Principles of endocrinal disorders

PRINCIPLES OF PRINCIPLES OF ENDOCRINOLOGYENDOCRINOLOGY

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The specialty of endocrinology The specialty of endocrinology encompasses the study of glands encompasses the study of glands and the hormones they produce.and the hormones they produce.


Hormones play an important Hormones play an important functional role in all organ systemfunctional role in all organ system


HormoneHormone

Describes the dynamic actions of Describes the dynamic actions of these circulating substances as these circulating substances as they elicit cellular responses and they elicit cellular responses and regulate physiologic processes regulate physiologic processes through feedback mechanisms.through feedback mechanisms.


The management of endocrine The management of endocrine disorders requires an disorders requires an understanding:understanding:– Areas as intermediary metabolism, Areas as intermediary metabolism,

reproductive physiology, bone reproductive physiology, bone metabolism, and growth. metabolism, and growth.

– Hormone secretion, hormone action, Hormone secretion, hormone action, and principles of feedback control and principles of feedback control systems.systems.


Scope of endocrinologyScope of endocrinology

Classic endocrine glands pituitary, Classic endocrine glands pituitary, thyroid, parathyroid, pancreatic thyroid, parathyroid, pancreatic islets, adrenal and gonads islets, adrenal and gonads communicate broadly with other communicate broadly with other organs through the nervous organs through the nervous system, hormones, cytokines, and system, hormones, cytokines, and growth factors.growth factors.


Through the production of Through the production of hypothalamic releasing factors, hypothalamic releasing factors, the central nervous system exerts the central nervous system exerts a major regulatory influence over a major regulatory influence over pituitary hormone secretion. pituitary hormone secretion.


The immune and endocrine The immune and endocrine systems are also intimately systems are also intimately intertwined.intertwined.

Hormones play an important role in Hormones play an important role in maintenance of blood pressure, maintenance of blood pressure, intravascular volume, and intravascular volume, and peripheral resistance in the peripheral resistance in the cardiovascular system.cardiovascular system.


New hormonesNew hormones

InhibinInhibin GhrelinGhrelin LeptinLeptin


NATURE OF HORMONESNATURE OF HORMONES


Five major classesFive major classes

Amino acid derivativesAmino acid derivatives Small neuropeptidesSmall neuropeptides Large proteinsLarge proteins Steroid hormonesSteroid hormones Vitamin derivativesVitamin derivatives


Amino acid derivativesAmino acid derivatives– dopaminedopamine– catecholaminescatecholamines– thyroid hormonethyroid hormone


Small neuropeptidesSmall neuropeptides– gonadotropin-releasing hormone gonadotropin-releasing hormone

(GnRH)(GnRH)– thyrotropin-releasing hormone (TRH)thyrotropin-releasing hormone (TRH)– somatostatin somatostatin – vasopressinvasopressin


Large proteinsLarge proteins– insulininsulin– luteinizing hormone (LH)luteinizing hormone (LH)– PTHPTH


Steroid hormonesSteroid hormones– cortisolcortisol– strogenstrogen

Are synthesized from cholesterol-based Are synthesized from cholesterol-based precursorsprecursors


Vitamin derivativesVitamin derivatives– retinoids (vitamin A)retinoids (vitamin A)– vitamin Dvitamin D


HORMONE ANDHORMONE AND

RECEPTOR FAMILIES RECEPTOR FAMILIES


Amino acid derivatives and peptide Amino acid derivatives and peptide hormone interact with hormone interact with cell-cell-surface membrane receptors.surface membrane receptors.

Steroids, thyroid hormones, Steroids, thyroid hormones, vitamin D and retinoids are lipid-vitamin D and retinoids are lipid-soluble and interact with soluble and interact with intracellular nuclear receptors.intracellular nuclear receptors.


Cell-surface membraneCell-surface membrane receptorsreceptors


G protein-coupled seven-G protein-coupled seven-transmembrane (GPCR)transmembrane (GPCR)

Receptors Effectors Signalingpathways

B-adrenergicLH, FSH,TSHGlucagon PTHACTH GHRH

Gsadenylate cyclaseCa++ channels

Stimulation of cyclicAMP production.Calmodulin

-adrenergic G Inhibition of AMPcproduction

Somatostatin Activation of K+ Ca++chanels

TRH GnRH Gq G11 PhospholipaseC,diacylglycerol, IP3protein kinase C,voltage dependentCa++ channelswww.freelivedoctor.com

The glycoprotein hormone family The glycoprotein hormone family consisting of TSH, FSH, LH and consisting of TSH, FSH, LH and hCG, they are heterodimers that hCG, they are heterodimers that share the share the subunit in common, subunit in common, the the subunits are distinct and subunits are distinct and confer specific biologic actions.confer specific biologic actions.


Receptor Tyrosine KinaseReceptor Tyrosine Kinase

Receptors Effectors SignaligPathways

Insulin IGF- I Tyrosine kinasesIRS-1 to IRS-4

MAP Kinases, PI 3-Kinase, RSK


Cytokine receptor linked Cytokine receptor linked kinasekinase

Receptors Effectors SignalingPathways

GH, PRL JAK, tyrosine kinases STAT, MAP kinase,IRS-1, IRS-2


Intracellular nuclear Intracellular nuclear receptorsreceptors


Specificities for DNA binding sites, Specificities for DNA binding sites, the nuclear receptor family can be the nuclear receptor family can be subdivided:subdivided:– Type 1 receptors:; GR, MR, AR, ER, PR; Type 1 receptors:; GR, MR, AR, ER, PR;

that bind steroids.that bind steroids.– Type 2 receptors: TR, VDR, RAR, PPAR; Type 2 receptors: TR, VDR, RAR, PPAR;

that bind thyroid hormone, vitamin D, that bind thyroid hormone, vitamin D, retinoic acid or lipid derivatives.retinoic acid or lipid derivatives.


With few exception, hormone With few exception, hormone binding is highly specific for a binding is highly specific for a single type of nuclear receptor.single type of nuclear receptor.


Hormone Synthesis and Hormone Synthesis and ProcessingProcessing


Peptide hormonesPeptide hormones

Synthesis of peptide hormones and Synthesis of peptide hormones and their receptors occurs through a their receptors occurs through a classic pathway of gene classic pathway of gene expression:expression:

Transcription mRNA proteinTranscription mRNA protein

posttranslational protein processing posttranslational protein processing in-tracellular sorting, membrane in-tracellular sorting, membrane integration or secretionintegration or secretion


Endocrine genes contain Endocrine genes contain regulatory DNA elements similar to regulatory DNA elements similar to those found in many other genes, those found in many other genes, their exquisite control by other their exquisite control by other hormones also necessitates the hormones also necessitates the presence of specific hormone presence of specific hormone response elements.response elements.


Many hormones are embedded Many hormones are embedded within larger precursor polypeptides within larger precursor polypeptides that are proteolytically processed to that are proteolytically processed to yield the biologically active hormone.yield the biologically active hormone.

Examples: proopiomelanocortin Examples: proopiomelanocortin (POMC) ACTH; proglucagon (POMC) ACTH; proglucagon glucagon; proinsulin insulin; pro-glucagon; proinsulin insulin; pro-PTH PTH.PTH PTH.


Synthesis of most steroid hormones Synthesis of most steroid hormones is based on modifications of the is based on modifications of the precursor, cholesterol. Multiple precursor, cholesterol. Multiple regulated enzymatic steps are regulated enzymatic steps are required for the synthesis of required for the synthesis of testosterone, estradiol, cortisol and testosterone, estradiol, cortisol and vitamin D.vitamin D.

This large number of synthetic steps This large number of synthetic steps predisposes to multiple genetic and predisposes to multiple genetic and acquired disorders of acquired disorders of steroidogenesis.steroidogenesis.


Hormone secretion, Hormone secretion, transport and degradation.transport and degradation.


Peptide hormonesPeptide hormones

GnRH, insulin, GH: are stored in secretory GnRH, insulin, GH: are stored in secretory granules. As these granules.granules. As these granules.

As these granules mature, they are poised As these granules mature, they are poised beneath the plasma membrane for beneath the plasma membrane for imminent release into the circulation.imminent release into the circulation.

Stimulus for hormone secretion is a Stimulus for hormone secretion is a releasing factor or neural signal that releasing factor or neural signal that induces rapid changes in intracellular induces rapid changes in intracellular calcium concentrations.calcium concentrations.


Steroid hormonesSteroid hormones

Diffuse into the circulation as they Diffuse into the circulation as they are synthesized.are synthesized.

Their secretory rates are closely Their secretory rates are closely aligned with rates of synthesis. aligned with rates of synthesis.


Serum binding proteinsSerum binding proteins

Many hormones circulate in association Many hormones circulate in association with serum-binding proteins.with serum-binding proteins.

T4 and T3 binding to thyroxine-binding globulin T4 and T3 binding to thyroxine-binding globulin (TBG).(TBG).

Cortisol binding to cortisol-binding globulin (CBG).Cortisol binding to cortisol-binding globulin (CBG). Androgen and strogen binding to sex hormone-Androgen and strogen binding to sex hormone-

binding globulin (SHBG).binding globulin (SHBG). IGF-I and II binding to multiple IGF-binding proteins IGF-I and II binding to multiple IGF-binding proteins

(IGFBPs).(IGFBPs). GH interactions with GH-binding protein (GHBP)GH interactions with GH-binding protein (GHBP)


Hormone Action Through Hormone Action Through ReceptorsReceptors

Two major classesTwo major classes– Membrane receptors: Peptide Membrane receptors: Peptide

hormones and catecholamines.hormones and catecholamines.– Nuclear receptors: Small molecules Nuclear receptors: Small molecules

(that can diffuse across the cell (that can diffuse across the cell membrane) such as thyroid hormone, membrane) such as thyroid hormone, steroids, and vitamin D.steroids, and vitamin D.


Hormones bind to receptors with Hormones bind to receptors with specificity and a high affinity that specificity and a high affinity that generally coincides with the generally coincides with the dynamic ranger of circulating dynamic ranger of circulating hormone concentrations.hormone concentrations.


Low concentrations of free Low concentrations of free hormone rapidly associate and hormone rapidly associate and dissociate from receptors in a dissociate from receptors in a biomolecular reaction, such that biomolecular reaction, such that the occupancy of the receptor at the occupancy of the receptor at any given moment is a function of any given moment is a function of hormone concentration and the hormone concentration and the receptor´s affinity for the hormone.receptor´s affinity for the hormone.


Receptor numbers vary greatly in different Receptor numbers vary greatly in different target tissues, providing one of the major target tissues, providing one of the major determinants of specific cellular responses determinants of specific cellular responses to circulating hormones.to circulating hormones.

ACTH receptors are located almost exclusively ACTH receptors are located almost exclusively in the adrenal cortex.in the adrenal cortex.

FSH receptors are found only in the gonads.FSH receptors are found only in the gonads. In contrast, insulin and thyroid hormone In contrast, insulin and thyroid hormone

receptors are widely distributed reflecting the receptors are widely distributed reflecting the need for metabolic responses in all tissues.need for metabolic responses in all tissues.


Functions of hormonesFunctions of hormones


The physiologic functions of The physiologic functions of hormones can be divided into hormones can be divided into three general areas:three general areas:– Growth and differentiationGrowth and differentiation– Maintenance of homeostasisMaintenance of homeostasis– Reproduction.Reproduction.


GrowthGrowth

Multiple hormones and nutritional Multiple hormones and nutritional factors mediated the complex factors mediated the complex phenomenon of growth.phenomenon of growth.– Short stature may be caused by GH Short stature may be caused by GH

deficiency, hypothyroidism, Cushing`s deficiency, hypothyroidism, Cushing`s syndrome, precocious puberty or syndrome, precocious puberty or malnutrition. malnutrition. (Understanding these hormonal (Understanding these hormonal interactions is important in the diagnosis and interactions is important in the diagnosis and management of growth disorders).management of growth disorders).


Maintenance of Maintenance of Homeostasis Homeostasis

Thyroid hormone-controls about 25% of basal Thyroid hormone-controls about 25% of basal metabolism in most tissues.metabolism in most tissues.

Cortisol-exerts a permissive action for many Cortisol-exerts a permissive action for many hormones in addition to its own direct effects.hormones in addition to its own direct effects.

PTH-regulates calcium and phosphorus levels PTH-regulates calcium and phosphorus levels Vasopressin-regulates serum osmolality by Vasopressin-regulates serum osmolality by

controlling renal free water clearance.controlling renal free water clearance. Mineralocorticoids-control vascular volume and Mineralocorticoids-control vascular volume and

serum electrolyte (Na+, K+) concentrations.serum electrolyte (Na+, K+) concentrations. Insulin-maintains euglycemiain the fed and fastedInsulin-maintains euglycemiain the fed and fasted

states.states.www.freelivedoctor.com

ReproductionReproduction

Sex determination during fetal development.Sex determination during fetal development. Sexual maturation during pubertySexual maturation during puberty Conception, pregnancy, lactation and child-Conception, pregnancy, lactation and child-

rearing.rearing. Cessation of reproductive capability at Cessation of reproductive capability at

menopause.menopause. Each of these stages involves an Each of these stages involves an

orchestrated interplay of multiple orchestrated interplay of multiple hormoneshormones


Feedback controlFeedback control

Negative and positive is a Negative and positive is a fundamental feature of endocrine fundamental feature of endocrine systems.systems.

Each of the major hypotalamic-Each of the major hypotalamic-pituitary -hormone axes is pituitary -hormone axes is governed by negative feedback.governed by negative feedback.


Hormonal RhythmsHormonal Rhythms

Seasonal changes, the daily Seasonal changes, the daily occurrence of the light-dark cycle, occurrence of the light-dark cycle, sleep, meals, and stress are sleep, meals, and stress are examples of the many examples of the many environmental events that affect environmental events that affect hormonal rhythms.hormonal rhythms.


Hormone measurements Hormone measurements and endocrine testingand endocrine testing

Radioimmunoassays are the most Radioimmunoassays are the most important diagnostic tool in important diagnostic tool in endocrinology, as they allow sensitive, endocrinology, as they allow sensitive, specific, and quantitative specific, and quantitative determination of steady-state and determination of steady-state and dynamic changes in hormone dynamic changes in hormone concentrations.concentrations.

Radioimmunoassays use antibodies to Radioimmunoassays use antibodies to detect specific hormones.detect specific hormones.


Pathologic Mechanisms of Pathologic Mechanisms of Endocrine DiseaseEndocrine Disease


Endocrine diseases can be divided Endocrine diseases can be divided into three major types of into three major types of conditions:conditions:

Hormone excessHormone excess Hormone deficiencyHormone deficiency Hormone resistanceHormone resistance


Hormone excessHormone excess

Syndromes of hormone excess can Syndromes of hormone excess can be caused by neoplastic growth of be caused by neoplastic growth of endocrine cells, autoimmune endocrine cells, autoimmune disorder, and excess hormone disorder, and excess hormone administrationadministration


Hormone deficiencyHormone deficiency

Most examples of hormone deficiency Most examples of hormone deficiency states can be attributed to glandular states can be attributed to glandular destruction caused by autoimmunity, destruction caused by autoimmunity, surgery, infection, inflammation, surgery, infection, inflammation, infarction, hemorrhage or tumor infarction, hemorrhage or tumor infiltration.infiltration.

Mutations in a number of hormones, Mutations in a number of hormones, hormone receptors, transcription factors, hormone receptors, transcription factors, enzymes, and channels can also lead to enzymes, and channels can also lead to hormone deficiencies.hormone deficiencies.


Hormone resistanceHormone resistance

Most severe hormone resistance syndromes Most severe hormone resistance syndromes are due to inherited defects in membrane are due to inherited defects in membrane receptors, nuclear receptors, or in the receptors, nuclear receptors, or in the pathways that transduce receptor signals.pathways that transduce receptor signals.

In addition to these relatively rare genetic In addition to these relatively rare genetic disorders, more common acquired forms of disorders, more common acquired forms of functional hormone resistance include insulin functional hormone resistance include insulin resistance in type 2 diabetes mellitus, leptin resistance in type 2 diabetes mellitus, leptin resistance in obesity, and GH resistance in resistance in obesity, and GH resistance in catabolic states.catabolic states.


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Principles of endocrinal disorders