ACTH (Adrenocorticotropic Hormone): Peptide Profile

Adrenocorticotropic hormone—ACTH for short—is one of the body's master stress regulators. It doesn't show up in wellness marketing or longevity forums. It's not found in compounded peptide vials. But without it, your adrenal glands can't make cortisol, and you enter a life-threatening metabolic crisis within days.

ACTH is a 39-amino-acid peptide produced in the anterior pituitary gland. When stress signals arrive from the hypothalamus, pituitary cells cleave a precursor protein called proopiomelanocortin (POMC) into multiple bioactive fragments. ACTH is one of them. It travels through the bloodstream to the adrenal cortex, binds to melanocortin-2 receptors (MC2R), and flips on the molecular switches that produce cortisol—the hormone that helps you survive stress, infection, injury, and blood sugar crashes.

ACTH has been FDA-approved as a drug since 1952. Today, pharmaceutical ACTH appears in two forms: repository corticotropin injection (Acthar Gel) for treating autoimmune and inflammatory conditions, and cosyntropin (Cortrosyn) for diagnostic testing of adrenal function. Both products remain clinically relevant, particularly for conditions resistant to standard therapies.

This profile explains what ACTH is, how it works within the hypothalamic-pituitary-adrenal (HPA) axis, where it's used clinically, what the research shows, and what you need to know about its safety and legal status.

Quick Facts
What Is ACTH?
How ACTH Works: Mechanisms of Action
Clinical Uses of ACTH
ACTH in Research
Safety and Side Effects
Legal Status and Availability
Frequently Asked Questions
The Bottom Line

Quick Facts

Attribute	Details
Full Name	Adrenocorticotropic Hormone (Corticotropin)
Peptide Type	Pituitary hormone
Amino Acid Length	39 amino acids
Molecular Weight	4,540 Da
Precursor Protein	Proopiomelanocortin (POMC)
Primary Receptor	Melanocortin-2 Receptor (MC2R)
Primary Function	Stimulates cortisol production in the adrenal cortex
FDA-Approved Drugs	Acthar Gel (repository corticotropin injection), Cortrosyn (cosyntropin, ACTH 1-24)
Approved Indications	Infantile spasms, multiple sclerosis relapses, nephrotic syndrome, rheumatic disorders, adrenal function testing

What Is ACTH?

ACTH is a 39-amino-acid polypeptide hormone produced and secreted by corticotroph cells in the anterior pituitary gland. Its primary job is to regulate cortisol production. Cortisol is the body's main glucocorticoid—a steroid hormone that regulates metabolism, immune function, blood pressure, and the stress response.

The POMC Precursor

ACTH doesn't start out as ACTH. It begins as part of a much larger precursor protein called proopiomelanocortin (POMC). POMC is a 241-amino-acid polyprotein that gets processed into multiple bioactive peptides depending on which tissue is doing the processing and which enzymes are present.

In the anterior pituitary, POMC is cleaved predominantly into ACTH, β-lipotropin (β-LPH), and a 16 kDa N-terminal fragment. In the hypothalamus and intermediate lobe of the pituitary, POMC undergoes more extensive processing. ACTH itself gets further cleaved into α-melanocyte-stimulating hormone (α-MSH) and corticotropin-like intermediate peptide (CLIP). Other POMC fragments include β-endorphin (an opioid peptide) and several melanocortins with roles in pigmentation and metabolism.

This means ACTH shares structural features with melanocortin peptides. The first 13 amino acids of ACTH, counting from the N-terminus, contain the core sequence that activates melanocortin receptors. That overlap explains some of ACTH's secondary effects beyond cortisol production.

ACTH Sequence

The human ACTH sequence is:

SYSMEHFRWGKPVGKKRRPVKVYPNGAEDESAEAFPLEF

The N-terminal 24 amino acids (ACTH 1-24) contain the full biological activity needed to stimulate adrenal steroidogenesis. That's why cosyntropin—the synthetic form used in diagnostic testing—is just the first 24 amino acids. The remaining C-terminal residues (25-39) contribute to receptor binding affinity and half-life but aren't required for activity.

Release and Regulation

ACTH release is controlled by the hypothalamus through corticotropin-releasing hormone (CRH). When the hypothalamus detects stress—physical, emotional, or metabolic—it secretes CRH into the hypophyseal portal blood. CRH travels to the anterior pituitary and binds to CRH receptors on corticotroph cells, triggering ACTH secretion.

ACTH then travels through the bloodstream to the adrenal cortex, where it binds to MC2R on the surface of zona fasciculata cells. This binding activates cortisol synthesis. Cortisol feeds back to both the hypothalamus and the pituitary to suppress further CRH and ACTH release. This negative feedback loop—called the hypothalamic-pituitary-adrenal (HPA) axis—keeps cortisol levels stable under normal conditions.

Dysregulation of the HPA axis shows up in multiple disease states. Too much ACTH leads to Cushing's disease. Too little ACTH (or adrenal destruction) causes adrenal insufficiency.

How ACTH Works: Mechanisms of Action

ACTH operates through multiple pathways. Its primary mechanism involves stimulating cortisol synthesis. But it also has direct immunomodulatory effects that don't depend on cortisol at all—these help explain why pharmaceutical ACTH works in some conditions where synthetic corticosteroids fail.

1. Steroidogenic Action via MC2R

ACTH binds to melanocortin-2 receptors (MC2R), which are seven-transmembrane G-protein-coupled receptors located on the surface of adrenocortical cells in the zona fasciculata. MC2R is unique among the five melanocortin receptors because it binds only ACTH—no other melanocortin peptides activate it.

MC2R requires a chaperone protein called melanocortin-2 receptor accessory protein (MRAP) to function. Without MRAP, MC2R doesn't reach the cell surface and remains nonfunctional. This dependence on MRAP makes MC2R pharmacologically distinct from other G-protein-coupled receptors.

When ACTH binds to MC2R, it activates a Gαs protein, which in turn activates adenylyl cyclase. This enzyme converts ATP into cyclic AMP (cAMP), raising intracellular cAMP levels. cAMP activates protein kinase A (PKA), a kinase that phosphorylates multiple downstream targets involved in steroidogenesis.

PKA's main targets include steroidogenic acute regulatory protein (StAR), which transports cholesterol from the outer to the inner mitochondrial membrane, and cytochrome P450 side-chain cleavage enzyme (P450scc), which catalyzes the first committed step in cortisol synthesis—the conversion of cholesterol to pregnenolone. ACTH also upregulates the expression of enzymes involved in later steps of cortisol biosynthesis, including 11β-hydroxylase.

In short, ACTH turns on the machinery that takes cholesterol and converts it into cortisol. This happens within minutes for acute cortisol release and hours for sustained synthesis. Chronic ACTH elevation also promotes adrenal growth—repeated stimulation causes hypertrophy and hyperplasia of the zona fasciculata.

2. Immunomodulatory Action via Other Melanocortin Receptors

Repository corticotropin injection (Acthar Gel) activates all five melanocortin receptors (MC1R through MC5R), not just MC2R. This is where things get interesting. MC1R, MC3R, and MC5R are expressed on immune cells—macrophages, B lymphocytes, and T lymphocytes. Activation of these receptors produces direct anti-inflammatory and immunomodulatory effects independent of cortisol production.

Studies have shown that melanocortin receptor agonists reduce pro-inflammatory cytokine production (TNF-α, IL-6, IL-1β), suppress macrophage activation, shift immune responses away from Th1 and Th17 profiles, and promote regulatory T cell activity. These effects help explain why Acthar Gel works in some autoimmune conditions even when patients have previously failed corticosteroid therapy.

The therapeutic mechanisms of ACTH were historically attributed entirely to corticotropic actions, but recent research has clarified that direct anti-inflammatory effects and immunomodulatory activity acting through melanocortin pathways play an important role.

3. Effects on Pigmentation

Because ACTH shares sequence homology with α-MSH, it can weakly activate MC1R, the melanocortin receptor expressed in skin melanocytes. This is why chronically elevated ACTH levels cause hyperpigmentation—a classic clinical sign of primary adrenal insufficiency (Addison's disease).

In Addison's disease, the adrenal glands fail to produce cortisol. Without cortisol's negative feedback, ACTH levels rise dramatically. High ACTH stimulates melanocytes, darkening the skin and mucous membranes. This pigmentation is most noticeable in areas exposed to friction or sun—knuckles, elbows, knees, and the inside of the mouth.

Clinical Uses of ACTH

ACTH has been used therapeutically for more than 70 years. Today, two main pharmaceutical forms are FDA-approved: repository corticotropin injection (Acthar Gel) for treating specific autoimmune and inflammatory conditions, and cosyntropin (Cortrosyn) for diagnostic testing.

1. Infantile Spasms (West Syndrome)

Acthar Gel is FDA-approved as monotherapy for the treatment of infantile spasms in infants and children under 2 years of age. Infantile spasms are a severe form of epilepsy characterized by clusters of sudden, jerking movements. The condition often appears between 3 and 12 months of age and is associated with developmental delays and poor neurological outcomes if left untreated.

The mechanism by which ACTH stops infantile spasms isn't fully understood. It's likely multifactorial, involving both steroidogenic effects (cortisol suppresses neuronal excitability) and direct neuronal effects mediated by melanocortin receptors in the brain. MC4R is expressed in regions involved in seizure generation and modulation.

2. Multiple Sclerosis Relapses

Acthar Gel is FDA-approved for the treatment of acute exacerbations of multiple sclerosis (MS) in adults. MS is an autoimmune disease where the immune system attacks myelin sheaths in the central nervous system, causing inflammation, demyelination, and neurological dysfunction.

Treatment typically involves Acthar Gel injections once daily for two to three weeks to treat a severe exacerbation. Clinical trials have demonstrated similar efficacies for ACTH and intravenous methylprednisolone in MS relapses. However, Acthar Gel may be an option for patients who can't tolerate high-dose IV steroids, don't respond adequately to corticosteroid treatment, or lack venous access.

Recent data show that patients experiencing an acute MS exacerbation who previously had suboptimal response to or were unable to tolerate methylprednisolone treatment showed positive clinical outcomes with fewer adverse events with ACTH gel.

The therapeutic benefit likely comes from a combination of cortisol-mediated immunosuppression and direct melanocortin receptor-mediated effects on immune cells and neural tissue. ACTH and melanocortins regulate anti-inflammatory and immunomodulatory functions involving lymphocytes, macrophages, and reduction of pro-inflammatory cytokines.

3. Nephrotic Syndrome and Glomerular Diseases

ACTH has a long history in treating nephrotic syndrome—a kidney disorder characterized by heavy proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Acthar Gel has re-emerged as a potentially effective therapy for nephrotic syndrome, particularly for patients who have failed more conventional immunosuppressive therapies.

ACTH shows benefits in proteinuria reduction across all etiologies of nephrotic syndrome, with its most substantial impact seen in membranous nephropathy (MN). In one study of patients with idiopathic membranous nephropathy, 27% achieved complete remission and 55% achieved partial remission despite having previously failed an average of 2.4 therapies.

Across five long-term ACTH studies in pediatric nephrotic syndrome, proteinuria response was shown in 71% of patients and was sustained up to 4.7 years following treatment.

The mechanism likely involves both steroidogenic and direct effects on podocytes (the kidney cells responsible for filtration barrier integrity) through melanocortin receptors. MC1R is expressed on podocytes, and melanocortin agonists have been shown to stabilize the actin cytoskeleton and reduce proteinuria in animal models.

4. Rheumatic and Autoimmune Disorders

Acthar Gel is FDA-approved for several rheumatic disorders, including rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, and dermatomyositis/polymyositis. The drug is typically reserved for patients who haven't responded to conventional disease-modifying antirheumatic drugs (DMARDs) or biologic agents.

Studies have examined repository corticotropin injection in patients with rheumatoid arthritis resistant to biologic therapies, showing improvements in disease activity scores and functional outcomes. Repository corticotropin injection has demonstrated steroid-sparing properties due to its unique anti-inflammatory and immunomodulatory mechanism of action through activation of melanocortin receptors in various cell types.

For autoimmune conditions, the immunomodulatory effects via MC1R, MC3R, and MC5R on lymphocytes and macrophages likely contribute as much as the cortisol-mediated effects.

5. Diagnostic Testing: ACTH Stimulation Test

Cosyntropin (Cortrosyn) is a synthetic ACTH 1-24 analog used in the ACTH stimulation test, the main medical test to diagnose adrenal insufficiency. The test assesses how well the adrenal glands respond to ACTH.

The procedure is straightforward:

A baseline cortisol level is measured
250 mcg of cosyntropin is administered intramuscularly or intravenously
Cortisol levels are measured again at 30 and 60 minutes post-injection

In healthy individuals, the cortisol level should rise to at least 18–20 μg/dL within 60 minutes. A blunted or absent response indicates adrenal insufficiency. A low baseline ACTH with a poor response suggests secondary or tertiary adrenal insufficiency (pituitary or hypothalamic causes). A high baseline ACTH with a poor response suggests primary adrenal insufficiency (Addison's disease, where the adrenal glands themselves are damaged).

The ACTH stimulation test is also used to diagnose non-classic congenital adrenal hyperplasia (NCCAH) by measuring 17-hydroxyprogesterone levels after stimulation.

Other FDA-Approved Indications

The FDA label for Acthar Gel includes additional indications such as allergic states, dermatologic diseases, ophthalmologic diseases, respiratory diseases (including pulmonary sarcoidosis), and edematous states. However, these indications are rarely used in modern practice given the availability of more specific and cost-effective therapies.

ACTH in Research

Beyond approved uses, ACTH and melanocortin receptor agonists are being studied in multiple research contexts.

HPA Axis Dysregulation

ACTH plays a central role in stress physiology. Dynamics of ACTH and cortisol secretion are critical to understanding diseases ranging from depression and PTSD to metabolic syndrome. Dysregulated HPA axis function—either overactivity or underactivity—is implicated in psychiatric disorders, chronic pain syndromes, and inflammatory diseases.

Research is exploring how chronic stress, circadian disruption, and early-life adversity reprogram HPA axis set points. The field is also investigating whether melanocortin receptor modulators could be used to restore normal HPA axis dynamics in patients with stress-related disorders.

Melanocortin System and Metabolism

The melanocortin system extends far beyond ACTH. α-MSH and other POMC-derived peptides act on MC3R and MC4R in the hypothalamus to regulate appetite, energy expenditure, and body weight. MC4R agonists are being developed as obesity treatments—setmelanotide, an MC4R agonist, is FDA-approved for rare genetic obesity disorders.

ACTH itself has limited effects on these pathways at physiological concentrations. But understanding how POMC processing is regulated in different tissues could lead to new therapies for metabolic disease.

Neuroprotection and Neuromodulation

Some research suggests that melanocortin receptor activation has neuroprotective effects. MC4R is expressed in multiple brain regions and modulates synaptic plasticity, neuroinflammation, and neuronal survival. Studies in animal models have shown that melanocortin agonists reduce infarct size after stroke and improve outcomes in models of traumatic brain injury.

Whether these effects translate to humans remains unclear. But the fact that ACTH works in infantile spasms—a condition where cortisol alone often fails—suggests that melanocortin signaling in the brain may have therapeutic potential.

Immune Regulation

Melanocortin receptors on immune cells are being explored as targets for treating inflammatory and autoimmune diseases. Selective MC1R or MC3R agonists could provide anti-inflammatory effects without the broad immunosuppression and metabolic side effects of corticosteroids.

This is an active area of drug development. Several companies are working on synthetic melanocortin analogs with improved receptor selectivity and pharmacokinetic properties.

Safety and Side Effects

ACTH stimulates cortisol production. That means its side effect profile overlaps significantly with corticosteroids—but with some important differences.

Common Side Effects

Short-term ACTH use (days to weeks) is generally well tolerated. Common side effects include:

Increased appetite and weight gain
Fluid retention and edema
Irritability and mood changes
Insomnia
Elevated blood pressure
Elevated blood glucose
Hypokalemia (low potassium) due to mineralocorticoid effects
Injection site reactions (pain, redness, swelling)

In infants treated for infantile spasms, potential side effects include irritability, increased appetite and weight gain, high blood pressure, low potassium in the blood, and high blood sugar, which typically resolve once ACTH is stopped.

Serious and Long-Term Risks

Prolonged ACTH exposure—especially at high doses—carries the same risks as chronic corticosteroid use:

Immunosuppression and increased infection risk: ACTH can suppress the immune system, making it harder to fight infections
Cushing's syndrome: Features include weight gain, severe fatigue and muscle weakness, high blood pressure, depression, cognitive impairment, purplish skin striae, easy bruising, loss of libido, diabetes, hirsutism, acne, and menstrual disorders
Osteoporosis and fractures from calcium loss
Adrenal suppression: Chronic ACTH exposure suppresses endogenous CRH and ACTH secretion. If ACTH is stopped abruptly, the HPA axis may not recover quickly, leading to adrenal crisis
Metabolic syndrome: Persistent hypercortisolemia increases risk of hyperglycemia, hypertension, dyslipidemia, and cardiovascular disease

Hypersensitivity Reactions

Acthar Gel is derived from porcine pituitary glands. Patients with allergies to pork products should not use it. Rare cases of anaphylaxis and angioedema have been reported.

Contraindications

ACTH is contraindicated in patients with:

Active infections (especially systemic fungal infections)
Recent surgery
Peptic ulcer disease
Congestive heart failure
Uncontrolled hypertension
Sensitivity to porcine proteins (for Acthar Gel)

Monitoring

Patients on ACTH therapy require regular monitoring:

Blood pressure and electrolytes (sodium, potassium)
Blood glucose (especially in diabetics)
Bone density (for long-term use)
Signs of infection
Mental health status

Legal Status and Availability

Prescription-Only Medication

ACTH is not available over the counter. Both Acthar Gel and cosyntropin are prescription-only drugs requiring a licensed healthcare provider's authorization.

FDA-Approved Drugs

Acthar Gel (repository corticotropin injection): Approved since 1952. Manufactured by Mallinckrodt Pharmaceuticals. Available as a repository (long-acting) injectable gel in vials containing 5 mL with 80 units per mL.
Cortrosyn (cosyntropin): Approved for diagnostic use. Available as a lyophilized powder for injection (250 mcg per vial).

Cost and Access

Acthar Gel is one of the most expensive drugs in the United States, with wholesale acquisition costs exceeding $38,000 per vial. This has led to significant controversy, access barriers, and scrutiny by insurance companies and payers. Most insurers require prior authorization and evidence of failure of less expensive therapies before approving Acthar Gel.

Cosyntropin is far less expensive and widely available for diagnostic testing.

Compounded Peptides

ACTH is not available through compounding pharmacies. The FDA does not permit compounding of complex peptide hormones like ACTH, particularly given the existence of FDA-approved products. Any seller offering "compounded ACTH" is operating illegally.

Off-Label Use

Like any prescription medication, ACTH can be prescribed off-label by physicians for conditions not listed in the FDA-approved labeling. However, given the cost, side effect profile, and availability of alternative therapies, off-label use is rare.

International Status

ACTH formulations are available in many countries under various brand names. Regulations vary by jurisdiction, but ACTH is universally classified as a prescription medication.

Frequently Asked Questions

Is ACTH the same as cortisol?

No. ACTH is a pituitary hormone that stimulates cortisol production. Cortisol is a steroid hormone made by the adrenal glands. ACTH tells the adrenals to make cortisol, but they are chemically and functionally different molecules.

Can I buy ACTH online or from a peptide supplier?

No. Legitimate ACTH products are prescription-only and manufactured by licensed pharmaceutical companies. Any website selling "ACTH peptide" without a prescription is operating illegally. These products are likely counterfeit, mislabeled, or contaminated. Do not use them.

What is the difference between Acthar Gel and cosyntropin?

Acthar Gel is a naturally derived mixture of ACTH and other pituitary peptides with a repository (long-acting) formulation used for therapeutic purposes. Cosyntropin is a synthetic version of the first 24 amino acids of ACTH, used for short diagnostic tests. Acthar Gel is given for days to weeks. Cosyntropin is given once during a single diagnostic procedure.

Why is Acthar Gel so expensive?

The high cost is due to a combination of factors: limited competition (Mallinckrodt holds the only FDA approval), complex manufacturing from animal tissue, small patient populations, and pricing strategies by the manufacturer. The drug's cost has been the subject of multiple Congressional hearings and legal challenges.

Can ACTH help with weight loss?

No. ACTH stimulates cortisol production, and chronic cortisol elevation promotes weight gain, particularly abdominal fat accumulation. While some POMC-derived peptides like α-MSH reduce appetite through MC4R, ACTH itself doesn't have this effect at therapeutic doses.

Does ACTH improve athletic performance?

ACTH is prohibited by the World Anti-Doping Agency (WADA) because it stimulates cortisol production, which can have anabolic and anti-inflammatory effects in the short term. However, there is no evidence that ACTH improves performance in healthy individuals, and chronic use causes muscle wasting, not muscle growth. Athletes should not use ACTH.

What happens if I have too little ACTH?

Low ACTH levels lead to secondary or tertiary adrenal insufficiency. Without ACTH stimulation, the adrenal glands don't produce enough cortisol. Symptoms include severe fatigue, weakness, low blood pressure, hypoglycemia, nausea, and confusion. This is a serious condition requiring cortisol replacement therapy.

What happens if I have too much ACTH?

Excessive ACTH production—usually from a pituitary tumor (Cushing's disease) or an ectopic ACTH-secreting tumor—leads to Cushing's syndrome. Features include weight gain, moon face, buffalo hump, purple striae, muscle weakness, hypertension, diabetes, osteoporosis, and psychiatric symptoms. Endogenous Cushing's syndrome shortens life expectancy due to infections, thromboembolic events, and cardiovascular disease. Treatment involves removing the source of ACTH excess.

Is ACTH used for anti-aging or longevity?

No. ACTH is not an anti-aging peptide. Chronic ACTH elevation accelerates aging-related processes by promoting cortisol excess, leading to muscle loss, bone loss, metabolic dysfunction, immune suppression, and increased cardiovascular risk. There is no credible rationale for using ACTH in anti-aging contexts.

The Bottom Line

ACTH is a 39-amino-acid pituitary hormone that plays a critical role in cortisol production and stress response. It's not a lifestyle peptide. It's not sold by compounding pharmacies. It's a prescription medication with FDA-approved indications for serious medical conditions: infantile spasms, multiple sclerosis relapses, nephrotic syndrome, rheumatic disorders, and diagnostic testing of adrenal function.

The two pharmaceutical forms—Acthar Gel and cosyntropin—are distinct products with different uses. Acthar Gel is a repository injection used therapeutically in patients who have failed other treatments. It works through a combination of steroidogenic effects (raising cortisol) and direct immunomodulatory effects mediated by melanocortin receptors on immune cells. Cosyntropin is a synthetic diagnostic agent used in a one-time test to assess adrenal responsiveness.

ACTH has a well-characterized safety profile. Short-term use is generally safe. Long-term use carries the same risks as chronic corticosteroid therapy: immunosuppression, metabolic dysfunction, bone loss, and adrenal suppression. Monitoring and careful patient selection are essential.

From a research perspective, ACTH and the broader melanocortin system remain active areas of investigation. The discovery that melanocortin receptors on immune cells, neurons, and metabolic tissues contribute to ACTH's therapeutic effects has opened new avenues for drug development. Selective melanocortin receptor agonists may offer the benefits of ACTH without the downsides of chronic cortisol elevation.

If you're reading this because you saw ACTH mentioned in a peptide forum, understand this: pharmaceutical ACTH is not something you experiment with. It's not available without a prescription. It doesn't belong in the same category as research peptides used off-label for wellness or performance. It's a potent hormonal drug with serious risks and a narrow set of legitimate medical uses. If you have a condition that might benefit from ACTH therapy, that's a conversation to have with an endocrinologist or specialist—not a decision to make based on online peptide vendor marketing.

ACTH is foundational to human physiology. It keeps your adrenal glands functioning and your cortisol levels stable. When it's used appropriately in patients who need it, it can be life-changing. But it's not a biohack. It's medicine.

Disclaimer

This article is for educational purposes only and is not intended as medical advice. ACTH is a prescription medication that should only be used under the supervision of a licensed healthcare provider. Do not attempt to self-administer ACTH or any prescription medication without proper medical oversight. If you believe you may benefit from ACTH therapy, consult a qualified physician. PeptideJournal.org does not sell peptides or medications and has no financial interest in any peptide vendors or pharmaceutical companies.

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