Adrenal Hormones Flashcards
1
Q
Adrenal Hormone
Functions
A
- 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
2
Q
Adrenal Gland
Gross Anatomy
A
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)
- Zona glomerulosa
-
Medulla: produces catecholamines
- Epinephrine and norepinephrine
3
Q
Adrenocortical Hormones
Structure
A
- 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.
4
Q
Adrenocortical Hormone
Production and Activity
A
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
5
Q
Cortisol Inactivation
A
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.
6
Q
Androgenic steroids
A
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
7
Q
Synthesis
of
Adrenal Cortex Hormones
A
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:
- 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
- Be converted by 3β-hydroxysteroid dehydrogenase into 17-α-OH-Progesterone.
- Undergo cleavage of the carbon 20-21 side-chain from the steroid by CYP17 to produce DHEA.
- 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
8
Q
Adrenarche
A
- 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
9
Q
Congenital Adrenal Hyperplasia
A
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
10
Q
ACTH
Function and Mechanism
A
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.
11
Q
Corticosterone Conversion
A
- Corticosterone released with cortisol but has a weaker glucocorticoid activity
- Peripheral tissues can convert corticosterone to cortisol via enzyme 11β-ketoreductase (11HSD1)
12
Q
Pulsatile Pattern
of
Cortisol Secretion
A
- 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
13
Q
Plasma Transport
of
Adrenal Steroids
A
- 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
14
Q
Catabolism of Adrenal Steroids
A
- 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
- Occurs after structural modifications occuring mainly in the liver increases the water solubility of molecules
- Assays that specifically detect androgens and corticosteroids in body fluids more commonly used.
15
Q
Adrenal Steroids
Mechanism
A
- 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
17
Q
Glucocorticoids
Metabolic Action in Response to Prolonged Fasting
A
- 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
18
Q
Glucocorticoids
Anti-Inflammatory Action
A
- 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
- Thus reduces the production of prostaglandins and leukotrienes
- Enzyme inhibits the activity of Phospholipase A (PLA)
- Mitigate the intensity of the allergic and immune response by reducing the number of circulating T and B lymphocytes and mastocytes
- Unclear mechanism
- Reducing the synthesis of nitric oxide causing decrease in capillary permeability
- Synthetic glucocorticoids extensively used in therapy
- Prednisolone
- Dexamethasone
24
Q
Cushing’s Syndrome
A
- 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
-
Protein Catabolism
30
Q
Synthesis
of
Adrenal Medulla Hormones
A
Tyrosine is the precursor for all three catecholamine hormones.
-
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
- L-DOPA converted to dopamine
- Dopamine taken up by secretory granules which contain all the needed enzymes to convert it to norepinephrine (NE)
- Most of the NE is methylated to epinephrine by PNMT (Phenylethanolamine N-methyltransferase)
- NE and E stored in secretory granules.
32
Q
Physiological Activities
of
Catecholamines
A
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
- Increase blood pressure by increasing:
- 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
