ACTH

Adrenocorticotropic hormone (ACTH), also called corticotropin, is a peptide hormone secreted by corticotroph cells of the anterior pituitary. Its principal endocrine target is the adrenal cortex, where it stimulates the synthesis and secretion of glucocorticoids, particularly cortisol.

ACTH forms the pituitary component of the hypothalamic-pituitary-adrenal (HPA) axis. Corticotropin-releasing hormone (CRH) released from the hypothalamus reaches anterior pituitary corticotrophs through the hypothalamo-hypophyseal portal circulation and stimulates ACTH secretion. ACTH then enters the systemic circulation and travels to the adrenal glands.

Within the adrenal cortex, ACTH acts most strongly on the zona fasciculata and zona reticularis. Cortisol produced in response to ACTH provides negative feedback to both the anterior pituitary and hypothalamus, creating a tightly regulated endocrine axis that responds to circadian signals and physiological stress.

Hormone Classification

ACTH is a peptide hormone composed of 39 amino acids. It is produced by enzymatic cleavage of a much larger precursor protein called proopiomelanocortin (POMC).

Because ACTH is water soluble, it acts through membrane-bound receptors rather than intracellular nuclear receptors.

Anterior Pituitary Origin

ACTH is produced in the adenohypophysis, particularly within the pars distalis of the anterior pituitary.

The cells responsible for ACTH synthesis and secretion are called corticotrophs.

Corticotroph Cells

Corticotrophs are specialized endocrine cells of the anterior pituitary. They synthesize POMC and process it to generate ACTH and related peptides.

Corticotroph activity is regulated primarily by hypothalamic CRH, with additional modulation by vasopressin and negative feedback from circulating glucocorticoids.

Proopiomelanocortin

Proopiomelanocortin (POMC) is the precursor polypeptide from which ACTH is derived. POMC can be processed differently in different tissues, producing several biologically active peptides.

The pattern of POMC cleavage depends on the enzymes expressed within a particular cell type.

POMC Processing

Within anterior pituitary corticotrophs, POMC is cleaved to generate ACTH and other peptide products. ACTH itself contains the amino acid sequence from which alpha-melanocyte-stimulating hormone can be derived in tissues with appropriate processing machinery.

This structural relationship helps explain why marked ACTH excess can be associated with increased pigmentation.

ACTH Structure

Human ACTH contains 39 amino acids. Its N-terminal region is essential for its steroidogenic activity at the adrenal cortex.

The peptide belongs to the melanocortin family of signaling molecules and acts through a melanocortin receptor expressed on adrenal cortical cells.

Hypothalamic Regulation

The principal hypothalamic regulator of ACTH secretion is corticotropin-releasing hormone (CRH).

CRH-producing neurosecretory neurons are concentrated within the paraventricular nucleus of the hypothalamus and project toward the median eminence.

CRH

Corticotropin-releasing hormone is released into the primary capillary plexus of the median eminence and transported to the anterior pituitary through hypophyseal portal vessels.

At the anterior pituitary, CRH binds receptors on corticotrophs and stimulates ACTH synthesis and secretion.

ACTH Secretory Pathway

Step	Event
1	Hypothalamic neurons synthesize CRH
2	CRH is released at the median eminence
3	Portal vessels carry CRH to the anterior pituitary
4	CRH stimulates corticotroph cells
5	POMC-derived ACTH is released
6	ACTH enters the systemic circulation
7	ACTH reaches the adrenal cortex
8	Adrenal glucocorticoid synthesis increases

Vasopressin and ACTH

Arginine vasopressin (AVP) can enhance ACTH secretion and acts synergistically with CRH at anterior pituitary corticotrophs.

This effect is particularly relevant during activation of the HPA axis by stress.

ACTH Receptor

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

MC2R is a G protein-coupled receptor specialized for ACTH signaling and is particularly important in the zona fasciculata and zona reticularis.

ACTH Receptor Signaling

Binding of ACTH to MC2R activates stimulatory G protein signaling and increases adenylyl cyclase activity.

This increases intracellular cyclic AMP and activates protein kinase A-dependent pathways that promote cholesterol availability and steroid hormone synthesis.

ACTH Signaling Sequence

Step	Event
1	ACTH binds MC2R on an adrenal cortical cell
2	Gs signaling is activated
3	Adenylyl cyclase activity increases
4	Intracellular cAMP increases
5	Protein kinase A signaling is activated
6	Cholesterol transport and steroidogenic activity increase
7	Cortisol synthesis and secretion increase

Adrenal Cortex

The adrenal cortex is the principal peripheral endocrine target of ACTH. It forms the outer portion of the adrenal gland and surrounds the adrenal medulla.

The cortex is organized into three histologically and functionally distinct zones: the zona glomerulosa, zona fasciculata, and zona reticularis.

Zones of the Adrenal Cortex

Zone	Major Hormonal Product	Relationship to ACTH
Zona glomerulosa	Aldosterone	ACTH has a limited acute influence, but angiotensin II and potassium are the principal regulators
Zona fasciculata	Cortisol	Strongly ACTH-dependent
Zona reticularis	Adrenal androgens	ACTH-dependent

Zona Fasciculata

The zona fasciculata is the thick middle layer of the adrenal cortex and the major site of cortisol synthesis.

ACTH is the principal trophic and secretory regulator of this zone.

Zona Reticularis

The zona reticularis forms the innermost layer of the adrenal cortex. It produces adrenal androgens, including dehydroepiandrosterone and related steroids.

ACTH provides important stimulation of steroidogenesis within this zone.

Zona Glomerulosa

The zona glomerulosa is the outermost cortical layer and produces the mineralocorticoid aldosterone.

Although ACTH can transiently influence aldosterone secretion, the renin-angiotensin-aldosterone system and extracellular potassium concentration provide the dominant physiological regulation.

ACTH and Cortisol

The most important endocrine effect of ACTH is stimulation of cortisol synthesis and secretion from the zona fasciculata.

Cortisol is a glucocorticoid with widespread effects on metabolism, cardiovascular physiology, immune responses, stress adaptation, and other organ systems.

Steroid Hormone Synthesis

Unlike peptide hormones, steroid hormones are not stored in large secretory vesicles. Their secretion depends substantially on their rate of synthesis.

ACTH therefore stimulates the biochemical machinery required to convert cholesterol into adrenal steroid hormones.

Cholesterol and Steroidogenesis

Cholesterol provides the precursor for adrenal steroid hormone synthesis. ACTH promotes cholesterol mobilization and its delivery to steroidogenic mitochondria.

This process is essential for rapid increases in cortisol synthesis.

StAR Protein

The steroidogenic acute regulatory protein (StAR) facilitates movement of cholesterol to the inner mitochondrial membrane, where steroidogenesis begins.

ACTH rapidly stimulates StAR-dependent cholesterol transport, making this an important acute regulatory step in cortisol production.

Cortisol

Cortisol is the principal glucocorticoid in humans. It is secreted primarily by the zona fasciculata in response to ACTH.

Cortisol circulates largely bound to plasma proteins and enters target cells, where it binds intracellular glucocorticoid receptors and modifies gene transcription.

Metabolic Effects of Cortisol

Cortisol helps maintain metabolic fuel availability, particularly during fasting and stress. It promotes hepatic gluconeogenesis, influences protein metabolism, and facilitates mobilization of energy substrates.

These effects are downstream consequences of activation of the CRH-ACTH-cortisol axis.

Immune Effects of Cortisol

Cortisol has powerful regulatory effects on immune and inflammatory responses. Elevated glucocorticoid activity can suppress production of inflammatory mediators and modify leukocyte function.

These actions are important physiologically and form the basis for the therapeutic use of synthetic glucocorticoids.

Cardiovascular Effects of Cortisol

Normal cortisol concentrations help maintain vascular responsiveness to catecholamines and contribute to cardiovascular homeostasis.

Severe cortisol deficiency can therefore contribute to hypotension and impaired circulatory responses to physiological stress.

Adrenal Androgens

ACTH also stimulates production of adrenal androgens within the zona reticularis.

Important adrenal androgen precursors include dehydroepiandrosterone (DHEA) and its sulfated form, DHEA-S.

ACTH and Aldosterone

ACTH can produce a transient increase in aldosterone secretion, but it is not the principal long-term regulator of mineralocorticoid production.

Aldosterone secretion is controlled mainly by angiotensin II and extracellular potassium.

Hypothalamic-Pituitary-Adrenal Axis

The HPA axis is a hierarchical neuroendocrine system linking the hypothalamus, anterior pituitary, and adrenal cortex.

It regulates basal glucocorticoid secretion and coordinates endocrine responses to many forms of physiological stress.

Basic HPA Axis

Level	Hormone	Major Target
Hypothalamus	CRH	Anterior pituitary corticotrophs
Anterior pituitary	ACTH	Adrenal cortex
Adrenal cortex	Cortisol	Multiple peripheral tissues and feedback sites

Cortisol Negative Feedback

Cortisol provides negative feedback at both the anterior pituitary and hypothalamic levels.

Increasing cortisol concentrations suppress ACTH production by corticotrophs and reduce hypothalamic CRH drive, limiting further activation of the HPA axis.

Feedback at the Pituitary

Glucocorticoids act on corticotroph cells to reduce POMC transcription and ACTH synthesis and secretion.

This direct pituitary feedback is an important mechanism preventing excessive cortisol production.

Feedback at the Hypothalamus

Cortisol also acts within the central nervous system to reduce CRH and related HPA-axis signaling.

The resulting decrease in hypothalamic stimulation further reduces ACTH secretion.

HPA Axis Feedback

Signal	Major Effect
CRH	Stimulates ACTH secretion
ACTH	Stimulates adrenal cortisol production
Cortisol	Provides negative feedback to pituitary and hypothalamus
Vasopressin	Can enhance CRH-mediated ACTH secretion

Pulsatile ACTH Secretion

ACTH is secreted in pulses rather than at a constant rate. These pulses contribute to corresponding fluctuations in cortisol secretion.

Pulsatility is superimposed on a strong circadian rhythm and can be modified by physiological stress.

Circadian Rhythm

ACTH and cortisol exhibit a pronounced circadian rhythm. In individuals with a conventional sleep-wake schedule, concentrations generally rise during the latter part of sleep and are highest around the early morning period.

Levels subsequently decline during the day and are usually lowest around the late evening or early nighttime period.

Suprachiasmatic Nucleus

The suprachiasmatic nucleus of the hypothalamus serves as the principal central circadian clock and influences the daily rhythm of the HPA axis.

Its signals ultimately affect CRH, ACTH, and cortisol secretion, coordinating adrenal glucocorticoid activity with the sleep-wake cycle.

ACTH and Stress

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

Increased ACTH raises cortisol production, helping the body adapt to challenges involving metabolism, cardiovascular demand, inflammation, trauma, illness, and other physiological disturbances.

Stress Response Pathway

Stage	Response
Central nervous system	Stress-related neural signals activate hypothalamic pathways
Hypothalamus	CRH and related signals increase
Anterior pituitary	ACTH secretion increases
Adrenal cortex	Cortisol secretion increases
Peripheral tissues	Metabolic, cardiovascular, and immune adaptations occur

ACTH and Adrenal Trophic Effects

ACTH does more than acutely stimulate steroid secretion. It also has trophic effects on the adrenal cortex, particularly the zona fasciculata and zona reticularis.

Chronic ACTH stimulation promotes maintenance and growth of these cortical zones, while prolonged ACTH deficiency can lead to cortical atrophy.

ACTH Excess

Persistent ACTH excess causes chronic stimulation of the adrenal cortex and can produce excessive cortisol secretion when the adrenal glands remain responsive.

High ACTH concentrations can also stimulate melanocortin receptors involved in pigmentation, particularly when ACTH elevation is marked.

Hyperpigmentation

Marked elevations of ACTH can produce hyperpigmentation. This occurs because ACTH and melanocyte-stimulating peptides share structural relationships through their common POMC precursor.

Hyperpigmentation is particularly associated with conditions in which loss of cortisol feedback causes very high ACTH secretion.

ACTH Deficiency

Deficient ACTH secretion reduces stimulation of the zona fasciculata and zona reticularis, causing decreased cortisol and adrenal androgen production.

Aldosterone secretion is relatively preserved because its principal regulation depends on the renin-angiotensin system and potassium rather than ACTH.

Primary Adrenal Insufficiency

In primary adrenal insufficiency, the adrenal cortex cannot produce adequate cortisol despite increased pituitary stimulation.

Loss of cortisol negative feedback causes CRH and ACTH concentrations to rise. Markedly elevated ACTH can contribute to hyperpigmentation.

Secondary Adrenal Insufficiency

Secondary adrenal insufficiency results from inadequate pituitary ACTH secretion. Reduced ACTH leads to deficient cortisol production and loss of trophic stimulation to the zona fasciculata and zona reticularis.

Unlike primary adrenal failure, ACTH is not elevated and hyperpigmentation is not expected from ACTH excess.

Tertiary Adrenal Insufficiency

Tertiary adrenal insufficiency results from deficient hypothalamic stimulation of pituitary ACTH secretion, often involving reduced CRH drive.

Suppression of the HPA axis after prolonged exposure to exogenous glucocorticoids is an important mechanism of central adrenal insufficiency.

Primary Versus Central Adrenal Insufficiency

Feature	Primary Adrenal Insufficiency	Central Adrenal Insufficiency
Primary defect	Adrenal cortex	Pituitary or hypothalamus
Cortisol	Reduced	Reduced
ACTH	Elevated	Low or inappropriately normal
Aldosterone	May be reduced	Usually relatively preserved
Hyperpigmentation	Can occur	Generally absent

Addison's Disease

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

Reduced cortisol removes negative feedback from the hypothalamus and pituitary, leading to increased CRH and ACTH secretion.

Cushing Disease

Cushing disease specifically refers to hypercortisolism caused by an ACTH-secreting pituitary corticotroph adenoma.

Excess ACTH stimulates bilateral adrenal cortisol production and can cause hyperplasia of ACTH-responsive cortical tissue.

Cushing Syndrome

Cushing syndrome is the broader clinical state produced by chronic excessive glucocorticoid activity, regardless of its cause.

ACTH measurements help distinguish ACTH-dependent from ACTH-independent causes of endogenous hypercortisolism.

ACTH-Dependent Cushing Syndrome

ACTH-dependent hypercortisolism results from excessive ACTH stimulation of the adrenal cortex. Causes include pituitary ACTH secretion and ectopic ACTH production.

The adrenal glands remain under excessive trophic and steroidogenic stimulation in these conditions.

ACTH-Independent Cushing Syndrome

When excessive cortisol is produced autonomously by an adrenal lesion, high cortisol suppresses hypothalamic CRH and pituitary ACTH through negative feedback.

ACTH concentrations are therefore typically reduced in ACTH-independent adrenal hypercortisolism.

Ectopic ACTH Production

Some nonpituitary tumors can produce ectopic ACTH. The resulting ACTH excess stimulates adrenal cortisol secretion independently of normal pituitary regulation.

High cortisol still suppresses pituitary ACTH production, but it cannot necessarily suppress autonomous ACTH secretion by the ectopic tumor.

Nelson Syndrome

After bilateral adrenalectomy for severe ACTH-dependent disease, removal of cortisol feedback can permit marked progression of an ACTH-producing pituitary corticotroph tumor in some patients.

This condition is associated with very high ACTH concentrations and prominent hyperpigmentation.

ACTH Stimulation Test

The ACTH stimulation test evaluates the ability of the adrenal cortex to produce cortisol in response to ACTH receptor stimulation.

A synthetic ACTH-related peptide is administered, and cortisol concentrations are measured before and after stimulation.

Cosyntropin

Cosyntropin is a synthetic peptide corresponding to the biologically active N-terminal portion of ACTH.

It activates adrenal ACTH receptors and is widely used in dynamic assessment of adrenal cortical reserve.

CRH Stimulation Testing

Administration of CRH can stimulate pituitary ACTH secretion and has been used in selected diagnostic evaluations of ACTH-dependent hypercortisolism.

Responses must be interpreted together with other biochemical, imaging, and clinical findings.

Dexamethasone Suppression

Dexamethasone is a potent synthetic glucocorticoid that can suppress hypothalamic CRH and pituitary ACTH through glucocorticoid negative feedback.

Dexamethasone suppression testing uses this physiological principle in the evaluation of hypercortisolism.

Exogenous Glucocorticoids

Prolonged treatment with exogenous glucocorticoids can suppress CRH and ACTH secretion through negative feedback.

Persistent ACTH suppression can cause atrophy of the zona fasciculata and zona reticularis, reducing endogenous cortisol production.

HPA Axis Recovery

After prolonged glucocorticoid-induced suppression, recovery of the HPA axis may require time because hypothalamic, pituitary, and adrenal components must regain normal activity.

This is one reason prolonged systemic glucocorticoid therapy may require gradual dose reduction rather than abrupt discontinuation in appropriate clinical circumstances.

ACTH and Congenital Adrenal Hyperplasia

In several forms of congenital adrenal hyperplasia, impaired cortisol synthesis reduces negative feedback on the hypothalamus and pituitary.

ACTH consequently increases and chronically stimulates the adrenal cortex, contributing to adrenal hyperplasia and increased production of steroid precursors proximal to the enzymatic block.

ACTH and Adrenal Size

Chronic changes in ACTH influence adrenal cortical morphology. Persistent ACTH excess can produce hyperplasia of responsive cortical zones.

Conversely, prolonged suppression of ACTH can cause atrophy of the zona fasciculata and zona reticularis.

ACTH Versus CRH

Feature	ACTH	CRH
Primary source	Anterior pituitary corticotrophs	Hypothalamic neurons
Primary target	Adrenal cortex	Anterior pituitary corticotrophs
Primary circulation	Systemic circulation	Hypophyseal portal circulation
Major effect	Stimulates cortisol synthesis	Stimulates ACTH secretion

ACTH Versus Cortisol

Feature	ACTH	Cortisol
Primary source	Anterior pituitary	Adrenal cortex
Hormone class	Peptide	Steroid
Primary target within HPA axis	Adrenal cortex	Hypothalamus and pituitary for feedback
Major role	Stimulates adrenal steroidogenesis	Produces systemic glucocorticoid effects and negative feedback

ACTH Versus Aldosterone Regulation

Feature	Cortisol	Aldosterone
Major cortical zone	Zona fasciculata	Zona glomerulosa
Major pituitary dependence	Strong ACTH dependence	Limited ACTH dependence
Principal regulator	ACTH	Angiotensin II and potassium
Major endocrine role	Glucocorticoid activity	Mineralocorticoid activity

ACTH Versus TSH

Feature	ACTH	TSH
Pituitary cell	Corticotroph	Thyrotroph
Primary peripheral gland	Adrenal cortex	Thyroid gland
Major hypothalamic regulator	CRH	TRH
Major peripheral feedback hormone	Cortisol	T3 and T4

ACTH Versus Growth Hormone

Feature	ACTH	Growth Hormone
Pituitary cell	Corticotroph	Somatotroph
Primary hypothalamic regulator	CRH	GHRH and somatostatin
Major endocrine target	Adrenal cortex	Multiple tissues and liver
Major downstream hormone	Cortisol	IGF-1

Anterior Pituitary Hormones

Hormone	Major Cell Type	Major Target
ACTH	Corticotroph	Adrenal cortex
TSH	Thyrotroph	Thyroid gland
GH	Somatotroph	Multiple tissues and liver
Prolactin	Lactotroph	Mammary gland
LH	Gonadotroph	Gonads
FSH	Gonadotroph	Gonads

Key Features of ACTH

Feature	Key Point
Full name	Adrenocorticotropic hormone
Alternative name	Corticotropin
Hormone class	Peptide hormone
Length	39 amino acids
Precursor	Proopiomelanocortin
Source	Anterior pituitary corticotrophs
Major hypothalamic regulator	CRH
Receptor	Melanocortin 2 receptor
Principal target	Adrenal cortex
Principal cortical zone	Zona fasciculata
Major hormone stimulated	Cortisol
Additional cortical target	Zona reticularis
Major feedback hormone	Cortisol
Regulatory axis	Hypothalamic-pituitary-adrenal axis
Secretory pattern	Pulsatile and circadian

Anatomical and Physiological Importance

ACTH provides the critical endocrine connection between the anterior pituitary and adrenal cortex. Hypothalamic CRH neurons first release CRH into the capillaries of the median eminence. The hypothalamo-hypophyseal portal circulation transports CRH to anterior pituitary corticotrophs, where it stimulates POMC synthesis and ACTH secretion.

ACTH then leaves the pituitary through the systemic circulation and reaches the adrenal glands. Within the adrenal cortex, it binds MC2R receptors, particularly on cells of the zona fasciculata and zona reticularis. Activation of cAMP-dependent signaling rapidly increases steroidogenesis and promotes cortisol and adrenal androgen production.

ACTH also maintains the structure and functional capacity of its target cortical zones. Chronic ACTH excess can cause adrenal cortical hyperplasia, while prolonged ACTH deficiency can lead to atrophy of the zona fasciculata and zona reticularis. The relative independence of the zona glomerulosa from ACTH explains why aldosterone secretion may remain comparatively preserved in central adrenal insufficiency.

The ACTH-cortisol system is regulated by both circadian and stress-related signals. ACTH secretion normally varies throughout the day and occurs in pulses, producing corresponding fluctuations in cortisol. During physiological stress, hypothalamic stimulation can increase rapidly, allowing increased ACTH and cortisol secretion to support metabolic, cardiovascular, and immune adaptations.

Cortisol closes the regulatory loop by providing negative feedback to the anterior pituitary and hypothalamus. This relationship explains many characteristic endocrine patterns seen in adrenal and pituitary disorders. Primary adrenal failure produces low cortisol with increased ACTH, while pituitary ACTH deficiency produces low cortisol with low or inappropriately normal ACTH. Autonomous adrenal cortisol excess suppresses ACTH, whereas an ACTH-secreting pituitary tumor can produce ACTH-dependent hypercortisolism.

Through its origin in anterior pituitary corticotrophs, derivation from POMC, stimulation by hypothalamic CRH, action on the adrenal cortex, trophic effects on cortical tissue, and regulation by cortisol feedback, ACTH forms the central pituitary component of the HPA axis.