Corticotropin — Infantile spasms, multiple sclerosis flares

What this is

Corticotropin, also known as adrenocorticotropic hormone (ACTH), is a 39-amino acid peptide hormone secreted by corticotroph cells of the anterior pituitary gland in response to corticotropin-releasing hormone (CRH) from the hypothalamus. It is the master regulator of glucocorticoid production: ACTH acts on melanocortin 2 receptors (MC2R) in the adrenal cortex to drive cortisol synthesis and secretion, and is an essential component of the hypothalamic-pituitary-adrenal (HPA) axis that governs the stress response, circadian cortisol rhythm, immune modulation, and metabolic homeostasis. ACTH is derived from the large precursor proopiomelanocortin (POMC), which is proteolytically processed in the anterior pituitary to yield ACTH, β-lipotropin, and β-endorphin; POMC processing in the intermediate pituitary yields alpha-MSH, CLIP, and other fragments.

As a pharmaceutical agent, ACTH exists in two clinically distinct forms: (1) Repository corticotropin injection (H.P. Acthar Gel; purified porcine ACTH in gelatin vehicle for slow absorption) — an FDA-approved drug for multiple indications including infantile spasms (West syndrome), acute exacerbations of multiple sclerosis, rheumatic disorders, nephrotic syndrome, and ophthalmic and dermatological inflammatory conditions; and (2) Cosyntropin (Cortrosyn; synthetic ACTH 1–24 truncated analog) — FDA-approved exclusively as a diagnostic agent for evaluating adrenocortical insufficiency via the ACTH stimulation test.

> Note on stored sequence: The stored 39-amino acid sequence (SYSMEHFRWGKPVGKKRRPVKVYPDGAEDQLAEAFPLEF) corresponds to porcine ACTH 1–39, not the canonical human sequence. Porcine and human ACTH differ at three C-terminal positions: residue 25 (Asp in porcine vs Asn in human), residue 30 (Gln in porcine vs Glu in human), and residue 31 (Leu in porcine vs Ser in human). This porcine sequence matches the source material for H.P. Acthar Gel (repository corticotropin injection), which is purified from porcine pituitary. Cosyntropin (used for adrenal stimulation testing) is synthetic ACTH 1–24 and is identical between porcine and human for that fragment. The readme prose covers both the human endogenous ACTH biology and the porcine-derived H.P. Acthar Gel drug product; readers should note that the stored sequence is porcine.

History

ACTH was discovered in 1933 when its adrenal-stimulating activity was identified in pituitary extracts. The 39-aa sequence was determined by Li et al. in the 1950s. The first clinical use was as an anti-inflammatory and immunosuppressive agent in the early corticosteroid era, when both ACTH and newly discovered cortisone were used interchangeably for inflammatory and autoimmune conditions. As synthetic corticosteroids with defined pharmacokinetics became available (prednisone, methylprednisolone, dexamethasone), ACTH fell out of general use for most inflammatory indications.

ACTH regained a specific niche in infantile spasms (IS, also called West syndrome), a catastrophic epilepsy of infancy with the triad of spasms, hypsarrhythmia on EEG, and neurodevelopmental arrest or regression. Clinical experience from the 1950s–1970s established that high-dose ACTH therapy produced electroencephalographic and clinical responses in IS. The mechanism of ACTH's anticonvulsant effect in IS is debated and may be independent of adrenocortical stimulation: ACTH binds MC4R and other melanocortin receptors in the hypothalamus and limbic system, potentially suppressing CRH-mediated excitability and modulating neuroinflammatory circuits. The 2012 American Academy of Neurology/Child Neurology Society practice parameter established ACTH and vigabatrin as the two first-line treatments for IS, with ACTH offering the best evidence for short-term EEG response (particularly in non-tuberous sclerosis complex etiology).

H.P. Acthar Gel remains FDA-approved with a broad label inherited from its pre-1962 approval status (it was grandfathered under the Kefauver-Harris Amendment). Its contemporary commercial positioning is primarily in infantile spasms and multiple sclerosis acute flares. The drug's high cost (among the most expensive drugs in the US by list price) has made it commercially controversial. Repository corticotropin should not be conflated with pharmacological doses of synthetic corticosteroids: its mechanism in each indication may involve ACTH-mediated cortisol as well as direct MC receptor-mediated effects.

What it does

ACTH binds exclusively to the melanocortin 2 receptor (MC2R) among the five melanocortin receptors (MC1R–MC5R). MC2R specificity is unique: ACTH binds MC2R with picomolar affinity and does not activate MC1R, MC3R, MC4R, or MC5R at physiological concentrations. MC2R is expressed predominantly in the adrenal cortex (zona fasciculata and zona reticularis), where its activation drives the StAR (steroidogenic acute regulatory) protein-dependent import of cholesterol into mitochondria, the rate-limiting step in cortisol biosynthesis.

Adrenocortical signaling cascade: ACTH → MC2R → Gαs → adenylyl cyclase → cAMP ↑ → PKA activation → (1) rapid phase: StAR phosphorylation → mitochondrial cholesterol import → cortisol synthesis within minutes; (2) chronic phase: transcriptional upregulation of steroidogenic enzymes (CYP11A1, CYP17A1, CYP21A2, CYP11B1) and trophic effects on zona fasciculata cell mass. Sustained ACTH exposure increases adrenal gland weight and cortisol secretory capacity; ACTH deficiency causes adrenocortical atrophy.

Physiological cortisol regulation: Under normal physiology, ACTH exhibits a circadian pattern with peak secretion in the early morning hours (06:00–08:00), driving the morning cortisol peak. ACTH pulses occur approximately every 60–90 minutes. CRH from the hypothalamic paraventricular nucleus is the primary stimulus; cortisol exerts negative feedback at both hypothalamic and pituitary levels (long-loop feedback). Stress (physical, psychological, inflammatory) overrides the circadian pattern and drives acute ACTH and cortisol release via CRH, vasopressin, and sympathetic nervous system input.

Anti-inflammatory and immunomodulatory actions: Cortisol produced downstream of ACTH has broad anti-inflammatory effects: glucocorticoid receptor (GR) activation suppresses NF-κB and AP-1 transcription factors, reducing production of IL-1β, IL-6, TNF-α, and prostaglandins. In addition, ACTH itself may have direct immunomodulatory effects via MC receptors on immune cells, independent of cortisol — a pharmacological distinction relevant to the use of repository corticotropin vs. synthetic steroids.

ACTH stimulation test (Cosyntropin): Synthetic ACTH 1–24 (cosyntropin, 250 μg IV/IM) is used diagnostically to test adrenal responsiveness. A peak cortisol ≥18–20 μg/dL at 30 or 60 minutes post-injection is considered a normal response, ruling out primary adrenal insufficiency (Addison's disease). A blunted response indicates primary or secondary adrenocortical insufficiency.

Evidence

• ACTH receptor (MC2R) molecular pharmacology (Fridmanis et al. 2017, Frontiers in Endocrinology): This review provides a comprehensive molecular characterization of MC2R, the exclusive ACTH receptor. Key findings: MC2R is the most pharmacologically selective melanocortin receptor — it binds full-length ACTH (1–39) and the active core ACTH (1–24) but is unable to bind any MSH peptides. This selectivity maps to a unique binding pocket. The accessory protein MRAP (melanocortin receptor accessory protein 1) is essential for MC2R trafficking to the cell surface and functional ACTH signaling — MRAP deficiency causes familial glucocorticoid deficiency type 2 (ACTH resistance). MC2R expression is highest in adrenal zona fasciculata, with lower expression in adipose tissue, skin, and immune cells, potentially mediating some of the extra-adrenal effects attributed to ACTH. The picomolar ACTH sensitivity of MC2R contrasts with the nanomolar sensitivity of MC1R/MC3R/MC4R/MC5R for MSH peptides, making ACTH the only physiological ligand of MC2R at circulating concentrations. This receptor exclusivity is the molecular basis for the specificity of the ACTH stimulation test [10.3389/fendo.2017.00013].

• ACTH in infantile spasms (West syndrome): Multiple randomized and open-label trials have established ACTH (repository corticotropin or synthetic ACTH) as a first-line treatment for infantile spasms. The 2004 UKISS trial (O'Callaghan et al., Lancet) randomized 42 infants to ACTH or vigabatrin and showed spasm cessation in 73% with ACTH vs. 54% with vigabatrin at 14 days. The 2012 AAP/CNS practice parameter classified ACTH as a Level B recommendation (probably effective) with the best evidence for short-term EEG and clinical response. The mechanism may include both cortisol-mediated suppression of CRH (which is hypothesized to be epileptogenic in developing brains) and direct melanocortin receptor-mediated anticonvulsant actions on limbic circuits. High-dose ACTH (150 IU/m²/day) is typically used for IS; adverse effects include hypertension, irritability, cushingoid features, and infection risk during the short-course treatment.

• ACTH for MS acute flares: Repository corticotropin was a standard treatment for MS relapses before high-dose IV methylprednisolone (IVMP) became the standard. The 1970 Rose trial showed that ACTH reduced relapse severity and duration vs. placebo. Direct comparison of ACTH vs. IVMP shows equivalent clinical outcomes (time to relapse resolution, EDSS improvement), but IVMP is preferred due to cost, convenience, and predictability. H.P. Acthar Gel retains FDA approval for MS acute exacerbations, and some patients with steroid-refractory relapses may respond to repository corticotropin, possibly via the direct MC receptor-mediated mechanisms that differ from simple glucocorticoid replacement.

Myths and misconceptions

• "Corticotropin and corticosteroids are interchangeable" — ACTH (corticotropin) stimulates the adrenal gland to produce endogenous cortisol; synthetic corticosteroids (prednisone, methylprednisolone, dexamethasone) bypass the adrenal gland and act directly on glucocorticoid receptors. The clinical effects overlap but are not identical: ACTH produces predominantly cortisol (not aldosterone or androgens in significant amounts at therapeutic doses in most contexts), while synthetic steroids vary in glucocorticoid potency, mineralocorticoid activity, and receptor binding kinetics. ACTH also has direct effects via MC receptors on immune cells and the CNS that synthetic corticosteroids do not replicate.
• "The ACTH stimulation test uses the same drug as H.P. Acthar Gel" — Cosyntropin (used for the stimulation test) is synthetic ACTH 1–24 — a truncated 24-aa analog that retains full adrenocortical stimulating activity. H.P. Acthar Gel is purified porcine full-length ACTH (39 aa) in a gelatin depot. These are different pharmaceutical products with different molecular compositions, routes of administration (IV or IM bolus vs. SC depot), pharmacokinetics (rapid vs. sustained), and indications.
• "High ACTH always means Cushing's disease" — Elevated ACTH can arise from multiple causes: pituitary corticotropinoma (Cushing's disease, the most common ACTH-dependent Cushing's syndrome), ectopic ACTH syndrome (small cell lung cancer, carcinoid, thymoma), primary adrenal insufficiency (Addison's disease — high ACTH due to loss of cortisol negative feedback), CRH-secreting hypothalamic tumors, or physiological stress. The distinction between Cushing's disease and ectopic ACTH requires CRH stimulation testing, petrosal sinus sampling, and imaging — not ACTH level alone.

Common questions

What is the mechanism of ACTH in infantile spasms, beyond cortisol production? The anticonvulsant mechanism of ACTH in infantile spasms is incompletely understood but may involve multiple pathways. Cortisol suppresses CRH gene expression in the hypothalamus; elevated CRH in the developing hippocampus has been shown to produce seizures in rodent models and is hypothesized to contribute to IS pathophysiology. Additionally, ACTH directly activates MC4R receptors in limbic regions independent of adrenal cortisol, potentially exerting direct neuroprotective and anticonvulsant effects. Evidence supporting a cortisol-independent effect includes: (1) some patients with bilateral adrenalectomy (who cannot produce cortisol) still respond to ACTH for IS; (2) MC4R-deficient mice show altered seizure susceptibility; (3) synthetic ACTH analogs lacking adrenocortical activity have shown anticonvulsant properties in some preclinical models.

Why is H.P. Acthar Gel so expensive, and is the cost justified? H.P. Acthar Gel's list price has risen dramatically since Questcor (later Mallinckrodt) acquired the product in 2001, making it among the most expensive drugs in the US by annual treatment cost. The FDA-approved label is broad (grandfathered), but the primary contemporary use cases are infantile spasms and MS flares. For infantile spasms, randomized trial evidence supports short-course ACTH efficacy (comparable to vigabatrin), and the severe consequences of undertreated IS (intellectual disability, autism, refractory epilepsy) give short-course treatment high clinical value despite cost. For other indications, the evidence base is largely historical (pre-1962), and the pharmacoeconomic justification is less clear.

How does primary adrenal insufficiency differ from secondary adrenal insufficiency in terms of ACTH? In primary adrenal insufficiency (Addison's disease — adrenal gland itself is damaged or absent), the pituitary responds to low cortisol by secreting high ACTH — ACTH levels are markedly elevated. In secondary adrenal insufficiency (pituitary failure) or tertiary adrenal insufficiency (hypothalamic CRH deficiency, often from chronic exogenous glucocorticoid use), ACTH is low or inappropriately normal despite low cortisol. This distinction is clinically critical: primary AI requires both glucocorticoid and mineralocorticoid replacement; secondary/tertiary AI requires glucocorticoid replacement only (aldosterone is regulated by the renin-angiotensin system, not ACTH).

Clinical trials

ClinicalTrials.gov lists 40 registered studies for corticotropin as of 2026.

Key trials:

• NCT01367964 — Repository corticotropin injection (H.P. Acthar Gel) for infantile spasms (completed)
• NCT03465111 — Repository corticotropin for lupus nephritis (completed)
• NCT04461535 — H.P. Acthar Gel for relapsing MS (active)
• NCT02818660 — Repository corticotropin for amyotrophic lateral sclerosis (completed)
• NCT01600222 — Corticotropin gel for rheumatoid arthritis flares (completed)
• NCT01093157 — Acthar for nephrotic syndrome in diabetes (completed)

Related peptides

• Melanotan II — synthetic MC1R/MC4R agonist; derived from alpha-MSH (same POMC precursor family); tanning and sexual function; not MC2R selective
• Sermorelin — GHRH analog; anterior pituitary peptide hormone like ACTH but targets somatotrophs for GH release
• Leuprolide — GnRH agonist; another anterior pituitary regulatory peptide (gonadotroph axis)

References

• Fridmanis D, Roga A, Klovins J. ACTH Receptor (MC2R) Specificity: What Do We Know About Underlying Molecular Mechanisms? Front Endocrinol (Lausanne). 2017;8:13. [10.3389/fendo.2017.00013]