Cushing's Disease
Once a diagnosis has been confirmed, treatment is available.
Resection of pituitary tumor is the standard first-line treatment1
Pituitary surgery is the recommended first choice of treatment to bring cortisol levels back to normal, but recurrence after surgery is possible.1 There are secondary treatments to help lower cortisol levels.
Secondary treatment can include repeat surgery, radiotherapy, and/or drug therapy that targets adrenal steroidogenesis, somatostatin and dopamine receptors in the pituitary gland, and glucocorticoid receptors.1
For those who cannot have surgery, radiotherapy and/or drug therapy are the available treatment options.
Monitoring cortisol levels closely after post-surgical tumor resection
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Within 48 hours post-surgery, most patients in remission* develop a glucocorticoid withdrawal syndrome associated with circulating cortisol levels of <2 μg/dL.2
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Serum cortisol levels <2 μg/dL after surgery are associated with remission and a low recurrence rate of approximately 10% at 10 years.3
*Remission is generally defined as morning serum cortisol values <5 μg/dL (<138 nmol/L) or UFC <28-56 nmol/d (<10-20 μg/d) within 7 days of selective tumor resection.4
Pharmacotherapy can be used to manage high cortisol levels5
Pharmacologic therapy may be an appropriate therapeutic option for patients with persistent disease after surgery.6
Patients appropriate for pharmacologic therapy:6,7
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Those who are ineligible or unwilling to undergo transsphenoidal surgery (TSS)
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As a second-line treatment in patients for whom TSS did not induce remission (before considering bilateral adrenalectomy or radiotherapy)
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Those waiting for the effects of radiotherapy
Surgery may not be curative
Recurrence rates after surgery1
Published recurrence rates vary between 5% and 35%
with half of recurrences appearing within the first 5 years after surgery and half after up to 10 years or more.
Published recurrence rates can vary greatly between centers and the experience of the surgeon.
Therapeutic targets in Cushing’s disease1
Target: Pituitary tumor
One class of medications directly targets the pituitary tumor in the brain. This helps to lower levels of adrenocorticotropic hormone, or ACTH levels. Lower ACTH results in lower cortisol levels and may help many of your symptoms.
Pituitary gland:
- Somatostatin analog
- Dopamine agonist: cabergoline
Target: Adrenal glands (cortisol production)
Cortisol is made in the adrenal glands located on top of the kidneys. This class of medications target the adrenal glands to stop them from making too much cortisol. By directly lowering cortisol levels, this can reduce the symptoms that are caused by too much cortisol.
Adrenal gland:
- Steroidogenesis inhibitors: ketoconazole, levoketoconazole‡, metyrapone, and osilodrostat†
- Adrenolytic drug: mitotane
Target: Cortisol receptors
There is another class of medicines that doesn’t actually reduce ACTH or cortisol levels. These medications bind to cortisol receptors found throughout the body. The cortisol that is made in the adrenal glands is then not able to attach to these receptors. This will reduce the symptoms caused by too much cortisol.
Glucocorticoid receptor:
- Antagonist: mifepristone
Approved in the US for the control of diabetes or glucose intolerance secondary to hypercortisolism in patients who failed surgery or are not surgical candidates.5
†FDA-approved medication for the treatment of Cushing’s disease.
‡FDA-approved medication for the treatment of Cushing’s syndrome.
Adult patients with CD who cannot undergo pituitary surgery or for whom surgery has been ineffective?
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REFERENCES: 1. Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol. 2021;9(12):847-875. doi:10.1016/S2213-8587(21)00235-7. 2. Lonser RR, Nieman L, Oldfield EH. Cushing’s disease: pathobiology, diagnosis, and management. J Neurosurg. 2017;126(2):404-417. doi: 10.3171/2016.1.JNS152119. 3. Biller BM, Grossman AB, Stewart PM, et al. Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab. 2008;93(7):2454-2462. doi: 10.1210/jc.2007-2734. 4. Lacroix A, Feelders RA, Stratakis CA, et al. Cushing’s syndrome. Lancet. 2015;386(9996):913-927. doi: 10.1016/S0140-6736(14)61375-1. 5. Nieman LK, Biller BM, Findling JW, et al. Treatment of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;100(8):2807-2831. doi: 10.1210/jc.2015-1818. 6. Pivonello R, De Leo M, Cozzolino A, Colao A. The treatment of Cushing’s disease. Endocr Rev. 2015;36(4):385-486. doi: 10.1210/er.2013-1048. 7. Morris D, Grossman A. The medical management of Cushing’s syndrome. Ann NY Acad Sci. 2002;970:119-133. doi: 10.1111/j.1749-6632.2002.tb04418.x. 8. Tritos NA, Biller BM, Swearingen B. Management of Cushing disease. Nat Rev Endocrinol. 2011 May;7(5):279-89. doi: 10.1038/nrendo.2011.12. 9. Nishioka H, Yamada S. Cushing’s Disease. J Clin Med. 2019 Nov 12;8(11):1951. doi: 10.3390/jcm8111951. 10. Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing’s syndrome. Lancet. 2006 May 13;367(9522):1605-17. doi: 10.1016/S0140-6736(06)68699-6. 11. Johnston PC, Kennedy L, Hamrahian AH, et al. Surgical outcomes in patients with Cushing’s disease: the Cleveland clinic experience. Pituitary. 2017;20(4):430-440. doi: 10.1007/s11102-017-0802-1.