ActhEdit
Acth, or adrenocorticotropic hormone, is a small but pivotal peptide hormone produced by the anterior pituitary that drives the adrenal cortex to synthesize and release cortisol and related steroids. It sits at the core of the hypothalamic-pituitary-adrenal axis, receiving cues from every-day stress and circadian rhythms and translating them into a hormonal signal that helps the body respond to stress, regulate metabolism, and maintain immune balance. In medicine, ACTH preparations have long been used for diagnostic testing and for selected therapeutic indications, though their use is tempered by questions about cost, effectiveness, and appropriate clinical context.
ACTH is secreted from the corticotroph cells of the anterior pituitary as part of the larger proopiomelanocortin (POMC) precursor, and its production is tightly controlled by corticotropin-releasing hormone (CRH) from the hypothalamus. The release of ACTH stimulates the adrenal cortex to produce glucocorticoids, primarily cortisol, as well as androgens. Cortisol then exerts negative feedback on the hypothalamus and pituitary to modulate further ACTH secretion. This regulatory loop is essential for maintaining homeostasis in response to stress, fasting, infection, and energy balance. For readers exploring the biology of this system, see adrenocorticotropic hormone in the context of the hypothalamic-pituitary-adrenal axis and the role of the cortisol feedback loop.
Biology and physiology
Synthesis and regulation
ACTH derives from the processing of the POMC precursor in the cells of the anterior pituitary. The release of ACTH is driven by CRH from the hypothalamus and is modulated by physiological cues, including the circadian rhythm and stress. The pulsatile nature of ACTH secretion helps coordinate the timing of cortisol production. The entire axis operates as a refined endocrine system that integrates signals from the brain with endocrine outputs to influence metabolism, immune function, and cardiovascular stability. For an overview of related peptide hormones and melanocortin signaling, see proopiomelanocortin and melanocortin receptors.
Mechanism of action
ACTH acts primarily on the adrenal cortex by binding to the melanocortin 2 receptor (MC2R) on target cells, triggering the synthesis and release of glucocorticoids such as cortisol. This glucocorticoid response supports gluconeogenesis, vascular responsiveness, and anti-inflammatory effects in the short term, while long-term exposure requires careful monitoring due to potential adverse effects. In addition to its endocrine effects, ACTH signaling intersects with other pathways involved in energy balance, immune regulation, and tissue remodeling. For several of these pathways, see melanocortin 2 receptor and cortisol.
Forms and pharmacology
In clinical use, ACTH is administered as either the natural peptide (often through brand-name formulations) or as synthetic fragments such as cosyntropin, a 24–amino-acid peptide that mimics part of the ACTH molecule to stimulate the adrenal cortex in diagnostic testing. Cosyntropin is widely used for testing adrenal function because it activates cortisol production without the broader pharmacological effects of full-length ACTH. See cosyntropin and repository corticotropin for related formulations. For a historical and practical perspective on the products used to harness ACTH biology, see discussions of Acthar Gel and other ACTH preparations.
Clinical uses and testing
Diagnostic testing
The ACTH stimulation test is a standard tool for assessing adrenal reserve and the integrity of the hypothalamic-pituitary-adrenal axis. By administering ACTH or cosyntropin and measuring the adrenal cortisol response, clinicians can differentiate primary adrenal insufficiency from secondary causes linked to pituitary or hypothalamic dysfunction. See ACTH stimulation test for more on methodology and interpretation.
Therapeutic indications
ACTH preparations have a long history of use in selected inflammatory and autoimmune conditions. Historically, high-dose ACTH therapy has been employed for severe inflammatory states and certain dermatologic and neurologic conditions. In contemporary practice, glucocorticoids are often preferred due to cost, dosing flexibility, and a well-understood safety profile, but ACTH remains an option in specific scenarios, especially when patients have contraindications to steroids or when particular formulations are indicated. Therapeutic uses are influenced by clinical guidelines, evidence from trials, and considerations of patient access.
A notable specialty indication is infantile spasms (West syndrome), where ACTH has been used as a first-line therapy in many centers. Outcomes can vary and must be weighed against the risk of side effects and the availability of alternative treatments. See infantile spasms for more on this condition and its treatment history. In neurology and autoimmune diseases, ACTH has sometimes served as an alternative when other therapies are unsuitable; however, many guidelines now favor steroid regimens or other targeted therapies where evidence is strongest. See multiple sclerosis and psoriasis for discussions of conditions where ACTH has been used in the past or in limited contexts.
Formulations and access
Two major classes of ACTH products are in use: natural ACTH peptides and synthetic fragments like cosyntropin. Additionally, repository corticotropin injections (often marketed under names such as Acthar Gel) remain available in some markets, though they may be accompanied by high costs and complex reimbursement considerations. The interplay of pricing, insurance coverage, and patient access is a major policy focus in discussions about ACTH therapies, particularly for rare indications or long-term regimens. See Acthar Gel for product-specific discussions, and cosyntropin for a synthetic alternative used primarily in testing.
Safety, controversies, and policy considerations
Safety and adverse effects
Because ACTH therapies ultimately raise cortisol levels, they carry a risk profile similar to systemic glucocorticoids, including weight gain, hypertension, glucose intolerance, mood changes, osteoporosis, and infection risk with long-term use. The risk-benefit balance depends on the condition being treated, the dose, and the duration of therapy. Clinicians weigh these factors alongside comorbidities and patient preferences, aiming for the lowest effective dose and the shortest necessary duration.
Controversies and debates
In markets where ACTH therapies are expensive, debates center on cost, access, and value. Critics argue that extremely high prices can limit patient access and strain public and private payers, while proponents emphasize the importance of rewarding innovation and ensuring supply chains for rare indications. From a policy perspective, the emphasis is often on balancing patient access with incentives for pharmaceutical innovation, ensuring transparent pricing, and using evidence-based guidelines to minimize wasteful or off-label use. In the clinic, ongoing debates focus on selecting the most appropriate agent (full ACTH vs. cosyntropin vs. other therapies) and on adherence to evidence-based indications rather than marketing-driven practices. See cushing's syndrome and diabetes mellitus for conditions where glucocorticoid excess can compound existing health risks.
Economic and regulatory considerations
The economics of ACTH therapies are entwined with regulatory approval, manufacturing costs, and reimbursement structures. Some formulations have faced scrutiny over pricing and utilization in off-label contexts. A conservative, market-oriented approach tends to favor evidence-based prescribing, cost containment, and competition that can drive value for patients and payers alike, while maintaining access to essential therapies for those who stand to benefit most. See pharmaceutical pricing and healthcare policy for related topics.