Steroids of the Adrenal Cortex

• What are the three zones of the adrenal cortex and the main steroid each produces?

  • Zona glomerulosa → Mineralocorticoids (mainly aldosterone)
  • Zona fasciculata → Glucocorticoids (mainly cortisol)
  • Zona reticularis → Androgens (mainly DHEA and androstenedione)
• What is the precursor molecule for all adrenal cortex steroids?

  • Cholesterol
  • It is transported into mitochondria and converted into pregnenolone, the first committed step in steroidogenesis.
• What enzyme is responsible for converting cholesterol to pregnenolone, and where is it located?

  • Enzyme: Cholesterol side-chain cleavage enzyme (CYP11A1, also called desmolase)
  • Location: Mitochondria of adrenal cortex cells
• Which enzyme is unique to the zona glomerulosa and essential for aldosterone synthesis?

  • Aldosterone synthase (CYP11B2)
  • This enzyme catalyzes the final steps in converting corticosterone to aldosterone.
• What are the key enzymes involved in cortisol synthesis in the zona fasciculata?

  • 17α-hydroxylase (CYP17)
  • 21-hydroxylase (CYP21A2)
  • 11β-hydroxylase (CYP11B1)
• What enzyme is needed to produce androgens in the zona reticularis?

  • 17,20-lyase activity of CYP17
  • Converts 17-hydroxypregnenolone to DHEA
  • CYP17 is highly expressed with increased lyase activity in this zone
• How does ACTH regulate adrenal steroid synthesis?

  • Stimulates all zones but mainly zona fasciculata and reticularis
  • Increases cholesterol uptake and transcription of steroidogenic enzymes
  • ACTH has minimal effect on aldosterone synthesis (which is mainly regulated by angiotensin II and K⁺)
• Describe the role of mitochondria and smooth ER in adrenal steroid synthesis.

  • Mitochondria: Initial (cholesterol → pregnenolone) and final steps of aldosterone and cortisol synthesis
  • Smooth ER: Intermediate steps like hydroxylation and conversion of pregnenolone to progesterone derivatives
•  What regulates the synthesis of aldosterone in the zona glomerulosa?

  • Renin-angiotensin-aldosterone system (RAAS) via angiotensin II
  • Serum potassium levels (↑K⁺)
  • ACTH plays only a minor/acute regulatory role
• What are mineralocorticoids and where are they produced?

  • A class of steroid hormones produced in the 

  zona glomerulosa of the adrenal cortex.

  • The primary mineralocorticoid is 

  aldosterone, which plays a key role in regulating electrolyte and water balance.
• What is the main function of aldosterone?

  • Promotes sodium reabsorption and potassium excretion in the kidneys, particularly in the distal convoluted tubule and collecting duct.
  • This helps regulate blood pressure, blood volume, and electrolyte balance.
• How does aldosterone affect water retention?

  By increasing sodium reabsorption, aldosterone creates an osmotic gradient that promotes water reabsorption into the bloodstream. This increases blood volume and blood pressure.
• Which system primarily regulates aldosterone secretion?

  The renin-angiotensin-aldosterone system (RAAS). When blood pressure or sodium levels are low, renin is released, leading to the formation of angiotensin II, which stimulates aldosterone release from the adrenal cortex.
• What effect does aldosterone have on potassium levels?

  Aldosterone increases potassium excretion by enhancing its secretion into the urine. This helps maintain normal plasma potassium concentration.
• What is the role of the kidneys in mineralocorticoid function?

  The kidneys respond to aldosterone by:

  • Reabsorbing sodium into the bloodstream
  • Excreting potassium into the urine
  • Reabsorbing water passively following sodium. This occurs mainly in the distal nephron.
• What are the effects of excessive aldosterone (hyperaldosteronism)?

  • Hypertension (due to increased sodium and water retention)
  • Hypokalaemia (due to excess potassium excretion)
  • Metabolic alkalosis (from H⁺ ion loss)
• What are the effects of deficient aldosterone (hypoaldosteronism)?

  • Hyponatremia (low sodium)
  • Hyperkalemia (high potassium)
  • Hypotension (due to low blood volume)
  • Often seen in Addison’s disease
• What enzyme is involved in aldosterone synthesis and what stimulates its activity?

  Aldosterone synthase is the key enzyme, found in the zona glomerulosa. It is stimulated by angiotensin II, high plasma potassium, and ACTH (mildly).
• How do mineralocorticoids exert their action on target cells?

  Aldosterone binds to intracellular mineralocorticoid receptors (MR) in renal tubular cells. The hormone-receptor complex acts as a transcription factor, increasing expression of proteins like ENaC (epithelial sodium channels) and Na⁺/K⁺-ATPase, enhancing sodium reabsorption and potassium excretion.
• What is cortisol and where is it produced?

  A glucocorticoid hormone produced by the zona fasciculata of the adrenal cortex. It plays a central role in the body's stress response and helps regulate metabolism, immune function, and blood pressure.
• How does cortisol affect carbohydrate metabolism?

  Cortisol increases blood glucose levels by:

  • Stimulating gluconeogenesis in the liver
  • Inhibiting glucose uptake in muscle and adipose tissue (insulin antagonism)
  • Promoting glycogen synthesis in the liver (paradoxical but ensures glucose availability during stress)
• How does cortisol affect protein metabolism?

  Cortisol increases protein catabolism in muscle, releasing amino acids for:

  • Gluconeogenesis
  • Tissue repair (only when stress is resolved)Prolonged cortisol elevation can lead to muscle wasting.
• What is cortisol's effect on fat metabolism?

  Cortisol promotes lipolysis in limbs but increases lipid storage centrally (e.g., face, trunk). This redistribution can lead to central obesity in chronic stress or Cushing’s syndrome.
• How does cortisol influence the immune system?

  Cortisol is immunosuppressive and anti-inflammatory:

  • Decreases T-lymphocyte proliferation
  • Inhibits cytokine production
  • Reduces histamine release from mast cells
  • Suppresses phospholipase A2 → ↓ prostaglandins and leukotrienes
• What are cortisol's effects on the cardiovascular system?

  Cortisol maintains vascular tone and enhances the vasoconstrictive effects of catecholamines (e.g., norepinephrine).Chronic excess can cause hypertension.
• How does cortisol affect bone?

  Cortisol decreases bone formation by:

  • Inhibiting osteoblast activity
  • Increasing osteoclast resorption
  • Reducing calcium absorption in the gutChronic elevation may lead to osteoporosis.
• What is cortisol’s effect on mood and cognition?

  Cortisol affects brain function:

  • Can enhance alertness in acute stress
  • Chronic high levels linked to mood disorders, anxiety, and impaired memory (especially in the hippocampus)
• What role does cortisol play in the fetal period?

  Cortisol is crucial for fetal lung maturation by promoting surfactant production.It also contributes to maturation of the gastrointestinal tract, liver, and kidneys before birth.
• What is the main glucocorticoid involved in HPA axis feedback control?

  • CortisolIt plays a key role in negative feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis.
• Outline the basic sequence of the HPA axis leading to cortisol release.

  1. Hypothalamus releases CRH (corticotropin-releasing hormone)
  2. CRH stimulates the anterior pituitary to release ACTH (adrenocorticotropic hormone)
  3. ACTH stimulates the adrenal cortex (zona fasciculata) to produce cortisol
• What type of feedback loop regulates cortisol levels in the HPA axis?

  • Negative feedback loopCortisol inhibits both CRH (from the hypothalamus) and ACTH (from the anterior pituitary) secretion.
• How does cortisol inhibit CRH and ACTH production?

  • Cortisol binds to glucocorticoid receptors in the hypothalamus and anterior pituitary
  • This reduces transcription of CRH and ACTH, lowering their release and decreasing further cortisol production.
• What is the effect of chronic stress on the HPA axis?

  • Chronic stress leads to prolonged CRH and ACTH stimulation
  • This increases cortisol levels
  • Eventually, feedback sensitivity can decrease, leading to HPA axis dysregulation
• Why does aldosterone secretion not follow the same feedback control as cortisol?

  • Aldosterone is primarily regulated by the renin-angiotensin-aldosterone system (RAAS) and plasma K⁺ levels,
  • ACTH has a minor, short-term effect
  • Therefore, aldosterone is not tightly regulated by the HPA axis like cortisol is
• What would happen to ACTH and CRH levels if cortisol production is impaired (e.g. Addison’s disease)?

  • Cortisol ↓ → Negative feedback ↓ → CRH and ACTH ↑
  • This results in elevated ACTH and CRH due to the lack of feedback inhibition
• What happens to ACTH and cortisol in Cushing’s disease (pituitary adenoma)?

  • Pituitary adenoma produces excess ACTH → stimulates excess cortisol
  • Cortisol fails to inhibit ACTH due to the autonomous tumor, leading to persistently high cortisol and ACTH
• What is Cushing's syndrome?

  A disorder caused by prolonged high levels of cortisol, regardless of cause.
• What are the common causes of Cushing’s syndrome?

  Exogenous corticosteroid use, ACTH-secreting pituitary adenoma (Cushing’s disease), adrenal adenoma, or ectopic ACTH production.
• What are the key symptoms of Cushing’s syndrome?

  Central obesity, moon face, buffalo hump, muscle wasting, thin skin, hypertension, hyperglycaemia, osteoporosis, and immunosuppression.
• What is Conn’s syndrome?

  Primary hyperaldosteronism due to an aldosterone-producing adrenal adenoma.