Cortisol Metabolism – Function, Disorders & Diagnosis

What is Cortisol Metabolism?

Cortisol metabolism encompasses all biochemical processes involved in the production, transport, action, and degradation of cortisol in the human body. Cortisol is a glucocorticoid – a steroid hormone synthesised in the adrenal cortex that plays a key role in the stress response, blood glucose regulation, immune defence, and inflammatory processes.

Production of Cortisol

Cortisol production is governed by a tightly regulated hormonal cascade known as the hypothalamic-pituitary-adrenal (HPA) axis:

• The hypothalamus releases corticotropin-releasing hormone (CRH).
• CRH stimulates the pituitary gland to secrete ACTH (adrenocorticotropic hormone).
• ACTH travels through the bloodstream to the adrenal cortex, where it triggers cortisol synthesis from cholesterol.

Cortisol secretion follows a circadian rhythm: levels peak shortly after waking in the morning and are lowest during the night. Stress, sleep deprivation, and illness can significantly disrupt this rhythm.

Transport in the Blood

In the bloodstream, approximately 90% of cortisol is bound to transport proteins, primarily corticosteroid-binding globulin (CBG, transcortin) and albumin. Only the free, unbound fraction is biologically active and able to enter cells to exert its effects.

Mechanism of Action

Cortisol enters target cells and binds to the intracellular glucocorticoid receptor (GR). The resulting hormone-receptor complex translocates to the cell nucleus, where it regulates gene expression. Through this mechanism, cortisol influences a wide range of body functions:

• Metabolism: Raises blood glucose levels by promoting gluconeogenesis (formation of new glucose from non-carbohydrate sources) in the liver, and promotes the breakdown of fat and muscle tissue.
• Immune system: Suppresses inflammatory responses and dampens excessive immune reactions.
• Cardiovascular system: Increases blood pressure and cardiac output during stress.
• Central nervous system: Influences mood, memory consolidation, and alertness.
• Bones and muscles: Chronically elevated levels can lead to bone loss (osteoporosis) and muscle wasting.

Breakdown and Excretion

Cortisol is primarily metabolised in the liver. Enzymes – in particular 11β-hydroxysteroid dehydrogenases (11β-HSD) – inactivate cortisol and convert it into water-soluble metabolites that are excreted via the kidneys in the urine. The enzyme 11β-HSD1 is capable of reactivating inactive cortisone back into active cortisol in certain tissues such as adipose tissue and the liver – a process of significant relevance to local inflammation and fat metabolism.

Disorders of Cortisol Metabolism

Deviations in cortisol metabolism can lead to serious medical conditions:

• Cushing syndrome: Chronically elevated cortisol levels caused by a cortisol-producing tumour or long-term use of corticosteroid medications. Characteristic features include central weight gain, a rounded face (moon face), high blood pressure, and skin changes.
• Addison disease (adrenal insufficiency): Insufficient cortisol production due to damage to the adrenal cortex. Symptoms include fatigue, weight loss, low blood pressure, and skin hyperpigmentation.
• Chronic stress and burnout: Persistently elevated cortisol levels from ongoing stress can weaken the immune system, impair sleep, and increase the risk of cardiovascular disease.
• Metabolic syndrome: Dysregulation of local cortisol metabolism – for example, overactive 11β-HSD1 in adipose tissue – has been linked to obesity, insulin resistance, and type 2 diabetes.

Diagnosis of Cortisol Metabolism Disorders

Several diagnostic methods are available to assess cortisol metabolism:

• Serum cortisol: Blood sampling at defined times of day (usually in the morning) to capture the diurnal rhythm.
• 24-hour urinary cortisol: Measurement of total cortisol excretion over a full day.
• Salivary cortisol: Non-invasive measurement of free cortisol at multiple time points throughout the day, useful for assessing the circadian pattern.
• Dexamethasone suppression test: Administration of a synthetic corticosteroid (dexamethasone) to evaluate the responsiveness of the HPA axis.
• CRH stimulation test and ACTH stimulation test: Used for further investigation of hyper- or hypofunction.

Treatment of Cortisol Metabolism Disorders

Treatment depends on the underlying cause:

• For Cushing syndrome, options include surgical removal of the causative tumour, medications that inhibit cortisol synthesis (e.g., metyrapone, ketoconazole), or radiotherapy.
• For Addison disease, lifelong hormone replacement therapy with hydrocortisone (bioidentical cortisol) and, if necessary, fludrocortisone is required.
• For stress-related dysregulation, stress management strategies, adequate sleep, regular physical activity, and a balanced diet are of central importance.

References

1. Chrousos, G. P. (2009): Stress and disorders of the stress system. Nature Reviews Endocrinology, 5(7), 374-381. PubMed PMID: 19488073.
2. Stewart, P. M. & Krozowski, Z. S. (1999): 11beta-Hydroxysteroid dehydrogenase. Vitamins and Hormones, 57, 249-324. PubMed PMID: 10232054.
3. Nieman, L. K. (2018): Cushing syndrome: Update on signs, symptoms and biochemical screening. European Journal of Endocrinology, 173(4), M33-M38. PubMed PMID: 25005935.