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- All are chemical modifications of cholesterol
4 rings with 21 carbons

- Progesterone, glucocorticoids, and mineralocorticoids are 21-carbon steroids
- Androstanes are 19-carbon steroids
- Estranes (produced primarily in the ovaries) are 18-carbon steroid

Adrenocortical hormones



21 - pregnanes
19 - androstanes
18 - estranes


Synthesis of adrenocortical hormones

- Each layer is specialized to synthesize particular hormones

- Depending on the presence or absence of enzymes
(17,20- lyase in zona fasciculata: androgenic steroid
Aldosterone synthase in zona glomerulosa: aldosterone)


The rate-limiting reaction in steroidogenesis is the __ because cholesterol is stored in the cytoplasm and CYP11A1 (cholesterol desmolase) is located in the inner mitochondrial membrane

transfer of cholesterol from the outer to the inner mitochondrial membrane


- Principal mineralocorticoid
- Synthesized only by the zona glomerulosa
Due to presence of aldosterone synthase
Cannot synthesize glucocorticoids

- Regulated primarily by RAAS (Minimally influenced by ACTH)



Aldosterone: Transport and metabolism

- Only ~60% bind to plasma proteins, 40% in free form
- half-life: ~20 mins
- Almost all inactivated by the liver in one pass(Conjugated especially to glucuronic acid and to a lesser extent sulfates)
- Excretion
Bile then feces: ~25%
Urine: remaining


Aldosterone: Physiologic actions

Three actions on the late distal tubule and collecting ducts of the kidney:

1. Increases Na+ reabsorption (principal cells)
2. Increases K+ secretion (principal cells)
3. Increases H+ secretion (α-intercalated cells)


Aldosterone: Physiologic actions 2

Excess increases ECF Volume and arterial pressure but has only small effect on plasma sodium concentration.
>>Simultaneous osmotic absorption of almost equivalent amounts of water
>>Stimulate thirst and increased water intake


- Excess causes hypokalemia and muscle weakness

- Too little causes hyperkalemia and cardiac toxicity
Stimulates transport of potassium into ICF
Alters the electrical excitability of the nerve and muscle fiber membranes
Weakness of heart contraction, development of arrhythmia, heart failure

Physiologic Action of Aldosterone


Physiologic Action of Aldosterone in Colon, salivary glands and sweat glands

- Promotes Na+ and water absorption
- Effect on salivary glands: for conservation of salt when excessive quantities of saliva are lost
- Effect on sweat glands: for conservation of salt in hot environments


- has a proinflammatory, profibrotic effect on the cardiovascular system, causes LVH and remodeling
- Binds to mineralocorticoid receptor (MR), an intracellular receptor
- Similar to cortisol (alters gene expression)



Cellular Mechanism of Aldosterone

- Aldosterone diffuses readily to the interior of the tubular epithelial cells (Lipid soluble)

- Combines with receptor protein


Has a stereomolecular configuration that allows only aldosterone or very similar compounds to combine with it

receptor protein


Cellular Mechanism of Aldosterone 2

- Aldosterone-receptor complex diffuses into the nucleus

- mRNA, in conjunction with the ribosomes, causes protein formation.
(1) one or more enzymes and (2) membrane transport proteins required for sodium, potassium, and hydrogen transport through the cell membrane


Aldosterone: Regulation of secretion

- Almost entirely independent of regulation of cortisol and androgens by zona fasciculata and reticularis


Major stimuli for aldosterone production

1. Increased angiotensin II
2. Increased serum [K+]


What is the effect of increased sodium ion concentration in aldosterone secretion?

very slightly decreases aldosterone secretion


- is necessary for aldosterone secretion but has little effect in controlling the rate of secretion in most physiological conditions



Major actions of angiotensin II on the adrenal cortex

1. Specifically increase output of aldosterone
2. increased growth (hypertrophy) and vascularity of the zona glomerulosa; no effect on other two zones
3. increased StAR and aldosterone synthase enzyme activity


- Principal naturally occring glucocorticoid in humans
- Synthesized in zona fasciculata/ reticularis
- ≥ 95% of glucocorticoid activity of the adrenocortical secretions (Small but significant: corticosterone)



Cortisol is bound predominantly (>90%) when in circulation. Where?

1. cortisol-binding globulin (i.e. transcortin)
2. Albumin (5-7%)


Circulating half-life of cortisol?

60-90 minutes; Because of the high degree of binding in circulation


- predominant site of steroid inactivation
- inactivates cortisol and conjugates them so that they can be excreted more readily by the kidney



Mechanism of action

Acts through glucocorticoid receptor (GR)


How does Cortisol increase gene transcription?

1. Rapid translocation of the cortisol-GR complex into the nucleus
2. Cortisol-GR complex interacts with glucocorticoid response elements (GREs) in the DNA
3. Recruitment of coactivator proteins
4. Assembly of general transcription factors


How does Cortisol decrees gene transcription?

1. Rapid translocation of the cortisol-GR complex into the nucleus
2. Interaction with negative glucocorticoid response elements (GREs)
3. Recruitment of corepressor proteins; OR interference with ability of transcription factors to activate gene expression


Metabolic Action of Cortisol

- Catabolic and diabetogenic
- ↑ blood glucose
- Increase lipolysis


How does Cortisol increase blood glucose?

1. Stimulates gluconeogenesis in liver
- Enhance gene expression of hepatic gluconeogenic enzymes

2. Inhibit protein synthesis, ↑ proteolysis in muscle
- Provide rich source of carbon for hepatic gluconeogenesis


How does Cortisol promotes glucose sparing?

1. Decreases glucose utilization by tissues

2. Decreases insulin sensitivity of adipose tissue

3. ↓ Glut4-mediated glucose uptake
- Potentiates effects of catecholamines on lipolysis


How does Cortisol Act on Cardiovascular?

1. Permissive actions on catecholamines - Good cardiac output and blood pressure

2. Stimulates EPO synthesis