ACTH: When to Order This Test

What ACTH Is and Why It Matters

Adrenocorticotropic hormone (ACTH) is a 39-amino-acid peptide released by corticotroph cells in the anterior pituitary gland. It travels through the bloodstream to the adrenal cortex, where it drives cortisol synthesis and secretion. Measuring ACTH alongside cortisol tells clinicians where along the hypothalamic-pituitary-adrenal (HPA) axis a problem originates.

The HPA Axis in Brief

The hypothalamus secretes corticotropin-releasing hormone (CRH), which stimulates the pituitary to release ACTH. ACTH then signals the adrenal glands to produce cortisol. Cortisol feeds back to suppress both CRH and ACTH in a negative-feedback loop [1]. A disruption at any level of this axis produces a characteristic ACTH-cortisol pattern that guides diagnosis.

Why a Standalone Cortisol Level Is Not Enough

A low morning cortisol tells you the adrenal glands are underperforming. It does not tell you whether the fault lies in the adrenal glands themselves (primary) or in the pituitary's failure to send the ACTH signal (secondary). The 2016 Endocrine Society Clinical Practice Guideline on adrenal insufficiency states that "simultaneous measurement of ACTH and cortisol is recommended to establish the etiology of adrenal insufficiency" [2]. Without ACTH, you are guessing at half the equation.

Normal ACTH Ranges and How to Interpret Them

Most commercial reference laboratories report a normal morning ACTH range of 10 to 60 pg/mL (2.2 to 13.2 pmol/L), though exact cut-offs vary by assay platform [3]. Values must always be interpreted alongside a simultaneous serum cortisol drawn from the same morning sample.

Interpreting ACTH-Cortisol Pairs

A paired result tells a specific clinical story:

| ACTH Level | Cortisol Level | Most Likely Interpretation | |---|---|---| | High (>60 pg/mL) | Low (<3 µg/dL) | Primary adrenal insufficiency (Addison disease) | | Low (<5 pg/mL) | Low (<3 µg/dL) | Secondary adrenal insufficiency (pituitary or hypothalamic) | | High (>60 pg/mL) | High (>20 µg/dL) | ACTH-dependent Cushing syndrome | | Low (<5 pg/mL) | High (>20 µg/dL) | ACTH-independent Cushing syndrome (adrenal tumor) |

Time-of-Day Effects on Results

ACTH follows a sharp circadian rhythm. Levels peak between 6:00 and 9:00 AM and fall to their nadir near midnight [4]. A sample drawn at 2:00 PM may be physiologically low and lead to a false impression of pituitary suppression. The Endocrine Society recommends an 8:00 AM (±1 hour) fasting blood draw as the standard timing for baseline ACTH measurement [2].

Clinical Scenarios That Warrant an ACTH Test

Ordering ACTH is not a screening reflex. It answers a targeted diagnostic question.

Suspected Adrenal Insufficiency

The most common reason to order ACTH is a patient presenting with fatigue, weight loss, hypotension, or hyperpigmentation alongside a low morning cortisol (<3 µg/dL) or an equivocal cortisol (3 to 15 µg/dL). In a study of 1,245 patients evaluated for adrenal insufficiency at a European endocrine referral center, paired ACTH-cortisol measurement correctly classified the etiology in 89% of confirmed cases before dynamic testing [5]. That one blood draw shortens the diagnostic path significantly.

Primary adrenal insufficiency (Addison disease) affects roughly 100 to 140 per million adults in Western populations [6]. Autoimmune adrenalitis accounts for 80% to 90% of cases in high-income countries [2]. The hallmark laboratory finding is a markedly elevated ACTH (often >200 pg/mL) paired with a cortisol below 3 µg/dL.

Secondary adrenal insufficiency is more common, driven largely by chronic exogenous glucocorticoid use. In these patients, the pituitary's ACTH output is suppressed. ACTH will be low or inappropriately normal alongside low cortisol.

Suspected Cushing Syndrome

When 24-hour urinary free cortisol, late-night salivary cortisol, or the 1-mg overnight dexamethasone suppression test confirms hypercortisolism, the next step is determining whether it is ACTH-dependent or ACTH-independent [7]. The 2008 Endocrine Society Clinical Practice Guideline on Cushing syndrome recommends measuring plasma ACTH on at least two separate mornings to make this distinction [7].

An ACTH level persistently above 20 pg/mL in the setting of confirmed hypercortisolism points toward an ACTH-dependent source, most commonly a pituitary corticotroph adenoma (Cushing disease). A suppressed ACTH (<5 pg/mL) with high cortisol directs imaging to the adrenal glands.

After Pituitary Surgery or Radiation

Patients who have undergone transsphenoidal surgery for a pituitary adenoma, pituitary radiation therapy, or treatment for any sellar/parasellar mass need serial ACTH and cortisol monitoring. Hypopituitarism can develop months or years after radiation. The 2021 Endocrine Society guideline on pituitary incidentalomas recommends annual HPA-axis assessment for at least five years following pituitary radiation [8].

Chronic Glucocorticoid Taper

Patients being weaned off long-term supraphysiologic glucocorticoids (prednisone, dexamethasone, high-dose inhaled corticosteroids) may have prolonged ACTH suppression. A morning ACTH and cortisol drawn after holding the glucocorticoid for 24 hours helps determine whether the HPA axis has recovered enough to continue tapering [2].

Congenital Adrenal Hyperplasia Follow-Up

In patients with known 21-hydroxylase deficiency, ACTH levels help assess whether glucocorticoid replacement is adequate. Persistently elevated ACTH suggests under-replacement and ongoing adrenal androgen excess [9].

How to Collect and Handle the Sample

ACTH is notoriously unstable. Improper collection is a leading cause of falsely low results.

Pre-Analytical Requirements

The sample must be drawn into a pre-chilled EDTA (lavender-top) tube, placed immediately on ice, and centrifuged in a refrigerated centrifuge within 30 minutes [3]. At room temperature, ACTH degrades by approximately 20% within one hour and up to 50% within two hours [10]. A specimen that sits on a phlebotomy tray in a warm clinic will yield a misleadingly low ACTH value.

Patient Preparation

Patients should fast overnight and arrive for an 8:00 AM draw. Stress, illness, and acute pain all raise ACTH. Strenuous exercise within 12 hours before the draw can raise ACTH above baseline. The clinician should document any acute stressors or recent glucocorticoid exposure on the requisition, because the lab cannot account for context it does not know about.

Assay Considerations

Modern two-site immunometric (sandwich) assays have largely replaced older radioimmunoassays for ACTH measurement. The newer platforms show improved specificity but can still produce "hook effect" artifacts at extremely high ACTH concentrations (>1,000 pg/mL) seen in ectopic ACTH syndrome [11]. If ectopic ACTH is suspected and the reported value seems incongruent with the clinical picture, request serial dilution from the laboratory.

Dynamic Tests That Pair With Baseline ACTH

A baseline ACTH draw often leads to a dynamic test to confirm the diagnosis.

The Cosyntropin (ACTH) Stimulation Test

Cosyntropin is synthetic ACTH(1-24). The standard-dose test administers 250 µg intravenously or intramuscularly, then measures cortisol at 30 and 60 minutes. A peak cortisol >18 µg/dL (500 nmol/L) is traditionally considered a normal response, though some experts argue this threshold is assay-dependent [12]. The test primarily detects primary adrenal insufficiency; it may miss early or partial secondary adrenal insufficiency because the adrenal glands have not yet atrophied.

A low-dose cosyntropin test (1 µg) has been proposed as more sensitive for secondary adrenal insufficiency. A 2018 meta-analysis of 12 studies (N=1,209) found that the 1-µg test had a pooled sensitivity of 76% and specificity of 87% for secondary adrenal insufficiency, compared with 57% sensitivity and 95% specificity for the 250-µg test [13]. The trade-off is more false positives with the low dose.

The CRH Stimulation Test

Corticotropin-releasing hormone (CRH, 1 µg/kg or 100 µg IV) is administered, and ACTH and cortisol are measured at baseline and at 15, 30, 45, and 60 minutes. In ACTH-dependent Cushing syndrome, this test helps distinguish a pituitary adenoma (which typically shows a brisk ACTH rise of >50% above baseline) from an ectopic ACTH source (which usually does not respond) [7]. The test is not universally available and is most often performed in specialized endocrine centers.

Inferior Petrosal Sinus Sampling

When imaging and biochemical testing leave the ACTH source ambiguous, bilateral inferior petrosal sinus sampling (IPSS) is the gold standard for localizing pituitary ACTH production. A central-to-peripheral ACTH ratio of 2:1 at baseline (or 3:1 after CRH stimulation) confirms a pituitary source with sensitivity exceeding 95% [14]. Dr. Lynnette Nieman, a senior investigator at the National Institute of Diabetes and Digestive and Kidney Diseases, has noted that "IPSS should be performed in an experienced center because technical failure can produce misleading lateralization data" [7].

How to Lower Elevated ACTH

Treating high ACTH means treating the underlying cause, not the number itself.

Addressing Primary Adrenal Insufficiency

In Addison disease, ACTH is elevated because cortisol is low. Physiologic glucocorticoid replacement (hydrocortisone 15 to 25 mg/day in divided doses, or equivalent) restores negative feedback and lowers ACTH [2]. The goal is not to normalize ACTH completely but to use clinical symptoms, cortisol levels, and ACTH trends together. Over-replacement to suppress ACTH carries metabolic risk, including weight gain, glucose intolerance, and bone loss.

Treating Cushing Disease

When a pituitary adenoma is driving excess ACTH, transsphenoidal surgery is the first-line treatment. Remission rates after initial surgery range from 65% to 90% depending on tumor size and surgeon experience [15]. Medical therapies for persistent disease include pasireotide (a somatostatin-receptor ligand that reduces ACTH secretion), cabergoline (a dopamine agonist), and osilodrostat or ketoconazole (steroidogenesis inhibitors that block cortisol production at the adrenal level) [15].

Managing Ectopic ACTH Syndrome

Ectopic ACTH production by neuroendocrine tumors (small-cell lung cancer, bronchial carcinoids, thymic carcinoids) requires treatment of the underlying malignancy. When surgery is not feasible, medical adrenal blockade with metyrapone, ketoconazole, or mitotane can reduce cortisol while oncologic therapy proceeds [7].

How to Raise Low ACTH

A low ACTH level is not treated by giving ACTH. It signals that the pituitary or hypothalamus is failing to produce it.

Glucocorticoid Withdrawal Recovery

The most common cause of low ACTH is suppression from chronic exogenous glucocorticoid use. Recovery requires a slow, supervised taper. HPA-axis recovery after stopping long-term glucocorticoids takes a median of 6 to 9 months, though some patients remain suppressed for over 2 years [16]. Serial morning ACTH and cortisol measurements every 4 to 8 weeks during the taper guide the pace.

Pituitary Replacement Therapy

If low ACTH stems from a structural pituitary lesion (adenoma, surgery, radiation, infiltrative disease), the patient needs lifelong glucocorticoid replacement because the pituitary cannot be made to produce ACTH again in most cases. Hydrocortisone (15 to 25 mg/day) or prednisolone (3 to 5 mg/day) replaces the missing cortisol signal [2]. Patients must carry a medical alert identification and have an emergency injectable hydrocortisone kit for adrenal crisis prevention.

When NOT to Order ACTH

The test has clear indications but also clear non-indications.

Do not order ACTH as a general fatigue screen. Fatigue is ubiquitous, and a random ACTH drawn outside the morning window is uninterpretable. A morning cortisol alone is a reasonable first step; ACTH adds value only when cortisol is abnormal or equivocal. Do not order ACTH in a patient currently taking supraphysiologic glucocorticoids, as the result will predictably be suppressed. And do not repeat the test weekly during a glucocorticoid taper. The axis recovers slowly. Checking every 4 to 8 weeks is sufficient [2].