Osilodrostat Improves Physical Manifestations of Hypercortisolism for Most Adults

Osilodrostat is associated with improvements in physical manifestations of hypercortisolism and reductions in mean body weight and BMI in adults with Cushing’s syndrome, according to a speaker.

As Healio previously reported, in findings from the LINC 4 phase 3 trial, osilodrostat (Isturisa, Recordati) normalized mean urinary free cortisol level at 12 weeks in more than 75% of adults with Cushing’s disease. In new findings presented at the AACE Annual Scientific and Clinical Conference, most adults with Cushing’s syndrome participating in the LINC 3 phase 3 trial had improvements in physical manifestations of hypercortisolism 72 weeks after initiating osilodrostat, with more than 50% having no dorsal fat pad, supraclavicular fat pad, facial rubor, proximal muscle atrophy, striae, ecchymoses and hirsutism for women at 72 weeks.

Adrenal transparent _Adobe
Source: Adobe Stock

“Many patients with Cushing’s syndrome suffer from clinical manifestations related to hypercortisolism,” Albert M. Pedroncelli, MD, PhD, head of clinical development and medical affairs for Recordati AG in Basel, Switzerland, told Healio. “The treatment with osilodrostat induced a rapid normalization of cortisol secretion, and improvements in physical manifestations associated with hypercortisolism were observed soon after initiation of osilodrostat and were sustained throughout the study.”

Albert M. Pedroncelli

Pedroncelli and colleagues analyzed changes in the physical manifestations of hypercortisolism in 137 adults with Cushing’s syndrome (median age, 40 years; 77.4% women) assigned osilodrostat. Dose titration took place from baseline to 12 weeks, and therapeutic doses were administered from 12 to 48 weeks, with some participants randomly assigned to withdrawal between 26 and 34 weeks. An extension phase of the trial took place from 48 to 72 weeks. Investigators subjectively rated physical manifestations of hypercortisolism in participants as none, mild, moderate or severe. Participants were evaluated at baseline and 12, 24, 34, 48 and 72 weeks.

At baseline, the majority of the study cohort had mild, moderate or severe physical manifestations of hypercortisolism in most individual categories, including dorsal fat pad, central obesity, supraclavicular fat pad, facial rubor, hirsutism in women and striae. Central obesity was the most frequent physical manifestation rated as severe.

The percentage of participants with improvements in physical manifestations of hypercortisolism increased from week 12 on for all individual manifestations evaluated in the study, and improvements were maintained through week 72. At 72 weeks, the percentage of participants who had no individual physical manifestations was higher than 50% for each category except central obesity, where 30.6% of participants had no physical manifestations.

In addition to improvement in physical manifestations, the study cohort had decreases in body weight, BMI and waist circumference at weeks 48 and 72 compared with baseline.

“The main goal of treating patients with Cushing’s syndrome is to normalize cortisol secretion,” Pedroncelli said. “The rapid reduction and normalization of cortisol levels is accompanied by improvement in the associated clinical manifestations. This represents an important objective for patients.”

From https://www.healio.com/news/endocrinology/20220512/osilodrostat-improves-physical-manifestations-of-hypercortisolism-for-most-adults

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.

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[67] (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[2021].

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

figure 1

Overlapping clinical features of Cushing syndrome (CS), glucocorticoid withdrawal syndrome (GWS), and adrenal insufficiency (AI)

Table 1 Glucocorticoid Therapy Options After Surgery for CS

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[15,16,17,1834]. 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[4142]. In the first week or two after discharge, the most common cause for readmission is hyponatremia[4344], 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

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 [4546]. 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[4849].

Fig. 2

figure 2

Glucocorticoid withdrawal algorithm. TDD, total daily dose

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[5455]. 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[5657]. 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

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  21. 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

  22. 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

  23. 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

  24. 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

  25. 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

  26. 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

  27. 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

  28. 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

  29. 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

  30. 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

  31. 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

  32. 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

  33. 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

  34. 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

  35. 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

  36. 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

  37. 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

  38. 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

  39. 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

  40. 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

  41. 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

  42. 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

  43. 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

  44. 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

  45. 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

  46. 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

  47. 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

  48. 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

  49. 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

  50. 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

  51. 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

  52. 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

  53. 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

  54. 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

  55. 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

  56. 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

  57. 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

  58. 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

  59. 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

  1. Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, MI, USA

    Xin He & Richard J. Auchus

  2. Department of Medicine, Division of Endocrinology and Molecular Medicine, Medical College of Wisconsin, Milwaukee, WI, USA

    James W. Findling

  3. Endocrinology Center and Clinics, Medical College of Wisconsin, Milwaukee, WI, USA

    James W. Findling

  4. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA

    Richard J. Auchus

  5. 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.

About this article

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

From https://link.springer.com/article/10.1007/s11102-022-01218-y

Adrenal Fatigue: Faux Diagnosis?

This article is based on reporting that features expert sources.

U.S. News & World Report

Adrenal Fatigue: Is It Real?

You may have heard of so-called ‘adrenal fatigue,’ supposedly caused by ongoing emotional stress. Or you might have come across adrenal support supplements sold online to treat it. But if someone suggests you have the controversial, unproven condition, seek a second opinion, experts say. And if someone tries to sell you dietary supplements or other treatments for adrenal fatigue, be safe and save your money.

Tired man sitting at desk in modern office

(GETTY IMAGES)

Physicians tend to talk about ‘reaching’ or ‘making’ a medical diagnosis. However, when it comes to adrenal fatigue, endocrinologists – doctors who specialize in diseases involving hormone-secreting glands like the adrenals – sometimes use language such as ‘perpetrating a diagnosis,’ ‘misdiagnosis,’ ‘made-up diagnosis,’ ‘a fallacy’ and ‘nonsense.’

About 20 years ago, the term “adrenal fatigue” was coined by Dr. James Wilson, a chiropractor. Since then, certain practitioners and marketers have promoted the notion that chronic stress somehow slows or shuts down the adrenal glands, causing excessive fatigue.

“The phenomenon emerged from the world of integrative medicine and naturopathic medicine,” says Dr. James Findling, a professor of medicine and director of the Community Endocrinology Center and Clinics at the Medical College of Wisconsin. “It has no scientific basis, and there’s no merit to it as a clinical diagnosis.”

An online search of medical billing code sets in the latest version of the International Classification of Diseases, or the ICD-10, does not yield a diagnostic code for ‘adrenal fatigue’ among the 331 diagnoses related either to fatigue or adrenal conditions or procedures.

In a March 2020 position statement, the American Association of Clinical Endocrinologists and American College of Endocrinology addressed the use of adrenal supplements “to treat common nonspecific symptoms due to ‘adrenal fatigue,’ an entity that has not been recognized as a legitimate diagnosis.”

The position statement warned of known and unknown health risks of off-label use and misuse of hormones and supplements in patients without an established endocrine diagnosis, as well as unnecessary costs to patients and the overall health care system.

Study after study has refuted the legitimacy of adrenal fatigue as a medical diagnosis. An August 2016 systematic review combined and analyzed data from 58 studies on adrenal fatigue including more than 10,000 participants. The conclusion in a nutshell: “Adrenal fatigue does not exist,” according to review authors in the journal BMC Endocrine Disorders.

Adrenal Action

You have two adrenal glands in your body. These small triangular glands, one on top of each kidney, produce essential hormones such as aldosterone, cortisol and male sex hormones such as DHEA and testosterone.

Cortisol helps regulate metabolism: How your body uses fat, protein and carbohydrates from food, and cortisol increases blood sugar as needed. It also plays a role in controlling blood pressure, preventing inflammation and regulating your sleep/wake cycle.

As your body responds to stress, cortisol increases. This response starts with signals between two sections in the brain: The hypothalamus and the pituitary gland, which act together to release a hormone that stimulates the adrenal glands to make cortisol. This interactive unit is called the hypothalamic pituitary adrenal axis.

While some health conditions really do affect the body’s cortisol-making ability, adrenal fatigue isn’t among them.

“There’s no evidence to support that adrenal fatigue is an actual medical condition,” says Dr. Mary Vouyiouklis Kellis, a staff endocrinologist at Cleveland Clinic. “There’s no stress connection in the sense that someone’s adrenal glands will all of a sudden just stop producing cortisol because they’re so inundated with emotional stress.”

If anything, adrenal glands are workhorses that rise to the occasion when chronic stress occurs. “The last thing in the body that’s going to fatigue are your adrenal glands,” says Dr. William F. Young Jr., an endocrinology clinical professor and professor of medicine in the Mayo Clinic College of Medicine at Mayo Clinic in Rochester, Minnesota. “Adrenal glands are built for stress – that’s what they do. Adrenal glands don’t fatigue. This is made up – it’s a fallacy.”

The idea of adrenal glands crumbling under stress is “ridiculous,” Findling agrees. “In reality, if you take a person and subject them to chronic stress, the adrenal glands don’t shut down at all,” Findling says. “They keep making cortisol – it’s a stress hormone. In fact, the adrenal glands are just like the Energizer Bunny – they just keep going. They don’t stop.”

Home cortisol tests that allow consumers to check their own levels can be misleading, Findling says. “Some providers who make this (adrenal fatigue) diagnosis, provide patients with testing equipment for doing saliva cortisol levels throughout the day,” he says. “And then, regardless of what the results are, they perpetrate this diagnosis of adrenal fatigue.”

Saliva cortisol is a legitimate test that’s frequently used in diagnosing Cushing’s syndrome, or overactive adrenal glands, Findling notes. However, he says, a practitioner pursuing an adrenal fatigue diagnosis could game the system. “What they do is: They shape a very narrow normal range, so narrow, in fact, that no normal human subject could have all their saliva cortisol (levels) within that range throughout the course of the day,” he says. “Then they convince the poor patients that they have adrenal fatigue phenomena and put them on some kind of adrenal support.”

Loaded Supplements

How do you know what you’re actually getting if you buy a dietary supplement marketed for adrenal fatigue or ‘adrenal support’ use? To find out, researchers purchased 12 such supplements over the counter in the U.S.

Laboratory tests revealed that all supplements contained a small amount of thyroid hormone and most contained at least one steroid hormone, according to the study published in the March 2018 issue of Mayo Clinic Proceedings. “These results may highlight potential risks for hidden ingredients in unregulated supplements,” the authors concluded.

Supplements containing thyroid hormones or steroids can interact with a patient’s prescribed medications or have other side effects.

“Some people just assume they have adrenal fatigue because they looked it up online when they felt tired and they ultimately buy these over-the-counter supplements that can be very dangerous at times,” Vouyiouklis Kellis says. “Some of them contain animal (ingredients), like bovine adrenal extract. That can suppress the pituitary axis. So, as a result, your body stops making its own cortisol or starts making less of it, and as a result, you can actually worsen the condition rather than make it better.”

Any form of steroid from outside the body, whether a prescription drug like prednisone or extract from cows’ adrenal glands, “can shut off the pituitary,” Vouyiouklis Kellis explains. “Because it’s signaling to the pituitary like: Hey, you don’t need to stimulate the adrenals to make cortisol, because this patient is taking it already. So, as a result, the body ultimately doesn’t produce as much. And, so, if you rapidly withdraw that steroid or just all of a sudden decide not to take it anymore, then you can have this acute response of low cortisol.”

Some adrenal support products, such as herbal-only supplements, may be harmless. However, they’re unlikely to relieve chronic fatigue.

Fatigue: No Easy Answers

If you’re suffering from ongoing fatigue, it’s frustrating. And you’re not alone. “I have fatigue,” Young Jr. says. “Go to the lobby any given day and say, ‘Raise your hand if you have fatigue.’ Most of the people are going to raise their hands. It’s a common human symptom and people would like an easy answer for it. Usually there’s not an easy answer. I think ‘adrenal fatigue’ is attractive because it’s like: Aha, here’s the answer.”

There aren’t that many causes of endocrine-related fatigue, Young Jr. notes. “Hypothyroidism – when the thyroid gland is not working – is one.” Addison’s disease, or adrenal insufficiency, can also lead to fatigue among a variety of other symptoms. Established adrenal conditions – like adrenal insufficiency – need to be treated.

“In adrenal insufficiency, there is an intrinsic problem in the adrenal gland’s inability to produce cortisol,” Vouyiouklis Kellis explains. “That can either be a primary problem in the adrenal gland or an issue with the pituitary gland not being able to stimulate the adrenal to make cortisol.”

Issues can arise even with necessary medications. “For example, very commonly, people are put on steroids for various reasons: allergies, ear, nose and throat problems,” Vouyiouklis Kellis says. “And with the withdrawal of the steroids, they can ultimately have adrenal insufficiency, or decrease in cortisol.”

Opioid medications for pain also result in adrenal sufficiency, Vouyiouklis Kellis says, adding that this particular side effect is rarely discussed. People with a history of autoimmune disease can also be at higher risk for adrenal insufficiency.

Common symptoms of adrenal insufficiency include:

  • Fatigue.
  • Weight loss.
  • Decreased appetite.
  • Salt cravings.
  • Low blood pressure.
  • Abdominal pain.
  • Nausea, vomiting or diarrhea.
  • Muscle weakness.
  • Hyperpigmentation (darkening of the skin).
  • Irritability.

Medical tests for adrenal insufficiency start with blood cortisol levels, and tests for the ACTH hormone that stimulates the pituitary gland.

“If the person does not have adrenal insufficiency and they’re still fatigued, it’s important to get to the bottom of it,” Vouyiouklis Kellis says. Untreated sleep apnea often turns out to be the actual cause, she notes.

“It’s very important to tease out what’s going on,” Vouyiouklis Kellis emphasizes. “It can be multifactorial – multiple things contributing to the patient’s feeling of fatigue.” The blood condition anemia – a lack of healthy red blood cells – is another potential cause.

“If you are fatigued, do not treat yourself,” Vouyiouklis Kellis says. “Please seek a physician or a primary care provider for evaluation, because you don’t want to go misdiagnosed or undiagnosed. It’s very important to rule out actual causes that would be contributing to symptoms rather than ordering supplements online or seeking an alternative route like self-treating rather than being evaluated first.”

SOURCES

The U.S. News Health team delivers accurate information about health, nutrition and fitness, as well as in-depth medical condition guides. All of our stories rely on multiple, independent sources and experts in the field, such as medical doctors and licensed nutritionists. To learn more about how we keep our content accurate and trustworthy, read our editorial guidelines.

James Findling, MDFindling is a professor of medicine and director of the Community Endocrinology Center and Clinics at the Medical College of Wisconsin.

Mary Vouyiouklis Kellis, MDVouyiouklis Kellis is a staff endocrinologist at Cleveland Clinic.

William F. Young Jr., MDYoung Jr. is an endocrinology clinical professor and professor of medicine in the Mayo Clinic College of Medicine at Mayo Clinic in Rochester, Minnesota

From https://health.usnews.com/health-care/patient-advice/articles/adrenal-fatigue-is-it-real?

Free cortisol evaluation ‘useful’ after abnormal dexamethasone test

An assessment of free cortisol after a dexamethasone suppression test could add value to the diagnostic workup of hypercortisolism, which can be plagued by false-positive results, according to data from a cross-sectional study.

A 1 mg dexamethasone suppression test (DST) is a standard of care endocrine test for evaluation of adrenal masses and for patients suspected to have endogenous Cushing’s syndrome. Interpretation of a DST is affected by dexamethasone absorption and metabolism; several studies suggest a rate of 6% to 20% of false-positive results because of inadequate dexamethasone concentrations or differences in the proportion of cortisol bound to corticosteroid-binding globulin affecting total cortisol concentrations.

adrenal glands
Source: Adobe Stock

“As the prevalence of adrenal adenomas is around 5% to 7% in adults undergoing an abdominal CT scan, it is important to accurately interpret the DST,” Irina Bancos, MD, associate professor in the division of endocrinology at Mayo Clinic in Rochester, Minnesota, told Healio. “False-positive DST results are common, around 15% of cases, and as such, additional or second-line testing is often considered by physicians, including measuring dexamethasone concentrations at the time of the DST, repeating DST or performing DST with a higher dose of dexamethasone. We hypothesized that free cortisol measurements during the DST will be more accurate than total cortisol measurements, especially among those treated with oral contraceptive therapy.”

Diverse cohort analyzed

Bancos and colleagues analyzed data from adult volunteers without adrenal disorders (n = 168; 47 women on oral contraceptive therapy) and participants undergoing evaluation for hypercortisolism (n = 196; 16 women on oral contraceptives). The researchers assessed levels of post-DST dexamethasone and free cortisol, using mass spectrometry, and total cortisol, via immunoassay. The primary outcome was a reference range for post-DST free cortisol levels and the diagnostic accuracy of post-DST total cortisol level.

Irina Bancos

“A group that presents a particular challenge are women treated with oral estrogen,” Bancos told Healio. “In these cases, total cortisol increases due to estrogen-stimulated cortisol-binding globulin production, potentially leading to false-positive DST results. We intentionally designed our study to include a large reference group of women treated with oral contraceptive therapy allowing us to develop normal ranges of post-DST total and free cortisol, and then apply these cutoffs to the clinical practice.”

Researchers observed adequate dexamethasone concentrations ( 0.1 µg/dL) in 97.6% of healthy volunteers and in 96.3% of patients. Among women volunteers taking oral contraceptives, 25.5% had an abnormal post-DST total cortisol measurement, defined as a cortisol level of at least 1.8 µg/dL.

Among healthy volunteers, the upper post-DST free cortisol range was 48 ng/dL in men and women not taking oral contraceptives, and 79 ng/dL for women taking oral contraceptives.

Compared with post-DST free cortisol, diagnostic accuracy of post-DST total cortisol level was 87.3% (95% CI, 81.7-91.7). All false-positive results occurred among patients with a post-DST cortisol level between 1.8 µg/dL and 5 µg/dL, according to researchers.

Oral contraceptive use was the only factor associated with false-positive results (21.1% vs. 4.9%; P = .02).

Findings challenge guidelines

Natalia Genere

“We were surprised by several findings of our study,” Natalia Genere, MD, instructor in medicine in the division of endocrinology, metabolism and lipid research at Washington University School of Medicine in St. Louis, told Healio. “First, we saw that with a standardized patient instruction on DST, we found that optimal dexamethasone concentrations were reached in a higher proportion of patients than previously reported (97%), suggesting that rapid metabolism or poor absorption of dexamethasone may play a lower role in the rate of false positives. Second, we found that measurements of post-DST total cortisol in women taking oral contraceptive therapy accurately excluded [mild autonomous cortisol secretion] in three-quarters of patients, suggesting discontinuation of oral contraceptives, as suggested in prior guidelines, may not be routinely necessary.”

Genere said post-DST free cortisol performed “much better” than total cortisol among women treated with oral estrogen.

Stepwise approach recommended

Based on the findings, the authors suggested a sequential approach to dexamethasone suppression in clinical practice.

“We recommend a stepwise approach to enhance DST interpretation, with the addition of dexamethasone concentration and/or free cortisol in cases of abnormal post-DST total cortisol,” Bancos said. “We found dexamethasone concentrations are particularly helpful when post-DST total cortisol is at least 5 µg/dL and free cortisol is helpful in a patient with optimal dexamethasone concentrations and a post-DST total cortisol between 1.8 µg/dL and 5 µg/dL. We believe that DST with free cortisol is a useful addition to the repertoire of available testing for [mild autonomous cortisol secretion], and that its use reduces need for repetitive assessments and patient burden of care, especially in women treated with oral contraceptive therapy.”

Identified: the gene behind an unusual form of Cushing’s Syndrome

A team of scientists in Montreal and Paris has succeeded in identifying the gene responsible for the development of a food-dependent form of Cushing’s Syndrome, a rare disease affecting both adrenal glands.

In their study published in The Lancet Diabetes & EndocrinologyDr. Isabelle Bourdeau and Dr. Peter Kamenicky identify in the gene KDM1A the mutations responsible for the development of this unusual form of the disease.

The scientists also show, for the first time, that the disease is genetically transmitted.

Bourdeau is a researcher and a Université de Montréal medical professor practising at the CHUM Research Centre (CRCHUM), while Kamenicky works at the Hôpital de Bicêtre, part of the Assistance publique-hôpitaux de Paris network in France.

Cushing’s Syndrome is caused by the overproduction of cortisol, a steroid hormone, by the two adrenal glands located above the kidneys.

“When the tissues of the human body are exposed to this excess of cortisol, the effects for those with the disease are serious: weight gain, high blood pressure, depression, osteoporosis, and heart complications, for example,” said Bourdeau, co-lead author of the study with Dr. Fanny Chasseloup, a colleague from the French team.

This discovery comes nearly 30 years after food-induced Cushing’s Syndrome was first described in 1992 by a research group led by Dr. André Lacroix at the CRCHUM and his colleagues Drs. Johanne Tremblay and Pavel Hamet.

The form of the disease being studied by Bourdeau and her colleagues is caused specifically by the abnormal expression of the receptors of a hormone named GIP (glucose-dependent insulinotropic peptide), in both adrenal glands of patients. This hormone is produced by the small intestine in response to food intake. For people with the disease, cortisol concentrations increase abnormally every time they ingest food.

The discovery of the genetic mechanism by the French and Quebec teams was made possible through the use of recent cutting-edge genetic techniques on tissues of patients including those investigated by Dr Lacroix at CHUM. Bourdeau was aided by CRCHUM researcher Martine Tétreault during the computer analyses related to the research project.

Earlier diagnosis thanks to genetic analysis

“In general, rare diseases are generally underdiagnosed in clinics,” said Bourdeau, the medical director of the adrenal tumors multidisciplinary team at the CHUM.

“By identifying this new gene, we now have a way of diagnosing our patients and their families earlier and thus offer more personalized medicine. At the CHUM, genetic analysis is already offered in our Genetic Medicine Division.”

In a remarkable demonstration of scientific cooperation, the Quebec and French teams were able to collect and study tissue specimens available in local and international biobanks in Canada, France, Italy, Greece, Belgium and the Netherlands.

Blood and adrenal gland tissue samples of 17 patients—mostly women—diagnosed with GIP-dependent Cushing’s Syndrome were compared genetically with those of 29 others with non-GIP-dependent bilateral adrenal Cushing’s Syndrome.

This was quite an accomplishment, given the rarity of the disease in the general population. It allowed the researchers to identify the genetic mutations of the KDM1A gene and to determine that the disease is genetically transmitted.

Since 2009, the CHUM has been designated as the adrenal tumors quaternary care centre of the Quebec Cancer Program.

About this study

Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing’s syndrome: a multicenter retrospective cohort study,” by Drs. Fanny Chasseloup, Isabelle Bourdeau and their colleagues, was published Oct. 13, 2021, in The Lancet Diabetes & Endocrinology. Funding was provided by the Agence nationale de la recherche, the Fondation du Grand défi Pierre Lavoie, the Institut national du cancer, the Fonds de recherche du Québec-Santé, INSERM and Assistance publique-hôpitaux de Paris.

About the CRCHUM

The University of Montreal Hospital Research Centre (CRCHUM) is one of North America’s leading hospital research centres. It strives to improve adult health through a research continuum covering such disciplines as the fundamental sciences, clinical research and public health. Over 1,850 people work at the CRCHUM, including more than 550 researchers and more than 460 graduate students

Media contact

  • Jeff HeinrichUniversité de MontréalTel: 514 343-7593
  • Lucie DufresneCentre hospitalier de l’Université de MontréalTel: 514 890-8000 p. 15380

From https://nouvelles.umontreal.ca/en/article/2021/10/15/identified-the-gene-behind-an-unusual-form-of-cushing-s-syndrome/

%d bloggers like this: