Adrenal Gland

Introduction
Polyfunctional organs
Adaptive responses to stress Maintenance of body water and salt balance Control of blood pressure Regulation of body fuel metabolism

Disorder of adrenal gland classic endocrinopathy

Cushing syndrome Addison disease Hyperaldosteronism Syndromes of congenital adrenal hyperplasia

Introduction
Three major categories adrenal hormones
Mineralocorticoids
E.g. Aldosterone Regulation of body salt balance

Glucocorticoids
E.g. Cortisol Body metabolisms of glucose

Androgens
E.g. dehydroepiandrosterone (sex-steroid precursors) Control the development and maintenance of masculine characteristics.

Weak Androgens
Androgens
Precursor for sex-hormone (sex-steroid) E.g.
Dehydroepiandrosterone (DHEA) Androstenedione

Converted to more potent sex hormones in peripheral target tissues.

ADRENAL GLAND
Located superior to the kidney Divided into: Outer cortex
90% of adrenal mass Consists of 3 zones
Zona glomerulosa,

Zona fasciculata, Zona reticularis

Inner medulla
10% of remaining adrenal mass Derived from subpopulation of neural crest cells (modified sympathetic ganglion

The Adrenal Gland

Anatomy and histology of the adrenal glands. The paired adrenal glands are located above the kidneys and are comprised of an outer cortex containing three functional zones and an inner medulla

Adrenal Cortex
Consists of 3 zones vary in both morphologic features and hormones they produce.
Zona glomerulosa
abundant smooth endoplasmic reticulum Produce aldosterone

Zona fasciculata
Thickest layer of the adrenal cortex (75%) Cells are larger and abundant of lipid clear cells Produce cortisol and androgens

Zona reticularis
Produce cortisol and androgens

Adrenal Cortex
Zona fasciculata and zona reticularis
Under regulation by ACTH
Alteration of ACTH level alters structure and function
Deficient ACTH atrophy of both zones Excess ACTH hyperplasia and hypertrophy

ACTH stimulation:
Zona fasciculata respond acutely by increased cortisol Zona reticularis maintain basal cortisol secretion by prolonged ACTH stimulation

Adrenalcortical Hormones Synthesis

Steroidogenesis steroid hormone synthesis Precursor cholesterol (plasma membrane/cytoplasmic pool Cholesterol transport into mitochondria by steroid acute regulatory protein (StaR) converted to pregnenolone by cytochrome P450 side-chain cleavage enzyme (P450scc). Cells in different sections of adrenal cortex different specific enzymatic features different synthetic pathways - result in different end product (hormones) from precursor pregnenolone - glucocorticoids - mineralocorticoids - androgens

Zones and Steroidogenesis

Zona glomerulosa Zona reticularis Zona fasciculata Enzymatic differences - Different regulation and secretory
products (hormones)

Zona glomerulosa
Lack of 17-hydroxylase Cannot synthesize 17-hydroxypregnenolone and 17 hydroxyprogesterone (precursors of cortisol and androgens) Synthesis of aldosterone primarily regulated by reninangiotensin system

Zona fasciculata and reticularis

Absence of P450also (aldosterone synthase) no aldosterone Only produce cortisol and androgens

Different zone in adrenal cortex with different enzymatic properties resulting different hormone synthesis from the same precursor Pregnenolone

Adrenalcortical Hormones Synthesis

Transport of cholesterol into mitochondria
Stimulated by steroid acute regulatory protein (StAR)

Conversion of cholesterol to pregnenolone

Removal of cholesterol side chain Catalyzed by P450 side chain cleavage (P450scc) enzyme Rate-limiting step of steroid hormone biosynthesis

Shuttling intermediaries between mitochondrion and endoplasmic reticulum for further enzymatic modification
Towards aldosterone and cortisol synthesis pathway, or Towards cortisol or sex-steroid precursor (androgens)

Biosynthesis of adrenal cortical hormones. Reactions shown in the yellow box are unique to the zona glomerulosa. Reactions shown in the blue box are seen in the zonae fasciculata. Reactions shown in the green box are seen in both the zona glomerulosa and reticularis. Reactions shown in the pink box are largely confined to the zona reticularis. Structural changes produced in each reaction are shown in red.

Enzymes and Relevance 21-Hydroxylase Accounts for 95% of genetic abnormalities in adrenal steroid hormone synthesis

Physiological Function Converts progesterone to 11deoxycorticosterone and 17hydroxyprogesterone to 11deoxycortisol

Consequence of deficiency - Decreased cortisol and aldosterone - Loss of sodium because of mineralocorticoid deficiency - Virilization because of excess androgen production - Excess 11-deoxycortisol and 11-deoxycorticosterone - Excess mineralocorticoid activity - Salt and water retention

11-Hydroxylase Second most frequent abnormality in adrenal in adrenal steroid hormone synthesis 11-Hydroxysteroid dehydrogenase type 2 Inhibited by glycyrrhetinic acid Metabolize the active forms of glucocorticoids into inactive forms that have less affinity for the mineralocorticoid receptor - Decrease in glucocorticoid inactivation in mineralocorticoid-sensitive cells - Excess mineralocorticoid activity Convert 11-deoxycorticosterone to corticosterone, 11-deoxycortisol to cortisol

Regulation and Secretion

ACTH
Trophic hormone of zona fasciculata and reticularis Major regulator of cortisol and androgen production
Other factors, e.g. neurotransmitters, neuropeptides, and nitric oxide also involved in regulation

ACTH in turn regulated by

CRH AVP Neurotransmitter Neuroendocrine control

ACTH Effects on Adrenal Cortex

Stimulate synthesis and secretion of steroid hormones
E.g. plasma levels of steroid hormone rise within minutes after ACTH administration

ACTH increases DNA, RNA and protein synthesis Chronic ACTH stimulation (excess)
Adrenocortical hyperplasia and hypertrophy

Deficiency in ACTH
Decreased steroidogenesis Adrenocortical atrophy Decreased adrenal gland weight Decreased protein and nucleic acid (DNA, RNA) content

ACTH and Steroidogenesis

ACTH binds to surface plasma membrane receptor
Activating adenylyl cyclase increases cAMP cAMP
Activates StAR transport of cholesterol into mitochondria Activates intracellular protein kinase A

Increase lipoprotein uptake by adrenal cortex Protein kinase A

Phosphorylates cholesterol esterase split cholesterol cholesterol-ester increases free cholesterol formation from

Cholesterol delivered to side chain cleavage enzyme

Conversion to pregnenolone Initiate steroidogenesis

Regulation of ACTH Secretion

1. Circadian rhythm (biological clock)

Endogenously driven, roughly 24-hour cycle in biochemical, physiological, or behavioural processes Superimposed on episodic secretion Regulate both the number and magnitude of CRH and ACTH secretory episodes Adjusted to the environment by internal or external cues
Altered by sleep pattern, light-dark exposure, feeding times Physical stresses, e.g. major illness, surgery, trauma, starvation Psychological stress, e.g. severe anxiety, endogenous depression, maniac-depressive suppression CNS and pituitary disorder Cushing syndrome Liver disease, chronic renal failure (affect cortisol metabolism) Alcoholism

Circadian Regulation of ACTH

Biological Clock

Diurnal ryhthm

ACTH

Cortisol

Regulation of ACTH Secretion

2. Stress responsiveness
Secretion of ACTH and cortisol responsive to physical stress E.g. physical stress
Surgery, hypoglycemia

Stress responses originate in CNS increase secretion of

Hypothalamic CRH Pituitary ACTH

If stresses are prolonged abolish circadian periodicity

3. Feedback inhibition
Secretion of CRH and ACTH inhibited by high cortisol level Occurs both at hypothalamus and pituitary

Feedback Inhibition of ACTH

The HPA axis model has three compartments, namely the hypothalamus, pituitary and adrenals. Neural signals trigger CRH secretion by the

hypothalamus. In turn, this signals to the pituitary to release ACTH which stimulates the adrenal gland to release cortisol. Cortisol acts on the hypothalamus and the pituitary to have a negative feedback effect on the release of CRH and ACTH

respectively.

Circulation of Adrenocorticoid Hormones

Cortisol and androgens circulate bound to plasma proteins reservoir of hormones
1) Corticosteroid-binding globulin (CBG)/Transcortin
Binds mainly cortisol

2) Albumin
Binds mainly to androgens, lesser extent to cortisol

Half-life of cortisol 60-90 mins depends on:

Extent of plasma protein binding Rate of metabolic inactivation

Under basal conditions

10% of cortisol free form biological active 75% of cortisol bound to CBG biological inert Remainder bound to albumin

Circulation of Adrenocorticoid Hormones

Aldosterone
50-70% - bound to either albumin or CBG 30-50% - free form Half life 15-20 mins Rapidly inactivated to tetrahydroaldosterone by liver

Metabolism of Adrenocorticoid Hormones

Metabolisms of adrenocorticoid hormones
Conjugation with glucuronide or sulphate groups Inactivate hormones Increase their water solubility (excreted in urine)

Metabolized through:
Liver
Major site of steroid catabolism and conjugation Hepatic conversion: e.g. enzymatic-mediated conversion from cortisol to tetrahydrocortisol or cortisone Hepatic conjugation: e.g. > 95% of cortisol/cortisone metabolites conjugated with glucuronic acid reenter circulation excreted in urine

Kidney
90% of metabolized steroids excreted by kidney

Steroid Hormone Receptors

Cortisol and aldosterone
Bind to mineralocorticoid receptors (MR) with similar affinity
Mineralocorticoid (e.g. aldosterone) and glucocorticoid (e.g. cortisol) receptors are closely related

Factors preventing cortisol-mediated mineralocorticoid receptors activation

1) Binding of cortisol by plasma binding proteins, e.g. CBG
Reduce amount of free cortisol to only 10%

2) Cortisol-cortisone shunt
11-HSD2 present in aldosterone target cells Convert cortisol to cortisone less affinity for MR

3) Discrimination between cortisol and aldosterone by MR

Aldosterone dissociates from MR 5x more slowly than cortisol

Oxidation of cortisol to cortisone renders the steroid incapable of binding to the mineralocorticoid receptor.

Cortisol-Cortisone Shunt
In classical aldosterone target tissues, e.g. kidney:
11-hydroxysteroid dehydrogenase type 2 (11-HSD2) Metabolizes cortisol to inactive cortisone Avoid binding of cortisol to mineralocorticoid receptors (MRs)

In other tissues, e.g. liver and skin

11-hydroxysteroid dehydrogenase type 1 (11-HSD1) Convert cortisone back to cortisol

Completing cortisol-cortisone shunt

Cortisol-Cortisone Shunt

11-hydroxysteroid dehydrogenase type II is an exclusive enzyme that acts in classical aldosterone target tissues to exclude cortisol from non-selective mineralocorticoid receptors through inactivation of cortisol to cortisone

Aldosterone
Mineralocorticoid produced by zona glomerulosa Hormone that increases the reabsorption of sodium ions and water and the release (secretion) of potassium ions in the distal tubules and collecting ducts of the kidneys
Increase blood volume increase blood pressure

Stimulated by
increase in plasma angiotensin II, ACTH, or potassium levels Deficiency in plasma sodium

Inhibited by
Atrial Natriuretic Factor (ANF) serves as negative regulator
Reduce synthesis of StAR and its gene expression

Regulation of Aldosterone Secretion

Forming of electrochemical gradient that facilitates transfer of intracellular potassium from tubular cells into urine. Sodium and water retention expand the extracellular volume and blood volume. Expansion of blood volume (ultimate result of sodium retention) negative feedback signal for regulation of renin and aldosterone secretion

Aldosterone: Bodys Major Mineralocorticoid

Function
Promote sodium reabsorption from urine into circulation Promote potassium excretion from circulation into urine Increase blood pressure

Aldosterone: Regulation
Renin-angiotensin system
Primary regulator Forming a negative feedback loop

Serum potassium concentration

Elevated serum potassium promote aldosterone secretion Negative feedback loop

ACTH
Minor role

Atrial Natriuretic Factor (ANF), dopamine

Negative regulator

Negative Feedback Regulation of Aldosterone

control via potassium
hyperkalemia

control via renin-angiotensin system

dehydration, Na+ deficiency, hemorrhage

( -)

aldosterone secretion from zona glomerulosa cells

decreased blood volume

negative feedback

decreased blood pressure decreased K+ reabsorption by kidneys ( -) renin secretion by kidneys normokalemia negative feedback activation of angiotensin II

aldosterone secretion ADH secretion increased thirst increased vasoconstriction

increased blood pressure

Renin-Angiotensin-Aldosterone System
Renin
Enzyme produced in juxtaglomerular apparatus (kidney) Rate limiting step for renin-angiotensin-aldosterone system

Secretion of renin controlled by:

Juxtaglomerular cells
Pressure transducers sense stretch of afferent arteriolar wall Sensitive to renal perfusion pressure

Macula densa
Chemoreceptor monitoring of sodium and chloride in distal tubule

Sympathetic nervous system

Modify release of renin in response to upright posture

Humoral factors
E.g. potassium, angiotensin II and atrial natriuretic peptide (ANP)

Renin-Angiotensin-Aldosterone System
Increased Renin Secretion Decreased Renin Secretion by: by: Low renal perfusion Elevated renal perfusion pressure pressure Low tubular sodium content High tubular sodium content (e.g. renal artery stenosis, (e.g. high sodium diets) hemorrhage, dehydration) Hypokalemia Hyperkalemia

Renin-Angiotensin-Aldosterone System

Renin-angiotensin-aldosterone and potassium-aldosterone feedback loops. Zona glomerulosa aldosterone production and secretion are determined by input from each loop.

Mechanism of Renin-Angiotensin-Aldosterone
Decrease in circulating blood volume decrease in renal perfusion pressure detected by renal juxtaglomerular cells Activated juxtaglomerular cells increase renin release Renin catalyzes conversion of angiotensinogen to angiotensin I Angiotensin-converting enzyme (ACE) from lung and renal epithelium catalyzes conversion of angiotensin I to angiotensin II and angiotensin III Angiotensin II and III stimulate adrenal zonal glomerulosa to release aldosterone Aldosterone stimulate sodium reabsorption and water retention preserve circulating blood volume Increased circulation of angiotensin II produce direct arteriolar vasoconstriction increase blood pressure

Renin-Angiotensin-Aldosterone

Renin-angiotensin-aldosterone axis

Angiotensin Pathway: Maintains BP , Volume & Osmolarity Angiotensinogen, ANGI, ANG II, rennin, & ACE

ANGIOTENSIN II - SUPPORT OF THE BLOOD PRESSURE Cardiac & Vascular Hypertrophy Vasoconstriction Direct Renal Sodium Retention

Cardiac Contractility

Angiotensin II

Aldosterone Secretion

Sympathetic Facilitation:

Thirst ADH Release

Central Nerve terminal

(ganglionic ?)

All known physiologic effects are mediated by the angiotensin II type 1 receptor

Aldosterone: Biosynthesis
Angiotensin II binds to surface G protein coupledreceptor
Activating phospholipase C cleavage of PIP2 Release of IP3 and DAG IP3
Increases intracellular Ca2+ level by stimulating release of Ca2+ from internal stores (ER)

DAG
Stimulate protein kinase C to activate calcium channel in the plasma membrane for influx of external Ca2+

Increased intracellular Ca level:

Induce synthesis of StAR protein, promoting transfer of cholesterol into mitochondria Increase intramitochondria Ca level stimulate enzymes critical for aldosterone synthesis, e.g. aldosterone synthase

Stimulation of aldosterone synthesis by angiotensin II (AII). AII accelerates the conversion of cholesterol to pregnenolone and 11- deoxycorticosterone to aldosterone. q, = subunits of the guanine nucleotide-binding protein. PLC = phospholipase C. DAG = diacylglycerol; IP3 = inositol trisphosphate; PKC = protein kinase C; CAM kinase II = calcium, calmodulindependent protein kinase II; StAR = steroid acute regulatory protein.

Aldosterone: Biosynthesis
Synthesis and secretion of aldosterone ONLY restricted to zona glomerulosa
Zonal-specific expression aldosterone synthase of

Biosynthesis
StAR-mediated cholesterol uptake into mitochondria Conversion of cholesterol to pregnenolone stimulated by P450Scc Pregnenolone converted to aldosterone catalyzed by aldosterone synthase

Aldosterone: Effects on Kidney

Aldosterone
Promote inward transport of sodium across epithelial cells (principal cells) of kidney tubules Promote outward transport of potassium and hydrogen ions into urine

Net effect
Increase osmotic potential within circulation Followed by water reabsorption (water retention) Expansion of intravascular circulating volume and pressure

Aldosterone: Mechanism of Action

Aldosterone (lipid-soluble) cross membrane plasma of principal cell at:
Distal tubule Cortical collecting duct

Binds to mineralocorticoid receptor (MR) Aldosterone-MR complex - initiates transcription for:

Sodium channels
Newly synthesized sodium channels inserted into luminal membrane of principal cells promote Na reabsorption

Sodium-potassium (Na/K) ATPase transporter

Newly synthesized Na/K ATPase transporter inserted into basolateral membrane of principal cells increase sodium resorption in exchange for potassium excretion

Mechanism of Na+ Selective Reabsorption in Collecting Duct

Figure 20-12: Aldosterone action in principal cells

Mechanisms of Aldosterone
Aldosterone-MR complex translocate into nucleus binds to glucocorticoid response element (GRE)
Function as transcription factor Increase expression of serum- and glucocorticoid-inducible kinase (Sgk 1)

Sgk 1
Phosphorylate and inactivate neural-precursor-cellexpressed,developmentally downregulated gene (Nedd)4-2
Nedd4-2 ubiquitin ligase degrade epithelial sodium channel

Increase number of sodium channels increased sodium reabsorption

Mechanisms of Aldosterone

Cortisol
Hormone under glucocorticoid family Produced by cells in zona fasciculata and zona reticularis Released in response to stress and a low level of blood glucose Under regulation of hypothalamic (CRH) pituitary (ACTH) adrenal (cortisol) axis Primary function increasing blood sugar through gluconeogenesis suppressing the immune system aiding in fat, protein, and carbohydrate metabolism

Negative feedback control of glucocorticoid secretion. CRH = corticotrophinreleasing hormone; AVP = arginine vasopressin (+) = stimulates. () = inhibits.

Glucocorticoid on Energy Metabolism

Absence of adrenal function, short period of fasting will results:
Hypoglycemia Depletion of muscle and liver glycogen Inability to produce glucose fr. non-glucose precursors (gluconeogenesis) Totally rely on dietary sugar for carbohydrate metabolism

Actions of glucocorticoid:
Promote proteolysis and inhibit protein synthesis in muscle and lymphoid tissues release of amino acid into blood for gluconeogenesis. Decrease glucose utilization by muscle and adipose tissue. Lower responsiveness/sensitivity of tissues to insulin. Increase amount and activity of enzymes involves in gluconeogenesis. Increase blood glycerol by lipolysis in adipose tissues.

Glucocorticoid: Molecular Mechanisms

Entry of glucocorticoid (cortisol) into target cells Binding of hormone to cytosolic glucocorticoid-receptors Hormone-receptor complex enter nucleus and interact with hormone response element on DNA Altered expression of specific genes and transcription of specific mRNA Production of new proteins elicits glucocorticoid response (may be inhibitory or stimulatory depends on the target cell)

Principal Effects of Cortisol

Effect on Protein Metabolism

Increase peripheral protein catabolism
Glucocorticoid inhibit DNA, RNA and protein synthesis Also accelerate protein catabolism from bone, muscle, connective tissues and lymphatic tissues
Accelerated catabolism deleterious effects of cortisol

Mobilization of amino acids from non-hepatic tissues to liver Proteocatabolic effect in all body cells except of the liver Decreased amino acids transport into extrahepatic tissues (muscles, lymphatic tissues)

Stimulate RNA and protein synthesis in liver

Effects on Glucose Metabolism

Hepatic glucose metabolism
Increase hepatic gluconeogenesis (6-10 folds) - stimulating gluconeogenic enzymes
E.g. Phosphoenolpyruvate carboxykinase and glucose-6-phosphatase

Mobilization of substrates for gluconeogenesis from extrahepatal tissues (amino acids, fatty acids) Stimulating glycogen synthetase activity enhance hepatic glycogen synthesis and storage Inhibit glycogen breakdown

Peripheral glucose metabolism

Inhibit peripheral glucose uptake and utilization (muscle and adipose tissue)
Lower responsiveness of cells/tissues to insulin

Effects on Fat Metabolism

Increase lipolysis
To release glycerol and free fatty acids substrates for hepatic gluconeogenesis

Mechanisms
Direct stimulation of lipolysis by glucocorticoids Decreased glucose uptake (lower glucose utilization stimulates the cells to utilize energy from fatty acids) Enhancement of lipolytic hormones by glucocorticoid

Results in increased centrally fat deposition

Increased appetite by high level of steroid Lipogenic effects of hyperinsulinemia

When youre not eating especially overnight or between meals, the body has to make its own sugar. The liver supplies sugar or glucose by turning glycogen into glucose in a process called glycogenolysis. The liver also can manufacture necessary sugar or glucose by harvesting amino acids, waste products and fat byproducts. This process is called gluconeogenesis.

Effects on Connective Tissue

Inhibit fibroblast
Decreased protein synthesis Proteocatabolic effect in all body cells

Lead to loss of collagen and connective tissue Results:

Thinning of skin Easy bruising Stria formation Poor wound healing

Effects on Bone
Inhibit bone formation by decreasing:
Cell proliferation RNA synthesis Protein Collagen Hyaluronate

Potentiate proresorptive actions of PTH and 1,25[OH]2D on bone Contribute to net bone resorption Promote bone loss

Effects on Calcium Metabolism

Reduces intestinal calcium absorption lower serum calcium
Through antagonism of 1,25(OH)2D action on intestine

Increase urinary calcium excretion

Hypercalciuria frequent feature of cortisol excess

Reduce tubular reabsorption of phosphate

Phosphaturia and decreased serum phosphate

Excess cortisol negative calcium balance

Resulted net bone resorption to maintain serum Ca level Causes osteoporosis

Effects of Glucocorticoid on Water Balance

In large amount, glucocorticoid present mineralocorticoid activity
Maintain body fluid volume maintain extracellular fluid volume. Support tissue perfussion

Glucocorticoid receptor is expressed in virtually all cells. Mineralocorticoid (e.g. aldosterone) and glucocorticoid (e.g. cortisol) receptors are closely related
They share 57% homology in the ligand-binding domain (hormonebinding site) and 94% homology in the DNA-binding domain (DNAbinding site). The mineralocorticoid receptors are not ligand-selective they have high affinity for both glucocorticoid and mineralocorticoid. Therefore, both aldosterone and cortisol bind the mineralocorticoid receptor with similar high affinity.

Effects of Glucocorticoid on Immune Function Anti-inflammatory effect

Inhibit synthesis of pro-inflammatory cytokines and mediators

inhibit released by macrophage, T-cells and other immune cells anti-inflammation. Glucocorticoid inhibit synthesis, release and action of proinflammatory cytokines and mediators . Inhibit histamine formation Stabilize lysosomal membrane inhibiting cellular degranulation.

Effect of glucocorticoids: anti-inflammatory effect

release from damage tissues: proteolytic enzymes, histamine, bradykinin
cortisol stabilizes lysosomal membrane

increase the blood flow in inflammed area vasodilatation

cortisol reduces degree of vasodilatation

leakage of plasma into damage area - clotting

cortisol decreases permeability of capillaries, prevents loss of plasma

infiltration by leukocytes
cortisol decreases migration of white blood cells suppresses immune system: reduction of T-lymphocyte

Anti-inflammatory actions of cortisol. Cortisol induces the formation of the inhibitor of nuclear factor B (I-B), which binds to nuclear factor B (NF-B) and prevents it from entering the nucleus and activating target genes. The activated glucocorticoid receptor (GR) also interferes with NF-B binding to its response elements in DNA thus preventing the induction of phospholipase A2 (PLA2), cyclo-oxygenase 2 (COX2), and the inducible nitric oxide synthase (iNOS). By blocking further production of TNF (tumor necrosis factor-) and IL-1 (interleukin-1) glucocorticoids disrupt the positive feedback cycle involving these cytokines. NO = nitric oxide.

Effects of Glucocorticoid on Immune Function

Glucocorticoid on immune system
Inhibit cytokine production by macrophage and T-cell. Decrease activation and proliferation of B-cell. Reduce circulating antibodies produced by B-cells decrease humoral (antibody) mediated immunity. Also decrease activation and proliferation of T-cell decrease cell-mediated immunity. Application of glucocorticoid in immune disorder:
Suppression of immune response that over-react (autoimmunity) Prevent rejection of transplanted tissues. Suppress allergic response

Cortisol inhibits proliferation of activated T cells by interfering with secretion of cytokines. IL-1 = interleukin-1; IL-2 = interleukinII; IFN- = interferon-.

Effects on Central Nervous System

Cortisol enter the brain
Alter behavior and cognitive function

Excessive cortisol
Initially causes euphoria Prolonged exposure various psychologic abnormalitues
E.g. Irritability, emotional , depression

Impairment in cognitive function memory and concentration Increased appetite, decreased libido and insomnia

Decreased cortisol
Decreased appetite Irritable, negativistic, and reclusive

Effects on Other Hormones

Cortisol affects thyroid function
Inhibit TSH synthesis and release Reduce responsiveness of pituitary to TRH Decrease level of thyroxine-binding globulin
Serum total T4 low normal Free T4 normal

Decrease conversion of T4 to T3, but increase conversion to rT3

Cortisol affects gonadal function

Inhibit gonadotropin (FSH and LH) secretion in male Suppress LH responsiveness to GnRH
Suppression of estrogen inhibition of ovulation and amenorrhea

To be continued..