Addressing glucocorticoid withdrawal syndrome in treatment of Cushing’s syndrome
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To achieve optimal outcomes in Cushing’s syndrome, both clinicians and patients need to be prepared for the type and duration of symptoms that patients may experience during treatment and recovery.
Endogenous Cushing’s syndrome is caused by chronic supraphysiologic exposure to cortisol, which can be due to adrenal tumors secreting excess cortisol or pituitary or ectopic tumors producing adrenocorticotropic hormone. Cushing’s syndrome manifests as a range of physical, neurocognitive, metabolic and biochemical abnormalities. Classic symptoms include weight gain, supraclavicular and dorsocervical fullness, muscle weakness, depression, hypertension, diabetes and low bone mass.
Treating Cushing’s syndrome is necessary to reduce morbidity and mortality, but the road to recovering normal cortisol production may be long and difficult. Treatment options to normalize cortisol include surgery, radiotherapy and pharmacotherapy.
Decreasing cortisol can evoke symptoms of glucocorticoid withdrawal syndrome, which is anticipated and a sign of favorable response to Cushing’s syndrome treatment; however, some glucocorticoid withdrawal syndrome symptoms overlap with those of recurrent Cushing’s syndrome and adrenal insufficiency. Therefore, when treating Cushing’s syndrome, clinicians and patients should be prepared to discern differences among these conditions to guide management.
Glucocorticoid withdrawal syndrome
Glucocorticoid withdrawal syndrome is the phenomenon of symptoms that present after withdrawal of chronic supraphysiologic exposure to endogenous or exogenous glucocorticoids; paradoxically, the symptoms occur despite biochemical evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression and treatment with supraphysiologic glucocorticoid replacement.
Glucocorticoid withdrawal syndrome symptoms that can occur after surgical remission or during pharmacotherapy of Cushing’s syndrome include myalgias, weakness, fatigue, mood swings, atypical depression and hypersomnia. Other common symptoms include nausea, anorexia and abdominal discomfort. As recovery continues, patients can also expect changes to their appearance due to gradual weight loss and fat redistribution.
Patients should be educated on glucocorticoid withdrawal syndrome symptoms and the potentially protracted course of treatment of Cushing’s syndrome, as this knowledge can encourage patients to safely adhere to treatment. Following surgical management, it can take 6 to 12 months or more after surgical remission to fully taper glucocorticoid treatment and for endogenous cortisol production to normalize. When managing Cushing’s syndrome with pharmacotherapy, glucocorticoid withdrawal syndrome symptoms should be expected when cortisol levels decline, particularly after any dose increases.
Managing symptoms
Glucocorticoid withdrawal syndrome, Cushing’s syndrome recurrence and adrenal insufficiency have overlapping but also differentiating symptoms. All three can present with similar symptoms of myalgias, fatigue and weakness.
Hypersomnia and anorexia are expected during glucocorticoid withdrawal syndrome, but insomnia and hyperphagia are concerning for possible Cushing’s syndrome recurrence. Weight loss occurs in both glucocorticoid withdrawal syndrome and adrenal insufficiency, whereas hypoglycemia and hypotension are suggestive of adrenal insufficiency.
If Cushing’s syndrome is treated with surgery, symptoms of adrenal insufficiency can be managed by adjusting glucocorticoid dosing; however, glucocorticoid withdrawal syndrome symptoms can still occur despite adequate cortisol replacement therapy.
Patients who have undergone pituitary surgery should also be evaluated for deficiencies in other pituitary axes that may be contributing to their symptoms. If Cushing’s syndrome is managed with pharmacotherapy, symptoms can be managed with medication dose adjustment, treatment pause or supplemental glucocorticoid therapy.
Symptoms of glucocorticoid withdrawal syndrome are an encouraging sign of treatment response. Musculoskeletal pain and weakness can be managed with nonsteroidal anti-inflammatory drugs and targeted physical therapy. Atypical depression and mood changes can be managed with antidepressants or cognitive therapy. Patients with poor appetite may benefit from diets that maximize nutritional density and protein intake for muscle recovery.
If the severity of glucocorticoid withdrawal syndrome symptoms interferes with a patient’s ability to work, temporary disability documentation can be considered.
Regular monitoring of Cushing’s syndrome signs and symptoms should be performed and accompanied by cortisol testing to assess treatment efficacy and inform adjustments to pharmacotherapy or glucocorticoid replacement. Furthermore, because the reduction in cortisol with Cushing’s syndrome treatment can substantially improve hyperglycemia, hypokalemia, hypertension and dyslipidemia, these biochemical and clinical parameters should be monitored; antihyperglycemic agents, potassium supplementation and cardiovascular medications should be tapered or discontinued accordingly.
Glucocorticoid replacement following surgery
Glucocorticoids should generally be withheld for 24 to 48 hours after surgery for Cushing’s syndrome, then initiated once consecutive serum cortisol values are less than 2 µg/dL to 5 µg/dL, which is indicative of successful tumor resection. However, glucocorticoids should be provided immediately if symptoms of adrenal insufficiency arise.
Once in surgical remission, patients should start glucocorticoid replacement at doses three to four times higher than physiologic dosing. Doses are tapered gradually, generally once every 4 to 6 weeks, per clinical assessment of patient tolerance. During this taper, because it can be challenging for clinicians to differentiate between glucocorticoid withdrawal syndrome and adrenal insufficiency symptoms, patients can temporarily increase glucocorticoid dosing and evaluate for symptom progression.
Once physiologic glucocorticoid dosing on a circadian schedule is reached and patients feel clinically ready for further tapering, biochemical testing of the HPA axis should be completed to guide glucocorticoid discontinuation. Basal HPA axis testing can be completed at 4- to 6-week intervals, followed by dynamic testing if basal testing is equivocal or to confirm HPA axis recovery. Glucocorticoid withdrawal syndrome symptoms are expected during the taper, but patients should be reassured that these symptoms typically improve and eventually resolve as the HPA axis recovers.
Management during medical treatment
Patients can experience glucocorticoid withdrawal syndrome symptoms at the onset of medical Cushing’s syndrome treatment and should be educated to expect fatigue, myalgias and anorexia with treatment. Concurrently, clinicians must differentiate glucocorticoid withdrawal syndrome from adrenal insufficiency due to overtreatment of Cushing’s syndrome: Vomiting, hypoglycemia and hypotension should prompt concern for adrenal insufficiency, and pharmacotherapy should be reduced or paused, with or without initiation of glucocorticoid replacement. The potential for symptoms to be attributable to specific side effects of the pharmacotherapy should also be considered.
An important principle of pharmacotherapy in Cushing’s syndrome is to avoid rapidly normalizing cortisol. Instead, medications should be cautiously titrated to gradually decrease hypercortisolism, with the goal of evoking mild to moderate glucocorticoid withdrawal syndrome symptoms. Biochemical and clinical assessments should then be completed to evaluate response to treatment. Medication dosing can then be incrementally increased when biochemical and/or clinical benefits plateau and glucocorticoid withdrawal syndrome symptoms resolve.
One treatment option that can help avoid overtreatment is the block-and-replacement strategy. This involves completely blocking endogenous cortisol production while simultaneously providing exogenous glucocorticoid replacement at physiologic (or higher) dose levels. Presuming that patients are compliant with taking both the Cushing’s syndrome medication and glucocorticoid replacement, this strategy facilitates greater control of glucocorticoid exposure and lowers the risk for adrenal insufficiency. Based on the mechanism of action of each drug, this approach is an option for the steroidogenesis inhibitors osilodrostat (Isturisa, Recordati), levoketoconazole (Recorlev, Xeris Biopharma) and (off-label use) metyrapone (Metopirone, HRA Pharma) and ketoconazole, or for the adrenolytic agent mitotane (Lysodren, Bristol Myers Squibb), but not for the glucocorticoid-receptor blocker mifepristone.
Conclusion
Glucocorticoid withdrawal syndrome due to the sharp decrease in supraphysiologic cortisol production with Cushing’s syndrome treatment is similar to withdrawal from addictive substances. Following chronic excess exposure to cortisol, the body and brain become dysphoric after steroids are abruptly withdrawn.
It is important for patients to be aware that glucocorticoid withdrawal syndrome may cause them to feel worse before they start to feel better. Recovery after surgery can span a year or more, and pharmacologic Cushing’s syndrome treatment can be lifelong. Glucocorticoid withdrawal syndrome symptoms inevitably remit, yet chronic morbidities from Cushing’s syndrome (myopathy and cognitive dysfunction) can persist despite cure. Glucocorticoid withdrawal syndrome can be difficult to manage, but the medical and ancillary therapies discussed here can help patients and clinicians navigate the protracted recovery process.
Reference:
- He X, et al. Pituitary. 2022;doi:10.1007/s11102-022-01218-y.
For more information:
Xin He, MD, MBA, is director of endocrinology at Signature Healthcare in Brockton, Massachusetts.
Richard J. Auchus, MD, PhD, is professor of pharmacology and internal medicine in the division of metabolism, endocrinology and diabetes at the University of Michigan. He can be reached at: rauchus@med.umich.edu.
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