Cortisol: the pathway in the body

This page shows the biochemical pathway behind the laboratory value Cortisol: which stations follow one another, which enzymes carry out each step and which cofactors they use. Every statement has a source. The page describes general textbook knowledge and says nothing about any individual person.

In brief

Cortisol is a steroid hormone that the adrenal cortex builds from cholesterol. In tissues it binds the glucocorticoid receptor, which docks onto DNA in the nucleus and helps set how many genes are read.

The pathway step by step

1. CRH → ACTH CRH receptor CRH reaches the pituitary gland through fine blood vessels. There it binds to its receptor and triggers the release of the hormone ACTH into the blood. Source 1
2. ACTH → Cholesterol MC2 receptor In the adrenal cortex, ACTH binds to its receptor MC2R. The transport protein StAR then carries cholesterol, the starting material of all steroid hormones, into the mitochondrion. Source 2
3. Cholesterol → Pregnenolone CYP11A1 · StAR (transport), NADPH The enzyme CYP11A1 cleaves the side chain off cholesterol. This produces pregnenolone, the common precursor of all steroid hormones. Source 2
4. Pregnenolone → 17-OH-progesterone 3β-HSD2, CYP17A1 The enzymes 3β-HSD2 and CYP17A1 convert pregnenolone into 17-hydroxyprogesterone. In the middle layer of the adrenal cortex (zona fasciculata), this route leads to cortisol. Source 2
5. 17-OH-progesterone → Cortisol CYP21A2, CYP11B1 · NADPH CYP21A2 turns this into 11-deoxycortisol, and CYP11B1 in the mitochondrion finally into cortisol. The adrenal cortex releases cortisol into the blood. Source 2
6. Cortisol in the blood → Cortisol in the cell Cortisol acts inside the cell. How much of it is active there is co-regulated by the two enzymes 11β-HSD1 and 11β-HSD2 – they are regarded as gatekeepers of cortisol action in tissues. Source 5
7. Cortisone → Cortisol in the cell 11β-HSD1 · NADPH Cortisol acts inside the cell. How much of it is active there is co-regulated by the two enzymes 11β-HSD1 and 11β-HSD2 – they are regarded as gatekeepers of cortisol action in tissues. Source 5
8. Cortisol in the cell → Glucocorticoid receptor Without hormone, the glucocorticoid receptor sits in the cytoplasm, bound to helper proteins such as Hsp90. When cortisol binds, the receptor is released and moves into the nucleus. Source 6
9. Glucocorticoid receptor → Receptor in the nucleus In the nucleus, the receptor binds to specific DNA segments and switches genes on or off there. It also dampens other gene switches such as NF-κB and AP-1. Source 6
10. Receptor in the nucleus → Gene expression By this route cortisol acts on numerous processes, including intermediary metabolism, the immune system, the circulation and bone growth. Source 6
11. Cortisol in the blood → Feedback Cortisol signals back on itself: it slows the production and release of CRH and ACTH. In this way the body limits the height and duration of the rise in cortisol. Source 6, 1

Cofactors in this pathway

• Cholesterol — Starting material from which CYP11A1 removes the side chain to make pregnenolone Source 2In the ORY catalogue as a laboratory value: Cholesterin / Fettstoffwechsel
• NADPH — Electron donor for CYP11A1, CYP17A1, CYP21A2, CYP11B1 and for 11β-HSD1 Source 2, 5
• Iron — Central atom in the haem of the cytochrome P450 enzymes that carry out the individual steps Source 8, 2In the ORY catalogue as a laboratory value: Eisen
• Vitamin B2 (FAD, FMN) — Flavin cofactor of the reductases that pass electrons from NADPH to the steroid enzymes Source 8
• NAD⁺ — Hydrogen acceptor of 3β-HSD2 in the adrenal gland and of 11β-HSD2 in the kidney Source 2, 5In the ORY catalogue as a laboratory value: NAD⁺ (Nicotinamidadenindinukleotid)
• Zinc — Building block of the two zinc fingers with which the glucocorticoid receptor binds DNA Source 9, 6In the ORY catalogue as a laboratory value: Zink

What acts on this pathway

• Glucocorticoid drugs — Medicines containing glucocorticoids use the same feedback loop. It is described that they can dampen the body's own stress axis, and that the axis needs time to restart after they are stopped. Source 7, 6

Sources

1. Herman JP, McKlveen JM, Ghosal S et al. Regulation of the Hypothalamic-Pituitary-Adrenocortical Stress Response. Compr Physiol 2016 · PubMed 27065163
2. Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev 2011 · PubMed 21051590
3. Oster H, Challet E, Ott V et al. The Functional and Clinical Significance of the 24-Hour Rhythm of Circulating Glucocorticoids. Endocr Rev 2017 · PubMed 27749086
4. Meyer EJ, Nenke MA, Rankin W et al. Corticosteroid-Binding Globulin: A Review of Basic and Clinical Advances. Horm Metab Res 2016 · PubMed 27214312
5. Chapman K, Holmes M, Seckl J. 11β-hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action. Physiol Rev 2013 · PubMed 23899562
6. Oakley RH, Cidlowski JA. The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease. J Allergy Clin Immunol 2013 · PubMed 24084075
7. Priya G, Laway BA, Ayyagari M et al. The Glucocorticoid Taper: A Primer for the Clinicians. Indian J Endocrinol Metab 2024 · PubMed 39371659
8. Pinto JT, Cooper AJ. From cholesterogenesis to steroidogenesis: role of riboflavin and flavoenzymes in the biosynthesis of vitamin D. Adv Nutr 2014 · PubMed 24618756
9. Siegel KR, Kassotis CD. Friend and Foe?: Metals as Facilitators and Disruptors of Steroid Nuclear Receptor Signaling. Toxicol Sci 2026 · PubMed 42608812

Related pathways

• Cholesterol and lipoproteins — cholesterol
• Progesterone — cholesterol
• DHEA — cholesterol
• Estradiol — cholesterol
• Testosterone — cholesterol

As of 2026-09-16. Draft written by Claude to schema v2; sources checked in PubMed; expert approval pending
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