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PathophysiologyPathophysiology of of thth E d i S tE d i S tthethe Endocrine SystemEndocrine System

B. Marinov, MD, PhDB. Marinov, MD, PhD

Pathophysiology Department Pathophysiology Department Medical University of PlovdivMedical University of Plovdiv

Endocrine system

Central:Central:

HypothalamusHypothalamus

PituitaryPituitary

PinealPineal

PeripheralPeripheral ThymusThymus

ThyroidThyroid

ParathyroidParathyroid ParathyroidParathyroid

AdrenalAdrenal

Endocrine pancreasEndocrine pancreas

Ovaries Ovaries

TestesTestes

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HormonesHormones

Definition: Hormones are chemical messengers secreted

Chemically hormones are of Chemically hormones are of three basic typesthree basic types::

by endocrine organs and transported throughout the body where they exert their action on specific cells called target cells.

SteroidSteroid (glucorticoids and mineral corticoids).(glucorticoids and mineral corticoids).

MonoacidsMonoacids analoganalog--derivated from amino acid tyrosine derivated from amino acid tyrosine (T3 and T4)(T3 and T4)

PeptidesPeptides (ACTH, TSH or ADH)(ACTH, TSH or ADH)

Mechanism of hormonal action

1. Polypeptide hormones &

catecholaminesMembrane receptor,

activating of G-protein and change in enzyme activity

2. Steroid hormones & T3/T4 Cytoplasmatic receptor

influencing gene expression

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Functional rangeFunctional rangeof the endocrine systemof the endocrine system

Response to stress and injury.Response to stress and injury.

Behavioral reactionsBehavioral reactions

Growth and development.Growth and development.

ReproductionReproduction Reproduction.Reproduction.

HomeostasisHomeostasis

Energy metabolism.Energy metabolism.

ModulationModulation

Hormones

Growth Development Reproduction

Inteligence

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HypothalamusHypothalamus--

pituitarypituitary--

peripheral glandsperipheral glandsinteractionsinteractionsinteractionsinteractions

HormonesHormones,,released from the anterior pituitaryreleased from the anterior pituitary

Anterior pituitary (Adenohypophysis)

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Acromegaly Gigantism

Occurs during adulthood Begins during childhood

WHY are patients who suffer gigantism taller than those who suffer acromegaly?

HormonesHormonesreleased from of posterior pituitaryreleased from of posterior pituitary

Antidiuretic hormone(ADH)

Oxytocin

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Feedback loop mechanism

Negative feedback mechanismNegative feedback mechanism

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Possitive feed back mechanismPossitive feed back mechanism

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Primary endocrinopathyPrimary endocrinopathy

With hypofunctionWith hypofunctionAplasia & HypoplasiaAplasia & HypoplasiaDamageDamage ((autoimmuneautoimmune))YatrogenicYatrogenic

With hyperfunctionWith hyperfunctionHyperplasiaHyperplasiaTumorTumor

With dysfunctionWith dysfunction

Primary endocrinopathy

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Secondary endocrinopathy Secondary endocrinopathy

Altered feedback loopsAltered feedback loops

Altered transportAltered transport ((Proteins, AbProteins, Ab))

Receptor defectsReceptor defects (10(1033--101055)*)*

Alt d h l i t tiAlt d h l i t ti Altered hormonal interactionsAltered hormonal interactions((permissive effectspermissive effects))

* up- and down- regulation

Secondary endocrinopathy

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Endocrine dysfunctions Endocrine dysfunctions Can be divided into five broad categoriesCan be divided into five broad categories

Subnormal hormonal productionSubnormal hormonal production, resulting from malformation, or , resulting from malformation, or absent of the endocrine glands, or the gland could be diseased, or absent of the endocrine glands, or the gland could be diseased, or destroyed or secretions are block.destroyed or secretions are block.

Hormonal excessHormonal excess tends to caused severe disease.tends to caused severe disease.

Production of abnormal hormoneProduction of abnormal hormone cause by a gene cause by a gene mutation.mutation.

Disorder of hormonal receptorsDisorder of hormonal receptors..

Ab li f h lAb li f h l b li (l k fb li (l k f Abnormality of hormonal transportAbnormality of hormonal transport or metabolism (lack of or metabolism (lack of protein to bind the hormones, results in increase free level of protein to bind the hormones, results in increase free level of the hormone)the hormone)

Mechanisms of endocrine diseaseMechanisms of endocrine disease

Endocrine disorders result from hormone Endocrine disorders result from hormone d fi i h hd fi i h hdeficiency, hormone excess or hormone deficiency, hormone excess or hormone resistanceresistance

Almost without exception, hormone Almost without exception, hormone deficiency causes diseasedeficiency causes disease One notable exception is calcitonin deficiencyOne notable exception is calcitonin deficiency One notable exception is calcitonin deficiencyOne notable exception is calcitonin deficiency

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DeficiencyDeficiency usually is due to destructive processusually is due to destructive process

Mechanisms of endocrine Mechanisms of endocrine diseasedisease

DeficiencyDeficiency usually is due to destructive process usually is due to destructive process occurring at gland in which hormone is produced occurring at gland in which hormone is produced —— infection, infarction, physical compression by infection, infarction, physical compression by tumor growth, autoimmune attacktumor growth, autoimmune attack

Adison’s disease

Mechanisms of endocrine Mechanisms of endocrine diseasedisease

Hormone excess may be due to overproduction Hormone excess may be due to overproduction by gland that normally secretes it or by a tissueby gland that normally secretes it or by a tissueby gland that normally secretes it, or by a tissue by gland that normally secretes it, or by a tissue that is not an endocrine organ. that is not an endocrine organ.

Endocrine gland tumors produce hormone in an Endocrine gland tumors produce hormone in an unregulated manner. unregulated manner.

Cushing’s Syndrome

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Mechanisms of endocrine Mechanisms of endocrine diseasedisease

Alterations in receptor number and Alterations in receptor number and f tif ti lt ilt i d i di dd i di dfunctionfunction result in eresult in endocrine disordersndocrine disorders

Most commonly, an aberrant increase in Most commonly, an aberrant increase in the level of a specific hormone will cause a the level of a specific hormone will cause a decrease in available receptorsdecrease in available receptors

Type II diabetes

Thyroid glandThyroid gland

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Thyroid hormonesThyroid hormones

The glands contain two The glands contain two types of cellstypes of cells

T3=9% of the hormone T3=9% of the hormone secreted is in active form.secreted is in active form.types of cellstypes of cells

Follicular cells which Follicular cells which produce T3 and T4produce T3 and T4

Parafocicullar cells Parafocicullar cells which secrete which secrete thyrocalcitoninthyrocalcitonin

secreted is in active form.secreted is in active form.

T4=90% of the hormone T4=90% of the hormone secreted is bounded to secreted is bounded to protein as a storage form; protein as a storage form; this form is inactive until this form is inactive until converted to T3converted to T3yy converted to T3.converted to T3.

Thyroid hormones - functions

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Pathophysiologic variants of

hypofunction

Hypothyroidism Hypothyroidism -- etiologyetiology

PrimaryPrimary ((thyroidthyroid) ) hypothyroidismhypothyroidism

L f f ti l th id tiL f f ti l th id tiLoss of functional thyroid tissueLoss of functional thyroid tissue

Chronic autoimmune thyroiditisChronic autoimmune thyroiditis

Transitory autoimmune thyroiditisTransitory autoimmune thyroiditis

131131I and external radiation therapyI and external radiation therapy

Postoperative hypothyroidismPostoperative hypothyroidism

Transitory hypothyroidismTransitory hypothyroidism

Infiltrative involvement of the thyroid glandInfiltrative involvement of the thyroid gland

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Hypothyroidism Hypothyroidism -- etiologyetiology

Biosynthetic defectsBiosynthetic defects

Hereditary defectsHereditary defects

Iodine deficiencyIodine deficiencyyy

Iodine excessIodine excess

Antithyroid factorsAntithyroid factors

CentralCentral (secondary)(secondary) hypothyroidismhypothyroidism

Hypothyroidism Hypothyroidism -- etiologyetiology

PituitaryPituitary

HypothalamicHypothalamic

Generalized resistance to thyrid Generalized resistance to thyrid hormoneshormones

Drugs: Dopamine, Amiodarone, LithiumDrugs: Dopamine, Amiodarone, Lithium

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Signs and symptoms of hypothyroidismSigns and symptoms of hypothyroidism

Exhaustion

Depression

Dry coarse skin

Cold intolerance

Constipation Constipation

Weight gain

Mental retardationMental retardation ((IQIQ<75)<75)

Class IQ

Profound mental retardation Below 20

Severe mental retardation 20–34

Moderate mental retardation 35–49

Mild mental retardation 50–69

Borderline mental retardation 70–79

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Hyperfunction of the thyroid Hyperfunction of the thyroid glandgland

ThyreotoxicosisThyreotoxicosis=

T3 and T4 ↑

HyperthyroidismEctopic thyroid

hormone productionHyperthyroidism

Primaryor

Secondary

hormone production

Pathophysiologic variants of

hyperfunction

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HyperthyroidismHyperthyroidism

Definition: Excess of TH in the bodyDefinition: Excess of TH in the body

Causes increase in metabolic rateCauses increase in metabolic rate

Cardiac rate and stroke volume Cardiac rate and stroke volume Peripheral blood flow Peripheral blood flow Oxygen consumption Oxygen consumption Body temperature Body temperature

HyperthyroidismHyperthyroidism

Grave’s disease (Basedow)Grave’s disease (Basedow) Grave s disease (Basedow)Grave s disease (Basedow)

Toxic adenomaToxic adenoma

Iodine induced hyperthyroidismIodine induced hyperthyroidism

Hyperthyroidism due to ectopic TSH Hyperthyroidism due to ectopic TSH productionproductionproductionproduction

Inappropriate TSH secretionInappropriate TSH secretion

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Disease of Graves (Basedow) - pathogenesis

Signs and sysmptoms of Signs and sysmptoms of

hyperthyroidismhyperthyroidism

FatigueFatigue

Difficulty sleepingDifficulty sleeping

Hand tremorsHand tremors

Weight loss despite Weight loss despite increase appetiteincrease appetite

HoarsenessHoarseness

DyspneaDyspnea

TachycardiaTachycardia

Increase blood volumeIncrease blood volume

increased COincreased CO Skin =warm, moist, Skin =warm, moist,

smooth,flushedsmooth,flushed

Amenorrhea Amenorrhea

PalpitationsPalpitations

ExophthalmosExophthalmos

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Patients with Patients with hyperthyroidismhyperthyroidism

Ectopic thyroid hormone Ectopic thyroid hormone productionproduction

Drug induced (yatrogenic) Drug induced (yatrogenic) thyreotoxicosisthyreotoxicosis

FunctionallyFunctionally--active metastases of active metastases of thyroid carcinomathyroid carcinomathyroid carcinomathyroid carcinoma

Struma ovariiStruma ovarii

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The adrenal glandsThe adrenal glands

The adrenal glands are bilaterally located The adrenal glands are bilaterally located b h kid d i t f tb h kid d i t f tabove each kidney and consist of two above each kidney and consist of two

tissues in one gland:tissues in one gland:

CortexCortex --outer layerouter layer

MedullaMedulla -- inner portioninner portion MedullaMedulla inner portioninner portion

Functional morphology

of the adrenal glandsglands

75%

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Adrenal medullary hormones

Disorder of the adrenal medullaDisorder of the adrenal medulla

Pheochromocytoma a benign tumor of the Pheochromocytoma a benign tumor of the adrenal medulla leading to hyper productionadrenal medulla leading to hyper productionadrenal medulla leading to hyper production adrenal medulla leading to hyper production of epinephrine and nonepinephrin.of epinephrine and nonepinephrin.

Ectopic cells in the abdomen or along the Ectopic cells in the abdomen or along the gangliaganglia

•• Excess of adrenal medulla hormonesExcess of adrenal medulla hormones

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Pheochromocytoma: An Overview

Variants of adrenal gland abnormal Variants of adrenal gland abnormal functionfunction

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Disorders of the adrenal cortex.Disorders of the adrenal cortex.

Cushing’s SyndromeCushing’s Syndrome•• Caused by excess of cortisol production or byCaused by excess of cortisol production or by•• Caused by excess of cortisol production or by Caused by excess of cortisol production or by

excessive use of cortisol or other similar steroid excessive use of cortisol or other similar steroid (glucorticoid)(glucorticoid)

Addison’s DiseaseAddison’s Disease•• Addison’s disease is a severe or total deficiency of Addison’s disease is a severe or total deficiency of

the hormones made in the adrenal cortex causethe hormones made in the adrenal cortex causethe hormones made in the adrenal cortex, cause the hormones made in the adrenal cortex, cause by a destruction of the adrenal cortex.by a destruction of the adrenal cortex.

Etiology of Cushing’s Etiology of Cushing’s SyndromeSyndrome

Endogenous or exogenous.Endogenous or exogenous. Tumors: oat cell carcinomas, renal, Tumors: oat cell carcinomas, renal,

ovarian,lungs, thymus, pancreas or other ovarian,lungs, thymus, pancreas or other organs organs

Chronic administration of glucocorticoids or Chronic administration of glucocorticoids or ACTH or iotrogenic cause.ACTH or iotrogenic cause.

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Etiology of Cushing’s SyndromeEtiology of Cushing’s Syndrome

A pituitary tumor producing ACTH A pituitary tumor producing ACTH ti l ti th d l t thti l ti th d l t thstimulating the adrenals to growth stimulating the adrenals to growth

(hyperplasia) and to produce too much (hyperplasia) and to produce too much cortisol.cortisol.

It is the most common type and is called It is the most common type and is called ypypCushing’s disease. It is the cause of 70% of Cushing’s disease. It is the cause of 70% of spontaneous Cushing’s syndrome.spontaneous Cushing’s syndrome.

Signs and Symptoms of Cushing’s Signs and Symptoms of Cushing’s SyndromeSyndrome

HypertensionHypertension KetosisKetosis HypertensionHypertension

HypervolemiaHypervolemia

HyperglycemiaHyperglycemia

KetosisKetosis

ImmunosupressionImmunosupression

OsteoporosisOsteoporosis

Hypokalemia Hypokalemia Emotional liabilityEmotional liability

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Cushing syndrome

Clinical signs of Cushing syndrome

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Buffalo hump and moon faceBuffalo hump and moon face

Addison’s DiseaseAddison’s Disease

Hypofunction of the adrenal cortex.Hypofunction of the adrenal cortex.

Autoimmune reaction in which the body immune Autoimmune reaction in which the body immune system erroneously makes antibodies against the system erroneously makes antibodies against the cells of the adrenal cortex and slowly destroys it.cells of the adrenal cortex and slowly destroys it.

Other rare infections can causes Addison ‘s Other rare infections can causes Addison ‘s disease : TB, CMV, fungal infections, and adrenal disease : TB, CMV, fungal infections, and adrenal cancer.cancer.

Rare disorder can occur at any age; most common Rare disorder can occur at any age; most common among adult white womenamong adult white women

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Addison’s Disease etiologyAddison’s Disease etiology

PrimaryPrimary adrenal insufficiency is caused by adrenal insufficiency is caused by gradual destruction of the outer layer of gradual destruction of the outer layer of the adrenal glands by the body own the adrenal glands by the body own immune system. immune system.

Lack or decreased glucocorticoid and Lack or decreased glucocorticoid and i l ti idi l ti idmineral corticoid.mineral corticoid.

Addison’s Disease etiologyAddison’s Disease etiology

SecondarySecondary adrenal insufficiency results from adrenal insufficiency results from deficient pituitary ACTH secretion from deficient pituitary ACTH secretion from dysfunction or destruction of hypothalamus or dysfunction or destruction of hypothalamus or the anterior pituitary gland. the anterior pituitary gland.

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Signs and symptons of Signs and symptons of addison’saddison’s

Ch i f tiCh i f ti N / itiN / iti Chronic fatigue Chronic fatigue

Muscle weaknessMuscle weakness

Loss of appetite Loss of appetite

Nausea/vomiting.Nausea/vomiting.

Low blood Pressure Low blood Pressure

Hyperpigmentation Hyperpigmentation

Weight lossWeight loss Irritability/depressionIrritability/depression

Adisson diseaseAdisson disease

J.F. Kenedy

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Diagnostic findings in Addison Diagnostic findings in Addison diseasedisease

Primary diseasePrimary disease Secondary diseaseSecondary disease

Increased ACTHIncreased ACTH

Decrease cortisolDecrease cortisol

Abnormal ACTH Abnormal ACTH stimulation teststimulation test

Decrease ACTHDecrease ACTH

Decreased CortisolDecreased Cortisol

Normal ACTH Normal ACTH stimulation teststimulation test stimulation teststimulation test

Thank you !Thank you !