP then interacts with other proteins downstream to cause a change in cell behavior.
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i.
It binds to and activates a protein (cAMP-dependent protein kinase) causing dissociation
between its regulatory and catalytic subunits.
ii.
The protein kinase then phosphorylates other proteins
iii.
The change in the activity of these proteins brings about the response of the cell.
6. The action of cAMP is eventually terminated by its breakdown to noncyclic AMP.
7. Reaction catalyzed by the enzyme phosphodiesterase.

Phospholipase C:


When the ligand binds to the receptor, a membrane-bound enzyme phospholipase C (PLC) is activated.
PLC hydrolyzes PIP2, a phosphatidylinositol, into two second messengers, inositol triphosphate (IP 3) and
diacylglycerol (DAG), which then go on to influence intracellular calcium levels.

Inositol triphosphate (IP3)
1) IP3 stimulates the release of calcium into the cytosol from intracellular stores. IP3, after
entering the cytosol, binds to calcium channels on the outer membranes of the endoplasmic
reticulum and opens them.
2) The IP3-sensitive calcium then stimulates the release of further calcium from other IP3sensitive, intracellular stores, so that a wave of calcium ions spreads rapidly across the
cytoplasm.
3) Calcium ions have many effects on metabolic processes (see below).

1)
Diacylglycerol (DAG)
Activates the membrane-bound
enzyme protein kinase C (PKC).
2)
This enzyme phosphorylates
intra-cellular proteins which can
act on a variety of metabolic
pathways within the cell
cytoplasm and nucleus.
3)
However, for DAG to activate
PKC, there needs to be a
cytosolic increase in calcium
ions which is one of the
functions of IP3.
8

Calcium as a second messenger:

By means of active transport systems in the plasma
membrane and cell
organelles, Ca2+ is maintained at an extremely low
concentration in the cytosol.

Two sources available to provide an increase in
cytoplasmic Ca2+ conc.
1. Receptor activation:
a. Plasma-membrane calcium channels open
in response to a first messenger; the receptor
itself may contain the channel, or the
receptor may activate a G protein that opens
the channel via a second messenger.
b. Calcium is released from the endoplasmic
reticulum; this is mediated by second
messengers, particularly IP3 and calcium
entering from the extracellular fluid.
c. Active calcium transport out of the cell is
inhibited by a second messenger.
2. Opening of voltage-sensitive calcium channels




Calcium is able to bind to intracellular binding
proteins, altering conformation and activating their
function.
Major calcium binding proteins in muscle are
troponins, and calmodulins in non-muscle cells.
Active calcium-calmodulin complex interacts with
various proteins such as protein kinases.
 Activation or inhibition of calmodulin-dependent protein kinases leads, via phosphorylation, to
activation or inhibition of proteins involved in the cell’s ultimate responses to the first messenger.
Ca2+-calmodulin can also stimulate calcium pump activity, thus leading to increased uptake of calcium by
intracellular stores.
1.6 Explain how steroid hormones are synthesised and released into the
circulation.
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


Steroid hormones are lipid soluble and can diffuse through cell membranes easily.
Thus, they are mainly synthesised (in the gonads and adrenal glands) when required from precursor
molecules (as a result of enzyme-induced reactions within the cell cytoplasm).
Initial precursor: cholesterol
o Can be synthesised by the endocrine cells from acetate.
o Can reach the cell following its transport in the blood associated with lipoproteins.
Cholesterol is a precursor for 5 steroid hormone classes:
i.
Progestins (e.g. progesterone)
- Help mediate the menstrual cycle and pregnancy
ii.
Glucocorticoids (e.g. Cortisol)
- Affect metabolism of carbohydrate, protein and lipids
iii.
Mineralcorticoids (e.g. Aldosterone)
- Maintain salt and water balance
iv.
Androgens (e.g. Testosterone)
- Affect maturation and function of secondary sex organs (male sexual
determination).
v.
Oestrogens
- Promote female sexual development.
Immediate synthesis occurs when specific enzymes are activated within the cytoplasm to act on precursor
molecules (i.e. cholesterol).
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
Once the hormone is released from the cell (by diffusion), it is bound to a plasma protein in circulation,
with only a small proportion remaining unbound.
Major Pathways of Steroid Hormone Synthesis:
1.7 Describe the receptors and mechanisms of action of steroid hormones.


Receptors mainly found in nucleus (sometimes in cytoplasm)
The receptors for lipid-soluble messengers, once activated by hormone binding, act in then nucleus as
transcription factors to increase or decrease the rate of gene transcription.
Mechanism of Action
1. Circulating steroid hormones are released from their
binding proteins and pass into target cell.
2. The messenger diffuses across the cells plasma
membrane and nuclear membrane to enter the
nucleus and binds to the receptor there.
3. The activated receptor then functions in the nucleus
as a transcription factor.
4. The receptor binds to a specific sequence of
nucleotides in a hormone-regulated gene called a
hormone response element. This increases the rate
of that gene’s transcription into mRNA.
5. The mRNA formed enters the cytosol and directs the
synthesis (on ribosomes) of the protein encoded by
the gene.
6. Increases conc of that protein.
Hormones can influence two stages in the synthesis of protein:
i.
The transcription of the code from DNA to mRNA
ii.
The translation of the mRNA code to the synthesis of the protein on the ribosomes.
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1.8 Define the terms negative and positive feedback and explain how any
individual hormone system is controlled.



Negative feedback: an increase or decrease in the variable being regulated brings about responses that move
the variable in the direction opposite to the direction of the original change
(i.e. in blood glucose; when blood glucose is high, it is senses by cells in the pancreas and insulin is secreted,
which causes the blood glucose to fall, sufficiently back to normal where insulin secretion is inhibited
Positive feedback: a hormone acts as a stimulus of its own production. The signal generator is stimulated by
the action which its signal produces.
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Session 1 – Hypothalamus and Pituitary
andPituiocrinology
Learning objectives – the hypothalamo-adenohypophysial axis
1.
Draw a labelled diagram showing how hypothalamic hormones reach their target cells in the adenohypophysis (anterior
pituitary) using the terms hypothalamic nuclei, neurosecretions and hypothalamo-hypophysial portal system.
2.
Identify the six chief adenohypophysial hormones and relate them to the hypothalamic hormones which control them,
indicating whether the latter hormones stimulate or inhibit their production.
3.
Describe the general features of synthesis, storage and release of the adenohypophysial hormones, including the preprohormone and prohormone stages when relevant.
4.
Describe the principal physiological actions of corticotrophin (ACTH), thyrotrophin (TSH) and the two gonadotrophins (LH
and FSH).
5.
Draw a diagram illustrating direct, indirect and short negative feedback loops, using the hypothalamo-adenohypophysialthyroidal axis for your example.
6.
Describe the growth promoting and metabolic actions of somatotrophin (growth hormone).
7.
Draw a labelled diagram illustrating the various controlling influences on somatotrophin release.
8.
List the various actions of prolactin indicating which one is its principal physiological effect.
9.
Draw a labelled diagram illustrating how prolactin release is controlled, using the term neuroendocrine reflex arc.
10. Explain why hyperprolactinaemia is associated with a contraceptive effect on the reproductive system
Intro:
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Hypothalamus endocrine function closely associated with that of the hypophysis (pituitary gland)
Pituitary gland lies in a pocket of the sphenoid bond at the base of the brain, just below the hypothalamus.
Pituitary is connected to the hypothalamus by the infundibulum, a stalk containing nerve fibres and small
blood vessels.
Pituitary composed of two adjacent lobes: anterior (adenohypophysis) and posterior (neurohypophysis)
Secretions by hypothalamic neurones are released into the anterior pituitary via the hypophysial-portal
blood system.
The capillaries at the base of the hypothalamus (the median eminence) recombine to form the
hypothalamo-pituitary portal vessels.
 Offers a local route for blood flow directly from the hypothalamus to the anterior pituitary.
 Blood flows from primary capillary plexus in median eminence to the secondary capillary plexus in
the adenohypophysis via a venus portal system (hypothalamo-hypophysial portal system).
Secretions also released into a capillary network in the posterior pituitary.
1.1 Draw a labelled diagram showing how hypothalamic hormones reach their
target cells in the adenohypophysis (anterior pituitary) using the terms
hypothalamic nuclei, neurosecretions and hypothalamo-hypophysial portal
system.
rd
3 ventricle
Hypothalamic Nuclei
Neurones to median
eminence
Neurosecretions
releasing/inhibiting
hormones
Adenohypophysis
Adenohypophysial
hormones
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andPituiocrinology
1.2 Identify the six chief adenohypophysial hormones and relate them to the
hypothalamic hormones which control them.
Adenohypophysial hormones:
1. Proteins:
1. Somatotrophin (growth hormone, GH)
2. Prolactin (PRL)
2. Glycoproteins:
3. Thyrotrophin (thyroid-stimulating hormone, TSH)
4. Gonadotrophin (Luteinizing hormone, LH)
5. Gonadotrophin (Follicle-stimulating hormone, FSH)
3. Polypeptides:
6. Corticotrophin (ACTH)
Hypothalamic releasing and inhibiting hormones:

Somatotrophin-releasing hormone (SRH or Growth hormone-releasing hormone, GHRH)
+
Stimulates Somatotrophin

Somatostatin (SS)

Thyrotrophin-releasing hormone (TRH)

Dopamine (DA)

Gonadotrophin releasing hormone (GnRH)

Corticotrophin-releasing hormone (CRH)

Vasopressin (VP) or ADH
- Inhibits Somatotrophin
+ Stimulates Thyrotrophin
+ Stimulates Prolactin
- Inhibits Prolactin
+ Stimulates Luteinizing hormone and Follicle-stimulating hormone
+ Stimulates Corticotrophin
+ Stimulates Corticotrophin
1.3 Describe the general features of synthesis, storage and release of the
adenohypophysial hormones, including the pre-prohormone and prohormone
stages when relevant.





The peptides are initially synthesized as much larger pre-prohormones according to their specific gene
sequences.
Following transcription, and translation on the RER, pre-prohormone loses signal peptide sequence and becomes
prohormone.
Prohormone then transferred to the Golgi complex where the final products of enzme action are packaged into
granules (storage).
Inside the granules, various specific protease enzymes then cleave the prohormone into its bioactive hormone
component.
The hormones are stored in secretory granules within the cytosol and are released into the bloodstream via
exocytosis.
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andPituiocrinology
1.4 Describe the principal physiological actions of corticotrophin (ACTH),
thyrotrophin (TSH) and the two gonadotrophins (LH and FSH).
Corticotrophin (ACTH)


ACTH stimulates the zonae fasciculate and reticularis within the cortex of the adrenal gland and boosts the
synthesis of corticosteroids, mainly glucocorticoids but also mineralcorticoids and sex steroids (androgens)
Mechanism: binds to specific membrane receptors on its target cells, and adenyl cyclase is activated.
 Generation of intracellular cAMP results in increased protein kinase A activity, and
phosphorylation of intracellular proteins.
Thyrotrophin (TSH)



Stimulates the thyroid gland to secrete two of its own hormones, the iodothyronines triiodothyronine (T 3)
and thyroxine (T4)
Increases vascularity of the thyroid, and the follicular cells increase in size and number- results in enlarged
thyroid (goitre).
Mechanism: binds to its membrane receptor on the follicular cells of the thyroid. The receptor is linked to a
Gs protein which activates adenyl cyclase. Protein kinase A is then activated, and this results in
phosphorylation of intracellular proteins.
Gonadotrophins (LH and FSH)

LH:





In females: acts on ovaries to stimulate ovarian steroid hormone production.
In follicular stage of menstrual cycle: stimulates production of androgens (androstenedione)
Stimulates final maturation of the oocyte
Stimulates progestogen synthesis by outer granulosa cells.
Stimulates ovulation itself


In males: stimulates interstitial Leydig cells which secrete testosterone.
LH necessary to initiate spermatogenesis.

Mechanism: binds to membrane receptors in target cells and activates associated G protein complex which
stimulates adenyl cyclase. cAMP generation activates protein kinase activation and phosphorylation of
intracellular proteins. (Similar for both gonadotrophins)

FSH:




In females: stimulates follicular development in the ovary.
Stimulates aromatase enzyme activity in granulosa cells during early follicular stage of menstrual
cycle. Thus, androgens are aromatized to oestrogens.
During pre-ovulatory stage, FSH stimulates outer later of granulosa cells to synthesise LH receptors.
In males: acts on Sertoli cells and initiates spermatogenesis
14
andPituiocrinology
1.5 Draw a diagram illustrating direct, indirect and short negative feedback
loops, using the hypothalamo-adenohypophysial-thyroidal axis for your example.

Consider the chain where, the hypothalamus secretes a hormone, called thyrotrophin releasing hormone (TRH)
which stimulates the secretion of thyrotrophin (TSH) in the adenohypophysis which in turn stimulates the
thyroid to release thyroxine (T3) or triiodothyronine (T4)

Direct negative feedback: when the levels of T3 or T4 rise high enough, it starts to stimulate its own inhibition
by inhibiting the secretion of the thyrotrophin (TSH) in the adenohypophysis. (this is done by the T3/T4
molecules attaching to receptors in the adenohypophysis)
Indirect negative feedback: when the levels of T3/T4 rise high enough it starts to stimulate its own inhibition
by inhibiting the secretion of the thyrotrophin releasing hormones (TRH) in the hypothalamus, which in turn
produces less thyrotrophin (TSH) in the adenohypophysis which ultimately results in less T3/T4 in the thyroid
gland.
Auto (short-loop) negative feedback: this is where the adenohypophysial hormones can influence their own
release by having a feedback influence on the secretion of their release-stimulating or release-inhibiting
hypothalamic hormones. (i.e. in this case the thyrotrophin inhibiting its own release by inhibiting the
production of thyrotrophin releasing hormone (TRH) in the hypothalamus.


Indirect -ve
Auto -ve
Hypothalamus
TRH
Direct -ve
Adenohypophysis
Thyrotrophin (TSH)
Thyroid
T3 and T4
1.6 Describe the growth promoting and metabolic actions of somatotrophin.



Somatomedins (IGF I & IGF II) are synthesized which stimulate cell proliferation (i.e. they are mitogenic)
and/or cell differentiation depending on tissue involved.
There are two somatomedins which are synthesised following the stimulation of the hepatocytes by
somatotrophin (somatotrophin has an indirect effect on growth and development and somatomedins have a
direct effect on growth and development).
Because they have insulin-like effects as well as growth-promoting action they are known as insulin-like growth
factors (IGF-I has greater growth-promoting effect whilst IGF-II has greater insulin-like activity)
Metabolic actions:



Stimulate amino acid transport into cells, e.g. muscle.
Stimulate protein synthesis (via aa transport and increasing synthesis and activity of ribosomes).
Increased cartilaginous growth.
15
andPituiocrinology
- Anti-insulin effects:
 Stimulation of lipid metabolism – fatty acid production
(renders adipocytes more sensitive to lipolytic stimuli).
 Antagonises the effect of insulin on glucose uptake by
peripheral cells.
 Stimulates hepatic gluconeogenesis.
 Decrease glucose utilisation (due to increased insulin
resistance)
= increased blood glucose concentration.
1.7 Draw a labelled diagram illustrating the
various controlling influences on
somatotrophin release.

Most important influence exerted by
GHRH

Lesser influence from SS.

Blood level of circulating somatotrophin
can have inhibitory effect (short –ve
feedback loop)

Circulating concentrations of
somatomedins can also have an effect by
negative feedback loops at hypothalamic
and/or adeno-hypophysial levels.

Oestrogens stimulate production by
altering number of receptor sites for
hypothalamic hormones on the
somatrotrophes.
16
andPituiocrinology
1.8 List the various actions of prolactin indicating which one is its principal
physiological effect.

Principal function: initiation and maintenance of lactation in postpartum women as well as growth and
development of beasts.
However, other effects include:
1. Stimulates generation of LH receptors in the gonads of both sexes.
 In males: LH receptors synthesised in Leydig cells
 In females: LH receptors synthesised in corpus luteum.
2. Provides the body with sexual gratification after sexual acts (refractory period in males)
3. Interacts with immune system: stimulates lymphocyte proliferation.
4. Renal sodium/Na+ reabsorption (natriuretic action)

1.9 Draw a labelled diagram illustrating how prolactin release is controlled, using
the term neuroendocrine reflex arc.







Prolactin release primarily under control of the hypothalamus which receives afferent impulses initiated
from sensory receptors, particularly around nipples in lactating women.
Dominant hypothalamic influence is inhibitory via dopamine.
Thyrotrophin-releasing hormone stimulates prolactin release from lactotrophe cells.
Thyroxine also decreases the number of TRH receptor sites while oestrogens increase their availability
Main physiological stimulus for prolactin release is when infant suckles at breast.
Tactile receptors around nipple stimulated and increased afferent nerve activity reaches hypothalamus.
Neuroendocrine reflex arc involves inhibition of dopamine release and stimulation of TRH release from
hypothalamic neurones into hypothalamo-hypophysial portal system.
Stressors
Higher centres
+
+
+
TRH
DA
+
EFFERENT
ENDOCRINE
PATHWAY
PROLACTIN
SUCKLING
Stimulation
of tactile receptors
Neural afferent
limb
Adenohypophysis
+
-
AFFERENT NEURAL
PATHWAY
oestrogens
iodothyronines
BREAST(post-partum)
MILK PRODUCTION
Neuroendocrine Reflex Arc:
Higher centres
Hypothalamus
Dopamine/TRH
Tactile receptors
Suckling breast
Hypothalamus
Adenohypophysis
Prolactin
Milk production in breast
Endocrine
efferent limb
17
andPituiocrinology
1.10 Explain why hyperprolactinaemia is associated with a contraceptive effect
on the reproductive system.




Excessive prolactin production interferes with hypothaloamo-pituitary-gonadal axis.
Inhibition of reproductive axis because of increased dopamine (which inhibits prolactin) – as a result of
short-loop feedback effect of raised plasma prolactin level.
Men become impotent, lose libido and become infertile.
Women develop amenorrhoea or oligomenorrhoea and may not ovulate
Summary table of the hypothalamo-adeno-hypophysial axis:
+
18
andPituiocrinology
Learning objectives: the hypothalamo-neurohypophysial axis
1.
Draw a simple labelled diagram identifying the principal features of the neurohypophysial system.
2.
Name the two neurohypophysial hormones and indicate how their chemical structures differ.
3.
Describe the principal steps involved in the synthesis, storage and release of the neurohypophysial hormones.
4.
Name the receptors for vasopressin and the major intracellular pathway activated through each receptor.
5.
Name target cells for each of the vasopressin receptors.
6.
List the principal physiological actions of the neurohypophysial hormones.
7.
Relate the actions of the hormones to their receptor types.
8.
Draw a labelled diagram illustrating the principal physiological action of vasopressin on renal water reabsorption.
9.
Describe the control systems involved in the production of the neurohypophysial hormones
10. Draw a simple diagram illustrating the neuroendocrine reflex arc for oxytocin.
2.1 Draw a simple labelled diagram identifying the principal features of the
neurohypophysial system.

The posterior pituitary is an outgrowth of
the hypothalamus and is neural tissue.

The cells associated with the
neurohypophysis are neurones which have
their cell bodies grouped together in the
supraoptic and paraventricular nuclei in
the hypothalamus.

The unmyelinated axons of the two nuclei
pass through the infundibulum and end
within the posterior pituitary in close
proximity to capillaries.

The neurones are mainly magnocellular
neurones which pass through the median
eminence and terminate near capillaries
the neurohypophysis.
Paraventricular nucleus
Supraoptic nucleus
Median
Eminence
Other parts of CNS
HYPOTHALAMUS
NEUROHYPOPHYSIS
(Posterior pituitary)
ADENOHYPOPHYSIS
(Anterior pituitary)
VASOPRESSIN
OXYTOCIN

Some smaller neurones (parvocellular
neurones) which originate in the
paraventricular nuclei release their neurosecretions into the primary capillary plexus in the median
eminence or send their axons to other parts of the brain.

Most of the posterior pituitary capillaries drain into the main bloodstream (via the jugular veins), which
carries the hormones to the heart to be distributed to the entire body
19
andPituiocrinology
2.2 Name the two neurohypophysial hormones and indicate how their chemical
structures differ.


The two principal secretory products of magnocellular neurones are vasopressin (ADH) and oxytocin.
They are both synthesised in the supraoptic and paraventricular nuclei, and they are transported down the
axons to the posterior pituitary.
The neurones are referred to as vasopressinergic or oxytocinergic (depending on which hormone they produce.)
Two forms of vasopressin identified:
 one contains amino acid arginine (arginine vasopressin, AVP) – found in most mammals including humans
 other contains lysine (lysine vasopressin, LVP) – found in hippopotamus and pigs
Both vasopressin and oxytocin are 9 amino acid nonapeptides consisting of a 6 amino acid ring (with two
cysteines linked by disulphide bonds at positions 1 and 6) and a chain of three amino acids.
Structure of oxytocin differs by only 2 amino acids:
 isoleucine instead of phenylalanine at position 3
 leucine for arginine at position 8




Oxytocin
Arginine Vasopressin
1
2
Tyr
3
Cys
Tyr
3
S
Phe
S
4 Glu
Asn
5
2
4
Cys
Pro
Arg
Gly
6
7
8
9
S
Glu
Asn
5
Cys
S
Ile
(NH2)
1
Cys
Pro
Leu
Gly
6
7
8
9
(NH2)
2.3 Describe the principal steps involved in the synthesis, storage and release of
the neurohypophysial hormones.
1. Synthesis occurs in cell bodies of magnocellular neurones in the supraoptic and paraventricular nuclei in the
hypothalamus.
2. Are initially synthesized as larger prohormones (pro-vasopressin and pro-oxytocin)
 Genes for both prohormones consist of exons separated by introns.
 Exon 1 regions contain vasopressin or oxytocin sequences
 Exon 2 regions contain sequences for proteins called neurophysins (released in equimolar amounts
with respective hormones).
 Exon 3 contains sequence for a glycopeptides, GP (only for vasopressin).
3. Molecular complexes become incorporated into granules which migrate down nerve axons as a result of
axoplasmic flow (axonal transport).
4. During migration the prohormone is cleaved by basic endopeptidases into the mature hormone and the
associated neurophysin.
5. Granules collect at nerve terminals and in the Herring bodies along the nerve axons.
6. Nerve endings lie close to capillaries in posterior lobe of pituitary
7. Release associated with arrival of action potentials at nerve endings which depolarise terminal membranes.
 Influx of calcium ions causes fusion of granules with the nerve terminal membrane
8. Granule contents released into bloodstream by exocytosis (neurophysins released with hormones, but they are
not bound to each other).
SP
AVP
Neurophysin
GP
Prevasopressin
GP
Pro-vasopressin
Glycosylation, disulhphide bridging, folding
AVP
Neurophysin
Cleavage and exocytosis
AVP
Neurophysin
GP
20
andPituiocrinology
2.4 Name the receptors for vasopressin and the major intracellular pathway
activated through each receptor.





Two main receptors identified and sequenced- called v1 and v2 receptors.
The v2 receptors are found on the baso-lateral surface on epithelial principal cells on renal collecting ducts and
mediate in principal physiological action of the hormone (antidiuretic)
The v1 receptors are found in other target cells.
Additional receptor similar to v1 identified- called v1b, located on the adenohypophysis.
All receptors have seven transmembrane domains and are coupled to G proteins.
V1 Receptors – IP3 and DAG pathways




When the ligand binds to the v1 receptor, a membrane-bound enzyme phospholipase C (PLC) is
activated by the associated G protein.
PLC hydrolyzes PIP2, a phosphatidylinositol, into two second messengers, inositol triphosphate (IP 3) and
diacylglycerol (DAG), which then go on to increase intracellular calcium levels.
Calcium ions have an affect on various metabolic pathways.
DAG activates protein kinase C, which phosphorylates intracellular proteins and can act on metabolic
pathways.
V2 Receptors – cAMP pathway

Receptors linked via G proteins to adenyl cyclase, which is activated when vasopressin binds.
 Adenyl cyclase synthesizes the second messenger cyclic adenosine monophosphate (cAMP) from
ATP.
 cAMP then binds to and activates protein kinase A
 Protein kinase A activates other intracellular mediators
 Which increase the production and action of aquaporin-2 molecules.
 Vasopressin stimulates the insertion into the luminal membrane, by exocytosis, of a particular
group of aquaporin water channels made by the collecting-duct cells.
2.5 Name target cells for each of the vasopressin receptors.



V1a:



V1b

V2

Arterial/smooth muscle (vasoconstriction, platelet adhesion)
Hepatocytes (glycogenolysis)
CNS neurons (behavioural and other effects, memory?)
Adenohypophysial corticotrophs (enhanced ACTH release)
Basolateral membrane of collecting duct (distal nephron) (water reabsorption)
2.6 List the principal physiological actions of the neurohypophysial hormones.
Oxytocin


Stimulates contraction of the smooth muscle of the myometrium during parturition.
Stimulates contraction of myoepithelial cells surrounding the ducts of lactating mammary glands
during lactation
Vasopressin




Principal action in renal collecting duct, where it stimulates water reabsorption.
Arteriolar vasoconstriction
ACTH release (along with CRH) – it is an ACTH secretagogue
Affect learning and memory- act as neurotransmitters/modulators
21
andPituiocrinology



Effects on the CNS- aggression, blood pressure regulation
Synthesis of blood coagulation factor (VIII and Von Wilebrandt factor)
Stimulates hepatic glycogenolysis
2.7 Relate the actions of the hormones to their receptor types.
(See point 2.4)
2.8 Draw a labelled diagram illustrating the principal physiological action of
vasopressin on renal water reabsorption.
Apical
membrane
1.
2.
3.
4.
5.
6.
Basolateral
membrane
Vasopressin binds to the V2 receptors on the basolateral of the epithelial principal cells and the associated G protein is
activated.
G protein is able to exchange a GDP molecule for GTP causing the alpha subunit to move away from the body of the Gprotein.
This activates adenylate cyclase, which causes GTP to give up a phosphate in order to make cAMP from ATP.
cAMP activates protein kinase A (PKA) molecules.
This causes water channels (aquaporins) which are contained in vesicles called aggrephores to move to the luminal
membrane. (specifically aquaporin-2)
This causes the water to move through the epithelial cells and into the plasma (the water leaves the epithelial cells via
aquaporin-3 and aquaporin-4 on the basolateral membrane)
2.9 Describe the control systems involved in the production of the
neurohypophysial hormones
Vasopressin
1. Stimulus: a decreased amount of water in the blood causes an increased plasma osmolality;
 This is detected by osmoreceptors in the hypothalamus, which send axons to the cell bodies of
supraoptic and paraventricular nuclei in the hypothalamus.
22
andPituiocrinology

This causes the release of vasopressin from the neurohypophysis which causes an increased uptake of
water from the collecting duct, decreasing in the plasma osmolality.
2. Stimulus: a decreased blood volume as a result of haemorrhage.
 Reduced circulating volumes stimulate VP release through activation of low pressure mechanoreceptors
in the left atria and central veins and high pressure baroreceptors in the carotid sinus and aortic arch.
 A decrease in the arterial blood volume leads to a decreased frequency of action potentials from these
various stretch receptors; this stimulates the release of vasopressin by decreasing the inhibitory effect
normally operated by this baroreceptor reflex pathway.
 The increased vasopressin causes vasoconstriction, which causes an increase in arterial blood pressure
3. Higher centres also exert a profound influence over neurohypophysial hormone release. Stimuli such as
emotional or surgical stress may cause massive release of vasopressin.
Oxytocin
1. Stimulus: Oxytocin release is stimulated in the lactating mother by suckling.
 Tactile receptors in the breasts, especially around the nipples, initiate action potentials which
propagate along afferent nerve fibres through the spinal cord and midbrain to the hypothalamus.
 The oxytocinergic cell bodies in the paraventricular and supraoptic nuclei are stimulated and cause the
release of oxytocin. The oxytocin causes the myoepithelial cells to contract (in the breast) leading to
milk ejection.
2. Stretch receptors in the vagina/uterus also stimulate action potentials in the afferent pathways, leading to
vasopressin release. This causes the smooth-muscle cells of the myometrium to contract.
3. Higher brain centres have also play a role in the control of oxytocin release. It is thought that emotional stress
leads to inhibition of lactation.
2.10 Draw a simple diagram illustrating the neuroendocrine reflex arc for
oxytocin.
Milk-ejection reflex:
23
Session 2 – Insulin Secretion and Intermediary Metabolism
Learning Objectives
1.
Explain why the blood glucose concentration is closely regulated and list the hormones that control it.
2.
Draw a labelled diagram illustrating the relationship between the different types of cell in the islets of Langerhans. Describe
the endocrine pancreas.
3.
Give an overview of the principal metabolic pathways for carbohydrates, proteins and fats, and the hormones that regulate
these pathways.
4.
Describe the structure of a typical islet of Langerhans, identifying the different cellular components and their principal
endocrine secretions.
5.
Describe the main features of insulin synthesis, storage and secretion.
6.
List and describe the principal actions of insulin
7.
Discuss the insulin receptor and its function.
8.
Draw a labelled diagram illustrating the factors which regulate the release of insulin.
9.
Describe the synthesis, storage and secretion of glucagon.
10. List and describe the principal actions of glucagon.
11. Draw a labelled diagram illustrating the factors which regulate the release of glucagon.
12. Describe in your own words what the diagnosis of diabetes means to patients (video)
13. Describe the beta-cell sensing mechanism of glucose
14. Describe the endocrine regulation of intermediary metabolism
2.1 Explain why the blood glucose concentration is closely regulated and list the
hormones that control it.






Glucose is a vital energy substrate as the CNS depends almost entirely on it as its source of energy.
Blood glucose is closely regulated as low glucose concentrations (below 4 and 5 mMol) can lead to
hypoglycaemia, whereby brain function is impaired.
If levels drop further (below 2mMol), it can lead to unconsciousness, coma and even death.
Conversely, if the blood glucose level is raised, hyperglycaemia can result which can lead to diabetic coma,
and if levels are not brought down immediately, can result in death.
Normal blood glucose levels are between 4 and 5mMol.
There are several hormones which control glucose levels…
Decrease levels: insulin.
Increase levels: glucagon, adrenaline, cortisol and somatotrophin
2.2 Draw a labelled diagram illustrating the relationship between the different
types of cell in the islets of Langerhans. Describe the endocrine pancreas.

Most of the pancreas (98%) is associated with exocrine
secretions via ducts to the small intestine.

Small clusters of endocrine cells within the pancreatic
tissue (remaining 2%) are called the islets of
Langerhans

Three main types of islet cells identified:
 α-cells secrete glucagon
 β-cells cells secrete and insulin
 δ cells are associated with somatostatin

In humans the α and δ cells lie peripheral (away from
center) to the more central β cells, which account for
60% of the total.

All three types of cell contain secretory granules inside
their cytoplasm, as well as intracellular components
such as RER, Golgi and microtubules.
24







The α-cells have more numerous and denser concentrations of granules in their cytoplasm than the β cells, but
the α cells are generally smaller.
δ cells contain numerous more uniform granules, which are less dense
than those of either α or the β cells
Type F cells have also been found on the periphery and these secrete
pancreatic polypeptides
Gap junctions have been observed between the various cells of the
islets,
 These could represent areas of direct intercellular
communication. (small molecules/ions can cross from cell to cell
at these gap junctions)
Tight junctions are also present, these involve the fusion of the outer
cell membranes.
 These tight junctions may close off some intercellular spaces.
 Hormones secreted into these spaces could then be
concentrated in these temporarily isolated fluid compartments
and thus exert powerful influences over the secretions of other
islet cells. This possible mechanism for intercellular
communication is called paracrine control.
Blood flows from the periphery to the core of the islets.
The arterial blood supply is from the splenic, hepatic and superior
mesenteric arteries, while the venous blood drains directly into the
portal vein, reaching the liver directly.
2.3 Give an overview of the principal metabolic pathways for carbohydrates,
proteins and fats, and the hormones that regulate these pathways.
1. Carbohydrates:
Metabolic pathways in glucose
metabolism (related to hormones):
1 Glycolysis:
Conversion of glucose to pyruvate
End products: pyruvate and ATP
Hormone action: THROXINE and
INSULIN increase glycolysis
2 Gluconeogenesis:
Synthesis of glucose from amino
acids, pyruvate and other
noncarbohydrates
Hormone action: enhanced by
CORTISOL, GLUCAGON, THYROXINE
and SOMATOTROPHIN
3 Glycogenesis:
Synthesis of glycogen from glucose
Hormone action: INSULIN increases
glycogenesis in muscle and liver cells
4 Glycogenolysis:
Breakdown of glycogen to glucose
Hormone action: enhanced by
GLUCAGON, ADRENALINE and
THYROXINE
Other hormone actions:
 Somatostatin: inhibits glucagon release from α cells and insulin from bcells
 Somatotrophin, Cortisol: antagonises insulin (decreased glucose uptake)
 ACTH: enhances release of cortisol
 Thyroxine: enhances absorption of sugars from intestine.
25
2. Proteins


Protein anabolism is the process by which protein are rebuilt from their amino acids (aka anabolic amino acid
synthesis)
Protein catabolism is the process by which proteins are broken down to their amino acids. This is also called
proteolysis.
Catabolism:


Digestion breaks protein down to amino acids. If amino acids are in excess of the body's biological
requirements, they are degraded and used for energy or stored as fat.
This degradation occurs almost entirely in the liver, and begins with a process called deamination.
Deamination:





Removal of amino groups from amino acids.
Amino group gives rise to a molecule of ammonia and is replaced by an oxygen to form a keto acid.
Deamination breaks the amino group down into ammonia and what is termed the carbon skeleton.
Ammonia is converted to urea, filtered through the kidneys, and excreted in urine.
The carbon skeleton (a keto acid) which is composed of carbon, hydrogen, and oxygen can then by used
either for protein synthesis, energy production (ATP), or converted to glucose by gluconeogenesis.
Transamination:

The second means of removing an amino group is known as transamination and involves transfer of the
amino group from an amino acid to a keto acid.
Oxidation of Deaminated Amino Acids:



The Keto acid can be oxidised to relase energy for metabolic purposes.
The keto acid is changed into an appropriate chemical substance that can enter the Krebs Cycle.
This substance is then degraded by the cycle and used for energy in the same way that acetylCoA is
used.
Gluconeogenesis:

Certain deaminated amino acids are similar to the substrates normally used by the cells to synthesise
glucose or fatty acids.
Anabolism:


After entry into cells, amino acids are combined by peptide linkages, under the direction of mRNA and
ribosomes, to form cellular proteins.
However, many intracellular proteins can be decomposed again to amino acids by lysosomal digestive enzymes.
Release of amino acids from the cells:




When plasma amino acid concentration galls below normal, amino acids transported out of cells to
replenish supply in the plasma.
Various hormones able to alter the balance between tissue proteins and circulating amino acids.
Somatotrophin and insulin INCREASE the formation of tissue proteins.
Glucocorticoids INCREASE the concentration of circulating amino acids.
Hormonal Regulation of Protein metabolism:
Somatotrophin:



Increases the rate of synthesis of cellular proteins.
Enhances to transport of amino acids through the cell membranes
And/or accelerates the DNA and RNA transcription and translation processes for protein synthesis.
Insulin:



Depresses gluconeogenesis (conserves amino acids)
Accelerates amino acid transport into cells, could be stimulus to protein synthesis.
Increases availability of glucose to the cells, so use of amino acids for energy becomes reduced.
Glucocorticoids:


Decrease the quantity of protein in most tissues while increasing the amino acid concentration in the
plasma
Increase protein catabolism in extra hepatic tissues and decrease protein synthesis, providing more
amino acids to the liver for gluconeogenesis.
Testosterone:

Increase protein synthesis in muscle (increase in contractile proteins)
26
Thyroxine:


Causes increased protein synthesis and degredation.
The overall effect is catabolic
Glucagon:

Increases urea production- amino acids are used for gluconeogenesis (stimulated by glucagon) and the
resulting amino groups incorporated into urea.
3. Fats



The metabolism of fatty acids consists of catabolic processes which generate energy and primary metabolites
from fatty acids, and anabolic processes which create biologically important molecules.
Triacylglycerol (ingested form of fatty acids), whether in the form of chylomicrons (microscopic lipid particles)
or other lipoproteins, is not taken up directly by any tissue, but must be hydrolyzed outside the cell to fatty
acids and glycerol, which can then enter the cell.
The main pathways of lipid metabolism are lipolysis, betaoxidation and lipogenesis.
Catabolism:


After digestion, most of the fats are carried in the blood as chylomicrons
Majority of fat in body is stored in specialised cells called adipocytes.
Lipolysis:




Triglycerides undergo lipolysis (hydrolysis by lipases) and are broken down into glycerol and fatty acids.
Once released into the blood, the hydrophobic free fatty acids bind to serum albumin for transport to
tissues that require energy.
The glycerol also enters the bloodstream and is absorbed by the liver or kidney where it is converted to
glyceraldehyde-3-phosphate
It can then enter the glycolysis or glucogenesis pathway
Beta-Oxidation



Lipolysis and beta-oxidation occurs in the mitochondria of liver and muscle.
It is a cyclical process in which two carbons are removed from the fatty acid per cycle.
Results in formation of fatty acid residue and acetyl coA, which proceeds through the Krebs cycle to
produce ATP, CO2, and water.
Anabolism:
Lipogenesis:





Synthesis of triglycerides from fatty acids, glycerophosphate, and non-fat materials, especially
carbohydrate.
Occurs mainly in the liver, but also in adipose tissue. Takes place in cytoplasm.
Cytoplasmic acetyl coA transfers its acetyl group to another molecule of acetyl coA, forming a 4 carbon
chain.
Repetition of this builds up long-chain fatty acids, 2 carbons at a time.
Triglycerides can be formed by linking fatty acids to each of the three hydroxyl groups in glycerol.
Hormonal Regulation of Fat metabolism:
Somatotrophin:


Increases mobilisation of fatty acids from adipose tissue.
Enhance the conversion of fatty acids to acetyl-CoA to use for energy.
ACTH:

Ketogenic effect (i.e. Cushing’s disease)
Insulin:


In adipose tissue, stimulates fat deposition
Inhibits lipolysis
Glucocorticoids:



Promotes mobilisation of fatty acids from adipose tissue.
Enhances oxidation of fatty acids.
Increases lipolysis, which provides more glycerol to the liver for gluconeogenesis.
Throxine:


Increases lipolysis
Increases beta-oxidation of free fatty acids by the cells
27
Glucagon:
 Increases lipolysis- inhibition of fatty acid synthesis ‘shunts’ substrates towards glycolysis.
Adrenaline/Noradrenaline:
 Increases mobilisation of fatty acids and rapid breakdown of triglycerides by activating triglyceride
lipase.
Overview of Carbohydrate, Protein and Fat Metabolism:
2.4 Describe the structure of a typical islet of Langerhans, identifying the
different cellular components and their principal endocrine secretions.


Islets contain four cell types.
- Beta cells located on the centre of each islet (60% of cells) secrete insulin
- Alpha cells located on peripheral outer rim of islet secrete glucagon
- Delta cells are intermixed and secrete somatostatin
- F cell – secretes pancreatic polypeptide (unknown function)
Gap junctions link beta cells to each other, alpha cells to each other, and alpha to beta cells for rapid
communication.
 Tight junctions allow concentrations of secreted hormones to build up and exert a paracrine effect on
surrounding cells.
 Portal blood supply allowed blood from beta cells to bathe the alpha and delta cells, for rapid
communication.
2.5 Describe the main features of insulin synthesis, storage and secretion.
Synthesis:
1. Takes place on beta cells within the islets of Langerhans
2. Initially synthesised as preproinsulin via mRNA translation.
28
3. Removal of its signal peptide during insertion into the endoplasmic reticulum generates proinsulin
(a single chain polypeptide)
4. Proinsulin folds spontaneously
upon itself so that two disulphide
bridges are formed.
5. Proinsulin is incorprotated into
granules at the Golgi body and
the C-peptide is cleaved by
proteolysis within the granules.
6. This forms the mature insulin
molecule and the C peptide.
Storage:
7. Insulin stored within the
granules, partly as polymers and
partly complexed with zinc.
8. Secretory granules accumulate in
the cytoplasm.
Release:
9. Insulin secretion is triggered by rising blood
glucose levels (detected by Glucokinase).
10. Starting with the uptake of
glucose by the GLUT2 transporter,
the glucose is phosphorylated by
the rate-limiting enzyme
glucokinase. The glycolytic
phosphorylation of glucose causes
a rise in the ATP:ADP ratio.
11. This rise inactivates the potassium
channel that depolarizes the
membrane, causing calcium
channels to open up allowing
calcium ions to flow inward.
12. The rise in levels of calcium leads
to the exocytotic release of insulin
from their storage granule.
13. 80% of insulin is degraded in the
liver and kidneys.
2.6 List and describe the
principal actions of insulin

Decreases blood glucose
concentration (carbohydrate
metabolism): by the following
mechanisms1) Increases uptake of
glucose by target cells by directing the insertion of glucose transporters (GLUT-4) into cell
membranes. As glucose enters the cells, blood glucose concentration is decreased.
2) Promotes formation of glycogen from glucose in muscle and liver via enhanced glycogen synthase
activity.
3) Insulin also inhibits glycogenolysis (inhibits glycogen phosphorylase).
4) Decreases gluconeogenesis by increasing the production of fructose 2,6-biphosphate, so substrate is
directed away from formation of glucose
29

Decreases blood amino acid concentration (protein metabolism):
5) Stimulates active transport of amino acids into peripheral cells
6) Stimulates protein synthesis directly.
7) Decreases protein catabolism (because of the increased glucose utilisation)

Decreases blood fatty acid and ketone concentrations (fat metabolism):
8) Stimulates cellular uptake and oxidation of glucose by adipose tissue
9) Activates lipoprotein lipase of endothelial cells which catalyses hydrolysis of triglycerides
bound to lipoproteins and stimulates movement of fatty acids into adipocytes.
10) Stimulates lipogenesis in hepatic and adipose tissues and fat storage.
11) Inhibits lypolysis
2.7 Discuss the insulin receptor and its function.






Insulin receptor is a tetramer with two α subunits and two β subunits.
The α subunits are extracellular and contain the insulin binding sites.
β subunits span the membrane and have tyrosine kinase activity
When insulin binds to the receptor, the tyrosine kinase autophosphorylates the β subunits.
The phosphorylated receptor then phosphorylates intracellular proteins.
This initiates a signal transduction cascade which stimulates and activates the glucose transporter (GLUT4)
to transport glucose into the cell.
2.8 Draw a labelled diagram illustrating the factors which regulate the release of
insulin.

The principle stimulus for the
release of insulin is an increase
in blood glucose concentration.
As blood glucose level rises
above 4 mmol/l it stimulates
release of insulin and the
synthesis of further insulin.

Certain amino acids also
stimulate insulin secretion (e.g.
arginine)

The dominant effect of
sympathetic activity seems to
inhibit insulin production,
however sympathetic activity on
β cells seems to have a
stimulatory effect on insulin
release. Stress also inhibits
insulin release as it is associated
with sympathetic mediators.
30




Stimulation of parasympathetic has the opposite effect to sympathetic ones (on the whole) and cause the
release of insulin.
Somatostatin has inhibitory effect on insulin release.
Glucagon exerts a stimulatory effect on β cells directly as hormones are released into the interstitial spaces and
have a paracrine effect.
Certain gastrointestinal hormones such as gastrin and secretin bring about a stimulatory response on the release
of insulin. (This is how the body prepares for high blood glucose levels following a meal)
2.9 Describe the synthesis, storage and secretion of glucagon.



Glucagon is a polypeptide synthesised on the RER of the alpha cells of the islets of Langerhans.
It is initially transcribed as pre-proglucagon which is modified within the vesicles formed at the Golgi body first
to a proglucagon molecule and then finally to glucagon.
The hormone is then stored in the granules in the cell cytoplasm until released by exocytosis.
2.10 List and describe the principal actions of glucagon.




In contrast to insulin (which acts on liver, adipose and muscle), glucagon only acts on the liver.
Principal effect is to raise blood glucose concentration.
1) Increases glycogenolysis and prevents recycling of glucose into glycogen
2) Increases gluconeogenesis by activating enzymes. Also increases the extraction of amino
acids from blood by liver cells, making a greater availability to be converted into glucose
Increases blood fatty acid concentration.
3) Increases lypolysis by activating adipose cell lipase. Increases plasma level of fatty acids
and glycerol. Glycerol can be used in gluconeogenesis. Fatty acids can be metabolised,
sparing glucose as a substrate.
4) Inhibits storage of triglycerides in the liver
Increases urea production.
5) Stimulates transport of glucogenic amino acids to the liver. Amino acids used for
gluconeogenesis so remaining amino groups excreted as urea.
2.11 Draw a labelled diagram illustrating the factors which regulate the release of
glucagon.
31
2.12 Describe in your own words what the diagnosis of diabetes means to
patients (video)




Type I Diabetes Mellitus is defined as an elevated glucose level where insulin is required to prevent
ketoacidosis.
Type II Diabetes Mellitus is more common and a much more considerable health burden. It is defined in
terms of glucose but is also related to hypertension and dyslipidaemia.
Treatment is by way of treating symptoms, complications (morbidity) and preventing mortality.
For the patient, it means they must change their lifestyle in several ways. For example, smokers must cease
smoking, a balanced diet must be enforced (possibly for the whole family), and the patient must also
comply with a regime of treatment (most likely drugs – possible tablets (antihypertensive) or administration
of insulin injections).
2.13 Describe the beta-cell sensing mechanism of glucose

Glucokinase acts as a glucose receptor on
pancreatic β cells.

When glucose levels rise, glucose enters the
cell via GLUT2 transporters.

Glucokinase mediates phosphorylation of
glucose to glucose-6-phosphate (G6P), which
is the first step of both glycogen synthesis
and glycolysis.

Phosphorylation of glucose causes ATP:ADP
ratio to rise, which closes the K+ channels,
depolarising the membrane.

This causes calcium channels to open up,
allowing calcium ions to flow inwards.

The rise in calcium concentration stimulates
the exocytotic release of insulin from its
secretory granules.
2.14 Describe the endocrine regulation of intermediary metabolism
See objective 2.3 and refer to these diagrams:
1. Proteins
Glucogenesis in liver
Occurs in muscle
32
2. Fats
Occuring in adipoctytes
1. Carbohydrates
33
Session 3– Diabetes Mellitus
Weight control and obesity. Failure of intermediary metabolism regulation.
Learning objectives:
1.
2.
3.
4.
List the principal signs and symptoms of diabetes mellitus, and relate them to the underlying pathophysiology.
Distinguish between Diabetes Mellitus types 1 and 2.
Explain the aetiology of type 1 diabetes mellitus.
Define insulin resistance and explain how it is related to diabetes, dyslipidaemia, hypertension and ischaemic heart
disease.
Describe the consequences of insulin resistance on glucose, lipid and protein metabolism
Describe the physiology and risks of obesity.
Describe the pathophysiology of type 2 diabetes
5.
6.
7.
3.1 List the principal signs and symptoms of diabetes mellitus, and relate them to
the underlying pathophysiology.



Diabetes mellitus is a metabolic disorder due to either a deficiency of insulin or a hyporesponsiveness to it.
It is characterised by hyperglycaemia as well as other signs as distinct from a single disease or condition.
Signs:
1. Glycosuria (loss of glucose in urine)



In relative of total absence of insulin blood glucose levels rise, sometimes as high as 600mg/dl.
The renal proximal tubes normally reabsorb all the glucose filtered by the glomeruli unless blood
level exceeds 180mg/dl (renal threshold).
The hyperglycaemia of diabetes exceeds this threshold forcing glucose to be excreted in the
urine (glycosuria) as it is not reabsorbed.
2. Polyuria (increased amount of urine produced)


Loss of glucose in urine causes osmotic diuresis because the osmotic effect of glucose inthe
tubules greatly decreases the tubular reabsorption of fluid.
Diuresis may also be partly due to inhibition of vasopressin release from neurohypophysis.
3. Polydipsia (thirst and increased fluid intake)


Excessive water loss causes dehydration and thirst resulting in a large fluid intake.
Elevated glucose causes dehydration of tissue cells, as there is increased osmotic pressure in the
extra-cellular fluid causing osmotic transfer of water out of the cells.
4. Weight loss and polyphagia (excessive eating)


A net increase in protein catabolism and lipolysis
Also caused by decreased glucose and protein utilisation of the body.
5. Diabetic ketoacidosis





When body depends almost entirely on fat for energy, level of keto acids increases.
Excess of acetyl coenzyme A accumulates in liver as it cannot be utilised in the Krebs Cycle.
Then it is converted to acetoacetic acid. This is reduced to β-hydroxybutyric acid or
decarboxylated to acetone (three substances known as ketone bodies)
Increases concentration of hydrogen ions.
Characterised by heavy and deep breathing (Kussmaul breathing) and acetone breath.
3.2 Distinguish between Diabetes Mellitus types 1 and 2.


In type 1 Diabetes (Insulin-Dependent Diabetes Mellitus) the hormone is completely or almost completely
absent from the islets of Langerhans and plasma and therapy with insulin is essential.
In type 2 Diabetes (Noninsulin-Dependent Diabetes Mellitus) the hormone is often present in plasma at
relatively low levels whilst there is a decreased sensitivity of body tissues to insulin.
Insulin
Glucose
Glycosuria
Ketones
Weight
Type I Diabetes
Total failure to secrete
Hyperglycaemia
Frequent urinating
Ketonuria
Weight loss
Type II Diabetes
Inadequate relative to the blood-glucose levels
Hyperglycaemia
Less frequent urinating (but osmotic symptoms present)
Dyslipidaemia
No, but some 60% are obese
34
3.3 Explain the aetiology of type 1 diabetes mellitus.





Accounts for around 25-30% of all diabetic cases (90% under the age of 35).
The body’s own immune system mistakenly develops autoimmune antibodies against its own beta cells (islet
cell antibodies, ICA, and insulin antibodies, IAA, found in newly diagnosed cases).
The tendency to develop these abnormal antibodies may be hereditary.
Reaction to certain viral infections (mumps and Cocksackie viruses) or other environmental toxins may also
trigger abnormal antibody production.
Thus the beta cells are destroyed or damaged enough to inhibit insulin production. Therefore patient is
totally dependent on insulin for survival.
3.4 Define insulin resistance and explain how it is related to diabetes,
dyslipidaemia, hypertension and ischaemic heart disease.
Insulin resistance:






Diminished ability of cells to respond to insulin adequately in fat, muscle and liver cells.
Normal levels of insulin do not trigger glucose absorption in these cells.
In adipose tissue: causes increase lipolysis of triglycerides resulting in elevated fatty acid levels.
In liver cells: increases gluceoneogenesis and glycogenolysis which causes a rise in overall blood
glucose levels.
In muscle cells: reduces glucose uptake and utilisation.
Obesity plays a factor: excess adipose tissue may downregulate the production of insulinsensitive glucose transporters.
Dyslipidaemia:


Abnormal levels of lipid in the blood.
In diabetes, lack of insulin promotes lipolysis in adipose tissue and increases
delivery of free fatty acids to the liver.
The reduced lipoprotein lipase activity reduces VLDL clearance (very low density
lipoproteins synthesised n the liver).

Hypertension:

Insulin causes an increase in sodium retention which increases blood pressure.
Ischaemic heart disease:


Insulin resistance has a negative effect on lipid production.
This can lead to elevated VLDL and LDL levels and low HDL levels. HDLs protect
the body against atherosclerosis
Without insulin, plaque deposits build up increasing the risk of ischaemic heart
disease.
Also, the narrowed arteries contribute to the hypertension.


These factors are
known as Syndrome X
(metabolic syndrome)
– a combination of
factors that increase
ones risk for
cardiovascular disease
and diabetes
3.5 Describe the consequences of insulin resistance on glucose, lipid and protein
metabolism
Glucose metabolism:


Increases as gluconeogenesis and glycogenolysis take place. (Increase in HGO).
There is a low insulin to glucagon ratio (especially in type 1).
Lipid metabolism:



increased lipolysis of triglycerides causes the release of glycerol and non-esterified fatty acid (NEFA),
especially from omental fat.
However there is enough insulin to suppress ketogenesis (production of ketones from excess acetyl coA
which is brought about by the metabolism of the lipolysis products- glycerol) – explains low prevalence of
ketonuria in type II.
decreased lipoprotein lipase, which decreases HDL cholesterol, which in turn decreases the clearance of
LDLs
35
Protein metabolism:

Increased proteolysis as the amino acids produced support hepatic gluconeogenesis.
3.6 Describe the physiology and risks of obesity.
Obesity is an excess of body fat that frequently results in an impairment of health. It defined in terms of many
factors:
 Weight
 BMI (Body Mass Index)
 Expressed as weight (kilograms) divided by height (in metres 2)
 26-30 BMI classified as overweight.
 The waist to hip ratio (showing central adiposity)
 Visceral fat or central obesity (male-type or apple-type obesity) has a much stronger correlation,
particularly with cardiovascular disease, than the BMI alone.
 There is also a definition incorporating morbidity and mortality.
 The prevalence of obesity increases with time, and is related to ethnicity, age and sex.

Risk factors:
 type 2 diabetes
 heart disease
 stroke
 hypertension
 sleep apnea etc.

Leptin



Leptin is an important protein hormone that is released by adipocytes (adipose tissue).
It is essential in the control of food intake and is released in proportion to the amount of fat in adipose cells
The hormone acts on the hypothalamus to cause a reduction in food intake by inhibiting the release of
neuropeptide Y (a hypothalamic neurotransmitter than stimulates eating).
3.7 Describe the pathophysiology of type 2 diabetes







Represents the majority of all diabetics seen in most populations.
Due to defect in insulin resistance (or insulin sensitivity) and insulin secretion (as disease progresses).
Although insulin resistance is the primary factor inducing hyperglycemia in NIDDM, an as-yet-unidentified defect
in beta-cell function prevents these cells from responding to the hyperglycemia in normal fashion.
Insulin is often present in plasma at normal or even above-normal levels.
Lipolysis and ketogenesis remain inhibited explaining low prevalence of ketonaemia and ketonuria.
Central obesity (fat concentrated around the waist in relation to abdominal organs, and not subcutaneous fat, it
seems) is known to predispose individuals for insulin resistance, possibly due to its secretion of adipokines (a
group of hormones) that impair glucose tolerance
Histology of pancreas may show normal islets, occasionally enlarged and more numerous.
36
Session 3– The Thyroid and Iodothyronines
Learning objectives
1.
2.
3.
4.
5.
6.
Describe the anatomy of the thyroid and the structure of the follicles.
List the main hormones produced by the follicular and parafollicular cells of the thyroid.
Describe by means of a labelled diagram the principal features of iodothyronine synthesis, storage and release.
Describe the physiological actions of the iodothyronines.
Explain the mechanism(s) of action of the iodothyronines.
Describe the control mechanisms of iodothyronine production with particular reference to the hypothalamo-pituitarythyroidal axis.
Describe the principal clinical effects of excess circulating iodothyronines, and name the condition described.
Describe the principal clinical effects associated with a deficiency in circulating iodothyronines, and name the condition
described.
Understand the principles of treatment issues in the individual patient.
7.
8.
9.
3.1 Describe the anatomy of the thyroid and the structure of the follicles.








Bilobed gland located immediately below the larynx on either side
of and anterior to the trachea.
Two lobes connected together by a thin band of tissue called the
isthmus.
The thyroid gland originates from the back of the tongue, from a
dimple at the back of the tongue known as the foramen caecum.
It is composed of large numbers of closed follicles (150-300μm in
diameter) which are filled with a secretory substance called
colloid.
Each follicle is lined with cuboidal epithelioid cells (follicular cells)
that secrete T3 and T4 into the interior of the follicles.
The follicular cells selectively absorb iodide ions from the blood
for the production of thyroid hormones.
Once the secretion has entered the follicles, it must be absorbed
back through the follicular epithelium into the blood before it can
function in the body.
Parafollicular cells are dispersed between the follicles.
3.2 List the main hormones produced by the follicular and parafollicular cells of
the thyroid.
Follicular cells:


Thyroxine (T4)
Tri-iodothyronine (T3)
Parafollicular cells:

Calcitonin (which prevents calcium mobilisation from bone and reduces
calcium level in the blood).
3.3 Describe using a diagram the features of iodothyronine synthesis, storage and
release.
Diagram is below explanation:
Synthesis:
1. The follicular cells concentrate iodide using an active pump mechanism in the basal membrane. The
intracellular iodide concentration is usually 25-30 times greater than the plasma concentration. This process is
called iodide trapping.
2. Once inside the cell iodide is rapidly oxidised to active iodine by hydrogen peroxide in the presence of thyroid
peroxidase. This enzyme is located near the apical membrane.
3. Most of the reactive iodine is ‘organified’ by incorporating them into the tyrosine residues within thyroglobulin
molecules. Thyroglobulin is a large glycoprotein synthesised in the follicular cells containing approx. 140
tyrosine residues. Thyroglobulin iodinated by one iodine is called mono-iodotyrosine (T1). When two iodines
react with thyroglobulin, di-iodotyrosine (T2) is formed.
4. An internal coupling reaction between the iodinated tyrosyls (still contained within the thyroglobulin) occurs.
 The coupling of two di-iodotyrosine groups (T2) produces tetra-iodothyronine or thyroxine (T4)

The combination of di-iodotyrosine (T2) with mono-iodotyrosine (T1) produces tri-iodothyronine (T3)
5. The thyroglobulin containing the iodothyronines is secreted into the colloid.
37
Storage:
6. Each thyroglobulin molecule contains around 3 thyroxine molecules and 1 tri-iodothyronine molecule. The
thyroid hormones are stored in this form within the colloid.
Release:
7. When stimulated by thyrotrophin, follicular cells absorb colloid molecules via endocytosis at the apical surface.
(The colloid contains the thyroglobulin molecules with the iodothyronines.)
8. Lysosomes containing hydrolytic protease enzyme bind with colloid-rich endosomes.
9. The protease liberates the tri-iodothyronine and thyroxine from the thyroglobulin molecule.
10. The free thyroid hormone then diffuses out of the lysosome and through the basal membrane of the cell into
the general circulation, where they bind to carrier proteins for transport to target cells.


Around 90% of the hormone excreted is thyroxine (T4), and 10% tri-iodothyronine (T3) however most of the
thyroxine is eventually converted to T3 in the liver and kidney.
T3 is about four times as potent as thyroxine.
I- ions are 25-30 times more
abundant in follicular cells
compared to the blood
I* represents an iodine radical, reacting almost instantly
upon its formation with Thyroglobulin. The reaction
between the iodine radical and Thyroglobulin is
iodination.
Pump for I- which
traps the iodide
ions into the
follicular cells
The T’s on the
Thyroglobulin
represent
Tyrosil groups
The number next to
the T’s, i.e. a 1 or
a 2, represents the
number of I- bound
i.e. Colloid is
iodinated
Thyroglobulin.
Lysosomes contain m mainly proteases. These fuse with the iodinated
protein (Thyroglobulin), and then the T3 & T4 are removed and taken
into the blood.
3.4 Describe the physiological actions of the iodothyronines.
1. Increased basal metabolic rate of almost all tissues in the body (BMR) – associated with increased O2
consumption and production of heat.
2. Essential for skeletal growth and development
3. Increases carbohydrate metabolism- increases rate of absorption of glucose by intestinal tract, and enhances
glycolysis, gluconeogenesis and glycogenolysis.
4. Increased fat metabolism- lipolysis in adipose tissue mobilises lipids, resulting in increased free fatty acid in the
blood. However, oxidation of fatty acids also enhanced.
5. Increased protein metabolism: both catabolism and anabolism stimulated, but excess induces degredation.
6. Increased vitamin A synthesis from carotene (increased carotene in hypothyroidism makes skin appear yellow)
7. Potentiates the action of catecholamines on the heart (due to upregulation of β-receptors)
38
3.5 Explain the mechanism(s) of action of the iodothyronines.

The general effect of thyroid hormone is
to modulate gene expression, by
stimulating or inhibiting the
transcription of certain genes.
1. Thyroid hormones are lipid soluble
and penetrate the plasma
membranes of target cells with
relative ease.
2. Thyroid receptors (TR) have a 10fold greater affinity for T3 than for
T4. Therefore, almost all of the
thyroxine is deiodonated by one
iodide ion, forming tri-iodothyronine
(T3)
3. The thyroid hormone receptors are
located in the nucleus, either
attached to the DNA genetic strands
or in close proximity to them. Upon binding to thyroid hormone they become activated and initiate
transcription.
4. The T3-receptor complex first dimerizes with another receptor (forming a homodimer) and in this form
interacts with specific base sequences of DNA called hormone response elements.
5. This alters the rate of transcription of these genes into mRNA and subsequent new protein synthesis.

Another mechanism of action is the direct stimulation of mitochondria.
 In most tissues (exceptions being the brain, spleen and testes) thyroid hormone increase the number
and size of mitochondria.
 This stimulates the activity of enzymes in the respiratory chain ultimately increasing the formation of
ATP.
 One of the enzymes that becomes increased is Na,K-ATPase. This increases the rate of transport of both
sodium and potassium through the cell membranes of some tissues (Na + pumped out in exchange for K+).
 Thyroid hormone also causes the cell membranes of most cells to become permeable to sodium ions,
therefore further activating the sodium pump.
3.6 Describe the control mechanisms of iodothyronine production with particular
reference to the hypothalamo-pituitary-thyroidal axis.

The adenohypophysial hormone thyrotrophin (thyroid stimulating hormone) regulates most aspects of iodothyronine synthesis and release from the thyroid.
1. Stimulates iodide uptake by increasing the activity of the iodide pump or increasing the number of
pumps on the basal membrane of follicular cells.
2. Stimulates iodination of the tyrosine groups in thyroglobulin and increases coupling to form the thyroid
hormones.
3. Increases peroxidase activity (when iodide is oxidised to iodine)
4. Increases proteolysis of the thyroglobulin molecules already stored in the follicles, thus liberating
thyroxine and tri-iodothyronine.
5. Stimulates the synthesis of thyroglobulin itself.
6. Increases the number of follicular cells

Thyrotrophin’s actions are mediated by activation of membrane-bound adenyl cyclase and subsequent cAMP
generation.
Thyrotrophin release is controlled by the hypothalamic hormone TRH (thyrotrophin-releasing hormone) which
reaches the adenohypophysial thyrotrophe cells via the local portal blood system.
Somatostatin has an inhibitory effect on thyrotrophe cells.
Circulating T3 and T4 levels have a controlling influence on TRH levels by exerting direct negative feedback at
the adenohypophysial level and indirect negative feedback at the hypothalamic level.
Oestrogens increase TSH secretion as they stimulate the synthesis of TRH receptors in the adenohypophysis.
Environmental temperature effects T3 and T4 production. Exposure to cold environments increases levels of T4 in
plasma.





39
3.7 Describe the principal clinical effects of excess circulating iodothyronines,
and name the condition described.
Hyperthyroidism


Hyperthyroidism is the result of excess thyroid hormone production, resulting in an overactive metabolism and
increased speed of all the body’s processes.
Major causes of hyperthyroidism are: 1) Graves’ disease 2) Nodular toxic goitre (Plummer’s Disease

Graves disease:
-
-

Nodular toxic goitre (Plummer’s disease):
-

Caused by an antibody-mediated auto-immune response.
Body produces TSAb (Thyroid Stimulating Antibodies) which bind to the receptors for TSH and
chronically stimulate them.
They induce continual activation of the cAMP system of cells, with resultant development of
hyperthyroidism.
High level of T4 and T3 secretion caused by TSAb suppresses TSH secretion from adenohypophysis.
The antibodies also bind to TSH receptors expressed in retroorbital tissue behind the eye. This causes
exopthalamos (bulging of the eye) due to increased volume and oedema of retroorbital fat as well as
degeneration of extraocular muscles.
Pretibal myxoedema is sometimes caused by infiltration of antibodies of the dermal and subdermal
laters resulting in thickening of the skin in the lower legs. (not to be confused with myxodema of
hypothyroidism)
Usually develops in older people.
Characterised by autonomous function of one of more thyroid adenomas.
Thyroid gland develops lumps or nodules that become overactive and trap excess iodine and produce
too much thyroid hormone.
Function in the remainder of the gland is inhibited as TSH levels drop.
Hyperthyroidism symptoms:
-
Intolerance to heat
Increased sweating
Mild to extreme weight loss
Diarrhoea
Weakness
Fatigue, but inability to sleep
-
Loss of libido
Goitre
40
3.8 Describe the principal clinical effects associated with a deficiency in
circulating iodothyronines, and name the condition described.
Hypothyroidism





Most cases of hypothyroidism are also autoimmune disorders and represent the end result of a cell-mediated
destructive immune response directed against the thyroid follicular cell.
However, in some cases a TSH receptor-blocking anti-body can be identified.
May also be due to a defect in thyroid hormone biosynthesis.
Primary hypothyroidism: is a lack of thyroid hormones due to a disease of the thyroid gland itself.
Secondary hypothyroidism: involves decreased activity of the thyroid due to a failure in the pituitary gland.

Hashimoto’s disease: primary hypothyroidism
-

The body’s own anti-bodies attack the cells of the thyroid.
Antibodies to thyroid peroxidase and/or thyroglobulin cause the destruction of follicles within the
thyroid gland.
Goitre is usually not present, but is still a feature.
Clinical features:
 Generalised tiredness and lethargy
 Bradycardia
 Neuromuscular symptoms such as muscle cramps, weakness
 The skin is dry and flaky. Hair loss (alopecia) is common.
 Voice becomes deep and husky and some weight gain
 Females may show heavy periods (menorrhagia) and be infertile. Impotence and decreased
libido common in males.
 Mental sluggishness
Endemic Colloid Goitre:
-
In certain areas of the world (mountainous) such as the Swiss Alps there is insufficient iodine present in
the soil leading to low dietary iodine consumption.
Lack of iodine prevents production of T3 and T4, but does not stop the production of thyroglobulin.
Because there are no circulating levels of T3 and T4 to inhibit TSH production by the adenohypophysis,
large amounts are secreted.
This results in the secretion of large amounts of thyroglobulin (as colloid) into the follicles so the gland
grows larger.
Because there is a lack of iodine, thyroxine and tri-iodothyronine production does not take place within
the thyroglobulin and does not suppress TSH production.

Myxoedema:
- Results from the accumulation of hyaluronic acid and chondroitin sulphate as tissue gel in the
interstitial spaces in the skin.
- Signs include bagginess under the eyes and swelling of the face.

Atherosclerosis:
- Lack of thyroid hormone increases quantity of blood cholesterol as there is decreased liver excretion of
cholesterol in the bile.
- Increase in blood cholesterol associated with increased atherosclerosis

Cretinism:
- Caused by extreme hypothyroidism during fetal life, infancy and childhood.
- Congenital cretinism: congenital lack of a thyroid gland.
- Endemic cretinism: results from lack of iodine in diet.
- Iodothyronines are important for physical and well as neural growth, so in the absence of these
hormones a physically and mentally impaired baby is born.
- Unless hormone replacement is begun within weeks, the condition is irreversible.
41
3.9 Understand the principles of treatment issues in the individual patient.
42
Session 4– The Adrenals and the Corticosteroids
Learning objectives
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Describe the anatomy of the adrenal gland, identifying the medulla and the cortical zones.
List the main hormonal products from the adrenal medulla and the adrenal cortex.
Draw simple pathways identifying the main intermediates in the synthesis of the adrenal steroids.
State that the adrenal steroids exert their main effects via intracellular receptors and genomic mechanisms.
Identify the main mineralocorticoid in humans and describe its principal actions.
Describe the control mechanisms for mineralocorticoid hormones.
Identify the main glucocorticoid in humans and describe its principal actions.
State that cortisol plays an important role in the endocrine response to stress.
Describe the principal features of the hypothalamo-pituitary-adrenal axis.
State that adrenal androgen production in women can be clinically important in conditions of overproduction.
Describe the effects of excess and deficiency of cortisol.
Recognise the necessity for adrenal steroids for survival.
4.1 Describe the anatomy of the adrenal gland, identifying the medulla and the
cortical zones.








There are two adrenal glands, situated one
on top of each kidney.
They are found at the level of the 12th
thoracic vertebrae and receive their blood
supply from the adrenal arteries.
Each adrenal gland comprises two
endocrine organs- the adrenal medulla and
the adrenal cortex.
The medulla is a modified nervous tissue
derived from the neural crest and can be
regarded as a collection of postganglionic
sympathetic neurons in which the axons
have not developed.
The cortex is derived from mesenchymal
cells forming the primitive outer layer.
It is organised histologically into three
zones- the outer zona glomerulosa, the
middle zona fasciculate and inner zona
reticularis.
Blood flows from the cortex inwards, which
is physiologically important as some cortex
hormones stimulate the medulla. The left
adrenal vein drains into the left renal vein,
but the right adrenal vein drain straight
into the inferior vena cava
Spleen located next to left adrenal (can be
damaged from surgery- adrenalectomy).
4.2 List the main hormonal products from the
adrenal medulla and the adrenal cortex.
Adrenal medulla: chromaffin cells secrete the catecholamines
adrenaline (80%) and noradrenaline (20%). These are released in
response to sphlanchnic nerve stimulation.
Adrenal cortex: secretes steroid hormones (corticosteroids)
which control either salt and water balance (mineralocorticoids:
aldosterone secreted by the zona glomerulosa) or regulate
metabolic processes (glucocorticoids: cortisol secreted by the
zone reticularis and zona fasciculate). Zona fasciculate also
secretes small amounts of androgens.
43
4.3 Draw simple pathways identifying the main intermediates in the synthesis of
the adrenal steroids.







Hormones of the adrenal cortex are all derived from cholesterol.
Cholesterol can be synthesised within the cells from acetyl coenzyme A or taken up from low-density
lipoproteins in the circulation.
It is stored within cytoplasmic lipid droplets in the cells in the adrenal cortex.
Cholesterol is released from the lipid droplets by action of cholesterol esterase, when stimulated by ACTH.
It is then converted to prognenolone in the mitochondria. This step is also regulated by ACTH and is the ratelimiting step in steroid biosynthesis.
Prognenolone is then transferred to the smooth endoplasmic reticulum. It undergoes further modifications here,
each step catalysed by a specific enzyme system. This forms the three main classes of steroids.
There are four types of cytochrome P-450 enzymes located within the cell in different compartments.
Cholesterol
Pregnenolone
17-hydroxy-pregnenolone
DEHYDROEPIANDROSTERONE
(DHEA)
Progesterone
17-hydroxy-progesterone
ANDROSTENEDIONE
11 deoxy-corticosterone
11-deoxycortisol
CORTICOSTERONE
CORTISOL
ALDOSTERONE
Androgens
Glucocorticoid
Mineralocorticoid
4.4 State that the adrenal steroids exert their main effects via intracellular
receptors and genomic mechanisms.








Principal effect of aldosterone is to stimulate sodium reabsorption in exchange for K+ and H+ ions in the distal
convoluted tubule (and sweat glands, large intestines and salivary glands).
Because of its lipid solubility aldosterone diffuses readily into the tubular epithelial cells.
In the cytoplasm, the aldosterone binds to a highly specific intracellular receptor protein.
The hormone-receptor complex diffuses into the nucleus where it may undergo further alterations.
The complex induces transcription of specific portions of DNA (hormone response elements) into mRNA.
Cytoplasmic proteins are then synthesised on the ribosomes.
These proteins may act by increasing the permeability of the luminal membrane to sodium ions and by
stimulating the sodium-potassium exchange pump in the basolateral membrane.
Cortisol is also lipid-soluble and can penetrate target cell membranes to bind to intracellular receptors.
44
4.5 Identify the main mineralocorticoid in humans and describe its principal
actions




Aldosterone accounts for about 90% of mineralocorticoid activity.
Stimulates Na+ reabsorption in the distal convoluted tubule in the kidney. It does this by:
1) Increasing the availability of luminal Na+ channels
2) Increasing synthesis and insertion of Na+,K+-ATPase into the basolateral membrane
3) Increasing synthesis of some of the enzymes involved in the Krebs Cycle, thus making more
energy available to the cell.
Stimulates excretion of H+ and K+ ions.
The same effect is exerted on sweat glands, salivary glands and in the colon (to prevent loss of sodium in
faeces).
4.6 Describe the control mechanisms for meneralocorticoid hormones.



Primary regulator of aldosterone is angiotensin II produced by the renin-angiotensin system.
An increase in plasma K+ and Na+ concentration also stimulates the release of aldosterone.
ACTH has a minor role in regulation- it stimulates conversion of cholesterol to prognenolone (permissive effect)
Renin-Angiotensin System:

Renin is produced by juxtaglomerular cells
located on the terminal part of the
afferent arterioles.

Following stimulation of the cells renin is
released into the blood stream. It cleaves
10 amino acids of a plasma protein called
angiotensinogen (produced in the liver) to
form angiotensin I.

Angiotensin I then undergoes further
cleavage of 2 amino acids to form the
active molecule angiotensin II. This is
catalysed by Angiotensin Converting
Enzyme (ACE) found in high concentrations
in the lungs.

Angiotensin II stimulates the cells of the
renal zona glomerulosa to produce
aldosterone.

It is also a potent vasoconstrictor when present in the circulation. It increases total peripheral resistance and
therefore renal perfusion pressure.

It also promotes thirst and stimulates the release of ADH by acting on circumventricular organs outside the
blood-brain barrier.
45
Control of renin release:
1. Decreased renal perfusion pressure: decrease in afferent arteriolar blood pressure may be detected
directly by JG cells or by adjacent intrarenal baroreceptors. Can be caused by haemorrhage, salt and
water loss and postural hypotension.
2. Direct stimulation via renal sympathetic nerves. JG cells can be directly innervated by renal sympathetic
nerves that stimulate renin secretion. Circulating catecholamines can stimulate renin release directly by
acting on alpha receptors on these cells.
3. Change in the concentration of sodium (or chloride) ions in the renal tubular fluid flowing past the
macula densa (located near the ends of the ascending loops of Henle.) When there is decreased chloride
or sodium concentration, the rate of renin release is increased.
4. Vasopressin (ADH) suppresses renin secretion and there is evidence of direct negative feedback effects
by angiotensin II and aldosterone on release of the enzyme from JG cells.
4.7 Identify the main glucocorticoid in humans and describe its principal actions.
4.8 State that cortisol plays an important role in the endocrine response to stress.

Main glucocorticoid is cortisol. It has the following physiological effects at normal concentrations:

Effects
1.
2.
3.
4.
5.




on intermediary metabolism:
Promote glycogenesis in the normal state- stimulating glycogen storage in the liver
Promote gluconeogenesis in the fasting state- to provide glucose for brain metabolism
Stimulate protein catabolism- to provide amino acids for gluconeogenesis
Inhibit glucose uptake in the muscle and adipose tissue- antagonises insulin and raises blood glucose
Enhance fatty acid mobilisation from adipose tissue by potentiating the lipolytic effects of
catecholamines and somatotrophin.
Maintenance of normal circulatory function:
6. Potentiate vasoconstrictor effects of catecholamines to maintain vascular resistance.
7. Decrease vascular permeability to help maintain blood volume.
Adaptation to stress:
8. In stressful situations cortisol is released- increases vascular contractility so enhances the ability of
vascular muscle to contract in response to stimuli such as adrenaline. Also increases intermediary
metabolism to produce glucose as a source of energy. By mobilising amino of amino acids, damaged
tissues can use these to form new proteins. (Still not completely sure of cortisol’s significance during
stress).
Effects on immune system:
9. Suppress immune response. Decrease the number of circulating lymphocytes and eosinophils as well as
decrease antibody production. Used therapeutically to suppress rejection of transplanted organs.
10. They also have anti-inflammatory activity by reducing the amount of T cells and antibodies present at
the site of inflammation. Decreases fever by reducing release of interleukin-1 from white blood cells. In
the same way, cortisol has an anti-allergic effect.
Mineralocorticoid activity:
11. Cortisol has a small degree of mineralocorticoid activity despite being present in circulation at high
concentrations. Type 1 aldosterone receptor binds to cortisol just as much as it binds to aldosterone.
However, cortisol is inactivated by 11αHSD enzyme which converts it into cortisone.
4.9 Describe the principal features of the hypothalamo-pituitary-adrenal axis.





Secretion of glucocorticoids are under the
control of adenohypophysial hormone
corticotrophin (ACTH)
The release of ACTH itself is controlled by
the hypothalamic hormone corticotrophinreleasing hormone CRH.
Vasopressin released into the hypothalamohypophysial portal system stimulates
corticotrophin release by acting
synergistically with CRH.
Cortisol exerts direct negative feedback on
ACTH release via the adenohypophysis.
Indirect negative feedback is also exerted
via the hypothalamus.
Cytokines (such as interleukin-1) also
stimulate ACTH release from the
adenohophysis and CRH release from the
hypothalamus
46
4.10 State that adrenal androgen production in women can be clinically
important in conditions of overproduction.






Androgential syndrome: associated with excessive androgen secretion causing masculinisation effects in the
female throughout the body.
This may be due to an androgen-secreting tumour or it may be congenital.
If congenital it is known as congenital adrenal hyperplasia and is a result in an enzyme deficiency required for
the cortisol synthesis.
This leads to elevated ACTH secretion from the adenohypophysis is not inhibited. This leads to increased
androgen secretion.
Females develop facial hair, a deeper voice and growth of the clitoris to resemble a penis.
Treatment with glucocorticoids corrects the deficiency and decreases the secretion of ACTH.
4.11 Describe the effects of excess and deficiency of cortisol.
Hyperadrenalism (excess):

Cushing’s syndrome:


Produced by excessive quantities of glucocorticoids secreted by the adrenal cortex.
This is a result of excess ACTH secretion by a pituitary tumour (specifically known as Cushing’s disease) or
by ectopic secretion by a tumour elsewhere in the body. This leads to adrenal hyperplasia.
It may also be caused by a cortisol-secreting tumour.
Characterised by mobilisation of fat from lower part of the body and deposition in the thoracic and upper
abdominal regions (buffalo torso).
Weight gain occurs due to steroid-induced lipogenesis.
Acne and hirsutism occurs due to associated adrenal androgen release.
Total appearance of face characterised as ‘moon-face’
Hypertension may also occur (due to sodium retention) and hyperglycemia (due to steroid-induced
gluconeogenesis)
Loss of protein synthesis in lymphoid tissues leads to suppressed immune system so patient may die of
infection. Lack of protein deposition in the bone causes severe osteoporosis.








Primary aldosteroneism (Aldosterone excess):

Due to excess mineralocorticoid secretion caused by a tumour of the adrenal cortex (zona glomerulosa
cells).
This leads to K+ depletion and increased Na+ and water retention.
Results in hypertension, muscle weakness and hypokalemia.


Hypoadrenalism (deficiency):

Addison’s disease:



Deficient secretion of all adrenocortical hormones, commonly due to autoimmune destruction of the gland.
In rare cases can be caused by tuberculous destruction of the adrenal glands.
Lack of aldosterone secretion decreases sodium retention, so sodium ions, calcium ions and water are lost
into urine in great amounts.
This decreases the extracellular fluid volume (leading to hypotension)
Hyperkalaemia and mild acidosis may develop as K+ and H+ ions are not secreted in exchange for sodium
reabsorption
Lack of cortisol secretion makes it impossible to maintain normal blood glucose concentrations as glucose is
not being synthesised by gluconeogenesis (hypoglycaemia)
Characterised by lethargy, weakness and weight loss.
Because of lack of cortisol, patient highly susceptible to deteriorating effects of stress (Addisonian Crisis).
Patient needs immediate administration of glucocorticoids.
Melanin pigmentation of exposed skin is characteristic is Addison’s disease. This is due to increased
secretion of ACTH (as there is no cortisol to inhibit it). The ACTH stimulates formation of melanin from
melanocytes.






4.12 Recognise the necessity for adrenal steroids for survival.

Aldosterone promotes reabsorption of Na+ and secretion of K+. Without mineralocorticoids the K+ ion of
extracellular fluid would rise and Na+ and Cl- concentrations would decrease. The extracellular fluid volume
and blood vole also become reduced. This leads to hypotension and death. The glucocorticoids allow a person
to resist the destructive effects of stress as well as maintain blood glucose levels.
47
Session 5– The Gonads
Learning objectives
1.
2.
3.
4.
5.
Describe the stages of gametogenesis and the process of steroidogenesis in male and female gonads.
Draw simple flow charts illustrating the synthesis of progesterone, 17b-oestradiol and testosterone.
Label diagrams illustrating the principal structures of the testes and ovaries.
Describe the principal ovarian and endometrial changes that occur during the menstrual cycle.
Relate the synthesis of the major gonadal steroids in males and females to the relevant hormones of the hypothalamoadenohypophysial axis.
6. Describe how the cyclic production of ovarian steroids is linked to the endometrial, cervical and other changes of the
menstrual cycle.
7. Describe the actions of the gonadal steroids in males and females.
8. Identify the principal features of the control systems operating on the production of the gonadal steroids, with particular
reference to negative and positive feedback loops, in males and females.
9. Define the terms primary and secondary amenorrhoea.
10. List the principal causes of infertility with particular references to endocrine causes.
11. Name the two major functions of the testes and, with the use of a simple diagram, describe how they are regulated by the
hypothalamo-pituitary axis.
12. With the use of simple diagrams that distinguish between the follicular (early, mid, late) and luteal phases of the menstrual
cycle, summarise the endocrine regulation of ovarian function.
5.1 Describe the stages of gametogenesis and the process of steroidogenesis in
male and female gonads.
Males

Spermatogenesis:

In an adult male, the testes serve two major functions- the production of human
male gametes (spermatogenesis) and the production of steroid hormones
Spermatogonia
(steroidogenesis).
(mitotic
division)
Spertmatogenesis occurs in all the seminiferous tubules of the testes during
active sexual life as the result of stimulation by anterior pituitary gonadotrophic
hormones.
Primary spermatocyte
Seminiferous tubules contain large numbers of germinal epithelial cells called
(first meiotic division)
spermatogonia, located in two to three layers along the outer border of the
tubular epithelium. These continually proliferate to replenish themselves, and a
portion of them differentiate through definitive stages of development to form
Secondary spermatocyte
sperm.
(second
meiotic division)
1. Primordial spermatogonia divide to form primary spermatocytes.
2. The primary spermatocytes migrate centrally into the adluminal
compartment and push past between adjacent Sertoli cells by disrupting
Spermatid
the tight junctions which link them to each other. (Some primary
spermatocytes continually return to the quiescent stage, providing a pool
of spermatogonia to be activated in later life).
Spermatozoa
3. Primary spermatocytes undergo the first meiotic division to form
secondary spermatocytes.
4. Each short-lived secondary spermatocyte undergoes a second meiotic division to produce two haploid
spermatids. (During meiosis there is a reduction in number of chromosomes from 46 to 23)
5. The secondary spermatocytes and spermatids are embedded within the Sertoli cells which nurse and
physically change them. They contain glycogen and one of their functions is to provide energy to the
developing cells.
6. The spermatids are released into the seminiferous tubules where they finally mature into
spermatozoa. The process takes around 70 days.
7. From the seminiferous tubules, spermatozoa pass into the epididymis where they mature and are stored
until ejaculation takes place.


Germ cells

Steroidogenesis:



Androgens induce growth and maintain development of the male genital tract.
The principal sources in the male are the interstitial Leydig cells situated between the seminiferous tubules.
Testosterone is the main testicular androgen. It can be converted to a much more potent androgen called
dihydrotestosterone (DHT) in tissues containing 5α-reductase.
Cholesterol
Pregnenolone
17-OH-pregnenolone
Dehydroepiandrosterone
DIHYDROTESTOSTERONE
Androstenedione
TESTOSTERONE
48
Females



1.
2.
3.
4.
5.
6.
7.
8.

Ovaries serve two functions in adult females: the production of mature gametes (ova) by oogenesis and the
production of steroid hormones oestrogen and progesterone (steroidgenesis).
Oogenesis
At birth, a female contains around 1 million oocytes. Regression of most of these cells (atresia) occurs from
birth to puberty, when only a few hundred thousand remain.
The formation of primordial germ cells or oogonia is completed during fetal development of the ovary due to
mitosis.
Still in the fetus, the oogonia develop into diploid primary oocytes and begin a first meiotic division.
The first meiotic division is arrested at the first prophase until ovulation.
The first meiotic division occurs only in those ripe ova released at ovulation forming two daughter cells, each
with 23 chromosomes.
However, one of the daughter cells (the secondary oocyte) retains virtually all the cytoplasm. The second
daughter cell, called the polar body, is small and non-functional.
The second meiotic division takes place after fertilization in the oviduct.
The second polar body is eliminated and the mature ovum is formed.
Net result is oogenesis is that one primary follicle can only produce one ovum. With spermatogenesis one
primary spermatocyte can produce four viable spermatozoa.
Follicular development:
1. In the ovary, the primary oocytes are arranged in primary follicles. Each primary follicle consists of an oocytes
surrounded by a single later of granulosa cells.
2. From puberty onwards, in response to a rise in the gonandotrophic hormone FSH at the beginning of each
menstrual cycle, several follicles begin to develop by proliferation of the granulosa cells.
3. The granulosa cells also secrete a mucopolysaccharide which forms a thick layer (the zona pellucida) separating
the primary follicle from the inner granulosa cells
4. Two more distinct layers are formed. The theca interna is the inner glandular and vascular layer (secrete
oestrogen) whilst the theca externa is the fibrous outer tissue.
5. Shortly after this, the granulosa cells secrete a follicular fluid which gradually accumulates and enlarges the
intrafollicular space forming the atrum.
6. Once this is formed, the granulosa and theca cells proliferate even more rapidly and each of the growing
follicles becomes an antral follicle.
7. Although at the start of menstruation around 15 follicles develop into antral follicles, only one (the dominant
follicle) continues to develop, whilst the rest undergo atresia.
8. At one polar end of the follicle, the cells of the granulosa are collected into a mass and project into the cavity
of the follicle. This is termed the cumulus oophorus.
9. At the time of ovulation the primary oocytes completes its first meiotic division and becomes a secondary
oocytes.
10. The cumulus separates from the follicle wall so that it and the secondary oocytes float free in the antral fluid.
The mature follicle is called the Graafian follicle.
49
11. Around the middle of the ovarian cycle (day 14) ovulation occurs. The follicle ruptures and the secondary
oocytes and its surrounding granulosa are released into the peritoneal cavity.

Steroidogenesis:




The ovary secretes oestrogens and progesterone.
17β-oestradiol is the main oestrogen produced, but oestrone is also secreted.
They are synthesised from cholesterol.
Progesterone is secreted by the corpus luteum and is present only during the luteal phase. It acts as a precursor
for other steroid hormones.
Oestrogen is produced by the granulosa cells of the follicles and is also produced after ovulation by the corpus
luteum.
During synthesis progesterone and testosterone are produced first. Then during the follicular stage, all the
testosterone and most of the progesterone are converted to oestrogens by the granulosa cells.


5.2 Draw simple flow charts illustrating the synthesis of progesterone, 17boestradiol and testosterone.
Cholesterol
Progesterone
17-hydroxy-progesterone
ANDROSTENEDIONE
Oestrone
Testosterone
17β-Oestradiol
50
5.3 Label diagrams illustrating the principal structures of the testes and ovaries.

Testicle:
Sertoli Cells
 These form the seminiferous tubules.
 Synthesise FSH and androgen
receptors.
 In response to the FSH, they produce
various molecules including inhibin.
 They are intimately associated with
developing spermatocytes.
Leydig Cells…
 These lie outside the seminiferous
tubules.
 They synthesise the LH receptors.
 Are the principal sources of testicular
androgens (mainly testosterone).
5.4 Describe the principal ovarian and endometrial changes that occur during the
menstrual cycle.
Overview:
Average length: 28 days.
Menses: The first signs of bleeding signal the
start of a new menstrual cycle and bleeding
continues for about 3-5 days.
Follicular phase (Proliferative): This is
followed by a period of growth and
development during which ovarian follicles
mature and the cells of the endometrium
proliferate.
Ovulation: occurs around day 14 due to an LH
surge.
Luteal phase: (Secretory): the corpus luteum
develops and secretes both oestrogens and
progesterone. Oestrogens promote
proliferative activity of the endometrium
while the endometrial glands become
distended with nutrients (due to
progesterone)
If implantation does not occur, the corpus
luteum regresses, there is a rapid fall in the
secretion of oestrogen and progesterone and
51
the endometrium undergoes shrinkage. Cell death occurs followed by menstrual bleeding.
Follicular stage/Proliferative stage:
Ovarian cycle:






Just before the beginning of each cycle there is a slight rise in FSH (because plasma oestrogen level is low,
exerting little negative feedback).
This rise stimulates the development of around 6-12 primary follicles. (Exact development described in
objective 5.1).
Due to LH and FSH binding to receptors, the granulosa cells of the follicles secrete oestrogen so blood oestrogen
levels rise.
As the plasma concentration increases it exerts a negative feedback on FSH production. There is no inhibitory
effect on LH.
The removal of FSH stimulus on follicular growth results in the atresia of those antral follicles which are still
FSH dependent. The one dominant follicle carries on developing as it is the most advanced (has increased FSH
and LH receptors as well as its own intrinsic positive feedback system.)
The plasma oestrogen level rises sharply over the next 4 to 5 days as the remaining Graafian follicle continues
to ripen. Follicular androgen production also increases.
Endometrium cycle:





Once the endometrial from the previous cycle has been shed (by day 5) the underlying endometrial cells
undergo proliferation and growth.
This coincides with increasing production of oestrogens from the developing ovarian follicle.
Oestrogens stimulate the growth of secretory glands and blood vessels that become coiled.
The endometrial glands of the cervical epithelium secrete a watery mucus that forms channels to help guide
the sperm in the proper direction into the uterus.
Oestrogen also induces synthesis of progesterone receptors, so endometrium can respond to the progesterone
produced by the corpus luteum at the beginning of the secretory phase.
Ovulation:
Ovarian cycle:






The raised oestrogen level, if maintained for a minimum period of 36 hours, now has a positive feedback effect
on the hypothalamo-adenohypophysial system.
Around 2 days before ovulation, there is a rapid surge in LH (and to a lesser extent FSH).
The two hormones act synergistically to cause rapid swelling of the Graafian follicle.
The LH has the effect on granulosa and theca cells of converting them more to progesterone-secreting cells and
less oestrogen.
The ultimate effect of the LH and FSH surge is to cause the follicle to rupture (due to activation of collagenase
that digest the follicular wall) and the process of ovulation takes place.
The ovum is released into the peritoneal cavity.
Luteal phase/Secretory phase:
Ovarian cycle:






After ovulation, the remaining granulosa cells enlarge and turn the follicle into the corpus luteum.
The corpus luteum continues to produce oestradiol and progesterone under the influence of LH.
As LH levels are falling, the effect of oestradiol will once again become negative feedback and so reduce LH
levels.
By about day 25, LH levels are not sufficient to maintain corpus luteum stimulation to produce oestradiol or
progesterone and therefore it degenerates (involution). Menstruation follows.
As there is no oestradiol or progesterone, there is no inhibition of the pituitary and so FSH secretion resumes
and the cycle commences again.
However, if implantation of a blastocyst occurs at about day 20 then the resulting trophoblast will secrete
human chorionic gonadotrophin (HCG) which has LH like activity and causes maintenance of the corpus luteum,
which will continue to secrete oestrogen and progesterone, thus maintaining the endometrium.
Endometrium cycle:


Following establishment of corpus luteum, progesterone and oestradiol are secreted in increasing quantities.
Oestrogen causes slight proliferation of endometrium, whilst progesterone causes marked swelling and
secretory development (coiling of blood vessels and glands).
52




Glands secrete large supplies of nutrients such as glycogen, to the uterus which would provide ideal conditions
for the developing blastocyst.
If implantation does not occur, the levels of progesterone and oestrogen fall along with the degeneration of the
corpus luteum.
This causes the vasoconstriction of blood vessels in the endometrium, followed by necrosis. This leads to
haemorrhage.
The bleeding stops after 5 days and is followed by the generation of a new endometrial lining.
5.5 Relate the synthesis of the major gonadal steroids in males and females to the
relevant hormones of the hypothalamo-adenohypophysial axis.
Males

Hypothalamic neurones that terminate in the median
eminence, when stimulated, release gonadotrophinreleasing hormone (GnRH) into the hypothalamohypophysial portal system. A brief burst of action
potentials is fired approx. every 2 hours.

Release of GnRH into the anterior pituitary stimulates
gonadotrophe cells to secrete LH and FSH in a pulsating
manner.

Testosterone is secreted by the interstitial cells of
Leydig in the testes when they are stimulated by LH. It is
required for spermatogenesis.

Testosterone has an indirect inhibitory effect on the
hypothalamus of decreasing the secretion of GnRH. This
in turn causes a corresponding decrease in FSH and LH
secretion.

There is also a weak direct negative feedback effect
exerted on the anterior pituitary gland to diminish LH
secretion.

FSH acts on the Sertoli cells causing them to grow and
release various spermatogenic substances. To initiate
spermatogenesis both FSH and testosterone are
necessary.

FSH is inhibited by a hormone synthesised by the Sertoli cells called inhibin.

Its synthesis is stimulated by FSH, and it exerts a direct negative feedback effect on the anterior pituaitary to
decrease FSH production.

It also has a slight indirect negative feedback on the hypothalamus, inhibiting the secretion of GnRH.
Females
Early follicular phase:
 The anterior pituitary gland secretes greatly increased amounts of FSH followed by LH at the beginning of
each menstrual cycle.
 This LH acts on the thecal cells to produce androgens whilst the FSH acts on the granulosa cells to
aromatize thecal androgens to oestrogens. Results in slowly rising plasma oestrogen concentration.
 As oestrogen concentration rises it exhibits a negative feedback effect on FSH production, which falls
around day 9.
Mid-follicular phase
 By the beginning of the second week one follicle has become dominant whilst the other FSH-dependent
antral follicles undergo atresia. The reason for this is that the dominant follicle’s granular cells have
achieved a greater sensitivity to FSH because of increased number of FSH receptors, so less is needed to
stimulate them. The granulosa cells have also become stimulated by LH as well, due to the production of LH
receptors.
 The rising level of oestrogens exerts a negative feedback over the secretion of GnRH by the hypothalamus
and the secretion of gonadotrophins by acting on the pituitary itself.
53

FSH falls more than LH because the granulosa cells also secrete inhibit which has a negative feedback on its
secretion.
Ovulatory phase:
 The inhibitory effect of oestrogen on gonadotrophin secretion only occurs at relatively low plasma
oestrogen concentrations (i.e. during early/mid-follicular phase)
 The raised oestrogen level, if maintained for 36 hours now has a positive feedback effect on the
hypothalamo-adenohypophysial axis.
 This results in a rapid surge of LH, and to a lesser extent FSH.
 This induces ovulation.
Luteal phase:
 Decrease in oestrogen production at ovulation removes the positive feedback on gonadotrophin release.
 Although LH and FSH levels fall, they are still sufficiently high to stimulate the newly formed corpus luteum
to secrete progesterone and oestrogens (as well as inhibin).
 The progesterone exerts negative feedback on the hypothalamus, decreasing the secretion of GnRH and
ultimately, the release of LH and FSH.
 Unless pregnancy occurs, the corpus luteum degenerates as there is no gonadotrophin support.
 The decrease in oestrogen and progesterone levels remove the negative-feedback effect on the secretion of
FSH and LH.
 After the endometrial lining is shed, a new group of follicles is stimulated to mature.
54
5.6 Describe how the cyclic production of ovarian steroids is linked to the
endometrial, cervical and other changes of the menstrual cycle.
Covered in objective 5.4
5.7 Describe the actions of the gonadal steroids in males and females.
Males
Testosterone:





Stimulates the growth and development of the male genital tract, i.e. testes, accessory organs etc.
At puberty, stimulate the increase in scrotal capacity to accommodate the growing testes.
Testosterone produced by the Leydig cells binds to the androgen-binding protein in the Sertoli cells and is
converted to oestrogens and dihydroxytestosterone (DHT). The function of testicular oestrogens is unknown,
but DHT is required to maintain spermatogenesis (without it the process is halted at the primary spermatocyte
stage).
Accessory sex glands provide secretions for the nourishment and optimal environment for spermatozoa, e.g.
fructose for metabolic activity.
Androgens develop secondary sexual characteristics – muscle growth, facial and body hair growth, deeper voice,
libido, recession of the hair line etc.
Females:
Oestrogen: any substance which induces mitosis in the endometrium









Stimulate the development and maintenance of the uterus, fallopian tubes, cervix, vagina, etc.
Stimulates the synthesis of progesterone receptors in the uterine tissues during the proliferative phase.
Stimulates output of watery mucus from he cervical glands which is favourable to the survival and transport of
spermatozoa.
Causes the vaginal epithelium to proliferate and show increased conification.
The development of secondary sexual characteristics – broader hips, accumulation of fat in the breasts and
buttocks, sexual libido, and effects on the CNS.
Stimulates growth and development of the ductile system in the breasts.
Helps to conserve bone (osteoporosis occurs in post-menopausal women)
Regulates the menstrual cycle, and induces the LH surge.
Increases renal salt (and water) reabsorption by stimulating angiotensinogen production in the liver.
Progesterone: any substance which induces secretory changes in the endometrium








The most potent is progesterone, as it does not only have its own endocrine effects – it is a precursor to other
hormones.
It controls secretory changes in the endometrium.
Modifies composition of the cervical mucus, making it thicker and less easily penetrable by spermatozoa.
Stimulates growth of the alveolar system in the breasts during pregnancy.
Raises the basal body temperature after ovulation, which is a useful indication that ovulation has taken place.
Has an effect on the CNS and the brain – which causes premenstrual syndrome (PMS).
Regulates the menstrual cycle.
Decreases sodium reabsorption.
Inhibin:

Suppresses FSH secretion by pituitary gonadotrophs.
5.8 Identify the principal features of the control systems operating on the
production of the gonadal steroids, with particular reference to negative and
positive feedback loops, in males and females.




Covered in objective 5.5. All feedback loops covered with the exception of prolactin (diagram on next page).
Prolactin is controlled by the inhibitory influence of dopamine.
Oestrogen and thyrotrophin-releasing hormone stimulate its secretion.
Elevated prolactin levels (hyperprolactinaemia) inhibit LH and FSH secretion.
55
-
Hypothalamus
+
Dopamine
TRH
Adenohypophysis
PROLACTIN
5.9 Define the terms primary and secondary amenorrhoea.
Primary amenorrhoea:






Relates to females who fail to develop secondary sexual characteristics by age 14 or who fail to menstruate
by age 16. It can be a result of:
Reproductive outflow tract abnormalities (i.e. androgen insensitivity syndrome)
Ovarian disorders (i.e. gonadal dysgenesis due to chromosomal abnormalities)
Pituitary disorders (i.e. adenomas)
Hypothalamic disorders (excersize/stress/weight-loss-related)
Endocrine disorders (hypothyroidism: elevated TSH results in elevated prolactin)
Secondary amenorrhoea:





Cessation of menstruation for more than 6 months in a normal female of reproductive age that is not due to
pregnancy. Can be due to:
Ovarian disorders (i.e. premature ovarian failure)
Hypothalamic disorders (i.e. stress, athletic sports etc.)
Endocrine disorders (i.e. excessive androgen production or polycysitic ovarian disease.)
Pituitary disorders (i.e. microadenomas)
5. 10 List the principal causes of infertility with references to endocrine causes.
Infertility is the inability to naturally conceive a child or to carry a pregnancy to full term
Male





Chromosome disorders such as Kleinfelter’s Syndrome (XXY).
Hypopituitaryism – FSH or LH deficiency.
Primary testicular failure (which is autoimmune endocrinopathy).
Hyperprolactinaemia
Hypothyroidism.
Female





Menopause.
Hypothalamic/pituitary tumours (prolactinoma) – this interferes with GnRH or LH/FSH release, and
therefore ovulation and menstruation are inhibited.
Hyperthyroidism.
Premature menopause (primary ovarian failure).
Turner’s Syndrome.
56
5.11 Name the two major functions of the testes and, with the use of a simple
diagram, describe how they are regulated by the hypothalamo-pituitary axis.

In an adult male, the testes serve two major functions- the production of human male gametes
(spermatogenesis) and the production of steroid hormones (steroidogenesis).
5.12 With the use of diagrams that distinguish between follicular (early, mid,
late) and luteal phases of the menstrual cycle, summarise endocrine regulation of
ovarian function.

Already covered in objective 5.5
Summary:
57
Session 6- The Parathyroids and Calcium Metabolism
Learning objectives:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
List the functions of calcium in the body.
Identify the principal organs involved in calcium metabolism.
Identify the bone cells and their functions.
List the principal hormones which regulate blood calcium ion concentration, and their sites of synthesis.
Briefly describe how parathormone, 1,25-dihydroxycholecaciferol and calcitonin are synthesized.
Describe the principal effects of parathormone, 1,25-dihydroxycholecaciferol and calcitonin on bone, the
kidneys and the intestinal tract.
Describe the mechanisms of action of parathormone, 1,25-dihydroxycholecaciferol and calcitonin.
Explain how parathormone, 1,25-dihydroxycholecaciferol and calcitonin production are controlled, identifying
the principal stimulus in each case.
List the principal causes of hypocalcaemia.
List the principal causes of hypercalcaemia.
Distinguish between primary, secondary and tertiary hyperparathyroidism.
6.1 List the functions of calcium in the body.
Calcium has a number of essential physiological functions including:
1. Maintenance of membrane permeability to sodium ions
2. Maintenance of excitability of nerve and muscle
3. Release of neurotransmitters, many hormones and exocrine secretions
4. Muscle contraction
5. Formation of bond and teeth
6. Coagulation of blood
7. Production of milk
8. Activity of many enzymes.






99% of the calcium in the body is found in bones where it provides strength and rigidity to the skeletal
framework.
99% of it is found as complex hydrated calcium salt (hydroxyapatite) crystals which is not available for rapid
mobilisation.
1% is present as calcium phosphate salts which is readily exchangeable and provides an immediate buffer to
sudden changes in blood calcium concentration (which it is in equilibrium with).
Normal concentration of calcium in plasma is 2.3 and 2.6 mmol/l.
50% of the calcium is unbound and ionised and the remainder is bound either to plasma proteins or associated
with ions such as citrate or lactate. The bound and ionized calcium are in dynamic equilibrium with each other.
Only the free (unbound) Ca2+ is bioactive.
6.2 Identify the principal organs involved in calcium metabolism.





Pathways by which calcium can enter or
leave the extracellular fluid are the GI
tract and the kidneys, respectively.
Calcium is taken in through the GI tract
(about 1g/day)
About 150mg/day is actually taken up by
the blood and the rest is excreted out
along with the rest of the faeces.
Once in the blood calcium can either be
stored in bone cells or it passed out with
the urine through the kidneys (100mg). A
very small amount is lost in dead cells,
such as hair and nails.
Other organs which are involved in the
calcium metabolism include the
parathyroids and the thyroid gland.
6.3 Identify the bone cells and their functions.


Bone consists of three cell types and a collagen matrix containing the calcium salts.
Osteoblasts: synthesise and lay down new bone matrix.
58


Osteocytes: are the most numerous cells and are formed from osteoblasts
once surrounded by new bone. They have long cytoplasmic processes
that make contact with their neighbours by tight junctions. They
play an essential role in the exchange of calcium between
extracellular fluid and bone.
Osteoclasts: stimulate bone resorption (the breakdown of bond
matrix to release calcium and phosphate into extracellular fluid) by
releasing lysosomal proteolytic enzymes such as collagenase.
6.4 List the principal hormones which regulate
blood calcium ion concentration, and their sites of
synthesis.


Calcium ion concentration in the blood is increased by:
1. Parathormone from the parathyroid glands
2. Vitamin D3 metabolites (calcitriol a.k.a 1,25dihydroxycholecaciferol) synthesised in the liver
Calcium in concentration is decreased by:
3. Calcitonin made in the parafollicular cells of the thyroid
6.5 Briefly describe how parathormone, 1,25-dihydroxycholecaciferol and
calcitonin are synthesized.
Parathormone:
 Parathormone is a large single-chain polypeptide consisting of 84 amino acids.
1. The initial precursor molecule called pre-proparathormone, which contains the signal peptide, consists of 115
aa.
2. The signal sequence is lost as the molecule enters the endoplasmic reticulum.
3. The remaining proparathormone sequence (90 aa) is present only in small concentrations in the glands.
4. Cleavage of the precursor molecule occurs in the Golgi complex, with PTH then packaged into secretory
granules prior to the release process.
1,25-dihydroxycholecaciferol (Calcitrol):
1. Natural vitamin D3 is called cholecalciferol, this is obtained either through the diet or synthesised in the skin by
the action of UV light on 7-dehydrocholesterol.
2. Cholecalciferol is then converted to 25-hydroxycholecaliferol (by an enzyme called 25-hydrolylase) in the liver,
where it is then stored.
3. The 25-hydroxycholecalciferol is then converted to the bio active 1,25- dihydroxycholecalciferol (the bioactive
form) in the kidneys by an enzyme called 1α-hydroxylase.
Calcitonin:


Is a polypeptide of 32 amino acids synthesised in the parafollicular cells of the thyroid.
Like other peptide enzymes it is initially synthesised as a large precursor prohormone sequence
6.6 Describe the principal effects of parathormone, 1,25-dihydroxycholecaciferol
and calcitonin on bone, the kidneys and the intestinal tract.
Parathormone:



The actions of parathormone are directed at raising the plasma calcium concentration and also decreasing
the phosphate concentration:
In the bone:
1. Stimulates osteoclastic and osteocytic activities.
2. Depresses the osteoblastic activity. This has the overall effect of increased bone resorption, which in
turn means there is increased calcium concentration in the extracellular fluid.
In the kidneys:
3. Increases tubular reabsorption of calcium, and increases phosphate excretion (by inhibiting reuptake in
the proximal and distal tubules). The resulting fall in plasma phosphate stimulates calcium release from
the bone and prevents the deposition of calcium phosphate.
59

4. It stimulates 1α hydroxylase, which brings about the production of 1,25-dihydroxycholecalciferol (which
also increases extracellular calcium concentrations)
The intestinal tract:
5. PTH stimulates the absorption of calcium ions and phosphate ions from the gastrointestinal tract
indirectly as it stimulates calcitrol production in the kidney.
Calcitriol:




The actions of calcitriol are directed at raising the plasma calcium and phosphate concentration in
conjunction with PTH.
In the bone:
1. Increases calcification of the matrix. Part of this effect is indirect and due to the intestinal absorption
of calcium and phosphate ions.
2. Increases osteoblast proliferation and osteoblast protein synthesis.
In the kidneys:
3. Increases tubular reabsorption of calcium AND phosphate from the distal tubules of the renal nephrons.
4. Stimulates active absorption of calcium and phosphate from the small intestine.
Calcitonin:




Net effect is to lower blood calcium concentration if it rises above 2.5 mmol/l.
In the bone:
1. Inhibits osteoclast activity, preventing bone resorption. Results in a decreased supply of calcium to the
extracellular compartment.
In the kidneys:
2. Causes the urinary excretion of sodium, chloride, calcium and phosphate.
6.7 Describe the mechanisms of action of parathormone, calcitrol and calcitonin.
Parathormone:






Binds to specific receptors on the plasma
membranes of its target cells.
In kidney and bone cells, PTH binding to its
receptor results in G protein subunit dissociation
and catalytic unit activation.
The catalytic unit is adenyl cyclase and its
stimulation results in activation of the
intracellular second messenger cyclic AMP (for
detailed explanation see pages 3 and 4).
The cAMP then activates protein kinase in the
target cell and this phosphorylates intracellular
proteins associated with PTH actions on cellular
activity.
No PTH receptors have been identified on the
main target cells: osteoclasts. Instead they have
been found on osteoblasts.
It is likely that, in addition to inhibiting osteoblastic activity, PTH also stimulates the synthesis of
osteoclastic stimulating factor (OSF) with stimulates osteoclastic activity.
Calcitriol:





Vitamin D3 metabolites being steroids, enter their
target cells and bind to cytoplasmic receptors.
The hormone-receptor complex then enters the
nucleus and binds to specific sequences in the
promoter regions of various genes. This leads to mRNA
synthesis.
As a consequence of its nuclear action, protein
synthesis is stimulated by calcitrol.
The new proteins (such as osteocalcin) are probably
involved in calcium transport mechanisms across cells
and mitochondrial membranes.
In the intestines: calcium-binding protein is
synthesised, which promotes calcium absorption
across the intestinal mucosa.
60
Calcitonin:



Binds to transmembrane G-protein linked receptor,
which is coupled to an adenyl cyclase catalytic unit.
Cyclic AMP is generally believed to be an intracellular
second messenger in the renal target cells and
osteoclasts.
It also has a more direct action by binding to membrane
receptors and causing Ca2+ release into the surrounding
extracellular fluid, e.g. from bone.
6.8 Explain how parathormone, 1,25dihydroxycholecaciferol and calcitonin
production are controlled, identifying the
principal stimulus in each case.
Parathormone:




Blood calcium level is an important factor in the
control of PTH release.
The direct negative feedback by calcium ions on
the parathyroid glands is the principal regulatory
mechanism.
Other stimuli include catecholamines and
dopamine. They induce the release of pre-formed
PTH from membrane-bound granules through a
cAMP-protein kinase mechanism.
Calcitriol inhibits PTH release partly by inhibiting
PTH synthesis and partly because its own actions
are mediated by an increase in intracellular
calcium ion concentration.
Calcitriol:





Regulation of production occurs principally at the second hydroxylation stage in the kidneys.
Parathormone stimulates 1α-hydroxylase activity while calcitonin inhibits it.
Low plasma phosphate and prolactin also stimulate the enzyme.
Synthesis is also controlled by the negative feedback of calcitriol itself.
If calcium and phosphate concentrations are normal, most of the vitamin is transformed in the kidney to
inactive derivatives.
Calcitonin:


Plasma calcium level is the only established control mechanism.
The gastrointestinal hormone gastrin also has a stimulatory effect on calcitonin release from parafollicular
cells.
6.9 List the principal causes of hypocalcaemia.



Hypocalcaemia: the presence of low serum calcium levels in the blood (usually below 1.8mmol/L) or an ionised
calcium level of less than 1.1 mmol/L
Mainly occurs due to a deficiency of parathyroid hormone, inefficient parathyroid hormone, or Vitamin D
deficiency. Can be due to error during thyroid surgery (iatrogenic cause) Other principal causes include:
Endocrine:
 Hypoparathyroidism (decreased levels of parathyroid hormone)
 Pseudohypoparathyroidism
 Vitamin D deficiency
6.10 List the principal causes of hypercalcaemia.


Hypercalcaemia: the presence of elevated calcium levels in the blood (above 2.6mmol/l).
Symptoms are more common at high calcium levels (12.0 mg/dL or 3 mmol/l).
61



Severe hypercalcemia (above 15-16 mg/dL or 3.75-4 mmol/l) is considered a medical emergency: at these
levels, coma and cardiac arrest can result.
Causes:
Endocrine:
 Primary and tertiary hyperparathyroidism
 Ectopic (paraneoplastic) hypercalcaemia (breast cancer or lung cancer causes production of
parathyroid hormone-related protein).
 Hyperthyroidism
 Adrenocortical insufficiency
Non-endocrine:
 Paget’s disease
 Vitamin D excess
6.11 Distinguish between primary, secondary and tertiary hyperparathyroidism.

Primary hyperparathyroidism results from a dysfunction in the parathyroid glands themselves, with
oversecretion of PTH.
 The most common cause is a benign parathyroid adenoma that loses its sensitivity to circulating
calcium levels. Usually, only one of the four parathyroid glands is affected.

Secondary hyperparathyroidism caused by an underlying problem, usually due to chronic renal failure.
 Excessive PTH is released by the parathyroid glands in response to the chronically low calcium
concentration.
 This causes the parathyroid glands to be overworked and hypertrophy occurs.

Tertiary hyperparathyroidism if secondary hyperparathyroidism is left untreated, parathyroid gland
hypertrophy becomes irreversible.
 Correction of the underlying cause does not result in reduces PTH.
 The parathyroid glands become autonomous in its activity.
62

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