lOMoARcPSD|4188894

Endocrinology - Lecture notes 12,13,14,15

Mammalian Physiology (University College London)

StuDocu is not sponsored or endorsed by any college or university

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)
 lOMoARcPSD|4188894

Physiology Lecture (12) Notes ENDOCRINOLOGY;

Introduction to the Endocrine System;

Endocrine System;
> One of the two communication systems of the body, the other being the nervous system.
> The endocrine system operates through chemical messengers or hormones which
circulate in the blood to target organs.
> Hormones co-ordinate the minute to minute and day to day functions of the various
tissues of the animal
> Hormones help regulate such diverse activities such as
- Growth and development of physical, sexual and mental characteristics
- Utilization of nutrients by the cells
- Adjustments of salt and water balance
- Metabolic rate
- Dealing with stress

Principal Endocrine Glands;

> The principal endocrine organs are ;
- The pituitary
- The Thyroid
- Parathyroid
- Adrenals
- Gonads (Ovaries/Testes)
> Other organs such as the islets of Langerhans, heart. Gastrointestinal tract, brain and
kidney also secrete hormones
> Definitions;
- Endocrine Cells; Secrete hormones into a blood vessel and hormone transported
to target cells
- Paracrine cells; Secrete hormones which act on neighboring cells
- Autocrine cells; secrete hormones which act on the same cell
- Neuroendocrine cells; Secrete hormones from neural axon terminals straight
into blood stream

Hormones;

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

> Can be made from a number of molecules;

- Proteins or polypeptides eg. Insulin
- Glycoproteins eg. LH, FSH and TSH
- Derivatives of the amino acid tyrosine eg; adrenaline, thyroid hormones (T3 and
T4)
- Steroids derived from cholesterol
- Lipid-derived molecules such as prostaglandins
> Regulate a number of biochemical processes
- Growth; development of physical sexual and mental characteristics
- Growth hormones, thyroid hormones, testosterone and estrogens
- Utilization of nutrients by cells
- Insulin glucagon, cortisol, growth adrenaline
- Adjustment of salt and water balance
- Aldosterone, vasopressin (ADH) Atrial Naturistic Factor (ANF) )
- Metabolic Rate
- Thyroid Hormones
- Dealing with Stress
- Cortisol, adrenaline

Major Categories of Hormones;

> Amines; (amino acid tyrosine based)
- Eg; Adrenaline, dopamine, thyroid hormone
> Steroid; Derived form Cholesterol
- Eg; Testosterone, Estrogens
> Proteins
- Eg; Glyco-proteins eg TSH, LH, FSH

Classification of Hormones;
> Hydrophilic;
- Will not enter cells and must bind to cell surface receptors
- Receptors are integral membrane proteins
- Hormones can be stored in secretory vesicles
- Eg; adrenaline, HGH, vasopressin
> Hydrophobic;
- Will enter cells and receptor is a soluble protein inside cytoplasm and can enter
nucleus
- Hormones cannot be stored and are synthesized on demand
- Eg; Thyroid hormones T3 Vitamin D3

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

> Peptide and protein hormones, adrenaline etc., are stored as pre-formed molecules in
secretory vesicles.
> A stimulus will cause the release of the secretory vesicles by exocytosis where the
plasma membrane fuses with the vesicle membranes leading to the release of their
contents to the cell exterior
> Steroids on the other hand are lipophilic and are therefore not stored in cells
- They are synthesized on demand from cholesterol

Transport of Hormones in the Blood;

> Most peptides and protein hormones are hydrophilic and therefore circulate in the
blood in the free form
- Steroid hormones and thyroxine are hydrophobic and are therefore transported in
the blood bound to serum proteins
- Eg; thyroxine binds to thyroxine binding globulin, cortisol binds to cortisol
binding protein
> Each globulin is specific to it’s hormone;
- Only the free circulating hormone is “active”
- remainder acts as a reservoir
- Therefore, hormone levels can be altered just by changes in the level of the binding
proteins themselves.

Half Life T½ of Hormones;

> Hormones have to be removed from circulation and this is done by the kidney, liver and
occasionally lungs
- The rate of clearance will determine the half-life of the hormone and this will vary
with the different hormones (rate of their metabolism).
- Half-life (T1/2) of a hormone is defined as the time required to reduce the
circulating hormone concentration by half.
> Example; If the [adrenaline] = 30 um at T=0 and is now 15um at T=30s, then
the half life of adrenaline = 30 seconds

How Hormones Work;

> Hormones interact with specific receptors on target cells
- The receptor can be either localized the cell surface or in the nucleus
- Most hydrophilic molecules act on the cell surface, but steroid hormones and
thyroid hormones have their own receptors in the nucleus
> Hydrophobic hormones;
- Work on a longer timescale than hydrophilic hormones

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

Hydrophilic Hormones;
> Hormones acting at the cell surface act by generating second messengers or by
tyrosine phosphorylation of specific target proteins
> They use a three-component system, consisting of RECEPTOR, G-PROTEIN and
ENZYME to make intracellular messengers ~800GPCRs in the human genome and 17 G
alpha proteins
> Two examples of second messenger systems which are widely used;
- (1) Receptor interacts with a GTP binding proteins Gs and this protein activates
adenylate cyclase.
- Adenylate cyclase catalyzes the conversion of ATP to cAMP.
- cAMP interacts with a specific protein kinase A (PKA) and this stimulates
phosphorylation of target proteins.
- Phosphorylation regulates the function of target proteins

- Serine, threonine and tyrosine residues in proteins can be phosphorylated by ATP

- Phosphorylation can change the “activity” status of the protein, eg an enzyme can
be ‘activated’ or ‘deactivated’
- Phosphorylated proteins are dephosphorylated by enzymes called phosphatases

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

- (2) Receptor interacts with GTP binding proteins Gq and this protein activates the
enzyme phospholipase C.
- Phospholipase C catalyses the hydrolysis of a membrane lipid
phosphatidylinositol (4,5) bisphosphate (PIP2) to release two second
messenger;
- Inositol (1,4,5) – trisphosphate (IP3)) and diacylglycerol.
- IP3 is responsible for causing an increase in cytosol [Ca 2+] by opening IP3 – gated
channels t the endoplasmic reticulum and diacylglycerol activates protein
kinase C (PKC)

> The second messengers cAMP, diacylglycerol, Ca 2+ control many of

the cellular functions of the cell (other second messengers are
cGMP)
- Receptors that activate G-proteins are often referred to as
GPCRs (G-protein-coupled receptors)
- These receptors have SEVEN transmembrane regions

Tyrosine Phosphorylation as a Signal

Transduction Event;
> Insulin receptors are single transmembrane proteins and
contain tyrosine kinase activity
- Insulin causes tyrosine phosphorylation of target proteins
and activates the enzyme PI3K
- PI3K phosphorylates PIP2 to PIP3 and this activates a protein kinase PKB
(Protein kinase )
> Growth Hormone and Prolactin receptors are single membrane spanning proteins
and their mode of signaling is through JAK-STAT signaling pathways
- JAK (Janus kinase) is a tyrosine kinase and phosphorylates STAT (Signal
Transducer and Activator of Transcription)
- STAT enters the nucleus and promotes transcription of genes.
> Phosphorylation of proteins regulates activity – another molecular SWITCH
commonly used in cells.

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

Steroid Hormones and Thyroid Hormones are Lipid-

Soluble Hormones;
> These hormones circulate in the blood bound to globulins
- The unbound hormone enters the cells from the blood and binds to a receptor in
the nucleus.
- The complex binds to DNA and activates the transcription of specific genes.
- The mRNA directs the synthesis of specific proteins, enzymes etc.

Negative Feedback;
> Negative Feedback is defined as a signal produces a response which feeds back on the
signal generator to decrease the level of the signal
- In order to regulate hormones released by this mechanism, the first hormone
(Hormone A) is released from Cell A.
- Hormone A acts on Cell B (eg; anterior pituitary) to trigger the release of Hormone
B.
- Hormone B acts on Cell A to inhibit production of Hormone A
> Thus many of the hormones of the anterior pituitary which are trophic hormones and
which act on other endocrine glands such as the thyroid, adrenal cortex, to stimulate
production of other hormones are controlled by negative feedback.

Organisation of the Endocrine System; Hypothalamus

and the Pituitary;
> The pituitary is located at the roof of the mouth and is responsible for controlling many
of the endocrine organs such as the thyroid, adrenals and gonads and is thus regarded
as the master gland of the body.
- The pituitary itself is controlled by the hypothalamus which receives inputs from
the CNS
> The pituitary can be subdivided into the anterior (adenohypophysis) and the
posterior )neurohypophysis).
- In the lower animals (reptiles, Amphibia) a third intermediary lobe is present
which is responsible for the hormone melanocyte stimulating hormone (MSH).

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

Control of the Endocrine System;

> Since the primary role of the endocrine system is one of control, it is useful to consider
the possible mechanisms available for control;
> Hypothalamus/Pituitary Axis;
- Posterior Pituitary is an example of Neurohormone secretion

> Acronyms;
- GnRH – Gonadotrophin Releasing hormone
- GHRH – Growth hormone RH
- TRH – Thyrotropin RH
- CRH – Corticotrophin RH
- FSH – Follicle Stimulating Hormone*
- LH – Luteinizing Hormone*
- TSH – Thyroid Stimulating Hormone*
- ACTH – Adrenocorticotrophin
- IGF – Insulin like Growth Factor
- T3/T4 – Thyroid Hormones
- *Glycoproteins Made of two subunits Alpha and Beta subunits

Anterior Pituitary;
> The anterior pituitary synthesizes and secretes 6 hormones stored in these cells;
- Somatotrophs – Stores Growth hormone
- Lactotrophs – Stores Prolactin
- Gonadotrophs – stores FSH/LH
- Corticotrophs – stores ACTH
- Thyrotrophs – Stores Thyroid stimulating hormone

> (1) Growth Hormone (GH);

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

- A polypeptide hormone which is specific-specific. GH has powerful effects on growth

and metabolism.
- Absence results in dwarfism an excess results in gigantism
- Functions; Effects of GH on two time scales; corresponding to a long term growth
effect and short term effect on metabolism
> (2) Prolactin;
- Resembles GH in structure. Its main function is to induce mammary gland growth
and milk secretion essential for lactation.
- Levels of prolactin is high in pregnancy due to the increase in the size and number
of prolactin-secreting cells stimulated by estrogens.
- Higher prolactin levels in females compared to males generally
- Prolactin has effects on salt and water balance in non-mammals as well as in
controlling behavior
- In birds it induces nest building activity
> (3) ACTH and MSH – a polypeptide of 39 amino acids
- ACTH controls the secretion of adrenal cortex hormones eg cortisol. ACTH also
stimulates the growth of the adrenal gland (known as the trophic effect)
- It is synthesized as part of a Proopiomelanocortin precursor coded by the POMC
gene.
- POMC molecule can be processed differently depending on its cellular site.
- In the anterior pituitary, it is made into ACTH and beta-endorphin an opioid
peptide having analgesic effects
- In the intermediate lobe, processing of the POMV molecules leads to MSH
formation. In reptiles and Amphibia, MSH is formed in the intermediary lobe of the
pituitary
- MSH acts on melanocytes to stimulate the dispersion of melanin granules, which
causes skin darkening and permits the animal to blend with its environment.
> (4) TSH, FSH and LH;
- They are all glycoproteins composed of two subunits, beta and alpha.
- The alpha subunit is the same for all three hormones.
- Beta subunit confers specificity.
- FSH and LH are involved in reproductive physiology
- TSH stimulates the thyroid and like ACTH, it also has a “trophic” effect on the gland.

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

What controls the secretions of pituitary Hormones?

> The hypothalamus controls the anterior pituitary.
- Releasing hormones from the hypothalamus arrive directly to the pituitary via the
portal veins, so that they do not get diluted out into the general circulation
- TRH controls section of TSH
- GHRH controls secretion of GH
- CRH controls secretion of ACTH
- GnRH controls secretion of LH and FSH
- PRH controls release of prolactin
> The hypothalamus also constrains hormones that inhibit section from the anterior
pituitary;
- Somatostatin inhibits growth hormone secretion
- Dopamine inhibits prolactin release
> The releasing hormones and the inhibitory hormones are stored in neurons in axon
terminals in the hypothalamus. The neurons are in synaptic contact with a host of
neurotransmitters
- Noradrenergic and cholinergic fibers and neuropeptides; VIP, Angiotensin II
and neurotensin.

The Posterior Pituitary;

> The posterior pituitary is derived from the neural tissue and consists of the terminals of
neurosecretory cells and is responsible for the section of two hormones;
- Oxytocin and vasopressin
- The cell body of the neurosecretory cells reside in the hypothalamus.
- Synthesis of the hormones occurs in the cell body and are transported down the
nerve terminal by fast axonal transport
> Oxytocin; has two main functions
- Lactation – stimulates ejection of milk from the mammary glands
- Parturition – contraction of the smooth muscle of the uterus
> Vasopressin (also known as ADH – anti-diuretic hormone);

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

- This acts on the kidney to permit water to be re-absorbed, making the urine
concentrated and making water available to dilute the osmolarity of body fluids.
> Positive Feedback;
- This is a system in which the signal generator is stimulated by the response,
which it induces.
- This is intrinsically unstable control system but there are a few specific biological
systems where such a control system is operative
- During childbirth (parturition) and during lactation
- In both cases oxytocin is involved

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

Physiology Lecture (13) Notes ENDOCRINOLOGY;

Endocrinology of the Reproductive Systems;

What Makes Male and Female;

> Sex differentiation under control;
- Y chromosome has the SRY gene; Sex determining Region of the Y chromosome)
- SRY gene dictates that a testes is made
- But Endorines dictates development
- Testosterone and glycoprotein hormone called Mullerin inhibiting
Hormone (MIH) require for male development
- In their absence, female characteristics develop

> Before 7-8 weeks of gestation, the sex of the embryo is indeterminate
- All embryos acquire dual ductal systems – the Mullerian Duct and the Wolffian
duct
- Mullerian duct gives rise to the fallopian tubes and uterus and Wolffian duct
give rise to Vas deferens and Seminal vesicles
- In the female the mullerian ducts develop and the Wolffian ducts degenerate
(default route)
- In the male, Mullerin inhibiting hormone causes the Mullerian duct to degenerate
and the testosterone differentiates the Wolffian ducts and also causes virilization of
the external genitalia (requires testosterone to be converted into 5-hydro-
testosterone).

Spermatogenesis;
> Sperm cells are produced continually in the testes throughout life.
> The structural organization of the testes is important in the control of sperm
maturation.
- The spermatogenic tubules consist of SERTOLI cells and germ cells
- The LEYDIG cells (also known as interstitial cells) present in the interstitium
contains the enzymes for the production of androgens (mainly testosterone)
- The anterior pituitary is stimulated to produce both LH and FSH by GnRH from the
hypothalamus.

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

- The secretion of GnRH is episodic resulting in the intermittent secretion of LH in 8-

14 pulses/24hours in adult males.
- Pulsatile secretion of FSG also occurs but of smaller amplitude
- FSH acts on Sertoli cells (also known as nurse cells) which surround the sperms
during different sages of maturation
- LH acts on Leydic cells and stimulates the synthesis and secretion of
testosterone
- Testosterone maintains spermatogenesis but is unable to initiate the process
- Sertoli cells have to be primed by FSH
- This testosterone and FSH control the rate of production of spermatozoa.

> Secretions from accessary glands;

- Seminal vesicles (60%)
- Prostate (20%)
- Bulbo-urethal glands
- All added to spermatozoa to form SEMEN
- Sperm count; 100 million sperms/ml (200 million a day)
- Secretions provide nutrients (fructose)
- Maintain pH of 6.5 (alkaline)
- LH acts on Leydig cells to produce testosterone
- FSH acts on Sertoli cells to initiate spermatogenesis

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

> Testosterone inhibits LH secretion at the level of the pituitary and GnHR secretion
from the hypothalamus via negative feedback.
- Sertoli cells also produce INHIBN, a polypeptide hormone that acts on the anterior
pituitary, to inhibit the release of FSH

Female Reproductive Physiology;

> The ovaries have a dual function of producing germ cells and of secreting female
sex hormones
- Oocytes are the cells from which ova will be formed by meiotic (reduction) cell
division and this is only completed after puberty under the influence of LH.
- Oocytes are surround by a single layer of granulosa cells – this constitutes the
primary follicle.

> Ovarian Cycle – produces mature oocyte every 28 days

> Uterine Cycle – provides the environment for the fertilized ovum to develop
> Release of germ cells in Cyclical;
- This is reflected by the corresponding cyclic structural and functional changes
throughout the female reproductive system
- These hanges are dependent on two inter-related cycles;
- Ovarian and Uterine (menstrual) cycle.

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

- Both these cycles, although variable, last approximately 28 days

- The menstrual cycle is controlled y the ovarian cycle via sex hormones.

The Ovary;
> At birth, there are 1 million oocytes
> By puberty there are 100,000 – 500,000 only
> Each oocycte reaches maturity at intervals of 28 days
> Oocytes are exhausted by age 50 approx so a woman ultimately need s 500 oocytes

The Ovarian Cycle;

> The hypothalamus releases Gonadotrophin releasing hormone (GnRH)
- This stimulates the Ant. Pit. To secrete FSH
- This acts on the ovarian follicle, to initiate maturation and become the Gaafian
follicle
- This will release the ovum into the fallopian tubes (OVULATION)
- The developing follicle synthesizes oestrogens which acts to inhibit production of
GnRH and FSH by the hypothalamus and pituitary respectively.
- The fall in FSH levels and the increase in oestrogens cause the ant. Pit. To release
LH
- LH triggers ovulation 12 hours later by the multicomponent mechanism.
- The ruptured follicle becomes the CORPUS LUTEUM, which in turns starts to
produce both oestrogen and PROGESTERONE
- In an infertile cycle, the corpus luteum only lasts for 10 days after which it
regresses.
- If pregnancy does occur, the corpus luteum is maintained for at least 3 months

Follicle Phase;

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

> Estrogen synthesized by the developing follicle

- Reaches a peak 2 days before ovulation
- The estrogen peak is responsible for the surge of both LH/FSH release
- hours after LH/FSH peak ovulation takes place
> Estrogen secreted by follicle has two major effects;
- Suppresses FSH release at low concentrations
- At high concentrations it stimulates a surge of both LH and FSH

Luteal Phase;
> After ovulation the corpus luteum , under the influence
of LH secretes both estrogen and progesterone;
- Therefore secretory endometrium develops
- Inhibition of secretion of FSH/LH
- Decreases in LH leads to degeneration of Corp. Lut.
And a corresponding decrease in estrogen and
progesterone
- Endometrium beings to slough at conclusion of day
28

Uterine Cycle;
> The uterus has three layers;
- A thin layer in contact with the body cavity
- A thick muscular layer myometrium
- A mucous membrane lining the uterine cavity
endometrium
> During the course of the uterine cycle the endometrium
undergoes cyclic structural changes which can be
divided into three stages.
> (1) The proliferative stage where the endometrial
cells proliferate under the influence of oestrogens
(secreted by the developing follicle)

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

> (2) The secretory phase during which the glands in the endometrial wall become
more complex and start to secrete mucus.
- Progesterone secreted by the corpus luteum induces the secretory phase of the
uterine cycle
- To be maintained in the secretory phase, the presence of both progesterone and
estrogens is required
- The combined effect of these hormones prepares the endometrial lining of the
uterus for implantation of the fertilized egg.
> (3) Menstrual phase – In the absence of fertilization, the corpus luteum degenerates,
estrogens and progesterone levels fall, and the endometrium breaks down and sheds its
outer layers.

Pregnancy;
> Fertilization normally occurs in the fallopian tubes.
- The zygote develops into a blastocyst by a series of rapid cell divisions
- The blastocyst sends invading trophoblast cells into the endometrium
eventually forming the synctiotrophoblast cells.
- These secrete a hormone HUMAN CHORIONIC GONADOTROPHIN (HGC)
which can be detected in maternal plasma and urine within 9 days of
conception.
- HGH is a glycoprotein with alpha and beta subunits
- The alpha subunit is identical to that of TSH, FSH and LH>
- The beta subunitss 80% homologous with that of LH.
- HGC maintains the function of the corpus luteum.
- Normally the corpus luteum would regress after 10 days but for pregnancy to
proceed the endometrium has to be maintained by the presence of progesterone
and estrogens secreted by the corpus luteum.
- HGC maintains the corpus luteum in the same way that LH does
- Later on when the placenta has developed (9-12 weeks) the role of secreting
estrogens and progesterone is taken over by the placenta, and the secretion of
HGC declines and the corpus leteum can now regress.
- Detection of HCG in the urine forms the basis of the pregnancy test.
> Zygote also secretes HUMAN PLACENTAL LACTOGEN (HPL);
- Causes growth of the mammary glands

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

> The secretion of oestrogens and progesterone is maintained at a high level

throughout pregnancy which ensures the continue upkeep of the endometrium and
also suppresses further ovulation.
- They also maintain the uterine musculature and inhibit T-lymphocyte –
mediated tissue rejection.
- The synctiotrophoblast also secretes another hormone, HUMAN CHORIONIC
SOMATOMAMMOTROPHIN (HCS) (also known as HPL)
- The structure of HCS is similar to prolactin and growth hormone
- Its major function is to direct maternal metabolism by stimulating lipolysis to
maintain a constant flow of fuel, especially glucose to the fetus
- It also stimulates the growth of the mammary glands

Parturition;
> The signal for childbirth comes from the fetus
- Certain undefined stimuli (possibly stress) act upon the fetal hypothalamus to
trigger the release of ACTH from the fetal pituitary.
- ACTH causes the release of corticosteroids from the fetal adrenal cortex and
they cause a fall in the placental progesterone concertation
- Progesterone inhibits uterine contracts by preventing prostaglandin synthesis.
- Prostaglandins induce powerful uterine contractions
- Once contractions are initiated, it dilates the cervix and stimulates stretch
receptors in the cervical wall
- This signals the release of oxytocin
- This produces further uterine contractions (positive feedback) leading to the
expulsion of the fetus

Lactation;
> Lactation can carry on for months;
- During lactation, fertility is reduced, primarily mediated by prolactin
- Prolactin suppresses the release of GnRH
> Lactation can be suppressed by dopamine (bromocriptine – dopamine agonist) which
depresses prolactin release

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

- Dopamine antagonists allow prolactin release and hence milk synthesis

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

Physiology Lecture (14) Notes ENDOCRINOLOGY;

Adrenal Glands: Physiology of Stress;
Location of the Adrenal Gland;
> The adrenals are small ‘cocked-hat’ shaped glands that are located on top of the
kidneys.
> The adrenal gland is composed of two distinct types of tissue;
- The outer part, CORTEX, secretes steroid hormones
- The inner part, MEDULLA, secretes catecholamines (adrenaline, noradrenaline,
dopamine)
> Secretions from both parts of the gland are concerned with, amongst other things,
mediating the body’s response to stress.
> The flow of blood is such that the steroid hormones secreted from the cortex pass
through the medulla before getting diluted in general circulation.

The Adrenal Gland;

> Medulla-accounts for 10-20% of the total adrenal gland
- It consists of secretory cells containing adrenaline (80%)
- And also noradrenaline (20%)
- Each medullary cell is innervated by cholinergic sympathetic neuron.
- Acetylcholine (Ach) stimulates the medullary cells to release
catacholamines
- The effects of catecholamines are on many cell types by interaction with either –
or -adrenergic receptors.
- -Adrenergic receptors use the phospholipase C pathway
- -adrenergic receptors use cAMP as their second messenger.
- The effects of catecholamines are to prepare the animal for “flight” it therefore
has;
- (a) metabolic effects (eg; glycogenolysis, lipolysis, gluconeogenesis) which are
geared to increasing circulating levels of glucose and making fuel available
- (b) cardiovascular effects; increase in cardiac output and heart rate
- (c) re-direction of blood flow from non-essential organs like viscera to muscle

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

> Adrenal Cortex; The cortex secretes three classes of steroid hormones. Each class of
hormone is secreted from a separate zone;
- (1) Mineralocorticoids (eg; aldosterone) is synthesized in the outer zone, the
zona glomerulosa
- (2) Glucocorticoids (eg; cortisol) form the middle zone, zona fasciculate. This
zone is the widest and consists of long cords of columnar cells.
- (3) Sex hormones (eg; androgens and estrogens) synthesized from the inner
layer, zona reticularis.
- The hormones are synthesized on demand from cholesterol
> Total weight; 6 – 10g
- Medulla derived from neruoectodermal tissue
- Cortex derived from mesodermal tissue
> The adrenal gland; essential for life;
- Blood glucose regulation – CORTISOL
- Protein turnover – CORTISOL
- Na+ and K+ balance – ALDOSTERONE
- Survival in times of stress – CORTISOL AND ADRENALINE
- Modulation of tissue response in injury – CORTISOL

Cortisol;
> This hormone is required for survival or the stressed organism.
- Cortisol stimulation is controlled by ACTH released from the anterior pituitary
> Cortisol has very generalized effects on the body.
- The most important effect is to stimulate the conversion of protein to glucose
- The storage of glucose as glycogen in the liver
- Thus the hormone maintains an energy supply during starvation
> It also affects;
- Fat metabolism
- Increased lipolysis -> glycerol fatty acids -> liver
- Central Nervous system function
- Skeletal turnover
- Proteolysis -> amino acids -> liver
- Immune responses
- Immunosuppression and anti-inflammatory
> It causes two major changes in the body;
- Raises blood glucose levels (regulation of metabolism)
- Adaptive to stress-immunosuppressive, anti-allergic, anti-inflammatory
> Regulation of Cortisol;
- Low glucose levels, diurnal rhythm and stress all release Corticotrophin
releasing hormone (CRH) from hypothalamus
- Causes pituitary to release ACTH
- Cortisol released from adrenal cortex
- Negative feedback from cortisol to hypothalamus and pituitary inhibits release
of CRH and ACTH – stops cortisol release
> Too much cortisol; Cushing’s syndrome
- Redistribution of body fat; wasting of muscle, hyperglycemia
- Due to increased output of ACTH
- Hypersecretion of CRH
- Lung tumors often produce ACTH

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

- Patients with chronic inflammatory disorders receiving treatment with

corticosteroids
> Stress trigger;

Aldosterone (a Mineralocorticoid);
> This hormone has two principal functions;
- It sustains extracellular fluid volume by conserving body sodium
- Prevents overload of potassium by stimulating its excretion.
> Thus, aldosterone secretion is stimulated by increases in plasm potassium or in
response to reduction in fluid volume
> Angiotensin II is the direct mediator of aldosterone release.
- Na deprivation, loss of volume
- Renin from kidney
- Angiotensin II stimulates adrenal cortex to release aldosterone
- ACTH also stimulates aldosterone release
> Aldosterone stimulates the production of sodium channels ENaC that are inserted to
apical membrane to effect sodium transport
> Stimulates production of Na-K ATPase

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

> Renin-Angiotensin system;

> Synthesis of adrenal hormones from cholesterol

- In the adrenal cortex, cholesterol is converted into aldosterone (Zona glomerulsa)
Cortisol (zona fasciculate) and androgens/estrogens (zona reticlaris)
- Many of the intermediates in the synthesis of these hormones are shared and
because of their lipid soluble nature, the intermediates can leak out of cells into
neighboring zones

- Absence of enzymes that block the synthesis of glucocorticoids (enzymes 1 or 2)

will lead to overspill into the other pathways.

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

- In an attempt to compensate, more ACTH will be released and as a result excess

androgens will be produced
- In females, this will lead to virilisation (masculainisation)
- In prepubertal males (boys), premature development of male sexual characteristics
can occur

The Adrenal Medulla;

> The medulla is composed of Chromaffin cells
- Sympathetic postganglionic neurons,
- The cells are filled with granules containing;
- Adrenaline 80%/NorA 20%
- Adenosine Triphosphate (ATP)
- Opioid peptides
- Granules, secreted by exocytosis
- Chromaffin cells are responsible for the synthesis, storage and release of
catecholamines;

> Adrenergic receptors;

- Adrenaline; plays an important role in the fight or flight response
- Does so by increasing blood flow to muschles, heart output, and blood sugar
- Also dilates the pupils
- Adrenergic Receptors are GPCRs

> Actions of Catecholamines;

-  -> cAMP,  -> PLC

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

- Metabolic;
- ; Gluconeogenesis (liver)
- ; Glycogenosis, lipolysis
- Cardiovascular;
- ; Blood pressure increase
- ; Heart rate increases, cardiac contractility
- Visceral;
- ; Sweating, dilation of pupils
- ; Muscle relaxation in GI tract, urinary, bronchial

Glucose Homeostasis – Islet of Langerhans;

> Secretion from the islets of Langerhans is concerned with regulation of blood glucose.
- More than a million small clusters of cells known as the Islet of Langerhans are
scattered throughout the pancreas
- 70% of cells are beta cells that produce INSULIN
- The remainder are alpha cells (secreting glucagon) (20%)
- As well as delta cells that secrete somatostatin (10%)
- Somatostatin inhibits the secretion of insulin
> Insulin is a protein hormone that exerts widespread influence on metabolism
- It stimulates the storage of glucose, amino acids and fatty acids
- Its principal action is to stimulate glucose intake into most cells, especially muscle
and fat cells.
- In muscle cells, glucose is stored as glycogen and do need insulin
- However insulin is important for converting the glucose into glycogen for
storage
- Insulin lowers blood glucose levels
- Resting levels of glucose = 5.6mM (1mg/ml)
- After meal concertation will rise to 7-8mM
- High glucose levels stimulate insulin release
> Glucagon a protein, acts antagonistically to insulin
- It stimulates the mobilization of glucose, fatty acids and amino acids from storage
depots
- Glucagon’s principal action is to raise blood sugar level by stimulating liver cells
to convert glycogen to glucose GLYCOGENOLYSIS
- Also by stimulating liver cells to make glucose from non-carbohydrates
GLUCONEGENESIS

Regulation of Insulin and Glucagon;

> Secretion of insulin and glucagon is directly controlled by blood glucose level.
- Blood glucose is 5.6mM (90mg/100ml)
- After a meal, an increase in blood glucose will stimulate the release of insulin
- As the cells take up glucose, levels in blood will drop, and insulin secretion
decreases accordingly.
- When one has not eaten for several hours, the glucose levels will decrease to
70mg/100ml
- This causes release of glucagon

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

- The insulin-glucagon system is a powerful mechanism for keeping the blood

glucose normal
- This is vital since the brain cells are totally dependent upon a continuous supply of
glucose (110g of glucose per day)
> Other Hormones important in maintaining adequate levels of glucose in times of stress
and starvation are;
- Adrenaline, cortisol and growth hormone
- Adrenaline stimulates glycogenosis to raise blood glucose,
- Cortisol mobilises fat and stimulates amino acid uptake into cells for
glycogenesis
- Growth hormone allows for adjustments in starvation conditions
- When glucose levels drops in the blood, GH is released
- It increases utilization of fats thus sparing glucose and amino acids
- Glucose is conserved for use by the brain and amino acids conserved for
protein synthesis

Diabetes Mellitus;

> Insulin deficiency; results in high plasm glucose HYPERGLYCAEMIA

- Glucose in urine and therefore loss of water.
- Breakdown of fat and proteins to provide alternative metabolic fuel
- Daily injections of insulin required to survive (Type I Diabetes Mellitus)

> Consequences of chronically high elevated glucose levels;

- Changes in the lens of the eye
- Degenerative changes in the retina and peripheral nerves
- Thickening of the filtration membrane of the nephron
- Glycosylation of proteins
- Haemoglobin; used to monitor high glucose levels in the blood

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

> The principal disorder associated with pancreatic hormones is diabetes mellitus
- Diabetes is the third most common cause of death
- (1) TYPE I – Juvenile onset diabetes where there is a dramatic decrease in beta
cells in the pancreas leading to insulin deficiency
- Juvenile-onset diabetes can be treated with insulin injections
- (2) TYPE II – Maturity-onset diabetes where the secretion of insulin is normal but
the cells are no longer responsive to insulin.
- This form of diabetes is common (over 90%)
- Usually in overweight persons over age 40
- Treatment is usually maintaining an appropriate body weight and carefully
managing diet
- Insulin resistance in common; in this case, insulin is present but the cells do not
respond to it
- Insulin stimulated glucose uptake is impaired due to defects in Signal
Transduction
- Defects can occur in Akt phosphorylation or in the proteins that mediate
GLUT4 translocation to the cell surface

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

Physiology Lecture (15) Notes ENDOCRINOLOGY;

The Thyroid Gland and Control of Growth
Hormone;

The aims of this lecture;

> To understand the way by which the thyroid gland synthesizes and stores thyroid
hormones
> How the thyroid hormones at on their cells via the nuclear thyroid hormone
receptor
> Review pathophysiological actions of thyroid hormones
> The important of growth hormone and the role of other hormones including thyroid
hormones, insulin, cortisol, vitamin D, parathyroid hormone and calcitonin, in
growth and the physiology of the skeleton
> The growth spurt
> Consider the factors which govern the overall size of tissues and organs

The Thyroid Gland;

> The thyroid gland produces thyroxine (T4) and tri-iodothyronine (T3) both derived
from tyrosine.
- These hormones increase basal metabolic rate and oxygen utilization allowing
the individual to respond to energy needs, fuel supply, and thermal environment
- Thyroid hormones are also critical for normal growth, maturation of the fetus
and the child

> Functions of the thyroid gland;

- (1) Synthesis of thyroid hormones – three major steps are involved in the
synthesis uptake and concentration of iodide into the gland
- (2) Oxidation and incorporation of the iodide into the gland
- (3) Coupling of two iodinated tyrosine molecules to form T3 and T4
> Neither iodination nor coupling occurs with free tyrosine residues
- The gland consists of follicles which are epithelial cells surrounding a space
containing “colloid”
- Colloid contains thyroglobulin, and it is on thyroglobulin that these reactions
take place

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

- The thyroid hormones formed remain linked to thyroglobulin, which allows the
hydrophobic hormone to be stored, their release into circulation requires
proteolytic cleavage.

Thyroid Hormone Structure;

> The thyroid hormone synthetic process occurs in three major steps;
- Production and accumulation of the raw materials
- Synthesis of the hormones on a scaffold of precursors
- Release of the free hormones from the scaffold and secretion into blood
> Each of these processes is stimulated by thyroid stimulating hormone from the anterior
pituitary gland
> Binding of TSH to its receptors on thyroid epithelial cells stimulates synthesis of the
iodine transporter, thyroid peroxidase and thyroglobulin
> Thyroid hormones are derivatives of the amino acid tyrosine covalently bound to
iodine
- The principal hormones are
- THYROXINE (L – 3,5,3’,5’-tetraiodothyronine) T4
- TRIIODOTHYRONINE (L – 3,5,3’-triiodothryonine) T3

- Iodination is inhibited naturally by substance in cabbages

- Drugs; thiourea or propylthioluracil are used to inhibit an overactive
thyroid
- Iodide uptake can be inhibited by bromide, nitrate, thiocyanate

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

Regulation of the Thyroid;

> The thyroid gland is controlled by TSH, which is released from the anterior pituitary
- The secretion of TSH is in turn controlled by TRH from the hypothalamus
- TSH is controlled by negative feedback system mediated by thyroid hormones in
the blood.
- The thyroid hormones suppress secretion of TSH as well as TRH.
- TSH interacts with its receptor on the thyroid cell membrane to cause an
increase in cAMP
- This results in the increase in the synthesis of fresh thyroid hormone stores, as well
as causing an increase in the release of thyroid hormones
- TSH also has a trophic effects on the gland causing an increase in DNA-
synthesis and cell division

Effects of Thyroid Hormones;

> Thyroid hormones enter cells and binds to its receptor in the nucleus thereby
initiating gene transcription
- The thyroid hormone affects most cells.
- Thyroid hormones act on the liver, kidney, heart, nervous system, and skeletal
muscle sensitizing these tissues to adrenaline and stimulating cellular
respiration, oxygen consumption and metabolic rate
- The acceleration of metabolism stimulated by thyroid hormones leads to a rise
in heat production
- This is of major importance in the thermoregulation of many
vertebrates.
> Thyroid hormones have an important effect on development
- The developmental effects only occur in the presence of GH, and vice versa
- Absence of thyroid hormones during this period leads to impairment of both
neural and sexual development.
> Thyroid Hormone Receptor;
- He unliganded thyroid hormone receptor (TR) is located in the nucleus bound
to DNA at the thyroid hormone response element (TRE)
- I the absence of T3, the TR dimerizes with the retinoid X receptor and
associates with co-repressor proteins

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

- The binding of T3 leads to dissociation of these factors, the recruitment of

transcriptional co-activators and a sequence of events recruiting DNA-
dependent RNA polymerase leading to transcription
> T3 is more bioactive that T4
- Deiodination of thyroxine to tri-iodothryonine by type 1 and type 2
selenodeiodinase causes increased thyroid hormone activity
- Inactivation of T4 and T3 by the formation of reverse T3 and di-iodothyronine
(T2) by type 3 selenodeiodinase causes decreased activity

The Control Of Growth;

> Growth occurs at the level of the cells, tissues, and the whole body
- Normal growth is influenced by many factors; genetic and environmental.
- A number of hormones are involved in the regulation of growth and development
including growth hormone, thyroid hormones and sex steroids
- After birth growth velocity progressively declines until puberty when there is a
growth spurt
- Adult height is achieved by the end of puberty, and growth in stature ceases.

Growth of the Skeleton;

> Bone is a dynamic tissue which continually undergoes remodeling and renewal even
during adulthood.
- Around 5 – 7% of total bone mass is recycle each week during adulthood as the
skeleton responds to the changing demands placed upon it
- It consists of osteoid, an organic matrix, strengthened by the deposition of complex
crystals of calcium and phosphate (hydroxyapatite)
- There are 3 types of bone cells;
- Osteoblasts which secrete organic matrix
- Osteocytes are mature bone cells
- Osteoclasts which are responsible for the of old bone during growth and
remodeling of the skeleton.
- Growth of the long bones is responsible for the increase in height seen during
adolescence.
- Growth occurs through the proliferation and hypertrophy of cartilage cells
at the growth plates of the long bones followed by their subsequent
mineralisations
- During fetal life the skeleton is laid down as a cartilage “model” which becomes
ossified
- Ossification is not complete until the third decade of life
- The areas of cartilage between the diaphysis and epiphysis of long bones are
called growth plates
- Stem cells (chondroblasts) lying beneath the plates give rise to proliferating
clones of cells (chondrocytes) which extend into the diaphysis of the bone
- As they progress they mature and later degenerate
- Calcification occurs with the innermost layer of cells
- After puberty the growth plate thins as it is replaced by bone and the diaphysis
and epiphysis fuse
- No further increase in length is possible after fusion

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

Important Hormones for Growth;

> Growth Hormone
> Thyroid Hormones – fetal development
> Vitamin D metabolites
> Parathyroid Hormones
> Gonadal steroids
- Normal secretion of insulin is required, whereas too much cortisol inhibits growth
> When puberty ends; sex steroids have increased;
- Androgens in boys
- Oestorogens in girls
- These close the growth plate – growth stops

Hormonal Control of Growth;

> The anterior pituitary peptide growth hormone (GH) has a dominant effect on
postnatal growth
- GH exerts both metabolic and growth promoting effects
- GH directly stimulates the formation of cartilage by chondrocytes and enhances
the rate of uptake and incorporating of amino acids into protein
- GH exerts a number of indirect effects through IGFs (Insulin-like growth factors)
- IGFs stimulate the clonal expansion of chondrocytes and the formation of
the organic bone matrix
- Many hormones in addition to GH are involved in the regulation of growth
- Thyroxine is required for growth from the early fetal periods onwards and plays
an important part in maturation of the CNS
- Excessive secretion (or therapeutic administration) of corticosteroids can
inhibit normal growth and maturation of the skeleton in children
- Small imbalances in insulin secretion and plasma glucose seem also to interfere
with normal development
- Calcitriol (an active metabolite of vitamin D) stimulates the intestinal uptake of
calcium and seems to be essential for growth, calcification and remodeling of the
skeleton
- Parathyroid hormone stimulates the activity of the osteoblasts and is important
for the normal growth of bone.
- The co-operative action of the gonadal steroids and pituitary GH underlie the
growth spurt of puberty.
- Both oestradiol and testosterone stimulate the stimulate the secretion of GH,
which in turn increases the rate of long bone growth.
- The male and female sex steroids also exert specific effects that give rise to the
secondary sex characteristics and the differences in musculoskeletal
morphology between males and females
> The regulation of GH; both GHRH (10aa) and somatostatin (14aa) are small
hypothalamic peptides
- Both act on G-protein coupled receptors on somatotrophs;
- GRHR activates adenylyl cyclase
- Somatostatin acts via PLC
- A single chain protein
- 2 disulphide bonds
- 2 forms; 22 kD (20 kD minor)

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)

 lOMoARcPSD|4188894

- Half – life ` 15 mins

- Similar to prolactin

Tissue Growth;
> Tissues are either non-regenerating (such as nerve) or regenerating
- The latter include those which continually renewal (skin, blood cells etc. )
- And those like the liver, which can regenerate to tissue loss or damage
> Organs increase in size by cell division, by increasing in cell size and by an increase in
the volume of intercellular material
- In non-regenerating tissues, cell division stops when the tissue has reached
appropriate size.
- Under normal conditions, differentiated cells adjust their rate of proliferation to
requirements in response to a variety of signals
- Failure to do so results in the formation of a benign or malignant neoplasm
- Malignant neoplasms are poorly differentiated , grow rapidly and
metastasize
- A cell may be transformed into a cancer cell when its DNA undergoes
mutation and the expression of certain genes is altered
- Specific cancer promoting genes and tumour – suppressor genes have
been discovered.

Downloaded by Omed Zarifi (omed.zarifi@yahoo.co.uk)