Adrenal Hormones

There are 2 primary portions of the adrenal glands, the adrenal medulla and the adrenal cortex. Each of these areas secretes different hormones and has different regulatory mechanisms. The adrenal medulla is the inner portion of the gland, secreting epinephrine and, to a lesser degree, norepinephrine. These hormones function in conjunction with the sympathetic nervous system and contribute to the fight-or-flight response. The adrenal cortex is the outer portion of the gland and is part of the hypothalamic-pituitary-adrenal axis. The cortex secretes mineralocorticoids, glucocorticoids, and androgens. The mineralocorticoid aldosterone is primarily involved in fluid volume and potassium regulation. The glucocorticoids (e.g., cortisol) provide the body with immediate energy and have antiinflammatory properties. The androgens stimulate secondary sex characteristics.

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Overview

Regions of the adrenal gland

The adrenal glands have 2 primary areas with separate functions and regulatory mechanisms.

  • Adrenal medulla:
    • Inner portion
    • Secretes catecholamines
    • Functions in conjunction with the sympathetic nervous system
  • Adrenal cortex:
    • Outer portion
    • All cortical hormones are synthesized from cholesterol
    • Has 3 different zones:
      • Zona glomerulosa: secretes mineralocorticoids
      • Zona fasciculata: secretes glucocorticoids
      • Zona reticularis: secretes androgens
    • Part of the hypothalamic-pituitary-adrenal (HPA) axis
Zones of the adrenal cortex and medulla and their hormonal products

Zones of the adrenal cortex and medulla and their hormonal products

Image by Lecturio.

Hypothalamic-pituitary-adrenal (HPA) axis

Hormones secreted by the adrenal cortex (not the medulla) are controlled by, and help regulate, the HPA axis.

  • The hypothalamus (paraventricular nucleus) secretes corticotropin-releasing hormone (CRH).
  • CRH stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH).
  • ACTH stimulates the adrenal cortex to synthesize and release all of the cortical hormones:
    • Mineralocorticoids
    • Glucocorticoids
    • Androgens 
  • Negative inhibition within the HPA axis:
    • ACTH inhibits further CRH release.
    • Cortisol (the primary glucocorticoid) inhibits both CRH and ACTH.
  • Other factors that can stimulate the HPA axis:
    • Stresses:
      • Physical (e.g., exercise)
      • Mental (e.g., fear)
      • Biochemical (e.g., low blood sugar)
    • Biologic rhythms:
      • Circadian rhythms
      • Rhythms associated with growth and development
Hypothalamic-Pituitary-Adrenal Cortex Axis

Flowchart showing the hypothalamic-pituitary-adrenal cortex axis
ACTH: adrenocorticotropic hormone
CRH: corticotropin-releasing hormone

Image by Lecturio.

Adrenal Cortex Hormones: Mineralocorticoids

Mineralocorticoid overview

  • Primary hormone: aldosterone
  • Secreted from the zona glomerulosa within the adrenal cortex
  • Synthesized by aldosterone synthase
  • Regulation:
    • Partially under the control of ACTH
    • Renin-angiotensin-aldosterone system (see below)
  • Effects:
    • ↑ Blood pressure (↑ water reabsorption from the kidneys)
    • ↑ Serum Na+ (↓ urinary excretion of Na+)
    • ↓ Serum K+ (↑ urinary excretion of K+)
    • ↑ Serum pH (↑ urinary excretion of H+)

The renin-angiotensin-aldosterone system (RAAS)

The RAAS is one of the primary regulators of blood pressure, total body water, serum sodium levels, and pH balance in the body.

  • Angiotensinogen: secreted by hepatocytes
  • Renin: 
    • Secreted by the macula densa cells within the kidneys 
    • Converts angiotensinogen to angiotensin I 
  • ACE:
    • Secreted by pulmonary vascular endothelium
    • Converts angiotensin I to angiotensin II
  • Angiotensin II: 
    • Stimulates the zona glomerulosa in the adrenal cortex to release aldosterone 
    • Induces vasoconstriction of the efferent renal arteriole
    • Stimulates Na+ and water reabsorption in the renal tubules
  • Aldosterone:
    • Stimulates production of the following proteins within the principle cells in the distal renal tubules:
      • Na+/K+-ATPase on the basolateral side
      • Epithelia sodium channels (ENaCs) on the lumen side: allow Na+ reabsorption from the lumen into the principal cells
      • Renal outer medullary potassium channel (ROMK) on the lumen side: allows excretion of K+ into the urine
    • Stimulates Na+ reabsorption from the renal tubules
      • Water follows the Na+ 
      • Creates a negative electrical gradient across the lumen, promoting the secretion of K+ and H+ into the urine
  • Factors that normally trigger the RAAS (and thus ↑ aldosterone):
    • ↓ Renal perfusion:
      • ↓ Blood pressure
      • ↓ Effective blood volume
    • ↑ Serum potassium (K+)
    • ↓ Sodium delivery to the kidney
    • ↑ Sympathetic tone

Adrenal Cortex Hormones: Glucocorticoids and Androgens

Glucocorticoids

  • Hormones:
    • Cortisol 
    • Corticosterone
  • Secreted from the zona fasciculata
  • Effects: respond to immediate stressors
    • ↑ Immediately available energy through: 
      • Fat and protein catabolism → ↑ blood amino acid and lipid levels
      • Gluconeogenesis
      • Appetite stimulation
    • ↑ RBCs
    • ↑ Serum calcium from bone resorption (leads to ↓ bone mineral density over time)
    • Antiinflammatory effects:
      • ↓ Inflammation
      • ↓ Blood vessel permeability
      • Long-term exposure suppresses the immune system.
  • Regulated by the HPA axis

Androgens

  • Hormones: 
    • DHEA
    • Androstenedione 
  • Secreted from the zona reticularis
  • Androgens can be converted to testosterone and estrogens in peripheral tissue (primary source of estrogen in postmenopausal women).
  • Effects:
    • Important for secondary sex characteristics
    • Stimulates axillary, pubic, and male-pattern facial hair

Hormones Secreted by the Adrenal Medulla

Hormones and their regulation

  • The adrenal medulla secretes catecholamines:
    • Epinephrine (80%)
    • Norepinephrine (20%)
  • Synthesized from dopamine within chromaffin cells (modified sympathetic neurons)
  • Controlled by the sympathetic nervous system (rather than the hypothalamus/pituitary):
    • Preganglionic nerve fibers synapse with the chromaffin cells.
    • Acetylcholine from the preganglionic nerve fibers stimulates the nicotinic type 2 receptors on the chromaffin cells.
    • Chromaffin cells release the catecholamines directly into the blood.
    • Catecholamines stimulate α- and β-adrenergic receptors throughout the body.
Differences between the nerve and hormone pathways used for sympathetic signaling

Differences between the nerve and hormone pathways used for sympathetic signaling:
The adrenal medulla is considered a modified sympathetic ganglion because of its ability to convert nerve stimuli into endocrine signals.

Image by Lecturio.

Effects

The primary purpose of the medullary catecholamines is to supplement the effects of the sympathetic nervous system. Because these substances are released directly into the bloodstream as hormones, their effects last longer than when catecholamines are released as neurotransmitters. These effects include characteristics of the fight-or-flight response:

  • ↑ Blood pressure
  • ↑ HR
  • ↑ Circulation to skeletal muscles
  • ↑ Respirations and bronchodilation
  • ↑ Blood glucose levels by:
    • Stimulating glycogenolysis 
    • Stimulating gluconeogenesis 
    • Inhibiting insulin release
  • ↓ Digestion

Clinical Relevance

There are a number of clinical conditions that result from abnormalities of the adrenal hormones. Some of the most clinically important include:

  • Pheochromocytoma: rare catecholamine-secreting tumors arising from the chromaffin cells of the adrenal medulla. The presentation of pheochromocytoma is typically with treatment-resistant hypertension, episodic headaches, sweating, and tachycardia. Diagnosis is made via laboratory assessment showing elevated serum catecholamines and adrenal imaging studies. These tumors are benign 90% of the time, and surgical resection is the only curative treatment.
  • Adrenal insufficiency: refers to the inadequate production of glucocorticoids, mineralocorticoids, and adrenal androgens. Diagnosis is made by measuring cortisol levels and ACTH levels and with ACTH stimulation testing. Management involves glucocorticoid and mineralocorticoid replacement therapy.
    • Addison’s disease (primary adrenal insufficiency): Etiologies include autoimmune disease, infections, and malignancy, among others. 
    • Secondary and tertiary adrenal insufficiency: due to the decreased production of ACTH within the pituitary. This insufficiency can also occur because of prolonged glucocorticoid therapy. 
  • Congenital adrenal hyperplasia (CAH): group of autosomal recessive disorders that cause a deficiency of an enzyme (most commonly 21-hydroxylase) needed in cortisol, aldosterone, and androgen synthesis. Clinical manifestations include ambiguous genitalia in genotypic females, salt wasting, and hypoglycemia. A less severe form, known as nonclassical CAH, also exists; this form typically presents in puberty. Lifelong glucocorticoid replacement is needed. 
  • Cushing syndrome: condition resulting from chronic exposure to excess glucocorticoids. Etiologies include chronic glucocorticoid intake, increased adrenal secretion of cortisol, and increased pituitary or ectopic secretion of ACTH. Typical clinical features include central obesity, thin, bruisable skin, abdominal striae, secondary hypertension, hyperglycemia, and proximal muscle weakness. Diagnosis involves urinary and/or salivary cortisol testing along with a low-dose dexamethasone suppression test, measurement of ACTH levels, and possibly imaging. 
  • Hyperaldosteronism: increased secretion of aldosterone from the adrenal cortex. Hyperaldosteronism may be primary (resulting from autonomous secretion (known as Conn syndrome)) or secondary (resulting from physiologic secretion caused by stimulation of the RAAS). Hyperaldosteronism presents with hypertension, hypokalemia, and metabolic alkalosis. Diagnosis involves measuring plasma aldosterone and renin activity levels, along with imaging to look for hormone-secreting tumors. Management involves the use of aldosterone receptor antagonists and surgical excision of any aldosterone-secreting tumors.
  • Hypoaldosteronism: condition resulting from low levels of aldosterone. Hypoaldosteronism can be caused by decreased aldosterone production or by a peripheral resistance to aldosterone. When the condition occurs as a result of an acquired decrease in renin production from the kidneys, the condition is referred to as renal tubular acidosis (RTA) type 4. Most individuals are asymptomatic and diagnosed when routine lab evaluation demonstrates hyperkalemia and a mild hyperchloremic metabolic acidosis, prompting further workup.

References

  1. Saladin, K. S., Miller, L. (2004). Anatomy and physiology, 3rd ed., pp. 648–649. 
  2. Williams, G. H., Dluhy, R. G. (2008). Disorders of the adrenal cortex. In: Fauci, A. S., Braunwald, E., Kasper, D.L., et al. (Eds.) Harrison’s Internal Medicine, 17th ed., p. 2266.
  3. Rajkumar, V. (2021). Hypoaldosteronism. StatPearls. Retrieved March 10, 2021, from https://www.statpearls.com/ArticleLibrary/viewarticle/23254 
  4. Young, W. F. (2020). Pathophysiology and clinical features of primary aldosteronism. UpToDate. Retrieved March 9, 2021, from https://www.uptodate.com/contents/pathophysiology-and-clinical-features-of-primary-aldosteronism
  5. Merke, D. P. (2020). Genetics and clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. UpToDate. Retrieved January 21, 2020, from https://www.uptodate.com/contents/genetics-and-clinical-presentation-of-classic-congenital-adrenal-hyperplasia-due-to-21-hydroxylase-deficiency

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