ERS19 Physiology Of Adrenal Cortex And Medulla Flashcards
Adrenal glands
Outer adrenal cortex:
- 3 concentric layers (記: GFR)
- Zona glomerulosa (10%) (oval / ball shape)
- Zona fasciculata (80%) (polyhedral, foamy like due to lipid droplets —> stored cholesterol esters to make steroid hormones)
- Zona reticularis (10%) (irregular)
Inner adrenal medulla:
- Chromaffin cells (large columnar)
—> innervated by preganglionic sympathetic fibres (from spinal cord)
—> release hormones upon stimulation from nervous system (functionally equivalent to post-ganglionic sympathetic neurons)
Blood supply:
- From Cortex into Medulla
- Hormones in Cortex control Medulla hormone secretion
Adrenal Cortex Hormones
Corticosteroid / Steroid / Adrenocortical steroids
- from Cholesterol (through series of enzyme-mediated transformations)
- differ only in ring structure and side chains
- lipid soluble
—> move freely pass cell membrane
—> bind to receptor —> attach to DNA —> activate gene transcription —> protein
—> response time: hours - days
Zona granulosa, Zona fasciculata, Zona reticularis
Zona granulosa:
- ***Mineralocorticoid (Aldosterone) —> Na reabsorption, K excretion (Salt balance in kidney)
Zona fasciculata:
- ***Glucocorticoid (Cortisol) —> Facilitate mobilisation of energy stores to glucose in response to stress
Zona reticularis:
- ***Sex steroids (Androgens) —> Very small quantities (overshadowed by gonads), important for early development of male sex organs in childhood, puberty, sex drive
Synthesis of Adrenocortical steroids
- From Cholesterol (through series of enzyme-mediated transformations in ER, Mitochondria)
—> ***shuttling of steroids between 2 different organelles - Synthesised ***on demand
- Each zone in Adrenal cortex express different set of enzymes
- Common enzymes:
-
Steroidogenic acute regulatory protein ( StAR protein)
- first rate-limiting step
- transfer of cholesterol from cytoplasm to inner mitochondrial membrane
Major groups of Enzymes in Adrenal cortex:
CYP450 monooxygenase gene family
-
**CYP11A1 (Cholesterol Desmolase)
- Cholesterol converted to Pregnenolone
—> **Pregnenolone: immediate precursor for all Adrenocortical steroids - CYP11B2 (Aldosterone synthase) / CYP11B1:
- 93% homology
- encoded on same chromosome next to each other
- cross activity of genes translocated to that region
Physiological effects of Aldosterone
Aldosterone bind to Mineralocorticoid receptor (MR) in **distal tubule
—> activation of MR
—> translocation into nucleus
—> bind to HRE in regulatory region of target gene promoters
—> **Na/K-ATPase (Basolateral membrane)
—> **ENaC + **ROMK (renal outer medullary K channel) (Apical membrane)
—> Na reabsorption + K excretion + indirect H2O reabsorption
Regulation of Aldosterone secretion
**Low Na, Low BP, High K
—> Renin by Juxtaglomerular cells
—> Angiotensinogen
—> Angiotensin I
—> Angiotensin II
—> Angiotensin II receptor on **adrenal cortex
—> Angiotensin II stimulate ***expression of steroidogenic enzymes (e.g. Aldosterone synthase)
—> Aldosterone production
—> Na reabsorption + K excretion + indirect H2O reabsorption
***Disorders related to Aldosterone
Hyperaldosteronism: Excessive secretion of Aldosterone
Causes:
- ***Aldosterone-producing adenoma (Conn’s syndrome)
- ***Inheritable aldosterone synthase (CYP11B2) hyperactivity (crossing-over happen between promoter regions of 11B1, 11B2 genes —> ACTH-sensitive promoter —> ACTH now also stimulate aldosterone synthase)
- ***Abnormal activation of RAAS system (Renovascular disease)
Symptoms: - ***Hypertension - ***Hypokalaemia —> ***Alkalosis (loss of K stimulate H/K-ATPase in collecting duct, try to absorb more K by pumping away H) —> Shallow respiration —> Irritability —> Constipation —> ***Weakness in muscle (Outflux of K from cell into extracellular region —> further hypopolarise cells —> ***difficult to fire action potential) —> Arrhythmia —> Lethargy —> Thready / Weak pulse
Hypoaldosteronism: Deficient in aldosterone secretion
Causes:
- ***Adrenal insufficiency
- ***Aldosterone synthase (CYP11B2) deficiency
- ***Renal insufficiency (∵ Diabetic nephropathy —> low Renin level)
- Anti-hypertensive drugs (ACE inhibitors, A2R antagonists, Renin inhibitors etc.)
Symptoms:
- ***Hypotension
- ***Hyperkalaemia
- ***Metabolic acidosis
- Arrhythmia
- ***Muscle cramps (∵ resting potential less hyperpolarised —> too much muscle contraction, but later cannot repolarise)
- Abdominal cramps
Cortisol and Stress
Cortisol:
- in response to single stimulant —> ACTH from HPA-axis (essential component of an individual’s capacity to cope with stress)
- induction of cortisol production ***within several minutes
HPA axis:
- Hypothalamus: CRH
—> released into median eminence in response to stress
—> controlled by CNS: CRH neurons (Parvocellular neurons in PVN) innervated by afferent projections from ***multiple brain regions
- Brainstem (Solitary nucleus): receives inputs that signal major homeostatic perturbations (***internal stress e.g. blood loss, respiratory distress, visceral / somatic pain etc.)
- Amygdala: involves in ***negative emotions, fear, mood etc.
- Hippocampus: stress regulatory centre that suppress HPA axis (***Inhibit CRH release)
- Pituitary: ACTH
- Adrenal cortex: Cortisol
Physiological effects of Cortisol
Cortisol bind to Glucocorticoid receptor (GR) within cell
—> activated GR binds to GRE —> **enhance of gene transcription / transactivation
—> activated GR also binds to other transcription factor (e.g. CREB) —> **repression of gene transcription / transrepression
Physiological functions:
-
**Energy balance and metabolism
- ↑ Gluconeogenesis by ↑ hepatic expression of enzymes in gluconeogenesis
- ↑ Proteolysis in muscle —> a.a. for gluconeogenesis
- Inhibit insulin secretion, ↑ pancreatic β-cell apoptosis
- ↓ Glucose uptake in peripheral tissues by stopping trafficking of GLUT-4 onto membrane (~ GH action)
- **NO Glycogenolysis - ***Induction of Catecholamines synthesis in Adrenal medulla
- ***Anti-inflammatory + Immuno-suppressive effect
- Inhibit histamine release from mast cells
- Interfere with T-cell production
- ↓ production of pro-inflammatory cytokines
Inhibit non-essential physiological response not released to stress handling
- Bone and connective tissue
- ↓ bone formation by inhibiting Osteoblast proliferation
- ↑ bone resorption by inducing Osteoclast maturation
- Inhibit function of chondrocytes in cartilage
- Inhibit fibroblasts proliferation —> ↓ collagen formation - ***Reproductive function (~ Prolactin)
- ↓ GnRH release
- Inhibit LH, FSH synthesis and release
***Disorders related to Cortisol
- Cushing’s syndrome: Excessive cortisol level in our body (Primary disorder)
- Hyperglycaemia
- Hypertension
- Fat redistribution / deposition on abdomen —> Obesity / Stretch marks on abdomen and thighs
- ↑ Susceptibility to infection
- Osteoporosis (↑ fracture risk) - Adrenal insufficiency / Addison’s disease (Primary adrenal insufficiency)
- underactive adrenal glands —> insufficient Corticosteroid production
- Damaged adrenal gland / Adrenal cortex lack enzyme for steroid production (e.g. CAH)
- ↓ Aldosterone: Hyperkalaemia, Metabolic acidosis, Low Na (Low BP, vomiting), Dehydration
- ↓ Cortisol: Hypoglycaemia
- ↑ ACTH (∵ lack of -ve feedback)
—> Darkening of skin (ACTH bind to MC1R of melanocytes)
—> Massive ↑ of adrenal androgens —> Hirsutism, Ovarian dysovulation
***Adrenal androgens
Male:
- Negligible contribution to active androgens
- Majority by gonads
Women:
- 50% of active androgens
- Growth of axillary / pubic hair
Synthesis and Secretion:
- under ACTH control
- but **NO -ve feedback from androgens on ACTH / CRH secretion
—> **↓ Cortisol (Primary disorder) —> Dramatic ↑ in ACTH —> Massive ↑ of adrenal androgens
OR
—> ***Cushing’s disease (excess ACTH) —> Massive ↑ of adrenal androgens
Excessive adrenal androgens:
- Hirsutism (e.g. in Cushing’s disease)
- Ovarian dysovulation (i.e. one of causes of polycystic ovarian syndrome)
Polycystic ovarian syndrome
Too much male hormone in female
—> affect development and release of eggs
—> **lack of ovulation
—> irregular / no menstrual period
—> poor fertility
—> immature eggs remain in ovary —> **thickening of ovarian walls —> ***cysts formation
Symptoms:
- irregular / no menstrual period
- excess body, facial hair
- acne
- pelvic pain
Hormones from Adrenal Medulla
Chromaffin cells:
- conversion of Tyrosine into Catecholamines (i.e. a.a. derivative hormones)
- E (80%), NE (20%)
- Tyrosine —(Tyrosine hydroxylase, rate-limiting)—> L-DOPA —> NE —(PNMT)—> E
**Under control of:
1. SNS via preganglionic neurons
Stress sensed by **Amygdala
—> SNS activation
—> ACh from preganglionic neurons innervating Chromaffin cells
—> ACh binds to nicotinic receptors on Chromaffin cells membrane
—> membrane depolarisation (Na influx)
—> Ca entry
—> ***Tyrosine hydroxylase activation (by phosphorylation)
—> Catecholamines secretion
- Cortisol from Adrenal Cortex
—> ***induction of PNMT gene expression (rely on very high [Cortisol])
Physiological effects of Adrenomedullary Catecholamines
2 major types of Adrenergic receptor:
- α receptors (α1-2) —> bind both NE/E
- β receptors (β1-3) —> bind E mainly (esp. β2)
(X rmb:
α1: Gαq —> PLC —> IP3, DAG —> ↑ Ca, PKC
α2: Gαi —> ↓ cAMP
β: Gαs —> ↑ cAMP)
Divergent effects due to differential affinities for different adrenergic receptors
General effects (Fight/Flight) (***Rmb: ↑CO, ↑HR, ↑BP, ↑respiration):
- ***↑ Glycogenolysis
- ***↑ Gluconeogenesis
- ↑ Lipolysis
- ↑ Calorigenesis
- ↑ Glucagon secretion
- ↑ Muscle K uptake
- ***↑ HR
- ↑ Contractility
- ↑ Platelet aggregation
- ***↑ Sweating
- ***Dilation of pupils
- Bronchodilation
Short term and Long term response to stress
Short term (via SNS —> Catecholamines secretion):
- Fight/Flight response
- ↑ Glycogenolysis (only present in short term response)
Long term (via ACTH —> Cortisol): - NO change in glycogen storage
