Endocrine SystemEndocrine SystemEndocrine System

Dr. Carmen RexachDr. Carmen RexachPhysiologyPhysiology

Mt San Antonio CollegeMt San Antonio College

Relationship between endocrine and neural physiology

• Both neurons and endocrine cells can secrete into the blood stream

• Endocrine cells and neurons generate electrical potentials when depolarized

• Peptides produced by endocrine cells have neurotransmitter function & can act as hormones

• A single cell can produce biogenic amine neurotransmitters and peptide hormone molecules

• A single gene can be transcribed/translated to produce either peptide neurotransmitter or hormone

Structural classification of hormones

• Amino Acid derivatives• Peptide hormones• Lipid derivatives

Amino Acid Derivatives

• Derivatives of Tyrosine– Catecholamines

• epinephrine and norepinephrine(adrenal medulla)

• dopamine (hypothalamus)– Thyroid hormones

• T3, T4

• Derivatives of Tryptophan– Melatonin (pineal gland)

Peptide Hormones

• Short polypeptides (<200 amino acids)– ADH, ACTH, insulin, PTH, Calcitonin,

ANF, GI tract hormones and others• Proteins

– TSH,LH, FSH, erythropoietin, renin, inhibin

Lipid derivatives

• Steroid hormones – cholesterol derivatives– androgens, estrogens, progestins, hormones of adrenal

cortex, and others

• Eicosanoids– arachadonic acid derivatives– prostaglandins, leukotrienes, thromboxanes,

prostacyclins, etc.

Lipid derivatives

Prohormones and prehormones

• Prohormones– long chained precursor– cut and spliced to produce endproduct(s)

• Prehormones– produced in inactive form– require modification to become active– examples

• T4 T3 at target cell• testosterone• Vitamin D3

Response at the target cell

• Hormone must be recognized by specific cell receptor

• Hormone/receptor complex must be coupled to signal-transduction mechanism

• The generated signal must cause a change in intracellular processes by changing the activity or concentration of enzymes, carrier proteins, etc.

Hormone interactions• Synergistic and permissive effects

– synergistic: working together• additive (epinephrine, norepinephrine on heart)• complementary (FSH/LH on spermatogenesis)

– permissive: potentiation• increased response of target cell to a 2nd

hormone• increased activity of second hormone

• Antagonistic effects: opposition– insulin/glucagon

Hormone concentration• Half-life of hormone

– Time required for the blood [hormone] to be reduced to ½ reference level

• Minutes to days

• Concentration– physiological level

• amount necessary for normal function– pharmacological level

• too much– incidental binding to protein receptors with

similar structure but less affinity– secondary conversion into other products– Results: varying effects in body

Upregulation and downregulation

• Upregulation (Priming effect)– chronically low levels of hormone in ECF

leads to increase of number and sensitivity of protein receptors for that hormone

• Downregulation (Desensitization)– chronically high levels of hormone in the ECF

leads to decrease in the number and sensitivity of protein receptors for that hormone

– Prevented by pulsatile secretions

Relationship to NIDDM• Non-insulin dependent diabetes

mellitus– obesity– increased sugar consumption leads to increase

in circulating insulin– chronic increase in insulin levels leads to

downregulation of insulin receptors on cell surfaces

– cells become refractory to insulin– can result in atrophy of the β cells and insulin

dependence

Mechanisms of hormone action

• Same category = similar mechanism• Determined by:

– location of receptor– cellular response to receptor activation

• Location of Receptor– Nonpolar hormones

• in nucleus of target cell• in cytoplasm of target cell

– Polar hormones• on outer surface of plasma membrane

Steroid and thyroid hormones

• Nonpolar– into plasma attached to carrier proteins– dissociate in blood near target– hormone into target

• moves into cell and binds to intracellular receptor

• alterations allow for direct binding to DNA• Result: genetic transcription (mRNA

synthesis)

Steroid hormones

Result: turn a keymetabolic pathwayon or off

Steroid Hormones: In nucleus

• DNA-binding domain of receptor binds to specific HRE of the DNA.

• Dimerization occurs.– Process of 2 receptor

units coming together at the 2 half-sites.

• Stimulates transcription of particular genes.

Thyroid hormones

T4

T3

Result: turn key enzymesin a metabolicpathway on oroff

Mechanism of Thyroid Hormone Action

• T4 passes into cytoplasm and is converted to T3.

• Receptor proteins located in nucleus.– T3 binds to ligand-binding

domain. – Other half-site is vitamin

A derivative (9-cis-retinoic) acid.

• DNA-binding domain can then bind to the half-site of the HRE.

– Two partners can bind to the DNA to activate HRE.

• Stimulate transcription of genes.

Peptide hormones• Polar = restricted to cell surface• Utilize second messenger system

Second messenger = cAMP

α

Adenylate cyclase

ATP cAMP +Pi

PO43-Protein kinase

G-protein

Result: Turn key enzyme in a metabolicpathway on or off

Second messenger = Ca++

α adrenergic receptor

epi

PLC

PIP2 IP3DAG

Ca++

Ca++

Protein kinase

calmodulin

Epi Can Act Through Two 2nd Messenger Systems

Remember• Different hormones have different

effects on same target cell• Response of target cell to same

second messenger can differ in different cells

Endocrine glands and their products

Endocrine glands and Endocrine glands and their productstheir products

Pituitary gland

structure

Anterior pituitary

• Trophic effects:– High blood

[hormone] causes target organ to hypertrophy.

– Low blood [hormone] causes target organ to atrophy.

Hormones of anterior pituitary• GH = somatotropin

– Generalized growth promoting effects• TSH = thyrotropin

– Regulates activity of thyroid gland• ACTH = corticotropin

– Regulates activity of adrenal cortex• PRL = prolactin

– Mammary growth, development, lactogenesis• Gonadotropins

– FSH = folliculotropin– LH = leutotropin

Pituitary hormones: pars intermedia & posterior

• Pars intermedia– MSH– Beta (β)-endorphins

• Posterior pituitary– ADH– oxytocin

Hypothalamic Control of Posterior Pituitary

• Hypothalamus neuron cell bodies produce:– ADH: supraoptic

nuclei.– Oxytocin:

paraventricularnuclei.

• Transported along the hypothalamo-hypophyseal tract.

• Stored in posterior pituitary.

• Release controlled by neuroendocrinereflexes.

Hypothalamic control of anterior pituitary

• Hypothalamopituitary portal vessel• releasing hormones: polypeptides released by

the hypothalamus– TRH TSH– CRH ACTH– GnRH FSH/LH– GHRH GH

• inhibiting hormones– PIH PRL– Somatostatin GH

Negative feedback loops

HypothalamusIncreased secretion hormone #1

Anterior pituitaryIncreased secretion hormone #2

3rd Endocrine glandIncreased secretion hormone #3

Target cells of hormone #3Respond to hormone #3

stimulus

Increased plasma hormone #1

Increased plasma hormone #2

Increased plasma hormone #3

-

-

-

Positive feedback effect• Amplifies initial biological effect of

hormone

estradiol LH

Pituitary gland disorders

Acromegaly

Identical twins

Acromegaly vs. Gigantism

Influence of higher brain functions

• Emotions• Stress• Circadian rhythms

– somatotropin released in greatest quantities during first 90 minutes of sleep

– estradiol on GnRH response

Adrenal gland

Functions of the adrenal cortex• Mineralocorticoids

– zona glomerulosa– aldosterone = Na+/K+ regulation

• Glucocorticoids– zona fasciculata– cortisol and corticosterone– protein and carbohydrate

metabolism• Sex steroids

– zona reticularis– androgens and estrogens =

maintenance of secondary sex characteristics

Adrenal Cortex

Stress and the adrenal gland

• Stimulate pituitary-adrenal axis due to chronic controlled stress– increased secretions of ACTH– increased secretions of glucocorticoids

• Sympathetic response– stimulation of adrenal medulla– response to physical challenge or

physically challenging stressors

Stress and the Adrenal Gland• Three phase

response– 1) Alarm phase

• Adrenal glands activated.

– 2) Stage of resistance

• Stage of readjustment.

– 3) Stage of exhaustion

• Sickness and/or death if readjustment is not complete.

Adrenal gland disorders: Cushing’s syndrome

Caused by excess production of ACTHClassic symptoms seen in this 23 y.o. female

hirsutism (face)central obesityhyperpigmentation & striae

Cushing’s syndrome

Thyroid gland

Thyroid Hormones

• located just below the larynx

• largest of the pure endocrine glands

• Follicular cells secrete thyroxin

• Parafollicular cellssecrete calcitonin

Production of thyroid hormones

• 2I- + H2O2 I2– iodide enters cell by secondary cotransport with Na+

• I2 + HO CH2CHCOOH

• DIT + DIT T4• MIT + DIT T3

MIT

DITTyrosine

Tetraiodothyronine(thyroxine)

triiodothyronine

NH2

Production and release

• T3 and T4 produced.• TSH stimulates pinocytosis into the

follicular cell.– Enzymes hydrolyze T3 and T4 from

thyroglobulin.• Attached to TBG and released into

blood.

Secretion of T3/T4

• T4 circulates bound to protein• Protein allows for transport in the

plasma and through the cytosol in the cell for access to nuclear receptors

Binding proteins

• three major binding proteins produced in the liver– thyroxine-binding pre-albumin (TBPA)

• binds 70-75% of T4– thyroxine-binding globulin (TBG)

• binds 15-20% of T4– albumin

• 5-10% of T4

T3 vs T4

• Both of these are water insoluble, but certain binding proteins have greater affinity for T4

• T4 concentrations in humans 50x’s greater than T3

• Functions– T3 physiologically relevant hormone– T4 involved in negative feedback loop on pituitary

production of TSH & production of TRH by the hypothalamus

Effects • Protein synthesis• maturation of nervous system• increased BMR

– during prolonged fasting plasma T3 levels decrease (ever wonder why it is harder to loose weight when you start dieting?? Your body is prolonging your survival by minimizing its energy usage!)

• Thyroid diseases– Goiter– Graves disease– Cretanism/myxedema

Diseases of the Thyroid

• 1) Iodine-deficiency (endemic) goiter

• 2) Abnormal growth of the thyroid gland.

• 3) In the absence of sufficient iodine, cannot produce adequate amounts of T4 and T3.

• 4) Lack of negative feedback inhibition.

• 5) Stimulates TSH, which causes abnormal growth.

Goiter

Graves disease: hyperthyroidism

exopthalmos Digital clubbing

Myxedematous cretinism20-year-old African male with three cretin women of the same age

Characteristics:Mental retardationSevere growth retardationDelayed sexual maturationIncomplete maturation of featuresPuffy, thickened skin

hypothyroidism

Parathyroid gland

Parathyroid hormone• Major regulator of Ca++ metabolism• Effect

– increase plasma Ca++ by• stimulation of bone resorption• renal tubular Ca++ reabsorption• synthesis of 1,25-(OH)2-D3

– decrease plasma PO43-

• Regulated by plasma Ca++

concentration

RICKETS OSTEOMALACIA: 25 YO FEMALE

Pancreas: Islets of Langerhans

Islets of Langerhans• Four major cell types

– Alpha (α) cells = glucagon– Beta (β) cells = insulin– Delta (δ) cells = somatostatin (inhibition of

insulin, glucagon, and assimilation rate of nutrients in GI tract)

– F cells = pancreatic polypeptide (inhibits pancreatic exocrine secretion)

Pineal gland• Located in brain in

roof of 3rd ventricle

Pineal gland• Major site of melatonin synthesis

– highest levels of secretion at night• Controversial effects

– Alleviation of jet lag after transmeridialflights

– Antigonadal effects = inhibition of melatonin is trigger for puberty onset• Continuous light leads to early onset of

sexual development

Thymus

Thymus• Location: behind manubrium of

sternum• attains weight of approximately 40

grams at puberty, then begins to involute

• Function: development of immune response

• Hormone: thymosin– T cell education

GI tract, gonads, placenta• GI tract• Gonads

– Androgens– Estrogens– Progestones

• Placenta– Estrogens– Progesterone– Human chorionic gonadotropin– somatomamotropin