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Home , Adrenal cortex, Adrenal medulla, Anterior pituitary, Pancreatic islets, Parathyroid gland, Thyroid

In the beginning… Multi-celled Somebody take organism out the trash!

Evolutionary processes

Single-celled organism Who’s Making dinner? Cell responsible for Cells specialized for all physiological processes specific functions

How do cells communicate? 1) (electrical / chemical signaling) • Rapid / conscious or sub-conscious / internal or external communication 2) Endocrine system (chemical signaling) • Slow / sustained / sub-conscious / internal or external communication

Endocrine System

Hormone: Any substance produced and secreted by one cell that regulates another cell

See Tables 9.1 / 9.2 (Costanzo – pgs. 380 – 381)

Marieb & Hoehn – Figure 16.1 Endocrine System

Overview of Endocrine System:

Endocrine System: and the various cells that secrete / receive them

Gland Target Effect Cell

Pineal

Pituitary gland

Thyroid gland gland

Parathyroid gland

Adrenal gland

Testis

• Glandular secretory cells (epithelial tissue) • Release substances into surrounding tissues (ductless)

1 Endocrine System We will focus on the Overview of Endocrine System: classical endocrine system

Endocrine System: Hormones and the various cells that secrete / receive them

Gland Hormone Target Effect Cell

Endocrine (classic definition):

Gland Blood Hormone Target Cell Neuroendocrine:

Neuron Blood Hormone Target Cell Paracrine:

Cell Interstitial Fluid Hormone Target Cell Autocrine

Costanzo – Figure 9.1 Endocrine System

Overview of Endocrine System:

Endocrine System

Overview of Endocrine System:

Endocrine System: Hormones and the various cells that secrete / receive them

Gland Hormone Target Effect Cell

General Classes of Hormones: 1) Amines: • Derived from individual amino acids • May incorporate inorganic ions

Triiodothyronine (T3)

Majority of amines inactivated in or at site of action

2 Costanzo – Figure 9.2 Endocrine System inactivated by blood, Overview of Endocrine System: liver, and

Endocrine System: Hormones and the various cells that secrete / receive them

Gland Hormone Target Effect Cell

Generally, General Classes of Hormones: single responsible 2) Peptides: for each hormone • Most common type of hormone Preprohormone • Composed of amino acids (3 – 200+ a.a.) • Synthesis follows Central Dogma

Signal Prohormone (e.g., ) cleaved

May be glycosylated or phosphorylated

basal (continuous) stimulus-coupled secretion (episodic)

Endocrine System inactivated by liver; Overview of Endocrine System: cleared through kidneys / intestines Endocrine System: Hormones and the various cells that secrete / receive them

Gland Hormone Target Effect Cell

General Classes of Hormones: 3) Steroids: • Derived from

(basic cyclic hydrocarbon arrangement)

• Complex biosynthetic pathways • Very little stored ( soluble) Biosynthesis occurs primarily in smooth ER…

Endocrine System

Overview of Endocrine System:

Endocrine System: Hormones and the various cells that secrete / receive them

Gland Hormone Target Effect Cell

Target Cells: Cells specialized to respond to hormones

Alter cells by changing identities, activities, Specific receptors or quantities of present (2000 – 10,000)

• Cell activity primarily regulated by # of active receptors present

**** Up Regulation / Down Regulation **** Depends on affinity of receptors, but does not define why change has occurred (e.g., activation / inactivation)

• Cell changes may be: 1) prolonged and irreversible (e.g., ) 2) transient and reversible (e.g., ‘fight-or-flight”)

3 Endocrine System

Overview of Endocrine System:

Endocrine System: Hormones and the various cells that secrete / receive them

Gland Hormone Target Effect Cell

• Hormones differ in mechanism of action:

2nd Messenger Systems

• Utilized by large, charged hormones (e.g., peptides) • Receptors located on cell surface

A) -linked receptors • Binding of hormone directly activates enzyme (e.g., kinase)

B) G -linked receptors

Costanzo – Figure 9.6 Endocrine System

Overview of Endocrine System:

Endocrine System: Hormones and the various cells that secrete / receive them

Gland Hormone Target Effect Cell

• Hormones differ in mechanism of action: Primarily responsible for changing gene rate

2nd Messenger Systems Internal Receptor Systems

• Utilized by large, charged hormones (e.g., peptides) • Utilized by hydrophobic hormones (e.g., steroids) • Receptors located on cell surface • Receptors located in cytoplasm / nucleus

Domains A) Enzyme-linked receptors • Binding of hormone directly activates enzyme (e.g., kinase) A / B: Initiates DNA binding (e.g., transcription factors) B) -linked receptors C: Actively binds DNA (zinc fingers – highly conserved) Primarily responsible for changing D: Hinge region (goes through conformational change) cell activity E: Hormone-binding region

Costanzo – Figure 9.7 Endocrine System

4 Endocrine System

Overview of Endocrine System:

Endocrine System: Hormones and the various cells that secrete / receive them

Gland Hormone Target Effect Cell

• Hormone levels maintained via feedback mechanisms:

Long loop (-) (-) (+) (+) (+) (+) Hypothalamus Hormone Target tissue

(-) (-) (+)

Ultra-short loop Short loop

A) : Some feature of hormone action, directly or indirectly, inhibits further secretion of the hormone B) Positive Feedback: Some feature of hormone action, directly or indirectly, enhances further secretion of the hormone

Endocrine System Property Amines* Peptides Steroids

Feedback regulation Yes Yes Yes of synthesis

Storage of Several days One day Very little hormone

Mechanism of Exocytosis Diffusion secretion

Plasma protein Rarely Rarely Yes binding

Lifetime in blood Seconds Minutes Hours

Time course of action Seconds Minutes – Hours Hours – Days

Plasma Plasma Receptors Cytosolic / Nuclear membrane membrane

Endocrine System

Hypothalamus / Pituitary gland

5 Norris ( , 3rd ed.) – Figure 4.4 Endocrine System

Hypothalamus / Pituitary Gland:

The hypothalamus and pituitary gland function in a coordinated fashion to orchestrate multiple endocrine system

Pituitary gland composed of both epithelial and neural tissue: (part of )

Rathkey’s pouch (oral )

Anterior pituitary (adenohypophysis) • Contains glandular cells (neurohypophysis) • Contains hypothalamic neurons Hadley (Endocrinology, 5th ed.) – Figure 5.2

Endocrine System

Hypothalamus / Pituitary Gland:

The hypothalamus is in direct control of the pituitary by both neural and hormonal mechanisms

The connection between the hypothalamus and posterior pituitary is neural:

• Neural cell bodies located in hypothalamus • (SON) Hypothalamus • Paraventricular nucleus (PVN)

• Posterior pituitary collection of • Release into neighboring bed ( – OT; antidiuretic hormone – ADH)

Hadley (Endocrinology, 5th ed.) – Figure 7.1

Endocrine System

Hypothalamus / Pituitary Gland:

The hypothalamus is in direct control of the pituitary by both neural and hormonal mechanisms

The connection between the hypothalamus and is neural and endocrine:

• Neural cell bodies located in hypothalamus with axonal endings at (ME): • Supraoptic nucleus (SON) • Paraventricular nucleus (PVN) • (ARC) • (POA) • (SCN) • Hypothalamic neurons release regulatory hormones at ME: • Releasing hormones (stimulatory effect) • Inhibiting hormones (inhibitory effect)

Hadley (Endocrinology, 5th ed.) – Figure 7.1

6 Endocrine System

Hypothalamus / Pituitary Gland:

The hypothalamus is in direct control of the pituitary by both neural and hormonal mechanisms

The connection between the hypothalamus and anterior pituitary is neural and endocrine:

• Regulatory hormones travel to anterior pituitary via hypothalamic-hypophysial portal system:

1 capillary bed

Portal vessels 1

2 capillary bed 2 Important Implications:

1) Regulatory hormones delivered to pituitary rapidly and in [high] 2) [High] of regulatory hormones do not appear in systemic circulation Hadley (Endocrinology, 5th ed.) – Figure 7.1

Endocrine System

Hypothalamus / Pituitary Gland:

The hypothalamus is in direct control of the pituitary by both neural and hormonal mechanisms

Acidophil Basophil The connection between the hypothalamus and anterior pituitary is neural and endocrine:

• Regulatory hormones activate / inhibit cells in the anterior pituitary:

A) Acidophils: (granules bind acid stains) 1) Somatotrophs ( – GH; ~ 20%) 2) Lactotrophs ( – PRL; ~ 15%) • Cell # varies according to sex / age

B) Basophils: (granules bind basic stains) 1) Corticotrophs (adrenocorticotrophic hormone – ACTH; ~ 15%) 2) Thyrotrophs (-stimulating hormone TSH; ~ 5%) 3) Gonadotrophs (follicle-stimulating hormone – FSH; – LH; Chromophobes (immature / support cells; ~ 30 %) ~ 15%)

Endocrine System These hormones target endocrine Anterior Pituitary Hormones: (TSH = thyroid gland; LH / FSH = ), Group I: (TSH / FSH / LH) up regulating activity of glands • Consists of two subunits: -subunit (~ 92 – 93 a.a. residues) and  sub-unit (~ 110 – 145 a.a. residues); connected via disulfide bond

CHO • Sub-units coded by different CHO • Biological activity dependent on S S variation in  sub-unit

 S S 

S S CHO CHO

• Large carbohydrate component (~ 15 – 30% MW of molecule) • Assists in folding protein / prevention of proteolytic breakdown

Human chorionic (HCG) structurally related to family Norris (Vertebrate Endocrinology, 3rd ed.) – Figure 4.14

7 Costanzo (, 4th ed.) – Figure 9.9 Endocrine System

Anterior Pituitary Hormones:

Group II: Pro-opiomelanocortin derivatives (ACTH) • Post-translational modification of POMC (prohormone); results in production of multiple hormones

• Hormone production dependent on present

MSH: Controls color change in many ; little activity in 39 a.a. residues

Up regulates adrenal Produces analgesic cortex activity effects in CNS Addison’s disease Melanocyte-stimulating Stimulates hormone (MSH) in

Endocrine System GHRH: Growth hormone releasing Anterior Pituitary Hormones: hormone

Group III: Single-chain peptide hormones (GH / PRL) SRIF (): Somatotropin release-inhibiting A. Growth Hormone: Arcuate hormone • 191 a.a. residues; two internal disulfide nucleus bonds (-) (+) Hypothalamus (+)

GHRH SRIF (+) (-)

Anterior Pituitary (-) Regulation of GH Secretion: • Secreted in pulsatile pattern (2 hr. bursts) Growth Hormone •  rate during puberty (growth spurt) Somatomedins (IGF) Stimulatory Factors Inhibitory Factors Somatomedins (IGF) Hyperglycemia Starvation Obesity Target tissue / Senescence

Endocrine System Synergisms with Anterior Pituitary Hormones: / sex steroids Group III: Single-chain peptide hormones (GH / PRL)

A. Growth Hormone: Growth Hormone indirect actions direct actions

Liver Fat cells Insulin-like (lipolysis) growth factors (IGF-1; ) Somatomedins Carbohydrate

Fat cells Chondrocytes Muscle FFA Glycerol

Lipogenesis Cartilage formation Protein synthesis Diabetogenic Activity (anti-insulin effects) growth

8 Endocrine System

Anterior Pituitary Hormones:

Group III: Single-chain peptide hormones (GH / PRL)

A. Growth Hormone: Pathophysiology:

During early development: In adulthood:

Gigantism ( GH) Pituitary ( GH) ( GH) Cause: Pituitary tumor Cause: Multiple causes Cause: Pituitary tumor Treatment: Somatostatin analogs Treatment: Exogenous GH Treatment: Somatostatin analogs

Endocrine System

Anterior Pituitary Hormones:

Group III: Single-chain peptide hormones (GH / PRL)

B. Prolactin: • 198 a.a. residues; three internal disulfide bonds (tonically inhibited majority of time) (+) Hypothalamus

Dopamine (-)

Anterior Regulation of GH Secretion: Pituitary • Up regulated during pregnancy /

• Primarily under inhibitory regulation Prolactin Stimulatory Factors Inhibitory Factors Sleep Somatostatin Target tissue

Endocrine System

Anterior Pituitary Hormones:

Group III: Single-chain peptide hormones (GH / PRL)

B. Prolactin: Prolactin

Pituitary tumor

Breast Inhibits

• Simulates growth / development • Decreased fertility during of mammary tissue breast-feeding (puberty / pregnancy) • Simulates production of milk proteins / free fatty acids / lactose Pathophysiology: (suckling stimulation) Hyperprolactinemia Work in conjunction with and Symptoms: Galactorhea / Cause: Multiple causes Treatment: Bromocriptine ( agonist)

9 Endocrine System Hypothalamus Posterior Pituitary Hormones: Oxytocin / Antidiuretic Hormone: OT = paraventricular nuclei ADH = supraoptic nuclei • Homologous 9 a.a. residues Posterior Pituitary Neurophysins assist in transporting OT / ADH down OT (hormone binding proteins)

• Bioactive hormone synthesized from prohormones

ADH

ADH OT

Neurophysin II Neurophysin I

OT / ADH genes on same chromosome Glycoprotein but on different DNA strands

Propressophysin Norris (Vertebrate Endocrinology, 3rd ed.) – Figure 6.2 / 6.3 Prooxyphysin

Endocrine System

Posterior Pituitary Hormones: Stimulatory Factors Inhibitory Factors A. Oxytocin: Infant cues (e.g., sound) Opiods (endophins)

Oxytocin Pitosin: Synthetic agonist

Breast (Suckling) Uterus (Dilation of cervix)

• Simulates movement of milk down • Triggers powerful rhythmic duct system to nipple contractions of uterus (milk letdown reflex) (child birth)

Endocrine System

Posterior Pituitary Hormones: Stimulatory Factors Inhibitory Factors  plasma osmolarity  plasma osmolarity B. Antidiuretic Hormone: Hypovolemia Ethanol

Antidiuretic Hormone

(Blocks ADH release From pituitary) Kidneys

• Stimulates water reabsorption from kidney filtrate

10 Endocrine System

Posterior Pituitary Hormones: B. Antidiuretic Hormone: V2 receptor ADH AQP3 Interstitial fluid (basal) R Gs AC

ATP cAMP AQP2 H2O

PKA PKI

AQP2 Lumen of (apical)

1) ADH binds with receptor; activates cAMP pathway 2) Protein kinase triggers water channels (Aquaporin – 2) to embed in apical plasma membrane

Endocrine System

Posterior Pituitary Hormones: Stimulatory Factors Inhibitory Factors  plasma osmolarity  plasma osmolarity B. Antidiuretic Hormone: Hypovolemia Ethanol ADH is also drop called (AVP) Antidiuretic Hormone

Kidneys Blood Vessels

• Stimulates water reabsorption • Triggers contraction of vascular from kidney filtrate smooth muscle

Pathophysiology: Symptoms: Large volumes of urine Concentrated body fluids Insipidus Cause: No ADH produced (e.g., bad gene) ‘a tasteless passer through’ Unresponsive kidney (e.g., bad AQP2) Treatment: ADH analogue (e.g., Desmopressin)

Endocrine System

Thyroid gland

11 Endocrine System

Thyroid Gland : • Bi-lobed gland located in throat region • Derived from of embryonic alimentary canal (Thyroglossal stalk) • embedded in tissue

Colloid: Thyroid hormone storage material (located in lumen)

Can store 1 week worth of thyroid hormones

Production of hormones not tightly regulated

Follicle: Cluster of follicular cells (thyrocytes – simple cuboidal) surrounding lumen (as large as 1 cm)

colloid

Endocrine System

Thyroid Hormone: • ; derived from • Requires Tyrosine • Two forms:

90%

Thyroxine (T4) • 4 iodine atoms • Tetraiodothyronine Goiter

10%

Triiodothyronine (T3) • 3 iodine atoms Iodized …

12 Endocrine System []cell 20x – 40x greater Thyroid Hormone – Synthesis: than [iodide]plasma

Step 1: Accumulation of inorganic iodide (follicular cells):

I- 2º Blood Na+ - - I I Na+ 1º Active Transport K+

Basal Apical membrane membrane

Goitrogens: Dietary exist: Chemicals that block iodine

uptake by the thyroid Example: - • Percholate ion (ClO4 ) Competitive Sweet potatoes • Thiocyanate (SCN-) inhibitors (cyanogenic glucosides)

Endocrine System

Thyroid Hormone – Synthesis: Blood

Interstitial space Basal surface

I-

ER

TG

Golgi

TG Apical TG surface

Step 2: Synthesis of thyroglobin (TG): • Glycoprotein (contains 4 – 8 tyrosine residues)

• Synthesized in rough ER; packaged in Golgi apparatus; stored as colloid

Endocrine System

Thyroid Hormone – Synthesis: Blood

Interstitial space Basal surface Single iodide = monoiodotyrosine (MIT) - Glucose I Double iodide = (DIT) G5P

ER NADP NADPH

TG

Golgi O2 H2O2 TG Ii Apical TG surface TP

DIT DIT MIT DIT TG-I Step 3: Iodination of tyrosine residues (thyroglobin): (PTU) • Inorganic iodide oxidized by • Requires hydrogen peroxide • Triggers iodination of tyrosine residues

13 Endocrine System

Thyroid Hormone – Synthesis: Only a fraction of tyrosine coupled (~ 10%)

Step 4: Coupling of iodinated • Two iodinated tyrosines coupled together DIT + MIT = triiodothyronine; DIT + DIT = tetraiodothyronine

• Much more T4 than T3 synthesized (10x)

Endocrine System

Thyroid Hormone – Synthesis: Blood

Interstitial space T3 & T4 Basal surface (recycled) - Endolysosome I- / tyrosine Glucose I G5P TG Enzymes

NADP NADPH ER

TG

Golgi O2 H2O2 TG Ii Apical TG TG surface TP

DIT DIT MIT DIT T4 T3 TG-I Step 5: Hydrolysis of thyroglobin (releases hormone) • Colloid engulfed to form endosome () • Endosome + lysosome (hydrolytic enzymes) = endolysosome

• T3 / T4 released into blood ()

Endocrine System T3 / T4 somewhat Thyroid Hormone – Transport: hydrophobic ( solubility) • Majority of circulating thyroid hormones bound to carrier proteins:

Thyroxine-binding globulin (~ 75%) (~ 20%) • Single polypeptide chain • 4 polypeptide chains (2 binding sites)

• Carrier proteins synthesized by liver • Protect hormones from clearance

• Provide reservoir (T4 half-life = 7 days)

• Higher affinity for T4 Albumin (~ 5%) • Single polypeptide chain

14 Endocrine System T3 is the more active form of Thyroid Hormone – Activation: thyroid hormone at the tissues

Remember: 10x more T4 than T3 in circulation

• Conversion occurs at tissue level:

A) ~ 45% of T4 converted to T3 (5’-iodinase) • Biologically active; lost via kidney after sulfur conjugation

B) ~ 55% of T4 converted to rT3 (reverse T3; 5’-iodinase) • Biologically inactive; lost rapidly via kidney

 During starvation, 5’-iodinase inhibited, thus lowering O2 consumption and metabolic rate (brain 5’-iodinase not affected…)

Endocrine System

Thyroid Hormone – Regulation: paraventricular nucleus

Hypothalamus

TRH Thyroid-releasing TSH stimulates release of T3 / T4: (+) hormone Down-regulates •  iodide uptake TRH receptors (Thyrotrophs) Anterior •  synthesis of Pituitary •  endocytosis / hydrolysis of thyroglobulin (-) TSH Mechanism of action = G-protein / cAMP pathway (+)

Additional Additional Thyroid gland Stimulatory Factors Inhibitory Factors Thyroid-stimulating I- excess immunoglobulins (Wolff-Chaikoff effect) T3 / T4

Target tissues

Endocrine System T3 binds to intracellular Thyroid Hormone – Action: receptor (nuclear)

Thyroid hormone (T3)

Increases basal Increases Promotes CNS metabolic rate (BMR) cardiac output maturation

•  Na+/K+ ATPase activity •  (Newborn ( O2 consumption) •  stroke volume Hypothyroid Test) ( heat production) (triggers synthesis of 1-adrenergic receptors)

Increases Promotes energy substrates growth

•  glucose absorption •  bone formation Synthesis of •  glucogenolysis •  bone maturation key metabolic •  (works in synergy with enzymes •  lipolysis GH and somatomedins) •  “Fountain of Youth” restriction =  thyroid hormones = longer life

15 Endocrine System

Thyroid Hormone: First characterized endocrine disorder Pathophysiology: (~ 1850)

Cretinism (insufficient thyroid hormones) (excess thyroid hormones)

Symptom(s):  Symptom(s):  basal metabolic rate Weight gain / lethargy Weight loss / excitability  heat production (cold sensitivity)  heat production (prolific sweating) Decreased cardiac output Increased cardiac output Exophthalmos  thyroid-stimulating Growth / mental retardation (perinatal) Goiter immunoglobulins

Cause(s): (autoimmune) Cause(s): Graves’ disease Hypothalamic / pituitary failure (e.g., tumor) I- deficiency Hypothalamic / pituitary failure Congenital (e.g., genetic) Treatment(s): Drug administration (e.g., propylthiouracil) Treatment(s): Hormone replacement Radioactive ablation (131I-)

Endocrine System

Adrenal gland

Marieb & Hoehn – Figure 16.13 Endocrine System

Adrenal Gland Anatomy:

• 2 glands; located superiorly to each kidney Cortex • Two disparate regions: Medulla covered last term… • Inner zone (20% of tissue) • Neuroectodermal origin () • Release (epinephrine / ) Kidney • Outer zone (80% of tissue) • Derived from mesoderm () • Release hormones

Adrenal glands, when corrected for weight, receive the highest blood flow of any in the body

16 Endocrine System

Adrenal Hormones:

A) • Outermost layer; organized into whorls • Synthesizes mineralcorticoids

B) • Middle layer; organized into cords • Synthesizes

C) • Innermost layer; many reticular fibers • Synthesizes

Endocrine System Step 1: Adrenal Hormones – Synthesis: Uptake of cholesterol (plasma) Blood Step 2: • Enters via LDL complexes (LDL = low-density lipoproteins) Synthesis of Cholesterol • Occurs in mitochondria adrenocortical cell

cholesterol Step 3: (rate limiting step) desmolase Synthesis of various hormones Pregnenolone

zona zona zona 3-hydroxysteroid fasciculata 17-hydroxlase reticularis 17-hydroxlase glomerulosa dehydrogenase Progesterone 17-hydroxypregnenolone 17-hydroxypregnenolone

21-hydroxlase 3-hydroxysteroid 17,20-lyase dehydrogenase

11 Deoxycorticosterone 17-hydroxyprogesterone

3-hydroxysteroid 11-hydroxlase 21-hydroxlase dehydrogenase

Corticosterone 11 Deoxycortisol

11-hydroxlase synthase Lack of enzymes in various zones equates Aldosterone to different products

Endocrine System

Adrenal Hormones – Regulation: paraventricular nucleus Cortisol / Adrenal androgens: (-) • Display diurnal pattern that is pulsatile Hypothalamus

• 10 pulses / day CRH corticotropin-releasing hormone • Highest in morning (+)

(Corticotrophs) Anterior Pituitary (-)

ACTH (+) ACTH secretion drives pattern: •  cholesterol uptake by mitochondria Adrenal cortex •  cholesterol desmolase activity Mechanism of action = G-protein / cAMP pathway Cortisol Additional Additional Stimulatory Factors Inhibitory Factors Target tissues Sleep-wake transition Opiods Stress ADH

17 Endocrine System  [K+] in interstitial fluid directly stimulates aldosterone release Adrenal Hormones – Regulation:

Aldosterone: • - system (RAS) regulates release Triggers: 1) Kidneys measure blood pressure • Juxtaglomerular cells (JG cells) •  pressure = renin 2) Kidneys measure [Na+] in filtrate • Macula densa cells •  [Na+] = renin release

Renin Angiotensinogen Angiotensin I (renin substrate – liver)

Angiotension – converting enzyme (ACE)

Zona glomerulosa Angiotensin II (2 min. half-life) •  cholesterol demolase activity G-protein / IP & DAG pathway •  activity 3

Endocrine System

Adrenal Hormones – Action: Adrenocortical steroids binds to Cortisol

Stimulation of gluconeogenesis Diabetogenic Activity (anti-insulin effects)

Cortisol Amino Glucose acids FFA Glucose

(-) (-) Proteolysis Gluconeogenesis Protein Lipolysis Lipogenesis synthesis

Glucose Muscle Fat Protein Muscle Cell Liver Cell Fat Cell Glucose (hyperglycemia)

Endocrine System

Adrenal Hormones – Action: Adrenocortical steroids binds to Intracellular receptor Cortisol

Stimulation of Maintenance of Manipulation gluconeogenesis vascular responsiveness of sleep cycles Diabetogenic Activity (triggers up-regulation of •  REM sleep  -adrenergic receptors) (anti-insulin effects) 1 •  awake time Recall: Largest bursts of cortisol just before waking Suppression of Inhibition of / immune response bone formation •  lipocortin synthesis •  collagen synthesis (inhibits production) •  production • proliferation of T  •  intestinal Ca2+ absorption •  release of histamine

Immunosuppressive drugs

18 Endocrine System

Adrenal Hormones – Action: Adrenocortical steroids binds to Intracellular receptor

Aldosterone Androgens

•  Na+ reabsorption ♂ = limited function •  K+ secretion Kidney •  H+ secretion ♀ = major

Interestingly, aldosterone receptors in the kidney also have high affinity for cortisol – Potential problem? • development of pubic / YES – but… axillary hair • (sex drive) 11 –hydroxysteroid dehydrogenase cortisol cortizone found in [high] high receptor low receptor In renal tissue affinity affinity

Endocrine System Cushing’s Syndrome Adrenal Hormones: (Excess glucocorticoids; adrenal hyperplasia) Pathophysiology:

Addison’s Disease Cushing’s Disease (Primary adrenocortical insufficiency) (Enhanced secretion of ACTH)

Symptom(s): Hypoglycemia Symptom(s): Hyperglycemia Weight loss / weakness Central obesity / round face

Hyperkalemia Buffalo hump Metabolic acidosis Muscle wasting Hypotension Hypertension Loss of sex drive androgens Virilization(women) Decreased pubic / axillary hair

Hyperpigmentation:  circulating ACTH Cause(s): Pituitary (tumor)

Cause(s): Adrenal cortex destruction (autoimmune) Treatment(s): Tumor removal

Treatment(s): Hormone replacement therapy

Endocrine System

Adrenal Hormones: Pathophysiology:

Conn’s Disease (Primary )

Symptom(s): Increased ECF volume Hypertension Hypokalemia Metabolic alkalosis

Cause(s): Adrenal hyperplasia

Treatment(s): Aldosterone antagonists Tumor removal (surgery)

19 Endocrine System

Pancreatic Hormones

Endocrine System

Pancreas Anatomy:

Embryonic origin: Liver (endoderm) Pancreas

Endocrine cells clustered in (islets of Langerhans)

Both exocrine and endocrine function:

Exocrine = Digestive enzymes (5% of cells) Endocrine = blood glucose regulation

Pancreatic islets composed of:

-cells: Periphery of islets; produce (20% of cells) -cells: Center of islets; produce insulin D-cells: Scattered; Produce somatostatin (SST) (65% of cells)

Marieb & Hoehn (Human Anatomy and Physiology, 8th ed.)– Figure 16.13 Costanzo (Physiololgy, 4th ed.) – Figure 9.26

Endocrine System First hormone to: 1) Be isolated from animal source for therapy Pancreatic Hormones: 2) Have protein structure determined A. Insulin: 3) Have mechanism of action determined • Polypeptide; 2 chains (A = 21 a.a.; B = 30 a.a.) connected via two disulfide bonds

Synthesized from single chain (pro-insulin) Gene = Chromosome 11 Connecting peptide (C peptide)

Connecting protein cleaved in Golgi apparatus

A chain

However: Levels measured medically to determine endogenous rate of insulin production

B chain No physiological function known for C peptide… Costanzo (Physiology, 4th ed.) – Figure 9.27

20 Endocrine System Additional Additional Stimulatory Factors Inhibitory Factors Pancreatic Hormones: Increased [a.a.] Fasting G Increased [fatty acids] Exercise A. Insulin: Cortisol Somatostatins Regulation: (facilitated diffusion)

GLUT 2 Glucose levels in blood most important regulator of insulin secretion:  - cell 1) Glucose transported into β cells Glucose 2) Glucose metabolized to produce Glucose kinase ATP (substrate level phosphorylization) Glucose-6-phosphate 3) ATP closes ATP-sensitive K+ channels • Depolarizes membrane ATP K+ 4) Depolarization opens voltage-gated Ca2+ channels

5) Increased intracellular Ca2+ levels Ca2+ Ca2+ triggers insulin secretion

Endocrine System Insulin receptor: Pancreatic Hormones: Tetramer; composed of 2 A. Insulin:  subunits and 2  subunits Mechanism of Action: 1 Insulin binds to  subunits; triggers conformational change

P

enzyme + ATP enzyme - P

2 3 (endocytosis) Tyrosine kinase autophosphorylates; Insulin-receptor complex internalized; phosphorylates intracellular either degraded, stored, or recycled enzymes / proteins Costanzo (Physiology, 4th ed.) – Figure 9.29

Endocrine System ‘Hormone of Abundance’ Pancreatic Hormones: Ensures that excess nutrients are stored for future use A. Insulin: Actions on Target Tissues: Insulin also enhances uptake Insulin of by cells

Decrease blood glucose Increase fat deposition; Increase protein synthesis; concentrations decrease lipolysis decrease blood [a.a.]

Liver Fat Muscle Glycogen cell cell cell glycogen lipolysis Proteins Fatty cellular synthetase acids respiration Glucose-6-phosphate a.a. lipogenesis glucokinase

Glucose Glucose Glucose

 # of GLUT 4 Glucose Glucose Amino acids Glucose transporter proteins

21 Endocrine System

Pancreatic Hormones: Diabetes mellitus ‘a sweet passer through’ A. Insulin: Pathophysiology:

Symptom(s) Cause of symptom

• Increased blood concentrations of glucose, • Decreased glucose and uptake by amino acids, and fatty acids cells; increased lipolysis of fats

• Metabolic ketoacidosis (‘fruity’ breath) • Increased conversion of fatty acids to ketoacids

• Increased urine output and • Increased glucose load in kidney filtrate

• Hyperkalemia • Increase in K+ exiting cells

Type I: Type II: Biguanide drugs (insulin-dependent; juvenile-onset) (non-insulin-dependent; adult-onset)

Cause: Cause: Decrease in # of -cells Down-regulation of insulin receptors (autoimmune) (target cells)

Treatment: Treatment: Insulin replacement therapy Caloric restriction / weight reduction

Endocrine System

Pancreatic Hormones: Diabetes mellitus ‘a sweet passer through’ A. Insulin: Pathophysiology:

Obesity linked with Type II diabetes:

Over-eating (adulthood)

Word of warning:

Normal # fat cells; Reduced # of increased size insulin receptors

Cellular desensitization  insulin to insulin

Endocrine System ‘Hormone of Starvation’ Pancreatic Hormones: Promotes mobilization and utilization of stored nutrients B. Glucagon: • Single chain polypeptide Actions on Target Tissues:

(29 a.a. residues) Glucagon

Increase blood Increase blood glucose Regulation: concentrations concentrations • Stimulates • Stimulates lipolysis • Decreased blood glucose levels • Stimulates gluconeogenesis stimulate secretion (targets liver cells) Fatty acids used as substrate for Additional Additional gloconeogenesis Stimulatory Factors Inhibitory Factors Increased [a.a.] Insulin Mechanism of action = G-protein / cAMP pathway (CCK) Somatostatins

Digestive hormone

22 Endocrine System ‘Hormone of Moderation’ Pancreatic Hormones: Regulates the responses of insulin and glucagon to ingestion of food C. Somatostatin: • Single chain polypeptide Actions on Target Tissues: (14 a.a. residues) Somatostatin

Decrease insulin secretion

Regulation:  blood (+) • Increased blood levels of all nutrient [glucose] forms stimulate secretion  - cells (-)  - cells (+) Additional Additional Stimulatory Factors Inhibitory Factors Glucagon Insulin (-) D - cells

Endocrine System ‘Hormone of Moderation’ Pancreatic Hormones: Regulates the responses of insulin and glucagon to ingestion of food C. Somatostatin: • Single chain polypeptide Actions on Target Tissues: (14 a.a. residues) Somatostatin

Decrease Decrease insulin secretion glucagon secretion

Regulation: (+)  blood • Increased blood levels of all nutrient [glucose] forms stimulate secretion  - cells (-)  - cells

Additional Additional Stimulatory Factors Inhibitory Factors Glucagon Insulin

(+) D - cells

Endocrine System

Calcium Regulation

23 Costanzo (Physiololgy, 4th ed.) – Figure 9.32 Endocrine System Key element in numerous Forms of Ca2+ in Blood: physiological functions

(albumin) Only form of Ca2+ that is biologically active

(e.g., phosphate)

Hypocalcemia: Hypercalcemia: Decrease in plasma [Ca2+] Increase in plasma [Ca2+] • Hyper-reflexia • Lowers • Spontaneous twitching • Polyuria / polydipsia threshold • Muscle potential • Hyporeflexia • Tingling / numbness Chvostek sign • Lethargy / coma

Costanzo (Physiololgy, 4th ed.) – Figure 9.34 Endocrine System

Overall Ca2+ :

Individual in Ca2+ balance: 350 = 150 + 200

(continuous)

Saliva, pancreatic & digestive

Three hormones tightly regulate Ca2+ levels: 1) (PTH) 2) 3)

Endocrine System

Calcium Regulation Hormones: A. Parathyroid hormone: • Produced by parathyroid glands

• Single chain polypeptide (84 a.a. residues)

Small glands (~ 4) embedded on dorsal surface of thyroid gland

Chief cell

• ProPTH modified to active hormone in Golgi apparatus (6 a.a. removed) • Chief Cells = PTH Oxyphil • Biologic activity resides entirely in the N-terminal 34 amino acids • Oxyphils = ?

24 Endocrine System

Calcium Regulation Hormones: A. Parathyroid hormone: Regulation: Ca2+ Sensing Receptors

 [Ca2+] =  PTH

Response occurs within seconds

Acidic a.a. residues = binding sites

• Influenced directly by plasma [Ca2+]

Activation of Ca2+ sensing receptors

triggers G protein / IP3 & DAG; shuts down PTH secretion • Mg2+ triggers similar events Multiple Ca2+ binding sites on extracellular domain Costanzo (Physiololgy, 4th ed.) – Figure 9.34

Endocrine System

Calcium Regulation Hormones: Responsible for increase in plasma [Ca2+] A. Parathyroid hormone: Actions on Target Tissues:

PTH

Increases Increases Ca2+ Increases Ca2+ reabsorption at kidney absorption at small intestine PTH & (indirect action; activates (bone marrow) 3- Decreases PO4 vitamin D production) Cytokines reabsorption at kidney (e.g., IL-6) (phosphaturia)  activity / recruitment Enhances Ca2+ resorption by lowering solubility constant 2+ 3- ([Ca ] x [PO4 ]) at bone

 resorption of bone Mechanism of action = G-protein / cAMP pathway

Costanzo (Physiololgy, 4th ed.) – Figure 9.34 Endocrine System

Overall Ca2+ Homeostasis:

PTH

(indirectly)

PTH

Three hormones tightly regulate Ca2+ levels: 1) Parathyroid hormone (PTH) 2) Calcitonin 3) Vitamin D

25 Endocrine System Humoral Hypercalcemia Calcium Regulation Hormones: of Malignancy: Tumors secrete PTH-related peptide; A. Parathyroid hormone: homologous with PTH Pathophysiology:

Hyperparathyroidism

Symptoms: Symptoms:

• Hypercalcemia • •  bone resorption •  bone resorption •  kidney Ca2+ reabsorption •  kidney Ca2+ reabsorption •  intestinal Ca2+ absorption •  intestinal Ca2+ absorption • Hypophosphatemia • Hyperphosphatemia 3- 3- •  kidney PO4 reabsorption •  kidney PO4 reabsorption Cause: Cause:

• (primary) • Thyroid surgery (cancers, etc.) • Renal failure (secondary) • Autoimmune / congenital

Treatment: Treatment:

• Surgery (primary ) • Ca2+ / Vitamin D supplements

Endocrine System

Calcium Regulation Hormones: Produced by parafollicular cells (C cells) of thyroid gland B. Calcitonin: • Single chain peptide

(32 a.a. residues) Actions on Target Tissues:

Calcitonin Intra-chain disulfide ring

Decreases bone resorption Calcitonin Regulation: Osteoclast activity / recruitment • Increased plasma [Ca2+] stimulates secretion • Utilize calcium sensing receptors  resorption of bone Overall, physiological role uncertain; changes in levels do not trigger derangement Mechanism of action = G-protein / cAMP pathway Ca2+ metabolism

Endocrine System Vitamin: Calcium Regulation Hormones: An organic compound that must C. Vitamin D: be obtained from the diet.

Diet 7 - Dehydrocholesterol Precursor to cholesterol

Photolysis

Diet Cholecalciferol

(Vitamin D3)

26 Endocrine System

Calcium Regulation Hormones: Irradiated food = adequate amount of vitamin (developed countries) C. Vitamin D: • Derived in of humans by action of ultraviolet light:

Reserve substrates

Vitamin D deficiency can result from lack of irradiation to skin

(Transcalciferin)

Endocrine System

Calcium Regulation Hormones: C. Vitamin D: • Additional modifications necessary for activation of Vitamin D

25-hydroxylase 25-OH-cholecalciferol Liver

•  [Ca 2+] Cholecalciferol Kidney 1α-hydroxylase •  PTH (Vitamin D3) •  [phosphate]

Regulation: • Regulation of Vitamin D synthesis occurs at the level of the kidney 1,25-(OH)2-cholecalciferol Active form

Endocrine System Responsible for increase in 2+ 3- Calcium Regulation Hormones: plasma [Ca ] & [PO4 ] C. Vitamin D: (associated with laying down new bone) () Actions on Target Tissues:

Vitamin D

Increases Increases Increases 2+ 3- 2+ 3- Ca & PO4 absorption Ca & PO4 absorption bone resorption at small intestine at kidneys

• Induces synthesis of (Unique from PTH which • Works with PTH to 3- calbindin D-28 K decreases PO4 reabsorption) stimulate osteoclast activity ???

Cytosolic transport protein Mineralized old bone is resorbed to (4 Ca2+ / protein) 2+ 3- provide Ca and PO4 for new bone

Mechanism of action = Internal Receptor System

27 Endocrine System Vitamin D Resistance: Calcium Regulation Hormones: Kidney unable to produce active hormone C. Vitamin D: • Absence of 1α-hydroxylase Pathophysiology: • Chronic renal failure

Vitamin D deficiency

Rickets: (children) (adults) Osteomalacia: Symptoms: Symptoms: • Growth failure / skeletal deformities • Softening of weight-bearing

Cause: Cause: • Inadequate sunlight / diet • Inadequate sunlight / diet Treatment: Treatment: • Vitamin D supplements • Vitamin D supplements

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