Endocrine Physiology

Contents
1. Introduction to Endocrinology, Hypothalamo,
Pituitary Axis
2. Pituitary gland
3. Pituitary Dysfunction
4. Thyroid Physiology
5. Thyroid Disorders
6. Adrenal Cortex
7. Adrenal Medulla
8. Other Endocrine Organs
9. Calcium Homeostasis
 Endocrine System
Introduction to Endocrinology • Consists of ductless glands which secretes
and chemicals (hormones) into blood.
• Hormones are transported in blood to target
Hypothlamo-Pituitary Axis cells.
Professor Sampath Gunawardena • This system helps in coordination of body
Department of Physiology systems to adjust to the changing demands of
Faculty of Medicine the external and internal environment.
University of Ruhuna
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Coordination of Body Functions E

N
D
• Neural – neurotransmitters at synapses- act locally C
(focussed action) R
• Endocrine – hormones released into blood acting on I
cells at another location (broad effects) N
• Neuroendocrine- neurones secreting substances E
which travels in blood and acts at distant sites
S
• Paracrine- secretions affecting the neighbouring cells Y
(e.g. inflammatory mediators) S
• Autocrine- secreted substance affecting the same cell T
(e.g. cell growth factors) E
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 Neural Vs Hormonal Control Chemical structure of hormones
• Neural controls are generally very fast (within • Three general classes of hormones
seconds) and focussed – Peptide hormones (by anterior and posterior
• Hormonal control generally takes a longer pituitary, pancreas, parathyroid) – stored in
secretory vesicles
time (minutes to hours to even months - in
case of GH, thyroxine) and effects are – Steroid hormones (by adrenal cortex, ovaries,
testes, placenta) – synthesised from cholesterol
broadcasted. Some hormones act fast e.g.
and are not stored
norepinephrine, epinephrine
– Derivatives of amino acid tyrosine (by thyroid,
adrenal medulla) – synthesised and stored
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Feedback Control of Hormone Secretion

• Negative Feedback – prevents oversecretion

of hormones (thyroxine on TSH secretion)
• Sometimes positive feedback – Feedback
effects of oestogen on LH

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Hypothalamus, pituitary, thirst and negative feedback loop helping homeostasis
Variations in hormone secretion
• Cyclical variations of hormonal secretion
• Diurnal variations
• Seasonal changes
• Changes occur with sleep
• Changes occur with stages of development
and ageing.

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Transport of Hormones in Blood

• Dissolved in the plasma – water-soluble
hormones like catecholamines and peptides
• Bound to plasma proteins – Steroid hormones
and thyroxine – small amount remain in
plasma as free form which is the active form
(also important for feedback). Bound fraction
serves as a reservoir.

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 Transport of Hormones in Blood Mechanism of action of hormones
• Binding protein levels may alter in certain
• Act by binding to receptors on target cells
conditions, and also by medicines (e.g. TBG
– Cell membrane receptors- protein, polypeptide or
level may be reduced in liver disease, renal
catecholamines
disease, malnutrition. It may be elevated in
– Cytoplasmic receptors – steroids, thyroxine
pregnancy) (thyroxine-receptor complex goes to the nucleus
• Passage through liver or lungs may destroy and binds to DNA)
certain hormones

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Investigating the endocrine system

Adaptations occur at receptor level disorders
• Downregulation of receptors • Baseline measurement of hormone level
• Less number of active receptors when hormone is in – (consider diurnal variation, cyclical variation etc)
excess • Suppression tests
– Dexamethasone suppression test for steroid assessment,
• Upregulation of receptors Glucose tolerance test for GH secreting tumours
• More receptors when the hormone is deficient • Stimulation tests
– Synacthen test (based on the measurement of s. cortisol
Desensitization before and after an injection of synthetic ACTH)
• Type of downregulation in which receptors are
chemically modified to make them less responsive.
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 Hypothalamo-Pituitary Axis
• Pituitary gland is one of the most important
endocrine glands because it secretes many
hormones.
• It controls several other endocrine glands –
thyroid, adrenal cortex, ovaries, testes
• Hypothalamus controls the activity of the
pituitary gland (Hypothalamo-pituitary axis)
– Hypothalamo-pituitary tract – posterior pituitary
(neural connection)
– Hypothalamo- hypophysial portal system –
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Six main anterior pituitary hormones Hypothalamic releasing hormones

ACTH – Adrenocorticotrophic hormone

TSH – Thyroid stimulating hormone CRH – Corticotrophin-releasing hormone
LH – Luteinizing hormone TRH – Thyrotropin-releasing hormone
FSH – Follicle-stimulating hormone GnRH – Gonadotropin-releasing hormone
GH- Growth Hormone GRH – Growth hormone-releasing hormone
Prolactin PIH – Prolactin inhibitory hormone (Dopamine)
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 Importance of the Hypothalamo-
Role of Hypothalamus
Hypophysial Portal System
• Hypothalamus receives information from
• Hypothalamic releasing/inhibitory hormones are external and internal environment (e.g. light,
secreted in very minute quantities vision, stress, emotions, pain, level of
• If they are released into the general circulation, hormones, volume and osmo receptors, from
skin-touch etc.)
concentration would be very low.
• Upon receiving these information
• Through the portal system these little amounts hypothalamus controls the secretory functions
are directly carried to the pituitary gland of the pituitary gland by secreting releasing or
inhibitory hormones
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Human Hypothalamus Hypothalamic Regulatory Mechanisms

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 Hypothalamo-Pituitary Tract Damage to Pituitary Stalk
• Neural connection between hypothalamus • Causes suppression of all the anterior pituitary
and the posterior pituitary gland hormones except prolactin.
• Cell bodies of the nerves are located at • In fact, there is hypersecretion of prolactin.
supraoptic and paraventricular nuclei of the • Why?
hypothalamus.
• They synthesise ADH and Oxytocin
• Carried to the posterior pituitary along the
nerve fibres and stored until released from the
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What happens to ADH level with

pituitary stalk damage?

• There is initial deficiency.

• Then the damaged nerve endings recover and
in few weeks ADH secretion becomes normal.

References
Ganong’s Review of Medical Physiology
Kumar & Clarks Clinical Medicine

The End
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 Pituitary Gland

Prof. Sampath Gunawardena

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Embryological Development Posterior Pituitary Gland

• Posterior pituitary originates as an evagination of the floor of the third ventricle
• Secretes two hormones:
– Anti diuretic hormone (ADH)- also known as
arginine vasopressin
– Oxytocin
• Both are nona-peptides (9 amino acid
peptides)
• Hormones are synthesised in the
supraoptic and paraventricular nuclei of
• Anterior pituitary arises from the Rathke’s pouch, an evagination the hypothalamus (magnocellular neurons)
of the roof of the pharynx
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 Mechanism of release Mechanism of Release Contd…
• Increase in osmolality or low blood volume
• Action potentials are carried along the leads to initial steady increase in firing of
axons to the nerve endings axons followed by a prolonged pattern of
• Causes Ca+2 dependent exocytosis of high frequency, phasic discharge (bursts
hormones from the nerve endings which of discharge alternating with periods of
are located in the posterior pituitary silence). These phasic bursts are not
• Stimulation of nipple causes synchronized, synchronous in different vasopressin-
high frequency burst of discharge leading secreting neurons
to release of oxytocin • Helps to maintain a prolonged increase in
the output of vasopressin
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Control of ADH Secretion

• Increased secretion
– Increased plasma osmotic pressure
– Decreased ECF volume
– Pain, emotion, stress, exercise
– Nausea, vomiting
– Angiotensin II
• Decreased secretion
– Decreased plasma osmotic pressure
– Increased ECF volume
– Alcohol
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 Effects of ADH (Vasopressin) Disorders of ADH
• Acts on the collecting ducts – on V2 • Diabetes Insipidus (DI)
receptors causing insertion of aquaporin-2 – Cranial DI– Deficiency of ADH secretion
water channels which leads to increased – Nephrogenic –collecting ducts do not respond
reabsorption of water to ADH. Either a defect in the V2 receptor or
• Acts on blood vessels – on V1A receptors aquaporin-2 water channel (ADH level is not
reduced)
• Acts on liver – on V1A receptors –
glycogenolysis • Patients with DI has polyuria
• Acts on anterior pituitary - V1B receptors • Syndrome of inappropriate hypersecretion
(also called V3) – increases ACTH secretion of ADH (SIADH)
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Oxytocin Actions of Oxytocin

• Oxytocin primarily acts on the breasts – on
• Stimulus – touch receptors in the breast, myoepithelial cells causing ejection of milk
particularly around the nipple (milk ejection reflex)
• Other stimuli – Genital stimulation, emotional • Oxytocin also causes contraction of the
stimuli (e.g. crying infant) uterine smooth muscle – important in child
birth, prevention of postpartum haemorrhage
• May play a role in leuteolysis

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 Anterior Pituitary – cell types Growth Hormone
• Increased secretion
– Hypoglycaemia, Fasting
– Exercise
ACTH – by corticotropes •Chromophobes – Inactive secretory
– Protein meal, Arginine (a.a.)
TSH – thyrotopes cells – Going to sleep
LH, FSH – Gonadotropes •Chromophils – Oestrogen, androgen, glucagon, L-DOPA,
GH – Somatotropes •Acidophils – GH, Prolactin
Prolactin - Lactotropes •Basophils – ACTH, TSH, FSH
thyroid hormones
LH • Decreased secretion
– REM sleep, Glucose, Cortisol, FFA, GH, IGF-1,
Medroxyprogesterone
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Variation in GH secretion Effects of GH

• Adolescents have the highest circulating • Anabolic hormone- increased protein
level of GH followed by children and then synthesis, +ve nitrogen and phosphorus
adults balance, a rise in plasma phosphorous
level and a fall in blood urea nitrogen.
• GH levels decline in old age
• Ca++ absorption increases from GIT
• Diurnal variation –relatively low levels of
• Na+ and K+ excretion is reduced
GH during day time. During sleep bursts of
(independent of adrenal hormone action)
GH secretion occurs (hypothalamus
• Excretion of a.a. 4-hydroxyproline is
dependent –GHRH and somatostatin)
increased indicating increased synthesis
• Ghrelin also has stimulating effect of soluble collagen by GH
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 Effects of GH contd.. GH and somatomedins
• Diabetogenic (increased hepatic glucose
output, anti-insulin effect on muscle) • Somatomedins are polypeptides secreted
by the liver (and other tissues)
• Ketogenic – increases FFA
• In humans only circulating somatomedins
• Increase the ability of pancreas to respond
are IGF-I and IGF-II.
to insulin secreting stimuli such as arginine
and glucose (no direct increase of insulin • Structurally close similarity to insulin (C
secretion due to GH) peptide not separated and A chain is
extended)
• Stimulates synthesis of somatomedins
from the liver (IGF-I and IGF-II)
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IGF-I and IGF-II Direct and indirect actions of GH

• IGF-I is not dependent on GH before birth,
but is dependent on GH after birth
• IGF-II is largely independent of GH and
plays a role in the growth of the fetus.
• GH acts on cartilage and convert stem
cells into cell that responds to IGF-I.
Locally produced and circulating IGF-I
then acts on them to increase the growth.
• Circulating IGF-I alone is also effective
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 Feedback regulation of GH
secretion
• In those whose epiphyses have not yet
GHRH
fused, chondrogenesis is increased, more
bone matrix laying
• Prolonged excessive exposure to GH
leads to
– Gigantism – in those whose epiphyses have
not yet fused
– Acromegaly – in those whose epiphyses have
already fused (adults)

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Effect of hormones on growth

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 Prolactin
• Secreted by the anterior pituitary
• Some stimuli for prolactin secretion are
same as those of GH secretion (but some
act in the opposite direction) – see table

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Regulation of prolactin
Stimuli for prolactin secretion
secretion
• PRH and PIH (Dopamine) • Suckling stimulates prolactin secretion
• Normally, secretion is kept under inhibition (touch receptors in the breast, specially
• Pituitary stalk damage –increased around the nipple)
secretion • Sleep
• Stress
• Strenuous exercise
• Sexual intercourse
• TRH
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 Prolactin, pregnancy and Prolactin, pregnancy and
lactation lactation Contd…
• During pregnancy prolactin concentration
• About 8 days after delivery, prolactin
increases until term.
levels come back to non-pregnant levels
• Together with high oestrogen,
progesterone and hCG – breast • Prompt increase with suckling
development (growth) occurs • Magnitude of increase drops when
• High levels of oestrogen inhibits secretion continues to breast feed for > 3 months
of milk. • With prolonged lactation, milk seceretion
• At delivery, placenta separates – continues even when the prolactin levels
oestrogen concentration drops – milk are in the normal range
formation increases
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Other Effects of Prolactin

• Prolactin inhibits GnRH secretion, inhibits
the effects of GnRH on pituitary and
antagonizes the action of gonadotropins
on the overy – So breast feeding delays
resumption of menstrual cycles after child
birth

» The End

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 Hypopituitarism
• Selective or multiple deficiencies of
pituitary hormones
Pituitary Dysfunction • Selective deficiencies are rare
• Multiple deficiencies result from tumours
Prof. Sampath Gunawardena or destructive lesions – progressive loss of
anterior pituitary function (fig. in the next
slide – order of loss- from left to right)
• Hyperprolactinaemia
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Panhypopituitarism
• Deficiency of all anterior pituitary
hormones – due to tumour, surgery or
radiotherapy
• Posterior pituitary hormone deficiency
occurs only if the tumour or disease
process involves the hypothalamus

Loss of function
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 Sheehan’s syndrome Clinical Features
• Sheehan syndrome – Postpartum pituitary • Mild deficiencies – may not have any symptoms
necrosis –due to PPH –What are the • Symptoms and signs are due to reduced
symptoms and signs? function of target endocrine organs – e.g.
– Hypothyroid features - slowness (mental and
• Sheehan syndrome Vs pituitary stalk physical), dry skin, cold intolerance, tiredness and
damage – Difference in prolactin level malaise,
• Symptoms of Sheehan syndrome: inability – Adrenal insufficiency -hypotension, hyponatraemia,
cardiovascular collapse
to establish lactation, No menstruation, – Gonadal deficiency – Loss of libido, loss of secondary
Failure to regrow shaven pubic hair, sexual hair, amenorrhoea, impotence
features of hypothyroidism etc.. – GH deficiency – generally no clinical features except
in children.
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Clinical Features contd… Investigations and treatment

• Some symptoms and signs are due to • Hormone concentrations- stimulation tests
intracranial space occupying lesion – may be required – e.g Insulin tolerance
Headache, visual field defects (bitemporal test – GH and ACTH should increase in
hemianopia due to compression of optic normal individuals
chiasm), cranial nerve palsies • Thyroxin levels
• Longstanding hypopituitarism causes • Treatment – Hormone replacement
pallor with hairless skin and well nourished therapy – steroids and thyroid hormones
appearance (due to hypothyroidism) are essential for life- GH is given for
• In children – GH deficiency -Dwarfism growing children with hypopituitarism
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 Disorders of ADH secretion Excess Pituitary Hormone
(Posterior Pituitary) Secretion
• Diabetes Insipidus (DI) • Growth Hormone excess – Gigantism or
– Cranial DI– Deficiency of ADH secretion Acromegaly
– Nephrogenic DI –collecting ducts do not • Large extremities, Organomegaly, Osteoporosis,
respond to ADH. Either a defect in the V2 Prognathism, Change in appearance,
receptor or aquaporin-2 water channel (ADH Galactorrhoea, Carpal tunnel syndrome,
level is not reduced) symptoms and signs due to pituitary
• Patients with DI has polyuria enlargement – Visual field defects, headache
etc, interdental separation, large tongue,
• Syndrome of inappropriate hypersecretion Hirsutism, Thick greasy skin, hypertension,
of ADH (SIADH)
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Soft tissue – Heal pad sign

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 Investigations and treatment Prolactin secreting tumours
• Hyperprolactinaemia
• GH level – basal or during Glucose – Causes: prolactinoma, pituitary stalk damage, Drugs
tolerance test like metochlopramide, domperidon
– Physiologically – during pregnancy, lactation and
• IGF level –always high severe stress
• Visual field – bitemporal hemianopia • Clinical features
• Imaging of the skull – Galactorrhoea, oligomenorrhoea or amenorrhoea,
decreased libido, Subfertility
Treatment – Surgical removal, pituitary
• Treatment – Bromocriptine, surgical removal,
radiotherapy, Somatostatin analogues radiation therapy

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 5/12/2020

THYROID PHYSIOLOGY

Mahinda Kommalage
Department of Physiology

Objectives of the lecture

At the end of the lecture, you will be

able ....
Compare different thyroid hormone.
Describe transport mechanism of thyroid hormone.
Describe mechanism in thyroid receptor.
Describe different functions/ effects of thyroxine.
Describe regulation of thyroid hormone.

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 5/12/2020

Relevance..
Diseases related thyroid - hypo and hyper…..
Nervousness, anxiety, or crankiness, weakness, increased heat, Losing weight
suddenly, palpitations (pounding in your heart), more bowel movements,
tremor, sleep problems, thinning skin, brittle hair, menstrual cycle
abnormality…

Interpret investigation results – hormones levels

Removal of gland – treatment after that.

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 5/12/2020

Thyroid hormones
Determine level of tissue metabolism.
Main hormones secreted –
thyroxine (T4)
triiodothyronine (T3)
secretes calcitonin - a calcium-lowering hormone.
Secretes 103 nmol of T4, 7 nmol of T3, and 3.5 nmol
of RT3 per day.
T3 - short half life.
Secreted T3 and T4 are metabolized in the liver.

Transport in Plasma
Small free active forms.
Large amounts of T3,T4 are bound to plasma
proteins.
Albumin
Thyroxine-binding prealbumin (TBPA) (transthyretin)
Thyroxine-binding globulin (TBG).

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 5/12/2020

Transport in Plasma
Equilibrium free and bound forms in the circulation.
Free hormone Bound hormone

Conditions increase or decrease of TBG?, What happen to free T3/T4 if

sudden change of TBG?

TBG levels are elevated in estrogen-treated patients

and during pregnancy.

Receptors

Receptors for thyroid hormones are hormone-sensitive

nuclear transcription factors.
Receptor activation increases or decreases the
expression of a variety of different genes.

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 5/12/2020

T3 more active

Intracellular thyroid hormone receptors have a very

high affinity for triiodothyronine.
90 % of the thyroid hormone molecules that bind with
the receptors is triiodothyronine.

Functions Vs influences

Thyroid hormone influence many systems.

Hyper or hypo-thyroidism with result malfunctions.

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 5/12/2020

Calorigenic action

Increase the O2 consumption, protein and fat

catabolised.
Increase the number/activity of mitochondria.
Increase activity of the membrane-bound Na+-K+
ATPase in many tissues.
But not in brain and some other tissue.
Endogenous protein and fat stores are catabolized and
lead to weight is lost.

CVS

Increase heart rate and force of contraction.

Vasodilation in most body tissues, thus increasing blood
flow.
Peripheral resistance decrease
Therefore, pulse pressure increase
Increases levels of renal Na+ and water absorption -
expanding blood volume.

6
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Nervous System

Increased activation of the reticular activating system

Increased responsiveness to catecholamines.
Effects on brain development.
Effects on reflexes - reaction time of stretch reflexes is
shortened in hyperthyroidism.

Respiratory system

Increase rate and depth of respiration.

Due to increase metabolic activities in tissue.

7
 5/12/2020

GIT
Increase gastric motility.
Increase secretion of gastric juices.

Carbohydrate metabolism

Increase the rate of absorption of carbohydrate from

the gastrointestinal tract.
Stimulates many aspects of carbohydrate metabolism -
uptake of glucose by the cells, enhanced glycolysis,
enhanced gluconeogenesis.

8
 5/12/2020

Fat metabolism

Lower circulating cholesterol levels.

Lipids are mobilized rapidly from the fat tissue
Increases the free fatty acid concentration in the
plasma and greatly accelerates oxidation of free
fatty acids by the cells.

Growth/development

Effects on Growth - essential for normal growth and

skeletal maturation - In hypothyroid children, bone
growth is slowed and epiphysial closure delayed.
Promote growth and development of the brain during
fetal life and for the first few years of postnatal life.
Growth hormone secretion is depressed in absence of
thyroid hormones.

9
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List action so far….

Other functions

Thyroid hormones and the catecholamines are

interrelated - propranolol and other β blockers are
used in the treatment of thyrotoxicosis.

10
 5/12/2020

Other functions

Thyroid hormones are necessary for hepatic conversion

of carotene to vitamin A – yellow skin in
hypothyroidism.
Milk secretion - decreased in hypothyroidism.
Essential for normal menstrual cycles and fertility.

Formation of Thyroid hormones

Iodine is a raw material - Iodine deficiency cause
malfunction.
With iodide excess ?, Find it!.
TSH increase Na+/I– symporter (uptake process).
Circulating hormone can be normal up to 2 months
without iodine - colloid act as a reservoir.
Secretes T4, T3, and RT3.
RT3 is not biologically active.

11
 5/12/2020

Formation of Thyroid hormones

T3 is also formed in the peripheral tissues by
deiodination of T4. (action of deiodinases)
Free active form release from gland, then bind
(why..? Large pool, prevent excess uptake to cells?).
Different deiodinases act on thyroid hormones - D1,
D2, and D3 – differently in different tissue.
Secreted T3 and T4 are metabolized in the liver.
What happen in prolonged starvation? – T3 decrease and RT3
increase and come back. ? Preserve energy.

Deiodination
Majority of circulating T3 is formed by deiodination
of T4.
Smilarly, majority of RT3 is formed by deiodination
of T4
Deiodinases appear to be responsible for
maintaining differences in T3/T4 ratios in the various
tissues in the body.
In the brain, high levels of deiodinase activity
ensure high supply of active T3.
Reduced deiodinases activity in some diseases - ?

12
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Regulation

By level of pituitary TSH.

TSH is regulated by thyrotropin-releasing hormone
(TRH) from hypothalamus.
Negative feedback fashion by circulating free T4 and
T3.
What happen with sudden rise of binding protein? –
free form low, TSH increases and production increase and come
to new equilibrium.

13
 5/12/2020

TSH

TSH is a glycoprotein.
TSH – facilitate
iodide binding/uptake process
synthesis
secretion of thyroglobulin into the colloid
endocytosis of colloid.

14
 5/12/2020

TSH

Secretion is pulsatile - starts to rise at about 9

PM, peaks at mid night, and then declines during
the day.
T3 & T4 inhibit secretion and synthesis of TSH

TSH

Large amounts of hCG can activate thyroid receptors -

tumors of placental origin gives hyperthyroid features.
Dopamine and somatostatin act at the pituitary level to
inhibit TSH secretion (? physiologic role not significant).
Glucocorticoids also inhibit TSH secretion.
Stress has an inhibitory effect on TSH secretion.

15
 5/12/2020

TRH

Increased thyroid hormones production in cold

condition - effect of TRH (less important in adults).

16
 • This power point slide show is only to upload to the
Learning Management System (LMS) of the Faculty of
Medicine (FOM), University of Ruhuna (UOR). This was
Thyroid Dysfunctions done to facilitate online learning of medical students of the
FOM, UOR during the pandemic of covid-19.
Prof. K.G. Somasiri

Objectives Actions of thyroid hormone

• Heart – ↑ β receptors, ↑response to catecholamine,
Describe the physiological basis for the clinical
• Adipose tissues – lipolysis
features of following conditions.
Hypothyroidism (myxoedema and cretinism) • Muscles - ↑ protein breakdown
Hyperthyroidism including Graves disease • Bone – promote normal growth and development
Interpret the results of the thyroid hormone • Nervous system – promote normal brain development
assay • Gut - ↑ rate of CHO absorption, motility
Classify goiter according to the features of the • Lipoprotein – formation of LDL receptors
gland and relate them to causes for goiters. • Other – calorigenic, ↑ BMR
Thyroid dysfunctions Hypothyroidism
• Hypothyroidism • Causes
• Myxoedema; in adults • Thyroid gland
• Cretinism; in children • Pituitary
• Hyperthyroidism (Thyrotoxicosis) • Hypothalamic
• Graves disease • Iodine deficiency
• Toxic goiter • Drugs
• Treatment with thyroxin
• Ectopic thyroid tissues

Facial appearance of myxedema Features of myxoedema

• Appearance – deposition of myxomatouse material in the skin
• Puffy face • Low BMR – lack of calorigenic action
• Due to infiltration of skin with • Coarse and sparse hair -
water retaining complex • Dry yellow skin – reduce hepatic conversion of vit. A
carbohydrates • Poor cold tolerance - lack of calorigenic action
• Can be seen in hands, feet and • Slow mentation, poor memory – lack of reticular stimulation
other parts
• Elevated cholesterol – lack of formation of LDL receptors
• Bradycardia – action on SA node (Not having normal action)
Cretinism - Causes Cretinism - Features
• Maternal iodine deficiency • Addition to features of myxedema
• Fetal thyroid dysgenesis • Large tongue
• Inborn errors of thyroid hormone synthesis • Short stature – infantile body proportions when they grow
• Placental crossing of maternal anti-thyroid antibodies • Umbilical hernia
• Fetal hypopituitary hypothyroidism • Large abdomen

Cretinism Comparison of myxedema with a other child

• Myxomatouse skin
• Large protruded tongue • Potbelly
• Umbilical hernia • Infantile body proportions
• Pot belly appearance • Short stature
 Early diagnosis and treatment will prevent
Prevention
cretinism
• Screening at birth
• Life-long treatment

Hyperthyroidism - causes Thyrotoxicosis - features

• Graves disease • Weight loss – calorigenic action
• Solitary nodule • Hyperphagia - calorigenic action
• Multinodular goiter with a active nodule • Nervousness – stimulation of reticular activating system
• TSH secreting tumor • Heat intolerance - calorigenic action
• Increase pulse pressure – peripheral vasodilatation and increase CO
• Ectopic thyroid tissues
• Tachycardia – action on SA node (↑ β receptors)
• Administration of thyroxin
• Fine tremor – CNS action
• Warm soft skin with sweating - calorigenic action
• High BMR - calorigenic action
Eye signs – exophthalmos
• Lid lag
• Lid retraction
• Proptosis
• Deposition of material and cell infiltration behind the eye

• Other features of graves

• Preitibial myxedema

Investigations TSH Free T4 Free T3

Thyrotoxicosis Low High High

• Free T4
• Free T3
Primary High Low or low- Normal or low
• TSH hypothyroidism normal

TSH deficiency Low-normal Low or low- Normal or low

or subnormal normal

T3 toxicosis low Normal High

Goiter - Enlargement of thyroid gland
• Types
• Smooth enlargement
• Nodular goiter
• Solitary nodule
• Multinodular

Goiter - causes Iodine deficiency

• Iodide deficiency – endemic goiter • Endemic areas
• Smooth enlargement • Low iodine leads to low thyroxin (low normal in early stages)
• multinodular
• Common during pubertal age and during pregnancy
• Graves diseases
• Smooth enlargement
• Increase TSH
• Hypothyroidal • Development of goiter
• Inborne errors of iodine metabolism • Smooth in early stages nodular in late stages
• Infiltrative • Occasionally nodule can go into toxic state
• • Iodination of salt reduces the incidence
 Adrenal Cortex

Mahinda Kommalage
MBBS, PhD
Department of Physiology

Objectives of the lecture

At the end of the lecture, you should be able to
Describe main hormone produce by adrenal cortex
and the cortical layers important for each.
Describe the function, mechanism of action each
hormone.
Describe the regulation of each hormone secretion.
Describe the abnormalities related to these
hormones.

1
 Relevance…
Many diseases – Cushing syndrome,
Conn’s syndrome, Addison’s diseases,
Adrenogenital syndrome, …..etc.

Adrenal Cortex

The Adrenal Cortex – 3 distinct layers.

zona glomerulosa – aldosterone only in this layer
zona fasciculata –
zona reticularis - adrenal androgens
dehydroepiandrosterone (DHEA) and
Androstenedione (small amounts of
estrogens and some glucocorticoids)
All 3 layers secrete - corticosterone

2
Three main hormones type
Mineralocorticoids – effect on Na+ & K+
excretion and then extra cellular volume.
Glucocorticoids – effect on glucose &
protein metabolism.
Adrenal Androgens - Very little effect in
normal amount, masculinization (male
features)

3
 Transport in blood
90% to 95% of the cortisol in the
plasma binds to plasma proteins.
a globulin - cortisol-binding globulin (CBG) or
transcortin.
When CBG level change, total cortisol change, but
free form constant.
Lesser extent to albumin.
60% of circulating aldosterone combines with the
plasma proteins.
Aldosterone has short half life than cortisol.

4
 Degradation
Adrenal steroids are degraded mainly in the liver.
Conjugated especially to glucuronic acid and to a
lesser extent to sulfates.
25% conjugates are excreted in the bile.
Rest is excreted in the urine.
Diseases of the liver depress the rate of
inactivation of adrenocortical hormones.

Mineralocorticoids
Aldosterone - very potent, accounts for about
90% of all mineralocorticoid activity
Cortisol - very slight mineralocorticoid activity, but
large quantity secreted.
Desoxycorticosterone – 3% of mineralocorticoid ,
potent aldosterone, but very small quantities
secreted.

5
 Mineralocorticoids

Corticosterone - slight mineralocorticoid

activity
Cortisone - synthetic, slight
mineralocorticoid activity
9a-Fluorocortisol - synthetic, slightly
more potent than aldosterone

Effects of Aldosterone
Increases absorption of Na+ tubular
epithelial cells.
Increases secretion of K+ by the renal
tubular epithelial cells.
Increases extracellular fluid volume and
arterial pressure.
Increase aldosterone - only a small
effect on plasma sodium concentration
due water retention.

6
 Effects of Aldosterone
Excess amounts are secreted –
Transient Na+ retention – with water and
developed hypertension
Water retention can dilute Na+ (concentration will
not change much)
Due to increase water in body, kidney excretion
of both salt and water increase - aldosterone
escape. (Due to ANP)

Effects of Aldosterone
Excess amounts are secreted –
K+ concentration falls – severe muscle weakness
often develops.
Mild degree of alkalosis - secretion of H+ in
exchange for sodium in the intercalated cells of
the cortical collecting tubules.

7
Effect on ENaC channels
Increasing the insertion of these channels
into the cell membrane.
Slower effect to increase the synthesis of
ENaCs.

8
 Effects of Aldosterone

Low secretion –
Diminishing the amount of Na+ in the
extracellular fluid and extracellular fluid
volume.

High K+ cause serious cardiac toxicity.

Effects of Aldosterone

Stimulates Na+ and K+ transport in

sweat glands
salivary glands
intestinal epithelial cells.

9
 Regulation of Aldosterone
Secretion
Increased K+ concentration in the
extracellular fluid greatly increases – direct stimulation.
Increased activity of the renin-angiotensin system
increases.
ACTH from the anterior pituitary gland is
necessary for aldosterone secretion but has little
effect in controlling the rate of secretion.
(deoxycorticosterone secretion control by ACTH, not by
Angiotensin II).

Increased sodium ion concentration in the extracellular

fluid very slightly decreases.

Renin-angiotensin system
A drop in ECF volume/intra-arterial vascular
volume lead to
increase in renal nerve discharge
decreases renal arterial pressure
Then increase renin secretion
Decline in plasma Na+ of about 20 mEq/L stimulates
aldosterone secretion (but changes of this magnitude are
rare)
Plasma K+ level need increase only 1 mEq/L to stimulate
aldosterone secretion

10
11
Regulating factors of Na+ excretion
Aldosterone
GFR
ANP
osmotic diuresis
Tubular reabsorption independent of
aldosterone

Glucocorticoids
Cortisol - very potent, accounts for about 95%
all glucocorticoid activity
Corticosterone - provides about 4% all
glucocorticoid activity, less potent.
Cortisone - synthetic
Prednisone - synthetic
Methylprednisone - synthetic
Dexamethasone - synthetic

12
 Functions of Glucocorticoids
Stimulation of Gluconeogenesis.
1. Cortisol increases conversion of amino acids into
glucose in the liver cells.
2. Cortisol mobilize amino acids from
the extrahepatic tissues mainly from muscle. (amino
acids available for gluconeogenesis).
Increase plasma glucose level
Decreased glucose utilization by cells (but not in
brain and the heart) - an anti-insulin action in peripheral
tissues and make diabetes worse.

Functions of Glucocorticoids
Reduction in cellular protein - decreased
protein synthesis and increased catabolism
of protein
Increases liver and plasma proteins.
Increased blood amino acids - transport is
diminished to extrahepatic cells & increased
to hepatic cells.
Mobilization of fatty acids.

13
 Permissive action of Glucocorticoids
Small amounts of glucocorticoids must be
present for some action of some hormone.
Calorigenic effects of glucagon and
catecholamines
catecholamines for
lipolytic effects
pressor responses (blood pressure)
bronchodilation.

Functions of Glucocorticoids
Resisting stress. (what is stress?)
Increase ACTH with stress
Life-saving
activate the sympathetic nervous system
(circulating glucocorticoids may be maintenance of vascular
reactivity to catecholamines)
rapid mobilization of amino acids & fats for
energy & synthesis of other compounds.

14
 Functions of Glucocorticoids
Anti-inflammation
block the early stages of the inflammation
process.
Cortisol blocks the inflammatory response to
allergic reactions.
Use as drug

Functions of Glucocorticoids
Effect on blood cells – Decrease ‘BEL’ & increase
RBC.
Decreases the output of both T cells and antibodies
from the lymphoid tissue.
Water excretion - Inability to excrete water in
adrenal insufficiency. (read about ‘glucose fever’)

15
 Action in cells
How does it act in cellular level –
RNA/DNA, protein synthesis, read...

Regulation of cortisol secretion

ACTH –
control by corticotropin-releasing factor.
physical or mental stress - enhanced secretion
within minutes.
Afferent nerve from many parts of the brain to
paraventricular nuclei (hypothalamus) - emotional
stresses, and fear, anxiety.
Circadian Rhythm of Glucocorticoid Secretion –
(CRF, ACTH, cortisol are high in the early
morning).

16
Regulation of cortisol secretion
ACTH –
Increase the responsiveness to subsequent
ACTH on adrenal cortical cells.

17
ACTH & MSH
Proopiomelanocortin (POMC) the
precursor of ACTH as well MSH.
With increase of ACTH more POMC
produce and making more MSH.

18
Adrenal Androgens
Male sex hormones from adrenal cortex.
Moderately active – less than 20% of
Testosterone.
Dehydroepiandrosterone - important
one. (17-ketosteroid dehydroepiandrosterone)
progesterone & estrogens are secreted
in minute quantities.
Regulated by ACTH (Not by
Gonadotropin/LH)

Adrenal Androgens
Very little effect in normal amount
In excessive amount – masculinization.
In adult male – no special effect.
In male child – precocious development of
secondary sexual characteristics.
(Precocious pseudopuberty)
Female – pseudo-hermaphroditism &
adrenogenital syndrome.

19
Abnormalities of adrenal
hormones

Hypoadrenalism (Addison’s
Disease)
Production of mineralocorticoid &
glucocorticoid is low.
Hypotension
Fasting make severe hypoglycemia.
Can lead to addisonian crisis and death.

20
Hypoadrenalism (Addison’s
Disease)
Production of mineralocorticoid &
glucocorticoid is low.
hyponatremia, hyperkalemia,
mild acidosis develop – K+ & H+ to be
secreted in exchange for Na+
reabsorption.
Hypotension
Inability to cope with stress.

Hypoadrenalism (Addison’s
Disease)
Fasting make severe hypoglycemia.
Spotted pigmentation in skin – MSH
activity of ACTH & Increase secretion of
MSH.

21
Primary Aldosteronism -
Conn’s Syndrome
Secretes large amounts of aldosterone.
Hypokalemia
slight increase in extracellular fluid
volume and blood volume.
Very slight increase in plasma sodium
concentration.
Hypertension.
Renin secretion depressed.

Secondary hyperaldosteronism

High plasma renin activity.

Due to cirrhosis, heart failure,
nephrosis.
renal artery constriction >renal
ischemia > elevated renin secretion >
aldosterone increased

22
 Adrenal hyperplasia
Mutation of the gene for the steroidogenic
acute regulatory (StAR) protein which is
essential for movement of cholesterol into
the mitochondria in adrenal gland/gonads.
ACTH secretion increases and accumulation
of large numbers of lipoid droplets in the
adrenal.
Female genitalia develop regardless of
genetic sex.

Adrenogenital Syndrome
adrenocortical tumour secretes excessive
quantities of androgens.
A condition in female with virile
characteristics
growth of a beard, a much deeper voice,
occasionally, Baldness, masculine distribution
of hair on the body and the pubis, growth of
the clitoris to resemble a penis, masculine
characteristics.

23
 Adrenogenital Syndrome
Production of cortisol and aldosterone are
generally reduced due congenital deficiency.
ACTH secretion and consequently
production of precursor steroids are
increased.
These steroids are converted to androgens,
producing virilization.(Male features in
female)
Masculization will be marked later in the life.

Cushing’s Syndrome
Hypersecretion by the adrenal cortex
Abnormal amounts of cortisol, but excess
androgens may cause effects.
ACTH dependent and ACTH independent.
What is cushing’s disease???

24
Cushing’s Syndrome
Condition/the clinical picture due to
excess of cortisol production
excessive use of cortisol or other similar steroid
(glucocorticoid).

It can be
ACTH independent – adrenal tumors, prolong
use as a treatment.
ACTH dependent – ACTH secreting tumors –
Anterior pituitary, Lungs etc.

25
 Cushing’s Syndrome
Fat redistribution

Upper-body obesity, rounded face

Increased fat around the neck – ‘buffalo hump’.
Thinning arms and legs.

Cushing’s Syndrome
Excess protein catabolism

Skin becomes fragile, thin

Poor wounds healing, bruises easily
Hair is thing
Bones are weakened – osteoporosis (with rib
and spinal column fractures)
weak muscles.

26
 Cushing’s Syndrome
Precipitate insulin-resistant diabetes
Amino acid from protein catabolism convert
to glucose
Decrease peripheral utility of glucose.

Cushing’s Syndrome
Mineralocorticoid effect of cortisol
Salt and water retention
K+ depletion and weakness
Hypertension – (also due direct effect on blood vessels)

Can produce mental changes – increased appetite,

insomnia, euphoria……. Psychoses.
Acne
Irregular or stopped menstrual periods in females.
Erectile dysfunction in males.

27
More…
glucose fever…
Different reasons for Cushing syndrome
Glucocorticoids use as drug – use,
action, problems
Very slight increase in plasma sodium
concentration in Conn’s syndrome
……aldosterone escape …..

28
 Adrenal Gland
Adrenal Gland ; Adrenal Cortex, Adrenal Medulla
Adrenal medulla
• A sympathetic ganglion; postganglionic neurons
have lost their axons and become secretory cells
Adrenal Medulla • Cells secrete when stimulated by the
preganglionic nerve fibers that reach the gland
via the splanchnic nerves
• Adrenal medullary hormones work mostly to
Prof R S J Lenora
prepare the body for emergencies, “fight-or
flight” responses.
Prof R S J Lenora, Only for Medical Student teaching 2

Adrenal medullary hormones Metabolism of catecholamines …

• Catecholamines
• In circulation conjugated to sulfate.
-Epinephrine mainly
- about 95% of the dopamine
-Norepinephrine
- 70% of norepinephrine
-Dopamine (minor amount)
- 70 % epinephrine
• Sulfate conjugates are inactive and their
• Norepinephrine (PNMT) Epinephrine
function is unsettled.
• PNMT= Phenylethanolamine-N-methyltransferase
• PNMT available in adrenal medulla & Brain • Recumbent humans, On standing, the
• PNMT induced by glucocorticoids Norepinephrine level increases by 50–100%
• Norepinephrine released from sympathetic nerve • Small amount of epinephrine is secreted from
endings also present in blood intrinsic cardiac adrenergic (ICA) (Function?)
Prof R S J Lenora, Only for Medical Student teaching 3 Prof R S J Lenora, Only for Medical Student teaching 4
 Catabolism of … Condition affecting on secretion
• Half-life of ~ 2 min in circulation
• Mostly methoxylated & oxidized to
vanillylmandelic acid [VMA]
Urinary excretion
• 50% of the secreted catecholamines as free or
conjugated metanephrine and
normetanephrine,
• 35% as VMA
• Small amounts of free norepinephrine and
epinephrine are excreted.
Prof R S J Lenora, Only for Medical Student teaching 5 Prof R S J Lenora, Only for Medical Student teaching 6

Effects of Epi & Norepinephrine CVS effects

• Mimic the effects of noradrenergic nervous • E & NE increase the force and rate of contraction
of the isolated heart (β1 receptors)
discharge • Increase myocardial excitability – causing
• Metabolic effects - glycogenolysis in liver and extrasystoles and, occasionally, more serious
skeletal muscle, mobilization of free fatty acids cardiac arrhythmias
(FFA), increase plasma lactate, and stimulation Effect of TPR
• Norepinephrine produces vasoconstriction in
of the metabolic rate. most vessels (α1 receptors)
• Effects are brought by actions on α and β • Epinephrine dilates the blood vessels in skeletal
adrenergic receptors. muscle and liver (β2 receptors)
• Epinephrine overbalances the vasoconstriction
• α receptors - α1 and α2 produced by epinephrine else where
• β receptors - β1 , β2 , and β3 • Total peripheralProfresistance drops
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teaching
 Slow infusion of norepinephrine Slow infusion of Epi, Norepi CVS effects
• Systolic and diastolic blood pressures rise
• Hypertension ----stimulates carotid and aortic
baroreceptors ----------reflex bradycardia
(overrides direct cardioacceleratory effect of NE) -
---- CO falls

Epinephrine
Widens the pulse pressure --- Baroreceptor
stimulation is insufficient to obscure the direct
effect of the hormone on the heart ----HR & CO
increase
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teaching

Effects…
On CNS
• Epinephrine and Norepinephrine increase • Increase Metabolic rate independent of liver
alertness of brain • Blood lactate level increases.
• Epinephrine usually evokes more anxiety and fear • Initial rise in metabolic rate may be due to
i. Cutaneous vasoconstriction ---------Decrease
On blood glucose heat loss--- Body temperature rise in body
• Glycogenolysis (E & NE) temperature and /or increased muscular
• Increase cAMP activity
• In addition, the catecholamines increase the ii. Oxidation of lactate in the liver.
secretion of insulin and glucagon (β-adrenergic)
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teaching teaching
 Epinephrine or norepinephrine
Threshold for catecholamines
injection
• Threshold for Cardiovascular and metabolic effects of NE is
• Plasma K+ increase initially due to release of K+ about 1500 pg/mL, (Five times of resting value of 300).
from liver) Epinephrine threshold
• Prolonged effect is falling plasma K+ due to • Tachycardia when plasma Epi is twice the resting value (50).
increased K+ entry into skeletal muscle by β 2 • Increased systolic blood pressure and lipolysis at 75 pg/mL
• Hyperglycemia, increased plasma lactate, and decreased
receptors ) diastolic blood pressure is about 150 pg/mL
• α-mediated decrease in insulin secretion is about 400 pg/mL
• Plasma epinephrine often exceeds these thresholds.
• Plasma norepinephrine rarely exceeds the threshold for its
cardiovascular and metabolic effects, and most of its effects
are due to its local release from postganglionic sympathetic
neurons
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teaching teaching

Regulation of Ad medullary Hormone Secretion

Pheochromocytoma
• Certain drugs act directly on adrenal medulla
• Physiologic stimuli is through nervous system • Adrenal medullary tumor secrete norepinephrine,
• Catecholamine secretion is low in basal states and/ or epinephrine
• Secretion of epinephrine and norepinephrine is • Produce sustained hypertension
reduced further during sleep. • 15% of epinephrine-secreting tumors secrete
• Part of the diffuse sympathetic discharge in episodically, producing
“emergency function of the sympathoadrenal system.”
• Prepares for flight or fight response - intermittent bouts of palpitations
• Metabolic effects of circulating catecholamines are in - headache
certain situations
- glycosuria
- Catecholamine action in animals exposed to cold
environment - extreme systolic hypertension
- Glycogenolytic effect in hypoglycemia Same symptoms are produced by intravenous
injection of a large dose of epinephrine.
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teaching
Thanks
Comments Pl test to 071 761 2390
Viber or WhatsApp.

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teaching
 Melatonin
Melatonin is released from the richly vascularized pineal gland into blood and CSF

The pineal gland arises from the roof of the third ventricle in the diencephalon and
Hormones produced in organs is encapsulated by the meninges.

other than main endocrine glands The pineal stroma contains glial cells and pinealocytes with features suggesting that
they have a secretory function.
Like other endocrine glands, it has highly permeable fenestrated capillaries.
Dr. D. C. Wijewickrama
Senior Lecturer In infants, the pineal is large.
Dept. of Physiology Faculty of Medicine, It begins to involute before puberty and small concretions of calcium phosphate and
University of Ruhuna carbonate (pineal sand) appear in the tissue.

Because the concretions are radiopaque, the pineal is

often visible on x-ray films of the skull in adults.
Displacement of a calcified pineal from its normal
position indicates the presence of a space-occupying
lesion such as a tumor in the brain.

This presentation is prepared as a learning aid for medical students during COVID-19 pandemic. This is intended to used only through Learning Management
System of the Faculty of Medicine, University of Ruhuna

Light–dark cycle in the

The pineal gland is controlled by the amount of light or “time pattern” of light environment
seen by the eyes each day – leading to diurnal change in melatonin secretion

Retinohypothalamic nerve fibers

Melatonin synthesis and secretion are increased during the dark period of the
day and maintained at a low level during daylight hours
Suprachiasmatic nucleus
Melatonin may be the timing signal to coordinate events with the light–dark cycle preganglionic postganglionic
neurons
in the environment eg. Sleep pattern, some hormone secretion sympathetic
neurons
Melatonin plays at least some role in controlling sexual drive and reproduction in preganglionic
Superior cervical ganglion
humans. sympathetic
Postganglionic neurons
sympathetic
neurons

Pineal gland

Diurnal variation in Through blood CSF To the anterior pituitary

secretion of melatonin
 Hormones of the Heart
Clinical uses
• Natriuretic hormones
• For jet lag • 3 types
• shift-work disorder – atrial natriuretic peptide (ANP) – in heart and brain
• insomnia – brain natriuretic peptide (BNP) – in heart (more) and brain
• helping blind people establish a day and night cycle. – C-type natriuretic peptide (CNP) - in brain, pituitary,
kidneys, vascular endothelial cells

ANP and BNP circulate, whereas CNP acts predominantly in a paracrine

fashion

They are released in response to hypervolemia

These peptides leads to natriuresis and antagonize the action of various

vasoconstrictor agents leading to lowering of blood pressure

ANP and CVP

Immersion in water up to the neck Thus, it is clear that the atria respond directly to stretch.
The rate of ANP secretion is proportional to the degree to which the atria are
stretched by increases in CVP.
Counteracts the effect of gravity on the circulation
BNP secretion is proportional to the degree to which the ventricles are
Increases central venous pressure stretched.

Increases atrial pressure Plasma levels of both hormones are elevated in congestive heart failure, and
their measurement is used in the diagnosis of CCF.

ANP secretion is increased Decreases the secretion of

renin and aldosterone Heart failure stage

Rising from the supine to the standing position

Decrease central venous pressure

Decrease in plasma ANP

 ANP and the kidney ANP and the blood vesseles
ANP and BNP in the circulation act on the kidneys ANP

Dilate afferent arterioles and Act on the renal tubules to inhibit Inhibits renin secretion
relax mesangial cells Na+ reabsorption (DT/CT)
Decreases the Counteract the Increase in capillary
Increase glomerular filtration responsiveness of the zona pressor effects of permeability
glomerulosa to angiotensin II catecholamines

Natriuresis (increase Na+ excretion in urine) and diuresis Extravasation of fluid

Relaxation of vascular smooth
muscle in arterioles and venules
Decline in blood pressure

Ghrelin (“hunger hormone”) (Orexigenic) Leptin ("satiety hormone”) (Anorexigenic)

The main site of ghrelin synthesis and secretion is the oxyntic cells of the stomach Leptin is a peptide hormone secreted by fat cells.
It has many physiological effects, but it is especially important in regulating
Also produced in the hypothalamus and by the intestine appetite and energy balance (inhibits appetite, stimulates thermogenesis)

Has marked GH-stimulating activity and is the third regulator of GH secretion Increased amount of adipose tissue
(GHRH, somatostatin are the other two)

Produce increased amounts of leptin

Appears to be involved in the regulation of food intake - stimulating feeding
Released into the blood
Blood levels of ghrelin rise during fasting, peak just before eating, and then fall
rapidly after a meal Moves across the blood-brain barrier by facilitated diffusion to enter the brain

Stimulates leptin receptors at multiple nuclei in the hypothalamus

Initiates multiple actions that decrease fat storage

 Leptin and obesity
These multiple actions that decrease fat storage include;
Obese people
(1) decreases production in the hypothalamus of appetite stimulators, such as NPY
and AGRP (AgRP and NPY increase appetite and decrease metabolism and energy Plasma leptin levels increase in proportion with increasing adiposity
expenditure)

(2) releases α-MSH and activation of melanocortin receptors (Acting in the Continue to eat despite of having very high levels of leptin
hypothalamus, α-MSH suppresses appetite)

(3) Increases production of corticotropin-releasing hormone, that decrease food ?? Leptin resistance
intake

(4) increases sympathetic nerve activity (through neural projections from the Genetic mutations
hypothalamus to the vasomotor centers), which increases metabolic rate and
energy expenditure
Defective leptin receptors in
Fat cells unable to produce leptin
(5) decreases insulin secretion by the pancreatic beta cells, which decreases energy the hypothalamus
storage

Thus, leptin is an important hormone which signals the brain that enough Marked hyperphagia and morbid obesity occur
energy has been stored and intake of food is no longer necessary.

Other explanation for the failure of leptin to prevent increasing adiposity in Feedback mechanism for
obese individuals are;
control of food intake
There are many redundant systems that control feeding behaviour (eg.
neuropeptides and neural circuits)

social and cultural factors that can cause continued excess food intake
even in the presence of high levels of leptin.
 Leptin and other diseases Leptin and puberty
For puberty to occur a critical body weight must normally be reached
Deficient glucose utilization and deficient sensing of hormones
(insulin, leptin, CCK) that regulate satiety, by the hypothalamus
Young women who engage in strenuous athletics and girls with anorexia
nervosa lose weight and stop menstruating
?? hyperphagia in diabetes
If these girls start to eat and gain weight, they menstruate again, that is,
they “go back through puberty.”

Leptin may be the link between body weight and puberty

In the rare metabolic disease congenital lipodystrophy, in which fat depots
fail to develop

There is marked insulin resistance

This resistance is reduced by giving leptin

• References
1. Ganong's Review of Medical Physiology
2. Guyton & Hall Physiology Review
 Melatonin
Melatonin is released from the richly vascularized pineal gland into blood and CSF

The pineal gland arises from the roof of the third ventricle in the diencephalon and
Hormones produced in organs is encapsulated by the meninges.

other than main endocrine glands The pineal stroma contains glial cells and pinealocytes with features suggesting that
they have a secretory function.
Like other endocrine glands, it has highly permeable fenestrated capillaries.
Dr. D. C. Wijewickrama
Senior Lecturer In infants, the pineal is large.
Dept. of Physiology Faculty of Medicine, It begins to involute before puberty and small concretions of calcium phosphate and
University of Ruhuna carbonate (pineal sand) appear in the tissue.

Because the concretions are radiopaque, the pineal is

often visible on x-ray films of the skull in adults.
Displacement of a calcified pineal from its normal
position indicates the presence of a space-occupying
lesion such as a tumor in the brain.

This presentation is prepared as a learning aid for medical students during COVID-19 pandemic. This is intended to used only through Learning Management
System of the Faculty of Medicine, University of Ruhuna

Light–dark cycle in the

The pineal gland is controlled by the amount of light or “time pattern” of light environment
seen by the eyes each day – leading to diurnal change in melatonin secretion

Retinohypothalamic nerve fibers

Melatonin synthesis and secretion are increased during the dark period of the
day and maintained at a low level during daylight hours
Suprachiasmatic nucleus
Melatonin may be the timing signal to coordinate events with the light–dark cycle preganglionic postganglionic
neurons
in the environment eg. Sleep pattern, some hormone secretion sympathetic
neurons
Melatonin plays at least some role in controlling sexual drive and reproduction in preganglionic
Superior cervical ganglion
humans. sympathetic
Postganglionic neurons
sympathetic
neurons

Pineal gland

Diurnal variation in Through blood CSF To the anterior pituitary

secretion of melatonin
 Hormones of the Heart
Clinical uses
• Natriuretic hormones
• For jet lag • 3 types
• shift-work disorder – atrial natriuretic peptide (ANP) – in heart and brain
• insomnia – brain natriuretic peptide (BNP) – in heart (more) and brain
• helping blind people establish a day and night cycle. – C-type natriuretic peptide (CNP) - in brain, pituitary,
kidneys, vascular endothelial cells

ANP and BNP circulate, whereas CNP acts predominantly in a paracrine

fashion

They are released in response to hypervolemia

These peptides leads to natriuresis and antagonize the action of various

vasoconstrictor agents leading to lowering of blood pressure

ANP and CVP

Immersion in water up to the neck Thus, it is clear that the atria respond directly to stretch.
The rate of ANP secretion is proportional to the degree to which the atria are
stretched by increases in CVP.
Counteracts the effect of gravity on the circulation
BNP secretion is proportional to the degree to which the ventricles are
Increases central venous pressure stretched.

Increases atrial pressure Plasma levels of both hormones are elevated in congestive heart failure, and
their measurement is used in the diagnosis of CCF.

ANP secretion is increased Decreases the secretion of

renin and aldosterone Heart failure stage

Rising from the supine to the standing position

Decrease central venous pressure

Decrease in plasma ANP

 ANP and the kidney ANP and the blood vesseles
ANP and BNP in the circulation act on the kidneys ANP

Dilate afferent arterioles and Act on the renal tubules to inhibit Inhibits renin secretion
relax mesangial cells Na+ reabsorption (DT/CT)
Decreases the Counteract the Increase in capillary
Increase glomerular filtration responsiveness of the zona pressor effects of permeability
glomerulosa to angiotensin II catecholamines

Natriuresis (increase Na+ excretion in urine) and diuresis Extravasation of fluid

Relaxation of vascular smooth
muscle in arterioles and venules
Decline in blood pressure

Ghrelin (“hunger hormone”) (Orexigenic) Leptin ("satiety hormone”) (Anorexigenic)

The main site of ghrelin synthesis and secretion is the oxyntic cells of the stomach Leptin is a peptide hormone secreted by fat cells.
It has many physiological effects, but it is especially important in regulating
Also produced in the hypothalamus and by the intestine appetite and energy balance (inhibits appetite, stimulates thermogenesis)

Has marked GH-stimulating activity and is the third regulator of GH secretion Increased amount of adipose tissue
(GHRH, somatostatin are the other two)

Produce increased amounts of leptin

Appears to be involved in the regulation of food intake - stimulating feeding
Released into the blood
Blood levels of ghrelin rise during fasting, peak just before eating, and then fall
rapidly after a meal Moves across the blood-brain barrier by facilitated diffusion to enter the brain

Stimulates leptin receptors at multiple nuclei in the hypothalamus

Initiates multiple actions that decrease fat storage

 Leptin and obesity
These multiple actions that decrease fat storage include;
Obese people
(1) decreases production in the hypothalamus of appetite stimulators, such as NPY
and AGRP (AgRP and NPY increase appetite and decrease metabolism and energy Plasma leptin levels increase in proportion with increasing adiposity
expenditure)

(2) releases α-MSH and activation of melanocortin receptors (Acting in the Continue to eat despite of having very high levels of leptin
hypothalamus, α-MSH suppresses appetite)

(3) Increases production of corticotropin-releasing hormone, that decrease food ?? Leptin resistance
intake

(4) increases sympathetic nerve activity (through neural projections from the Genetic mutations
hypothalamus to the vasomotor centers), which increases metabolic rate and
energy expenditure
Defective leptin receptors in
Fat cells unable to produce leptin
(5) decreases insulin secretion by the pancreatic beta cells, which decreases energy the hypothalamus
storage

Thus, leptin is an important hormone which signals the brain that enough Marked hyperphagia and morbid obesity occur
energy has been stored and intake of food is no longer necessary.

Other explanation for the failure of leptin to prevent increasing adiposity in Feedback mechanism for
obese individuals are;
control of food intake
There are many redundant systems that control feeding behaviour (eg.
neuropeptides and neural circuits)

social and cultural factors that can cause continued excess food intake
even in the presence of high levels of leptin.
 Leptin and other diseases Leptin and puberty
For puberty to occur a critical body weight must normally be reached
Deficient glucose utilization and deficient sensing of hormones
(insulin, leptin, CCK) that regulate satiety, by the hypothalamus
Young women who engage in strenuous athletics and girls with anorexia
nervosa lose weight and stop menstruating
?? hyperphagia in diabetes
If these girls start to eat and gain weight, they menstruate again, that is,
they “go back through puberty.”

Leptin may be the link between body weight and puberty

In the rare metabolic disease congenital lipodystrophy, in which fat depots
fail to develop

There is marked insulin resistance

This resistance is reduced by giving leptin

• References
1. Ganong's Review of Medical Physiology
2. Guyton & Hall Physiology Review
 Types of Bones
• Cortical (Compact bone)
• Trabecular bone (spongy)
Bone Metabolism and Calcium
Homeostasis

Prof. Janaka Lenora

2
Prof Janaka Lenora. Only for teaching Medical Students

Components of Bones Functions of Bones

• Protect vital organs
• Helpful in locomotion
• Cells
– Osteoblasts
• Homeostasis of Ca2+, PO43-
– Osteoclasts
– Osteocytes

• Bone matrix • Bone metabolism

– Type I collagen, + Osteocalcin
- Bone Formation
• Minerals - Bone Resorption
– Calcium hydroxyapatites -Ca10(PO4)6(OH)2
3
(Bone turnover) 4
Prof Janaka Lenora. Only for teaching Medical Students Prof Janaka Lenora. Only for teaching Medical Students
 Bone growth Bone Formation and Resorption
• Osteoblast
• Bone formation - modified fibroblasts
– Endochondrial -Lay down collagen
– Intramembranes
• Epiphysis • Osteoclast – derived from monocyte
• Diaphysis family
• Epiphysial plate – Erode and absorb previously formed bone
– Acidify the area – dissolve hydroxyapatite
• Closure of epiphysis
– Acid proteases
• Remodeling – faster in newborn
– breakdown the collagen
5 6
Prof Janaka Lenora. Only for teaching Medical Students Prof Janaka Lenora. Only for teaching Medical Students

Bone turnover
• Continuous process of bone formation and
resorption (coupled)
• Bone formation predominates in childhood
and up to 3rd decade of life
• Balanced state of formation and resorption
3rd -5th decades
• In adults, about 10% bone undergo
turnover yearly
• Bone resorption predominates after 5th
decade 7
Prof Janaka Lenora. Only for teaching Medical Students
Prof Janaka Lenora. Only for teaching Medical Students
 Calcium Homeostasis Serum Calcium
• S Ca range from 8.5-10.5mg/dL (2.12-2.62 mM)
• Total body calcium 1.1 Kg (27.5 mol) • Ionized (free) Ca 4.65-5.25 mg/dL (1.16-1.31mM)
– 99% in the skeleton
• 40-50 % bound to proteins, phosphate and citrate ions
• Plasma Ca -10 mg/dL (5meq/L, 2.5mmol/L) • Protein bound fraction increase in alkalosis
50% Free fraction (ionized)
• S-Total Ca fluctuate with S-Alb.
40 % Albumin Bound,
10% bound to phosphate and citrate • In dehydration S-Ca should be corrected as
S Total Ca-0.8mg/dL to every 1g/dL elevation of S-
Alb beyond 4.0g/ dL.
9 10
Prof Janaka Lenora. Only for teaching Medical Students Prof Janaka Lenora. Only for teaching Medical Students

Cont..
• Intra cellulat fluid Ca conc 10x 10-6 M
ECF Ca conc 10x 10-3M) Calcium Homeostasis
1000 times less than ECF. • Bone calcium pool
– Readily exchangeable pool
• Within cell charge -50 mv – Stable pool - slowly exchangeable
Interchange with plasma calcium
• Efflux of Ca to cell and celular death is – regulated by PTH, active Vit. D
prevented by
• Filtered and 98-99% reabsorbed in the kidney
-ATP dependant Ca pumps and channels – proximal tubule,
(Na+/ Ca++ exchange) – ascending limb of the LH,
-binding of ICF Ca to proteins and ER, – distal tubule - regulated by parathyroid hormone
Mitochondria ect..
• Absorption in the gut
11 – regulated by 1,25-dihydroyxycholecalciferol 12
Prof Janaka Lenora. Only for teaching Medical Students
Prof Janaka Lenora. Only for teaching Medical Students
 Functions of Free Calcium
• Vital second messenger (Enzyme &
Homone)
• Blood coagulation
• Muscle contraction
• Nerve functions
• Needed for cell devision
• Cell adhesion
• Pl membrane intergrity
• Protein secretion
Prof Janaka Lenora. Only for teaching Medical Students
13
• Glycogen metabolism 14
Prof Janaka Lenora. Only for teaching Medical Students

Hypocalcaemic Tetany
• Low extracellular calcium
• Nerves and muscles are more excitable
(neuromuscular transmission is inhibited)

• Spasms of skeletal muscles (specially

muscles in extremities)
– Laryngeal muscles
– Carpal and pedal muscles (carpo-pedo spasm)
– Chvostek’s sign and Trousseau’s sign can be
elicited in latent tetany
15 16
Prof Janaka Lenora. Only for teaching Medical Students
Prof Janaka Lenora. Only for teaching Medical Students
• End of Section I
• Please go to Lecture II

Prof Janaka Lenora. Only for 17

teaching Medical Students