Cortisol: the pathway in the body · Biomarker & Blood Analysis

Cortisol is part of the pathway “Cortisol”. This page shows the whole pathway; the station of Cortisol is highlighted.

Where this laboratory value sits: Cortisol — adrenal cortex. CYP21A2 turns this into 11-deoxycortisol, and CYP11B1 in the mitochondrion finally into cortisol. The adrenal cortex releases cortisol into the blood. It makes it anew as needed and stores hardly any. Source 2

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. It adjusts metabolism to stressors and dampens inflammation.

The pathway step by step

Each station states what the compound does there. Three signs: ↑ supplies — builds up or makes available · ↓ depletes — inhibits, consumes or withholds · ↕ both, depending on amount. Behind it stands what the statement rests on: established physiology, observed in studies, or contested. The signs do not grade; they name the direction.

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. ACTH also keeps the cells of the adrenal cortex ready. Source 1↑ supplies ACTH drives the adrenal cortex: through the receptor MC2R it starts cortisol production within minutes and, over the longer term, keeps the cells and their steroid-making enzymes ready. established physiology Source 2, 1
   ⚖ When the balance tips

   too much — If a lot of ACTH is present for a long time, the adrenal cortex makes more steroid-making enzymes and the tissue grows in size; production of cortisol and its precursors runs harder.

   too little — If little ACTH arrives for a long time, the cortex makes less cortisol and its cortisol-producing layer shrinks; when ACTH rises again, it needs a while before it works fully again.

   established physiology · Source 2, 7

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. This transport sets the pace of cortisol production. Source 2↑ supplies Cholesterol is the raw material of all steroid production. The slowest step is its route with StAR to the inner mitochondrial membrane; how fast it runs determines how much cortisol can form. established physiology Source 2
   ⚖ When the balance tips

   too much — If plenty of cholesterol is present, more cortisol does not form by itself: the pace is set by transport through StAR, and ACTH controls that.

   too little — If little cholesterol gets into the mitochondrion, for example because StAR works poorly, all steroid hormones stall at once, and cholesterol accumulates as fat in the cortical cells.

   established physiology · 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. All steroid hormones branch off from here. Source 2↑ supplies Pregnenolone is the switch point of all steroid hormones: depending on which enzymes a cell has, it is built on into cortisol, aldosterone or sex hormones. CYP11A1 needs electrons from NADPH for this. established physiology Source 2
   ⚖ When the balance tips

   too much — If a lot of pregnenolone forms, it is distributed over the routes open in the respective layer of the adrenal cortex; in the zona fasciculata the main route leads to cortisol.

   too little — If little pregnenolone is available, less supply reaches all following steroid hormones at once, because each of them is built from this one precursor.

   established physiology · 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. If 17-hydroxyprogesterone builds up, more androgens form from it. Source 2↑ supplies 17-Hydroxyprogesterone is the precursor at which CYP21A2 continues the route to cortisol. CYP17A1 and CYP21A2 need electrons from NADPH for this, passed on by a flavin reductase. established physiology Source 2, 8
   ⚖ When the balance tips

   too much — If 17-hydroxyprogesterone builds up because CYP21A2 converts little, it is diverted via CYP17A1 towards the androgens; the adrenal gland then releases more androgens.

   too little — If CYP17A1 forms little 17-hydroxyprogesterone, pregnenolone flows into the route without this step; more aldosterone precursors and less cortisol are formed.

   established physiology · 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. It makes it anew as needed and stores hardly any. Source 2↑ supplies The adrenal cortex stores hardly any cortisol; it makes it anew as needed. That is why release follows the ACTH signal within minutes and the amount in the blood reflects ongoing production. established physiology Source 2, 1
   ⚖ When the balance tips

   too much — If the cortex makes a lot of cortisol, it slows CRH and ACTH through feedback; the drive for new cortisol production then eases again.

   too little — If CYP11B1 works poorly, 11-deoxycortisol builds up and less cortisol forms; the weaker feedback then lets ACTH rise.

   established physiology · Source 2, 1

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. 11β-HSD1 raises the amount, 11β-HSD2 lowers it. Source 5↕ both, depending on amount How much cortisol acts in a cell depends not only on the blood but on the enzymes on site: 11β-HSD1 raises the amount, 11β-HSD2 lowers it. The NADPH for 11β-HSD1 is supplied by the enzyme H6PDH. established physiology Source 5
   ⚖ When the balance tips

   too much — If 11β-HSD1 is highly active in a tissue, more cortisol forms there than the blood level shows; in animal models this shifts metabolism in the liver and fat tissue towards glucose production and fat storage.

   too little — If 11β-HSD1 regenerates little cortisol, the cell depends more on cortisol from the blood. If at the same time little NADPH from H6PDH is available, the enzyme reverses direction and turns cortisol into cortisone.

   observed in studies · 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. 11β-HSD1 raises the amount, 11β-HSD2 lowers it. Source 5↕ both, depending on amount How much cortisol acts in a cell depends not only on the blood but on the enzymes on site: 11β-HSD1 raises the amount, 11β-HSD2 lowers it. The NADPH for 11β-HSD1 is supplied by the enzyme H6PDH. established physiology Source 5
   ⚖ When the balance tips

   too much — If 11β-HSD1 is highly active in a tissue, more cortisol forms there than the blood level shows; in animal models this shifts metabolism in the liver and fat tissue towards glucose production and fat storage.

   too little — If 11β-HSD1 regenerates little cortisol, the cell depends more on cortisol from the blood. If at the same time little NADPH from H6PDH is available, the enzyme reverses direction and turns cortisol into cortisone.

   observed in studies · 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. If a lot of cortisol is present for long, the cell makes fewer receptors. Source 6↑ supplies The receptor translates the hormone into a signal: only bound cortisol releases it from Hsp90, and only then does it reach the nucleus. How many receptors a cell carries helps determine how strongly it responds. established physiology Source 6
   ⚖ When the balance tips

   too much — If a lot of cortisol occupies the receptor for a long time, the cell makes fewer new receptors; its response to the same amount of hormone is then weaker.

   too little — If few receptors are present or altered forms such as GRβ predominate, the cell responds only weakly even to plenty of cortisol.

   observed in studies · 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. It needs zinc to bind DNA. Source 6↕ both, depending on amount At the DNA the receptor acts in two directions: it switches genes on, for example for glucose production, and slows others, such as inflammatory genes driven by NF-κB and AP-1. It needs zinc to bind DNA. established physiology Source 6, 9
   ⚖ When the balance tips

   too much — If a lot of receptor reaches the nucleus, metabolic genes are switched on more strongly and inflammatory and immune genes are slowed more strongly; the immune response is then dampened.

   too little — If little receptor reaches the nucleus, NF-κB and AP-1 are slowed less, and inflammatory messengers are read for longer.

   established physiology · 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. The liver makes more glucose, and inflammatory reactions are dampened. Source 6↕ both, depending on amount The genes cortisol switches adjust the body to stressors: the liver makes more glucose, protein and fat are broken down for energy, and inflammatory reactions are dampened. established physiology Source 6
    ⚖ When the balance tips

    too much — If a lot of cortisol acts for a long time, breakdown prevails: muscle and bone protein is broken down, blood glucose stays higher, and the immune response is dampened.

    too little — If little cortisol acts, a counterpart to insulin and to inflammation is missing: blood glucose falls more easily between meals, and inflammatory reactions run less restrained.

    established physiology · 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. If the brake acts for long, the axis then needs time to start up again. Source 6, 1↓ depletes The feedback acts as a brake: through glucocorticoid and mineralocorticoid receptors in the hypothalamus and pituitary, cortisol inhibits the release of CRH and ACTH. So the axis returns to rest after a stressor. established physiology Source 1, 6
    ⚖ When the balance tips

    too much — If feedback brakes strongly and for a long time, for example through glucocorticoid medicines, the body's own axis rests; after stopping them it needs time until CRH, ACTH and cortisol start up again.

    too little — If feedback brakes weakly, for example because few glucocorticoid receptors respond in the brain, the axis stays active for longer after a stressor in animal models, and cortisol falls more slowly.

    observed in studies · Source 7, 1

Further stations

• CRH — hypothalamus Nerve cells in the hypothalamus release the hormone CRH. Triggers are stressors of any kind and a daily rhythm set by the internal clock in the hypothalamus. Cortisol slows its release again. Source 1, 3↑ supplies CRH is the starting signal of the axis: it stimulates the release of ACTH in the pituitary. How strongly depends on stressors and time of day; cortisol itself slows CRH release through feedback. established physiology Source 1, 3
  ⚖ When the balance tips

  too much — If a lot of CRH is released, the pituitary releases more ACTH and the adrenal cortex makes more cortisol; feedback by cortisol sets a limit to this rise.

  too little — If little CRH reaches the pituitary, it releases less ACTH; the adrenal cortex then makes less cortisol, and the morning rise is flatter.

  established physiology · Source 1, 3

• Cortisol in the blood — mostly bound to protein In the blood, cortisol is mainly bound to the transport protein CBG. The amount follows a daily rhythm: highest in the early morning, lowest around midnight. Only the free, unbound part enters the cells. Source 4, 3↕ both, depending on amount CBG keeps most of the cortisol bound: this forms a reserve but keeps it away from the cells, because only the free part acts. At sites of inflammation an enzyme cleaves CBG and releases cortisol there. established physiology Source 4
  ⚖ When the balance tips

  too much — If there is a lot of cortisol in the blood, the binding sites of CBG eventually fill up; the free, active part then grows faster than the bound part.

  too little — If there is little cortisol in the blood, almost all of it is bound to CBG and little free hormone reaches the tissues. If only CBG is scarce, the total falls while the free part can stay the same.

  established physiology · Source 4

• Cortisone — inactive form In the kidney, the enzyme 11β-HSD2 converts cortisol into inactive cortisone. In the liver and other tissues, 11β-HSD1 turns it back into active cortisol. This keeps the kidney's mineralocorticoid receptor reserved for aldosterone. Source 5↕ both, depending on amount Cortisone is the resting form: 11β-HSD2 switches cortisol off in the kidney and so keeps it away from the mineralocorticoid receptor, which stays reserved for aldosterone. 11β-HSD1 recovers active cortisol from cortisone. established physiology Source 5
  ⚖ When the balance tips

  too much — If a lot of cortisone forms, 11β-HSD1 in the liver and fat tissue has more starting material from which to make cortisol again locally.

  too little — If little cortisol is converted to cortisone because 11β-HSD2 works poorly, cortisol occupies the mineralocorticoid receptor in the kidney; the kidney then retains more sodium and water and excretes more potassium.

  established physiology · Source 5

Cofactors in this pathway

• Cholesterol — Starting material from which CYP11A1 removes the side chain to make pregnenolone; StAR sets the pace Source 2In the ORY catalogue as a laboratory value: Cholesterin / Fettstoffwechsel
• NADPH — Electron donor for CYP11A1, CYP17A1, CYP21A2, CYP11B1 and for 11β-HSD1; without it every step stalls Source 2, 5
• Iron — Central atom in the haem of the cytochrome P450 enzymes that carry out the individual steps; no haem, no conversion 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; without FAD the flow stalls Source 8
• NAD⁺ — Hydrogen acceptor of 3β-HSD2 in the adrenal gland and of 11β-HSD2 in the kidney; this lets 11β-HSD2 switch cortisol off 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; without them no gene switching 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

Whole pathway: Cortisol

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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