Adrenal gland

The adrenal gland is a paired retroperitoneal organ located on the upper pole of each kidney. It receives its arterial supply from the superior, middle, and inferior suprarenal arteries and drains into the right and left suprarenal veins. The adrenal gland has two layers: the adrenal cortex (outer layer), which is derived from the mesoderm, and the adrenal medulla (inner layer), which is derived from neural crest cells. The adrenal medulla is composed of chromaffin cells, which secrete catecholamines (norepinephrine, epinephrine, dopamine). The adrenal cortex consists of three layers: the zona glomerulosa, the zona fasciculata, and the zona reticularis, which are responsible for the synthesis of mineralocorticoids, glucocorticoids, and androgens (precursors for estrogen and testosterone) respectively. Mineralocorticoids regulate renal sodium and water reabsorption and potassium excretion, while glucocorticoids play an important role in glucose metabolism. Diseases of the adrenal glands include adrenal insufficiency (due to an infection, hemorrhage, autoimmune destruction), hyperaldosteronism (due to hyperplasia, adenoma), and hypercortisolism (due to hyperplasia, adenoma, exogenous administration).

Overview

• Two endocrine glands that produce steroid hormones and adrenaline
• Size: height and thickness ∼ 5 cm; width 1–2 cm
• Location
  • Primary retroperitoneal organs
  • Each gland is located superior to the upper pole of the kidney
  • Enclosed by the renal fascia and adipose capsule of the kidney
• Embryology
  • Adrenal cortex: derived from mesoderm
  • Adrenal medulla: derived from the neural crest

Function

• Adrenal cortex: outer layer that produces steroid hormones
• Adrenal medulla: inner part of the gland that produces catecholamines

Vasculature

• Arterial blood supply
  • Superior suprarenal artery (from the inferior phrenic artery)
  • Medial suprarenal artery (from the abdominal aorta)
  • Inferior suprarenal artery (from the renal artery)
• Venous drainage
  • Right suprarenal vein into the inferior cava vein
  • Left suprarenal vein into the left renal vein
• Lymph drainage: left aortic lymph nodes; right caval lymph nodes

The left suprarenal vein merges into the left renal vein; the right suprarenal vein merges directly into the inferior vena cava!

Innervation

• Sympathetic: major and minor splanchnic nerves
• Parasympathetic: vagal nerve

Adrenal cortex

• Surrounded by a fibrous capsule
• Layers of the cortex
  • Zona glomerulosa
    • Description: cells arranged in oval clusters surrounded by connective tissue from the fibrous capsule
    • Function: mineralocorticoid synthesis
  • Zona fasciculata
    • Description: cells arranged in straight columns that are separated by small fibrous septa
    • Function: glucocorticoid synthesis
  • Zona reticularis
    • Description: small cells arranged in an irregular netlike formation surrounded by connective tissue and capillaries
    • Function: androgen synthesis

GFR → MGA = The layers of the adrenal cortex from outside to inside are GFR (G = Zona Glomerulosa, F = Zona Fasciculata, R = Zona Reticularis). They are the Managing General Agents of some hormone synthesis.

Adrenal medulla

• Large chromaffin cells with many secretory granules (catecholamine storage)
  • Chromaffin cells originate in the neural crest and migrate to the paraganglia and adrenal medulla during embryonic development.
  • Tumors originating from chromaffin cells are called pheochromocytomas.
• Function: synthesis of catecholamines

The cells of the adrenal medulla are modified sympathetic cells that are controlled by cholinergic synapses.

Common synthesis pathway for all steroid hormones: cholesterol (precursor) → pregnenolone via cholesterol desmolase

Going from outside to inside, the hormones produced in each layer: The deeper you go, the sweeter it gets: Salt (Na⁺ and mineralocorticoids, zona glomerulosa), Sugar (glucocorticoids, zona fasciculata), and Sex (androgens, zona reticularis)

The RAAS regulates the release of mineralocorticoids!

General

• Mineralocorticoids: aldosterone
• Site of synthesis: zona glomerulosa

Synthesis

Regulation: renin-angiotensin-aldosterone system (RAAS)

• Positive feedback
  • ↑ Angiotensin II: renal hypoperfusion (e.g., hypotension, stimulation of β₁ receptors in the kidney) → kidneys release renin → renin converts angiotensinogen (produced in the liver) to angiotensin I (AT I) → conversion of AT I to angiotensin II through angiotensin-converting enzyme (ACE, mostly produced in the lungs) → angiotensin II acts as a strong vasoconstrictor and induces the secretion of aldosterone by the adrenal cortex
  • ↑ Serum potassium concentration
• Negative feedback: ANP

Function

• Mechanism: binds to intracellular mineralocorticoid receptors in the distal tubule and collecting duct of the kidney
  • ↑ Na⁺/K⁺-ATPase in the basolateral membrane → transports Na⁺ out and K⁺ into the tubule cells
  • ↑ Apical H⁺-ATPase
  • ↑ Na⁺ channels ENaC (epithelial natrium channel) and K⁺ channels ROMK (renal outer medullary potassium channel) in the luminal membrane
• Effect: ↑ Na⁺ resorption; ↑ H₂O resorption; ↑ K⁺ excretion; ↑ H⁺ excretion → ↑ extracellular fluid, ↑ blood pressure, ↓ K⁺, ↑ pH

Aldosterone stimulates the sodium and water retention and potassium excretion in the kidney!

General

• Glucocorticoids: mainly cortisol
• Site of synthesis: zona fasciculata
• Important cofactor: Vitamin C

Synthesis

Regulation: hypothalamic-pituitary gland-adrenal cortex feedback mechanism

• Mechanism: corticotropin-releasing hormone (CRH) → ↑ secretion of adrenocorticotropic hormone (ACTH) in the pituitary gland → ↑ secretion of glucocorticoids in the adrenal cortex
• Positive feedback: trigger CRH release
  • Pain, stress (psychological/physical)
  • Pyrogens, adrenaline, histamine
  • Hypoglycemia, hypotension
• Negative feedback: glucocorticoids
• Circadian rhythm: early morning ↑ serum CRH levels → ↑ cortisol levels

Cortisol inhibits the secretion of CRH and ACTH via negative feedback, which, in turn, results in a decrease in cortisol secretion.

Function

• Metabolism: mobilize energy reserves
  • ↑ Gluconeogenesis: to maintain blood glucose levels
  • ↑ Glycogen synthesis: to maintain glucose storage
  • ↑ Protein catabolism
  • ↑ Lipolysis
  • ↑ Appetite
  • ↑ Insulin resistance
  • Inhibitory effect on bone metabolism and stimulation of bone degradation: direct inhibition of osteoblastic activity and inhibition of osteoclast apoptosis
• Immunosuppression and antiphlogistic effect: complex mechanisms
  • ↓ Lymphocytes, eosinophils, and monocytes
  • ↑ RBCs, ↑ Platelets, ↑ Neutrophil granulocytes (overall WBC increases)
  • Inhibition of T-cell and B-cell responses
  • Inhibition of cytokine synthesis and secretion (e.g., IL-2)
  • ↓ Mast cell activation and histamine release
• ↓ Wound healing
• Permissive effect on catecholamines (e.g., increase in blood pressure )
• Mild mineralocorticoid effect: increase in blood pressure, potassium excretion
• Clinical use of glucocorticoids in the treatment of inflammatory and autoimmune conditions and allergic reactions (see article on glucocorticoids)

General

• Androgens: intermediate sex steroids in the adrenal cortex
  • Dehydroepiandrosterone (DHEA)
  • DHEAS (Dehydroepiandrosterone sulfate)
  • Androstenedione
• Site of synthesis: zona reticularis

In both men and women, DHEA and androstenedione are produced in the adrenal cortex, which are precursors for testosterone and estrogen. Testosterone is produced by Leydig cells in the testes in men and, to a lesser degree, ovarian stroma in women.

Synthesis

• 17α-hydroxylase: converts pregnenolone → 17-hydroxypregnenolone → dehydroepiandrosterone (DHEA)
  • Defective enzyme → rare form of congenital adrenal hyperplasia that results in male pseudohermaphroditism and delayed puberty in females
• 3β-hydroxysteroid dehydrogenase: converts DHEA → androstenedione
• DHEA and intermediates (e.g., androstenedione) are secreted by the adrenal cortex
• Further processing occurs in the target tissue: gonads, brain, adipose tissue , skin, bone, placenta (see function below)

Regulation: hypothalamic-pituitary gland-adrenal cortex feedback mechanism

• Corticotropin-releasing hormone (CRH) → ↑ secretion of adrenocorticotropic hormone (ACTH) in the pituitary gland → ↑ secretion of androgens in the adrenal cortex

Function

• Mechanism: Adrenal androgens (DHEA and androstenedione) serve as precursors of:
  1. More potent androgens
     • Androstenedione → testosterone
     • Testosterone → dihydrotestosterone (DHT) via 5α-reductase
       • Defective 5α-reductase → 5α-reductase deficiency
       • 5α-reductase inhibitors (e.g., finasteride) inhibit the conversion → used to treat BPH
       • DHT is a potent form of testosterone
         • Causes hair follicles to transform into terminal hair in androgen sensitive areas
           • Upper lip, chin, upper abdomen, and back.
         • Idiopathic hirsutism affects 5-10% of female patients
           • 10% of cases arise from hyperandrogenism of adrenal origins
  2. Estrogen (in men and postmenopausal women )
     • Aromatase: converts testosterone → estradiol and androstenedione → estrone
• Effects of androgens
  • Male sexual differentiation during embryonic development
  • Male pubertal development of secondary sexual characteristics (e.g., growth spurt, increased muscle mass, penile growth, deepening of the voice, Adam's apple growth, acne)
  • Spermatogenesis
  • Increased libido
  • Anabolic effects on muscles and bones
  • Stimulate erythropoiesis (↑ RBCs)
  • Influence behavior (e.g., aggression)
• Effects of estrogen
  • Female sexual differentiation during embryonic development
  • Female pubertal development of secondary sexual characteristics
  • See Estrogen and associated diseases for details

Generally, the effects of androgens in women only become apparent in cases of androgen excess (e.g., PCOS, androgen-secreting tumors).

References:^[1][2][3]

General

• Catecholamines: norepinephrine, epinephrine, dopamine
• Site of synthesis
  • Regions of the CNS
  • Chromaffin cells of the adrenal medulla
  • Postganglionic adrenergic neurons
• Stimuli
  • Sympathetic activation ("fight and flight")
  • Cortisol from the adrenal cortex

Synthesis

Epinephrine has the shortest half-life of the catecholamines.

Stress results in an increased production of catecholamines and glucocorticoids.

Degradation

• Enzymatic degradation via catecholamine-O-methyltransferase (COMT) and monoamine oxidase (MAO)
  • MAO inhibitors (antidepressant drugs) prevent the degradation of catecholamines in the CNS → elevated concentration of catecholamines in synaptic cleft → improve depressive symptoms
• End-stage metabolite: vanillylmandelic acid (VMA)
  • VMA has diagnostic value: elevated urinary excretion in patients with pheochromocytoma and neuroblastoma

The end-stage metabolite of epinephrine and norepinephrine is vanillylmandelic acid. Urinary excretion of VMA has diagnostic value in pheochromocytoma and neuroblastoma!

Function

• Sympathetic activation → fight-or-flight reaction
• Mechanism: catecholamines bind to various adrenergic receptors (with differing functions depending on the respective G protein; see table below) located on different organs and tissue → trigger specific responses with the ultimate goal to prepare for a fight-or-flight reaction

Important diseases associated with the adrenal cortex

• Hypocortisolism
• Hypercortisolism
• Primary hyperaldosteronism (Conn syndrome)
• Congenital adrenal hyperplasia (CAH)
• Androgen-secreting tumors

Important diseases associated with the adrenal medulla

• Pheochromocytoma
• Neuroblastoma