Consecutive resections of double pituitary adenoma for resolution of Cushing disease: illustrative case.

BACKGROUND: Double pituitary adenomas are rare presentations of two distinct adenohypophyseal lesions seen in <1% of surgical cases. Increased rates of recurrence or persistence are reported in the resection of Cushing microadenomas and are attributed to the small tumor size and localization difficulties. The authors report a case of surgical treatment failure of Cushing disease because of the presence of a secondary pituitary adenoma. OBSERVATIONS: A 32-year-old woman with a history of prolactin excess and pituitary lesion presented with oligomenorrhea, weight gain, facial fullness, and hirsutism. Urinary and nighttime salivary cortisol elevation were elevated. Magnetic resonance imaging confirmed a 4-mm3 pituitary lesion. Inferior petrosal sinus sampling was diagnostic for Cushing disease. Primary endoscopic endonasal transsphenoidal resection was performed to remove what was determined to be a lactotroph-secreting tumor on immunohistochemistry with persistent hypercortisolism. Repeat resection yielded a corticotroph-secreting tumor and postoperative hypoadrenalism followed by long-term normalization of the hypothalamic-pituitary-adrenal axis. LESSONS: This case demonstrates the importance of multidisciplinary management and postoperative hormonal follow-up in patients with Cushing disease. Improved strategies for localization of the active tumor in double pituitary adenomas are essential for primary surgical success and resolution of endocrinopathies.

Alcohol-induced Cushing syndrome: report of eight cases and review of the literature.

Introduction: Alcohol-induced hypercortisolism (AIH) is underrecognized and may masquerade as neoplastic hypercortisolism [Cushing syndrome (CS)] obscuring its diagnosis. Objective and methods: In order to characterize AIH, we performed a chart review of eight patients (4 males and 4 females; 2014-2022) referred for evaluation and treatment of neoplastic hypercortisolism - six for inferior petrosal sinus sampling, one due to persistent CS after unilateral adrenalectomy, and one for pituitary surgery for Cushing disease (CD). Five underwent dDAVP stimulation testing. Results: All eight patients had clinical features of hypercortisolism and plasma ACTH levels within or above the reference interval confirming hypothalamic-pituitary mediation. All had abnormal low-dose dexamethasone suppression test and increased late-night salivary cortisol. Only one had increased urine cortisol excretion. In contrast to CD, the 5 patients tested had blunted or absent ACTH and cortisol responses to desmopressin. Two had adrenal nodules and one had abnormal pituitary imaging. Most patients underreported their alcohol consumption and one denied alcohol use. Elevated blood phosphatidyl ethanol (PEth) was required in one patient to confirm excessive alcohol use. All patients had elevations of liver function tests (LFTs) with AST>ALT. Conclusion: AIH is an under-appreciated, reversible cause of non-neoplastic hypercortisolism that is indistinguishable from neoplastic CS. Incidental pituitary and adrenal imaging abnormalities as well as under-reporting of alcohol consumption further confound the diagnosis. Measurement of PEth helps to confirm an alcohol use disorder. Elevations of LFTs (AST>ALT) and subnormal ACTH and cortisol responses to dDAVP help to distinguish AIH from neoplastic hypercortisolism.

Recognition of Nonneoplastic Hypercortisolism in the Evaluation of Patients With Cushing Syndrome.

The evaluation of suspected hypercortisolism is one of the most challenging problems in medicine. The signs and symptoms described by Dr Harvey Cushing are common and often create diagnostic confusion to even experienced endocrinologists. Cushing syndrome is classically defined as neoplastic hypercortisolism resulting from an ACTH-secreting tumor or from autonomous secretion of excess cortisol associated with benign or malignant adrenal neoplasia. The increasing recognition of the negative cardiometabolic effects of mild cortisol excess without overt physical signs of Cushing syndrome has led to more screening for endogenous hypercortisolism in patients with adrenal nodular disease, osteoporosis, and the metabolic syndrome. However, sustained or intermittent activation of the dynamic hypothalamic-pituitary-adrenal axis caused by chemical (alcohol), inflammatory (chronic kidney disease), psychologic (major depression), and physical (starvation/chronic intense exercise) stimuli can result in clinical and/or biochemical features indistinguishable from neoplastic hypercortisolism. Nonneoplastic hypercortisolism (formerly known as pseudo-Cushing syndrome) has been recognized for more than 50 years and often causes diagnostic uncertainty. This expert consultation describes two patients with features of Cushing syndrome who were referred for inferior petrosal sinus sampling for the differential diagnosis of ACTH-dependent hypercortisolism. Both patients were discovered to have nonneoplastic hypercortisolism: one from a covert alcohol use disorder and the other to chronic kidney disease. This consultation emphasizes the value of a good history and physical examination, appropriate laboratory testing, and the desmopressin acetate stimulation test to aid in distinguishing neoplastic from nonneoplastic hypercortisolism.

Wide Variability in Catecholamine Levels From Adrenal Venous Sampling in Primary Aldosteronism.

INTRODUCTION: While adrenal venous sampling (AVS) differentiates between the unilateral and bilateral disease in patients with primary aldosteronism (PA), it is unknown if AVS can determine laterality of pheochromocytoma in patients with bilateral adrenal masses. This study analyzes adrenal vein (AV) epinephrine and norepinephrine levels in nonpheochromocytoma patients to determine the "normal" range. MATERIALS AND METHODS: We reviewed patients who underwent AVS for PA between 2009 and 2019 at a single institution; pheochromocytoma was excluded. Aldosterone, cortisol, epinephrine, and norepinephrine levels were obtained from the inferior vena cava (IVC), left adrenal vein (LAV), and right adrenal vein (RAV). Successful AV cannulation was defined by an AV/IVC cortisol ratio of ≥3:1 or an AV epinephrine level ≥364 pg/mL. Plasma measurements (pg/mL) are median values with interquartile ranges; normal ranges for epinephrine and norepinephrine are 10-200 pg/mL and 80-520 pg/mL, respectively. RESULTS: AVS was performed in 172 patients in 405 AVs (173 LAV and 232 RAV). Median epinephrine levels were IVC = 19 (14 and 34), LAV = 3811 (1870 and 6915), and RAV = 2897 (1500 and 5288). Median norepinephrine levels were IVC = 325 (186 and 479), LAV = 1450 (896 and 2050), and RAV = 786 (436 and 1582). There was a difference between LAV and RAV epinephrine levels (P = 0.024) and between LAV and RAV norepinephrine (P = 0.002) levels. CONCLUSIONS: This extensive experience with AVS demonstrated a wide range of "normal" AV catecholamine levels in patients without pheochromocytoma, which suggests that the utility of AVS to determine disease laterality in patients with pheochromocytoma and bilateral adrenal nodules is likely to be limited.

Glucocorticoid Withdrawal Syndrome following treatment of endogenous Cushing Syndrome.

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.

Selective Glucocorticoid Replacement Following Unilateral Adrenalectomy for Hypercortisolism and Primary Aldosteronism.

CONTEXT: An institutional study previously demonstrated that cosyntropin stimulation testing on postoperative day 1 (POD1-CST) identified patients at risk for adrenal insufficiency (AI) following unilateral adrenalectomy (UA) for adrenal-dependent hypercortisolism (HC) and primary aldosteronism (PA), allowing for selective glucocorticoid replacement (GR). OBJECTIVE: This study re-evaluates the need for GR following UA for patients with HC and PA in a larger cohort. METHODS: A prospective database identified 108 patients who underwent UA for mild autonomous cortisol excess (MACE) (n = 47), overt hypercortisolism (OH) (n = 27), PA (n = 22), and concurrent PA/HC (n = 12) from September 2014 to October 2020; all underwent preoperative evaluation for HC. MACE was defined by the 1 mg dexamethasone suppression test (cortisol >1.8 µg/dL), with ≥5 defined as OH. GR was initiated for basal cortisol ≤5 or stimulated cortisol ≤14 (≤18 prior to April 2017) on POD1-CST. RESULTS: Fifty-one (47%) patients had an abnormal POD1-CST; 54 (50%) were discharged on GR (27 MACE, 20 OH, 1 PA, 6 PA/HC). Median duration of GR was OH: 6.0 months, MACE: 2.1 months, PA: 1 month, PA/HC: 0.8 months. Overall, 26% (n = 7) of patients with OH and 43% (n = 20) of patients with MACE did not require GR. Two (2%) patients with OH had normal POD1-CST but developed AI several weeks postoperatively requiring GR. None experienced life-threatening AI. CONCLUSION: POD1-CST identifies patients with HC at risk for AI after UA, allowing for selective GR. One-quarter of patients with OH and nearly half of patients with MACE can forgo GR after UA. Patients with PA do not require evaluation for AI if concurrent HC has been excluded preoperatively.

Utility of Epinephrine Levels in Determining Adrenal Vein Cannulation During Adrenal Venous Sampling for Primary Aldosteronism.

OBJECTIVE: In patients with primary aldosteronism, adrenal venous sampling (AVS) is performed to determine the presence of unilateral or bilateral adrenal disease. During AVS, verification of catheter positioning within the left adrenal vein (AV) and the right AV by comparison of AV and inferior vena cava (IVC) cortisol levels can be variable. The objective of this study was to determine the utility of AV epinephrine levels in assessing successful AV cannulation. METHODS: This was a single institution, retrospective review of patients who underwent AVS with cosyntropin stimulation for primary aldosteronism between 2009 and 2018. Successful cannulation of the AV was defined by an AV/IVC cortisol ratio selectivity index (SI) ≥3:1. Epinephrine thresholds to predict catheter placement in the AV were determined using logistic regression. The calculated epinephrine thresholds were compared with previously published thresholds. RESULTS: AVS was performed on 101 consecutive patients and, based on the SI, successful cannulation of the left AV and right AV occurred in 98 (97%) and 91(90%) patients, respectively. The calculated optimal epinephrine threshold to predict AV cannulation was 364 pg/mL (sensitivity, 92.1%; specificity, 94.6%) and the calculated optimal AV/IVC epinephrine ratio threshold was 27.4, (sensitivity, 92.1%; specificity, 91.3%). Among the 14 patients with failed AV cannulation, 3 patients would have been considered to have successful AVS using AV epinephrine levels >364 pg/mL and AV/IVC epinephrine ratio >27.4 thresholds. CONCLUSION: Obtaining 2 right AV samples routinely as well as AV and IVC epinephrine levels during AVS could prevent unnecessary repeat AVS in patients with failed AV cannulation based on cortisol-based SI <3:1.

Consensus on diagnosis and management of Cushing's disease: a guideline update.

Cushing's disease requires accurate diagnosis, careful treatment selection, and long-term management to optimise patient outcomes. The Pituitary Society convened a consensus workshop comprising more than 50 academic researchers and clinical experts to discuss the application of recent evidence to clinical practice. In advance of the virtual meeting, data from 2015 to present about screening and diagnosis; surgery, medical, and radiation therapy; and disease-related and treatment-related complications of Cushing's disease summarised in recorded lectures were reviewed by all participants. During the meeting, concise summaries of the recorded lectures were presented, followed by small group breakout discussions. Consensus opinions from each group were collated into a draft document, which was reviewed and approved by all participants. Recommendations regarding use of laboratory tests, imaging, and treatment options are presented, along with algorithms for diagnosis of Cushing's syndrome and management of Cushing's disease. Topics considered most important to address in future research are also identified.

Rethinking the management of immune checkpoint inhibitor-related adrenal insufficiency in cancer patients during the COVID-19 pandemic.

Introduction: The coronavirus disease 2019 (COVID-19) is currently a major pandemic challenge, and cancer patients are at a heightened risk of severity and mortality from this infection. In recent years, immune checkpoint inhibitor (ICI) use to treat multiple cancers has increased in oncology, but equally has raised the question of whether ICI therapy and its side-effects is harmful or beneficial during this pandemic. Methods: A combination of published literature in PubMed between January 2010 and December 2020, recommended guidelines in non-cancer patients, and clinical experience was utilized to outline recommendations on glucocorticoid timing and dosing regimens in ICI-treated patients presenting with AI during this COVID-19 pandemic. Results: The potential immune interaction between ICIs and COVID-19 require major consideration because these agents act at the intersection between effective cancer immunotherapy and increasing patient susceptibility, severity and complications from the SARS-CoV-2 sepsis. Furthermore, ICI use can induce autoimmune adrenal insufficiency (AI) that further increases infection susceptibility. Thus, ICI-treated cancer patients with AI may be at greater risk of COVID-19 infection. Glucocorticoids are the cornerstone for replacement therapy, and for treatment and mitigation of adrenal crisis and relief of mass effects in ICI-related hypophysitis. High-dose glucocorticoids have also been used with cytotoxic chemotherapy as part of cancer treatment, and iatrogenic AI may arise after glucocorticoid discontinuation that increases the risk of adrenal crisis. Furthermore, in patients who develop the "long COVID-19" syndrome, when to discontinue glucocorticoid therapy becomes crucial to avoid unnecessary prolongation of therapy and the development of iatrogenic hypercortisolemia. Conclusion: During the COVID-19 pandemic, much of cancer care have been impacted and an important clinical question is how to optimally manage ICI-related AI during these unprecedented times. Herein, we suggest practical recommendations on the timing and dosing regimens of glucocorticoids in different clinical scenarios of ICI-treated cancer patients presenting with AI during this COVID-19 pandemic.

New Cutoffs for the Biochemical Diagnosis of Adrenal Insufficiency after ACTH Stimulation using Specific Cortisol Assays.

CONTEXT: The normal cortisol response 30 or 60 minutes after cosyntropin (ACTH[1-24]) is considered to be ≥18 µg/dL (500 nmol/L). This threshold is based on older serum cortisol assays. Specific monoclonal antibody immunoassays or LC-MS/MS may have lower thresholds for a normal response. OBJECTIVE: To calculate serum cortisol cutoff values for adrenocorticotropic hormone (ACTH) stimulation testing with newer specific cortisol assays. METHODS: Retrospective analysis of ACTH stimulation tests performed in ambulatory and hospitalized patients suspected of adrenal insufficiency (AI). Serum samples were assayed for cortisol in parallel using Elecsys I and Elecsys II immunoassays, and when volume was available, by Access immunoassay and LC-MS/MS. RESULTS: A total of 110 patients were evaluated. Using 18 µg/dL as the cortisol cutoff after ACTH stimulation, 14.5%, 29%, 22.4%, and 32% of patients had a biochemical diagnosis of AI using the Elecsys I, Elecsys II, Access, and LC-MS/MS assays, respectively. Deming regressions of serum cortisol were used to calculate new cortisol cutoffs based on the Elecsys I cutoff of 18 µg/dL. For 30-minute values, new cutoffs were 14.6 µg/dL for Elecsys II, 14.8 µg/dL for Access, and 14.5 µg/dL for LC-MS/MS. Baseline cortisol <2 µg/dL was predictive of subnormal stimulated cortisol values. CONCLUSION: To reduce false positive ACTH stimulation testing, we recommend a new serum cortisol cutoff of 14 to 15 µg/dL depending on the assay used (instead of the historical value of 18 µg/dL with older polyclonal antibody assays). Clinicians should be aware of the new cutoffs for the assays available to them when evaluating patients for AI.

Corticotroph tumor progression after bilateral adrenalectomy (Nelson's syndrome): systematic review and expert consensus recommendations.

BACKGROUND: Corticotroph tumor progression (CTP) leading to Nelson's syndrome (NS) is a severe and difficult-to-treat complication subsequent to bilateral adrenalectomy (BADX) for Cushing's disease. Its characteristics are not well described, and consensus recommendations for diagnosis and treatment are missing. METHODS: A systematic literature search was performed focusing on clinical studies and case series (≥5 patients). Definition, cumulative incidence, treatment and long-term outcomes of CTP/NS after BADX were analyzed using descriptive statistics. The results were presented and discussed at an interdisciplinary consensus workshop attended by international pituitary experts in Munich on October 28, 2018. RESULTS: Data covered definition and cumulative incidence (34 studies, 1275 patients), surgical outcome (12 studies, 187 patients), outcome of radiation therapy (21 studies, 273 patients), and medical therapy (15 studies, 72 patients). CONCLUSIONS: We endorse the definition of CTP-BADX/NS as radiological progression or new detection of a pituitary tumor on thin-section MRI. We recommend surveillance by MRI after 3 months and every 12 months for the first 3 years after BADX. Subsequently, we suggest clinical evaluation every 12 months and MRI at increasing intervals every 2-4 years (depending on ACTH and clinical parameters). We recommend pituitary surgery as first-line therapy in patients with CTP-BADX/NS. Surgery should be performed before extrasellar expansion of the tumor to obtain complete and long-term remission. Conventional radiotherapy or stereotactic radiosurgery should be utilized as second-line treatment for remnant tumor tissue showing extrasellar extension.

Prospective Evaluation of Late-Night Salivary Cortisol and Cortisone by EIA and LC-MS/MS in Suspected Cushing Syndrome.

CONTEXT: Late-night salivary cortisol (LNSC) measured by enzyme immunoassay (EIA-F) is a first-line screening test for Cushing syndrome (CS) with a reported sensitivity and specificity of >90%. However, liquid chromatography-tandem mass spectrometry, validated to measure salivary cortisol (LCMS-F) and cortisone (LCMS-E), has been proposed to be superior diagnostically. OBJECTIVE SETTING AND MAIN OUTCOME MEASURES: Prospectively evaluate the diagnostic performance of EIA-F, LCMS-F, and LCMS-E in 1453 consecutive late-night saliva samples from 705 patients with suspected CS. DESIGN: Patients grouped by the presence or absence of at least one elevated salivary steroid result and then subdivided by diagnosis. RESULTS: We identified 283 patients with at least one elevated salivary result; 45 had an established diagnosis of neoplastic hypercortisolism (CS) for which EIA-F had a very high sensitivity (97.5%). LCMS-F and LCMS-E had lower sensitivity but higher specificity than EIA-F. EIA-F had poor sensitivity (31.3%) for adrenocorticotropic hormone (ACTH)-independent CS (5 patients with at least 1 and 11 without any elevated salivary result). In patients with Cushing disease (CD), most nonelevated LCMS-F results were in patients with persistent/recurrent CD; their EIA-F levels were lower than in patients with newly diagnosed CD. CONCLUSIONS: Since the majority of patients with ≥1 elevated late-night salivary cortisol or cortisone result did not have CS, a single elevated level has poor specificity and positive predictive value. LNSC measured by EIA is a sensitive test for ACTH-dependent Cushing syndrome but not for ACTH-independent CS. We suggest that neither LCMS-F nor LCMS-E improves the sensitivity of late-night EIA-F for CS.

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.

BACKGROUND: Cushing's disease is a rare endocrine disorder characterised by cortisol overproduction with severe complications. Therapies for cortisol reduction are often necessary. Here we report the outcomes from the pivotal phase III study of osilodrostat (a potent oral inhibitor of cytochrome P450 11B1, mitochondrial [11ß-hydroxylase]; Novartis Pharma AG, Basel, Switzerland) in patients with Cushing's disease. METHODS: LINC 3 was a prospective, multicentre, open-label, phase III study with a double-blind randomised withdrawal period, that comprised four periods. Patients aged 18-75 years, with confirmed persistent or recurrent Cushing's disease (defined as mean 24-h urinary free cortisol [UFC] concentration >1·5 times the upper limit of normal [ULN] and morning plasma adrenocorticotropic hormone above the lower limit of normal) who had previously had pituitary surgery or irradiation, or were newly diagnosed and who refused surgery or were not surgical candidates, were recruited from 66 hospital sites and private clinical practices in 19 countries. In period 1, open-label osilodrostat was initiated in all participants and adjusted every 2 weeks (1-30 mg twice daily; film-coated tablets for oral administration) on the basis of mean 24-h UFC concentration and safety until week 12. In period 2, weeks 13-24, osilodrostat was continued at the therapeutic dose determined during period 1. In period 3, beginning at week 26, participants who had a mean 24-h UFC concentration of less than or equal to the ULN at week 24, without up-titration after week 12, were randomly assigned (1:1), via an interactive-response technology, stratified by osilodrostat dose at week 24 and history of pituitary irradiation, to continue osilodrostat or switch to placebo for 8 weeks. Participants and investigators were masked to treatment assignment. Ineligible participants continued open-label osilodrostat. In period 4, weeks 35-48, all participants were given open-label osilodrostat until core-study end. The primary objective was to compare the efficacy of osilodrostat versus placebo at the end of period 3. The primary endpoint was the proportion of participants who had been randomly assigned to treatment or placebo with a complete response (ie, mean 24-h UFC concentration of ≤ULN) at the end of the randomised withdrawal period (week 34), without up-titration during this period. The key secondary endpoint was the proportion of participants with a complete response at the end of the single-arm, open-label period (ie, period 2, week 24) without up-titration during weeks 13-24. Analysis was by intention-to-treat for all patients who received at least one dose of osilodrostat (full analysis set; key secondary endpoint) or randomised treatment (randomised analysis set; primary endpoint) and safety was assessed in all enrolled patients who received at least one dose of osilodrostat and had at least one post-baseline safety assessment. LINC 3 is registered with ClinicalTrials.gov, NCT02180217, and is now complete. FINDINGS: Between Nov 12, 2014, and March 22, 2017, 202 patients were screened and 137 were enrolled. The median age was 40·0 years (31·0-49·0) and 106 (77%) participants were female. 72 (53%) participants were eligible for randomisation during the withdrawal phase, of whom 36 were assigned to continue osilodrostat and 35 were assigned to placebo; one patient was not randomly assigned due to investigator decision and continued open-label osilodrostat. More patients maintained a complete response with osilodrostat versus with placebo at week 34 (31 [86%] vs ten [29%]; odds ratio 13·7 [95% CI 3·7-53·4]; p<0·0001). At week 24, 72 (53%; 95% CI 43·9-61·1) of 137 patients maintained a complete response without up-titration after week 12. Most common adverse events (ie, occurred in >25% of participants) were nausea (57 [42%]), headache (46 [34%]), fatigue (39 [28%]), and adrenal insufficiency (38 [28%]). Hypocortisolism occurred in 70 (51%) patients and adverse events related to adrenal hormone precursors occurred in 58 (42%) patients. One patient died, unrelated to study drug, after the core study phase. INTERPRETATION: Twice-daily osilodrostat rapidly reduced mean 24-h UFC and sustained this reduction alongside improvements in clinical signs of hypercortisolism; it was also generally well tolerated. Osilodrostat is an effective new treatment option that is approved in Europe for the treatment of endogenous Cushing's syndrome and in the USA for Cushing's disease. FUNDING: Novartis Pharma AG.

Important Management Considerations In Patients With Pituitary Disorders During The Time Of The Covid-19 Pandemic.

OBJECTIVE: In December 2019, a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused an outbreak of coronavirus disease 2019 (COVID-19) that resulted in a global pandemic with substantial morbidity and mortality. Currently, there is no specific treatment or approved vaccine against COVID-19. The underlying associated comorbidity and diminished immune function of some pituitary patients (whether caused by the disease and its sequelae or treatment with excess glucocorticoids) increases their risk of contracting and developing complications from COVID-19 infection. METHODS: A review of studies in PubMed and Google Scholar published between January 2020 to the time of writing (May 1, 2020) was conducted using the search terms 'pituitary,' 'coronavirus,' 'COVID-19', '2019-nCoV', 'diabetes mellitus', 'obesity', 'adrenal,' and 'endocrine.' RESULTS: Older age and pre-existing obesity, hypertension, cardiovascular disease, and diabetes mellitus increase the risk of hospitalization and death in COVID-19 patients. Men tend to be more severely affected than women; fortunately, most men, particularly of younger age, survive the infection. In addition to general comorbidities that may apply to many pituitary patients, they are also susceptible due to the following pituitary disorder-specific features: hypercortisolemia and adrenal suppression with Cushing disease, adrenal insufficiency and diabetes insipidus with hypopituitarism, and sleep-apnea syndrome and chest wall deformity with acromegaly. CONCLUSION: This review aims to focus on the impact of COVID-19 in patients with pituitary disorders. As most countries are implementing mobility restrictions, we also discuss how this pandemic has affected patient attitudes and impacted our decision-making on management recommendations for these patients. ABBREVIATIONS: ACE = angiotensin-converting enzyme; AI = adrenal insufficiency; ARB = angiotensin receptor blocker; ARDS = acute respiratory disease syndrome; COVID-19 = coronavirus disease 2019; CPAP = continuous positive airway pressure; DI = diabetes insipidus; DM = diabetes mellitus; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.

Mifepristone Increases Thyroid Hormone Requirements in Patients With Central Hypothyroidism: A Multicenter Study.

PURPOSE: Mifepristone is a glucocorticoid and progesterone receptor blocker that can be used for patients with hyperglycemia and Cushing syndrome in whom surgery failed to achieve remission or who were ineligible for surgery. We report a case series of patients with Cushing disease (CD) and central hypothyroidism that presented with increased levothyroxine requirements during mifepristone therapy. METHODS: Retrospective longitudinal case series of patients with CD and central hypothyroidism treated with mifepristone in a retrospective database at four pituitary centers in the United States. RESULTS: Five patients with CD were found, all women, median age 50 (interquartile range 47 to 64.5). They received mifepristone because no adequate response or intolerance to other drugs was observed. Mifepristone initiation was associated with a decrease in free thyroxine levels, mandating a dose increase of a median 1.83 (1.71 to 3.5) times the initial dose of levothyroxine to achieve normal levels. Weight loss was seen in four of five patients, ranging from 3.2 to 42.6 kg in up to 54 months of follow-up. CONCLUSIONS: Although the mechanism behind the decrease in thyroid hormone level is unknown, intestinal malabsorption, decreased residual thyroid function and increased inactivation of T4 via deiodinases are all potential causes. Whereas therapies for hypercortisolism aim to decrease features of hypercortisolemia such as weight gain and depression, hypothyroidism can hamper these goals. This case series raises awareness on the importance of assessment of thyroid status in patients receiving mifepristone to optimize clinical outcomes.

A commentary on Diagnosing Cushing's disease in the context of renal failure.

The diagnosis of endogenous hypercortisolism (Cushing's syndrome) is extremely challenging. Chronic kidney disease (CKD) increases the activity of the hypothalamic-pituitary-adrenal axis making the diagnosis of Cushing's syndrome even more challenging. This is particularly so since urine free cortisol (UFC) testing is not useful in CKD. The case report by Stroud et al. in this issue of the European Journal of Endocrinology highlights this problem by finding normal UFC in a patient with pituitary ACTH-dependent Cushing's syndrome. Elevated late-night salivary cortisol (LNSC) testing was diagnostic and pituitary adenomectomy was curative. LNSC measurement is the diagnostic test of choice in patients with suspected Cushing's syndrome, particularly in the presence of CKD..

Assay-Specific Spurious ACTH Results Lead to Misdiagnosis, Unnecessary Testing, and Surgical Misadventure-A Case Series.

The proper clinical evaluation of pituitary and adrenal disorders depends on the accurate measurement of plasma ACTH. The modern two-site sandwich ACTH immunoassay is a great improvement compared with older methods but still has the potential for interferences such as heterophile antibodies and pro-opiomelanocortin (POMC) and ACTH fragments. We report the cases of five patients in whom the diagnosis or differential diagnosis of Cushing syndrome was confounded by erroneously elevated results from the Siemens ACTH Immulite assay [ACTH(Immulite)] that were resolved using the Roche Cobas or Tosoh AIA [ACTH(Cobas) and ACTH(AIA), respectively]. In one case, falsely elevated ACTH(Immulite) results owing to interfering antibodies resulted in several invasive differential diagnostic procedures (including inferior petrosal sinus sampling), MRI, and unnecessary pituitary surgery. ACTH(Cobas) measurements were normal, and further studies excluded the diagnosis of Cushing syndrome. In three cases, either Cushing disease or occult ectopic ACTH were suspected owing to elevated ACTH(Immulite) results. However, adrenal (ACTH-independent) Cushing syndrome was established using ACTH(AIA) or ACTH(Cobas) and proved surgically. In one case, ectopic ACTH was suspected owing to elevated ACTH(Immulite) results; however, the ACTH(Cobas) findings led to the diagnosis of alcohol-induced hypercortisolism that resolved with abstinence. We have concluded that ACTH(Immulite) results can be falsely increased and alternate ACTH assays should be used in the diagnosis or differential diagnosis of clinical disorders of the hypothalamic-pituitary-adrenal axis.