Mechanism of Action
MC2R and Adrenal Steroidogenesis
ACTH binds MC2R (a Gs-coupled GPCR expressed exclusively in the adrenal cortex) with high specificity. MC2R activation elevates cAMP, activating PKA and stimulating cholesterol transport to mitochondria via StAR protein. This is the rate-limiting step of cortisol (and other glucocorticoid) synthesis. ACTH also maintains adrenocortical cell size and number via trophic effects.
Extra-Adrenal Effects
ACTH binds MC1R, MC3R, MC4R, and MC5R (the other alpha-msh/" class="wiki-internal-link">melanocortin receptors) at higher concentrations. MC1R activation on melanocytes stimulates melanin production (explaining hyperpigmentation in high-ACTH states like Addison's disease). MC4R activation suppresses appetite. The anti-inflammatory effects of H.P. Acthar Gel may involve melanocortin receptor activation on immune cells independent of the adrenal axis.
Research Summary
Adrenal Function Diagnosis (Cosyntropin Test)
Standard of CareThe cosyntropin (ACTH 1-24) stimulation test is the gold standard for diagnosing adrenal insufficiency. A peak cortisol response < 18-20 ug/dL at 30-60 min after 250 ug IV cosyntropin indicates adrenal insufficiency. Low-dose cosyntropin (1 ug) may improve sensitivity for detecting partial adrenal insufficiency. This test is performed millions of times annually worldwide.
Infantile Spasms
Clinical EvidenceH.P. Acthar Gel (repository corticotropin injection) is FDA-approved and the most effective treatment for infantile spasms (West syndrome) in infants. Response rates of 50-90% for spasm cessation have been reported. The mechanism may involve direct melanocortin receptor effects on developing brain circuits beyond adrenal steroidogenesis.
Athletic Performance
WADA ProhibitedACTH is prohibited by WADA in-competition due to its ability to elevate endogenous cortisol levels acutely, which can have anti-inflammatory and performance-relevant effects. ACTH also has potential for abuse in stress-response optimization and post-competition recovery contexts.
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Research Protocols
| Goal | Dose | Frequency | Route |
|---|---|---|---|
| Standard cosyntropin stimulation test | 250 ug IV or IM | Single dose | Intravenous or intramuscular |
| Low-dose cosyntropin test | 1 ug IV | Single dose | Intravenous |
| Infantile spasms (H.P. Acthar Gel) | 150 IU/m2/day IM divided twice daily | Daily x 2 weeks then taper | Intramuscular |
ACTH is WADA prohibited in competition. Cosyntropin use should be only for legitimate diagnostic purposes. Clinical use requires physician oversight.
Interactions
Safety Profile
Cosyntropin single-dose diagnostic use has an excellent safety profile with rare anaphylaxis risk. Chronic ACTH / H.P. Acthar Gel use causes all the adverse effects of glucocorticoid excess: Cushingoid features, glucose intolerance, hypertension, osteoporosis, and adrenocortical atrophy on cessation. WADA prohibited in competition. Not for athletic performance enhancement.
References
- [1]Bornstein SR, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(2):364-389.
- [2]Lux AL, et al. The United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin. Lancet Neurol. 2004;3(8):461-468.
- [3]Aguilera G. HPA axis responsiveness to stress: implications for healthy aging. Exp Gerontol. 2011;46(2-3):90-95.