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I. CORTICOSTEROIDS

  • The corticosteroids include mineralocorticoids, glucocorticoids, and other adrenal hormones.
  • The two adrenal glands are each approximately 4 grams and are located at the superior poles of the two kidneys. They are described as triangular or pyramidal in shape.
  • Adrenal Medulla (20% of the gland, inner layer):
    • Part of the Sympathetic Nervous System.
    • Produces epinephrine and norepinephrine (fight or flight hormones, also known as catecholamines).
  • Adrenal Cortex (outer layer):
    • Produces corticosteroids.

II. SYNTHESIS AND SECRETIONS OF ADRENOCORTICAL HORMONES

A. ADRENAL CORTEX

  • Comprises three distinct layers:
    1. Zona Glomerulosa (15%):
    • Responsible for mineralocorticoids, specifically aldosterone.
    • Cells contain aldosterone synthase, the only cells capable of secreting aldosterone.
    • Secretion is stimulated by angiotensin II (part of the Renin-Angiotensin-Aldosterone system) and extracellular fluids with elevated potassium.
    1. Zona Fasciculata (75%):
    • The thickest layer.
    • Major products include glucocorticoids (cortisol and corticosterone) along with small amounts of adrenal androgens and estrogens.
    • Regulated primarily through ACTH from the hypothalamic-pituitary-adrenal axis.
    1. Zona Reticularis:
    • Secretes adrenal androgens (dehydroepiandrosterone and androstenedione) and small amounts of estrogens and glucocorticoids.
    • Regulation occurs through ACTH and cortical androgen-stimulating hormone.

B. SYNTHESIS OF ADRENOCORTICAL HORMONES

  • Around 80% of cholesterol utilized for steroid synthesis comes from low-density lipoproteins (LDLs) in circulating plasma.
  • LDLs bind to specific receptors forming coated pits in adrenocortical cell membranes that internalize cholesterol via endocytosis.
  • The rate-limiting step in synthesis is the cleavage of cholesterol by the enzyme cholesterol desmolase to produce pregnenolone, with subsequent conversions taking place in mitochondria and the endoplasmic reticulum.
  • Congenital adrenal hyperplasia results from a mutation in 21-hydroxylase, which blocks aldosterone and cortisol synthesis, leading to increased androgen production and masculinizing effects.

C. MINERALOCORTICOIDS

  • Aldosterone is the most significant mineralocorticoid, accounting for approximately 90% of mineralocorticoid activity.
  • Deoxycorticosterone is less potent (1/30 the potency of aldosterone) and secreted in minimal quantities.
  • Corticosterone has slight mineralocorticoid activity.

D. GLUCOCORTICOIDS

  • Cortisol provides around 90-95% of glucocorticoid activity.
  • Corticosterone provides approximately 4% of glucocorticoid activity; it is less potent than cortisol.
  • Cortisone is nearly as potent as cortisol.
  • Synthetic glucocorticoids like prednisone (4x more potent than cortisol), methylprednisolone (5x more potent), and dexamethasone (30x more potent) are utilized in medical treatments.

E. ADRENOCORTICAL HORMONES

  • In plasma, approximately 90–95% of cortisol binds to plasma proteins, mainly cortisol-binding globulin, which is also known as transcortin. It also attaches to albumin, slowing its clearance and providing a relatively long half-life (60-90 mins).
  • Aldosterone has a shorter half-life (20 mins), with only about 60% binding to plasma proteins and the rest existing in free form, functionally active.
  • The liver metabolizes both hormones, conjugating cortisol to glucuronic acid and sulfate (resulting in inactive metabolites) for urinary excretion.

III. FUNCTIONS OF MINERALOCORTICOIDS

A. RENAL AND CIRCULATORY EFFECTS OF ALDOSTERONE

  • Excess aldosterone increases extracellular fluid (ECF) volume and arterial pressure, with a minor impact on plasma sodium concentration. When sodium is reabsorbed in the tubules, water follows due to osmotic forces.
  • Increased ECF sodium levels stimulate thirst and Antidiuretic Hormone (ADH) secretion.
  • Aldosterone enhances renal tubular sodium reabsorption and potassium secretion, primarily in the principal cells of the distal tubules and collecting ducts. Conditions like hypokalemia and muscle weakness occur from excess aldosterone, while aldosterone deficiency leads to hyperkalemia and potential cardiac toxicities.
  • A decrease in blood pressure stimulates juxtaglomerular cells in the kidneys to release renin, which leads to the production of Angiotensin II and subsequent aldosterone release, promoting sodium and water reabsorption and raising blood pressure.
  • “Aldosterone Escape” refers to the body's adaptation to excess aldosterone, leading to sodium and water excretion, stabilizing blood pressure despite aldosterone's buildup. This escape phenomenon does not occur in adrenal pathologies.

B. OTHER EFFECTS OF ALDOSTERONE

  • Aldosterone promotes sodium and potassium transport in epithelial tissues such as sweat, salivary, and intestinal glands, which helps to conserve body salt during conditions of high perspiration or sodium loss.
  • It significantly affects sodium absorption in the intestines, mitigating sodium loss through stools.
  • In the absence of aldosterone, sodium absorption is diminished, leading to dehydration and diarrhea.

C. CELLULAR MECHANISM OF ACTION

  • Aldosterone's lipid solubility allows it to diffuse easily through cellular membranes into renal epithelial cells, where it binds to a specific cytoplasmic mineralocorticoid receptor.
  • The activated receptor complex translocates to the nucleus, stimulating mRNA synthesis that leads to the production of key proteins for sodium and potassium active transport, requiring time (30 minutes for new RNA) before observable effects on ion transport are noted.

IV. REGULATION OF ALDOSTERONE SECRETION

  • Aldosterone secretion is intricately tied to ECF electrolyte concentrations, blood volume, arterial pressure, and various renal operations. Specific conditions influencing aldosterone release include:
    • Increased ECF potassium levels (potent stimulator).
    • Increased angiotensin II levels (potent stimulator).
    • Slightly elevated ECF sodium levels (inhibitory influence).
    • Increased levels of Atrial Natriuretic Peptide (ANP), released due to cardiac atrial stretch (which inhibits aldosterone secretion).

V. FUNCTIONS OF GLUCOCORTICOIDS

A. EFFECTS OF CORTISOL ON CARBOHYDRATE METABOLISM

  • Cortisol's principal role is to elevate glucose production in the liver by increasing gluconeogenesis (6-10 times) and enhancing the enzyme machinery necessary for amino acid conversion to glucose.
  • It promotes the mobilization of amino acids from peripheral tissues, particularly muscle, increasing overall amino acid availability for gluconeogenesis.
  • Cortisol antagonizes insulin's ability to inhibit gluconeogenesis, leading to increased blood glucoselevels (100-200 mg/dL) and contributing to insulin resistance (adrenal diabetes).

B. EFFECTS OF CORTISOL ON PROTEIN METABOLISM

  • Cortisol decreases protein stores in all tissues except the liver by reducing protein synthesis and increasing catabolism, resulting in muscle weakness.
  • It raises liver and plasma protein levels, counteracting overall protein depletion elsewhere.

C. EFFECTS OF CORTISOL ON FAT METABOLISM

  • Cortisol increases fatty acid mobilization from adipose tissue, enhancing fatty acid concentrations in plasma and promoting fatty acid oxidation.
  • This switches cellular energy utilization from glucose to fatty acids during stress or starvation, which is essential for preserving body glycogen and glucose.
  • Chronic excess cortisol leads to a specific type of visceral obesity, characterized by fat deposits in the thorax and abdomen, creating a “buffalo torso” and “moon face” associated with Cushing’s syndrome.

D. IMPORTANCE IN RESISTING STRESS AND INFLAMMATION

  • Stress induces acute cortisol release via increased ACTH, allowing rapid amino acid and fatty acid mobilization during crises (e.g., infections, trauma, surgery).
  • Damaged tissues utilize newly accessible amino acids for repair,
    while glucocorticoids accelerate recovery by enhancing permeability of tissues to repair mechanisms.

E. ANTI-INFLAMMATORY EFFECTS OF HIGH LEVELS OF CORTISOL

  • Cortisol reduces inflammatory responses by stabilizing lysosomal membranes, minimizing proteolytic enzyme release during tissue damage.
  • It also inhibits WBC migration, phagocytosis, and reduces fever through diminished IL-1 release and inflammatory mediator levels.

VI. REGULATION OF CORTISOL SECRETION

  • Cortisol secretion is triggered by ACTH via the hypothalamic-pituitary-adrenal (HPA) axis, illustrating a negative feedback loop in endocrine regulation.
  • The process begins with Corticotropin-Releasing Factors (CRF) from the hypothalamus, acting on the anterior pituitary to release ACTH, which in turn stimulates cortisol production.
  • Cortisol exerts direct negative feedback to both the pituitary and hypothalamus, modulating its own secretion.

A. CIRCADIAN RHYTHM OF GLUCOCORTICOID SECRETION

  • Glucocorticoid secretion follows a cyclic pattern, characterized by elevated morning levels of CRF, ACTH, and cortisol, decreasing towards the evening. Plasma levels exhibit significant oscillations throughout the day, peaking an hour after waking.

B. PRO-OPIOMELANOCORTIN (POMC)

  • POMC is a precursor protein for several hormones, including ACTH and melanocyte-stimulating hormone (MSH).
  • It undergoes specific processing in various tissues (pituitary corticotroph cells, hypothalamic neurons) to produce various biologically active peptides.
  • The activation of melanocyte-stimulating hormones leads to melanin production in skin melanocytes, relating to pigmentation often observed in adrenal disorders.

VII. ADRENAL ANDROGENS

  • The adrenal cortex secretes androstenedione and dehydroepiandrosterone (DHEA), which are precursors for sex hormones.
  • These androgens play a minor role in male secondary sex characteristics due to weak effects in humans.
  • Females also secrete trace amounts of male sex hormones that can influence hair growth in pubic and axillary regions.

VIII. ABNORMALITIES OF ADRENOCORTICAL SECRETIONS

A. HYPOADRENALISM (ADRENAL INSUFFICIENCY) - ADDISON’S DISEASE

  • Characterized by insufficient adrenocortical hormone production due to adrenal cortex atrophy or injury.
  • Autoimmunity is responsible for 80% of the cases. Other causes include tuberculosis or cancer infiltrating adrenal tissues.
  • Treatment involves the administration of mineralocorticoids and glucocorticoids to manage symptoms.

B. MINERALOCORTICOID DEFICIENCY

  • Results in decreased aldosterone levels causing reduced sodium reabsorption in the kidneys, leading to hyponatremia, hyperkalemia, and shock.

C. GLUCOCORTICOID DEFICIENCY

  • Affects gluconeogenesis and compromises stress response, leading to weakness and susceptibility to infections.

D. MELANIN PIGMENTATION

  • Due to elevated ACTH in primary adrenal insufficiency, increased MSH output results in pigmentation changes in mucosal membranes and skin.

E. ADRENAL CRISIS

  • Known as Addisonian crisis; occurs due to inadequate glucocorticoid secretion during stress. Urgent glucocorticoid administration is necessary to avert shock or death.

F. HYPERADRENALISM (CUSHING’S SYNDROME)

  • Results from chronic excess cortisol production by the adrenal cortex.
  • Can be caused by pituitary adenomas, ectopic ACTH secretion, or chronic glucocorticoid therapy.
  • Symptoms include hypertension, characteristic fat distribution (buffalo torso, moon face), and increased blood glucose levels.

G. PRIMARY ALDOSTERONISM (CONN’S SYNDROME)

  • Typically due to an adrenal cortical tumor resulting in excess aldosterone.
  • Characterized by hypertension, hypokalemia, and muscle weakness. Treatment includes surgical removal or mineralocorticoid receptor antagonists.

H. ADRENOGENITAL SYNDROME

  • Due to adrenal tumors secreting excess androgens resulting in virilization effects, particularly in females, and precocious puberty in boys.