What is the management approach for disorders related to Adrenocorticotropic hormone (ACTH) and Proopiomelanocortin (POMC)?

From the Guidelines

Management of disorders related to Adrenocorticotropic hormone (ACTH) and Proopiomelanocortin (POMC) requires a targeted approach, with replacement therapy with hydrocortisone (15-25 mg/day in divided doses) or prednisone (5-7.5 mg/day) being essential for ACTH deficiency, as recommended by the most recent guidelines 1. The approach to managing ACTH and POMC disorders involves understanding the underlying pathophysiology and tailoring treatment to the specific condition.

• For ACTH excess conditions, such as Cushing's disease, first-line treatment typically involves transsphenoidal surgery to remove the pituitary adenoma.
• For ACTH deficiency, replacement therapy is crucial, with hydrocortisone being the preferred choice due to its ability to mimic the natural diurnal rhythm of cortisol.
• POMC deficiency disorders are treated with setmelanotide to activate melanocortin-4 receptors, along with hydrocortisone replacement for adrenal insufficiency. Key considerations in managing these disorders include:
• Regular monitoring of cortisol levels, metabolic parameters, and potential medication side effects
• Dose adjustments during stress or illness to maintain optimal hormone balance and minimize complications
• Education on stress dosing, emergency injections, and the use of a medical alert bracelet or necklace for adrenal insufficiency
• Endocrine consultation prior to surgery or high-stress treatments to plan for stress-dose corticosteroids, as emphasized in recent guidelines 1. The most recent and highest quality study 1 provides guidance on the management of immune-related adverse events, including adrenal insufficiency, in patients treated with immune checkpoint inhibitor therapy, highlighting the importance of prompt recognition and treatment of adrenal crisis with intravenous hydrocortisone.

From the FDA Drug Label

1. 1 Important Information Before Conducting Metopirone Testing Stop drugs affecting pituitary or adrenocortical function before administration of Metopirone in accordance with half-life of the drugs (consider at least 5 half-lives to avoid any interference with Metopirone testing). Assess ability of patient's adrenals to respond to exogenous ACTH before Metopirone is employed as a test [see Warnings and Precautions (5.1)] .
2. 1 Adrenal Insufficiency Metopirone may induce acute adrenal insufficiency in patients with reduced adrenal secretory capacity, as well as in patients with global pituitary insufficiency. The test should be performed in the hospital with close monitoring in case of suspected adrenal insufficiency Ability of adrenals to respond to exogenous ACTH should be demonstrated before Metopirone is employed as a test.

The management approach for disorders related to Adrenocorticotropic hormone (ACTH) and Proopiomelanocortin (POMC) involves:

• Stopping drugs that affect pituitary or adrenocortical function before administering Metopirone
• Assessing the ability of the patient's adrenals to respond to exogenous ACTH before employing Metopirone as a test
• Performing the test in a hospital with close monitoring in case of suspected adrenal insufficiency
• Demonstrating the ability of the adrenals to respond to exogenous ACTH before using Metopirone as a test 2

From the Research

Management Approach for Disorders Related to ACTH and POMC

The management of disorders related to Adrenocorticotropic hormone (ACTH) and Proopiomelanocortin (POMC) involves various approaches, including medication and surgery.

• Medications such as metyrapone, mitotane, and ketoconazole can be used to control hypercortisolemia in Cushing's syndrome, as seen in studies 3, 4.
• Combination therapy with mitotane, metyrapone, and ketoconazole can be an effective alternative to bilateral adrenalectomy for severe ACTH-dependent Cushing's syndrome 4.
• The role of POMC in the ACTH-cortisol dissociation of sepsis is complex, with increased circulating POMC contributing to adrenocortical steroidogenesis 5.
• In Cushing's disease, successful resection of the ACTH-secreting pituitary adenoma is the treatment of choice, resulting in immediate biochemical remission with preservation of pituitary function 6.

Treatment Options

Treatment options for disorders related to ACTH and POMC include:

• Metyrapone therapy, which has been shown to be effective in controlling cortisol excess in patients with Cushing's syndrome 3.
• Combination therapy with mitotane, metyrapone, and ketoconazole, which can avoid the need for emergency bilateral adrenalectomy in patients with severe hypercortisolism 4.
• Surgical management, such as resection of the ACTH-secreting pituitary adenoma, which is the treatment of choice for Cushing's disease 6.

Pathophysiology

The pathophysiology of disorders related to ACTH and POMC involves:

• The production of ACTH by a benign monoclonal pituitary adenoma, which stimulates secretion of cortisol by the adrenal glands 6.
• The role of POMC in the ACTH-cortisol dissociation of sepsis, with increased circulating POMC contributing to adrenocortical steroidogenesis 5.
• The importance of accurate and early identification of Cushing's disease for effective surgical management and optimal prognosis 6.