Adrenal Hormones

Question 1

Adrenal Hormone

Functions

Answer 1

• Plays a key role in allowing the body to adapt and compensate for alterations in the environment.
• Adjusts the functions of different organs and tissues to preserve body fluids and composition.
  
  • Replenishes lost salts, water, and organic substrates.
• Important in the maintenance of a finely regulated extracellular environment.
• Regulates the levels of water and ions necessary for excitable cells to function
• Ensures adequate supply of metabolic substrates to generate ATP

Question 2

Adrenal Gland

Gross Anatomy

Answer 2

Single organ which behaves as two seperate functional units.

• Cortex: produces steroids
  
  • Zona glomerulosa
    
    • Produces the mineralocortoid aldosterone
  • Zona fasciculata and zona reticularis
    
    • Both produce the glucocorticoids cortisol and corticosterone
    • Also the weak androgen dehydroepiandosterone (DHEA)
• Medulla: produces catecholamines
  
  • Epinephrine and norepinephrine

Question 3

Adrenocortical Hormones

Structure

Answer 3

• All adrenocortical hormones are derived from cholesterol.
  
  • Mostly dietary source.
  • Cholesterol stored in its ester form in lipid droplets.
• Hormones are very similar in structure.

Question 4

Adrenocortical Hormone

Production and Activity

Answer 4

Production

• Humans secrete 10x more cortisol than corticosterone.
• Much less aldosterone is secreted daily compared to glucocorticoids.

Activity

• Corticosterone has 1/5 the activity of cortisol.
• Because of the high similarity in structure there is minor cross reactivity between glucocorticoids and mineralocorticoids, however, because of respective amounts:
  
  • Glucocorticoids do not have a relevant mineralocorticoid activity
  • Aldosterone does not have a significant glucocorticoid effect

Question 5

Cortisol Inactivation

Answer 5

The enzyme 11 β-dehydrogenase (11HSD2) converts active cortisol to inactive cortisone.

Allows non-selective mineralocorticoid receptors to be predominantly activated by aldosterone.

Important in tissues which are elective targets of aldosterone.

Question 6

Androgenic steroids

Answer 6

Adrenal cortex produces two androgenic steroids:

Dehydroepiandrosterone (DHEA)

and

Androstenedione

• These are the 2 main androgenic hormones in females
  
  • Ovarian cells can make some adrogens as precursors for estradiol
• Major contribution of these hormones is supporting development in prepubesent girls and boys
• Pathologically exaggerated production of these can cause signs and symptoms of hormonal imbalance
  
  • More evident in females due to absence of testosterone
• Peripheral tissues can convert adrogenic steroids into testosterone and more potent dihydrotestosterone (DHT) as well as estradiol

Question 7

Synthesis

of

Adrenal Cortex Hormones

Answer 7

Cholesterol converted to pregnenolone in the mitochondria by cholesterol side-chain cleavage enzyme (CYP11A1).

Most of the remaining steps occur in the smooth endoplasmic reticulum.

• In the Zona fasciculata and Zona Reticularis:
  
  • Pregnenolone converted into 17-OH-Pregnenolone by CYP17 (17-α-hydroxylase).
  • 17-OH-Pregnenolone can either:
    
    1. Undergo cleavage of the carbon 20-21 side-chain from the steroid by CYP17 to produce DHEA.
       
       • The lyase activity of CYP17 does not become apparent before age 7-8 causing the appearance of circulating weak androgens ⇒ adrenarche
    2. Be converted by 3β-hydroxysteroid dehydrogenase into 17-α-OH-Progesterone.
  • 17-α-OH-Progesterone then hydroxylated at carbon 21 by CYP21A2 (21-hydroxylase) to produce 11-deoxycortisol.
  • 11-deoxycortisol transported back into the mitochondria where 11β-hydroxylase converts it to cortisol.
• In the Zona Glomerulosa:
  
  • Lacks the enzyme CYP17
  • Pregnenolone exclusively converted to progesterone by 3β-hydroxysteroid-dehydrogenase.
  • Progesterone converted by 21-hydroxylase into 11-deoxycorticosterone.
  • 11-deoxycorticosterone converted by 11-b-hydroxilase into corticosterone.
  • Corticosterone can either be:
    
    • Secreted into the blood
    • Converted into aldosterone by aldosterone synthase.
      
      • Enzyme is exclusively expressed in the Zona glomerulosa

Question 8

Adrenarche

Answer 8

• The lyase activity of CPY17 becomes apparent around 7-8 years of age
• Causes the appearance of circulating weak androgens termed adrenarche
• Independent from the onset of puberty
• Main physiological role is to regulate the development of pubic and axillary hair

Question 9

Congenital Adrenal Hyperplasia

Answer 9

Deficiency of 21-Hydroxylase (CYP21A2).

• Enzyme required for the synthesis of glucocorticoids and mineralocorticoids
• Defect in this enzyme leads to reduced or absent synthesis of corticosterone, aldosterone, and cortisol.
• Negative feedback on the hypothalamus/CRH and pituitary/ACTH by cortisol is absent.
• Plasma levels of ACTH increase
  
  • Exerts a trophic effect on the cells of Zona fasciculata and Zona reticularis of the cortex inducing adrenal hyperplasia
• In the absence of CYP21A2, the adrenal cortex can only synthesize steroids androgens
  
  • Females born with this condition present with ambiguous gentitalia ⇒ virilization
  • Later onset milder forms causes:
    
    • Excess hair in areas of the body where hair is normally not present or minimally evident such as chest, abdomen, and face (hirsutism)
  • Males present with much milder signs
• In severe cases the absence of cortisol and aldosterone rsults in:
  
  • Significant salt wasting
  • Hypovolemia
  • Hypotension
• Addison’s Disease has similar symptoms as congential adrenal hyperplasia but lacks the excessive adrenal androgens as observed with CYP21A2 deficiency

Question 10

ACTH

Function and Mechanism

Answer 10

Function

• ACTH directly regulates the synthesis and secretion of glucocorticoids and steroid androgens.
• Aldosterone output is minimally affected as this is controlled by the renin-angiotension system.

Mechanism

• ACTH binds the melanocortin-2 receptor and stimulates production of cAMP
• cAMP activates PKA
• PKA stimulates cholesteryl ester hydrolase (CEH) which is a key enzyme in hormone synthetic pathways
  
  • Facilitates the flow of cholesterol into the mitochondria
• Long-term potentiation of steroidogenesis by ACTH is achieved by regulation of gene expression for a variety of enzymes involved.

Question 11

Corticosterone Conversion

Answer 11

• Corticosterone released with cortisol but has a weaker glucocorticoid activity
• Peripheral tissues can convert corticosterone to cortisol via enzyme 11β-ketoreductase (11HSD1)

Question 12

Pulsatile Pattern

of

Cortisol Secretion

Answer 12

• Cortisol secreted in a pulsatile pattern of 10 secretory burts in a 24-hour period
  
  • Highest in the early morning before waking
  • Lowest early in the sleep cycle
• Pattern driven by ACTH
  
  • Process is mostly diurnal due to the close proximity of the hypothalamic-pituitary axis to the visual cortex and optic chiasm
  • Process is abolished by coma, blindness, or constant exposure to light or dark
• Stress, pain, trauma, infection, or exercise increases cortisol secretion overriding the diurnal release pattern
  
  • Stress also makes the long-loop feedback inhibition of cortisol on the hypothalamus less effective
  • Chronic stress and sustained ACTH levels can cause adrenal hypertrophy
  • The beta-endorphine that is co-secreted with ACTH can function as an analgesic supplement when pain is the main stimulus for secretion
• During trauma and infection macrophages release interleukins which stimulate ACTH release

Question 13

Plasma Transport

of

Adrenal Steroids

Answer 13

• Approximately 90% of adrenal steroids travel in the blood non-covalently bound to Corticosteroid-binding globulin (CBG)
  
  • Glycoprotein produced by the liver
  • Affinity of CBG is greater for glucocorticoids than for aldosterone
• Small fraction of hormones also bind to albumin
• Pool of free hormones is 3-4%
  
  • When hormones are cleared from the body more of the bound fraction released from carrier proteins and made available for physiological action

Question 14

Catabolism of Adrenal Steroids

Answer 14

• Only the free form can be cleared from the body
• Adrenal steroids have a relatively long half-life
• Main mechanism for excretion from the body is through the urine
  
  • Occurs after structural modifications occuring mainly in the liver increases the water solubility of molecules
    
    • Cortisol is conjugated with a glucuronic acid
    • Androgens conjugated with sulfuric acid
    • Metabolites formed are called 17-ketosteroids
      
      • Can be assayed in the urine as a measure of daily adrenal activity
• Assays that specifically detect androgens and corticosteroids in body fluids more commonly used.

Question 15

Adrenal Steroids

Mechanism

Answer 15

• Only the free form physiologically active
• Lipid soluble and easily crosses the plasma membrane
• Receptors are located in the cytoplasm (Type 1)
• Upon binding, hormone-receptor complex translocates into the nucleus where it binds specific regions of the DNA called glucocorticoid response elements
• Promotes gene expression and protein synthesis

Question 16

Physioloical Effects of Glucocorticoids

Answer 16

• Regulates physiological functions slowly and effects can take hours to become evident
• Activities of glucocorticoids almost invariably require changes in the protein composition of target cells
• Actions can be subdivided into 3 broad categories:
  
  • Reponse to prolonged fasting
  • Anti-inflammatory action
  • Preparation and response to stress
• Reductive list of additional effects:
  
  • Regulation of bone growth
  • Promote excretion of excess water by the kidneys by reducing water permeability of the collecting duct and inhibiting ADH
  • Regulation of thyroid hormone activities
  • Regulation of estrogen and progesterone activities

Question 17

Glucocorticoids

Metabolic Action in Response to Prolonged Fasting

Answer 17

• Within 1-2 days of a prolonged fast the body stabilizes blood glucose around 60-70 mg/dL.
  
  • Via glycogenolysis in the liver
  • Via gluconeogenesis in the liver and kidneys (main mechanism)
• Glucocorticoids promote:
  
  • Protein degradation in skeletal muscle to produce amino acid substrates for gluconeogenesis
  • Increases expression of gluconeogenic enzymes
  • Prevent the reutilization of free amino acids for protein synthesis
  • Implement mobilization and use of stored fat (lipolysis) in adipose tissue by increasing expression of two lipolytic enzymes:
    
    • Hormone-sensitive lipase (HSL)
    • Adipose triglyceride lipase (ATGL)
    • These enzymes hydrolyze triglycerides into fatty acids
    • Fatty acids released into the blood and taken up by tissues for synthesis of ATP
  • Stimulates liver to oxidize fatty acids into ketone bodies that provide energy for the CNS during last stages of fasting
    
    • Acetoacetate
    • β-hydroxybutyrate

Question 18

Glucocorticoids

Anti-Inflammatory Action

Answer 18

• Cortisol blocks the early stages of the inflammatory response by:
  
  • Reducing the synthesis of nitric oxide causing decrease in capillary permeability
    
    • Counteracting edema
  • Stimulates the synthesis of lipocortin
    
    • Enzyme inhibits the activity of Phospholipase A (PLA)
      
      • Thus reduces the production of prostaglandins and leukotrienes
        
        • Both powerful mediators of inflammation
  • Mitigate the intensity of the allergic and immune response by reducing the number of circulating T and B lymphocytes and mastocytes
    
    • Unclear mechanism
• Synthetic glucocorticoids extensively used in therapy
  
  • Prednisolone
  • Dexamethasone

Question 19

Glucocorticoids

Preparation and Response to Stress

Answer 19

• Cortisol prepares the body for stress by providing rapidly usable glucose by:
  
  • increasing expression and activity of gluconeogenic enzymes
  • Decreasing peripheral uptake and utilization of glucose
  • Collectively causes rise in blood glucose
  • Anabolic functions (protein and lipid synthesis) are inhibited
  • Catabolic functions (protein degradation and lipolysis) are promoted
• Glucocorticoids also promote the effect of catecholamines on smooth muscle
  
  • Maintains arterial blood pressure
  • Promotes bronchodilation

Question 20

Aldosterone

Regulation

Answer 20

• Release of aldosterone stimulated by low [Na⁺]_blood or low blood pressure
  
  • combined with increased ADH secretion
• Primarily regulated by the production of angiotensin II upon activation of the Renin-Angiotensin System
  
  • AT II increases ⇒ Aldosterone increases
• Secondarily regulated by potassium plasma levels
  
  • [K⁺] increases ⇒ aldosterone increases

Question 21

Aldosterone

Function

Answer 21

• Primary site for aldosterone activity is the kidneys
  
  • Promotes sodium retention and potassium excretion during urine formation
  • Major consequence of Na⁺ retention is the osmotic retention of water in the extracellular fluid compartment → increasing systemic blood pressure

Question 22

Aldosterone

Mechanism of Action

Answer 22

• Induces sodium reabsorption in the distal tubule and collecting duct of the nephron through increased activation (early phase) and expression (late phase) of Na⁺ channels located on the apical side of renal cells
  
  • Inflow of Na⁺ leads to passive water reabsorption and increased extracellular fluid.
  • May increase central venous and arterial blood pressure
• Increases the expression of the Na⁺/K⁺-ATPase on the basolateral membrane of renal cells
  
  • Allows reabsorbed Na⁺ to be transferred back into the plasma
  • This inherently increases the entry of K⁺ from plasma into the renal cell
• Promotes excretion of K⁺ from renal cells into urine
  
  • Since reabsorption of Na⁺ from the tubular urine makes the tubular lumen electronegative K⁺ readily leaves the cell and enters the lumen

Question 23

Excessive Glucocorticoid

Conditions

Answer 23

• ACTH-independent
  
  • Caused by adrenal adenomas or adenocarcinomas producing excessive levels of cortical hormones
  • Due to negative feedback by cortisol on the hypothalamic-pituitary axis the circulating levels of ACTH extremely low
    
    • Can lead to adrenal atrophy
  • Also includes conditions caused by excessive consumption of synthetic corticosteriods due to therapeutic treatment ⇒ iatrogenic
• ACTH-dependent
  
  • Caused by the overproduction of ACTH by a pituitary adenoma ⇒ Cushings disease
  • Caused by ectopic production of ACTH by a tumor ⇒ paraneoplastic syndrome
    
    • Ex. Pulmonary adenocarcinoma
      
      • Less common

Question 24

Cushing’s Syndrome

Answer 24

• Comprised by the signs and symptoms associated with an excess of glucocorticoids
• Common clinical features are determined by the exaggerated impact of normal physiological effects of glucocorticoids including:
  
  • Protein Catabolism
    
    • Massive protein breakdown in almost all tissues including liver
    • Muscle, bone, and subcutaneous tissue wasting
    • Muscle weakness
    • Osteoporosis
    • Pigmented purple striae in the skin
    • Elevated plasma amino acid levels
    • Decreased amino acid uptake by cells (except liver)
    • Decreased protein synthesis
    • Increased liver gluconeogenesis with amino acid substrates
  • Glucose mobilization
    
    • Liver glycogen stores filled and maintained
    • Liver gluconeogenesis produces and releases glucose into the blood
    • Peripheral cells uptake of glucose inhibited
    • Hyperglycemia results which is not reversed with insulin
  • Lipolysis and fat redeposition
    
    • Stimulate lipolysis in adipose tissue
    • Maximize the action of other lipolytic agents such as epinephrine and GH
    • Raise plasma levels of free fatty acids and promote oxidation
    • Fats are subcutaneously redeposited in the face (moon face), upper back (buffalo hump), and abdomen
  • Immunosuppression
    
    • Inhibits synthesis and release of peptides that mediate the immune and allergic responses
    • Motility and adhesion of immune cells inhibited

Question 25

Addison's Disease

Answer 25

A condition of adrenal insufficiency. Categorized as primary or secondary. **Primary** * Insufficiency of the adrenal cortex. * Can be genetically acquired as in deficiency of 21-hydroxylase. * Most commonly due to destruction of the gland from autoimmune causes. * ACTH plasma levels higher due to reduced negative feedback * ACTH produced by clevage of pre-POMC yielding various polypeptides including alpha-melanocyte-stimulating hormone (α-MSH) * Increase in α-MSH causes increased melanin production and abnormal hyperpigmentation * Glucocorticoid deficiency causes: * Hypotension * Hypoglycemia * Fatigue * Aldosterone deficiency causes: * Hyperkalemia * Possible alterations of cardiac function * Salt craving * Adrenal androgen deficiency causes decreased hair growth in females. **Secondary** * Caused by pituitary ACTH deficiency * Results in lack of glucocorticoids and androgens but not aldosterone

Question 26

Addisonian Crisis

Answer 26

* Hypotension and acute circulatory failure rapidly develops under stressful situations * Can lead to diagnosis of adrenal insufficiency * Symptoms include: * Vomiting * Abdominal pain * Hyponatremia * Hyperkalemia * Treated with cortisol replacement (dexamethasone) and administration of fluids and/or glucose.

Question 27

Conn's Syndrome

Answer 27

* **Primary aldosteronism** (excessive production of aldosterone) caused by an aldosterone-secreting tumor. * Effects exerted on the kidneys * Increased sodium reabsorption * Potassium and hydrogen ion secretion * Symptoms include: * Increase in extracellular fluid volume * Mild hypertension * Hypokalemia * Metabolic alkalosis

Question 28

Secondary Aldosteronism

Answer 28

* Can be caused by: * Primary over-production of renin * Stenosis of the renal artery * Detected by the Renin-Angiotensin System and interpreted as a reduction in the systemic blood pressure * The compensatory event is an increase in renin production causing increased aldosterone synthesis and secretion

Question 29

Adrenal Medulla Function

Answer 29

* Acts as part of the sympathetic nervous system. * Consists of chromaffin cells that produce: * 90% epinephrine * 10% norepinephrine * Ratio changes depending on type of stress stimulating the adrenal medulla * Hormones stored by the medulla and released when stimulated by the sympathetic ANS * Chromaffin cells receive input from multiple preganglionic cholinergic sympathetic nerve fibers * Adrenal medulla also releases some dopamine but this is not stored

Question 30

Synthesis of Adrenal Medulla Hormones

Answer 30

Tyrosine is the precursor for all three catecholamine hormones. 1. _Tyrosine_ converted to _di-hydroxy-phenylalanine_ (DOPA) by *tyrosine hydroxylase* * Rate-limiting step * Synthesis and activity of this enzyme stimulated by acetylcholine released by sympathetic fibers 2. _L-DOPA_ converted to _dopamine_ 3. Dopamine taken up by secretory granules which contain all the needed enzymes to convert it to norepinephrine (NE) 4. Most of the NE is methylated to epinephrine by *PNMT (*Phenylethanolamine N-methyltransferase) 5. NE and E stored in secretory granules.

Question 31

Secretion of Adrenal Medulla Hormones

Answer 31

* Dopamine is constitutively secreted during production. * Norepinephrine and epinephrine stored in secretory granules. 1. Ach released by sympathetic nerve fibers. 2. Ach binds to receptors and stimulates voltage-gated Ca²⁺ channels on the plasma membrane of chromaffin cells. 3. Influx of Ca²⁺ triggers exocytosis of granule content 4. Once in the blood stream, NE & E exert their maximal action for 10-30 seconds and a much weaker stimulation for several more minutes.

Question 32

Physiological Activities of Catecholamines

Answer 32

Fight-or-flight response NE and epinephrine act on alpha and beta adrenergic receptors. Epinephrine is 10x more active than NE. Opposes the action of insulin. (Called counter-regulatory hormones.) * Hemodynamic effects * Increase blood pressure by increasing: * heart rate * cardiac output * blood vessel tone * extracellular fluid volume * coronary and muscle blood vessel dilation * skin blood vessel contraction * Metabolic effects * Actions similar to glucocorticoids in that they are effective mobilizers of metabolic substrates * Stimulate glycogenolysis and gluconeogenesis in the liver * Induce bronchodilation and piloerection

Question 33

Catecholamines Catabolism & Excretion

Answer 33

* Degraded by two groups of enzymes: * *Monoamine oxidases (MAO)* * *Catecholamine-α-MethylTransferases (COMT)* * Enzymes are present in many organs * Clearance of catecholamines from the plasma results from: * Presynaptic re-uptake * Methylation * Oxidation * Excretion by liver and kidneys * Main urinary end product is vanillyl-mandelic acid (VMA)

Question 34

Pheochromocytoma

Answer 34

* Rare, mostly benign, tumor of chromaffin cells located either in the adrenal medulla or the extra-adrenal paraganglia * Causes an excess production of catecholamines * Clinical manifestations can range from dramatic to mild * Often mimic symptoms of other disorders such as: * Sweating * Pallor * Palpitations * Most common condition is paroxysmal severe hypertension on a background of normotension * Treatment includes: * Compounds which block the adrenergic alpha-receptors for 2 weeks to control BP * Followed by surgical resection of the tumor

Question 35

Diseases of Catecholamine Underproduction

Answer 35

* Usually does not cause any clinical manifestations as sympathetic ANS can more than adequately compensate * May have postural hypotension * May reveal an automonic dysfunction caused by: * diabetes * autoimmune disorders * infections