Aldosterone, Cortisol & Metabolic Functions

Adrenal Glands Introduction

• The human body needs a well-balanced extracellular environment
• Adrenal glands are crucial for maintaining this balance
• Two adrenal glands, each weighing approximately 4 grams
• Each adrenal comprises two endocrine organs: the cortex (80%) and the medulla (20%)
• The adrenal cortex develops from mesoderm
• The adrenal medulla develops from neural crest
• Each gland produces hormones within different chemical categories
• Hormones have different functions, mechanisms of action, and regulations

Adrenal Cortex Introduction

• The adrenal cortex consists of three zones: zona glomerulosa, zona fasciculata, and zona reticularis
• Produces adrenocortical hormones in distinct zones, due to enzyme distribution differences
• Mineralocorticoids, including aldosterone (in zona glomerulosa)
• Glucocorticoids, primarily cortisol (in zona fasciculata) and secondary in zona reticularis
• Sex hormones, including Dehydroepiandrosterone (DHEA) (in zona fasciculata and zona reticularis), often in greater amounts in the gonads

Adrenocortical Hormones Introduction

• Small amounts of aldosterone, cortisol, and DHEA are found in adrenocortical cells at any given time
• Cells produce and secrete these hormones on demand, rather than storing them
• Steroid hormones are lipophilic and diffuse into the bloodstream after synthesis.
• Steroid hormones are extensively bound to plasma proteins (CBG and albumin) keeping them from entering cells and getting excreted from the blood
• Free hormones interact with cell receptors and are cleared from the blood
• Bound hormones dissociate, replenishing free hormone in circulation
• Hormone-receptor complexes move to the nucleus, bind to complementary DNA segments
• This binding triggers gene transcription and new protein synthesis

Average Daily Production of Hormones by Adrenal Cortex

• Cortisol: 20 mg/day
• Aldosterone: 0.1 mg/day
• DHEA: 30 mg/day
• Production amounts vary significantly depending on physiological state

Aldosterone Function

• Acts on the distal and collecting tubes of the kidneys
• Regulates sodium and potassium levels and urine formation
• Maintains extracellular fluid volume and blood pressure
• Essential for life, as loss thereof results in circulatory shock
• Aldosterone action can be blocked by spironolactone
• Epithelial sodium channel (ENaC) proteins can be blocked by amiloride

Regulation of Aldosterone Production and Secretion

• Stimulators : Renin-angiotensin-aldosterone system is activated by factors related to reduction in sodium and blood pressure
  • Renin is released by the kidneys when blood sodium or volume decreases
  • Angiotensin II is a powerful stimulator of aldosterone production(angiotensin is converted from angiotensinogen by renin)
• Stimulators (Cont'd):
  • Increased plasma potassium directly stimulates adrenal cortex
  • Acute elevated ACTH stimulates aldosterone production
• Inhibitors :
  • Atrial natriuretic peptide (ANP) from the heart inhibits aldosterone production. ANP is released as a response to high blood pressure & increased volume
  • Chronic elevated ACTH

Aldosterone Escape Response

• A physiological process that regulates fluid retention and prevents hypertension despite high aldosterone levels
• Mechanisms: increased ANP secretion, pressure natriuresis, and reduced distal renal tubule sensitivity to aldosterone

Cortisol Function

• Metabolic: Increases blood glucose at protein & fat expense, especially during fasting.  - Inhibits glucose uptake by most tissues.   - Increases hepatic gluconeogenesis to replenish hepatic glycogen stores   - Stimulates protein degradation, specifically in muscles to provide amino acids for gluconeogenesis   - Facilitates lipolysis, increasing free fatty acids & glycerol to support gluconeogenesis, for energy supply.

• Permissive: Increases responsiveness to glucagon and catecholamines.

• Stress Adaptation: Provides energy during acute stress; significantly impacts reproduction due to the considerable energy cost of reproduction & decreasing reproductive axis function (hypothalamus, pituitary, and gonads)

• Anti-inflammatory & Immunosuppressive: Maintains homeostatic balance in response to tissue injury, inflammation, and immune responses. Excessive response can be harmful

Cortisol Secretion

• ACTH stimulates growth & secretory output in zona fasciculata & zona reticularis
• ACTH secretion is regulated by hypothalamic CRH
• Feedback loops between cortisol, ACTH, & CRH complete the control
• Diurnal rhythm and stress affect hypothalamic CRH secretion
• Cortisol concentration is highest in the morning and lowest at night. -Stress increases cortisol secretion significantly in response to factors including neurogenic stress (fear) and physical stress (surgery).

Adrenal Cortex & Sex Hormones: Function

• Adrenal cortex produces both androgens and estrogens in both sexes. However, these hormones are usually not powerful enough to induce obvious effects Under normal circumstances.
• Dehydroepiandrosterone (DHEA) is the only adrenal sex with biological significance.
• In males, DHEA is often overpowered by significant testosterone levels.
• In females, DHEA is a precursor for the intracellular production of estrogens and adrogens. DHEA governs androgen-dependent processes.

Adrenal Sex Hormones Secretion

• ACTH controls adrenal sex hormone secretion
• Adrenal sex hormones do not feedback on the hypothalamus-pituitary-adrenal axis.
• DHEA inhibits gonadotropin-releasing hormone, not CRH, as might be expected.
• A surge in adrenal androgen secretion occurs at puberty and peaks at age 25-30, gradually decreasing to below 15% of the peak value by age 60

Disorders of the Adrenal Cortex

• Number of adrenocortical function disorders is relatively uncommon.
• Hormone levels can either be excessively high or insufficient. 
• Specific disorders to be covered: – Aldosterone hypersecretion (primary and secondary) – Cortisol hypersecretion (Cushing's syndrome) – Adrenogenital syndrome – Adrenocortical insufficiency (primary Addison's and secondary)

Aldosterone Hypersecretion: Causes & Symptoms

• Causes: – Primary: Hypersecreting adrenal tumor of aldosterone-secreting cells (Conn's syndrome) – Secondary: Inappropriately high activity of the renin-angiotensin-aldosterone system (RAAS).
• Symptoms: – Increased whole body sodium, fluid, and circulating blood volume. – Excessive potassium depletion (hypokalemia) – Weakness and fatigue – High blood pressure (hypertension).

Cortisol Hypersecretion (Cushing's Syndrome): Causes

• Causes: -Adenomas of the anterior pituitary secreting large amounts of ACTH which in turn cause adrenal hyperplasia & excess cortisol secretion (Cushing's disease). -"Ectopic secretion" of ACTH by tumors elsewhere in the body (e.g., small cell carcinoma of the lung). -Abnormal function of the hypothalamus causing high levels of CRH, which stimulates excessive ACTH release. -Adenomas of the adrenal cortex. -Pharmacological use of exogenous corticosteroids.

Cushing's Syndrome Symptoms

• Symptoms related to the exaggerated effects of glucocorticoids:  - Excessive gluconeogenesis including high blood glucose (hyperglycemia) and glucose in the urine (glucosuria), which indicate adrenal diabetes.  - Protein shortage.  - Extra glucose deposited as fat in characteristic locations (abdomen, above shoulder blades, and face) with consequent weight gain.  - Muscle breakdown .  - Loss of muscle protein, leading to muscle weakness and fatigue.  - Skin of abdomen is protein poor, overstretched with irregular reddish purple linear streaks

Cushing's Syndrome Protein Symptoms

• Skin of the abdomen is protein poor with over-stretched areas and irregular red/purple streaks, indicative of poor collagen production.
• Loss of structural protein within small blood vessels, making the skin easily bruised.
• Wounds heal poorly due to depressed collagen production.
• Loss of collagen framework which leads to weakened skeletons and easily fractured bones even with minor injury
• Increased adrenal androgens cause acne, hirsutism, and amenorrhea in women. And decreased libido and impotence in men. High levels of mineralocorticoids lead to hypertension, hypokalemia, hypernatremia, and fluid retention

Adrenogenital Syndrome

• Adrenal androgen hypersecretion
• A masculinizing condition, more common than excess adrenal estrogen secretion
• Symptoms depend upon the age and sex of the affected individual when the hyperactivity first develops.
• Caused by inherited defects in cortisol pathways

Adrenal Androgen Hypersecretion: Symptoms

• Neonatal females: infants may exhibit male external genitalia, which is a major cause of female pseudohermaphroditism.
• Adult females: may experience hirsutism and other male secondary sexual characteristics.
• Prepubertal males: may manifest precocious pseudopuberty.
• Adult males: usually have already developed testosterone-driven growth

Adrenocortical Insufficiency

• One gland may be non-functional or removed allowing the second to function in place, often with hypertrophy & hyperplasia of the remaining gland.
• Both glands affected often show undersecretion of all layers (primary)
• Causes: autoimmune destruction of the adrenal cortex
• Secondary: associated with pituitary or hypothalamus abnormality and insufficient ACTH secretion. Only cortisol is deficient in this instance.

Primary Adrenocortical Insufficiency (Addison's Disease): Symptoms

• Aldosterone Deficiency: – Life-threatening; slow development of adrenal function loss – Potassium retention (hyperkalemia), reduced potassium loss in the urine – Disrupted cardiac rhythm – Sodium depletion (hyponatremia) – Excessive urinary loss of sodium leading to low extracellular volume and hypotension

Primary Adrenocortical Insufficiency (Addison's Disease): Symptoms and Treatment

• Cortisol Deficiency:
• Poor response to stress
• Hypoglycemia
• Reduced gluconeogenic activity
• Hyperpigmentation(due to high ACTH levels binding to closely related a-MSH receptors)
• Excessive ACTH secretion: due to lack of cortisol inhibiting action.
• Treatment includes reversal of hypotension & electrolyte abnormalities; administration of cortisol and mineralocorticoids.

Adrenal Medulla

• Contains chromaffin cells, modified postganglionic neurons
• Do not contain axon fibers connecting to effector organs
• Secrete adrenaline (80%) and noradrenaline
• Adrenaline and noradrenaline are released directly into the circulation upon stimulation by the preganglionic fibers.
• Adrenaline is the primary hormone produced exclusively by the adrenal medulla, while noradrenaline is produced by sympathetic postganglionic fibers
• Hormones are not essential for life

Function of Catecholamines: Effects on Organ Systems

• Catecholamines (especially adrenaline) participate in the fight-or-flight response
• Increases cardiac rate and strength increasing cardiac output
• Enhances arterial blood pressure
• Reduced digestion & bladder emptying
• Blood supply shifts to vital organs (heart and skeletal muscles) through vasodilation of coronary and skeletal muscle blood vessels
• Dilation of respiratory airways to improve respiration

Function of Catecholamines: Metabolic Effects

• Mobilizes stored carbohydrates & fats for muscle work
• Hepatic gluconeogenesis & glycogenolysis
• Muscle glycogenolysis
• Promotes lipolysis
• Inhibits insulin secretion & stimulates glucagon secretion to provide additional fuel
• Supporting adequate nourishment for the brain

Function of Catecholamines: Other Effects

• CNS: promotes arousal & alertness.
• Sweat production increases to eliminate extra heat.
• The lens of the eye flattens and pupils dilate for enhanced vision in response to perceived threats.
• Release of catecholamines is triggered by sympathetic input to the gland in response to injury, anger, anxiety, pain, cold, strenuous exercise, and hypoglycemia

Summary- Adrenal Cortex-Adrenal Hormones

• Aldosterone: regulates sodium, potassium, blood pressure (via RAAS); disorders—hypersecretion (Conn's syndrome), hyposecretion (hypotension, electrolyte imbalance).
• Cortisol: increases glucose, gluconeogenesis, anti-inflammatory; disorders—hypersecretion (Cushing's syndrome), hyposecretion (Addison's disease)
• DHEA: androgen precursor, minimal in males, significant in females—excess causes masculinization.
• Adrenal Medulla: secretes catecholamines (adrenaline & noradrenaline) during stress, increasing heart rate, blood pressure, glucose availability, promoting glycogenolysis & lipolysis and inhibiting insulin secretion—regulated by sympathetic stimulation. Effects include enhanced alertness, pupil dilation, and reduced digestive activity.

Recommended Reading

• Medical Sciences. Jeannette Naish. Chapter 10. Endocrinology and the Reproductive System.
• Endocrine and Reproductive Physiology. Bruce White, John Harrison, Lisa Mehlmann. Chapter 5. Hypothalamus-Pituitary Complex
• Master Medicine: Physiology. J McGeown. Chapter 8. Endocrine physiology.

Practice MCQ Questions

• Q1: Zona glomerulosa
• Q2: Mid-afternoon
• Q3: Aldosterone

Explore the roles of aldosterone and cortisol in regulating electrolyte balance and metabolic processes. Questions cover mechanisms of action, effects on glucose metabolism, and compensatory mechanisms. Understand hormonal responses in conditions like hyperaldosteronism.