Cortisol

Cortisol is the principal glucocorticoid hormone produced by the human adrenal cortex. It is synthesized predominantly within the zona fasciculata, the middle and largest layer of the adrenal cortex. Cortisol influences carbohydrate, protein, and lipid metabolism, supports the physiological response to stress, modifies immune and inflammatory activity, and contributes to maintenance of cardiovascular function.

Cortisol secretion is controlled primarily through the hypothalamic-pituitary-adrenal (HPA) axis. Corticotropin-releasing hormone (CRH) from the hypothalamus stimulates secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH then stimulates cortisol synthesis and secretion from the adrenal cortex.

Cortisol secretion also follows a characteristic circadian rhythm and can increase substantially during physiological stress. Circulating cortisol subsequently provides negative feedback to both the hypothalamus and anterior pituitary, helping regulate activity of the HPA axis.

Site of Production

Cortisol is produced primarily within the zona fasciculata of the adrenal cortex, with some glucocorticoid synthesis also occurring in the zona reticularis.

The adrenal cortex consists of three major histological zones, each characterized by a different pattern of steroid hormone production.

Adrenal Cortical Zones

Zone	Major Hormonal Products
Zona glomerulosa	Mineralocorticoids, particularly aldosterone
Zona fasciculata	Glucocorticoids, particularly cortisol
Zona reticularis	Adrenal androgens

Zona Fasciculata

The zona fasciculata is the thickest layer of the adrenal cortex. It lies between the zona glomerulosa externally and the zona reticularis internally.

Its steroid-producing cells are typically arranged in long cords or columns separated by sinusoidal capillaries. The cells contain abundant lipid droplets that store cholesterol and cholesterol esters used for steroidogenesis.

Glucocorticoids

Glucocorticoids are steroid hormones that influence metabolism and numerous physiological responses to environmental and internal stressors.

Cortisol, also called hydrocortisone, is the major naturally occurring glucocorticoid in humans.

Synthesis of Cortisol

Like other adrenal cortical steroids, cortisol is synthesized from cholesterol.

A simplified steroidogenic pathway is:

Cholesterol → Pregnenolone → 17-Hydroxypregnenolone → 17-Hydroxyprogesterone → 11-Deoxycortisol → Cortisol

Cholesterol

Cholesterol serves as the common precursor for glucocorticoids, mineralocorticoids, and adrenal androgens.

Adrenal cortical cells obtain cholesterol from circulating lipoproteins, intracellular stores, and endogenous cholesterol synthesis.

StAR Protein

The steroidogenic acute regulatory protein (StAR) facilitates transport of cholesterol toward the inner mitochondrial membrane.

This transport is an important regulated step in steroid hormone synthesis and is stimulated by ACTH in cortisol-producing cells.

Pregnenolone

Within mitochondria, cholesterol is converted to pregnenolone by the cholesterol side-chain cleavage enzyme, CYP11A1.

Pregnenolone subsequently undergoes enzymatic modifications that direct steroid synthesis toward cortisol and other adrenal hormones.

CYP17A1

CYP17A1 possesses 17α-hydroxylase activity that is important in cortisol synthesis.

This enzyme permits formation of 17-hydroxylated steroid intermediates required for progression through the glucocorticoid pathway.

21-Hydroxylase

21-hydroxylase, encoded by the CYP21A2 gene, converts 17-hydroxyprogesterone to 11-deoxycortisol.

Deficiency of this enzyme impairs cortisol production and is the most common cause of congenital adrenal hyperplasia.

11β-Hydroxylase

11β-hydroxylase, encoded by CYP11B1, catalyzes the final conversion of 11-deoxycortisol to cortisol within mitochondria.

Cortisol Synthesis Pathway

Stage	Product or Enzyme
Initial substrate	Cholesterol
First steroid product	Pregnenolone
Important hydroxylase	CYP17A1
21-hydroxylation	CYP21A2
Immediate precursor	11-Deoxycortisol
Final enzyme	11β-Hydroxylase, CYP11B1
Final product	Cortisol

Hypothalamic-Pituitary-Adrenal Axis

The HPA axis provides the major endocrine control system regulating cortisol production.

It consists functionally of the hypothalamus, anterior pituitary gland, and adrenal cortex.

Corticotropin-Releasing Hormone

Corticotropin-releasing hormone (CRH) is synthesized by neurons within the hypothalamus, particularly the paraventricular nucleus.

CRH is released into the hypothalamic-hypophyseal portal circulation and transported to the anterior pituitary.

ACTH

CRH stimulates corticotroph cells of the anterior pituitary to release adrenocorticotropic hormone (ACTH).

ACTH enters the systemic circulation and travels to the adrenal cortex, where it stimulates cortisol synthesis.

ACTH Formation

ACTH is derived from the larger precursor protein proopiomelanocortin (POMC).

Processing of POMC produces ACTH and additional peptide products.

ACTH Receptor

ACTH acts primarily through the melanocortin 2 receptor (MC2R) on adrenal cortical cells.

Activation of this receptor stimulates intracellular cyclic AMP signaling and promotes steroidogenesis.

ACTH and Cholesterol Availability

ACTH promotes cholesterol availability and stimulates mechanisms involved in cholesterol transport into mitochondria.

This enables rapid increases in steroid synthesis when greater cortisol secretion is required.

HPA Axis Pathway

A simplified pathway is:

Hypothalamus → CRH → Anterior pituitary → ACTH → Adrenal cortex → Cortisol

Negative Feedback

Cortisol participates in negative feedback regulation of the HPA axis.

Increasing circulating cortisol inhibits further secretion of CRH and ACTH, helping prevent excessive activation of the system.

Long-Loop Feedback

Cortisol produced by the adrenal cortex feeds back to both the hypothalamus and anterior pituitary.

This long-loop negative feedback is a fundamental mechanism regulating glucocorticoid concentrations.

Circadian Rhythm

Cortisol secretion varies predictably over the 24-hour day under normal conditions.

Concentrations generally rise during the latter portion of sleep, reach their highest levels around the early morning and awakening period, and decline during the day toward lower concentrations around the beginning of the normal sleep period.

Cortisol Awakening Response

In many individuals, cortisol concentrations increase further during the period shortly after awakening. This phenomenon is known as the cortisol awakening response.

The precise pattern varies among individuals and is influenced by sleep, circadian timing, stress, and other physiological factors.

Pulsatile Secretion

ACTH and cortisol are secreted in pulses rather than at completely constant rates.

This ultradian pattern is superimposed on the broader circadian rhythm of the HPA axis.

Stress Response

Physical and psychological stressors can activate the HPA axis and increase cortisol secretion.

Physiological stressors capable of increasing cortisol include major illness, trauma, surgery, hypoglycemia, and other conditions that challenge homeostasis.

Metabolic Functions

Cortisol influences the metabolism of carbohydrates, proteins, and lipids.

These actions help ensure the availability of metabolic substrates during fasting and physiological stress.

Carbohydrate Metabolism

Cortisol tends to preserve and increase circulating glucose availability by stimulating hepatic glucose production and modifying glucose utilization in peripheral tissues.

Gluconeogenesis

Cortisol promotes gluconeogenesis, the production of glucose from non-carbohydrate substrates, particularly within the liver.

It increases expression of enzymes involved in gluconeogenic pathways and helps make amino acids and other substrates available for hepatic glucose production.

Peripheral Glucose Utilization

Elevated glucocorticoid activity can reduce insulin-mediated glucose utilization in several peripheral tissues.

Together with increased hepatic glucose production, this effect helps maintain circulating glucose but can contribute to hyperglycemia when cortisol activity is excessive.

Insulin Resistance

Chronic cortisol excess can antagonize aspects of insulin action and contribute to insulin resistance.

This can increase blood glucose concentrations and stimulate compensatory insulin secretion.

Protein Metabolism

Cortisol influences protein turnover and can promote mobilization of amino acids from peripheral tissues.

These amino acids can subsequently be used for hepatic gluconeogenesis and other metabolic processes.

Protein Catabolism

When glucocorticoid activity is chronically excessive, increased protein catabolism can contribute to loss of muscle protein and thinning of protein-rich tissues.

Lipid Metabolism

Cortisol influences lipid mobilization, adipocyte function, and fat distribution.

Its effects vary according to tissue, nutritional state, insulin concentrations, and duration of glucocorticoid exposure.

Lipolysis

Cortisol can facilitate mobilization of fatty acids from adipose tissue, particularly in combination with other hormones active during fasting or stress.

Fat Distribution

Chronic glucocorticoid excess can produce characteristic redistribution of adipose tissue, with increased central adiposity despite catabolic effects in other tissues.

Metabolic Effects of Cortisol

Metabolic Area	Major Effect
Glucose	Promotes hepatic glucose production
Gluconeogenesis	Increased
Peripheral insulin sensitivity	Can decrease with glucocorticoid excess
Protein	Promotes availability of amino acids and can increase catabolism
Lipid	Modifies lipolysis and fat distribution

Cardiovascular Effects

Normal cortisol concentrations help maintain cardiovascular function and vascular responsiveness.

Cortisol supports the ability of blood vessels to respond appropriately to vasoconstrictor signals such as catecholamines.

Vascular Responsiveness

Glucocorticoids have a permissive effect on vascular responses to catecholamines.

Severe cortisol deficiency can therefore contribute to reduced vascular tone and hypotension.

Blood Pressure

Both cortisol deficiency and cortisol excess can influence arterial pressure.

Deficiency can contribute to hypotension, while chronic excess commonly contributes to hypertension through several renal, vascular, and metabolic mechanisms.

Immune Effects

Cortisol is an important regulator of immune activity.

Physiological glucocorticoid signaling helps limit excessive immune activation, while pharmacological or pathological glucocorticoid excess can produce substantial immunosuppressive effects.

Anti-Inflammatory Effects

Cortisol suppresses multiple components of inflammatory signaling.

It modifies gene transcription involved in cytokine production, inflammatory mediator synthesis, leukocyte activity, and vascular inflammatory responses.

Cytokines

Glucocorticoids can suppress production and action of numerous pro-inflammatory cytokines.

This contributes to their powerful anti-inflammatory effects.

Leukocytes

Glucocorticoids alter the distribution and activity of several leukocyte populations.

These effects contribute to the characteristic changes in circulating blood cells that can accompany elevated glucocorticoid concentrations.

Glucocorticoid Receptor

Cortisol exerts many of its effects through the intracellular glucocorticoid receptor.

The receptor is expressed in numerous tissues throughout the body.

Mechanism of Action

Because cortisol is lipid soluble, it diffuses through the plasma membrane of target cells and binds to glucocorticoid receptors in the cytoplasm.

The activated receptor complex can translocate to the nucleus and regulate gene transcription.

Genomic Effects

Many cortisol actions result from changes in transcription of specific genes.

These genomic effects can alter metabolic enzymes, inflammatory mediators, receptors, transport proteins, and other cellular components.

Non-Genomic Effects

Some glucocorticoid actions occur more rapidly than classical changes in gene transcription and are described as non-genomic effects.

These mechanisms complement the better-characterized genomic actions of glucocorticoid receptors.

Cortisol Transport in Blood

Most circulating cortisol is bound to plasma proteins.

The principal binding protein is corticosteroid-binding globulin (CBG), also called transcortin. A smaller fraction is bound to albumin, while only a small percentage circulates as free cortisol.

Corticosteroid-Binding Globulin

CBG is synthesized primarily by the liver and binds cortisol with relatively high affinity.

Changes in CBG concentrations can alter measured total cortisol without producing equivalent changes in free biologically active cortisol.

Free Cortisol

The unbound fraction of cortisol is biologically available to enter target cells.

Free cortisol can also be measured indirectly or directly in clinical assessment using appropriate biological samples and methods.

Cortisol Metabolism

Cortisol is metabolized in several tissues, particularly the liver, and its metabolites are ultimately excreted.

Local enzymatic conversion between cortisol and cortisone also regulates glucocorticoid exposure within specific tissues.

11β-Hydroxysteroid Dehydrogenase Type 1

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) can regenerate active cortisol from cortisone in several tissues.

This mechanism increases local glucocorticoid availability without requiring increased adrenal cortisol secretion.

11β-Hydroxysteroid Dehydrogenase Type 2

11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) converts cortisol into cortisone.

It is particularly important in mineralocorticoid-sensitive tissues because it protects mineralocorticoid receptors from excessive activation by cortisol.

Cortisol and Cortisone

Feature	Cortisol	Cortisone
Glucocorticoid activity	Biologically active	Substantially less active
Conversion to other form	Can be converted to cortisone by 11β-HSD2	Can be converted to cortisol by 11β-HSD1
Physiological significance	Major circulating glucocorticoid	Participates in local regulation of cortisol availability

Effects on Bone

Physiological glucocorticoid signaling participates in normal skeletal homeostasis, but chronic cortisol excess has detrimental effects on bone.

Excess glucocorticoids can reduce bone formation, alter calcium metabolism, and increase the risk of osteoporosis and fractures.

Calcium Metabolism

Excessive glucocorticoid activity can decrease intestinal calcium absorption and influence renal calcium handling.

These effects can contribute to impaired skeletal mineral balance during prolonged cortisol excess.

Effects on Muscle

Chronic cortisol excess can promote protein catabolism within skeletal muscle.

This can result in muscle wasting and weakness, particularly affecting proximal muscles.

Effects on Skin

Excess glucocorticoid activity can decrease connective tissue support and protein synthesis within the skin.

Consequences can include thinning of the skin, easy bruising, impaired wound healing, and formation of broad striae.

Effects on the Central Nervous System

Cortisol can influence mood, cognition, sleep, appetite, and behavioral responses to stress.

Both excessive and deficient glucocorticoid activity can be associated with neurological or psychological symptoms.

Cortisol and Growth

Chronic glucocorticoid excess can suppress normal growth in children.

This effect reflects interactions with growth hormone signaling, bone formation, protein metabolism, and other physiological systems.

Cortisol and Reproductive Function

Marked or chronic activation of the HPA axis can interact with the hypothalamic-pituitary-gonadal axis.

Glucocorticoid excess can therefore contribute to disturbances of reproductive hormone function.

Cushing Syndrome

Cushing syndrome is the clinical state produced by prolonged pathological exposure to excessive glucocorticoid activity.

The excess can result from endogenous cortisol production or administration of exogenous glucocorticoids.

Causes of Cushing Syndrome

Major categories include:

• Exogenous glucocorticoid administration
• Pituitary ACTH excess
• Ectopic ACTH secretion
• Autonomous adrenal cortisol production

Cushing Disease

Cushing disease specifically refers to Cushing syndrome caused by excessive ACTH secretion from a pituitary corticotroph adenoma.

The increased ACTH stimulates excessive cortisol production by the adrenal cortex.

ACTH-Dependent Cushing Syndrome

In ACTH-dependent Cushing syndrome, excessive ACTH drives increased adrenal cortisol synthesis.

The ACTH source may be pituitary or ectopic.

ACTH-Independent Cushing Syndrome

ACTH-independent Cushing syndrome results from autonomous cortisol production by the adrenal cortex.

Elevated cortisol suppresses hypothalamic CRH and pituitary ACTH through negative feedback.

Clinical Features of Cortisol Excess

Potential manifestations include:

• Central weight gain
• Hypertension
• Glucose intolerance or diabetes
• Proximal muscle weakness
• Skin thinning and easy bruising
• Broad striae
• Osteoporosis
• Increased susceptibility to infection
• Reproductive disturbances
• Neuropsychiatric changes

Adrenal Insufficiency

Adrenal insufficiency occurs when glucocorticoid production is inadequate for physiological requirements.

It may result from primary adrenal disease or from inadequate stimulation of the adrenal cortex by ACTH.

Primary Adrenal Insufficiency

Primary adrenal insufficiency results from dysfunction or destruction of the adrenal cortex itself.

Cortisol production falls, causing loss of negative feedback and a compensatory increase in ACTH secretion.

Addison Disease

Addison disease refers to primary adrenal insufficiency, classically resulting from destruction or dysfunction of the adrenal cortex.

Because the cortex itself is affected, deficiencies can involve both glucocorticoids and mineralocorticoids.

Hyperpigmentation

In primary adrenal insufficiency, increased POMC-derived peptide production associated with elevated ACTH can contribute to hyperpigmentation.

This finding is not expected from cortisol deficiency alone when ACTH concentrations are low.

Secondary Adrenal Insufficiency

Secondary adrenal insufficiency results from inadequate pituitary ACTH secretion.

Cortisol production decreases, while aldosterone secretion is usually relatively preserved because it is regulated primarily by angiotensin II and potassium.

Tertiary Adrenal Insufficiency

Reduced hypothalamic CRH drive can lead to inadequate ACTH secretion and reduced cortisol production.

Suppression of the HPA axis following prolonged exogenous glucocorticoid exposure is an important clinical context in which central adrenal insufficiency can occur.

Adrenal Crisis

Adrenal crisis is an acute state of severe adrenal insufficiency that can cause profound hypotension and circulatory instability.

It may occur when cortisol availability becomes critically inadequate during severe physiological stress or abrupt loss of glucocorticoid support.

Clinical Features of Cortisol Deficiency

Potential manifestations include:

• Fatigue
• Weakness
• Weight loss
• Hypotension
• Reduced tolerance of physiological stress
• Hypoglycemia in susceptible individuals
• Gastrointestinal symptoms

Primary Versus Secondary Adrenal Insufficiency

Feature	Primary	Secondary
Primary defect	Adrenal cortex	Pituitary ACTH secretion
Cortisol	Low	Low
ACTH	Usually elevated	Low or inappropriately normal
Aldosterone	May be deficient	Usually relatively preserved
Hyperpigmentation	Can occur	Not characteristic

Measurement of Cortisol

Cortisol can be assessed using blood, saliva, or urine depending on the clinical question.

Interpretation must consider circadian timing, binding proteins, medications, physiological stress, and the suspected endocrine disorder.

Serum Cortisol

Serum cortisol measures predominantly protein-bound plus free circulating cortisol.

Because cortisol follows a circadian rhythm, the time of sample collection is important when interpreting results.

Salivary Cortisol

Salivary cortisol reflects the free fraction of circulating cortisol and can be collected noninvasively.

Late-night salivary cortisol is commonly used in the evaluation of suspected endogenous cortisol excess because normal cortisol secretion should be low around the usual sleep period.

Urinary Free Cortisol

Urinary free cortisol reflects unbound cortisol filtered into urine over a collection period, commonly 24 hours.

It can be used as part of the biochemical evaluation of suspected hypercortisolism.

Dexamethasone Suppression Testing

Dexamethasone is a synthetic glucocorticoid that suppresses ACTH secretion through glucocorticoid negative feedback.

Failure of cortisol to suppress appropriately after dexamethasone administration can provide evidence of abnormal regulation of the HPA axis.

ACTH Stimulation Test

An ACTH stimulation test assesses the ability of the adrenal cortex to increase cortisol secretion following administration of synthetic ACTH.

It is commonly used in the evaluation of suspected adrenal insufficiency.

Plasma ACTH Measurement

Measurement of ACTH together with cortisol can help localize dysfunction within the HPA axis.

Low cortisol with elevated ACTH suggests primary adrenal dysfunction, whereas low cortisol with low or inappropriately normal ACTH suggests a central cause.

Cortisol and ACTH Patterns

Condition	Cortisol	ACTH
Primary adrenal insufficiency	Low	High
Secondary adrenal insufficiency	Low	Low or inappropriately normal
ACTH-dependent hypercortisolism	High	Elevated or inappropriately normal
Adrenal autonomous cortisol excess	High	Suppressed

Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) includes inherited disorders caused by deficiencies of enzymes involved in adrenal steroid synthesis.

Several forms impair cortisol synthesis and consequently increase ACTH secretion through loss of negative feedback.

21-Hydroxylase Deficiency

21-hydroxylase deficiency is the most common form of congenital adrenal hyperplasia.

Deficient CYP21A2 activity reduces cortisol synthesis and causes accumulation of steroid precursors that can be redirected toward adrenal androgen production.

11β-Hydroxylase Deficiency

Deficiency of 11β-hydroxylase also impairs cortisol synthesis.

Accumulation of upstream steroids, including 11-deoxycorticosterone, can produce a clinical pattern that includes androgen excess and mineralocorticoid-like effects.

Chronic ACTH Stimulation

When cortisol synthesis is impaired, reduced negative feedback causes increased ACTH secretion.

Persistent ACTH stimulation produces adrenal cortical hyperplasia, which accounts for the term congenital adrenal hyperplasia.

Cortisol and Exogenous Glucocorticoids

Synthetic glucocorticoids reproduce many actions of endogenous cortisol and are widely used therapeutically for their anti-inflammatory and immunosuppressive properties.

Prolonged exposure can suppress CRH and ACTH secretion through negative feedback.

HPA Axis Suppression

Chronic exogenous glucocorticoid therapy can suppress endogenous ACTH production.

Reduced ACTH stimulation can lead to functional atrophy of cortisol-producing regions of the adrenal cortex.

Withdrawal of Glucocorticoids

After prolonged glucocorticoid exposure, abrupt withdrawal can leave endogenous cortisol production temporarily inadequate because recovery of the HPA axis may require time.

This physiological principle explains why prolonged systemic glucocorticoid therapy may require gradual dose reduction under appropriate clinical circumstances.

Cortisol Versus Aldosterone

Feature	Cortisol	Aldosterone
Hormone class	Glucocorticoid	Mineralocorticoid
Primary adrenal zone	Zona fasciculata	Zona glomerulosa
Major regulator	ACTH	Angiotensin II and potassium
Major functions	Metabolism, stress response, immune regulation	Sodium, potassium and extracellular volume regulation
Major receptor	Glucocorticoid receptor	Mineralocorticoid receptor

Cortisol Versus Adrenal Androgens

Feature	Cortisol	Adrenal Androgens
Major cortical source	Zona fasciculata	Zona reticularis
Representative product	Cortisol	DHEA and DHEAS
Major role	Metabolic and stress regulation	Sex steroid precursor production
ACTH influence	Major	Important

Key Features of Cortisol

Feature	Key Point
Hormone type	Glucocorticoid steroid hormone
Primary production site	Zona fasciculata of adrenal cortex
Precursor	Cholesterol
Primary regulator	ACTH
Hypothalamic hormone	CRH
Major receptor	Glucocorticoid receptor
Major binding protein	Corticosteroid-binding globulin
Secretion pattern	Circadian and pulsatile
Metabolic effect	Supports glucose availability and mobilization of metabolic substrates
Immune effect	Restrains inflammatory and immune activity
Feedback	Inhibits CRH and ACTH secretion

Clinical Associations

Condition	Relationship to Cortisol
Cushing syndrome	Chronic excessive glucocorticoid exposure
Cushing disease	Pituitary ACTH excess causing cortisol excess
Primary adrenal insufficiency	Reduced adrenal cortisol production
Secondary adrenal insufficiency	Reduced cortisol caused by inadequate ACTH
Congenital adrenal hyperplasia	Selected enzyme deficiencies impair cortisol synthesis
Adrenal cortisol-producing tumor	Can cause ACTH-independent cortisol excess

Anatomical and Physiological Importance

Cortisol is the major glucocorticoid product of the adrenal cortex and represents the principal hormonal output of the zona fasciculata. Its secretion is closely integrated with hypothalamic and pituitary function through the HPA axis, allowing adrenal glucocorticoid production to respond to circadian signals and physiological stress.

Cortisol acts throughout the body. It supports glucose availability, influences protein and lipid metabolism, maintains vascular responsiveness, modifies immune and inflammatory activity, and affects bone, skin, muscle, the nervous system, and numerous other tissues. These widespread effects allow the body to adapt metabolically and physiologically to changing demands.

Precise regulation is essential because both excess and deficiency have major systemic consequences. Chronic cortisol excess produces Cushing syndrome, while inadequate cortisol production results in adrenal insufficiency and can become life-threatening during severe physiological stress. The synthesis, regulation, and actions of cortisol therefore form a central link between adrenal anatomy, endocrine physiology, metabolism, immune regulation, and the integrated stress response.