How to manage cyclic Cushing's syndrome when the trough cortisol level is still elevated?

Management of Cyclic Cushing's Syndrome with Elevated Trough Cortisol

For cyclic Cushing's syndrome with persistently elevated trough cortisol levels, combination therapy with adrenal steroidogenesis inhibitors should be used to aggressively normalize cortisol levels. 1

Understanding Cyclic Cushing's Syndrome

• Cyclic Cushing's syndrome is characterized by repeated episodes of cortisol excess interspersed with periods of normal cortisol secretion, though in some cases the trough levels may remain elevated 1, 2
• Multiple, periodic, sequential late-night salivary cortisol (LNSC) measurements are particularly useful for longitudinal surveillance of patients with cyclic Cushing's syndrome who exhibit weeks to months of normal cortisol secretion interspersed with episodes of cortisol excess 1
• The pathophysiology of cyclic Cushing's syndrome is largely unknown, but may involve a glucocorticoid positive-feedback loop in some cases 3

Treatment Approach for Elevated Trough Cortisol

First-Line Treatment Options

• For patients with persistent hypercortisolism even during trough periods, adrenal steroidogenesis inhibitors should be used as first-line medical therapy due to their reliable effectiveness 1
• Options include:
  • Osilodrostat - highest efficacy based on prospective clinical trials 1
  • Metyrapone - rapid onset of action (within hours) 1, 4
  • Ketoconazole - effective within days 1

Combination Therapy for Persistent Hypercortisolism

• When trough cortisol levels remain elevated, combination therapy is strongly recommended to maximize adrenal blockade 1
• Effective combinations include:
  • Ketoconazole with metyrapone - this maximizes adrenal blockade when monotherapy is insufficient 1
  • A steroidogenesis inhibitor plus a tumor-targeting agent (e.g., ketoconazole plus cabergoline) - especially beneficial if visible tumor is present 1
  • Triple therapy with cabergoline, pasireotide, plus ketoconazole or metyrapone for severe cases 1

Monitoring Treatment Response

• Regular monitoring for treatment efficacy is required, including:
  • Multiple serial tests of both urinary free cortisol (UFC) and LNSC 1
  • Morning cortisol values may be especially pertinent in patients taking higher medication doses in the evening versus morning 1
  • Clinical symptoms and comorbidities, especially weight, glycemia, and blood pressure 1

Special Considerations for Cyclic Cushing's Syndrome

• A block-and-replace regimen may be particularly useful for patients with cyclic Cushing's syndrome to maintain stable cortisol levels 1
• This approach involves complete blockade of cortisol production with steroidogenesis inhibitors while simultaneously providing glucocorticoid replacement 1, 5
• Caution is needed to avoid glucocorticoid over-replacement and inducing iatrogenic Cushing's syndrome 1

When Medical Therapy Fails

• If hypercortisolism remains very severe and not responsive to optimized medical therapy, including combinations, bilateral adrenalectomy should be considered to avoid worsening outcomes 1, 6
• For patients with ACTH-dependent cyclic Cushing's syndrome, pituitary radiation (with continued steroidogenesis inhibitors during the waiting period) may be considered as a second-line therapy 6

Potential Pitfalls and Caveats

• Monitoring for adrenal insufficiency is essential, especially when using higher doses of steroidogenesis inhibitors 1
• Risk for potentiating adverse effects with combination therapy, such as QTc prolongation, should be considered 1
• With metyrapone, monitor for hypokalemia and increased blood pressure due to mineralocorticoid precursor accumulation 4
• Liver function tests should be regularly monitored with ketoconazole, but treatment does not necessarily have to be discontinued if liver enzymes are mildly elevated yet stable 1

By aggressively targeting the persistently elevated cortisol levels with combination therapy, even during trough periods, patients with cyclic Cushing's syndrome can achieve better clinical outcomes and quality of life.