DATE: April 13, 2004

TIME: 9:30 A.M.

TITLE: Principles of Hormone Action

INSTRUCTOR: Dr. T.M. Lincoln

ASSIGNED READING: Boron & Boulpaep, Chapter 46

LECTURE OUTLINE

I. Messenger systems

A. Endocrine
B. Paracrine
C. Autocrine
D. Nervous system

II. Characteristics of hormones

A. Biochemical classification
B. Assay for hormone levels – the radioimmunoassay
C. Circulating forms
D. Feedback mechanisms

III. Mechanisms of hormone action

A. Cell membrane receptors

C Seven-transmembrane receptors
C G-protein coupled activation
C Second messenger systems
B. Tyrosine kinase receptors
C. Guanyly cyclase receptors
D. Intracellular receptors
C Steroid hormone receptors
C Transcription factors
DATE: Wednesday, April 14, 2004

TIME: 9:30 A.M.

TITLE: Endocrine Control Systems

INSTRUCTOR: Dr. T.M. Lincoln

ASSIGNED READING: Boron and Boulpaep, Chapter 46

LECTURE OUTLINE

I. Hypothalamic – Pituitary Gland Axis

A. Organization of hypothalamus
B. Organization of the pituitary gland
C Posterior pituitary
1. hypothalamic neuronal input
2. neurohormones released from the neurohypophysis
3. physiologic actions of neurohypophyseal hormones
C Anterior pituitary – control system
1. hypothalamic neuronal input
2. Releasing factors (hormones)
3. hypothalamo-hypophyseal tract
C. Hormones of the anterior pituitary gland
C Somatotrophin (growth hormone)
C Gonadotropins
C Corticotropins
C Thyrotropins
C Prolactin

II. Feedback control systems in the anterior pituitary

C Target gland hormones exert inhibitory action on hypothalamus and anterior
pituitary
C Releasing hormones regulated by target gland hormones
C Pulsatile release mechanisms

III. Pineal gland physiology

C Circadian rhythms
C Melatonin

IV. Rhythmic release of hypothalamic and pituitary hormones

DATE: Thursday, April 15, 2004

TIME: 9:30 A.M.

TITLE: Overall Fuel Metabolism

INSTRUCTOR: Dr. T.M. Lincoln

ASSIGNED READING: Boron & Boulpaep, Chapter 57, pp. 1211-1224; 1227-1230)

LECTURE OUTLINE

I. Metabolism defined
A. BMR – 20-25 kcal/kg body wt. (2300 kcal/day)
C Requires 200-250 ml oxygen/min
C CNS = 40% of BMR; skeletal muscle = 20-30%
C Proportional to lean body mass and surface area
B. Other energy output
C Food handling (diet –induced thermogenesis)
C Non-shivering thermogenesis
C Activities
C. Energy generation
C ATP = -12 kcal/mol in P-O bonds
C For BMR, 63 kg ATP turned over/day
C Respiratory Quotient

II. Energy storage and transfer

Input = Output + Stored; so,

Input – Stored = Output

C Fat stores account for 75% of energy reserves

C Protein stores – only used during prolonged fasting
C CHO (glycogen) – critical for CNS and short bursts of muscular work

A. Energy Transfer
C Glycogenolysis – muscle (75%) and liver (25%) – less than 1% of
reserves
C Gluconeogenesis – synthesis of glucose from non-CHO precursors
- Pyruvate, lactate, glycerol
- Amino Acids (except leu and lys)
- Not a simple reversal of glycolysis but separate pathways
B. Substrate use and synthesis
C Glucose and FFA are the two major energy substrates
C Plasma increases in FFA reduce glucose uptake
C Plasma increases in glucose reduce FFA uptake
 C Therefore, when glucose is plentiful (high carbohydrate meals), there is a
net conversion of glucose to fat (lipogenesis)
C Handling of glucose and FFA is regulated by insulin and glucagon

III. Metabolic pathways

A. Glucose is the central molecule (cellular and plasma levels regulated by uptake)
C Uptake into cells by facilitated diffusion
C Plasma concentration = 80 mg/dl (4.5 mM)
C 55% is terminally oxidized by CNS
C 30% of plasma glucose under control by insulin
C Circulating glucose = liver glucose output in 1 hr. Therefore, continuous
hepatic production of glucose is necessary to sustain CNS
B. Protein metabolism
C Avg. person has 10 kg protein
C 6 kg is metabolically active
C accounts for 20% of BMR
C Amino acids oxidized to CO2 and water with removal of urea
C Nitrogen balance (Amount secreted as ammonia and urea) = amt.
metabolized)
- If dietary protein < amt. secreted, negative N-balance
- If utilization > amt. secreted, positive N-balance
C. Fat
1. Amount used in oxidation (100 g) is approx. equal to intake normally
2. Ketogenesis

IV. Metabolic adaptations

A. Fasting
° Liver most important (supplies glucose via glycogenolysis for up to 12 hr)
° > 12 hr, gluconeogenesis
° Muscle increases FFA utilization; after several days fast, breaks down
protein
° After 3 days fast, energy expenditure drops, BMR decreases 20%, CNS
uses ketoacids
B. Exercise – short term ‘fasting’
- Short intense exercise energy supply is creatine phosphate (seconds)
- Anaerobic phase is glycogenolysis to glycolysis (minutes)
- Longer term phase is liver glycogenolysis and gluconeogenesis (hours)
V. Feeding behavior
A. Genetic influences apparent
° Body mass of adopted vs. biological offspring
° Monozygotic vs. dizygotic twins
° Identification of genes related to obesity in animal models
B. Environmental influences apparent
C. Physiology of feeding behavior
° Hypothalamus – caloric intake center
° Hunger center in lateral hypothalamus; satiety center in ventromedial
hypothalamus
° Afferent stimuli carry info regarding food load (sight, smell, etc.)
° Glucose in duodenum and portal vein inhibits eating behavior
° Signals within CNS are induced to either activate or inhibit feeding
behavior
D. Leptin
- Released by adipocytes when cell number and triglyceride contents
increase
- Binds to receptors in hypothalamus to reduce hunger
- Decreases NPY and increases sympathetic nervous system
- Decreases adipocyte mass
DATE: Monday, April 19, 2004

TIME: 9:30 A.M.

TITLE: The Endocrine Pancreas

INSTRUCTOR: Dr. T. M. Lincoln

ASSIGNED READING: Boron & Boulpaep, Chapter 50

LECTURE OUTLINE

I. Anatomy and function

C 1 million islets constituting 1-2% pancreatic mass
C Beta cells: 60-70% of islet mass
C Alpha cells: 20-25% of islet mass
C Delta cells: 10% of islet mass

A. Hormones released into pancreatic vein and then into the hepatic portal
circulation before returning to system circulation
B. Liver gets “first pass” look at hormones (greater concentrations)

II. Insulin
A. Insulin biochemistry
C MW = 6000; A chain (21 aa) and B chain (30 aa)
C Insulin binds 2 zinc atoms and is stored in granules
C Insulin biosynthesis:
Preproinsulin – (contains N-terminal signal peptide)
Proinsulin – single polypeptide cleaved and transported to Golgi
Insulin – “C” peptide cleaved to form mature insulin
B. Actions of insulin (overview)
C Increase glucose transport into tissues
C Increase lipogenesis
C Increase glycogenesis
C Increase amino acid transport and protein synthesis
C. Mechanisms of insulin secretion
C Major secretagogues are derived from digestive processes:
Glucose
Other carbohydrates
Amino acids (esp. basic and neutral aa)
Free fatty acids and ketoacids
C Hormones (glucagons, secretin, cholecystokinin, beta-agonists)
C Potassium ion
1. Mechanism of action of glucose
C Most important and potent secretagogue
C Binds to Glut-2 and is transported into Beta-cell by
 facilitate diffusion
C Phosphorylation of glucose by glucokinase
rate limiting step
traps glucose in cytosol
initiates glucose oxidation via glycolysis
C ATP/ADP ratio increases
C ATP-inhibited K-channel closes
C K efflux decreases and cell is depolarized
C Ca influx increases leading to secretory granule fusion with
plasma membrane
2. Two phases: an early rapid release phase that peaks in 1 minute,
and a slow phase that peaks at 1 hour
3. Oral glucose leads to greater insulin release than infused glucose
(possible that GI hormones augment release)
D. Regulation of insulin secretion
° Circulating insulin levels = 10 microunits/ml (6 X 10 M). Liver
exposed to 2 – 3 times this level
° Insulin circulates unbound to plasma proteins
° Sympathetic nervous system and epinephrine increase insulin secretion
(Beta-adrenergic action)
° Somatostatin and leptin decrease insulin secretion
° Insulin has negative feedback effects on its own secretion
E. Physiologic actions of insulin - INSULIN IS THE HORMONE OF
ABUNDANCE
° When influx of nutrients exceeds the demand, insulin induces STORAGE
° Liver:
1. Induces glucokinase which initiates glucose utilization
2. Activates glycogen synthase
3. Activates Phosphofructokinase and Pyruvate kinase (leading to
glucose oxidation which is important for fat storage)
4. Inhibits glycogen phosphorylase
5. Inhibits the expression and activity of gluconeogenic enzymes
(PEPCK and Fructose 1,6 diphosphatase/kinase)
6. Increases fatty acid synthetase and cholesterol synthase
° Muscle:
1. Stimulates glucose transport by increasing membrane expression
of Glut-4
2. Stimulates glycogen synthase and inhibits glycogen phosphorylase
3. Stimulates Na-dependent uptake of amino acids into muscle
4. Stimulates ribosome production and protein synthesis (anabolic
action)
° Adipose tissue:
1. Stimulates glucose transport by increasing membrane expression
of Glut-4
2. Inhibits hormone sensitive lipase (by activating cAMP
phosphodiesterase)
 3. Stimulates lipoprotein lipase
° Other actions:
1. Inhibits proteolysis and protein breakdown in tissues
2. Inhibits apoptosis in tissues
F. Cellular/molecular actions of insulin
G. Diabetes mellitus
C Type I (insulin-dependent): this is a primary deficiency of insulin
1. Beta cells destroyed – usually autoimmune disorder
2. hepatic glucose production is uninhibited
3. efficiency of peripheral glucose utilization reduced
4. caloric drain stimulates appetite and eating which exacerbates
hyperglycemia
5. plasma glucose levels exceed 300 mg/dl
6. urinary glucose output causes excessive secretion of salts and
water and hypovolemia
7. uninhibited lipolysis results in ketone acid production and
metabolic acidosis
8. negative nitrogen balance occurs as peripheral amino acid uptake
and protein synthesis are impaired
9. Non-enzymatic glucosylation of proteins implicated in damage to
tissues such as vasculature and lens leading to organ damage and
failure
10. Insulin replacement reverses these effects
C Type II (non-insulin dependent): this is insulin resistance
1. primary cause is unclear but is correlated with obesity (excessive
caloric intake leads to excessive insulin secretion)
2. insulin receptor become insensitive or down-regulated in face of
excessive insulin secretion
3. hyperglycemia accompanied by hyperinsulinemia shuts down
glucagon secretion (therefore, impairs lipolysis and
glycogenolysis)
4. this leads to the paradoxical excessive plasma glucose and
excessive fuel storage
5. because lipolysis is inhibited, type II diabetes does not result in
ketoacid production and metabolic acidosis
6. obesity (and hyperglycemia) lead to cardiovascular malfunction,
hypertension, atherosclerosis, fluid retention, and heart failure
7. therapy includes drugs which suppress hypoglycemia
III. Glucagon
A. Properties
C MW = 3500 (29 amino acids)
C Preproglucagon processed to glucagon and stored in granules of alpha
cells
C Circulates unbound at 50-100 pg/ml (2 X 10 M)
C Liver gets first-pass ‘look’ at glucagon and clears 50-75% on the first pass
B. Regulation of glucagons secretion
C Glucagon is secreted in response to fall in glucose levels (due to increased
demand or decreased intake)
C Hypoglycemia increases glucagon 2 – 4 fold
C Arginine, alanine and other amino acids increase glucagon secretion
C Glucagon suppresses its own secretion while increased glucose also
suppressed glucagon secretion (partially insulin-mediated)
C Glucagon levels vary much less than insulin levels following meals
primarily due to the dampening influence of insulin on glucagon secretion
C Fasting and exercise increase glucagon secretion
C. Actions of glucagons
C In every way, opposite those of insulin
C Liver is major target of glucagon where it:
1. mobilizes glucose release by stimulating glycogenolysis
2. stimulates gluconeogenesis by activating and inducing expression
of gluconeogenic enzymes
C Minor effects on adipose and muscle tissue
D. Biochemistry of glucagon action
C Activates adenyl cyclase and stimulates cAMP production
C PKA phosphorylates and activates glycogen phosphorylase
C PKA phosphorylates and inhibits pyruvate kinase
C PKA induces expression of PEPCK
C PKA phosphorylates and activates the fructose 2,6 – biphosphatase/kinase
bi-functional enzyme
E. Insulin:glucagon ratio
C Equals 2
C Fasting decreases the ratio while feeding increases ratio
C After a high Carbohydrate meal, ratio increases 10-fold in favor of insulin
C After a high Protein meal, both insulin and glucagon increase so ratio
remains around 2
- Insulin is anabolic – promotes protein utilization/synthesis
- Glucagon prevents decreased glucose output and hypoglycemia
that would occur with high insulin
- Less fat storage after protein meal compared with carbohydrate
meal
IV. Somatostatin
C 14 amino acid peptide secreted from delta cells
C Inhibits insulin and glucagon secretion
C Secretion stimulated by glucose, amino acids, FFA, and GI hormones
C Dampens excessive fluxes in insulin and glucagon levels
DATE: Monday, April 19, 2004

TIME: 1:00 P.M.

TITLE: Endocrine Control of Growth

INSTRUCTOR: Dr. T. M. Lincoln

ASSIGNED READING: Boron & Boulpaep, Chapter 47

LECTURE OUTLINE

I. Growth Hormone (GH) – aka Somatotrophin

C Acts mainly postnatal
C Increases bone mass and lean body mass
C Secreted by anterior pituitary somatotrophs (50% of the gland)
A. Structure and synthesis of GH
C Single polypeptide chain (22,000 MW) of 191 amino acids
C Member of “helix bundle proteins” that includes prolactin
C Synthesized as a prehormone with signal peptide
C Stored in secretory granules
C Synthesis stimulated by GHRH and inhibited by somatostatin
B. Secretion of GH – varies throughout lifetime
C GHRH – primary stimulus; increases cAMP and Calcium in somatotroph
C Somatostatin – physiologic inhibitor of GH and GHRH secretion;
decreases cAMP and Calcium
C Other factors:
1. acute fall in plasma glucose and FFA increase GH
2. insulin increases GH (by decreasing glucose)
3. amino acids increase
4. exercise, stress, and sleep increase GH
C GH under negative feedback control
C. Physiologic actions of GH
C Normal plasma levels are 10 M (can increase 50X)
C Bound to plasma protein resembling GH receptor
C Half-life = 20 min
1. Profound anabolic effects
C Liver produces insulin-like growth factors (IGFs) – aka,
somadomedins – in response to GH
C IGFs responsible for profound anabolic effects
2. IGF-1 and IGF-2 physiology
C Increase protein synthesis in muscle; increase amino acid
uptake
C Increase DNA, RNA, protein synthesis in chondrocytes
C Increase DNA, RNA, protein synthesis in most organs
C Sensitize gonads to LH and FSH to initiate sexual
 maturation
3. Metabolic effects of GH
C Increased lipolysis, decrease adiposity
C Increase glucose oxidation
C Decrease RQ
C “diabetogenic” actions on metabolism
D. Complementary actions between insulin and GH
C Ample protein intake: insulin and GH act together to increase tissue
growth
C Ample carbohydrate intake: insulin action for caloric storage
C moderates GH action on growth; GH helps prevent hypoglycemia
C Fasting: insulin falls and GH induces caloric mobilization

II. Molecular actions of GH and somatomedins

C Growth promoting actions accounted for by IGF-1 and IGF-2
C IGF-1 and IGF-2 bind to distinct membrane receptors
C IGF-1 receptor structurally similar to insulin receptor; IGF-2 receptor a single
polypeptide chain
C IGF-1 and 2 can bind to insulin receptor but only at high levels
C IGF-2 in particular is necessary for implantation, embryonic growth and fetal
development
DATE: Tuesday, April 20, 2004

TIME: 9:30 A.M.

TITLE: Thyroid Physiology

INSTRUCTOR: Dr. T.M. Lincoln

ASSIGNED READING: Boron & Boulpaep, Chapter 48

LECTURE OUTLINE

I. General History
C First endocrine gland to be associated with diseases due to deficiency or excess
secretion
C First hormone linked to regulation of metabolism

II. Synthesis and release of thyroid hormones

A. Thyroid Follicles
C Thyroid hormones synthesized by follicular (epithelial) cells surrounding
colloid material
C Hormones are actually produced and stored in colloidal space
C Major colloidal protein is thyroglobulin (330 kD) – synthesized and
secreted by follicular cells
B. Steps in the synthesis of thyroid hormones
1. Iodide Trap - Iodide anion is actively transported into follicular cells
2. Iodide is oxidized to iodine by thyroidperoxidase (TP) using hydrogen
peroxide
3. Organification – tyrosine residues in TG are iodinated by
thyroidperoxidase and hydrogen peroxide; products are monoiodotyrosine
(MIT) and diiodotyrosine (DIT)
4. Coupling – MIT + DIT = T3 (triiodothyronine) or
DIT + DIT = T4 (tetraiodothyronine – aka, thyroxine)
C 90% is T4; 10% is T3; trace of reverse T3
C T3 is form responsible for the biological effects
C About 10% of all tyrosines on TG are iodinated
C. Iodine Pool
C 400 micrograms avg diet
C 70 – 80 micrograms taken up
C Iodide is transported 30X against concentration gradient by Na/I symport
on basal membrane of follicular cells
C Iodide transport stimulated by TSH and cAMP
D. Thyroid hormone secretion
C Endocytosis of colloid at luminal membrane
C Transport and proteolysis to T4 and T3
C TSH and cAMP stimulate all aspects of secretion
 E. Role of TSH

III. Metabolism of thyroid hormones

A. Interconversion
C T4 is converted to T3 in most tissues by 5’-deiodinase
C Multiple forms of deiodinase in tissues
C T4 is dominant secretory form; serves as a prohormone for T3
C T3 can be further deiodinated to T2, T1, and T0 (inactive metabolites)
B. Circulating forms
C 99.97% of T4 and T3 circulate bound to plasma proteins
C Major binding protein is thyroxine-binding globulin (TBG)
C Others are albumin and transthyretin (TTR)
C Functions of binding proteins are to serve as a reservoir for T4 and
prevent loss of T4 and T3 in urine

IV. Molecular actions of thyroid hormones

C Enter cells via carrier-mediated, energy-requiring transport
C T3 binds chromatin-associated receptor/transcription factor (TR)
C T3 de-represses TR function and initiates gene expression in target cell

V. Physiologic effects of thyroid hormones

A. Metabolic effects
C Increases oxygen consumption in target tissues (225 to 400 ml/min)
C RQ not affected; both glucose and FFA oxidation increased
C Energy utilized by increased expression of Na/K-ATPase partially
responsible
C Uncoupling of mitochondrial ATP production partially responsible
C Increases glucose absorption from GI tract
C Increases protein turnover
B. Respiratory effects
C Increased respiration rate, minute ventilation, and ventilatory response to
hyper capnia and hypoxia
C Response to increased tissue oxygen utilization
C. Cardiac
C Direct effects – increased myosin beta/alpha expression, Na/K-ATPase,
beta-receptor density
C Indirect effects (more important) – increase carbon dioxide and heat
production leads to vasodilation and reflex beta-adrenegic stimulation
D. Tissue Growth and development
C Nonhuman primates (e.g., tadpole development) illustrative
C Endochondral ossification
C Long bone growth and remodeling
C Neuronal cell development
C Emotional and well-being

VI. Thyroid pathophysiology

C Hyperthyroidism – most common: Grave’s Disease
B Increased heat production
B Intolerance to warmth
B Nervousness
B Cardiac abnormalities
B Exopthalamus
B Goiter
B Hypothyroidism – idiopathic loss of follicular cell function
# Goiter
# Increased weight gain, decreased metabolism
# Increased fat deposit
# Intolerance to cold
# Mental retardation (cretinism)
DATE: Wednesday, April 21, 2004

TIME: 9:30 A.M.

TITLE: Hormonal Regulation of Calcium and Phosphate

INSTRUCTOR: Dr. T. M. Lincoln

ASSIGNED READING: Boron & Boulaep, Chapter 51

LECTURE OUTLINE

I. Key hormones: Parathyroid Hormone (PTH), Vitamin D (1,25-OH2-D3)

Systems affected: Bone, Intestinal Tract, Kidney

A. Calcium and Phosphate Pools

1. Calcium
C Ca is key regulator of cellular signaling and activity
C % dietary Ca absorbed is INVERSELY related to intake
C same amount taken in is excreted by intestine and kidney
C hormonal influences increase Ca absorbed in absence of adequate
dietary Ca and vice versa
C extracellular pool of 1000 mg is in equilibrium with a larger
rapidly exchanging pool provided mainly by bone
2. Phosphate
C integral component of proteins, carbohydrates, lipids, intermediary
metabolic products, ATP, and nucleic acids
C 85% is in bone
C 70% of phosphate ingested is absorbed by intestine and
immediately available to tissues
C excess is excreted by kidney
B. Bone Dynamics
C Stores 1 – 2 kg of body mineral (mostly Ca)
C Divided into two types of bone: cortical (80%) and trabecular
(20%)
C Trabecular bone with its greater surface area contributes more to
bone turnover
C Skeleton turns over about 10% per year in absence of new growth
C Major Cell Types; Osteoblasts, Osteocytes, Osteoclasts
1. Bone formation: the bone unit
C Formation is carried out by osteoblasts which synthesize and
secrete collagen into EC space
C 10 days required between osteoid formation and mineralization
C Major mineral: hydroxyapatite – Ca/P = 1.7 on molarity basis
C Osteoblasts work best on bone surface (concentric lamellae in
 cortical bone and linear lamellae in trabecular bone)
2. Bone resportion
C Osteoclasts carry out resorption by releasing collagenases,
phosphatases, and lysosomal enzymes
C Resorption is carried out in acidic environment created by HCl
secretion by osteoclast
C Paracrine signals from precursor cells initiate the process
3. Bone turnover under control of Vitamin D, PTH and (to some extent)
Calcitonin

II. Vitamin D – increases plasma ionized calcium

C Active form = 1,25 – (OH2) – D

C Increases Ca absorption from intestine
C Increases Ca resorption from bone

A. Formation
C Acquisition from diet and produced by irradiation of skin
C Previtamin D3 converted to D3
C D3 converted to inactive 25- OH-D3 in liver
C Kidney hydroxylates D3 to active 1,25 – (OH)2 – D by enzyme 1-alpha-
hydroxylase
B. Regulation of 1,25-(OH)2 – D formation
C Decreases in Ca stimulate PTH release
C PTH increases 1-alpha-hydroxylase
C Low Phosphate increases 1-alpha-hydroxylase
C. Vitamin D actions
C Nuclear receptor action similar to other steroid hormones
C Increases the expression of Ca pumps and Calbindin in target tissues
C Increases Ca absorption against concentration gradient (appr. 6 hr)
C Increases Phosphate absorption
C Increases Magnesium absorption
C Decreases osteoblastic activity and increases osteoclastic activity
C Represses PTH expression (neg. feedback)
III. PTH – increases plasma ionized calcium

C Secreted by Chief Cells in parathyroid gland

C Synthesized as a prepro hormone

A. Regulation of secretion
C Level of plasma calcium is the main regulatory influence
C Increased calcium flux causes a decrease in PTH secretion
B. Actions of PTH
C PTH receptor is coupled to adenyl cyclase and cyclic AMP
C Bone: increases osteolysis and osteoclastic activity
C Kidney: increases Ca resorption from ascending limb and distal tubule;
 decreases phosphate resorption from kidney and increases urinary
phosphate (prevents plasma calcium-phosphate precipitation)
C Kidney: increases 1-alpha hydroxylase and vitamin D formation
C. Coordinated actions of PTH on Ca/phosphate metabolism

IV. Calcitonin
C Inhibits osteoclastic activity
C Reduces plasma Ca levels
C Stimulates phosphate excretion
C Physiologic relevance unclear

V. Hormone Deficiencies and Excesses

A. Vitamin D
C Deficiency causes rickets
C Overproduction causes hypercalcemia, hypercaliuria, renal calculi
B. PTH
C Hypoparathyroidism (inadvertent removal) – hypocalcemia and rickets-
like syndrome
C Hyperparathyroidism (benign neoplasms) – hypercalcemia, hypercaliuria,
renal calculi
C Weakened bones and pain
DATE: Thursday, April 22, 2004

TIME: 9:30 A.M.

TITLE: Adrenal Physiology

INSTRUCTOR: Dr. T.M. Lincoln

ASSIGNED READING: Boron & Boulpaep, Chapter 49

LECTURE OUTLINE

I. Anatomic considerations
C Medulla – catecholamines
C Cortex – glucocorticoids and mineralocorticoids
C Cortex: 3 layers – zona glomreulosa, zona fasiculata, and zona reticularis

II. Adrenal corticosteroids – all derived from cholesterol

C Complex interconversion
C Cortisol is major corticoid in humans
C Required for life
A. Cortisol and cortisone
C All synthesized from complex oxidations of cholesterol esters
C Both cytosolic and mitochondrial enzymes/proteins involved
C Pregnenolone is most proximal precursor for all subsequent synthesis
C Family of mixed oxidases of the cytochrome P450 series is required for
synthesis and interconversion
C Cortisol and cortisone synthesized in the zona fasiculata
B. Androgens and estrogens
C Adrenal supplies non-gonadal sex steroids
C Dihydroepiandrosterone (DHEA) can be converted to testosterone in
tissues
C 50% of androgens needed by women arise from adrenal cortex
C Synthesis occurs in zona reticularis
C. Mineralocorticoids
C Aldosterone produced exclusively in zona glomerulosa
C 11-deoxycortisone and cortisol have some mineralocorticoid activity at
higher concentrations

III. ACTH
C Cyclic AMP serves as second messenger
C Cyclic AMP regulates immediate, short-term, and long-term effects of ACTH
C ACTH carefully regulated by elaborate feedback system

IV. Actions of glucocorticoids

C General effects include:
 - Metabolic effects (e.g., maintenance of glucose production from protein)
- Facilitation of other hormone actions (permissive actions)
- Immune system modulaltion
A. Molecular actions
C Steroid hormone receptor action
C Glucocorticoid receptor (GR) associated with heat-shock
protein (HSP) 90
C Binding of cortisol releases HSP-90 and activates
dimerization
C Translocation to nucleus and DNA
C Regulates gene expression from specific Glucocorticoid
Response Elements (GRE)
B. Effects on metabolism
C Cortisol is elevated at night during which it enhances
gluconeogenesis, lipolysis and ketogenesis (all necessary to
sustain metabolism during overnight fast)
C Cortisol inhibits muscle protein synthesis and stimulates
muscle proteolysis
C Cortisol stimulates the conversion of amino acids to
glucose (when liver glycogen stores are depleted, a
deficiency in gluconeogenesis from protein due to absence
of cortisol can result in death)
C Cortisol facilitates glycogen synthesis and storage to blunt
the hypoglycemic action of insulin
C Cortisol induces the expression of glucose – 6- phosphatase
(required for glucose release from liver)
C Cortisol inhibits glucose uptake in muscle and adipose
tissue and has an overall “diabetogenic” action
C. Other effects of cortisol
C Increases appetite and feeding behavior (via neuropeptide
Y release). Note: cortisol also increases leptin secretion
thereby blunting these effects
C Increases adipocyte differentiation (at high levels)
C Increases fat deposits in abdomen, trunk and face (at high
levels)
C Inhibits bone formation by decreasing osteoblastic activity
and reducing vitamin D transport from the GI tract
(osteoporosis-like effects)
C Cortisol is required for normal blood pressure maintenance
(mechanism unknown)
D. Anti-inflammatory activity
C Multiple sites of action
C Major influence to inhibit inducible NO synthase (iNOS)
expression

V. Mineralocorticoids
 C Only zona glomerulosa produces aldosterone
C Hormones bind to mineralocorticoid receptor (MR)
C MR present in most tissues; functions not entirely clear
C Stimuli for aldosterone production and secretion: Potassium, angiotensin II;
Atrial Natriuretic Peptide (ANP) potent inhibitor of secretion
C Actions include: mobilization of intracellular Na/K – ATPase; Na channel;
increased new expression of Na/K-ATPase and Na channel
C Cortisol and 11-deoxycortisone have weak MR binding activity
C Kidney expresses 11-beta-hydroxysteroid dehydrogenase (HSD) to metabolize
cortisol to inactive cortisone

VI. Pathophysiology of adrenal cortical function

C Addison’s disease – primary adrenocorticoid deficiency
- failure of all adrenal steroid synthesis
- weakness, fatigue, weight loss
- hypoglycemia, hyponatremia, hyperkalemia
C Secondary insufficiency due to pituitary abnormality (mineralocorticoid synthesis
retained)
C Cushing’s disease – excessive secretion of ACTH
- weight gain, protein wasting
- hyperglycemia, hypokalemia
- hypertension
- also, cortisone secretion from tumor (Cushing’s syndrome)