Cortisol is the main catabolic steroid in the human organism. In addition to tissue catabolism, cortisol plays a key role in virtually all chronic degenerative conditions, and the aging process in general.

Cortisol
Cortisol
Abbreviation F
Molecular formula C₂₁H₃₀O₅
Type Glucocorticoid steroid hormone
Administration Endogenous (produced by adrenal cortex); supplemental forms include oral hydrocortisone (Cortef), prednisone, dexamethasone
Bioavailability Oral: ~96% for hydrocortisone; cortisol is slightly more water soluble than progesterone
Synonyms Hydrocortisone, Compound F
Source Produced by the adrenal cortex from cholesterol via pregnenolone → progesterone pathway; body makes ~`20 mg` daily
Ray's verdict Generally hurts
Negative, fundamentally catabolic and aging, necessary for short-term survival but harmful when chronically elevated

It belongs to the glucocorticoid class of steroid hormones, synthesized in the adrenal cortex from cholesterol via the pregnenolone-progesterone pathway. Cortisol is the thing which has a short-term defensive reaction against stress. One of its main effects is to turn protein into sugar so that the sugar can be used for energy to increase adaptive ability to handle the stress.[1]

Dosing

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Endogenous production:

The body makes 20 mg of cortisol daily.

Synthetic equivalence:

Taking 10 mg of prednisone is equivalent to about 50 mg of cortisol or 2.5 times the daily amount made in-vitro. Cortef is Hydrocortisone which acts like cortisol.

Ray Peat's caution on supplementation:

William Jefferies' book created a lot of interest in cortisol supplementation (Cortef). "I don't think his arguments are correct. The amounts he sometimes prescribed weren't always safe." He knew people who followed Jefferies' prescription and got Cushing's symptoms.[2]

Diurnal rhythm:

Cortisol peaks ~8am and reaches its lowest between midnight and 4am.

History

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Etymology

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The name comes from Latin cortex ("bark" or "outer layer"), referring to the adrenal cortex, the outer layer of the adrenal gland that produces it, plus the "-ol" suffix for an alcohol group.

Edward Kendall isolated cortisol in 1949 and shared the 1950 Nobel Prize in Physiology or Medicine for characterizing adrenal cortex hormones and their anti-inflammatory effects.

The understanding of cortisol emerged from Hans Selye's pioneering stress research in the mid-20th century. The whole stress hormone system, the things that Hans Selye popularized and studied for many years, he was concentrating on the steroid system, and that's the most powerful stress-induced system.

Hans Selye had the concept of catatoxic steroids. They destroyed the toxin effect. The distinction matters: catatoxic steroids protect the organism by blocking toxin effects, without destroying the toxin directly.

After adrenalectomy, once tissue-stored steroids dissipate, moderate stress can kill animals because they did not have the adrenal resilience to meet the stress.

Felix Meerson later extended Selye's work to the mitochondrial level, exploring stress-limiting systems. Meerson's idea was that we have many layers of stress-limiting signals and hormones and processes, and it happens that the steroids are one major stress-limiting system where cortisol and serotonin and nitric oxide and estrogen activate the short-term stress reactions that can stimulate brief defense. If those continue, they destroy the organism.

Structure/Chemical properties

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  • Molecular formula: C₂₁H₃₀O₅
  • Type: Glucocorticoid steroid (21-carbon structure)
  • Solubility: Cortisol is a little more water soluble than progesterone, and a diurnal cycle can be seen in the saliva.

Biosynthesis pathway: The pituitary senses something wrong in the organism, increases its ACTH, which drives the adrenal glands in particular to take up cholesterol and to synthesize cholesterol from raw materials, and to direct the cholesterol into the mitochondrion to turn it into pregnenolone, progesterone, DHEA, and finally cortisol.

Before the cortisol stage of stress, the continuously activated adrenal tissue will be first producing pregnenolone, progesterone, and DHEA, and it's only when those aren't enough to handle the stress that the progesterone will be further converted into the cortisol.

Stress and cancer metastasis

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In 120 soldiers tested before deployment to Iraq, blunted cortisol reactivity raised war-zone PTSD risk only when a CO2 challenge also failed to raise testosterone.[3] Glucocorticoid-receptor positivity predicted poor outcome in triple-negative breast cancer; androgen-receptor positivity associated with lower grade and reduced recurrence risk, and DHT blocked dexamethasone-driven migration in GR/AR double-positive cells.[4] Chronic stress-driven glucocorticoid signaling couples to hepatic tryptophan kynurenine metabolism and liver cancer promotion in murine models.[5] Chronic stress elevates glucocorticoids, increases neutrophil extracellular trap formation, and creates a lung microenvironment that multiplies metastatic colonization; blocking neutrophil glucocorticoid receptors or digesting NETs with DNase I abolishes the effect.[6]

Function/Mechanism of Action

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Three weeks of physiological-dose corticosterone in mouse drinking water reproduced chronic-stress depression phenotypes and mPFC dendritic spine loss; ketamine rapidly restored many of the same synapses it had eliminated.[7] Calorie restriction raised total urinary cortisol output and calorie monitoring increased perceived stress, suggesting chronic dieting itself can elevate glucocorticoid burden.[8] In male chronic smokers, two 2.0 mg nicotine cigarettes raised plasma cortisol (with growth hormone and prolactin) significantly over two 0.2 mg nicotine cigarettes; levels had not returned to baseline 60 min after the higher-nicotine session.[9] Venous plasma nicotine after tobacco smoking correlated with cortisol (r=0.66).[10] Stress hormones acting through β2-adrenergic receptors on neutrophils released S100A8/A9 and oxidized lipids that reactivated dormant tumor cells via FGFR signaling; beta-blockade blocked awakening.[11] Post-infarction patients months after recovery maintained high resting cortisol and exaggerated stress catecholamine surges despite healed lesions. Chronic HPA overdrive may be a cardiovascular risk trait.[12] In type 2 diabetes, flatter diurnal cortisol profiles correlated with higher glucose levels independent of BMI, supporting glucocorticoid dysregulation as a direct contributor to hyperglycemia. Early-life poverty blunted pubertal testosterone trajectories and hippocampal volume growth, linking chronic stress-related HPA/HPG dysregulation to adult mood and regulatory deficits. COVID-19 inpatients with baseline cortisol above 744 nmol/L had mean survival of 15 days versus 36 days below that threshold, with levels exceeding those seen after major surgery.[13] Ten days of corticosterone or dexamethasone in rats raised hippocampal and cerebellar 5-lipoxygenase mRNA and protein with membrane translocation, linking glucocorticoid exposure to upregulated leukotriene synthesis in brain.[14] Glucocorticoid therapy increased cyclooxygenase-2 expression in nasal polyps in vivo, contradicting the assumption that steroids uniformly suppress COX-2.[15] Stress-induced cortisol signaling upregulated decidual FKBP51, which inhibited progesterone-receptor function and precipitated idiopathic preterm birth in mice and human tissue models.[16] Glucocorticoid receptor signaling in liver induced Hes1 and hepatic steatosis, linking cortisol excess to non-alcoholic fatty liver and dyslipidemia.[17] Glucocorticoids and DHT both suppressed gastric ILC2 IL-13 and CSF2, but only androgen receptor signaling reversed established gastric metaplasia without the atrophic pre-cancerous changes seen with chronic cortisol.[18] After acute stress, higher salivary cortisol predicted reduced charitable giving, especially in people with strong mentalizing ability, with corresponding changes in dorsolateral prefrontal donation signals on fMRI.[19] Nicotinamide with D-ribose supplementation for one week significantly reduced salivary cortisol while raising NAD+ and improving glucose tolerance in middle-aged adults.[20] In 131 young women, 15 minutes of stress-buffering group activity lowered ACTH in naturally cycling women but not in oral contraceptive users.[21] Dexamethasone raises amyloid-β production in neuronal and fibroblast models through glucocorticoid-driven 5-lipoxygenase upregulation; 5-LO blockade or genetic deletion abolishes the glucocorticoid-dependent Aβ increase.[22] In mice adapted to high-dose fluoxetine, plasma corticosterone responses to a 5-HT1A agonist and to forced exercise were blunted; Htr1a knockdown likewise lowered basal plasma corticosterone alongside ME/CFS-like fatigue behaviors.[23]

Glucocorticoid receptor antagonism and lifespan

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Mifepristone (glucocorticoid/progesterone receptor antagonist) extends mated female Drosophila lifespan via mitophagy and reduced midgut hypertrophy, acting through a pathway shared with rapamycin.[24] Wobbler mice (ALS model) show marked corticosterone elevation in adrenal glands, plasma, brain, and spinal cord alongside hypothalamic-pituitary-gonadal suppression.[25] Primary functions:

  1. Blood sugar maintenance: When adrenaline reaches a certain level and can't raise blood sugar from storage alone, cortisol activates, and that's the classic stress response that can be harmful because cortisol dissolves fragile tissues like the thymus first, turning them into sugar as soon as stored glycogen runs out.
  2. Protein → glucose conversion: If the liver lacks enough stored glycogen to release glucose under the influence of adrenaline, the body depends on cortisol to keep blood sugar steady; cortisol activates the conversion of protein to sugar and fat.
  3. Anti-inflammatory (acute): Progesterone and cortisol both prevent leakiness of capillaries and are antiinflammatory, though they are antagonists in other situations. They both stabilize mast cells, decreasing histamine and serotonin, and inhibit phospholipase and prostaglandin formation and release of various inflammatory cytokines, and protect the glycocalyx.
  4. Detoxification (at physiologic levels): A physiologically balanced amount of cortisol induces enzymes of detoxification, for example in the intestine.

Receptor mechanism: Prednisolone, dexamethasone, and cortisol are all glucocorticoid receptor agonists. The cortisol-GR complex translocates to the cell nucleus to exert systemic effects.

Glucocorticoid receptor sulfhydryl groups

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Beta-lapachone competitively inhibits glucocorticoid binding at the receptor ligand site without triggering the activation conformation, acting as a silent glucocorticoid-receptor antagonist; its inhibition is reversed by reducing agents (DTT, mercaptoethanol), which points to sulfhydryl groups required for receptor activation.[26]

Catalytic concentrations of adrenal cortical hormones inhibit reduced diphosphopyridine nucleotide (DPNH) oxidation in heart sarcosomes at the DPNH-cytochrome c reductase step; α-tocopherol competitively reverses this inhibition.[27]

Hair follicle stem cells

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Chronic stress elevates corticosterone (cortisol in humans), which keeps hair follicle stem cells in extended quiescence without re-entering growth phase; removing adrenal stress hormones restores regeneration even in aged mice.[28]

Fasting and steroidogenesis (women)

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Low-carbohydrate feeding in obese men shifted hepatic cortisol metabolism toward higher 11β-HSD1 regeneration and lower cortisol inactivation, independent of weight loss, linking macronutrient restriction to higher tissue glucocorticoid exposure.[29] In male athletes, a low-carbohydrate diet (about 30% of daily intake) during three consecutive days of intensive training (70-75% VO2max, 60 minutes per day) dropped the free testosterone:cortisol ratio 43% by the day after training, while a moderate-to-high carbohydrate diet (about 60% of intake) produced no significant change.[30] A meta-analysis of 27 studies found low- versus high-carbohydrate diets raise post-exercise cortisol, especially after exercise lasting 20 minutes or more, and that high-protein, low-carbohydrate diets lower both resting and post-exercise total testosterone.[31] A 48-hour fast in 20 healthy young women increased progestogen production and lowered relative mineralocorticoid, glucocorticoid, and androgen production; serum progesterone and aldosterone rose.[32]

Peripheral regeneration and 11β-HSD1

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Six weeks of daily treadmill training doubled pulmonary 11β-HSD1 expression in lean and obese mice, increasing local glucocorticoid activation.[33] In cultured human vascular smooth muscle cells, cortisol raised angiotensinogen and AT1 receptor mRNA, and angiotensin II raised 11β-HSD1 mRNA. In 27 human carotid samples the cortisol and angiotensin systems were strongly correlated, and their mutual amplification may favor atheroma.[34] Transgenic overexpression of 11β-HSD1 in adipose tissue produces visceral obesity, hyperglycemia, and hypertension in mice.[35]

Plasma and tissue cortisol

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Single blood or saliva cortisol numbers are a thin slice of glucocorticoid tone. In school-age twins, hair cortisol, diurnal saliva, and TSST stress reactivity converged on two only moderately correlated dimensions of HPA function rather than one interchangeable biomarker (latent diurnal and pervasive factors correlated about −0.39).[36] Acute stress reactivity also draws genetic variation that is largely distinct from diurnal and hair measures.[37]

In full-day center-based child care, salivary cortisol often rises from morning to afternoon (about 35% of infants and 71% of toddlers in one sample), while the same children more often show afternoon declines at home.[38] A rising child-care cortisol profile has also predicted lower weekend secretory IgA and more parent-reported illness.[39]

Most circulating cortisol is bound to corticosteroid-binding globulin (CBG); only a small free fraction is immediately available. Neutrophil elastase can cleave CBG at inflamed sites and release bound cortisol locally, so tissue exposure can rise without a matching rise in total plasma cortisol.[40]

11β-HSD1 regenerates active cortisol from circulating cortisone inside tissues, including the brain, amplifying local glucocorticoid action beyond what adrenal output alone predicts.[41] The kidney runs the opposite reaction through 11β-HSD2, turning cortisol into inactive cortisone. In a post-hoc analysis of a randomized placebo-controlled trial in overweight middle-aged and older adults, 350 mg/day of magnesium citrate taken for several months shifted that balance toward cortisone and modestly lowered active cortisol in full-day urine collections, with no change in total cortisol output.[42] Glucocorticoid receptor sensitivity further separates receptor signaling from the plasma total.

In 42 third-trimester pregnant women, a single morning plasma cortisol sample did not separate women with anxiety plus depression but without HIV from healthy controls (means 23.2 and 23.8 µg/dL), while DHEA sulfate was 42-49% lower in the anxious and depressed groups.[43] In rat hippocampal cultures, DHEA blocked the neurotoxicity of corticosterone.[44]

Tissue glucocorticoid exposure is therefore not the same as a plasma cortisol value.

Glucose and insulin

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In type 1 diabetes patients, glucose infusion induced Toll-like receptor and HMGB1 (pro-inflammatory) expression in mononuclear cells, while insulin infusion suppressed the same markers, a direct experimental demonstration that insulin is anti-inflammatory and unopposed glucose (as occurs when insulin signaling is blocked by stress hormones like cortisol) is pro-inflammatory.[45]

Medical uses/Effects

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Acute stress depleted hair-follicle melanocyte stem cells through sympathetic-noradrenaline signaling, directly linking stress hormones to premature hair graying.[46] Earwax gathered with a painless self-sampling device was proposed as a chronic cortisol measure less distorted by sampling stress than serum, with hair as a weaker long-term marker.[47] Chronic prednisolone raises hepatic NF-κB, iNOS, and nitrosative injury markers; vitamin D3 repletion normalizes these changes and lowers liver aminotransferases in rodent models.[48]

In healthy postmenopausal women followed for one year, oral DHEA 10 mg/day lowered cortisol more than transdermal estradiol 50 µg plus oral micronized progesterone 100 mg/day (HRT). DHEA also raised androgens; HRT did not. Both raised allopregnanolone about the same. When low-baseline-DHEA women took DHEA plus HRT, the cortisol drop was smaller than with HRT alone.[49]

Clinical use and conversion

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Legitimate uses:

  • Addison's disease: Addison's disease, with adrenal cortex degeneration, can cause cortisol deficiency, in which case progesterone would compensate.
  • Acute shock/stress: Short-term cortisol maintains capillary integrity and provides emergency fuel.
  • ACTH suppression: Since ACTH can interfere with ovarian function, cortisol can sometimes help the ovaries to make progesterone, by suppressing ACTH.

Conversion relationships:

Cortisol works in the body although the body can convert cortisol to cortisone. Synthetic cortisol-like drugs, such as prednisone are more like cortisol. Also, hydrocortisone is a drug that acts like cortisol.

Side/Adverse effects

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Excess cortisol can directly produce the main features of aging, including atrophy of skin, arteries, muscle, bone, the immune system, and parts of the brain.[50] Its suppression of mitochondrial respiration tracks its ability to raise intracellular calcium, and it blocks the thermogenic effect of sodium.[51]

Tissue catabolism (the hallmark problem):

The main features of aging can be produced directly by administering excessive amounts of cortisol. These features include atrophy of skin, arteries, muscle, bone, immune system, and parts of the brain, loss of pigment (melanin), deposition of fat in certain areas, and slowed conduction velocity of nerves. The physiology of aging (especially reproductive aging) overlaps the physiology of stress.

— Ray Peat[52]

Thymus destruction:

After the thymus is consumed and turned to sugar, cortisol starts breaking down muscle and then the skin. The brain, lungs and heart are spared from stress partly because they are very saturated in a healthy person with androgens, testosterone and DHEA especially, which block the breakdown function of cortisol.

It only takes about three hours typically for the thymus gland to disappear during profound stress.

In mice, cortisol emptied thymic lymphocytes within two days and raised macrophage and fibroblast proportions in a pattern resembling age involution, without the collagen rise of old thymus.[53]

Brain damage:

It is now clear that both stress and an excess of the glucocorticoid hormones cause brain damage (as well as damage to all other organs). Nerve cells are replaced by connective tissue cells.

Imaging studies of people under tremendous stress show drastic shrinkage of brain volume, so a chronically stressed person is literally running on empty.

Gut barrier compromise:

Cortisol compromises the gut barrier and increases the expression of the TLR4 receptors, meaning the blood floods with endotoxin and the body's reactivity to the toxin increases.

An unopposed excess causes destruction of detoxification enzymes, eliminating much of the intestine's barrier function, and leading to allergies. Endotoxin is known to destabilize and inactivate the bowel's detoxifying enzymes, just as an overdose of cortisol does.

Adrenal suppression:

High cortisol or glucocorticoid use can cause the adrenals to shrink to the point that suddenly stopping the supplement risks death from the absence of adrenal production. The adrenals will gradually recover over about a month if the person is well nourished after total suppression from too much cortisol.

Psychological effects:

Since cortisol has a destabilizing, pro-convulsant effect on the nervous system, there are likely to be psychological symptoms, from compulsive behavior to depression or seizures, associated with the other chronic conditions.

Mifepristone and terminal cancer

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Mifepristone (RU-486), originally developed as a glucocorticoid receptor antagonist before being repurposed as a progesterone-receptor antagonist for abortion, has been used off-label in a small compassionate-use case series for terminal cancers (lung, thymic, colon, brain, pancreatic) with no remaining treatment options, at a dose of around 200mg daily. Case reports describe stabilization or regression of tumors and survival well beyond expected prognosis in several patients. Cortisol promotes fatty acid synthase/oxidation and suppresses pyruvate dehydrogenase, the metabolic profile common to cancer generally.[54]

Mifepristone and type 2 diabetes

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In a randomized, double-blind, placebo-controlled crossover trial, glucocorticoid-receptor blockade with mifepristone in men with type 2 diabetes lowered fasting glucose and insulin and improved insulin sensitivity of free fatty acid, glycerol, and hepatic glucose output.[55] These are real trials showing improved glycemic control and insulin sensitivity, a meaningfully weaker result than "completely reversed" diabetes; no published trial has reported a cure or full remission with mifepristone alone.

Vascular calcification via the mineralocorticoid receptor

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Chronic exercise raises baseline cortisol, and over time cortisol acting through the mineralocorticoid receptor (not the glucocorticoid receptor) drives vascular smooth muscle cell calcification; the mineralocorticoid antagonist eplerenone blocks it while the glucocorticoid antagonist mifepristone does not.[56]

Obesity as a subclinical Cushing's syndrome

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The "obesity of middle age" pattern (central fat, moon face, buffalo hump, protein wasting) resembles Cushing's syndrome closely enough that a chronic, mild increase in ACTH and beta-endorphin activity has been proposed as a normal part of aging, rather than a separate pathology.[57]

Chronic stress and weight gain

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Mice on the same high-fat diet, same caloric intake, and same physical activity gained twice as much weight when chronically stressed compared to unstressed controls. Chronic stress silenced the lateral habenula, a brain region that normally shuts off reward signaling once satiety is reached, keeping food-reward signaling active regardless of energy need.[58]

Carbohydrate during weight lifting

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In young men, a 6% carbohydrate drink (vs non-caloric placebo) during a nine-station weight-lifting bout blunted the acute cortisol rise (7% vs 99% with placebo) while raising blood glucose and insulin. Over twelve weeks of progressive resistance training, carbohydrate during sessions continued to blunt cortisol versus rising cortisol in the placebo group, and was linked to larger type I (+19.1%) and type II (+22.5%) muscle-fibre area gains; cortisol-response differences accounted for 74% of type I and 52.3% of type II fibre-area variance.[59]

In 83 healthy men, 30 minutes of treadmill exercise at 70% heart-rate reserve dampened salivary cortisol to a Trier Social Stress Test 45 minutes later versus 30% or 50% HRR.[60] In a crossover trial in 14 male recreational athletes, 90 minutes of cycling raised cortisol most after 2 days on a diet under 10% carbohydrate, and the gap from a high-carbohydrate diet narrowed by 2 weeks. Resting cortisol did not differ between diets, and work output stayed lower on the low-carbohydrate diet.[61]

Vitamin E

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Four weeks of vitamin C (1000 mg/day) plus RRR-α-tocopherol (400 IU/day) limited the post-exercise plasma cortisol rise to about 120% of baseline versus about 170% on placebo after 2.5 hours of cycling at about 60% VO2max.[62] Twenty-eight days of ascorbic acid (500 mg/day) with RRR-α-tocopherol (400 IU/day) left post-exercise plasma cortisol flat after three hours of knee-extensor work while control subjects rose.[63] Intramuscular d-α-tocopherol (2000 mg IM before or after a four-hour transit) lowered hair cortisol fourteen days later versus saline in beef steers.[64] Gilthead seabream juveniles on a diet without vitamin E raised basal plasma cortisol from 3.91 to 21.70 ng/ml without an added stressor.[65]

Thyroid hormone

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In 8 healthy subjects, hydrocortisone infusions that copied the mild cortisol rise of a 56-hour fast lowered TSH, the TSH response to TRH, and serum total T3 about as much as fasting did.[66] In isolated rat kidney tubules, cortisol and dexamethasone inhibited the conversion of T4 to T3, and physiological concentrations of corticosterone also lowered T3 output (rat, in vitro).[67]

Fasting, protein meals, and cortisol

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In a meta-analysis of 13 human studies, fasting strongly raised serum cortisol, while very-low-calorie and milder low-calorie diets did not.[68] In 52 healthy subjects, a high-protein meal (4 g/kg) raised cortisol and ACTH, and smaller cortisol rises followed meals with 1 g/kg protein.[69] Glucocorticoids directly stimulate lipolysis in rat adipocytes through the cAMP-PKA pathway, which helps explain the high free fatty acids of hypercortisolemia.[70]

Sugar intake

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Good nutrition should include plenty of carbohydrate so that you don't have to rely on cortisone or cortisol to convert protein, amino acids into glucose and usually something more than 100 grams per day of carbohydrate, preferably in the form of, of sucrose.

— Ray Peat[71]

Glucocorticoids are released when psychological or physical stressors activate the hypothalamic-pituitary-adrenal stress axis. In rats given a human-equivalent dose of roughly 4 g/kg sucrose daily for three days (comparable to about 350-400g sugar per day in a person), the typical stress-induced rise in plasma corticosterone (the rodent analog of cortisol) was blunted, along with other HPA-axis stress measures, relative to unsupplemented controls.[72]

Forest walking and cortisol reduction

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A series of field experiments across 24 forests in Japan, involving 280 male subjects walking roughly 14 minutes through a forest versus a city environment, found significantly lower salivary cortisol, lower pulse rate, lower blood pressure, and greater parasympathetic (relative to sympathetic) nervous activity after the forest walks.[73] Japan's forestry agency built a national Shinrin-yoku (forest bathing) program on this and related research starting in 1982.

In 36 subjects who logged a self-chosen outdoor "nature experience" (no phones, reading, conversation, or hard exercise) at least three times a week over eight weeks, salivary cortisol fell on nearly every outing regardless of location or activity, sitting or walking. The steepest drop per minute occurred in the 20-30 minute window; benefit continued past 30 minutes but at a slower rate.[74]

Sweeteners

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Short-term whole-leaf Stevia intake raised urinary free cortisol, the cortisol/cortisone ratio, morning salivary cortisol, and blood pressure in a 16-person crossover trial; see Stevia.[75]

ACTH

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ACTH (adrenocorticotropic hormone) is the pituitary signal that drives adrenal cortisol output. Excess estrogen, or any stressor, causes the pituitary to secrete prolactin and ACTH; both act on the ovaries to stop progesterone production and contribute to tissue atrophy, and ACTH in turn stimulates cortisol secretion.[76]

Cortisol:DHEA ratio

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Cortisol:DHEA ratio is the ratio of cortisol to DHEA (or DHEA-S) in blood, hair, or nail tissue, used as a biomarker of chronic stress and metabolic rate.

Ratio over single measurement

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A single serum cortisol reading fluctuates through the day and is often unreliable on its own. Measuring cortisol against an antagonistic steroid such as DHEA-S, testosterone, or progesterone gives a more stable picture of chronic stress load. The cortisol/DHEA-S ratio has been proposed as one of the most reliable predictors of all-cause mortality, alongside roles in depression, cardiovascular health, and immune function.[77]

Alzheimer's disease

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A pilot study of Serbian patients found Alzheimer's patients had significantly higher serum cortisol than controls (398.85 vs. 337.40 nmol/L). The cortisol/DHEA-S ratio trended higher overall and was significantly higher among patients aged 65 to 75.[78][79]

Schizophrenia

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Elevated cortisol/DHEA and cortisol/testosterone ratios have also been linked to schizophrenia. Serotonin is the primary driver of cortisol production, and anti-serotonin treatments have lowered cortisol in Cushing's disease, giving a mechanistic link between high serotonin, high cortisol, and psychiatric illness.[80]

Lowering the ratio

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Aspirin, pregnenolone, progesterone, thyroid hormone, and DHEA supplementation have been proposed to lower the cortisol/DHEA-S ratio, either by suppressing cortisol production or raising DHEA.[78]

Hydrocortisone

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Hydrocortisone is the pharmaceutical name for cortisol itself, not a synthetic analog like prednisone, but the same molecule the adrenal glands produce. It is used as low-dose replacement therapy for adrenal insufficiency (Addison's disease), as an anti-inflammatory at higher doses, and topically for skin conditions. Ray Peat's writing on cortisone treats the adrenal glands' own output as something the body should generally need only in small, situational amounts, linking chronic excess directly to inadequate progesterone:[81]

The adrenal glands use it to produce their anti-stress hormones, and when there is enough progesterone, they don't have to produce the potentially harmful cortisone.

— Ray Peat[82]

In a progesterone deficiency, we produce too much cortisone, and excessive cortisone causes osteoporosis, aging of the skin, damage to brain cells, and the accumulation of fat, especially on the back and abdomen.

— Ray Peat[83]

Replacement-dose hydrocortisone restores a normal level when the adrenal glands genuinely underproduce it. The distinction is dose and indication, not the molecule itself. Using it to push cortisol above normal, or long-term at anti-inflammatory doses, reproduces the same risks as chronic stress-driven excess.

Prednisone and glucocorticoid drugs

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Prednisone is a synthetic glucocorticoid, converted in the liver to its active form prednisolone. It is prescribed for inflammation, autoimmune conditions, and allergic reactions by suppressing immune and inflammatory activity, the same basic action as the body's own cortisol/cortisone, at doses well above what the adrenal glands normally produce.

Dosing (Prednisone)

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Prednisone's cortisol-equivalence helps size how far "replacement" doses run above normal adrenal output: the adrenal glands make about 20 mg of cortisol a day, and 10 mg of prednisone is equivalent to roughly 50 mg of cortisol, about 2.5 times that daily amount. Prescribed replacement doses are often higher still. William Jefferies advised patients to take 30 to 40 mg a day because only about half of an oral dose is absorbed. Doses this far above normal production are inherently diabetogenic.[84] Cortisone (the class of hormone prednisone mimics) is something the body should need in only small, situational amounts. Chronically elevated cortisone ties specifically to inadequate progesterone, since progesterone is itself an anti-stress hormone the adrenal glands can use instead of escalating cortisone output:[81]

The adrenal glands use it to produce their anti-stress hormones, and when there is enough progesterone, they don't have to produce the potentially harmful cortisone.

— Ray Peat[85]

Chronic cortisone excess itself, not any one drug, as directly damaging:

In a progesterone deficiency, we produce too much cortisone, and excessive cortisone causes osteoporosis, aging of the skin, damage to brain cells, and the accumulation of fat, especially on the back and abdomen.

— Ray Peat[86]

Prednisone therapy reproduces exactly this state pharmacologically: it is effective precisely because it pushes glucocorticoid activity above the body's own baseline, which is also why long courses carry the same risks Peat attributed to endogenous excess: bone loss, thinned skin, muscle wasting, and fat redistribution to the trunk.

Risks and safety

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Prednisone suppresses the immune system and raises the risk of infection with any pathogen, and it is contraindicated in systemic fungal infections.[87] Listed adverse effects include osteoporosis and vertebral compression fractures, muscle weakness and muscle loss, hypertension, potassium loss, peptic ulcer, impaired wound healing, and thin fragile skin.[87] Adrenal suppression after a long course can last for months, so the label advises reducing the dose gradually and restarting hormone therapy if a stressful event occurs in that window.[87] Dose and duration are set by the prescriber.

Practice

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Short, acute courses for a real inflammatory or allergic emergency are a different situation from long-term daily use. Tapering rather than stopping abruptly matters because exogenous glucocorticoid suppresses the adrenal glands' own output.

See also

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References

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  1. ↑ Hans Selye, "Encyclopedia of Endocrinology", p. 12(Classifies corticoids' sugar- and salt-metabolism effects as subordinate to their life-maintaining (adrenal-replacement) action)
  2. ↑ Ray Peat, "Jefferies and cortisol supplementation," raypeatemails.com.
  3. ↑ Josephs RA, Cobb AR, Lancaster CL, Lee HJ, Telch MJ. "Dual-hormone stress reactivity predicts downstream war-zone stress-evoked PTSD," Psychoneuroendocrinology. 2017;78:76-84. doi:10.1016/j.psyneuen.2017.01.013. PMID 28178580.
  4. ↑ Kanai A, McNamara KM, Iwabuchi E, et al. "Significance of glucocorticoid signaling in triple-negative breast cancer patients: a newly revealed interaction with androgen signaling," Breast Cancer Res Treat. 2020;180(1):97-110. doi:10.1007/s10549-020-05523-7. PMID 31989378.
  5. ↑ Clarke G, Keane L, Cryan JF. "Hepatic tryptophan metabolism links chronic stress to liver cancer," Nat Metab. 2026;8(1):10-11. doi:10.1038/s42255-025-01446-z. PMID 41555011.
  6. ↑ Zhang B, He X, et al. "Chronic stress promotes metastasis via glucocorticoids," Cancer Cell. 2024. doi:10.1016/j.ccell.2024.01.013.
  7. ↑ Moda-Sava RN, Murdock MH, Parekh PK, et al., Liston C. "Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation," Science. 2019;364(6436):eaat8078. doi:10.1126/science.aat8078. PMID 30975859.
  8. ↑ Tomiyama AJ, et al. "Low calorie dieting increases cortisol," Psychosom Med. 2010. PMID 20368473.
  9. ↑ Wilkins JN, Carlson HE, Van Vunakis H, Hill MA, Gritz E, Jarvik ME. "Nicotine from cigarette smoking increases circulating levels of cortisol, growth hormone, and prolactin in male chronic smokers," Psychopharmacology (Berl). 1982;78(4):305-308. PMID 6818588.
  10. ↑ Xue Y, Morris M, Ni L, Guthrie SK, Zubieta JK, Gonzalez K, McConnell DS, Domino EF. "Venous plasma nicotine correlates of hormonal effects of tobacco smoking," Pharmacol Biochem Behav. 2010 Apr;95(2):258-262. PMID 20100507.
  11. ↑ Perego M, Tyurin VA, Tyurina YY, et al. "Reactivation of dormant tumor cells by modified lipids derived from stress-activated neutrophils," Sci Transl Med. 2020;12(572):eabb5817. doi:10.1126/scitranslmed.abb5817. PMID 33268511.
  12. ↑ Argüelles AE, et al. "Corticoadrenal and adrenergic overactivity in male patients with chronic myocardial infarction," J Steroid Biochem. 1973;4(4):427-432. PMID 4270621.
  13. ↑ Tan T, Khoo B, Mills EG, et al., Dhillo WS. "Association between high serum total cortisol concentrations and mortality from COVID-19," Lancet Diabetes Endocrinol. 2020;8(8):659-660. doi:10.1016/S2213-8587(20)30216-3. PMID 32563278.
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  76. ↑ Ray Peat, Aspects of Wholeness. "An excess of estrogen (or any stressor) causes the pituitary to secrete prolactin and ACTH, and both of these hormones act on the ovaries to stop progesterone production, and contribute in many other ways to the process of atrophy. ACTH, of course, stimulates the secretion of cortisol."
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  78. ↑ 78.0 78.1 cortisol/DHEA-S ratio (a sign of chronic stress or low metabolism) may drive Alzheimer Disease (AD), Georgi Dinkov, Haidut.me
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  82. ↑ Progesterone Pregnenolone & DHEA - Three Youth-Associated Hormones, Ray Peat newsletter Ray Peat, "From PMS to Menopause: Female Hormones in Context", p. 70(Adrenal hormones and cortisone)
  83. ↑ Progesterone Pregnenolone & DHEA - Three Youth-Associated Hormones, Ray Peat newsletter Ray Peat, "From PMS to Menopause: Female Hormones in Context", p. 70(Adrenal hormones and cortisone)
  84. ↑ Ray Peat, Ephemera: Emails & Exchanges from the Archives (2012-2024).
  85. ↑ Progesterone Pregnenolone & DHEA - Three Youth-Associated Hormones, Ray Peat newsletter
  86. ↑ Progesterone Pregnenolone & DHEA - Three Youth-Associated Hormones, Ray Peat newsletter
  87. ↑ 87.0 87.1 87.2 Prednisone tablets prescribing information, DailyMed.