HPA Axis in Mammals Notes

HPA Axis in Mammals

Learning Objectives
  • Review overall HPA axis including glands and major hormones, steroid synthesis, and genomic mechanisms of action of steroids.
  • Understand adrenal morphology and discrete tissue layers acting as endocrine glands.
  • Pair zones of adrenal glands with the hormones they produce, their regulation, and functions in mammals.
  • Familiarize with diseases and endocrine disrupting chemicals (EDCs) disrupting the HPA axis.
Overview of the HPA Axis
  • Major hormones include:
    • Glucocorticoids: cortisol, corticosterone, 11-deoxycortisol
    • Mineralocorticoids: aldosterone, deoxycorticosterone
    • Androgens: Dehydroepiandrosterone (DHEA)
  • Each hormone class produced in different adrenal regions and regulated by distinct mechanisms.
Adrenal Glands
  • Location: Situated above the kidneys, also known as suprarenal glands.
  • Structure:
    • Well-vascularized pairs: Humans have 3.5-4.5 g each.
    • Two distinct tissues:
    • Medulla: Chromaffin tissue from neural crest cells.
    • Cortex: Steroidogenic tissue from coelomic mesoderm.
  • Heterotopic Locations: Possible locations of either tissue type can occur throughout the abdomen.
Anatomy of Adrenal Glands
  • Cortex Zones:
    • Zona Glomerulosa (ZG):
    • Smaller cells with lower lipid content.
    • ACTH has a permissive effect on aldosterone release.
    • Zona Fasciculata (ZF):
    • Largest zone, cells arranged in columns, responsive to ACTH.
    • Primary glucocorticoid varies across species (humans: cortisol, rats: corticosterone).
    • Zona Reticularis (ZR):
    • Contains reticular fibers, primary site of adrenal androgen production, can also produce glucocorticoids.
Adrenal Medulla
  • Composed of chromaffin cells, serves as a sympathetic ganglia.
  • Innervated by the splanchnic nerve, releases norepinephrine and epinephrine upon stimulus.
Corticosteroid Synthesis
  • Derived from Cholesterol: Starting point comes from low-density lipoproteins in plasma.
  • Key Steps:
    1. Cholesterol transported from outer to inner mitochondrial membrane by StAR protein (rate-limiting).
    2. Cholesterol cleaved to pregnenolone by cytochrome P450.
    3. Pregnenolone converted to various steroids in smooth ER.
Release and Transport of Corticosteroids
  • Little storage; release rates reflect production rates.
  • Diurnal Patterns: Peaks between 6-9 AM, decreasing throughout the day.
  • Transport requires binding proteins (e.g., CBG, transcortin, albumin).
Corticosteroid Receptors
  • Two types found in cytosol:
    1. Mineralocorticoid Receptor (MR): Binds aldosterone and glucocorticoids.
    2. Glucocorticoid Receptor (GR): Binds cortisol and corticosterone.
    • Cortisol converted to cortisone in cells involved in mineral balance (by HSD11B2), which does not bind to MR well.
Glucocorticoids: Functions
  • Primarily involved in regulating energy metabolism:
    • Inhibit glucose utilization in peripheral tissues.
    • Stimulate gluconeogenesis and glycogen storage.
    • Mobilize fat stores for energy.
  • Also involved in:
    • Reproductive functions: Increased secretion at puberty, altered energy reserves.
    • Modulating immune response: Inhibit inflammation, production of antibodies.
Stress Responses
  • Acute Stressors: Initial response linked to epinephrine release.
  • Role of HPA axis in chronic stress responses: adaptive until chronic stress occurs.
  • General Adaptation Syndrome: Phases of stress response identified by Hans Selye:
    1. Alarm reaction: activation of sympathetic system.
    2. Resistance: prolonged glucocorticoid exposure leads to changes.
    3. Exhaustion: can lead to severe health issues, including death.
Pathophysiologies of HPA Axis
  • Cushing’s Disease/Syndrome:
    • Hypersecretion often due to pituitary adenoma or adrenal tumors.
    • Symptoms: Hyperpigmentation, soft skin, muscle wasting.
  • Addison’s Disease:
    • Hyposecretion of cortisol leads to excess ACTH production.
    • Symptoms: Hyperpigmentation, hypoglycemia.
  • Congenital Adrenal Hyperplasia:
    • Genetic defect affecting steroidogenic enzyme production.
    • Symptoms: Masculinization of external genitalia, short stature.
Aldosterone and Mineralocorticoids
  • Secreted by Zona Glomerulosa, mainly affects sodium and potassium balance.
  • Function: Promotes sodium reabsorption, potassium excretion in kidneys.
Renin-Angiotensin System
  1. Renin secretion in response to low BP or sodium levels.
  2. Renin converts angiotensinogen to angiotensin-I.
  3. Angiotensin-I converted to angiotensin-II in lungs.
  4. Angiotensin-II stimulates aldosterone release, regulates sodium/water balance.
Endocrine Disrupting Compounds (EDCs)
  • Lipophilic compounds can disrupt adrenal function.
  • Examples include DDT, PCBs, and the herbicide Atrazine.
Regulation of the Medulla and Catecholamines
  • Neural Pathways: Cholinergic stimulation of the medulla leads to catecholamine release.
  • Endocrine Pathways: ACTH stimulates epinephrine secretion via PNMT activity.
Physiological Responses to Stress
  • Responses include increased heart rate, vasodilation of skeletal muscle, general vasoconstriction, relaxation of bronchi, and mobilization of energy stores.
  • Adaptive significance lies in preparing the body for immediate physical response (fight-or-flight reaction).