Endocrine Physiology

Human Endocrine

Glands• In the brain:

• Hypothalamus• Pituitary gland• Pineal gland

• Adrenal gland• Pancreas • Ovary • Testis

Endocrine action

Endocrine system controls

physiology via chemical signals from

one part of the body to another

Target cell undergoes a biological

response

Cell to Cell Signaling

AUTOCRINE

Cell to Cell Signaling

AUTOCRINE

PARACRINE

Cell to Cell Signaling

AUTOCRINE

PARACRINE

ENDOCRINE

Neurocrine - neural

cells that release

chemical signals into

the bloodstream

Cell to Cell Signaling

Endocrine Signaling

Human Endocrine

Glands

Figure 18.1

The Endocrine System

FUNCTIONS

1. Regulate metabolic processes

2. Regulate rate of chemical reactions

3. Transport of substances thru membrane

4. Regulate water and electrolyte balance, blood

pressure

5. Vital roles in reproduction, development, growth

Classification of Hormones

1. Based upon chemical nature

2. Based upon function

Chemical Nature of Hormones

Hormones are

Peptides

Steroid

Amino Acid Derivatives

Chemical Classification of Hormones1. Amino hormones

-derived from tyrosine

2. Peptide and protein hormones

- Made up of peptide

3. Steroid hormones

– derived from cholesterol

Proteins & polypeptides Pituitary, Pancreas, Parathyroid.

b. Steroids Adrenal cortex and Sex hormones.

c. Amino acid derivatives Adrenal Medulla, Thyroid hormones.

Classification of hormones

Functional classifications

1. Releasing hormones

2. tropic (or Stimulating) hormones

3. Non-tropic hormones

Hypothalamus

Pituitary gland

Releasing hormones

Peripheral endocrine glands

Stimulating hormones

Hormonal axis

HormonesPeripheral organs

BRAIN

Hormone types 1. Polar:

• Most hormones.

• Bind to receptor protein on pm.

2.Lipophilic (nonpolar):• Cross pm, act inside target cells.

• Steroid hormones and thyroid hormones.

Hormones

Synthesis

Hormones

Synthesis

Secretion

In circulation

Mechanism of Action

Second messengers

Second messengers include

– cAMP or cGMP

– phospholipids diacylglycerol and inositol

triphosphate (DAG and IP3)

– calcium

One pathway-cAMP

Protein Kinases

Lipophilic hormones

- Inside cell: bind to nuclear hormone

receptors.

Transcription factors

• Transcription:

DNA is transcribed into messenger RNA.

This mRNA will then be translated (by

ribosomes) into proteins!

Lipophilic hormones

Effects of [Hormone] on Tissue

Response1. Blood levels

2. Number of receptors on target cells

3. Affinity of receptors for hormones

Regulation of receptor

1. Down regulation (desensitization):

2. Up regulation:

Catabolism

Liver

Kidney

Hypothalamic-Pituitary Axis

– Hypothalamic-Pituitary-Thyroid axis (HPT)

– Hypothalamic-Pituitary-Adrenal axis (HPA)

– Hypothalamic-Pituitary-Gonadal axis

(HPG)

Control of Hormone Secretion1. Negative Feedback mechanism

2. Positive Feedback mechanism

3. Hypothalamo-hypophyseal tract.

Negative Feedback Loop

Positive Feedback Control Parturition and suckling

•

Hypothalamic Control of Posterior Pituitary

(ADH)

(Oxy)

Any Questions??

Measurement of Endocrine function

1. Most used is radioimmunoassay (RIA)

-Hormones present in nanomolar to

picomolar range

2. Radioreceptor assays (RRA)

3. Bio-assays use target cell

4. ELISA

Pituitary Gland

Anterior and posterior pituitary glands.

Hormones of the anterior lobe

The Anterior Lobe

Anterior pituitary cells and hormones

Cell type Pituitary population

Product Target

Corticotroph 15-20% ACTH Adrenal glandAdipocytesMelanocytes

Thyrotroph 3-5% TSH Thyroid glandGonadotroph 10-15% LH, FSH Gonads

Somatotroph 40-50% GH All tissues, liver

Lactotroph 10-15% PRL Breastsgonads

Hormones of the Anterior Pituitary

1. Growth hormone (GH)

2. Prolactin

3. Thyroid stimulating hormone (TSH)

- also called thyrotropin

- stimulates milk production

- one of the growth promoting hormones

Hormones of the Anterior Pituitary con’t

4. Adrenocorticotrophic hormone (ACTH)

5. Leutinizing hormone (LH)

6. Follicular stimulating hormone (FSH)- stimulates follicular development

- promotes ovulation

- also called corticotropin

Hypothalamic Control of the Anterior Pituitary

GH or SomatotropinGH or Somatotropin

Secreted by somatotropes Secreted by somatotropes

Done indirectly – liver produces – Done indirectly – liver produces –

somatomedins or IGF’s – insulin somatomedins or IGF’s – insulin

growth factorsgrowth factors

Actions of GHActions of GH

Actions mediated by GH and IGF-1

GH-IGF actionsGH-IGF actions1.Protein synthesis1.Protein synthesis

• mRNAmRNA• GH enhances amino acid transport into GH enhances amino acid transport into

cellscells• Ensures protein anabolismEnsures protein anabolism• Suppresses protein catabolismSuppresses protein catabolism

•Protein sparing effectProtein sparing effect

2.Lipid metabolism2.Lipid metabolism•Release free fatty acids and Release free fatty acids and

glycerolglycerol•FFA’s used for energyFFA’s used for energy•Provides energyProvides energy

•3.Carbohydrate metabolism3.Carbohydrate metabolism•Glucose sparing effectGlucose sparing effect

4.Electrolyte balance4.Electrolyte balance• Na, K, ClNa, K, Cl-- retention – kidneys retention – kidneys

• Enhances Enhances CaCa++++ absorption – small intestines absorption – small intestines

• These electrolytes available for tissue These electrolytes available for tissue growthgrowth

5. Prolactin like action.5. Prolactin like action.

Physiological function of GH (somatotropin) :

↑Plasma FFA

↑Plasma glucose

↓Plasma amino acids

↓ Plasma urea

Metabolism

Condrocytes

↑Amino acid uptake

↑Protein synthesis

↑DNA,RNA synthesis

↑Chondroitin sulfate

↑Cell size and number

↑Linear growth

Muscle

↓ Glucose uptake

↑Amino acid uptake

↑ Protein synthesis

↑Lean body mass

Adipose tissue

↓Glucose uptake↑Lipolysis

↓ adiposity

Kidney, pancreas, intestine, islets,parathyroids, connective tissue,bone, heart, lungs

↑Protein synthesis

↑DNA,RNA synthesis

↑Cell size and number

↑Organ size↑Organ function

Growth hormone

Control of GH secretionSS GHRH

GH

IGF-1

Target tissue

⊕○-

⊕⊕

-○

Somatostatin: SSSomatotropin: GHSomatomedin: IGF-1

Regulation of Growth Regulation of Growth Hormone SecretionHormone Secretion

• GH secretion controlled primarily by GH secretion controlled primarily by

hypothalamic GHRH stimulation and hypothalamic GHRH stimulation and

somatostatin inhibition somatostatin inhibition

Regulation of GH releaseRegulation of GH release Augment GH Inhibit GH

Neurogenic Stage 3 and 4 sleep Stress Alpha agonists Beta antagonists

REM sleep Emotional deprivation

Metabolic Hypoglycaemia Fasting Amino acids

Hyperglycaemia High FFA Obesity

Hormonal GHrH Low IGF-1 Oestrogens Glucagon GHRPs

Somatostatin High IGF-1 Hypothyroidism High GC levels

Abnormalities of GH secretion :

Dwarfism

Acromegaly

Gigantism

– Pituitary dwarfsPituitary dwarfs are a result of are a result of

hyposecretionhyposecretion

– GigantismGigantism results from juvenile results from juvenile

hypersecretionhypersecretion

– AcromegalyAcromegaly results from adult results from adult

hypersecretion of GH hypersecretion of GH

Dwarfism

• Excessive Excessive Production Production during childhoodduring childhood

Growth Hormone Excess

• in childhood leads to GIGANTISM

GigantismGigantism

Identical twins, 22 years old, excess GH secretion

Features :

Tall stature

Bilateral gynecomastia

Large hands & feets

Coarse facial features

Loss of libido

• HandsHands• FeetFeet• JawsJaws

Acromegaly

Growth Hormone Excess

• in adulthood leads to ACROMEGALY

AcromegalyAcromegaly

• Progression of untreated Progression of untreated acromeglyacromegly

Prior

Early Onset

Full Development

Features :

Elongation and widening of mandible

Enlargement of sinuses causing prominent brow

Thickening of skin & coarsening of the facial features.

Kyphosis & Scoliosis.

Hypertrophy of body soft tissue

• With the life cycle the rate of growth is not even.

• Infancy has the highest rate decreasing until of spurt of growth caused by sexual maturity.

• Growth Rates differ according to the time of the life cycle.

• Growth hormone and Thyroxine are the most active.

• Sex hormones govern growth spurt at sexual maturity.

Posterior lobe

Posterior lobe

• Produces No Hormones .

• Stores and releases OT and ADH

Posterior pituitary

• Stores and releases 2 hormones that are

produced in the hypothalamus:

1. - Antidiuretic hormone (ADH)

2. - Oxytocin

posterior lobe (neurohypophysis)

Neurons of the supraoptic nucleus manufacture

antidiuretic hormone (ADH)

1. Decreases the amount of water lost at the kidneys

2. Elevates blood pressure

posterior lobe (neurohypophysis)

Neurons of the paraventricular nucleus

manufacture oxytocin

1. Stimulates contractile cells in mammary glands

2. Stimulates smooth muscle cells in uterus

Structures of ADH and oxytocin

Hypothalamic Control of Posterior Pituitary

(ADH)

(Oxy)

ADH

Antidiuretic hormone (ADH):

• aka vasopressin ( 1000:1)

• Synthesis

• Transport

• Release

Physiological effects of ADH :

1. The retention of water in excess of

solute by the kidney

2. In large doses, vasopressin elevates

arterial blood pressure

ADH (antidiuretic hormone):

• Stimulates fusion of aquaporin (water channel)

vesicles in the collecting duct.

• Results in (increased permeability to H20 and )

increased reabsorption of water.

Mechanism of Vasopressin Action

Figure 20-6: The mechanism of action of vasopressin

ADH increases renal tubular absorption of water

Regulation of ADH

• Administration of (sodium) cause ADH

release.

• Urea - ???

• Changes of 1-2%

Secretion of ADH–osmolality control

• decrease in blood volume, cardiac output, or

blood pressure.

• Hemorrhage

Secretion of ADH—hemodynamic control

• Hypovolemia

• Normally, pressure receptors tonically inhibit

ADH release.

• 5 to 10% change in volume

Secretion of ADH

Feedback Loop for ADH

Negative feedback

• The two major stimuli of ADH secretion

interact.

1. Changes in volume

2. changes Plasma osmolar.

• Hypovolemia sensitizes the ADH response

to hyperosmolarity.

Secretion of ADH

Regulators of

Vasopressin Release

Neuroendocrine reflexes• release hormones – nervous system signal

1. ADH – dehydration > osmolarity of blood – osmoreceptors detect

– ADH released = water conservation

2. >BP –stimulates stretch receptors in heart & certain arteries –

inhibits ADH release, > urine output, < BP

Regulation/Stimuli:

- Blood (or ECF)

osmolality/osmoreceptor

- Blood volume

- Others: alcohol, nicotine, barbiturates, etc.

Pituitary - Diabetes Insipidus

1. Diabetes insipidus

2. Nephrogenic diabetes insipidus

(receptor disease)

Clinical implications:

Diabetes Insipidus - clinical features:

• polyuria- 3-15 L/day

• SG < 1.005

• urine osmolality <200 mOsm/kg

• plasma osmolality > 287 mOsm/kg

• polydipsia

1.In uterus during parturition

2.In mammary gland during

lactation

Oxytocin

“Positive feedback loop”Oxytocin↑

Uterinecontraction

Cervixdilation

Labor

Oxytocin receptor↑x100

Estradiol

⊕⊕

Oxytocin secretion is stimulated by nursing

Oxytocin1. Childbirth – labor contractions – smooth muscle –

uterus

2. Lactating mothers – milk let-down effect

3. Surges –sexual arousal and orgasm – m & f

4. Feelings sexual satisfaction and emotional bonding

Control of oxytocin secretion• Stimuli:

• Stimulation of the “touch receptor”

1. Around the nipples Milk let-down or

“milk ejection reflex”

2. Genital tract stimulation

• Inhibition:

Neuroendocrine reflexes

• Infant suckling – hypothalamus – release OT = milk

ejection

• Cerebral cortex – trigger neuroendocrine reflexes

• Examples – lactating mother hears baby cry = milk

ejection reflex

Thyroid Gland First endocrine gland to be recognized.

Weighs about 15-25gm &has rich blood supply (4-6ml/gm/min).

Made up of multiple acini / follicles.

Between follicles “C cells/parafollicular cells ” are present Calcitonin.

Each follicle contains proteinaceous material called colloid which contains Thyroglobulin.

Follicular cells secrete T4 & T3.

Bio-synthesis :

i. Synthesis of thyroglobulin on ribosomes of ER.

ii. Iodide trapping.

T/P iodide ratio = 20-50:1

Trapping is brought by active transport (Iodide pump) which depends on Na+/k+ATPase.

TSH stimulates both iodide pump & Na+/k+ATPase.

Inhibited by Perchlorate, Thiocyanate.

iii. Oxidation of iodide ion:

Iodide converted to oxidised form of iodine , either nascent iodine (Io) or I3-

.

I- Ioor I3-.

Peroxidase H202

iv. Iodination of tyrosine & formation of thyroid hormones .

Binding of iodide with thyroglobulin is called “organification of thyroglobulin”.

Tyrosine Iodinase MIT & DIT

MIT + DIT T3 + Alanine.

DIT + DIT T4 + Alanine.

DIT + MIT rT3+ Alanine.

Coupling reactions

Thyroid peroxidase is probably involved in coupling & Iodination.

Thyroid Hormones

Storage of thyroglobulin (Tg):

Tg 30 T4 + few T3 molecules.

Large amount of thyroid hormones are stored in this form which is sufficient for 2-3 months.

Secretion of Thyroid Hormones

Stimulated by TSH Endocytosis of colloid on apical membrane Coupling of MIT & DIT residues

Catalyzed by TPO MIT + DIT = T3

DIT + DIT = T4

Hydrolysis of Thyroglobulin Release of T3, T4

Release inhibited by Lithium

Transport of thyroid hormones

Majority of circulating hormone is T4

98.5% T4

1.5% T3 Total Hormone load is influenced by serum

binding proteins (TBG, Albumin, TBPA) Thyroid Binding Globulin (TBG) 70% Albumin 15% Thyroid Binding PreAlbumin (TBPA) 10%

Regulation is based on the free component of thyroid hormone

Metabolism of Thyroid hormones

Actions of Thyroid hormones

♪ Metabolic actions.

♪On various systems.

♪On Growth.

♪ Interaction with Catecholamines.

1. Metabolic Actions :

A. Calorigenic

Increases O2 consumption & heat production by stimulating Na+-K+-ATPase (except in brain,spleen,

testes, uterus & Ant.pituitary).

Increases BMR.

Heat sensitivity inHyperthyroidism.

Some of calorigenic actions are due to lipolytic effect

BMR

K+ excretion

N2 excretion.

Vitamin deficiency

Uric acid & Urinary hexosamine excretion

B. Carbohydrate Metabolism :

Hyperglycemic.

Increase rate of reabsorption of glucose from GIT

Increases glycogenolysis in liver, muscle.

Increase gluconeogenesis.

Reduces secretion of insulin & accelerates its breakdown.

promotes Diabetes.

C. Fat metabolism :

Promotes cholesterol synthesis , but also promotes hepatic breakdown & biliary excretion of cholesterol.

Increases fecal excretion of cholesterol.

Reduction in plasma cholesterol levels.Causes lipolysis, promotes fatty acid oxidation by the cells.

i.e. breakdown > synthesis.

Therapeutically used to lower cholesterol levels

D. Protein metabolism :

Physiological doses stimulate both structural and functional protein synthesis.

Hyperthyroidismprotein catabolism.

Hypo decreased protein synthesis.

F. Electrolyte & water metabolism :Hyper+ve Mg++,-ve Ca2+,-ve Po4

- balance.

Hypo -ve Mg++,+ve Ca2+,+ve Po4- balance

E. Vitamin metabolism :

Converts ß carotenes to vit-A.

Hypo ß carotene accumulationyellowish skin.

Increases demand for coenzymes & vitamins.

2. On Various systems :

a.Blood :Stimulates erythropoiesis.

Hyperpolycythemia.

Hypo Normocytic normochromic & Megaloblastic anemia.

b. Cardio Vascular System :

c. Respiration :

Rate of metabolism

Utilization of O2 & formation of Co2

Rate & Depth of respiration.

d. GIT :Increases appetite & food intake.

Increases motility & secretions.

Hyper food intake motility Diarrhoea.

Hypo food intake motility Constipation.

e. Reproduction :Required for normal sexual & gonadal function.

In men :

Lack of TH’sloss of libido,oligospermia,sterility

Excess TH’s sometimes impotency.

In women :

Lack of TH’s Menorrhagia, polymenorrhoea, loss of libido, reduced fertility.

Helps in maintainence of milk secretion during lactation.

f. Skeletal muscle : Muscular weakness in both hyper &

hypothyroidism

Hypogeneralised depression of metabolism.

Hyper due to thyrotoxic myopathy which is due to

I. Excess TH’s break muscle proteins.

II. Excretion of creatine, less CP.

III. Heightened irritability of CNS.

g. On Sleep :Hyper constant tiredness & difficulty to sleep.

Hypo extreme somnolence with sleep sometimes lasting for 12 – 14 hours.

h. On Skin :Hyper Excess heat

Sweat production.

Cutaneous vasodilation.

Skin is soft , warm & wet.

Hypo skin is coarse, dry, scaly, cold & puffy.

Hypersensitive to cold.

i. On CNS :

Essential for normal development &growth of CNS.

In adult brain TH’s stimulate :

Branching of dendrites.

Myelination.

Increases no. of synapses.

In fetus & newborn stimulate growth of brain.

To assess function of CNS, reflex time is measured :

•Hyper Reflex time is shortened.

•Hypo Reflex time is prolonged.

wave frequency in EEG is reduced in Hypo & increased in Hyperthyroidism.

Some of effects on brain are probably 20 to increase responsiveness to catecholaminesstimulate RAS.

Growth & development of CNS :Thyroid & Ant.pituitary TSH system begins tofunction in fetus at about11weeks.Deficiency of TH’s during fetal & post natal life leads to “cretinism”.

Cretinism :Failure of normal growth & development of CNS.Delayed occurance of normal stages of child development

like holding head up, sitting, walking, speech.Anatomically brain is small & underdeveloped.Marked reduction in cerebral vascular bed.Decreased myelination, dendrite branching & decreased number of synapses.Deaf mutism & rigidity.Dwarfed, mentally retarded, pot bellies, protruding tongue

Hyperthyroidism

Increased excitabilityBecomes irritable, emotional, unstable, restless & anxious.Easily fatiguable.Fine rhythmic tremors in hands, tongue or eyeballs.

Hypothyroidism

Mental function is less.

Memory power is low.Somnolence.Slowness of thought & speech.Slow cerebration.Fatigue, depression.Coma on exposure to cold.

3. On growth :Required for normal growth & differentiation from the 1st day of newborn.

GH requires thyroxine to exert its full effect.

T3 has direct growth promoting effect .

4. Interaction with Catecholamines : TH’s sensitizes the tissues to catecholamines by increasing no. of receptors on cells.

ThyroidHormone Control

TRH Produced by Hypothalamus Release is pulsatile, circadian Downregulated by T4, T3

Travels through portal venous system to adenohypophysis

Stimulates TSH formation

TSH Produced by Adenohypophysis Thyrotrophs Upregulated by TRH Downregulated by T4, T3

Travels through portal venous system to cavernous sinus, body.

Stimulates several processes Iodine uptake Colloid endocytosis Growth of thyroid gland

Thyroid Function Tests Radio Active Iodine Uptake (RAIU). Estimation of serum total TH conc. TRH Levels. TSH Levels. BMR normal ±15% Serum Cholesterol Estimation. Reflex time. Biopsy & Scanning of thyroid gland.

Wolff-Chaikoff Effect Increasing doses of I- increase hormone synthesis

initially but higher doses cause cessation of hormone formation.

This effect is countered by the Iodide leak from normal thyroid tissue.

Jod-Basedow effect Aberration of the Wolff-Chaikoff effect Excessive iodine loads induce

hyperthyroidism Observed in several disease processes

Graves’ disease Multinodular goiter

Hypothyroidism Symptoms – fatigability, coldness, weight gain,

constipation, low voice Signs – Cool skin, dry skin, swelling of

face/hands/legs, slow reflexes, myxedema Newborn – Retardation, short stature, swelling of

face/hands, possible deafness Types of Hypothyroidism

Primary – Thyroid gland failure Secondary – Pituitary failure Tertiary – Hypothalamic failure

Causes :1.Congenital deficiency of the gland.2. Iodine deficiency in mother during pregnancy.3. Administration of Anti-Thyroid drugs during pregnancy.

Cretinism

Features : Periorbital puffiness Nose broad &flattened Eyes widely placed Tongue is large & protruding. Pot belly, sparse hair, umbilical hernia. Dwarf stature. Mentally retarded. IQ is very much less. Hypogonadism.

Myxedema :Features :Goiter Puffiness of face.Periorbital swelling.Loss of hair.Ptosis.Dry thick & rough & yellow skin.Low BMR.Hypersensitive to cold.Coarseness of eyes.Memory loss.Increase in serum cholesterol levels.

Hyperthyroid

Symptoms – Palpitations, nervousness, fatigue, diarrhea, sweating, heat intolerance

Signs – Thyroid enlargement (?), tremor

Lab workup TSH FT4 RAIU

Grave’s

Disease :

Features :Exopthalmosis.Goiter .Increased BMR.Heat intolerance.Thyrotoxic myopathy.Easy fatiguability.Osteoporosis.Skin warm, moist & soft.Tachycardia.Scanty periods.Thyroid diabetis.

Graves Most common cause of hyperthyroidism Result of anti-TSH receptor antibodies Diagnosis

Symptoms of hyperthyroidism Clinical exopthalmos and goiter Low TSH, normal/high FT4, anti-TSH Ab (Optional)

Treatments Medical – Propothyouracil, Methimazole, Propranolol Surgical – Subtotal Thyroidectomy Radiation

Calcium RegulationCalcium RegulationParathyroidParathyroid

CalciumCalcium Required for muscle contraction,

intracellular messenger systems, cardiac repolarization, hemostasis, membrane excitation, stabilisation of membrane, excitation secretion process of hormone & enzymes.

Exists in free (ionised) and bound states Albumin (40% total calcium) Phosphate and Citrate (10% total calcium)

Concentration of Ca2+ mediated by Parathyroid gland Parafollicular C cells Kidney & Bone.

Parathyroid gland

Parathyroid Parathyroid glands contains chief cells which secrete parathyroid hormone (PTH).

Its primary function is to keep the Ca2+ conc. In ECF & ICF constantly.

Actions :1.On Bones :

Increases plasma calcium & decreases plasma phosphate conc. by osteolytic effect.

Increases cAMPCa2+ entry into cell lactic acid & citric acid accumulates solubilises the bone Ca2+ is released.

cAMP itself causes resorption of Ca2+.

increases Osteoclast size, no. of osteoclast nuclei & osteoclast proliferation.

Hydrolyzes the organic bone matrix.

2. On Kidneys :Increases Ca2+ reabsorption from DCT.

Decreases Ca2+ excretion in urine.

Decreases reabsorption of phosphate from PCT & increases its excretion in DCT.

Promotes conversion of 25 HCC to 1,25 DHCC by activating 1 hydroxylase.Increases urinary excretion of Na+,K+,HCO3

-, & decreases excretion of NH4

+ & H+ causing metabolic acidosis.

3. On GIT :Enhances both Ca2+ & PO4

- absorption by increasing production of 1,25 DHCC.

Decreases Ca2+ conc. in milk, sweat, & GI fluids.

Regulation :

Stimulation of parathyroid

PTH

Mobilisation of Ca2+ from bones

Normal serum Ca2+

Serum Ca2+1.

2. Serum phosphate

PTH

Serum Ca2+

3. 1,25 DHCC 1/PTH Secretion

calcitonin•Secreted from “C cells/ parafollicular cells” of thyroid gland.

Actions : Decreases plasma Ca2+ & PO4

- conc.

Inhibits Osteoclast activity& its number.

Decreases renal formation of 1,25 DHCC.

Inhibits intestinal absorption of Ca2+ & PO4- .

Effect is greater in children than adults.

Regulation :

Vitamin-D

Plasma PO4- concentration

Hypoparathyroidism

Removal of parathyroid gland during thyroidectomy

Decreased serum ionised Ca2+conc. which results in tetany.

tetanyFeatures :

•Neuromuscular hyper excitability.

•Facial irritability (chovstek’s sign)

•Carpopedal spasm (Trousseaus sign)

•Visceral manifestations

•ECG changesST segment prolonged with abnormal T wave.

•Precipitate cataract formation.

Trousseau’s sign

Hyper parathyroidism Hyper parathyroidism

Primary tumours of parathyroid gland

Secondary as a compensation for hypocalcemia.

Features :Features : Weakness, lassitude, Hypotonia, thirst, Polyuria,

Anorexia, Nausea, Vomitting, Constipation

Nephrocalcinosis.

Demineralisation of bones producing painful bones

Multiple bone cysts (Osteitis fibrosa cystica) .

Increased plasma Alkaline Phosphatase conc.

rickets•Result of Vit-D deficiency.

•Causes : Inadequate intake of vit-D, Inadequate exposure to sun, kidney failure, liver dysfunction, defect in target cell receptors.

•Pathology : Deficiency in deposition of Ca2+ salts in bones, process of Ossification is abnormal.

Features :Deformed bones & bow legs.

Thickening of wrists & ankles.

Retarded growth, shortness of stature.

Delayed dentition.

Widening & cupping of epiphyseal cartilagenous plate.

Hypocalcemia, Hypotonia, Myopathy, Prominence of costochondral junction, Frontal bossing.

Osteomalacia Osteomalacia Adult rickets. Inadequate absorption of Ca2+ due to

deficiency of vit-D & Ca2+ in diet. Serum Ca2+ is low , 6-7mgs%. Mostly seen in females after multiple

pregnancies.

Features :Features : Bone pain & tenderness.

Fractures may occur.

Proximal Myopathy.

ADRENAL GLANDS

Adrenal Glands

Paired organs that cap the kidneys.

Each: outer cortex and inner medulla.

Adrenal cortex

Adrenal cortex:- stimulated by ACTH.- secretes corticosteroids- different regions secrete different hormones.- all made from cholesterol.

Adrenal Cortex

Corticosteroids include:- mineralocorticoids:- glucocorticoids - gonadocorticoids

Adrenal CortexMineralocorticoids: - aldosterone - targets kidneys - affects Na+ and K+ balance - stimulates transcription of Na+/K+ ATPase pump! - more aldosterone -> more Na+, water in body - stress -> CRH -> ACTH -> aldosterone ->

retain fluid -> high blood pressure!

Adrenal Cortex

Glucocorticoids (gc)- cortisol (aka hydrocortisone)- metabolism, more glucose in blood- stress -> large increase in gc- pharmacologically: suppress inflammation, asthma, rheumatoid arthitis

Adrenal Cortex

Gonadocorticoids:

-sex steroids

- include DHEA (precursor for estrogen, testosterone)

- not well understood

Aldosterone

Corticosterone

Deoxycorticosterone

18 OH Corticosterone

Progesterone

5 Pregnolone

Cholesterol

17 OH Pregnolone

17 OH Progesterone

Deoxycortisol

Cortisol

20,22 desmolase

DHEA

Androstenedione

Oestrone

Dihydrotestosteone

Androstenediol

Testosterone

Oestrodiol

5 Reductase

Cortisol Actions :

Metabolic actions.

On various systems.

Anti-inflammatory & Anti-immunity.

Stress adaptation.

Anti-growth effects.

Permissive actions.

1.Metabolic actions :

Carbohydrate metabolism :Carbohydrate sparing hormone, anti-insulin

effects.

Increases hepatic glycogenesis 6-10 fold.

Decreases rate of glucose utilization.

Adrenal Diabetis.

Impaired insulin action on tissues is due to its lipolytic effect.

Fat metabolism :Lipolytic .

Increases plasma FFA by promoting mobilisation of fatty acids from adipose tissue.

Enhances oxidation of fatty acids in the cells.

Protein metabolism :catabolic.

Reduces protein stores in all cells except in liver.

Increases liver & plasma proteins

Electrolyte & H20 metabolism :

Actions similar to Aldosterone, less potent.

Retention of Na+ & Cl-.

Excretion of K+ .

Maintains ECF volume, provides adequate GFR

Promotes diuresis by antagonising actions of ADH by destroying it.

2. On various Systems :

1.Blood : Lack of cortisol leads to Lymphocytosis, Eosinophilia, Neutropenia, Anaemia.

Increases platelet count & shortens blood clotting time.

2.CVS :

Required for maintenance of normal BP.

Improves myocardial performance by blocking Na+-Ca++ exchanger.

Permissive action to catecholamines & A-II

3. Renal :Increases GFR by decreasing preglomerular

resistance & by increasing RPF.

Essential for rapid excretion of water load.

Increases Ca++ & P04– excretion.

Generates NH4+ from glutamate in response to

acid loads.

4.GIT :

Promotes peptic ulcer formation.

Promotes absorption of water insoluble fats .

Decreases gastric mucosa cell proliferation.

5.Muscle :Maintains the contractility & work performance of

skeletal and cardiac muscle.

Increases ß adrenergic receptors in myocardium.

6. Connective tissue :Inhibits collagen synthesis and produces thinning of skin and walls of capillaries.

7. CNS :

Modulates excitability & behaviour.

Required for initiation & maintainence of REM sleep and accompanying easy arousability.

8.Bone :Increases bone resorption .

Decreases the systemic &local generation of IGF-1 molecules.

Antagonizes the action of Vit-D.

9. On Foetus :

Facilitates inutero maturation of CNS, retina, skin, GIT & lungs.

Increases rate of development of alveoli, flattening of lining cells, increases surfactant ynthesis.

3. Anti-inflammatory & anti-immunity action :

4. Stress adaptation :

Stress ACTH Cortisol

5. Permissive actions :Permissive actions of cortisol include

1.Glucagon & catecholamines to exert calorigenic effects.

2.Catecholamines to exert lipolytic effects.

3.Catecholamines to produce pressor respones & bronchodilation.

6. Anti-growth Effect :Large doses of vit-D antagonize action of vit-D

1.Decreases Ca++ reabsorption.

2.Inhibit mitosis of fibroblasts.

3.Cause degradation of collagen.

Osteoporosis Delays wound healing

Large doses leads to muscular weakness & atrophy.

Regulation of Cortisol secretion :

Cushing syndromeHypercortisolism.

It is a clinical disorder which results from the exposure of body tissues to sustained supraphysiological blood levels of corticosteroids, either endogenous in origin or iatrogenically produced.

Causes :

1. ACTH dependent causes

Bilateral adrenocortical hyperplasia.

Benign or malignant ACTH secreting

tumours.

Iatrogenic treatment with ACT

2. Non-ACTH dependent causes :

Adenomas or carcinomas of adrenal cortex.

Iatrogenic pharmacological doses of corticosteroids.

Cushing’s SyndromeCushing’s Syndrome– Central obesity– Moon face– Buffalo hump – Thin skin, easy bruising– Osteoporosis – Diabetes

– Excess hair growth– Irregular periods– Problems conceiving– Impotence

– High blood pressure– Fluid retention

changes in protein and fat metabolism

changes in sex hormones

salt and water retention

Cushing’s Syndrome

Treatment Treatment • Aminoglutethimide• Metyrapone• Ketoconazole• Etomidate• Trilostane• Octreotide

Aldosterone

Corticosterone

Deoxycorticosterone

Progesterone

5 Pregnolone

Cholesterol

18 OH Corticosterone

17 OH Pregnolone

17 OH Progesterone

Deoxycortisol

Cortisol

DHEA

Androstenedione

Oestrone

Dihydrotestosteone

Androstenediol

Testosterone

Oestrodiol

20,22 desmolase

17 OH

21 OH 21 OH

11 OH

18 OH

18 Oxidase

11 OH

17 HSO

3 HSD

5 Reductase17,20,

desmolase

17 HSO

3 HSD3 HSD3 HSD

Aminoglutethimide

MetyraponeKetoconazole

TrilostaneEtomidate

AldosteroneAldosterone

Produced in the zona glomerulosa of the adrenal cortex

Acts on the kidney via receptor binds glucocorticoids with equal affinity

Progesterone

5 Pregnolone

Cholesterol

17 OH Pregnolone

17 OH Progesterone

Cortisol

Androgens

Oestrogens

20,22 desmolase

17 OH3 HSD

17,20, desm

olase

3 HSD

Aldosterone

Corticosterone

Deoxycorticosterone

18 OH Corticosterone

21 OH

11 OH

18 OH

18 Oxidase

Aldosterone actions 1.Na+ & H2O reabsorption on CD & late DCT.

2. K+ secretion with Na+ reaborption.

3. H+ secretion with Na+ reaborption.

4. NH4+ excretion .

5. Stimulates Mg++ excretion.

6. Infusion of small doses causes increase BP.

7. Enhances Na+ absorption especially in colon, which prevents loss of Na+ in stools.

Control of Aldosterone Control of Aldosterone ReleaseRelease

ADRENAL CORTEXAldosterone

ECV K+

ReninRenin Substrate

(Angiotensinogen)

Angiotensin I

Angiotensin II

decrease BP Δ Na+

Macula DensaSNS Activity

ACE

ACTH

K+

Aldosterone SyndromesAldosterone Syndromes

Over production Conn’s Syndrome

Underproduction Addison’s Syndrome Congenital Adrenal

Hyperplasia

Primary Aldosteronism :Conn’s Syndrome It is a condition in which there is prolonged excessive secretion of aldosterone from an adrenocortical adenoma .

Features :

Hypernatremia, Hypokalemia, Hypervolemia, Hypertension.

Polyuria, Polydypsia.

Absence of edema, Alkalosis, Muscular weakness.

Secondary Aldosteronism : It is a condition in which oversecretion of Aldosterone is brought about by extra adrenal factors.

Features are same as primary aldosteronism except that edema is present.

Treatment :Spironolactones.

ACE inhibitors.

Amiloride diuretic.

Adrenogenital syndrome or Virilism :• Adrenocortical tumors secreting excessive quantities of androgens that cause intense musculinizing effects throughout the body.

•In females develops virile characters.

• Occasionally adrenal tumors secrete Estrogens to produce feminization in males , with enlargement of breasts, atrophy of testes and diminished sexual interest in woman.

Adrenal cortex Insufficiency Destruction of adrenal cortex

Eg: Addison disease.

Diminished secretion of ACTH due to Adenohypophyseal or Hypothalamic failure

Congenital failure of Cortisol secretion due to defects in the enzymes responsible for its synthesis.

Addison’s disease :• Chronic deficiency of both Mineralocorticoids and Glucocorticoids due to destruction of adrenal cortex.

Features :Muscular weakness.

Hypoglycemia, Hypovolemia, Hypotension.

Anemia.

Resistance to stress &infection

Disturbed electrolyte balance.

Anorexia, Nausea, Vomiting, & Weight loss.

Sometimes Vitiligo, change in pigmentation of skin.

Treatment : Replacement therapy with both Gluco & Mineralocorticoids.

Dexamethasone , Betamethasone, Prednisolone, Fludrocortisone.

Adrenal Medulla

Adrenal medulla:Derived from embryonic neural crest

ectoderm (same tissue that produces the sympathetic ganglia).

Controlled by preganglionic sympathetic innervation(is like a postganglionic neuron!)

Secretes adrenaline (aka epenephrine) (also secretes norepenephrine)

Bio-synthesis

Metabolism :

Actions :1.Intracellular actions :

• Adrenaline & NA produce different effects depending on type of Adrenergic receptors alpha & beta.

Effector organ Receptor Response

1.Eyeradial muscle contraction

Ciliary muscle ßRelaxation.

2. Metabolic actions :

•Both stimulates Gluconeogenesis, Glycogenolysis, Muscle Glycogenolysis i.e. Hyperglycemic. Adrenaline is more potent than NA.

•Both are lipolytic . NA is more potent than adrenaline.

3. On CVS :•Both increase force & rate of contraction of isolated heart.

•Increases myocardial excitability.

•NA produces vasoconstriction in most organs but Adrenaline dilates blood vessels in skeletal muscles & liver.

•When NA is infused slowly causes increase in both SBP &DBP, Pulse pressure, peripheral resistance and decreases heart rate & Cardiac output.

•Adrenaline causes increase in SBP, Pulse pressure,Heart rate & Cardiac output & Decreases DBP & peripheral resistance.

4. On CNS :

•Produces Anxiety, Apprehension, initial stimulation of breathing, Coarse tremors of extremities.

•Do not cross blood brain barrier.

5. On BMR :

•Increases BMR by 7-15%, also increases non shivering thermogenesis and diet induced thermogenesis.

•Epinephrine is important part of response to cold exposure& helps to regulate overall energy balance and energy stores.

6. On Blood :

•Increases RBC & Hb levels due to shift of stored RBC to circulating pool.

•WBC count increases due to shift of marginated pool to circulating pool.

7. On Skeletal muscle :

•Adrenaline increases muscular blood flow.

•Has Anticurare effect.

•Increases force of contraction.

8. Other effects :•Inhibits GI motor activity.

•Relaxation of bronchioles to improve gas exchange.

•Dilatation of pupils.

•Increases renin release from kidneys.

•Enhances thyroid hormone secretion.

•Adrenaline stimulates influx of potassium into muscle cells.

Actions of Dopamine•Causes vasodilation of renal & Splanchnic vessels and vasoconstriction in other areas.

•Positive Ionotrophic effect on heart.

•Moderate doses increase SBP and no change in DBP.

•Causes Natriuresis and may exert this effect by inhibiting renal Na+-K+ATPase.

Applied Aspects

Hyposecretion •Occurs during TB &malignant destruction of adrenal glands following Adrenalectomy.

•Produces probably no symptoms or other clinical features.

Parkinsonism :•Due to deficiency of Dopamine.

Hypersecretion Phaeochromocytoma :•A tumor consisting of Adrenal medullary tissue is called Phaeochromocytoma.

•Occurs in less than 1% of all cases of arterial hypertension, their diagnosis is important because they produce a type of hypertension which can be cured by surgery.

Physical features of Patient : Looks Anxious .

Skin is pale , cool, moist.

Pupils dilated.

Increase heart rate, but in some patients Bradycardia

Occurance of extrasystoles.

Increased BP, Occasionally 300/200mmHg.

Body temperature rised, Hyperglycemia, Increased BMR.

Treatment :Surgical removal of adrenomedullary tumor.

-receptor blocking drugs Ergot alkaloids, Phentolamine, Phenoxybenzamine.ß-receptor blockers PropanololReserpine depletes tissues of their stores of 5-HT & Catecholamines.

Regulation of Adrenomedullary secretion :

Adrenal Medulla

Adrenal medulla:Derived from embryonic neural crest

ectoderm (same tissue that produces the sympathetic ganglia).

Controlled by preganglionic sympathetic innervation(is like a postganglionic neuron!)

Secretes adrenaline (aka epenephrine) (also secretes norepenephrine)

Bio-synthesis

Metabolism :

Actions :1.Intracellular actions :

• Adrenaline & NA produce different effects depending on type of Adrenergic receptors alpha & beta.

Effector organ Receptor Response

1.Eyeradial muscle contraction

Ciliary muscle ßRelaxation.

2. Metabolic actions :

•Both stimulates Gluconeogenesis, Glycogenolysis, Muscle Glycogenolysis i.e. Hyperglycemic. Adrenaline is more potent than NA.

•Both are lipolytic . NA is more potent than adrenaline.

3. On CVS :•Both increase force & rate of contraction of isolated heart.

•Increases myocardial excitability.

•NA produces vasoconstriction in most organs but Adrenaline dilates blood vessels in skeletal muscles & liver.

•When NA is infused slowly causes increase in both SBP &DBP, Pulse pressure, peripheral resistance and decreases heart rate & Cardiac output.

•Adrenaline causes increase in SBP, Pulse pressure,Heart rate & Cardiac output & Decreases DBP & peripheral resistance.

4. On CNS :

•Produces Anxiety, Apprehension, initial stimulation of breathing, Coarse tremors of extremities.

•Do not cross blood brain barrier.

5. On BMR :

•Increases BMR by 7-15%, also increases non shivering thermogenesis and diet induced thermogenesis.

•Epinephrine is important part of response to cold exposure& helps to regulate overall energy balance and energy stores.

6. On Blood :

•Increases RBC & Hb levels due to shift of stored RBC to circulating pool.

•WBC count increases due to shift of marginated pool to circulating pool.

7. On Skeletal muscle :

•Adrenaline increases muscular blood flow.

•Has Anticurare effect.

•Increases force of contraction.

8. Other effects :•Inhibits GI motor activity.

•Relaxation of bronchioles to improve gas exchange.

•Dilatation of pupils.

•Increases renin release from kidneys.

•Enhances thyroid hormone secretion.

•Adrenaline stimulates influx of potassium into muscle cells.

Actions of Dopamine•Causes vasodilation of renal & Splanchnic vessels and vasoconstriction in other areas.

•Positive Ionotrophic effect on heart.

•Moderate doses increase SBP and no change in DBP.

•Causes Natriuresis and may exert this effect by inhibiting renal Na+-K+ATPase.

Applied Aspects

Hyposecretion •Occurs during TB &malignant destruction of adrenal glands following Adrenalectomy.

•Produces probably no symptoms or other clinical features.

Parkinsonism :•Due to deficiency of Dopamine.

Hypersecretion Phaeochromocytoma :•A tumor consisting of Adrenal medullary tissue is called Phaeochromocytoma.

•Occurs in less than 1% of all cases of arterial hypertension, their diagnosis is important because they produce a type of hypertension which can be cured by surgery.

Physical features of Patient : Looks Anxious .

Skin is pale , cool, moist.

Pupils dilated.

Increase heart rate, but in some patients Bradycardia

Occurance of extrasystoles.

Increased BP, Occasionally 300/200mmHg.

Body temperature rised, Hyperglycemia, Increased BMR.

Treatment :Surgical removal of adrenomedullary tumor.

-receptor blocking drugs Ergot alkaloids, Phentolamine, Phenoxybenzamine.ß-receptor blockers PropanololReserpine depletes tissues of their stores of 5-HT & Catecholamines.

Regulation of Adrenomedullary secretion :

pancreas Located in the curve of duodenum.Has both Exocrine & Endocrine function.Secretes major hormones Insulin & Glucagon and Amylin, Pancreastatin, Somatostatin, Pancreatic polypeptide minor role.Four types of cells, ß, D, F cells.

cells Glucagon ß cells Insulin Delta cells Somatostatin. F or PP cells Pancreatic polypeptide.

Insulin•Polypeptide containing two chains ( &ß) linked by disulfide bridges.•A chain21aa’s & B chain 30aa’s.•Biological activity resides in B chain.

Biosynthesis :• Synthesized in ER of ß cells.•Pre proinsulin Pro insulinInsulin

Insulin secretion :

Increased DecreasedD-glucose .Proteins.Keto acids , FFA.K+, Ca++

Glucagon.Gastric Inhibitory Peptide.Secretin, Cholecystokinin.Vagal activity, Ach.Sulfonyl urea drugs.

Fasting.ExerciseSomatostatin.Galanin.Pancreastatin, Leptins.Prostaglandin E2

K+ depletion.Thiazide diuretics.Insulin.

Mechanism of Action :

Actions :1.Metabolic actions : Carbohydrate

metabolism On liver On muscle On adipose tissue

Promotes glycogenesis & glycolysis.

Inhibits glycogenolysis & gluconeogenesis

Stimulates transport of glucose into cells.

Stimulates glycogenesis.

Increase muscle blood flow

Stimulates transport of glucose into adipose tissue.

Glucose is converted into glycerophosphate & fatty acids (minor)

Fat metabolism :

On liver On muscle On adipose tissueLipogenic & Anti-ketogenic.Glucose converted to fatty acidsFavours Cholesterol synthesisDecreases Apolipoprotein-B synthesis.

Suppresses lipoprotein lipase

Inhibits lipolysis.

Inhibits FFA uptake, Oxidation.

Inhibits Hormone Sensitive Lipase.

Stimulates use of keto acidsPromotes deposition of fat into adipose tissue.

Protein metabolism :•Anabolic hormone.•Stimulates Na+dependent transport of neutral aa’s across cell membrane in muscle.•Increases gene transcription.•Contributes to body growth by stimulating synthesis of macromolecules in bone, cartilage & stimulates transcription of growth factors such as IGF-I

Electrolyte metabolism :•Stimulates uptake of K+, Po4

-, Mg++ by cells.•Regulates K+ balance.•Increases renal reabsorption of K+, Po4

-, Mg++.

2. On CNS :Selected areas of brain (hypothalamus) requires insulin.Injection of insulin into cerebral ventricles decreases food intake.Continuous insulin excess increase body wt.& adipose mass increase leptin levels induces satiety.

3. On blood vessels : Overall vasodilator effect mediated by increase in NO synthesis.

4. Autocrine effects : ß cells also possess insulin receptors.

Essential for development of normal size islets and for glucose stimulated insulin release.

5. On Growth :• Essential for growth of an animal as GH is.•Insulin & GH acts synergistically to promote growth, each performing a specific function.

Regulation of Insulin secretion1. Substrate stimulation :by a feedback relationship with exogenous nutrient supply.

2. Hormonal control : GI hormones Glucagon, Secretin, CCK,

GIP,GLP-I. Glucagon. Growth hormone. Cortisol. Thyroid hormones. Human Placental Lactogen.

3. Electrolytes : K+ & Ca++. Mg++ has a modulatory effect.

4. Neural control : Parasympathetic Increases secretion. Sympathetic Decreases secretion.

5. Oral Hypoglycemic agents :• Tolbutamide.• Sulfonylurea drugs ( Glipizide, Glyburide,

Tolazamide).• Biguanides Penformin, metformin acts in

absence of insulin.

Diabetes mellitus

A clinical state which is associated with flow of sugar in urine which is due to deficiency of Insulin .

Causes : Insulin deficiency.

Increase in levels of antagonistic hormones (GH, Glucagon, Catecholamines, Cortisol).

Hereditary, Age, Obesity, Drugs like Alloxan, Streptozoticin etc…

Signs & Symptoms :•Hyperglycemia.•Glycosuria.•Polyuria.•Polydipsia.•Polyphagia.•Dehydration.•Loss of weight.•Ketonuria.•Poor resistance to infections.

Complications : Atherosclerosis. Microangiopathy :

Neuropathy Retinopathy Nephropathy Dermatopathy.

glucagon Promotes mobilisation rather than storage of fuels, especially glucose.

Actions opposite to insulin.

Actions :Have no influence on glucose uptake by peripheral tissues.Increases glycogenolysis & gluconeogenesis in liver.Lipolytic & Ketogenic hormone.Inhibits storage of Tg’s in liver.Have calorigenic action.Glucagon in very high conc. Causes +ve ionotrophic effect, increase blood flow to tissues, inhibits gastric acid secretion, enhances bile secretion.

causes natriuresis.Has a role in appetite.Stimulates secretion of Insulin, GH, Pancreatic somatostatin.

Regulation of Glucagon secretion

Stimulators InhibitorsAmino acids (Glucogenic).CCK, Gastrin.CortisolExerciseBeta adrenergic stimulators.Theophylline.Acetyl choline.

Glucose.SomatostatinSecretinFFA, Ketones.Insulin.GABAAlpha adrenergic stimulators

Glucagon secretion