Glucocorticoid Withdrawal Syndrome following treatment of endogenous Cushing Syndrome

Abstract

Purpose: Literature regarding endogenous Cushing syndrome (CS) largely focuses on the challenges of diagnosis, subtyping, and treatment. The enigmatic phenomenon of glucocorticoid withdrawal syndrome (GWS), due to rapid reduction in cortisol exposure following treatment of CS, is less commonly discussed but also difficult to manage. We highlight the clinical approach to navigating patients from GWS and adrenal insufficiency to full hypothalamic-pituitary-adrenal (HPA) axis recovery. Methods: We review the literature on the pathogenesis of GWS and its clinical presentation. We provide strategies for glucocorticoid dosing and tapering, HPA axis testing, as well as pharmacotherapy and ancillary treatments for GWS symptom management. Results: GWS can be difficult to differentiate from adrenal insufficiency and CS recurrence, which complicates glucocorticoid dosing and tapering regimens. Monitoring for HPA axis recovery requires both clinical and biochemical assessments. The most important intervention is reassurance to patients that GWS symptoms portend a favorable prognosis of sustained remission from CS, and GWS typically resolves as the HPA axis recovers. GWS also occurs during medical management of CS, and gradual dose titration based primarily on symptoms is essential to maintain adherence and to eventually achieve disease control. Myopathy and neurocognitive dysfunction can be chronic complications of CS that do not completely recover. Conclusions: Due to limited data, no guidelines have been developed for management of GWS. Nevertheless, this article provides overarching themes derived from published literature plus expert opinion and experience. Future studies are needed to better understand the pathophysiology of GWS to guide more targeted and optimal treatments.

Adrenal Cushing’s Syndrome Treated With Preoperative Osilodrostat and Adrenalectomy

“…The presentation could have also suggested glucocorticoid withdrawal, a state of relative hypocortisolism that might be seen in patients with long-term Cushing’s syndrome who undergo surgery to remove a tumor causing hypercortisolism. 7 Nevertheless, both conditions can be safely treated with hydrocortisone replacement. In retrospect, it appears that osilodrostat 2 mg twice daily plus hydrocortisone (in a block-and-replace strategy 8 ) might have been sufficient, and osilodrostat dose escalation might have not been necessary, despite the patient’s very high 24-hour mUFC at presentation.…”

Safety of Withholding Perioperative Hydrocortisone for Patients With Pituitary Adenomas With an Intact Hypothalamus-Pituitary-Adrenal Axis

“…Moreover, the taper program was adopted to avoid glucocorticoid withdrawal syndrome and unexpected adrenal insufficiency. 14 The cortisol level rebounded almost 2-fold on postoperative days 1 and 2, showing stress tolerance for pituitary surgery and a subsequent robust intrinsic response in these patients. 10,11,33,34 For patients with pituitary adenomas and an intact HPA axis, the literature reports that early postoperative adrenal insufficiency occurs in fewer than 25% of patients and is sustained in fewer than 20% of patients.…”

“… 9 , 10 , 11 , 12 There is consensus that patients with insufficient baseline HPA axis function or low serum cortisol levels after surgery for Cushing disease need glucocorticoid supplementation. 13 , 14 However, according to the nonrandomized studies, withholding perioperative glucocorticoids might be safe and not lead to a higher risk of postoperative adrenal insufficiency and could avoid glucocorticoid-related adverse events. 10 , 11 , 15 Two recent randomized clinical trials suggested that perioperative glucocorticoids would be safely withheld under intensive monitoring of postoperative serum cortisol levels.…”

“…Perioperative glucocorticoid supplementation has long been a routine practice for patients with pituitary adenomas . There is consensus that patients with insufficient baseline HPA axis function or low serum cortisol levels after surgery for Cushing disease need glucocorticoid supplementation . However, according to the nonrandomized studies, withholding perioperative glucocorticoids might be safe and not lead to a higher risk of postoperative adrenal insufficiency and could avoid glucocorticoid-related adverse events .…”

Perioperative Evaluation and Management of Patients on Glucocorticoids

“…Beyond cardiovascular instability and collapse, the symptoms of AI in the perioperative period can be subtle and may be missed due to their similarity to common postoperative complaints including anorexia, fatigue, nausea, vomiting, abdominal pain, muscle cramps, weakness, dizziness, and lethargy [ 62 ]. The clinical team must be aware of GC withdrawal symptoms that may occur in patients on chronic GC on a fast perioperative taper; these patients who may experience AI-type symptoms despite being maintained on supraphysiological GC doses [ 63 , 64 ].…”