Beyond Stress: How Cortisol Shapes Energy, Immunity, and Health.

Cortisol is often called the stress hormone, but it does much more than help us deal with pressure. It is made in the adrenal glands, small organs that sit on top of the kidneys. Cortisol is controlled by the brain through what is called the hypothalamic–pituitary–adrenal (HPA) axis. When the brain releases a signal called CRH, this triggers the pituitary gland to release ACTH, which then tells the adrenal glands to make cortisol. Levels naturally rise in the morning to wake us up and fall at night to help us sleep (1,2). This daily rhythm is known as the circadian rhythm, and the sharp rise just after waking is called the cortisol awakening response (3,4).

Cortisol is made from cholesterol and travels through the blood mostly attached to proteins, leaving a small amount free to act on tissues. Special enzymes in different organs can switch cortisol on or off, depending on the body’s needs (1,5,6).

One of cortisol’s main jobs is to manage energy. It raises blood sugar by helping the liver make new glucose, reduces how much sugar is taken up by muscles and fat, and breaks down fat and protein to use as fuel. It also lowers insulin while raising glucagon and adrenaline, all of which work together to keep blood sugar high when the body is under stress (1,7,8). These actions are helpful in the short term but, if cortisol stays high for too long, it can cause insulin resistance, belly fat gain, and even metabolic syndrome (6,9,10,11).

Cortisol also affects the immune system. It keeps inflammation under control by slowing down immune cells like T cells, B cells, and neutrophils. It also reduces how much inflammation-causing chemicals are released. This protects the body from harmful overreactions, but when cortisol remains high, the immune system becomes weak and infections are more likely (1,12,13,14,15,16).

Modern life can disrupt cortisol’s natural cycle. For example, shift workers who stay awake at night often have abnormal cortisol rhythms, which may increase their risk of heart disease, diabetes, and memory problems (17,18). New treatments are being developed to copy the natural ups and downs of cortisol in people with adrenal disease, such as using modified-release hydrocortisone to match the body’s daily pattern (19,20,21).

Doctors often measure cortisol levels to check adrenal health. Blood tests are usually done in the morning when levels should be highest. Special tests, such as the ACTH stimulation test or the dexamethasone suppression test, help find out if someone has too much cortisol, as in Cushing syndrome, or too little, as in Addison disease. Too much cortisol can cause weight gain, muscle loss, high blood pressure, and weak immunity, while too little can cause fatigue, low blood pressure, weight loss, and in severe cases, a dangerous adrenal crisis (1,22).

Cortisol is not just about stress. It is a master hormone that affects energy, sleep, immunity, and how the body reacts to challenges. Balanced levels keep us healthy and adaptable. When cortisol is out of balance, it can lead to serious health problems. Learning about how this hormone works can help us better understand the links between stress, metabolism, and long-term wellbeing.

References

1. Shea SA, Hilton MF, Hu K, Scheer FAJL. Existence of an endogenous circadian blood pressure rhythm in humans independent of behavior. Proc Natl Acad Sci U S A. 2011;108(15):6500–5.

2. Fries E, Dettenborn L, Kirschbaum C. The cortisol awakening response (CAR): facts and future directions. Int J Psychophysiol. 2009;72(1):67–73

3. Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, Cooper MS, et al. 11β-Hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev. 2004;25(5):831–66.

4. Seckl JR, Walker BR. 11β-Hydroxysteroid dehydrogenase type 1: a tissue-specific amplifier of glucocorticoid action. Endocrinology. 2001;142(4):1371–6.

5. Dinneen S, Alzaid A, Miles J, Rizza R. Metabolic effects of the nocturnal rise in cortisol on carbohydrate metabolism in normal humans. J Clin Invest. 1993;92(5):2283–90.

6. Rizza RA, Mandarino LJ, Gerich JE. Cortisol-induced insulin resistance in man: impaired suppression of glucose production and stimulation of glucose utilization due to a postreceptor defect of insulin action. J Clin Endocrinol Metab. 1982;54(1):131–8.

7. Anagnostis P, Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis DP. The pathogenetic role of cortisol in the metabolic syndrome: a hypothesis. J Clin Endocrinol Metab. 2009;94(8):2692–701.

8. Masuzaki H, Paterson J, Shinyama H, Morton NM, Mullins JJ, Seckl JR, et al. A transgenic model of visceral obesity and the metabolic syndrome. Science. 2001;294(5549):2166–70.

9. Andrew R, Phillips DI, Walker BR. Obesity and gender influence cortisol secretion and metabolism in man. J Clin Endocrinol Metab. 1998;83(5):1806–9

10. Webster JI, Tonelli L, Sternberg EM. Neuroendocrine regulation of immunity. Annu Rev Immunol. 2002;20:125–63.

11. Sapolsky RM, Romero LM, Munck AU. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev. 2000;21(1):55–89.12

12. Tsigos C, Chrousos GP. Hypothalamic–pituitary–adrenal axis, neuroendocrine factors and stress. J Psychosom Res. 2002;53(4):865–71.

13. Cain DW, Cidlowski JA. Immune regulation by glucocorticoids. Nat Rev Immunol. 2017;17(4):233–47.

14. Shimba A, Ejima A, Ikuta K. Pleiotropic effects of glucocorticoids on the immune system in circadian rhythm and stress. Front Immunol. 2021;12:706951. doi:10.3389/fimmu.2021.706951.

15. James SM, Honn KA, Gaddameedhi S, Van Dongen HPA. Shift work: disrupted circadian rhythms and sleep—implications for health and well-being. Curr Sleep Med Rep. 2017;3(2):104–12

16. Kervezee L, Cuesta M, Cermakian N, Boivin DB. Simulated night shift work induces circadian misalignment of the human peripheral blood mononuclear cell transcriptome. Proc Natl Acad Sci U S A. 2018;115(21):5540–5.

17. Debono M, Ghobadi C, Rostami-Hodjegan A, Huatan H, Campbell MJ, Newell-Price J, et al. Modified-release hydrocortisone to provide circadian cortisol profiles. J Clin Endocrinol Metab. 2009;94(5):1548–54

18. Venneri MA, Hasenmajer V, Fiore D, Sbardella E, Pofi R, Graziadio C, et al. Circadian rhythm of cortisol: implications for adrenal insufficiency diagnosis and treatment. Front Endocrinol (Lausanne). 2018;9:185.

19. Biddie SC, Conway-Campbell BL, Lightman SL. Dynamic regulation of glucocorticoid signalling in health and disease. Rheumatology (Oxford). 2012;51(3):403–12.

20. Liu PY. Rhythms in cortisol mediate sleep and circadian impacts on health. Sleep. 2024 Sep 9;47(9):zsae151. doi: 10.1093/sleep/zsae151. PMID: 38963818; PMCID: PMC11381560.

21. Litvinenko E, Merkulova K, Postnov D. Cortisol dynamics and sleep–wake switching: a modeling study. Eur Phys J Spec Top. 2024;233:579–88.

22. Takahashi JS, Bass J. Circadian integration of metabolism and energetics. Science. 2010;330(6009):1349–54.