Search the Community

Objective: This extended evaluation (EE) of the SONICS study assessed effects of levoketoconazole for an additional 6 months following open-label, 6-month maintenance treatment in endogenous Cushing’s syndrome. Design/Methods: SONICS included dose-titration (150–600 mg BID), 6-month maintenance, and 6-month EE phases. Exploratory efficacy assessments were performed at Months 9 and 12 (relative to start of maintenance). For pituitary MRI in patients with Cushing’s disease, a threshold of ≥2 mm denoted change from baseline in largest tumor diameter. Results: Sixty patients entered EE at Month 6; 61% (33/54 with data) exhibited normal mean urinary free cortisol (mUFC). At Months 9 and 12, respectively, 55% (27/49) and 41% (18/44) of patients with data had normal mUFC. Mean fasting glucose, total and LDL-cholesterol, body weight, body mass index, abdominal girth, hirsutism, CushingQoL, and BDI-II scores improved from study baseline at Months 9 and 12. Forty-six patients completed Month 12; 4 (6.7%) discontinued during EE due to adverse events. The most common adverse events in EE were arthralgia, headache, hypokalemia, and QT prolongation (6.7% each). No patient experienced ALT or AST >3× ULN, QTcF interval >460 msec, or adrenal insufficiency during EE. Of 31 patients with tumor measurements at baseline and Month 12 or follow-up, largest tumor diameter was stable in 27 (87%) patients, decreased in 1, and increased in 3 (largest increase 4 mm). Conclusion: In the first long-term levoketoconazole study, continued treatment through 12-month maintenance period sustained the early clinical and biochemical benefits in most patients completing EE, without new adverse effects. Read the whole article at https://eje.bioscientifica.com/configurable/content/journals$002feje$002faop$002feje-22-0506$002feje-22-0506.xml?t%3Aac=journals%24002feje%24002faop%24002feje-22-0506%24002feje-22-0506.xml&body=pdf-45566

Data presented at AACE 2022 detail levoketoconazole-specific effects observed among patients with endogenous Cushing's syndrome from the phase 3 LOGICS trial. New research presented at the American Academy of Clinical Endocrinology (AACE) annual meeting provides insight into the effects of treatment with levoketoconazole (Osilodrostat) among patients with endogenous Cushing’s syndrome. An analysis of data from a double-blind, placebo-controlled, randomized withdrawal study, results of the study demonstrate levoketoconazole provided benefits across a range of etiologies and provide evidence of levoketoconazole-specific effects through the withdrawal and reintroduction of therapy during the trial. “This LOGICS study showed that treatment with levoketoconazole benefitted patients with Cushing’s syndrome of different etiologies and a wide range in UFC elevations at baseline by frequent normalization of mUFC and concurrent improvements in serum cholesterol,” said Maria Fleseriu, MD, professor of medicine and neurological surgery and director of the Northwest Pituitary Center at Oregon Health and Science University, during her presentation. “The benefits observed were established as levoketoconazole-specific via the loss of therapeutic effect upon withdrawal to placebo and restoration upon reintroduction of levoketoconazole.” An orally administered cortisol synthesis inhibitor approved by the US FDA for treatment of endogenous hypercortisolemia in adult patients with Cushing’s syndrome considered ineligible for surgery, levoketoconazole received approval based on results of the phase 3 open-label SONICS trial, which demonstrated . Launched on the heels of SONICS, the current trial, LOGICS, was designed as phase 3, double-blind, placebo-controlled, randomized withdrawal study aimed at assessing the drug-specificity of cortisol normalization in adult patients with Cushing’s syndrome through a comparison of the effects of withdrawing levoketoconazole to placebo against continuing treatment. The trial began with an open-label titration maintenance phase followed by a double-blind randomized withdrawal phase and a subsequent restoration phase, with the randomized withdrawal and restoration phase both lasting 8 weeks. A total of 89 patients with Cushing’s syndrome received levoketoconazole to normalize mUFC. Of these, 39 patients on a stable dose for 4 weeks or more were included in the randomized withdrawal stage of the study. These 39, along with 5 completers of the SONICS trial, were randomized in a 1:1 ratio to continue therapy with levoketoconazole or placebo therapy, with 22 patients randomized to each arm. The primary outcome of interest in the study was the proportion of patients with loss of mean urinary free cortisol response during the randomized withdrawal phase of the study, which was defined as an mUFC 1.5 times the upper limit of normal or greater or an mUFC 40% or more above baseline. Secondary outcomes of interest included mUFC normalization at the end of the randomized withdrawal phase of the study and changes in comorbidity biomarkers. Overall, 21 of the 22 patients randomized to placebo during the withdrawal stage met the primary endpoint of loss of mUFC compared to just 9 of 22 among the levoketoconazole arm of the trial (treatment difference: -54.5% [95% CI, -75.7 to -27.4]; P=.0002). Additionally, at the conclusion of the randomization phase, mUFC normalization was observed among 11 patients in the levoketoconazole arm of the trial compared to 1 patient receiving placebo (treatment difference: 45.5% [95% CI, 19.2 to 67.9]; P=.0015). Further analysis indicated the restoration of levoketoconazole therapy was associated with a. Reversal of loss of contrail control in most patients who had been randomized to placebo. Investigators pointed out the mean change from randomized withdrawal baseline to the end of the randomized withdrawal period in total cholesterol was -0.04 mmol/L for levoketoconazole and 0.9 mmol/L for placebo (P=.0004) and the mean change in LDL-C was -0.006 mmol/L and 0.6 mmol/L, respectively (P=0.0056), with the mean increases in cholesterol observed among the placebo arm reversed during the restoration phase. In safety analyses, results suggest the most commonly reported adverse events seen with levoketoconazole treatment, during all study phases combined were nausea and hypokalemia, which occurred among 29% and 26% of patients, respectively. Investigators also pointed out liver-related events, QT interval prolongation, and adrenal insufficiency, which were respecified adverse events of special interest occurred among 10.7%, 10.7%, and 9.5% of patients receiving levoketoconazole, respectively. This study, “Levoketoconazole in the Treatment of Endogenous Cushing’s Syndrome: A Double-Blind, Placebo-Controlled, Randomized Withdrawal Study,” was presented at AACE 2022. Related Content: American Academy of Clinical EndocrinologyClinicalCushing's Syndrome From https://www.endocrinologynetwork.com/view/no-increased-risk-of-fracture-in-dkd-with-sglt2-inhibitors-vs-dpp-4-inhibitors

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. Introduction Endogenous neoplastic hypercortisolism - Cushing syndrome (CS) - is one of the most challenging diagnostic and management problems in clinical endocrinology. CS may be due to either a pituitary tumor (Cushing disease, CD), or a non-pituitary (ectopic) tumor secreting ACTH. ACTH-independent hypercortisolism due to unilateral or bilateral adrenal nodular disease has been increasingly recognized as an important cause of CS. Regardless of the cause of CS, the clinical manifestations are protean and include a myriad of clinical, biochemical, neurocognitive, and neuropsychiatric abnormalities. The catabolic state of hypercortisolism causes signs and symptoms including skin fragility, bruising, delayed healing, violaceous striae, muscle weakness, and low bone mass with fragility fractures. Other clinical features include weight gain, fatigue, depression, difficulty concentrating, insomnia, facial plethora, and fat redistribution to the head and neck with resultant supraclavicular and dorsocervical fullness[1]. Metabolic consequences of hypercortisolism including hypertension, diabetes, and dyslipidemia are common. In addition, women often experience hirsutism and menstrual irregularity, while men may have hypogonadism. Management options of CS include surgery, medications, and radiation. The preferred first line treatment, regardless of source, is surgery, which offers the potential for remission[2,3,4]. The primary literature, reviews, and clinical practice guidelines for CS have traditionally focused on the diagnosis, subtyping, and surgical approach to CS. This bias derives first from the profound diagnostic challenge posed in the evaluation of cortisol production and dynamics, given that circulating cortisol follows a circadian rhythm, exhibits extensive protein binding and metabolism, and rises acutely with stress. CD and ectopic ACTH syndrome may be difficult to distinguish clinically and biochemically, and inferior petrosal sinus sampling is required in many patients to resolve this differential diagnosis. Ectopic ACTH-producing tumors can also be small, and these tumors can escape localization despite the best current methods. Although diagnosis and initial surgical remission can be achieved in the majority of patient with CS at experienced centers, up to 50% of patients with CD will require additional therapies after unsuccessful primary surgeries or recurrence up to many years later[5]. For patients who do not achieve surgical cure or who are not surgical candidates, several medical treatment options are now available. Pharmacotherapies directed at the pituitary include pasireotide[6, 7] (FDA approved) and cabergoline[8]. Adrenal steroidogenesis inhibitors such as osilodrostat[9] (FDA approved), metyrapone[10], levoketoconazole[11] (FDA approved) and ketoconazole[12], as well as the glucocorticoid antagonist, mifepristone[13] (FDA approved), are now widely used to treat CS. Pituitary radiotherapy is an additional treatment option for CD but can take months to years to lower cortisol production. Bilateral adrenalectomy (BLA) provides immediate, reliable correction of hypercortisolism but mandates life-long corticosteroid replacement therapy, and, in patients with CD, may be complicated by corticotroph tumor progression syndrome in 25–40% of patients[14]. After successful surgery for CS, the rapid onset of adrenal insufficiency (AI) is anticipated and usually portends a favorable prognosis [15,16,17,18]; however, despite the use of post-operative corticosteroid replacement, the rapid reduction in cortisol exposure often results in an enigmatic phenomenon referred to as the glucocorticoid withdrawal syndrome (GWS). This article addresses the clinical presentation and the pathogenesis of GWS, as well as its distinction from AI. When available, appropriate references are provided. Statements and guidance provided without references are derived from expert opinion and experience. Clinical Presentation and Pathogenesis of GWS GWS occurs following withdrawal of supraphysiologic exposure to either exogenous or endogenous glucocorticoids of at least several months duration[19]. After surgical cure of endogenous CS, GWS is usually characterized by biochemical evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression with many signs and symptoms consistent with cortisol deficiency despite the use of supraphysiologic glucocorticoid replacement therapy. The degree of physical or psychologic glucocorticoid dependence experienced by patients may not correlate with the degree of HPA axis suppression[20, 21]. GWS symptom onset is typically 3–10 days postoperatively, often after the patient has been discharged from the hospital. The first symptoms of GWS vary but usually consist of myalgias, muscle weakness, fatigue, and hypersomnolence. Anorexia, nausea, and abdominal discomfort are common, but vomiting should raise concern for hyponatremia, cerebrospinal fluid leak, hydrocephalus, or other perioperative complications. Mood changes develop more gradually and range from mood swings to depression, and the fatigue with myalgias can exacerbate mood changes. An atypical depressive disorder has been described in many patients after CD surgery[22]. Weight loss should ensue in most patients but gradually and proportionate to the reduction in glucocorticoid exposure. It is important to complete a thorough symptom review and physical exam at postoperative visits, as the differentiation between GWS and bona fide AI – and even between GWS and recurrence of CS – can be challenging (Fig. 1). All three conditions are associated with symptoms of myalgias, weakness, and fatigue; however, rapid weight loss, hypoglycemia, and hypotension are suggestive of AI and the need for an increase in the glucocorticoid dose. In parallel, hypersomnia is more suggestive of GWS, while insomnia is more associated with recurrence of CS. Given the anticipation of GWS onset shortly after discharge and the potential for hyponatremia during this time, a widely employed strategy is a generous glucocorticoid dose for the first 2–3 weeks, at least until the first postoperative outpatient visit (Table 1). Fig. 1 Overlapping clinical features of Cushing syndrome (CS), glucocorticoid withdrawal syndrome (GWS), and adrenal insufficiency (AI) Full size image Table 1 Glucocorticoid Therapy Options After Surgery for CS Full size table The mechanisms responsible for the precipitation of the GWS after surgery for CS and the variability in its manifestations are not completely understood, yet alterations in the regulation of cortisol and cortisol-responsive genes appear to contribute. Down-regulation of corticotropin-releasing hormone (CRH) and proopiomelanocortin (POMC) expression, combined with up-regulation of cytokines and prostaglandins are likely to be important components of GWS. Low CRH has been associated with atypical depression[23], and CRH levels in cerebrospinal fluid of patients with CD are significantly lower compared to healthy subjects[24]. CRH suppression gradually resolves after surgical cure over 12 months during glucocorticoid replacement[25], illustrative of the slow recovery process. The expression of POMC, the ACTH precursor molecule, is also suppressed with chronic glucocorticoid exposure[26], and the normalization of POMC-associated peptides mirrors HPA axis recovery[19]. In the acute phase of glucocorticoid withdrawal, interleukins IL-6 and IL-1β, as well as tumor-necrosis factor alpha (TNFα) have been observed to rise[27], suggesting that glucocorticoid-mediated suppression of cytokines and prostaglandins is then released in GWS, and these cytokines induce the associated flu-like symptoms. Glucocorticoid replacement with dexamethasone 0.5 mg/d reduced but did not normalize IL-6 after 4–5 days[27], consistent with resistance to suppression during GWS. Acute Care: Perioperative Planning, Coaching, and Management For patients with CD, transsphenoidal surgery performed by an experienced surgeon achieves remission in about 80% of pituitary microadenomas and 60% of macroadenomas[28,29,30,31]. Post-operative AI and GWS are some of the most challenging phases of management for endocrinologists and one of the most disheartening for CS patients. Many patients report feeling unprepared for the postsurgical recovery process[32]. For these reasons, it is important to prepare the patient prior to surgery for the difficult months ahead, and the same considerations apply to the commencement of medical therapies, as will be discussed later. On the one hand, more potent glucocorticoids and higher doses reliably mitigate symptoms, but on the other hand, substitution of exogenous for endogenous CS delays recovery of the HPA axis and perpetuates CS-related co-morbidities. Limited data that compare management strategies preclude evidence-based decisions, yet some themes can be derived from expert opinion and extensive experience from CS centers. In centers dedicated to the management of CS, surgeons and endocrinologists work closely together through all phases of the process. Although the goal of primary surgery for CD is adenoma resection, the tumor might not be found and/or removed completely after initial exploration. To prepare for this possibility, the surgeon should determine in advance with the patient and endocrinologist what to do next in this situation – dissect further, perform a hypophysectomy or hemi-hypophysectomy, or stop the operation. The plan for perioperative testing and glucocorticoid treatment varies widely among centers. The conundrum faced in the immediate perioperative period is that withholding glucocorticoids allows for rapid testing and demonstration of remission; however, complete resection of the causative tumor causes AI from prolonged suppression of the HPA axis and concerns for acute decompensation. Abundant evidence has shown that post-pituitary adenomectomy patients are not at risk for an adrenal crisis when monitored closely in an intensive care unit or equivalent setting[33]. Many studies have confirmed that post-operative AI almost always suggests a remission of CD[15,16,17,18, 34]. A standard protocol includes securing serum electrolytes and cortisol, plasma ACTH, capillary blood glucose, blood pressure, and urine specific gravity every 6 h for 24–48 h while withholding all glucocorticoids. Consecutive serum cortisol values less than 2–5 µg/dL (we use < 3 µg/dL) are sufficient to document successful tumor resection and to begin glucocorticoid therapy[35]. Post-operative signs and symptoms of AI including vomiting, hyponatremia, hypoglycemia, and hypotension should also mandate immediate glucocorticoid support. Although not clinically useful in the immediate post-operative period, some investigators have shown that low ACTH and DHEAS levels may be better predictors of long-term remission than serum cortisol[36]. A similar strategy for the management of possible post-operative AI/GWS following unilateral adrenalectomy for nodular adrenal disease has recently been reported. A post-operative day 1 basal cortisol and its response to cosyntropin stimulation can reliably segregate those patients with HPA axis suppression requiring cortisol replacement from those with an intact HPA axis who do not need to be discharged with glucocorticoid therapy[37]. Once remission is achieved, exogenous glucocorticoid replacement should be initiated and maintained during the months required for HPA axis recovery. Several glucocorticoids and dosing options are available (Table 1), and the initial dose is generally 3- to 4-fold higher than the physiologic range and graded based on age, comorbidities, and severity of disease. Fludrocortisone acetate should also be initiated following BLA for patients who receive glucocorticoids other than hydrocortisone, the only glucocorticoid with mineralocorticoid activity. By comparison, post-BLA patients receiving supraphysiologic hydrocortisone doses usually do not need mineralocorticoid support until their dose is tapered to near physiologic replacement. In the acute postoperative period, several medical comorbidities accompanying CS may reverse rapidly and require medication adjustments[35]. In particular, insulin and oral hypoglycemic drugs, potassium-sparing diuretics such as spironolactone, and other cardiovascular drugs are typically tapered or discontinued as glucose counter-regulation and electrolyte balance change rapidly upon cortisol reduction. Due to the high risk of postoperative venous thromboembolism[38,39,40], prophylaxis is frequently recommended and continued for several weeks after discharge. Posterior pituitary manipulation can disturb water balance and result in serum sodium alterations, including transient or permanent central diabetes insipidus, and in rare cases the triphasic response of diabetes insipidus, followed by syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and finally permanent diabetes insipidus[41, 42]. In the first week or two after discharge, the most common cause for readmission is hyponatremia[43, 44], although the mechanisms responsible for this transient SIADH state are not known. For this reason, patients should be instructed to drink only when thirsty and not as an alternative to solid foods or for social reasons for 7–10 days after the surgery. Both diabetes insipidus and SIADH may not manifest for weeks after surgery; consequently, serum sodium should be monitored after hospital discharge as well [42]. Subacute Care: The GWS and HPA Axis Recovery When managing GWS symptoms, it is important to repeatedly emphasize to the patient that not only are GWS symptoms to be expected, but in fact these manifestations portend a favorable prognosis of sustained remission from CS. The most important treatment intervention is frequent reassurance to the patient that GWS typically resolves as the HPA axis recovers. Family members must be included in the conversation to help provide as much support as possible, as patients report that support from family and friends is the most helpful coping mechanism during the recovery process[32]. When appropriate, it may be necessary to provide the patient with temporary disability documentation, since GWS symptoms may be so severe to preclude gainful employment. The patient must know that the myalgias reflect the body’s attempts to repair the muscle damage, similar to the soreness experienced the day after resistance weight training, and these aches will eventually subside. Due to the challenges of differentiating between GWS and AI, a higher glucocorticoid dose can be briefly trialed to assess if this increased glucocorticoid exposure improves symptoms, but late-day dosing should be avoided to support recovery of the circadian rhythm. In parallel, the patient should be encouraged to adequately rest, particularly going to sleep early but limiting daytime sleep to short naps. Several other classes of medications can be trialed to target specific patient symptoms (Table 2). Antidepressants such as fluoxetine, sertraline, and trazodone might help to improve mood, sleep and appetite. A non-steroidal anti-inflammatory medication to address the musculoskeletal discomfort might be used early in the GWS, with the cyclooxygenase type 2 (COX-2) inhibitor celecoxib (100–200 mg once or twice daily) preferred when several weeks of daily treatment is needed, generally not more than 3 months. With anorexia and reduced food intake, adequate protein intake is necessary to allow muscle recovery. Egg whites, nuts, and lean meats are nutritionally dense and generally easy to tolerate despite poor appetite. Table 2 Pharmacotherapy and Ancillary Treatment Options for GWS Symptoms Full size table Following surgical remission, the duration of glucocorticoid taper can vary from 6 to 12 months or more, depending on age, severity of disease, and duration of disease [45, 46]. Monitoring for HPA axis recovery involves both clinical and biochemical assessments. Since the HPA axis is likely to remain suppressed with prolonged supraphysiologic glucocorticoid replacement, the first goal is to shift from all-day dosing to a circadian schedule as soon as possible, such as hydrocortisone 20 mg on rising and 10 mg in the early afternoon by 2–6 weeks after surgery. The advantages of hydrocortisone include rapid absorption for symptom mitigation, the ability to measure serum cortisol as a measure of drug exposure when helpful, and the relatively short half-life [47], which ensures a glucocorticoid-free period in the early morning when it is most critical to avoid prolonged HPA axis suppression and to enhance recovery. The second goal, which should not be attempted until GWS symptoms – particularly the anorexia and myalgias – are considerably improved, is to limit replacement to a single morning dose. Biochemical assessment should begin once patients are taking a physiologic dose of glucocorticoid replacement (total daily dose of hydrocortisone 15 to 20 mg per day) and clinically feel well enough to begin the final stage to discontinuation of glucocorticoid replacement (Fig. 2). Biochemical evaluation begins with basal testing, and dynamic assessment of adrenal function might be necessary to confirm completion of recovery. For basal testing, patients should not take their afternoon hydrocortisone dose (if prescribed) the day before testing and then have a blood draw by 0830 prior to the morning hydrocortisone dose on the day of testing. While a serum cortisol alone is adequate to taper hydrocortisone, a simultaneous plasma ACTH assists in gauging the state of HPA axis recovery. Often the ACTH and cortisol rise gradually in parallel, but sometimes the ACTH rises above the normal range despite a low cortisol, which indicates recovery of the hypothalamus (CRH neuron) and pituitary corticotrophs in advance of adrenal function. Serum DHEAS can remain suppressed for months to years after cortisol normalization, and a low DHEAS does not indicate continued HPA axis suppression. A rapid rise in DHEAS, in contrast, is concerning for disease recurrence, but a slow drift to a measurable amount in parallel with the cortisol rise is consistent with HPA axis recovery. Periodic assessment of electrolytes is prudent to screen for hyponatremia and hypo- or hyperkalemia as medications are changed, particularly diuretics. Hypercalcemia that is parathyroid-hormone independent might be observed during the recovery phase, probably related to the rise in cytokines that accompany resolution of hypercortisolemia[48, 49]. Fig. 2 Glucocorticoid withdrawal algorithm. TDD, total daily dose Full size image Basal testing is performed at 4- to 6-week intervals during glucocorticoid replacement. A rule of thumb is that the AM cortisol in µg/dL plus the morning dose of hydrocortisone in milligrams should sum to 15–20. Thus, once endogenous cortisol production is measurable, the hydrocortisone dose should be not more than 20 mg on arising. Once the AM cortisol rises to near 5 and then 10 µg/dL, the AM hydrocortisone dose is dropped to 15 and then 10 mg, respectively. Once the AM cortisol is 12–14 µg/dL, recovery is essentially complete, and the morning hydrocortisone dose is dropped to 5 mg for 4–6 weeks and then stopped or held for dynamic testing (Fig. 2). A clinical pearl related to HPA axis recovery is that patients who state that they are finally feeling better and getting over the GWS usually have started to make some endogenous cortisol, yet not enough to stop glucocorticoid tapering. Nevertheless, a smidgeon of endogenous cortisol production with the waning of GWS symptoms is a harbinger that HPA axis recovery is imminent. If basal testing is equivocal, dynamic testing might be necessary. The gold standard testing for central AI is the insulin tolerance test, which is rarely used, and metyrapone testing might be employed once the basal cortisol is > 10 µg/dL. Although designed to test for primary adrenal insufficiency, the cosyntropin stimulation test is often employed in this setting due to greater availability, simplicity, and safety than insulin or metyrapone testing. The duration of full HPA axis recovery can be highly variable depending on the individual and postoperative glucocorticoid dosing[50]. GWS During Medical Management of CS Patients who are not surgical candidates or do not have successful remission of CS following surgery may be offered medical treatment or BLA. After BLA, the GWS will ensue without eventual recovery of the HPA axis, so glucocorticoids are tapered until a chronic physiologic replacement dose is reached as described previously. With medical management, patients might also experience GWS, particularly at the onset of treatment. Therefore, patients must be counseled that the typical symptoms of fatigue, myalgias, and anorexia are not only possible but indeed expected, rather than “side effects” of the medication, with two caveats. First, as described for glucocorticoid replacement following surgical remission, the endocrinologist must distinguish GWS from AI due to over-treatment of CS. The same parameters of vomiting, hypotension, and hypoglycemia favor inadequate cortisol exposure and the need for dose reduction or treatment pause and/or supplementation with a potent glucocorticoid such as dexamethasone to reverse an acute event. Second, known adverse effects of the specific drug in use should be considered and excluded. The quandary of distinguishing GWS from over-treatment raises an important principle of medical management: under-dose initially and gauge primarily the severity of GWS symptoms in the first several days. The initial goal of medical therapy is not to rapidly achieve normal cortisol milieu, but rather to “dial in” just enough inhibition of cortisol production or receptor antagonism to precipitate mild to moderate GWS symptoms. Once GWS symptoms appear and/or a typical dose of the medication is achieved, further assessments, including glucose, serum cortisol and/or UFC (except when treated with mifepristone), clinical appearance, and body weight are conducted while the dose is maintained constant until GWS symptoms begin to dissipate. If the patient is not experiencing adequate clinical and/or biochemical benefit from the medication in the absence of GWS symptoms, the dose is gradually raised incrementally. This iterative process might require periodic dose reduction or perhaps even temporarily discontinuing the medication if the patient’s daily living activities are affected at any point in the process. For several medications, a block-and-replacement strategy is an option[3], particularly for very compliant patients for whom a priority is placed on avoidance of over-treatment. This strategy resembles thionamide-plus-levothyroxine therapy for the treatment of Graves disease. The patient is given both a generous dose of medication to completely block endogenous glucocorticoid production, plus simultaneous exogenous glucocorticoid therapy, titrated to replacement dose or greater. This approach allows for greater control over glucocorticoid exposure and low risk of AI, as long as the patient always takes both medications each day. Long-acting pasireotide, for example, would not be an appropriate drug for the block-and-replace strategy. Based on the drug mechanism of action, this block-and-replace strategy is feasible with ketoconazole or levoketoconazole, the 11β-hydroxylase inhibitors osilodrostat and metyrapone, and the adrenolytic agent mitotane (the latter three are off-label uses). Alternatively, the patient might be given a double replacement dose of glucocorticoid to take only if symptoms concerning for over-treatment occur, and the medical therapy for hypercortisolemia is then interrupted until the patient communicates with the endocrinologist. Treatment monitoring with medical management includes biochemical and symptom assessment. For all medications other than mifepristone, normalization of 24-hour UFC is the minimal goal [2]. Basal morning cortisol and late-night salivary cortisol may be more challenging to interpret in the setting of diurnal rhythm loss characteristic of CS. Because mifepristone blocks glucocorticoid receptors, ACTH and cortisol increase with treatment for most forms of CS; dose titration therefore relies on assessment of clinical features, glycemia, body weight, and other metabolic parameters [2]. For occult tumors, periodic imaging to screen for a surgical target and/or tumor regrowth is prudent, and a pause in treatment for repeat surgery might be indicated. The End Game: Comprehensive Recovery for the Patient with CS Besides navigating the GWS and shepherding recovery of the HPA axis, recovery from co-morbidities of CS must be addressed to the extent possible. Hypertension, hyperglycemia, hypokalemia, and dyslipidemia often improve substantially but do not always resolve. Insomnia, skin thinning and bruising, and risk of thrombosis also generally resolve, and associated treatments might be discontinued. Although there is usually an improvement in bone density and decreased fracture risk following correction of CS, anabolic and/or anti-resorptive therapies may be warranted in some patients. The deformities of vertebral compression fractures may be permanent, and some authors have recommended the use of vertebroplasty for symptom relief[51]. Violaceous striae and chronic skin tears might heal with hyperpigmentation, leaving “the scars of Cushing’s,” which can persist for a lifetime. These milestones or minor victories can be used as evidence of healing and encouragement for the patient during the dark days of the GWS, and these changes herald further improvements. Fat redistribution and significant weight loss take some weeks to manifest and usually follow next. The myopathy from CS is an example of a co-morbidity that rarely improves without targeted treatment, and the German Cushing’s Registry has provided evidence for chronic muscle dysfunction following cure of CS[52]. Recent data indicate that a low IGF-1 after curative surgery is associated with long-term myopathy [53]. This persistent myopathy is a common source of chronic fatigue following HPA axis recovery, which is unresponsive to glucocorticoids. For these reasons, an important ancillary modality is physical therapy, and an ideal time to initiate this treatment is at the first signs of HPA axis recovery when the GWS symptoms have subsided. A complete evaluation from an experienced physical therapist should focus on core and proximal muscle strength, balance, and other factors that limit function. Exercises targeting these factors (stand on one foot, sit-to-stand, straight-arm raises with 1- to 5-pound weights) rather than traditional gym exercises (arm curls, bench press, treadmill) are necessary to restore functional status and avoid frustration and injury when the patient is not yet prepared for the latter stages of recovery. Professional supervision of this initial phase is a critical component of the recovery process, and failure to attend to musculoskeletal rehabilitation – as would be routine following survival of a critical illness – risks long-term morbidities from a curable disease. Patients with CS often complain of cognitive defects, which usually improve but may not completely recover following treatment[54, 55]. Glucocorticoids are toxic to the hippocampus, and both rats treated with high-dose corticosterone and patients with CD experience reductions in hippocampal volume, which does not completely return to normal even with correction of hypercortisolemia[56, 57]. Because the hippocampus is an important brain region for memory, the main complaint is impaired formation of new memories and recall of recent events. When significant cognitive dysfunction persists, a formal neuropsychologic testing session is prudent, both to screen for additional sources of memory loss (degenerative brain diseases) and to identify aspects that might be amenable to functional management approaches. Cognitive therapy can be effective for mental health and overall disease coping strategies as well. Finally, for patients undergoing transsphenoidal surgery for CD, complications associated with pituitary surgeries in general should also be considered. Anterior pituitary hormone axes should be assessed biochemically and symptomatically for hypothyroidism and hypogonadism, as hypopituitarism is an independent predictor of decreased quality of life after surgical cure [58]. Hypopituitarism can not only complicate the assessment of GWS with overlapping symptoms such as fatigue, but treatment of hypopituitarism can also be important for GWS recovery. Prior to initiating physical therapy, testosterone replacement in male patients with hypogonadism should be optimized. Hypothyroidism can contribute to hyponatremia and can also slow the metabolism of glucocorticoids. Therefore, optimizing the treatment of hypothyroidism and hypogonadism prior to completing glucocorticoid taper is prudent. Growth hormone deficiency may also be evaluated in symptomatic patients in the setting of other anterior pituitary hormone deficiencies, although formal evaluation is best delayed for at least 6–12 months when HPA axis recovery has occurred or at least the glucocorticoid dose is reduced to a physiologic range [2]. Summary and Final Thoughts After a diagnosis of CS has been well established, a multidisciplinary team of endocrinologists and surgeons must design the best treatment strategy for the patient. Expectations and possible adverse side effects of surgery or pharmacotherapy should be reviewed with the patient. The GWS is a very difficult concept for patients to understand. It seems inconceivable to them that they could possibly feel worse (and that this is a good omen) six weeks after resolution of their hypercortisolism than they do pre-operatively; however, there are no studies that address whether comprehensive pre-operative patient education regarding GWS has any impact on the patient’s post-operative perception and outcome after successful surgery. An addiction metaphor is sometimes helpful: the patient’s body and brain has become addicted to steroids (cortisol) and after steroids are abruptly reduced, their body and brain are dysphoric — much like removal of any other addictive substance (e.g., opioids, alcohol, nicotine). The patient and their care team need to know that this treatment odyssey will be a marathon, not a sprint. It may take as long as 12–18 months for patients to have full HPA axis recovery, regression of GWS, and, most importantly, resolution of the devastating effects of chronic excessive glucocorticoid exposure. Conclusions GWS following surgery or during medical treatment of CS can be challenging to manage. There are currently no standard guidelines for management of GWS, but various available medical and ancillary therapies are discussed here. Studies are needed to better understand the pathophysiology of GWS to guide more targeted treatments. There may be yet unrecognized steroids produced by the adrenal glands, the withdrawal of which contributes to GWS symptoms[59]. Future observational and interventional studies would be beneficial for identifying optimal management options. References Carroll TB, Findling JW (2010) The diagnosis of Cushing’s syndrome. Rev Endocr Metab Disord 11:147–153. https://doi.org/10.1007/s11154-010-9143-3 Article PubMed Google Scholar Fleseriu M, Auchus R, Bancos I et al (2021) Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol 9:847–875. https://doi.org/10.1016/S2213-8587(21)00235-7 Article PubMed Google Scholar Nieman LK, Biller BMK, Findling JW et al (2015) Treatment of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 100:2807–2831. https://doi.org/10.1210/jc.2015-1818 CAS Article PubMed PubMed Central Google Scholar Biller BMK, Grossman AB, Stewart PM et al (2008) Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 93:2454–2462. https://doi.org/10.1210/jc.2007-2734 CAS Article PubMed PubMed Central Google Scholar Geer EB, Shafiq I, Gordon MB et al (2017) BIOCHEMICAL CONTROL DURING LONG-TERM FOLLOW-UP OF 230 ADULT PATIENTS WITH CUSHING DISEASE: A MULTICENTER RETROSPECTIVE STUDY. Endocr Pract 23:962–970. https://doi.org/10.4158/EP171787.OR Article PubMed Google Scholar Colao A, Petersenn S, Newell-Price J et al (2012) A 12-Month Phase 3 Study of Pasireotide in Cushing’s Disease. N Engl J Med 366:914–924. https://doi.org/10.1056/NEJMoa1105743 CAS Article PubMed Google Scholar Lacroix A, Gu F, Gallardo W et al (2018) Efficacy and safety of once-monthly pasireotide in Cushing’s disease: a 12 month clinical trial. Lancet Diabetes Endocrinol 6:17–26. https://doi.org/10.1016/S2213-8587(17)30326-1 CAS Article PubMed Google Scholar Pivonello R, De Martino MC, Cappabianca P et al (2009) The medical treatment of Cushing’s disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. J Clin Endocrinol Metab 94:223–230. https://doi.org/10.1210/jc.2008-1533 CAS Article PubMed Google Scholar Pivonello R, Fleseriu M, Newell-Price J et al (2020) Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase. Lancet Diabetes Endocrinol 8:748–761. https://doi.org/10.1016/S2213-8587(20)30240-0 CAS Article PubMed Google Scholar Ceccato F, Zilio M, Barbot M et al (2018) Metyrapone treatment in Cushing’s syndrome: a real-life study. Endocrine 62:701–711. https://doi.org/10.1007/s12020-018-1675-4 CAS Article PubMed Google Scholar Fleseriu M, Pivonello R, Elenkova A et al (2019) Efficacy and safety of levoketoconazole in the treatment of endogenous Cushing’s syndrome (SONICS): a phase 3, multicentre, open-label, single-arm trial. Lancet Diabetes Endocrinol 7:855–865. https://doi.org/10.1016/S2213-8587(19)30313-4 CAS Article PubMed Google Scholar Castinetti F, Guignat L, Giraud P et al (2014) Ketoconazole in Cushing’s disease: is it worth a try? J Clin Endocrinol Metab 99:1623–1630. https://doi.org/10.1210/jc.2013-3628 CAS Article PubMed Google Scholar Fleseriu M, Biller BMK, Findling JW et al (2012) Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome. J Clin Endocrinol Metab 97:2039–2049. https://doi.org/10.1210/jc.2011-3350 CAS Article PubMed Google Scholar Reincke M, Albani A, Assie G et al (2021) Corticotroph tumor progression after bilateral adrenalectomy (Nelson’s syndrome): systematic review and expert consensus recommendations. Eur J Endocrinol 184:P1–P16. https://doi.org/10.1530/EJE-20-1088 CAS Article PubMed PubMed Central Google Scholar Lindsay JR, Oldfield EH, Stratakis CA, Nieman LK (2011) The Postoperative Basal Cortisol and CRH Tests for Prediction of Long-Term Remission from Cushing’s Disease after Transsphenoidal Surgery. J Clin Endocrinol Metab 96:2057–2064. https://doi.org/10.1210/jc.2011-0456 CAS Article PubMed PubMed Central Google Scholar Hameed N, Yedinak CG, Brzana J et al (2013) Remission rate after transsphenoidal surgery in patients with pathologically confirmed Cushing’s disease, the role of cortisol, ACTH assessment and immediate reoperation: a large single center experience. Pituitary 16:452–458. https://doi.org/10.1007/s11102-012-0455-z CAS Article PubMed Google Scholar Ramm-Pettersen J, Halvorsen H, Evang JA et al (2015) Low immediate postoperative serum-cortisol nadir predicts the short-term, but not long-term, remission after pituitary surgery for Cushing’s disease. BMC Endocr Disord 15:62. https://doi.org/10.1186/s12902-015-0055-9 CAS Article PubMed PubMed Central Google Scholar Ironside N, Chatain G, Asuzu D et al (2018) Earlier post-operative hypocortisolemia may predict durable remission from Cushing’s disease. Eur J Endocrinol 178:255–263. https://doi.org/10.1530/EJE-17-0873 CAS Article PubMed PubMed Central Google Scholar Hochberg Z, Pacak K, Chrousos GP (2003) Endocrine Withdrawal Syndromes. Endocr Rev 24:523–538. https://doi.org/10.1210/er.2001-0014 Article PubMed Google Scholar Dixon RB, Christy NP (1980) On the various forms of corticosteroid withdrawal syndrome. Am J Med 68:224–230. https://doi.org/10.1016/0002-9343(80)90358-7 CAS Article PubMed Google Scholar AMATRUDA TT ND JR (1965) Certain Endocrine and Metabolic Facets of the Steroid Withdrawal Syndrome. J Clin Endocrinol Metab 25:1207–1217. https://doi.org/10.1210/jcem-25-9-1207 Article PubMed Google Scholar Dorn LD, Burgess ES, Friedman TC et al (1997) The Longitudinal Course of Psychopathology in Cushing’s Syndrome after Correction of Hypercortisolism. J Clin Endocrinol Metab 82:912–919. https://doi.org/10.1210/jcem.82.3.3834 CAS Article PubMed Google Scholar Chrousos GP, Gold PW (1992) The Concepts of Stress and Stress System Disorders: Overview of Physical and Behavioral Homeostasis. JAMA 267:1244–1252. https://doi.org/10.1001/jama.1992.03480090092034 CAS Article PubMed Google Scholar Kling MA, Roy A, Doran AR et al (1991) Cerebrospinal fluid immunoreactive corticotropin-releasing hormone and adrenocorticotropin secretion in Cushing’s disease and major depression: potential clinical implications. J Clin Endocrinol Metab 72:260–271. https://doi.org/10.1210/jcem-72-2-260 CAS Article PubMed Google Scholar Gomez MT, Magiakou MA, Mastorakos G, Chrousos GP (1993) The pituitary corticotroph is not the rate limiting step in the postoperative recovery of the hypothalamic-pituitary-adrenal axis in patients with Cushing syndrome. J Clin Endocrinol Metab 77:173–177. https://doi.org/10.1210/jcem.77.1.8392083 CAS Article PubMed Google Scholar Young EA, Kwak SP, Kottak J (1995) Negative feedback regulation following administration of chronic exogenous corticosterone. J Neuroendocrinol 7:37–45. https://doi.org/10.1111/j.1365-2826.1995.tb00665.x CAS Article PubMed Google Scholar Papanicolaou DA, Tsigos C, Oldfield EH, Chrousos GP (1996) Acute glucocorticoid deficiency is associated with plasma elevations of interleukin-6: does the latter participate in the symptomatology of the steroid withdrawal syndrome and adrenal insufficiency? J Clin Endocrinol Metab 81:2303–2306. https://doi.org/10.1210/jcem.81.6.8964868 CAS Article PubMed Google Scholar Ciric I, Zhao J-C, Du H et al (2012) Transsphenoidal surgery for Cushing disease: experience with 136 patients. Neurosurgery 70:70–80 discussion 80–81. https://doi.org/10.1227/NEU.0b013e31822dda2c Article PubMed Google Scholar Alexandraki KI, Kaltsas GA, Isidori AM et al (2013) Long-term remission and recurrence rates in Cushing’s disease: predictive factors in a single-centre study. Eur J Endocrinol 168:639–648. https://doi.org/10.1530/EJE-12-0921 CAS Article PubMed Google Scholar Capatina C, Hinojosa-Amaya JM, Poiana C, Fleseriu M (2020) Management of patients with persistent or recurrent Cushing’s disease after initial pituitary surgery. Expert Rev Endocrinol Metab 15:321–339. https://doi.org/10.1080/17446651.2020.1802243 CAS Article PubMed Google Scholar Stroud A, Dhaliwal P, Alvarado R et al (2020) Outcomes of pituitary surgery for Cushing’s disease: a systematic review and meta-analysis. Pituitary 23:595–609. https://doi.org/10.1007/s11102-020-01066-8 Article PubMed Google Scholar Acree R, Miller CM, Abel BS et al (2021) Patient and Provider Perspectives on Postsurgical Recovery of Cushing Syndrome. J Endocr Soc 5:bvab109. https://doi.org/10.1210/jendso/bvab109 Article PubMed PubMed Central Google Scholar AbdelMannan D, Selman WR, Arafah BM (2010) Peri-operative management of Cushing’s disease. Rev Endocr Metab Disord 11:127–134. https://doi.org/10.1007/s11154-010-9140-6 Article PubMed Google Scholar Costenaro F, Rodrigues TC, Rollin GAF et al (2014) Evaluation of Cushing’s disease remission after transsphenoidal surgery based on early serum cortisol dynamics. Clin Endocrinol (Oxf) 80:411–418. https://doi.org/10.1111/cen.12300 CAS Article Google Scholar Varlamov EV, Vila G, Fleseriu M (2022) Perioperative Management of a Patient With Cushing Disease. J Endocr Soc 6:bvac010. https://doi.org/10.1210/jendso/bvac010 Article PubMed PubMed Central Google Scholar El Asmar N, Rajpal A, Selman WR, Arafah BM (2018) The Value of Perioperative Levels of ACTH, DHEA, and DHEA-S and Tumor Size in Predicting Recurrence of Cushing Disease. J Clin Endocrinol Metab 103:477–485. https://doi.org/10.1210/jc.2017-01797 Article PubMed Google Scholar DeLozier OM, Dream SY, Findling JW et al (2022) Selective Glucocorticoid Replacement Following Unilateral Adrenalectomy for Hypercortisolism and Primary Aldosteronism. J Clin Endocrinol Metab 107:e538–e547. https://doi.org/10.1210/clinem/dgab698 Article PubMed Google Scholar Stuijver DJF, van Zaane B, Feelders RA et al (2011) Incidence of venous thromboembolism in patients with Cushing’s syndrome: a multicenter cohort study. J Clin Endocrinol Metab 96:3525–3532. https://doi.org/10.1210/jc.2011-1661 CAS Article PubMed Google Scholar van der Pas R, Leebeek FWG, Hofland LJ et al (2013) Hypercoagulability in Cushing’s syndrome: prevalence, pathogenesis and treatment. Clin Endocrinol (Oxf) 78:481–488. https://doi.org/10.1111/cen.12094 CAS Article Google Scholar van der Pas R, de Bruin C, Leebeek FWG et al (2012) The hypercoagulable state in Cushing’s disease is associated with increased levels of procoagulant factors and impaired fibrinolysis, but is not reversible after short-term biochemical remission induced by medical therapy. J Clin Endocrinol Metab 97:1303–1310. https://doi.org/10.1210/jc.2011-2753 CAS Article PubMed Google Scholar Kristof RA, Rother M, Neuloh G, Klingmüller D (2009) Incidence, clinical manifestations, and course of water and electrolyte metabolism disturbances following transsphenoidal pituitary adenoma surgery: a prospective observational study: Clinical article. J Neurosurg 111:555–562. https://doi.org/10.3171/2008.9.JNS08191 Article PubMed Google Scholar Yuen KCJ, Ajmal A, Correa R, Little AS (2019) Sodium Perturbations After Pituitary Surgery. Neurosurg Clin 30:515–524. https://doi.org/10.1016/j.nec.2019.05.011 Article Google Scholar Ghiam MK, Chyou DE, Dable CL et al (2021) 30-Day Readmissions and Coordination of Care Following Endoscopic Transsphenoidal Pituitary Surgery: Experience with 409 Patients. J Neurol Surg Part B Skull Base. https://doi.org/10.1055/s-0041-1729980 Article Google Scholar Bohl MA, Ahmad S, Jahnke H et al (2016) Delayed Hyponatremia Is the Most Common Cause of 30-Day Unplanned Readmission After Transsphenoidal Surgery for Pituitary Tumors. Neurosurgery 78:84–90. https://doi.org/10.1227/NEU.0000000000001003 Article PubMed Google Scholar Doherty GM, Nieman LK, Cutler GB et al (1990) Time to recovery of the hypothalamic-pituitary-adrenal axis after curative resection of adrenal tumors in patients with Cushing’s syndrome. Surgery 108:1085–1090 CAS PubMed Google Scholar Sippel RS, Elaraj DM, Kebebew E et al (2008) Waiting for change: Symptom resolution after adrenalectomy for Cushing’s syndrome. Surgery 144:1054–1061. https://doi.org/10.1016/j.surg.2008.08.024 Article PubMed Google Scholar Derendorf H, Möllmann H, Barth J et al (1991) Pharmacokinetics and Oral Bioavailability of Hydrocortisone. J Clin Pharmacol 31:473–476. https://doi.org/10.1002/j.1552-4604.1991.tb01906.x CAS Article PubMed Google Scholar Suzuki K, Nonaka K, Ichihara K et al (1986) Hypercalcemia in Glucocorticoid Withdrawal. Endocrinol Jpn 33:203–209. https://doi.org/10.1507/endocrj1954.33.203 CAS Article PubMed Google Scholar Oyama Y, Iwafuchi Y, Narita I (2021) A case of hypercalcemia because of adrenal insufficiency induced by glucocorticoid withdrawal in a patient undergoing hemodialysis. CEN Case Rep. https://doi.org/10.1007/s13730-021-00619-5 Article PubMed PubMed Central Google Scholar Berr CM, Di Dalmazi G, Osswald A et al (2015) Time to Recovery of Adrenal Function After Curative Surgery for Cushing’s Syndrome Depends on Etiology. J Clin Endocrinol Metab 100:1300–1308. https://doi.org/10.1210/jc.2014-3632 CAS Article PubMed Google Scholar Gad HEM, Ismail AM (2020) The role of vertebroplasty in steroid-induced vertebral osteoporotic fractures. Egypt Spine J 35:41–52. https://doi.org/10.21608/esj.2020.34844.1140 Article Google Scholar Vogel F, Braun LT, Rubinstein G et al (2020) Persisting Muscle Dysfunction in Cushing’s Syndrome Despite Biochemical Remission. J Clin Endocrinol Metab 105:e4490–e4498. https://doi.org/10.1210/clinem/dgaa625 Article PubMed Central Google Scholar Vogel F, Braun L, Rubinstein G et al (2021) Patients with low IGF-I after curative surgery for Cushing’s syndrome have an adverse long-term outcome of hypercortisolism-induced myopathy. Eur J Endocrinol 184:813–821. https://doi.org/10.1530/EJE-20-1285 CAS Article PubMed Google Scholar Andela CD, van Haalen FM, Ragnarsson O et al (2015) MECHANISMS IN ENDOCRINOLOGY: Cushing’s syndrome causes irreversible effects on the human brain: a systematic review of structural and functional magnetic resonance imaging studies. Eur J Endocrinol 173:R1–R14. https://doi.org/10.1530/EJE-14-1101 CAS Article PubMed Google Scholar Bride MM, Crespo I, Webb SM, Valassi E (2021) Quality of life in Cushing’s syndrome. Best Pract Res Clin Endocrinol Metab 35:101505. https://doi.org/10.1016/j.beem.2021.101505 CAS Article PubMed Google Scholar Starkman MN, Gebarski SS, Berent S, Schteingart DE (1992) Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing’s syndrome. Biol Psychiatry 32:756–765. https://doi.org/10.1016/0006-3223(92)90079-F CAS Article PubMed Google Scholar McEwen BS, Gould EA, Sakai RR (1992) The Vulnerability of the Hippocampus to Protective and Destructive Effects of Glucocorticoids in Relation to Stress. Br J Psychiatry 160:18–23. https://doi.org/10.1192/S0007125000296645 Article Google Scholar van Aken MO, Pereira AM, Biermasz NR et al (2005) Quality of Life in Patients after Long-Term Biochemical Cure of Cushing’s Disease. J Clin Endocrinol Metab 90:3279–3286. https://doi.org/10.1210/jc.2004-1375 CAS Article PubMed Google Scholar Zorumski CF, Paul SM, Izumi Y et al (2013) Neurosteroids, stress and depression: potential therapeutic opportunities. Neurosci Biobehav Rev 37:109–122. https://doi.org/10.1016/j.neubiorev.2012.10.005 CAS Article PubMed Google Scholar Download references Acknowledgements We thank Recordati Rare Diseases for their support with literature review and figure preparation to the authors’ designs. Funding XH is supported by grant T32DK07245 from the National Institutes of Diabetes and Digestive and Kidney Diseases. Author information Affiliations Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, MI, USA Xin He & Richard J. Auchus Department of Medicine, Division of Endocrinology and Molecular Medicine, Medical College of Wisconsin, Milwaukee, WI, USA James W. Findling Endocrinology Center and Clinics, Medical College of Wisconsin, Milwaukee, WI, USA James W. Findling Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA Richard J. Auchus Lieutenant Colonel Charles S. Kettles Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA Richard J. Auchus Contributions All authors contributed to the manuscript conception, design, and content. All authors read, edited, and approved the final manuscript. Corresponding author Correspondence to Richard J. Auchus. Ethics declarations Financial Interests Dr. Auchus has received research support from Novartis Pharmaceuticals, Corcept Therapeutics, Spruce Biosciences, and Neurocrine Biosciences and has served as a consultant for Corcept Therapeutics, Janssen Pharmaceuticals, Novartis Pharmaceuticals, Quest Diagnostics, Adrenas Therapeutics, Crinetics Pharmaceuticals, PhaseBio Pharmaceuticals, OMass Therapeutics, Recordati Rare Diseases, Strongbridge Biopharma, and H Lundbeck A/S. Dr. Findling has received research support from Novartis Pharmaceuticals and has served as a consultant for Corcept Therapeutics and Recordati Rare Diseases. Human Subjects and Animals No human subjects or animals were used to collect data for this manuscript. Additional information Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Electronic Supplementary Material Below is the link to the electronic supplementary material. Supplementary Material 1 Rights and permissions Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Reprints and Permissions Cite this article He, X., Findling, J.W. & Auchus, R.J. Glucocorticoid Withdrawal Syndrome following treatment of endogenous Cushing Syndrome. Pituitary (2022). https://doi.org/10.1007/s11102-022-01218-y Download citation Accepted15 March 2022 Published26 April 2022 DOIhttps://doi.org/10.1007/s11102-022-01218-y From https://link.springer.com/article/10.1007/s11102-022-01218-y

Abstract Objective We aimed to perform a systematic review and meta-analysis of all-cause and cause-specific mortality of patients with benign endogenous Cushing's syndrome (CS). Methods The protocol was registered in PROSPERO (CRD42017067530). PubMed, EMBASE, CINHAL, Web of Science and Cochrane Central searches were undertaken from inception to January 2021. Outcomes were the standardized mortality ratio (SMR), proportion and cause of deaths. The I 2 test, subgroup analysis and meta-regression were used to assess heterogeneity across studies. Results SMR was reported in 14 articles including 3,691 patients (13 Cushing's disease (CD) and 7 adrenal CS (ACS) cohorts). Overall SMR was 3.0 (95%CI 2.3-3.9; I 2=80.5%) for all CS, 2.8 (95%CI 2.1-3.7 I 2=81.2%) for CD and 3.3 (95%CI 0.5-6.6; I 2=77.9%) for ACS. Proportion of deaths, reported in 87 articles including 19,181 CS patients (53 CD, 24 ACS, and 20 combined CS cohorts) was 0.05 (95%CI 0.03, 0.06) for all CS subtypes with meta-regression analysis revealing no differences between CS subtypes (P=0.052). The proportion of deaths was 0.1 (10%) in articles published before 2000 and 0.03 (3%) in 2000 until the last search for CS (P<0.001), CD (p<0.001), and ACS (P=0.01). The causes of death were atherosclerotic diseases and thromboembolism (43.4%), infection (12.7%), malignancy (10.6%), active disease (3.5%), adrenal insufficiency (3.0%), and suicide (2.2%). Despite improved outcomes in recent years, increased mortality from CS persists. The causes of death highlight the need to prevent and manage co-morbidities in addition to treating hypercortisolism. Cushing's syndrome, mortality, meta-analysis, causes of death, meta-regression analysis Issue Section: META-ANALYSIS Accepted manuscripts Accepted manuscripts are PDF versions of the author’s final manuscript, as accepted for publication by the journal but prior to copyediting or typesetting. They can be cited using the author(s), article title, journal title, year of online publication, and DOI. They will be replaced by the final typeset articles, which may therefore contain changes. The DOI will remain the same throughout. PDF This content is only available as a PDF. © The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Excess mortality among people with endogenous Cushing syndrome (CS) has declined in the past 20 years yet remains three times higher than in the general population, new research finds. Among more than 90,000 individuals with endogenous CS, the overall proportion of mortality ― defined as the ratio of the number of deaths from CS divided by the total number of CS patients ― was 0.05, and the standardized mortality rate was an "unacceptable" three times that of the general population, Padiporn Limumpornpetch, MD, reported on March 20 at ENDO 2021: The Endocrine Society Annual Meeting. Excess deaths were higher among those with adrenal CS compared to those with Cushing disease. The most common causes of death among those with CS were cardiovascular diseases, cerebrovascular accident, infection, and malignancy, noted Limumpornpetch, of Songkla University, Hat Yai, Thailand, who is also a PhD student at the University of Leeds, Leeds, United Kingdom. "While mortality has improved since 2000, it is still significantly compromised compared to the background population.... The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism, infection control, and a normalized cortisol level," she said. Asked to comment, Maria Fleseriu, MD, told Medscape Medical News that the new data show "we are making improvements in the care of patients with CS and thus outcomes, but we are not there yet.... This meta-analysis highlights the whole spectrum of acute and life-threatening complications in CS and their high prevalence, even before disease diagnosis and after successful surgery." She noted that although she wasn't surprised by the overall results, "the improvement over time was indeed lower than I expected. However, interestingly here, the risk of mortality in adrenal Cushing was unexpectedly high despite patients with adrenal cancer being excluded." Fleseriu, who is director of the Pituitary Center at Oregon Health and Science University, Portland, Oregon, advised, "Management of hyperglycemia and diabetes, hypertension, hypokalemia, hyperlipidemia, and other cardiovascular risk factors is generally undertaken in accordance with standard of clinical care. "But we should focus more on optimizing more aggressively this care in addition to the specific Cushing treatment," she stressed. In addition, she noted, "Medical therapy for CS may be needed even prior to surgery in severe and/or prolonged hypercortisolism to decrease complications.... We definitely need a multidisciplinary approach to address complications and etiologic treatment as well as the reduced long-term quality of life in patients with CS." Largest Study in Scale and Scope of Cushing Syndrome Mortality Endogenous Cushing syndrome occurs when the body overproduces cortisol. The most common cause of the latter is a tumor of the pituitary gland (Cushing disease), but another cause is a usually benign tumor of the adrenal glands (adrenal Cushing syndrome). Surgery is the mainstay of initial treatment of Cushing syndrome. If an operation to remove the tumor fails to cause remission, medications are available. Prior to this new meta-analysis, there had been limited data on mortality among patients with endogenous CS. Research has mostly been limited to single-cohort studies. A previous systematic review/meta-analysis comprised only seven articles with 780 patients. All the studies were conducted prior to 2012, and most were limited to Cushing disease. "In 2021, we lacked a detailed understanding of patient outcomes and mortality because of the rarity of Cushing syndrome," Limumpornpetch noted. The current meta-analysis included 91 articles that reported mortality among patients with endogenous CS. There was a total of 19,181 patients from 92 study cohorts, including 49 studies on CD (n = 14,971), 24 studies on adrenal CS (n = 2304), and 19 studies that included both CS types (n = 1906). Among 21 studies that reported standardized mortality rate (SMR) data, including 13 CD studies (n = 2160) and seven on adrenal CS (n = 1531), the overall increase in mortality compared to the background population was a significant 3.00 (range, 1.15 – 7.84). This SMR was higher among patients with adrenal Cushing syndrome (3.3) vs Cushing disease (2.8) (P = .003) and among patients who had active disease (5.7) vs those whose disease was in remission (2.3) (P < .001). The SMR also was worse among patients with Cushing disease with larger tumors (macroadenomas), at 7.4, than among patients with very small tumors (microadenomas), at 1.9 (P = .004). The proportion of death was 0.05 for CS overall, with 0.04 for CD and 0.02 for adrenal adenomas. Compared to studies published prior to the year 2000, more recent studies seem to reflect advances in treatment and care. The overall proportion of death for all CS cohorts dropped from 0.10 to 0.03 (P < .001); for all CD cohorts, it dropped from 0.14 to 0.03; and for adrenal CS cohorts, it dropped from 0.09 to 0.03 (P = .04). Causes of death were cardiovascular diseases (29.5% of cases), cerebrovascular accident (11.5%), infection (10.5%), and malignancy (10.1%). Less common causes of death were gastrointestinal bleeding and acute pancreatitis (3.7%), active CS (3.5%), adrenal insufficiency (2.5%), suicide (2.5%), and surgery (1.6%). Overall, in the CS groups, the proportion of deaths within 30 days of surgery dropped from 0.04 prior to 2000 to 0.01 since (P = .07). For CD, the proportion dropped from 0.02 to 0.01 (P = .25). Preventing Perioperative Mortality: Consider Thromboprophylaxis Fleseriu told Medscape Medical News that she believes hypercoagulability is "the least recognized complication with a big role in mortality." Because most of the perioperative mortality is due to venous thromboembolism and infections, "thromboprophylaxis should be considered for CS patients with severe hypercortisolism and/or postoperatively, based on individual risk factors of thromboembolism and bleeding." Recently, Fleseriu's group showed in a single retrospective study that the risk for arterial and venous thromboembolic events among patients with CS was approximately 20%. Many patients experienced more than one event. Risk was higher 30 to 60 days postoperatively. The odds ratio of venous thromoboembolism among patients with CS was 18 times higher than in the normal population. "Due to the additional thrombotic risk of surgery or any invasive procedure, anticoagulation prophylaxis should be at least considered in all patients with Cushing syndrome and balanced with individual bleeding risk," Fleseriu advised. A recent Pituitary Society workshop discussed the management of complications of CS at length; proceedings will be published soon, she noted. Limumpornpetch commented, "We look forward to the day when our interdisciplinary approach to managing these challenging patients can deliver outcomes similar to the background population." Limumpornpetch has disclosed no relevant financial relationships. Fleseriu has been a scientific consultant to Recordati, Sparrow, and Strongbridge and has received grants (inst) from Novartis and Strongbridge. ENDO 2021: The Endocrine Society Annual Meeting: Presented March 20, 2021 Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape. Other work of hers has appeared in the Washington Post, NPR's Shots blog, and Diabetes Forecast magazine. She can be found on Twitter @MiriamETucker. From https://www.medscape.com/viewarticle/949257

~ RECORLEV® (levoketoconazole) New Drug Application is Supported by Previously-Reported Positive and Statistically Significant Results from the Phase 3 SONICS and LOGICS Studies ~ ~ Nearly 40 Percent of Prescription-Treated Endogenous Cushing’s Syndrome Patients in the U.S. Are Not Well-Controlled, Underscoring Need for New, Safe and Effective Pharmaceutical Options to Help Regulate Cortisol Levels ~ ~ If Approved Following a Projected 10-Month Review Cycle, RECORLEV is Anticipated to Launch in First Quarter of 2022 ~ DUBLIN, Ireland and TREVOSE, Pa., March 02, 2021 (GLOBE NEWSWIRE) -- Strongbridge Biopharma plc, (Nasdaq: SBBP), a global commercial-stage biopharmaceutical company focused on the development and commercialization of therapies for rare diseases with significant unmet needs, today announced that it submitted a New Drug Application (NDA) for RECORLEV® (levoketoconazole) for the treatment of endogenous Cushing’s syndrome to the U.S. Food and Drug Administration (FDA). The submission is supported by previously reported positive and statistically significant results of the SONICS and LOGICS trials: two Phase 3 multinational studies designed to evaluate the safety and efficacy of RECORLEV when used to treat adults with endogenous Cushing’s syndrome. “The submission of the New Drug Application for RECORLEV® (levoketoconazole) represents not only a significant milestone for Strongbridge but also for the Cushing’s syndrome community as a whole. As an organization focused on developing treatments for underserved rare disease patient populations, we are one step closer to helping address the needs of the estimated 8,000 Cushing’s syndrome patients in the U.S. who are treated with prescription therapy, many of whom, as we learned in our market research, are not well-controlled with current therapies,” said John H. Johnson, chief executive officer of Strongbridge Biopharma. “We look forward to working with the FDA through their review of our application, and we are actively preparing for the potential launch of RECORLEV in the first quarter of 2022, if approved.” RECORLEV, the pure 2S,4R enantiomer of the enantiomeric pair comprising ketoconazole, is a next-generation steroidogenesis inhibitor being investigated as a chronic therapy for adults with endogenous Cushing’s syndrome. Two Phase 3 studies have demonstrated substantial evidence of efficacy and safety in a combined study population of 166 patients that was representative of the adult drug-treated U.S. population with Cushing’s syndrome. The SONICS study met its primary and key secondary endpoints, demonstrating a statistically significant rate of mean urinary free cortisol normalization after six months of maintenance therapy without a dose increase (detailed results here). LOGICS, a double-blind, placebo-controlled randomized-withdrawal study, which also had statistically significant primary and key secondary endpoints, confirmed that the long-term cortisol-normalizing efficacy demonstrated in SONICS was due to use of levoketoconazole specifically (detailed results here). The long-term open-label extension study, OPTICS, is contributing safety information to the NDA. “We want to thank the patients, their families, investigators, collaborators, and employees who have contributed to the RECORLEV clinical program leading to this important regulatory milestone,” said Fredric Cohen, M.D., chief medical officer of Strongbridge Biopharma. RECORLEV has received orphan drug designation from the FDA and the European Medicines Agency for the treatment of endogenous Cushing's syndrome. Strongbridge will host a conference call tomorrow, Wednesday, March 3, 2021 at 8:30 a.m. ET to discuss the Company’s fourth quarter and full-year 2020 financial results and recent corporate highlights, including the RECORLEV NDA submission. About Cushing’s Syndrome Endogenous Cushing’s syndrome is a rare, serious and potentially lethal endocrine disease caused by chronic elevated cortisol exposure - often the result of a benign tumor of the pituitary gland. This benign tumor tells the body to overproduce high levels of cortisol for a sustained period of time, and this often results in undesirable physical changes. The disease is most common among adults between the ages of 30 to 50, and it affects women three times more often than men. Women with Cushing's syndrome may experience a variety of health issues including menstrual problems, difficulty becoming pregnant, excess male hormones (androgens), primarily testosterone which can cause hirsutism (growth of coarse body hair in a male pattern), oily skin, and acne. Additionally, the internal manifestations of the disease are potentially life threatening. These include metabolic changes such as high blood sugar, or diabetes, high blood pressure, high cholesterol, fragility of various tissues including blood vessels, skin, muscle and bone, and psychologic disturbances such as depression, anxiety and insomnia. Untreated, the five-year survival rate is only approximately 50 percent. About the SONICS Study SONICS is an open-label, Phase 3 study of RECORLEV as a treatment for endogenous Cushing’s syndrome that enrolled 94 patients at centers in North America, Europe and the Middle East. Following a screening phase, SONICS has three treatment phases: (1) Dose Titration Phase: Patients started RECORLEV at 150 mg twice daily (300 mg total daily dose) and titrated in 150 mg increments with the goal of achieving a therapeutic dose – a dose resulting in mUFC normalization – at which point titration was stopped; (2) Maintenance Phase: The dose was fixed and should not have been changed other than for safety reasons or loss of efficacy. At the end of the six-month maintenance phase, the mUFC response rate was measured; and (3) Extended Evaluation Phase: Patients continued on RECORLEV for another six months to evaluate long-term safety and tolerability and explore efficacy durability. About the LOGICS Study The Phase 3, multinational, double-blind, placebo-controlled, randomized-withdrawal study, LOGICS, randomized Cushing’s syndrome patients with baseline mean urinary free cortisol (mUFC) at least 1.5 times the upper limit of normal (ULN) following completion of a single-arm, open-label treatment phase of approximately 14 to 19 weeks, with RECORLEV individually titrated according to mUFC response. A total of 79 patients were dosed during the open-label titration-maintenance phase, 7 of whom had previously received RECORLEV during the SONICS study, and 72 who had not previously received RECORLEV. At study baseline, the median mUFC was 3.5 times the ULN, indicative of significant hypercortisolemia. A total of 44 patients (39 who had completed the titration-maintenance phase and five who directly enrolled from the SONICS study), were randomized to either continue RECORLEV (n=22) or to have treatment withdrawn by receiving a matching placebo regimen (n=22) for up to 8 weeks, followed by restoration to the prior regimen using blinded drug. Of the 44 patients randomized, 11 patients (25 percent) had previously received RECORLEV during the SONICS study. Patients who required rescue treatment with open-label RECORLEV during the randomized-withdrawal phase were considered to have lost mUFC response at the visit corresponding to their first dose of rescue medication. Patients who did not qualify for randomization were removed from open-label treatment prior to randomization and excused from the study. About RECORLEV RECORLEV® (levoketoconazole) is an investigational cortisol synthesis inhibitor in development for the treatment of patients with endogenous Cushing’s syndrome, a rare but serious and potentially lethal endocrine disease caused by chronic elevated cortisol exposure. RECORLEV is the pure 2S,4R enantiomer of ketoconazole, a steroidogenesis inhibitor. RECORLEV has demonstrated in two successful Phase 3 studies to significantly suppress serum cortisol and has the potential to be a next-generation cortisol inhibitor. The Phase 3 program for RECORLEV includes SONICS and LOGICS: two multinational studies designed to evaluate the safety and efficacy of RECORLEV when used to treat endogenous Cushing’s syndrome. The SONICS study met its primary and secondary endpoints, demonstrating a statistically significant normalization rate of urinary free cortisol at six months. The LOGICS study, which met its primary endpoint, is a double-blind, placebo-controlled randomized-withdrawal study of RECORLEV that is designed to supplement the long-term efficacy and safety information supplied by SONICS. The ongoing long-term open label OPTICS study will gather further useful information related to the long-term use of RECORLEV. RECORLEV has received orphan drug designation from the FDA and the European Medicines Agency for the treatment of endogenous Cushing's syndrome. About Strongbridge Biopharma Strongbridge Biopharma is a global commercial-stage biopharmaceutical company focused on the development and commercialization of therapies for rare diseases with significant unmet needs. Strongbridge’s rare endocrine franchise includes RECORLEV® (levoketoconazole), a cortisol synthesis inhibitor currently being studied in Phase 3 clinical studies for the treatment of endogenous Cushing’s syndrome, and veldoreotide extended release, a pre-clinical next-generation somatostatin analog being investigated for the treatment of acromegaly and potential additional applications in other conditions amenable to somatostatin receptor activation. Both RECORLEV and veldoreotide have received orphan drug designation from the FDA and the European Medicines Agency. The Company’s rare neuromuscular franchise includes KEVEYIS® (dichlorphenamide), the first and only FDA-approved treatment for hyperkalemic, hypokalemic, and related variants of primary periodic paralysis. KEVEYIS has orphan drug exclusivity in the United States. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the federal securities laws. The words “anticipate,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “project,” “target,” “will,” “would,” or the negative of these terms or other similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. All statements, other than statements of historical facts, contained in this press release, are forward-looking statements, including statements related to data from the LOGICS and SONICS studies, the potential advantages of RECORLEV, the anticipated timing for potential approval of a marketing authorization for RECORLEV and for the potential launch of RECORLEV, Strongbridge’s strategy, plans, outcomes of product development efforts and objectives of management for future operations. Forward-looking statements involve risks and uncertainties that could cause actual results to differ materially from those expressed in such statement, including risks and uncertainties associated with clinical development and the regulatory approval process, the reproducibility of any reported results showing the benefits of RECORLEV, the adoption of RECORLEV by physicians, if approved, as treatment for any disease and the emergence of unexpected adverse events following regulatory approval and use of the product by patients. Additional risks and uncertainties relating to Strongbridge and its business can be found under the heading “Risk Factors” in Strongbridge’s Annual Report on Form 10-K for the year ended December 31, 2019 and its subsequent Quarterly Reports on Form 10-Q, as well as its other filings with the SEC. These forward-looking statements are based on current expectations, estimates, forecasts and projections and are not guarantees of future performance or development and involve known and unknown risks, uncertainties and other factors. The forward-looking statements contained in this press release are made as of the date of this press release, and Strongbridge Biopharma does not assume any obligation to update any forward-looking statements except as required by applicable law. Contacts: Corporate and Media Relations Elixir Health Public Relations Lindsay Rocco +1 862-596-1304 lrocco@elixirhealthpr.com Investor Relations Solebury Trout Mike Biega +1 617-221-9660 mbiega@soleburytrout.com From https://www.biospace.com/article/releases/strongbridge-biopharma-plc-announces-submission-of-new-drug-application-for-recorlev-levoketoconazole-for-the-treatment-of-endogenous-cushing-s-syndrome-to-the-u-s-food-and-drug-administration/

Hello Everyone Keck Medicine of USC is currently enrolling people who have Cushing's Syndrome to participate in a clinical trial they are conducting. If you are interested or know someone who may benefit please email me at mlambert@threewire.com or call to make an appointment 800-USC-CARE