Acth ExcessEdit

ACTH excess refers to abnormally high secretion of adrenocorticotropic hormone (ACTH) by the pituitary or by ectopic sources, which drives excess production of cortisol by the adrenal cortex. Most often this occurs in the setting of ACTH-dependent Cushing's syndrome, where the elevated ACTH stimulates sustained hypercortisolism. The best-known ACTH-dependent form is Cushing's disease, an ACTH-secreting pituitary adenoma. In other cases, ectopic ACTH production from nonpituitary tumors such as small cell lung carcinoma or certain carcinoids can cause a similar hormonal picture. The condition is best understood as a spectrum within disorders of the hypothalamic–pituitary–adrenal axis (Hypothalamic–pituitary–adrenal axis), with the key clinical and laboratory challenge being to identify the source of excess ACTH and to manage the resulting hypercortisolism.

Pathophysiology and sources ACTH is produced by corticotroph cells of the anterior pituitary gland under regulation by hypothalamic corticotrophin-releasing hormone (CRH). ACTH stimulates the adrenal cortex to synthesize and release cortisol, which in turn feeds back to suppress further ACTH and CRH production. When ACTH is inappropriately high, the adrenal glands undergo bilateral hyperplasia and cortisol secretion rises well above normal ranges. The peptides derived from the same precursor, proopiomelanocortin (Proopiomelanocortin), account for a range of effects, including changes in skin pigmentation in some circumstances.

Most ACTH excess arises from two broad categories: - ACTH-dependent pituitary sources, most commonly a benign adenoma that secretes ACTH (Cushing's disease), or, less frequently, hyperplasia confined to the pituitary. - Ectopic ACTH secretion from nonpituitary tumors, such as small cell lung cancer, carcinoid tumor, or other neuroendocrine neoplasms, which can produce very high cortisol levels and present with a more abrupt onset and more pronounced hypokalemia or metabolic complications.

In ectopic ACTH syndrome, cortisol production can be particularly aggressive and may be accompanied by more severe metabolic disturbances than typical pituitary-driven disease. These differences influence diagnostic strategy and urgency of treatment.

Clinical presentation Hypercrtolisolism produces a characteristic, multisystem syndrome that includes: - Central obesity with facial rounding (moon face) and dorsocervical fat pad (buffalo hump) - Hypertension and glucose intolerance or type 2 diabetes - Facial plethora, easy bruising, and skin changes such as purple stretch marks - Muscle weakness, particularly in proximal muscles - Osteoporosis with fracture risk - In some patients, mood changes, sleep disturbance, and cognitive effects - In ectopic ACTH syndrome, you may see more rapid symptom development and pronounced electrolyte abnormalities such as hypokalemia due to mineralocorticoid effects of cortisol at high levels

Diagnostic approach A structured, stepwise approach helps distinguish ACTH excess from other causes of elevated cortisol and to locate the source of ACTH.

1) Screen for hypercortisolism - 24-hour urinary free cortisol (UFC) testing - Late-night (midnight) salivary cortisol or serum cortisol - Low-dose dexamethasone suppression testing These tests aim to confirm that cortisol production is inappropriately elevated and not subject to normal diurnal variation.

2) Determine ACTH dependence - Measure plasma ACTH. A high or inappropriately normal ACTH with elevated cortisol indicates ACTH dependence; a suppressed ACTH points to an ACTH-independent, adrenal-origin Cushings syndrome or exogenous steroids.

3) Localize the source - If ACTH-dependent, pituitary MRI is performed to assess for a corticotroph adenoma. If MRI is inconclusive or if clinical suspicion for an ectopic source remains high, further testing is used to distinguish pituitary from ectopic sources: - High-dose dexamethasone suppression test or CRH stimulation (less commonly used today) - Inferior petrosal sinus sampling (inferior petrosal sinus sampling) to compare central vs peripheral ACTH levels - Comprehensive imaging to search for ectopic sources (e.g., CT of chest and abdomen; sometimes dedicated imaging for neuroendocrine tumors) - If ACTH is suppressed or diagnosis remains uncertain, adrenal imaging may be performed to evaluate for an adrenal tumor or adrenal hyperplasia

4) Differential considerations - Pseudocushing syndromes (e.g., obesity, alcohol use disorder, major depressive disorder) can mimic biochemical features; careful clinical evaluation is required - Exogenous glucocorticoid exposure must be ruled out as a cause of cortisol elevation

Imaging and localization nuances Pituitary MRI is essential for suspected Cushing's disease, but microadenomas (often <10 mm) can be difficult to detect. When imaging is negative or equivocal, IPSS remains the reference test to confirm a pituitary source. For ectopic ACTH syndrome, CT or MRI of the chest, abdomen, and pelvis, as well as functional imaging when needed, helps locate the tumor. Adrenal imaging is generally reserved for ACTH-independent disease but can be informative if ACTH testing is inconclusive.

Treatment approaches The management of ACTH excess aims first at controlling the hypercortisolism and then at definitively addressing the underlying source of ACTH.

  • Pituitary sources (Cushing's disease)

    • Primary therapy is often transsphenoidal surgery to remove the pituitary adenoma. Success rates vary by tumor size and surgeon experience; many patients achieve remission, while others require additional treatments.
    • If surgery is not curative or not feasible, options include radiotherapy (conventional radiotherapy or stereotactic approaches such as Gamma Knife) or a combination of therapies.
    • When surgical or radiotherapeutic approaches are insufficient, medical therapy to suppress cortisol production can be employed. Medications include steroidogenesis inhibitors such as ketoconazole, metyrapone, and osilodrostat; glucocorticoid receptor antagonists such as mifepristone; and occasionally other agents like cabergoline for certain tumors. In severe cases, intravenous etomidate can be used acutely to control cortisol.
    • Emerging and adjunctive therapies include somatostatin analogs (e.g., pasireotide) for select pituitary tumors and individualized medical regimens guided by endocrinology specialists.

  • Ectopic ACTH syndrome

    • The definitive approach is to locate and treat the underlying nonpituitary tumor, which may involve surgical resection, radiotherapy, or systemic therapies for the tumor type.
    • Because cortisol excess can be life-threatening, temporary medical suppression of cortisol production is often required while tumor-directed therapies are pursued. Similar pharmacologic options apply as for pituitary sources.

  • Adrenal-directed strategies

    • In cases where ACTH-dependent disease cannot be controlled promptly or where other options are not possible, bilateral adrenalectomy may be considered to remove the source of cortisol production; this permanently eliminates cortisol excess but requires lifelong management to replace glucocorticoids and mineralocorticoids.

Prognosis and outcomes Outcomes have improved with advances in surgical techniques, targeted radiotherapy, and a growing arsenal of medical therapies to control cortisol. Remission rates after pituitary surgery are favorable for selected patients, especially with small, well-localized adenomas and experienced surgical teams. Nevertheless, long-term follow-up is important because relapses can occur, and chronic hypercortisolism carries risks for cardiovascular disease, metabolic syndrome, infections, and osteoporosis. In ectopic ACTH syndrome, prognosis hinges on the behavior and treatability of the underlying tumor, with cortisol control remaining essential to prevent complications even when oncologic control is challenging.

See also - Cushing's syndrome - Cushing's disease - ACTH - hypothalamic–pituitary–adrenal axis - pituitary adenoma - ectopic ACTH secretion - inferior petrosal sinus sampling - ketoconazole - metyrapone - osilodrostat - mifepristone - cabergoline