Adrenal Gland Function: Study Notes (ACBS 400A/500A)

Structure of Adrenal Gland

  • Two bean-shaped endocrine organs that secrete various hormones
  • Located near the cranial pole of the kidneys; Right gland is positioned slightly more cranial than the left
  • Surrounded by a thick capsule

Cortex vs Medulla

  • Adrenal gland has two main compartments:
    • Cortex (outer layer)
    • Medulla (inner core)

Cortex: Zona Glomerulosa

  • Outermost layer of the cortex
  • Produces mineralocorticoid aldosterone
    • Aldosterone helps regulate electrolyte balance
  • Histology: tight trabecular clusters of polygonal cells with moderate eosinophilic, slightly vacuolated cytoplasm and round nuclei
  • Minimal response to ACTH

Cortex: Zona Fasciculata

  • Central layer; thickest of the three cortical layers
  • Produces glucocorticoids: cortisol and corticosterone
    • Cortisol (in most species) with corticosterone in some species
    • Roles in glucose metabolism and stress responses
  • Most responsive region to ACTH
  • Histology: linearly arranged cords of polygonal epithelial cells with abundant eosinophilic cytoplasm and small non-staining vacuoles

Cortex: Zona Reticularis

  • Innermost cortical layer
  • Primarily produces androgen precursor sex hormones (adrenal androgens)
    • Necessary for production of testosterone and estrogen
  • Will produce small amounts of glucocorticoids
  • Histology: irregular cords of polygonal epithelial cells with small to moderate eosinophilic cytoplasm and few clear cytoplasmic vacuoles

Adrenal Medulla

  • Distinguishable from cortex by cellular organization: clusters and irregular trabeculae of chromaffin cells
  • Chromaffin cells have moderate granular, lightly basophilic cytoplasm and can appear brown due to staining of granules
  • Produces norepinephrine and epinephrine
  • Regulation: Controlled by the sympathetic nervous system (SNS)

Production of Adrenal Hormones

  • All adrenal hormones are derivatives of cholesterol
  • General process:
    • Side chain of cholesterol molecule is cleaved off to form pregnenolone
    • Step is regulated by ACTH and acts as a rate-limiting step for all adrenocortical hormones
    • Hydroxylation reactions modify pregnenolone to create different hormones
  • Hormones are not stored in adrenal cells; they are synthesized on demand when secretion is signaled
  • All hormones are lipid-soluble and diffuse from cortical cells into the extracellular fluid
  • In the bloodstream, they require transport proteins (e.g., corticosteroid-binding globulin)
  • Summary formula (representative pathway):
    • Cholesterol
      ightarrow Pregnenolone
    • Subsequent hydroxylations yield cortisol, corticosterone, aldosterone, and adrenal androgens

Regulation of Aldosterone

  • Primary regulatory pathway:
    • Low blood pressure or decreased renal perfusion → juxtaglomerular (JG) cells in the kidneys sense change and secrete renin into the bloodstream
    • Renin acts on angiotensinogen (produced by the liver) to form Angiotensin I
    • Angiotensin-converting enzyme (ACE) in lung capillaries converts Angiotensin I to Angiotensin II
    • Angiotensin II stimulates cells to secrete aldosterone and also causes widespread vasoconstriction (including efferent arterioles in the kidney)
    • Representative sequence: ext{Angiotensinogen}
      ightarrow ext{Angiotensin I}
      ightarrow ext{Angiotensin II}
      ightarrow ext{Aldosterone secretion}
  • Additional modulator: Atrial natriuretic peptide (ANP)
    • ANP is synthesized in atrial cells and released upon atrial stretch due to high blood pressure
    • ANP inhibits Na+ reabsorption in the renal collecting ducts; also inhibits parts of the renin–angiotensin–aldosterone system (RAAS)
    • Effects include inhibition of renin secretion, inhibition of angiotensin-induced aldosterone secretion, and increased glomerular filtration rate (GFR) → increased Na+ excretion

Regulation of Aldosterone: Additional Details

  • ANP effects in renal tubules promote natriuresis and diuresis, contributing to Na+ and water loss when blood pressure is high

Actions of Aldosterone

  • Renal effects:
    • Stimulates Na+ reabsorption in the ascending limb of the loop of Henle, collecting ducts, and distal renal tubules
    • Cl− follows passively to maintain electroneutrality
    • Increases secretion of K+ into the tubular lumen
  • Mechanism:
    • Aldosterone diffuses into target tissue and binds to a nuclear receptor
    • Activates transcription/translation of proteins that enhance apical Na+ channels (e.g., ENaC) and basolateral Na+/K+ pumps
    • Net effect: Na+ is actively reabsorbed from tubular fluid into the interstitial fluid; water follows passively; K+ is secreted into the lumen
  • Regulation of Na+ in blood:
    • Aldosterone does not directly regulate Na+ concentration in the blood; this is controlled by osmoreceptors in the hypothalamus which regulate ADH release

Regulation of Cortisol

  • Cortisol is the primary adrenal glucocorticoid; corticosterone is produced in smaller amounts (more prominent in amphibians, reptiles, birds, and some rodents)
  • Regulation involves the hypothalamic–pituitary–adrenal (HPA) axis:
    • Hypothalamus releases ACTH-releasing hormone (ACTH-RH) into the portal system
    • ACTH-RH stimulates corticotrophs in the anterior pituitary to secrete ACTH
    • ACTH acts on fasciculata cells of the cortex to stimulate cortisol synthesis via a cAMP pathway
    • Representative sequence: ext{ACTH-RH}
      ightarrow ext{ACTH}
      ightarrow ext{cortisol synthesis}
    • ACTH binding increases adenylyl cyclase activity, raises intracellular cAMP, and drives cortisol production
  • Feedback regulation:
    • Rising cortisol levels feed back to the hypothalamus and anterior pituitary to decrease ACTH-RH and ACTH release
  • Circadian rhythm and stress:
    • Cortisol is produced in a circadian pattern with highest levels in the morning and lowest in the evening
    • Stress can elevate cortisol production beyond the normal circadian peak
    • Chronic stress can lead to hypertrophy of cortisol-producing cells

Regulation of Cortisol: Additional Details

  • Cortisol can raise blood glucose levels but is not triggered by hypoglycemia per se
  • ACTH and CRH (ACTH-RH) are central to cortisol synthesis; cortisol provides negative feedback to limit further ACTH/CRH release
  • Interactions with other hormones (glucagon, epinephrine) help coordinate glucose metabolism during stress

Functions of Cortisol

  • Stress response and energy mobilization:
    • Stimulates gluconeogenesis and the production of glucose by leveraging amino acids from muscle tissue
    • Increases available glucose and maintains energy supply during stress
    • Decreases tissue sensitivity to insulin in adipose and lymphoid tissues, reducing glucose uptake from blood
    • Promotes lipolysis in adipose tissue, raising circulating free fatty acids
    • Stimulates protein catabolism in muscle, raising blood amino acids for gluconeogenesis
    • Inhibits DNA synthesis, slowing growth
    • Potentiates the effects of glucagon and epinephrine on glucose metabolism
  • Immune and inflammatory modulation (high cortisol levels):
    • Immunosuppressive effects include inhibition of prostaglandin production, reduced histamine release, decreased phagocytosis and antibody formation, stabilization of granulocyte lysosomal membranes to limit tissue damage, and reduced leukocyte emigration from vasculature
    • These actions help dampen prolonged inflammatory responses

Regulation of Androgens

  • Adrenal zona reticularis produces androgens such as dehydroepiandrosterone (DHEA) and androstenedione
  • Functional notes:
    • These adrenal androgens serve as precursors to testosterone and estrogens in peripheral tissues
    • They have minimal direct androgenic activity on male sexual characteristics but can be converted to testosterone in other tissues
    • In females, adrenal androgens contribute to bone density, muscle mass, and expression of estrous behaviors in some species
  • Regulation:
    • ACTH stimulates production, but the zona reticularis responds more to androgen-stimulating hormone (from the pituitary) that promotes adrenal androgen production
    • ACTH is a primary stimulator, with modulation by other hormonal signals

Any Questions?

  • Review the relationships between ACTH, cortisol, aldosterone, and their target tissues
  • Understand how changes in blood pressure, electrolyte balance, and stress influence adrenal hormone secretion
  • Be able to trace the RAAS pathway and the role of ANP in aldosterone regulation