System Components

Cortisol

• cannot be bioanalytically separated from endogenous cortisol [📖]
• major glucocorticoid
• Chemical properties
  • \(C_{21}H_{30}O_5\)
  • Average mass: 362.460 Da or g/mol [📖]
  • IUPAC name: 11β,17α,21-Trihydroxypregn-4-ene-3,20-dione
  • Molecule Type: Small molecule

Chemical Structure of Cortisol. Figure from ChEMBL.

Chemical structure of Cortisol. Created using py3Dmol tool.

Interactive chemical structure of Cortisol. Created using 3Dmol.js tool.

• a negative feedback on CRH and ACTH release, thereby inhibiting the HPA axis [📖]
• saturable plasma protein binding of cortisol occurring at high cortisol concentrations [📖]
• maturation factors
  • amount of body water
  • 80-85% in young infants
  • 55-60% in adults
  • fat content
  • 10-15% at birth
  • maturation of plasma proteins
  • ↓\([CBG]\) in neonates = ↑ \(CL_u\) [📖]

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CBG

• Corticosteroid-Binding Globulin

• low conc. relative to albumin

  • albumin: 35,000-50,000 mg/L [📖]
  • CBG: 14.9-67.1 mg/L [📖]
  • elevated:
    • pregnant women (2-3 fold) [📖]
    • synthetic oral oestrogens [📖]
    • Mitotane, an adrenolytic agent for adrenocortical carcinoma [📖]
    • some patients with chronic active hepatitis
  • reduced:
    • neonates (note: infants reach adult values) [📖]
    • patients with Cushing's syndrome (33.2 ± 5.6 mg/L) [📖]

• Saturation of CBG

  • at total cortisol concentrations (\(C_{tot}\)) above 200 ng/mL or 550 nmol/L [📖]
  • unbound cortisol concentration (\(C_{u}\)) increases disproportionally with respect to \(C_{tot}\)
• lower in neonates, whereas infants had reached adult values
• 3D structure [📖]

Chemical structure of CBG. Created using py3Dmol tool.

Interactive chemical structure of CBG. Created using 3Dmol.js tool.

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17-OHP

• 17-hydroxyprogesterone or 17-OH-Progesterone
• used as biomarker of CAH
• seems to have a circadian variation (>12 months) [📖]
• conc. range of 12-36 nmol/L -> target for therapy [📖]
  • note: when measured in the early morning before medication

Chemical structure of 17-OHP. Created using py3Dmol tool.

Interactive chemical structure of 17-OHP. Created using 3Dmol.js tool.

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ACTH

• AdrenoCorticoTrophic Hormone
• [link]
• Increased production in CAH
  • due to
  • feedback loop from decreased cortisol production
  • aldosterone insufficiency -> volume depletion -> vasopressin synthesis [📖]
  • leads to [📖]
  • adrenocortical hyperplasia as well as the
  • synthesis of adrenal androgens and androgen precursors,
  • synthesis of 17-OHP and androstenedione

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HPA-axis

• Hypothalamic-Pituitary-Axis
• follow a circadian rhythm
• Cortisol is inhibits the HPA axis
  • major glucocorticoid and
  • negative feedback on CRH and ACTH release
• Classic CAH
  • absence of negative feedback
  • increased production of corticotropin-releasing factor (CRF) in hypothalamus
  • increased production of adrenocorticotrophic hormone (ACTH) in pituitary gland
  • main reason for overproduction of androgens

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Steroid synthesis

• Steroid synthesis of mineralocorticoids, glucocorticoids and androgens
• healthy and CAH

Steroid synthesis pathway. Figures were adopted from PhD thesis of Johanna Melin.

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