Cortisol and Aldosterone: Endocrine Functions

• The lecture discusses the functions of adrenocortical hormones, specifically cortisol and aldosterone.
• Dr. Sovan Bagchi is the Professor of Physiology at Gulf Medical University.

Learning objectives

• Define cortisol and know where it is produced.
• Explain the process of cortisol synthesis.
• Identify the cellular binding and major physiological actions of cortisol.
• Describe the regulation of cortisol release by the adrenal gland.
• Define mineralocorticoids and specify their site of production.
• Explain aldosterone synthesis and transport.
• Identify the cellular binding and major physiological actions of aldosterone.
• Describe how the adrenal glands regulate the release of aldosterone.

Case Study

• A college roommate, AS, takes corticosteroid medication (prednisone) to prevent rejection of her transplanted kidney,
• Then needed more corticosteroids for emergency surgery, raising the question of why extra steroids were needed during stress.

What Is Cortisol?

• A steroid hormone produced in the adrenal gland, specifically in the zona fasciculata.
• Cortisol is a glucocorticoid that regulates glucose metabolism and is also known as a corticosteroid.

How Is Cortisol Synthesized?

• Cortisol production depends on adrenocorticotropic hormone (ACTH).
• Cortisol production steps:
  • Cholesterol synthesis using desmolase, STAR and ACTH.
  • Mitochondrial conversion.
  • Smooth endoplasmic reticulum.

How Does Cortisol Act on Tissues?

• Impacts many bodily functions because most cells possess glucocorticoid receptors (GRs) that bind to cortisol.

Transport and Receptor Binding

• About 90% of is bound to corticosteroid-binding globulin (CBG), also known as transcortin.
  • Synthesized in the liver, prolongs cortisol's half-life.
• Only about 3% travels freely in the plasma.
• Only unbound cortisol can enter cells and activate receptors.
• Total cortisol and CBG levels commonly elevate during pregnancy but free cortisol remains normal and the patient won't have high cortisol symptoms.

Diverse Effects

• A hormone crucial for life, and deficiencies have fatal consequences.
• Affects: glucose, overall metabolism, immune system, cognition, bone formation, and fetal development.

Metabolism

• Increases energy-generating substrates like glucose, glycerol, and amino acids for use during stress.
• Elevates serum glucose.
  • Gluconeogenesis, lowers glycogen formation (in the liver).
  • Reduces glucose uptake by decreasing GLUT4 transporters.
  • Leads to insulin resistance.
  • Decreases insulin and increases glucagon secretion.
• Affects serum glucose concentration
• Lipolysis generates glycerol for energy during stress
• Increases proteolysis into amino acids for energy or glucose conversion.
• Inhibits protein synthesis and lowers peripheral amino acid uptake in muscles.
• High cortisol levels (Cushing syndrome) causes insulin-resistant diabetes.

Maintaining Blood Pressure

• Supports normal pressure by up-regulating vasoconstricting a₁ receptors on arterioles.
• High concentrations trigger mineralocorticoid receptors (MRs), increasing sodium reabsorption, blood volume, and blood pressure.
• The MR shares the affinity.
• The mineralocorticoid effect is normally blocked by corticosteroid 11β-dehydrogenase, meaning cortisol would dominate MR signaling

Immunity and Wound Healing

• Impairs wound healing and suppresses the immune system
• Acts as an anti-inflammatory molecule that slows inflammations and immune reactions.
• Ultimately causes immune suppression and poor wound healing
• As a drug, it is used to limit inflammation in chronic inflammatory conditions like skin rashes.

Additional Cortisol Functions

• Bone formation decreases.
• Fetal lung development modulation.
  • Surfactant production
• Cognition and memory stimulation.
  • Terminal maturation and axon remodeling.
• Osteoblast activity is reduced by it.
• For premature labor, glucocorticoids are given to promote the baby’s lung development.
• Risk of osteoporosis is higher for people on chronic glucocorticoid drugs.

Increases Memory and Cognition

• Stimulates the formation of memories linked to both strong emotions, whether good or bad.
• Enhances alertness and cognition
• Through its effects on the hippocampus, amygdala, and frontal lobes.

Cortisol effects (BIG FIB acronym)

• Increases Blood pressure, Insulin resistance, Gluconeogenesis, lipolysis, and proteolysis.
• Decreases Fibroblast activity, Inflammation and immune response, and Bone production.

How Is Cortisol Secretion Regulated?

• This process involves stress, the hypothalamus, CRH, the anterior pituitary, ACTH, and the adrenal gland.
• Cortisol levels are highest upon waking up and decline during sleep.

Relation to stress

Stress -> paraventricular nucleus of the hypothalamus -> limbic system -> hypothalamus (CRH) -> ACTH (anterior pituitary) -> Cortisol

Mineralocorticoids

• Objectives include defining mineralocorticoids, their production site, aldosterone synthesis, transport, cellular binding, effects, and how adrenal glands regulate aldosterone release.
• Aldosterone is critical for maintaining blood volume.
• Responsible for the sodium and water reabsorption (secondary effect) in the kidney.
• Regulates potassium to excrete excess potassium.

Site of Production

• Steroid hormones created in the adrenal gland inside the zona glomerulosa.

How Is Aldosterone Synthesized?

• Cholesterol -> Pregnenolone using Demolase, ACTH, and StAR -> Progesterone -> Corticosterone -> Aldosterone using Angiotensin II in the smooth endoplasmic reticulum.
• Steroidogenic acute regulatory protein (STAR) is a rate-limiting enzyme.

Transport

• 50% of aldosterone binds to serum albumin
• 17% binds to corticosteroid-binding globulin (CBG)/transcortin.
• 30% circulates freely in the blood

Receptor Binding

• Binds to the mineralocorticoid receptor (MR; intracellular)
• MR equal affinity for mineralocorticoids and for cortisol
• The aldosterone-MR complex then enters the nucleus, binds to hormone response elements and modulating multiple genes expressions (repressing or enhancing their transcription)

What Does Aldosterone Do?

• Acts as a ligand-dependent transcription factor (TF).
• Alters cell signaling which regulated water and ion transport
• As a protection mechanism, corticosteroid 11ẞ-dehydrogenase isozyme 2 metabolizes cortisol to stop it binding to MR
• High levels of circulating cortisol does not dominate MR signaling

Actions in the Kidney

• Facilitates sodium reabsorption and potassium excretion.
  • Increasing the sodium channels on the lumen side of the cell.
  • Na+/K+-ATPase pump activity on the basolateral side of the cell
• Stimulates H+-ATPase on a-intercalated cells.
• This increases urinary potassium excretion.

Clinical Correlation

• Primary hyperaldosteronism can cause hypertension by continuously secreting aldosterone.

Actions Outside the Kidney

• Stimulates sodium reabsorption through its actions on receptors in the colon, salivary, and sweat glands,

How Is Aldosterone Secretion Regulated?

• Via Angiotensin II
  • Activation of the renin-angiotensin-aldosterone system (RAAS) occurs when there is a drop in blood pressure or blood volume.
  • RAAS activation generates angiotensin II.
• Via increased serum concentration
  • When serum potassium rises.
  • Increases renal potassium excretion.
• Circulating Adrenocorticotropic Hormone
  • The presence of ACTH is required for aldosterone synthesis

Test your Knowledge

• Aldosterone increases sodium reabsorption at the collecting ducts?
  • Stimulates insertion of Na+/K+-ATPase in principal cells
• Most potent stimulant of CRH release?
  • Stress

Explore the roles of cortisol and aldosterone in endocrine function. Questions cover cortisol's impact on insulin resistance, energy metabolism, and blood pressure. Also, explore aldosterone's regulation and its effects on blood pressure and potassium levels.