Relacorilant, a Selective Glucocorticoid Receptor Modulator in Development for the Treatment of Patients With Cushing Syndrome, Does Not Cause Prolongation of the Cardiac QT Interval.

OBJECTIVE: To assess the effect of relacorilant, a selective glucocorticoid receptor modulator under investigation for the treatment of patients with endogenous hypercortisolism (Cushing syndrome [CS]), on the heart rate-corrected QT interval (QTc). METHODS: Three clinical studies of relacorilant were included: (1) a first-in-human, randomized, placebo-controlled, ascending-dose (up to 500 mg of relacorilant) study in healthy volunteers; (2) a phase 1 placebo- and positive-controlled thorough QTc (TQT) study of 400 and 800 mg of relacorilant in healthy volunteers; and (3) a phase 2, open-label study of up to 400 mg of relacorilant administered daily for up to 16 weeks in patients with CS. Electrocardiogram recordings were taken, and QTc change from baseline (ΔQTc) was calculated. The association of plasma relacorilant concentration with the effect on QTc in healthy volunteers was assessed using linear mixed-effects modeling. RESULTS: Across all studies, no notable changes in the electrocardiogram parameters were observed. At all time points and with all doses of relacorilant, including supratherapeutic doses, ΔQTc was small, generally negative, and, in the placebo-controlled studies, similar to placebo. In the TQT study, placebo-corrected ΔQTc with relacorilant was small and negative, whereas placebo-corrected ΔQTc with moxifloxacin positive control showed rapid QTc prolongation. These results constituted a negative TQT study. The model-estimated slopes of the concentration-QTc relationship were slightly negative, excluding an association of relacorilant with prolonged QTc. CONCLUSION: At all doses studied, relacorilant consistently demonstrated a lack of QTc prolongation in healthy volunteers and patients with CS, including in the TQT study. Ongoing phase 3 studies will help further establish the overall benefit-risk profile of relacorilant.

Cushing syndrome and tertiary adrenal insufficiency from prolonged concomitant use of budesonide and posaconazole.

Budesonide is a 'non-absorbable' corticosteroid often used for gut graft versus host disease. Systemic exposure is usually minimal because of metabolism by cytochrome (CYP) 3A4 in enterocytes and the liver. However, concomitant use of posaconazole and voriconazole, inhibitors of CYP3A4 commonly used as antifungal prophylaxis in allograft patients receiving immunosuppression, can lead to substantial systemic steroid exposure. This paper describes a case of severe iatrogenic Cushing syndrome and tertiary adrenal insufficiency because of this interaction, highlighting the necessity for improved awareness of this phenomenon.

Overlooked complication of Cushing's syndrome: Reactivation of hepatitis B.

OBJECTIVE: Individuals infected with hepatitis B virus (HBV) are at increased risk of reactivation when they receive immunosuppressive therapies. Although exogenous corticosteroid use as immunosuppressive therapy is elaborated in current guidelines on HBV reactivation, Cushing's syndrome (CS) with endogenous hypercortisolemia is not addressed. We aimed to investigate the prevalence of HBV infection and discuss the necessity of antiviral prophylaxis in patients with CS as in other immunosuppressed patients. DESIGN AND PATIENTS: We included 72 patients with CS (Adrenocorticotropic hormone (ACTH) dependent or independent) who were screened for HBV between 2016 and 2021. Patients were categorized into three groups: overt, mild autonomous cortisol secretion (MACS), and remission according to the cortisol burden. Changes in patients' HBV serology and clinical findings over time were analyzed retrospectively. RESULTS: Twenty-six patients had overt hypercortisolism, 18 had mild autonomous cortisol secretion and 28 patients were in remission. Nineteen (26.3%) patients were anti-HBc IgG positive, 4 of them were chronic HBV and 15 were isolated anti-HBc IgG positive. HBsAg was positive in four (5.5%) of the patients, who were all compatible with inactive chronic HBV. While two patients developed HBV reactivation, HBV flare was observed in one patient. CONCLUSION: Since it is not always possible to achieve rapid remission in CS and these patients have long-term hypercortisolemia, we suggest that consensus should be reached on HBV serological assessment, standardization of follow-up, and planning of HBV prophylaxis in required instances in patients with CS especially in regions with a high prevalence of HBV infection.

Unmet needs on the current medical management of Cushing's syndrome: results from a Delphi panel of Italian endocrinologists.

BACKGROUND: Cushing's syndrome (CS) is a rare clinical condition caused by excessive cortisol secretion from adrenal glands. CS is associated with increased mortality and morbidity; therefore, a prompt diagnosis and an effective therapeutic approach are strongly necessary to improve the patient's clinical management. The first-line treatment for CS is surgery, while medical treatment has historically played a minor role. However, thanks to the availability of novel compounds, the possibility of improving hypercortisolism control using different drug combinations emerged. PURPOSE: No absolute recommendations are available to guide the therapeutic choice for patients with CS and, consequently, the awareness of unmet needs in CS management is growing. Although new data from clinical trials are needed to better define the most appropriate management of CS, an expert consensus approach can help define unmet needs and optimize the current CS management and treatment. METHODS: Twenty-seven endocrinologists from 12 Italian regions, working among the main Italian referral centers for hospital endocrinology where they take care of CS patients, were involved in a consensus process and used the Delphi method to reach an agreement on 24 statements about managing CS patients. RESULTS: In total, 18 statements reached a consensus. Some relevant unmet needs in the management of CS were reported, mainly related to the lack of a pharmacological treatment successful for the majority of patients. CONCLUSION: While acknowledging the difficulty in achieving complete disease control, a significant change in CS management requires the availability of medical treatment with improved efficacy and safety over available therapeutic options at the time of the current study.

Sodium dichloroacetate stimulates cardiac mitochondrial metabolism and improves cardiac conduction in the ovine fetus during labor.

Previous studies in our laboratory have suggested that the increase in stillbirth in pregnancies complicated by chronic maternal stress or hypercortisolemia is associated with cardiac dysfunction in late stages of labor and delivery. Transcriptomics analysis of the overly represented differentially expressed genes in the fetal heart of hypercortisolemic ewes indicated involvement of mitochondrial function. Sodium dichloroacetate (DCA) has been used to improve mitochondrial function in several disease states. We hypothesized that administration of DCA to laboring ewes would improve both cardiac mitochondrial activity and cardiac function in their fetuses. Four groups of ewes and their fetuses were studied: control, cortisol-infused (1 g/kg/day from 115 to term; CORT), DCA-treated (over 24 h), and DCA + CORT-treated; oxytocin was delivered starting 48 h before the DCA treatment. DCA significantly decreased cardiac lactate, alanine, and glucose/glucose-6-phosphate and increased acetylcarnitine/isobutyryl-carnitine. DCA increased mitochondrial activity, increasing oxidative phosphorylation (PCI, PCI + II) per tissue weight or per unit of citrate synthase. DCA also decreased the duration of the QRS, attenuating the prolongation of the QRS observed in CORT fetuses. The effect to reduce QRS duration with DCA treatment correlated with increased glycerophosphocholine and serine and decreased phosphorylcholine after DCA treatment. There were negative correlations of acetylcarnitine/isobutyryl-carnitine to both heart rate (HR) and mean arterial pressure (MAP). These results suggest that improvements in mitochondrial respiration with DCA produced changes in the cardiac lipid metabolism that favor improved conduction in the heart. DCA may therefore be an effective treatment of fetal cardiac metabolic disturbances in labor that can contribute to impairments of fetal cardiac conduction.

Treatment of Primary Pigmented Nodular Adrenocortical Disease.

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of adrenocorticotropin hormone (ACTH)-independent Cushing's syndrome (CS), which mainly occurs in children and young adults. Treatment options with proven clinical efficacy for PPNAD include adrenalectomy (bilateral or unilateral adrenalectomy) and drug treatment to control hypercortisolemia. Previously, the main treatment of PPNAD is bilateral adrenal resection and long-term hormone replacement after surgery. In recent years, cases reports suggest that unilateral or subtotal adrenal resection can also lead to long-term remission in some patients without the need for long-term hormone replacement therapy. Medications for hypercortisolemia, such as Ketoconazole, Metyrapone and Mitotane et.al, have been reported as a preoperative transition for in some patients with severe hypercortisolism. In addition, tryptophan hydroxylase inhibitor, COX2 inhibitor Celecoxib, somatostatin and other drugs targeting the possible pathogenic mechanisms of the disease are under study, which are expected to be applied to the clinical treatment of PPNAD in the future. In this review, we summarize the recent progress on treatment of PPNAD, in which options of surgical methods, research results of drugs acting on possible pathogenic mechanisms, and the management during gestation are described in order to provide new ideas for clinical treatment.

Longitudinal Monitoring of Hair Cortisol Using Liquid Chromatography-Mass Spectrometry to Prevent Hypercortisolism in Patients Undergoing Glucocorticoid Replacement Therapy.

OBJECTIVE: Currently available methods for endogenous cortisol monitoring in patients with hormonal insufficiency rely on measurements of plasma levels only at a single time point; thus, any kind of chronic exposure to cortisol is challenging to evaluate because it requires collecting samples at different time points. Hair cortisol levels acquired longitudinally better reflected chronic exposure (both cortisol synthesis and deposition) and may significantly contribute to better outcomes in glucocorticoid replacement therapies. DESIGN: Twenty-two patients on cortisol substitution therapy were monitored for plasma, urinary, and hair cortisol levels for 18 months to determine whether hair cortisol may serve as a monitoring option for therapy setting and adjustment. METHODS: Plasma and urinary cortisol levels were measured using standardized immunoassay methods, and segmented (∼1 cm) hair cortisol levels were monitored by liquid chromatography coupled to mass spectrometry. A log-normal model of the changes over time was proposed, and Bayesian statistics were used to compare plasma, urinary, and hair cortisol levels over 18 months. RESULTS AND CONCLUSIONS: Hair cortisol levels decreased over time in patients undergoing substitutional therapy. The residual variance of hair cortisol in comparison to plasma or urinary cortisol levels was much lower. Thus, longitudinal monitoring of hair cortisol levels could prove beneficial as a noninvasive tool to reduce the risk of overdosing and improve the overall patient health.

Levoketoconazole in the treatment of patients with endogenous Cushing's syndrome: a double-blind, placebo-controlled, randomized withdrawal study (LOGICS).

PURPOSE: The efficacy of levoketoconazole for endogenous Cushing's syndrome was demonstrated in a phase 3, open-label study (SONICS). This study (LOGICS) evaluated drug-specificity of cortisol normalization. METHODS: LOGICS was a phase 3, placebo-controlled, randomized-withdrawal study with open-label titration-maintenance (14-19 weeks) followed by double-blind, randomized-withdrawal (~ 8 weeks), and restoration (~ 8 weeks) phases. RESULTS: 79 patients received levoketoconazole during titration-maintenance; 39 patients on a stable dose (~ 4 weeks or more) proceeded to randomization. These and 5 SONICS completers who did not require dose titration were randomized to levoketoconazole (n = 22) or placebo (n = 22). All patients with loss of response (the primary endpoint) met the prespecified criterion of mean urinary free cortisol (mUFC) > 1.5 × upper limit of normal. During randomized-withdrawal, 21 patients withdrawn to placebo (95.5%) lost mUFC response compared with 9 patients continuing levoketoconazole (40.9%); treatment difference: - 54.5% (95% CI - 75.7, - 27.4; P = 0.0002). At the end of randomized-withdrawal, mUFC normalization was observed among 11 (50.0%) patients receiving levoketoconazole and 1 (4.5%) receiving placebo; treatment difference: 45.5% (95% CI 19.2, 67.9; P = 0.0015). Restoration of levoketoconazole reversed loss of cortisol control in most patients who had received placebo. Adverse events were reported in 89% of patients during treatment with levoketoconazole (dose-titration, randomized-withdrawal, and restoration phases combined), most commonly nausea (29%) and hypokalemia (26%). Prespecified adverse events of special interest with levoketoconazole were liver-related (10.7%), QT interval prolongation (10.7%), and adrenal insufficiency (9.5%). CONCLUSIONS: Levoketoconazole reversibly normalized urinary cortisol in patients with Cushing's syndrome. No new risks of levoketoconazole treatment were identified.

Cushing's disease: role of preoperative and primary medical therapy.

Transsphenoidal surgery is the first-line treatment for Cushing's disease. However, some situations may require the use of a primary medical treatment, such as in patients with severe life-threatening hypercortisolism, a situation which can be handled by fast-acting steroidogenesis inhibitors, instead of classical bilateral adrenalectomy. Primary medical treatment could also be considered in patients with non-severe hypercortisolism, but the evidence is far less convincing for its systematic use. The aim of this short review is to explain briefly the different circumstances in which primary medical therapy could be considered, the limits of this approach, and the way in which to initiate and monitor the treatment.

Treatment of Cushing's syndrome with osilodrostat: practical applications of recent studies with case examples.

Endogenous Cushing's syndrome (CS) is a rare endocrine condition frequently caused by a tumor resulting in elevated cortisol levels. Cushing's disease (CD) caused by an adrenocorticotropic hormone-secreting pituitary adenoma is the most common form of endogenous CS. Medical therapy for CD is mostly used as second-line treatment after failed surgery or recurrence and comprises several pituitary-directed drugs, adrenal steroidogenesis inhibitors, and a glucocorticoid receptor blocker, some of which are US Food and Drug Administration (FDA)-approved for this condition. The recent Pituitary Society consensus guidelines for diagnosis and management of CD described osilodrostat, an oral inhibitor of 11ß-hydroxylase, as an effective, FDA-approved medical therapy for CD. Because clinical experience outside clinical trials is limited, we provide here a review of published data about osilodrostat and offer example case studies demonstrating practical considerations on the use of this medication. Recommendations regarding osilodrostat are provided for the following situations: specific assessments needed before treatment initiation; monitoring for adrenal insufficiency, hypokalemia, and changes in QTc; the potential value of a slow up-titration in patients with mild disease; managing temporary treatment cessation for patients with CD who have acquired coronavirus disease 2019; monitoring for increased testosterone levels in women; exercising caution with concomitant medication use; considering whether a higher dose at nighttime might be beneficial; and managing cortisol excess in ectopic and adrenal CS. This review highlights key clinical situations that physicians may encounter when using osilodrostat and provides practical recommendations for optimal patient care when treating CS, with a focus on CD.

Glucocorticoid receptor blockers.

Mifepristone is the only glucocorticoid receptor antagonist currently approved for the treatment of Cushing's syndrome. Although originally developed as an abortifacient due to its blockade of the progesterone receptor, a number of case reports documented its efficacy as a glucocorticoid receptor blocker going back to 1985. The SEISMIC trial, published in 2012, provided sufficient data on efficacy and adverse effects for regulatory approval. Mifepristone provides clear benefits on glycemia, blood pressure, muscle weakness, body weight and the other myriad clinical manifestations of Cushing's syndrome. However, because it blocks the glucocorticoid receptor, blood cortisol and ACTH levels actually rise, rather than fall; this complicates patient management. Doses are adjusted based on clinical manifestations rather than hormone levels. Adverse effects include adrenal insufficiency due to overdosage, hypokalemia, and menorrhagia. Treatment of severe adrenal insufficiency requires high doses of dexamethasone. Other glucocorticoid receptor blockers without effects on the progesterone receptor are being developed. Because mifepristone inhibits CYP3A and CYP2C8/2C9, drug-drug interactions can occur. These potential adverse effects can largely be avoided with careful attention to detail. My opinion is that its current place in therapy is in patients with severe disease and in those not responding to other treatments.

Cushing's disease: adrenal steroidogenesis inhibitors.

Cushing's disease (CD), caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor, is the most common form of Cushing's syndrome (CS), accounting for approximately 70% of cases. CD requires a prompt diagnosis, an adequate treatment selection, and long-term management to limit hypercortisolism duration and long-term complications and improve patient outcomes. Pituitary surgery is the first-line option, which is non-curative in one third of patients, therefore requiring additional treatments. Medical therapy has recently acquired an emerging role, with the availability of several drugs with different therapeutic targets, efficacy and safety profiles. The current review focuses on efficacy and safety of steroidogenesis inhibitors, and particularly the historical drugs, ketoconazole and metyrapone, and the novel drugs levoketoconazole and osilodrostat, which seem to offer a rapid, sustained, and effective disease control. Ketoconazole should be preferred in females and in patients without severe liver disease; levoketoconazole may offer an alternative to classical ketoconazole, appearing characterized by a higher potency and potential lower hepatotoxicity compared to ketoconazole. Metyrapone should be preferred in males and in patients without severe or uncontrolled hypokalemia. Both ketoconazole and metyrapone may be preferred for short-term more than for long-term treatment. Osilodrostat may represent the best choice for long-term treatment, in patients with poor compliance to the multiple daily administration schedule, and in patients without severe or uncontrolled hypokalemia. Steroidogenesis inhibitors may be used alone or in combination, and associated with pituitary directed drugs, to improve the efficacy of the single drugs, allowing a potential use of lower doses for each drug, and hypothetically reducing the rate of adverse events associated with the single drugs. Clinicians may tailor medical therapy on the specific clinical scenario, considering disease history together with patients' characteristics and hypercortisolism's degree, addressing the needs of each patient in order to improve the therapeutic outcome and to reduce the burden of illness, particularly in patients with persistent or recurrent CD.

Growth hormone (GH) deficiency and GH replacement therapy in patients previously treated for Cushing's disease.

Several complications associated with active Cushing's disease may persist even years after complete and successful therapeutic remission of hypercortisolism. Growth hormone deficiency (GHD) shares many clinical features seen in patients with Cushing's disease, and its presence after disease remission (GHD-CR) might negatively influence and potentially worsen the systemic complications caused by previous hypercortisolism. GHD-CR is more prevalent in women, and compared to other causes of GHD, patients are younger at the onset of the pituitary disease, at diagnosis of GHD-CR and at start of GH therapy; prevalence of pituitary macroadenomas and visual abnormalities are lower, while prevalence of diabetes, hypertension, low bone mass, fractures, and worst quality of life, are higher. Serum IGF-1 levels are not useful for the diagnosis of GHD-CR and the application of GH stimulating tests requires some special attention in addition to the general recommendations for detecting GHD from other etiologies. In patients with active hypercortisolism, GH secretion is completely suppressed, but it may spontaneously and progressively recover over the years following successful therapy, meaning that GH testing may be performed at an appropriate time after remission for the correct diagnosis. Moreover, if the patient presents concomitant adrenal insufficiency, GH testing should only be carried out under adequate cortisol replacement therapy. GH therapy in children with GHD-CR improves adult height in the majority of patients, while GH therapy in adults has been associated with improvements in body composition, lipid profile and quality of life, but also with worsening of glucose metabolism.

The dopaminergic control of Cushing's syndrome.

Cushing's Syndrome (CS), or chronic endogenous hypercortisolism, is a rare and serious disease due to corticotroph pituitary (Cushing's disease, CD) and extra-pituitary (ectopic CS) tumours overproducing ACTH, or cortisol-secreting adrenal tumours or lesions (adrenal CS). The first-line treatment for CS is represented by the surgical removal of the responsible tumour, but surgery might be unfeasible or ineffective and medical treatment can be required in a relevant percentage of patients with CS, especially CD and ectopic CS. Corticotroph pituitary and extra-pituitary tumours, as well as adrenal tumours and lesions responsible for CS express dopamine receptors (DRs), which have been found to mediate inhibition of hormone secretion and/or cell proliferation in experimental setting, suggesting that dopaminergic system, particularly DRs, might represent a target for the treatment of CS. Dopamine agonists (DAs), particularly cabergoline (CAB), are currently used as off-label treatment for CD, the most common form of CS, demonstrating efficacy in controlling hormone secretion and tumour growth in a relevant number of cases, with the improvement of clinical picture, and displaying good safety profile. Therefore, CAB may be considered a reasonable alternative treatment for persistent or recurrent CD after pituitary surgery failure, but occasionally also before pituitary surgery, as adjuvant treatment, or even instead of pituitary surgery as first-line treatment in case of surgery contraindications or refusal. A certain beneficial effect of CAB has been also reported in ectopic CS. However, the role of DAs in the clinical management of the different types of CS requires further evaluations.

Two cases of infantile-onset primary generalized glucocorticoid hypersensitivity and the effect of mifepristone.

BACKGROUND: Primary generalized glucocorticoid hypersensitivity (PGGH) is a very rare disease caused by terminal organ hypersensitivity to glucocorticoids for which the aetiology is unknown. The incidence of PGGH is extremely rare, especially in children. To date, the literatures about the etiology, prognosis and treatment of PGGH are scarce. Aim of the study is describing the cases of two Chinese children with infantile-onset PGGH in one family, one of whom died and one who was treated with mifepristone. They are the two youngest children with PGGH reported in the literature. CASE PRESENTATION: Two siblings with infantile-onset PGGH were affected in this family. The main manifestations of patient 1 were typical Cushing's syndrome-like manifestations, significantly aggravated symptoms after physiological doses of glucocorticoids and very low levels of serum cortisol and adrenocorticotropin hormone (ACTH) during attacks. After being diagnosed with PGGH, he was given guidance to avoid glucocorticoids and took mifepristone therapy for 5 months, and his symptoms improved. Patient 2 was the younger brother of patient 1, with similar manifestations to his brother at the age of 4 months. Patient 2 ultimately died at the age of 9 months. CONCLUSION: PGGH is a very rare disease that can lead to death if not diagnosed and treated in a timely manner. This article describes the cases of the two youngest children with PGGH reported in the literature, one of whom improved after mifepristone treatment, and increases the knowledge of the clinical manifestations of and the treatment experience in PGGH.

Levoketoconazole improves clinical signs and symptoms and patient-reported outcomes in patients with Cushing's syndrome.

PURPOSE: The efficacy of levoketoconazole in treating hypercortisolism was demonstrated in an open-label phase 3 study (SONICS) of adults with endogenous Cushing's syndrome (CS) and baseline mean urinary free cortisol (mUFC) ≥ 1.5× ULN. Clinical signs and symptoms and patient-reported outcomes from the SONICS trial were evaluated in the current manuscript. METHODS: Patients titrated to an individualized therapeutic dose entered a 6-month maintenance phase. Secondary endpoints included investigator-graded clinical signs and symptoms of CS during the maintenance phase, and patient-reported quality of life (CushingQoL questionnaire) and depression symptoms (Beck Depression Inventory II [BDI-II]). RESULTS: Of 94 enrolled patients, 77 entered the maintenance phase following individualized dose titration. Significant mean improvements from baseline were noted at end of maintenance (Month 6) for acne, hirsutism (females only), and peripheral edema. These improvements were observed as early as Day 1 of maintenance for hirsutism (mean baseline score, 7.8; ∆ - 1.9; P < 0.0001), end of Month 1 for acne (mean baseline score, 2.8; ∆ - 1.2; P = 0.0481), and Month 4 for peripheral edema (mean baseline score, 1.0; ∆ - 0.5; P = 0.0052). Significant mean improvements from baseline were observed by Month 3 of maintenance for CushingQoL (mean baseline score, 44.3; ∆ + 6.9; P = 0.0018) and at Month 6 for BDI-II (mean baseline score, 17.1; ∆ - 4.3; P = 0.0043) scores. No significant mean improvement was identified in a composite score of 7 other clinical signs and symptoms. CONCLUSIONS: Treatment with levoketoconazole was associated with sustained, meaningful improvements in QoL, depression, and certain clinical signs and symptoms characteristic of CS. ClinialTrials.gov identifier: NCT01838551.

Dexamethasone measurement during low-dose suppression test for suspected hypercortisolism: threshold development with and validation.

BACKGROUND AND AIM: Dexamethasone Suppression Test (DST), recommended for Cushing's Syndrome (CS) diagnosis, explores the pituitary feedback to glucocorticoids. Its diagnostic accuracy could be affected by dexamethasone bioavailability, and therefore, we have developed and validated a dexamethasone threshold after 1-mg DST. MATERIALS AND METHODS: We studied 200 subjects: 125 patients were considered retrospectively and 75 were enrolled prospectively as the validation cohort. Serum dexamethasone, Late Night Salivary Cortisol (LNSC), and Urinary Free Cortisol (UFC) were measured with LC-MS/MS. Normal LNSC and UFC levels were used to exclude CS. The lower 2.5th percentile of dexamethasone distribution in non-CS patients with cortisol ≤ 50 nmol/L after 1-mg DST was used as threshold. RESULTS: 16 patients were CS and 184 non-CS (108 adrenal incidentaloma and 76 excluded CS); 4.5 nmol/L resulted the calculated threshold. Cortisol after 1-mg DST confirmed high sensitivity (100% at 50 nmol/L cut-off) and moderate-low specificity (63%, increased to 91% at 138 nmol/L) to diagnose CS in the whole cohort of patients. We could reduce the number of false-positive results (from 10 to 6 and from 7 to 4 in AI and excluded CS) considering adequate dexamethasone levels. Dexamethasone levels were not affected by hypercortisolism, age, gender, smoke, weight, and creatinine. 6% of non-CS patients did not achieve adequate dexamethasone levels (40% of tests with serum cortisol > 138 nmol/L after 1-mg DST). CONCLUSIONS: We developed and validated the routine dexamethasone measurement during 1-mg DST: it is independent from patient's clinical presentation, and it should be used to increase the specificity of serum cortisol levels.

Long-acting pasireotide improves clinical signs and quality of life in Cushing's disease: results from a phase III study.

PURPOSE: Cushing's disease (CD) is associated with significant clinical burden, increased mortality risk, and impaired health-related quality of life (HRQoL). This analysis explored the effect of long-acting pasireotide on clinical signs of hypercortisolism and HRQoL in a large subset of patients with CD. METHODS: In this phase III study (clinicaltrials.gov: NCT01374906), 150 adults with CD and a mean urinary free cortisol (mUFC) level between 1.5 and 5.0 times the upper limit of normal (ULN) started long-acting pasireotide 10 or 30 mg every 28 days with dose increases/decreases permitted based on mUFC levels/tolerability (minimum/maximum dose: 5/40 mg). Changes in clinical signs of hypercortisolism and HRQoL were assessed over 12 months of treatment and were stratified by degree of mUFC control for each patient. RESULTS: Patients with controlled mUFC at month 12 (n = 45) had the greatest improvements from baseline in mean systolic (- 8.4 mmHg [95% CI - 13.9, - 2.9]) and diastolic blood pressure (- 6.0 mmHg [- 10.0, - 2.0]). Mean BMI, weight, and waist circumference improved irrespective of mUFC control. Significant improvements in CushingQoL total score of 5.9-8.3 points were found at month 12 compared with baseline, irrespective of mUFC control; changes were driven by improvements in physical problem score, with smaller improvements in psychosocial score. CONCLUSIONS: Long-acting pasireotide provided significant improvements in clinical signs and HRQoL over 12 months of treatment, which, in some cases, occurred regardless of mUFC control. Long-acting pasireotide represents an effective treatment option and provides clinical benefit in patients with CD. CLINICAL TRIAL REGISTRATION NUMBER: NCT01374906.

A multicenter, phase 2 study to evaluate the efficacy and safety of osilodrostat, a new 11ß-hydroxylase inhibitor, in Japanese patients with endogenous Cushing's syndrome other than Cushing's disease.

This phase 2, single-arm, open-label, dose-titration, multicenter study evaluated osilodrostat (11ß-hydroxylase inhibitor) in Japanese patients with endogenous Cushing's syndrome (CS) caused by adrenal tumor/hyperplasia or ectopic adrenocorticotropic hormone syndrome. The primary endpoint was percent change from baseline to week 12 in mean urinary free cortisol (mUFC) at the individual patient level. Of the nine patients enrolled in the study, seven completed the 12-week core treatment period and two discontinued at or prior to week 12 due to adverse events (AEs). Of the seven patients who completed 12 weeks of study treatment, two completed 48 weeks of study treatment. Median osilodrostat exposure was 12 weeks. Median (range) average dose including dose interruption (0 mg/day) was 2.143 (1.16-7.54) mg/day. Median (range, population) percentage change in mUFC was -94.47% (-99.0% to -52.6%, n = 7) at week 12. At week 12, 6/9 patients were complete responders (mUFC ≤ upper limit of normal [ULN]) and 1/9 was a partial responder (mUFC > ULN but decreased by ≥50% from baseline). Most frequent AEs were adrenal insufficiency (n = 7), gamma-glutamyl transferase increase, malaise, and nasopharyngitis (n = 3 each). Serious AEs were seen in four patients. No deaths occurred in this study. In conclusion, osilodrostat treatment led to a reduction in mUFC in all nine patients with endogenous CS other than Cushing's disease (CD), regardless of disease type, with >80% reduction seen in 6/7 patients at week 12. The safety profile was consistent with previous reports in CD patients, and the reported AEs were manageable.

The effect of glucocorticoids on Thrombospondin-1, Osteocalcin and the Thrombospondin-1:Osteocalcin ratio in humans.

OBJECTIVE: Thrombospondin-1 (TSP1), a matricellular protein, and Osteocalcin (OCN), a noncollagenous protein secreted by osteoblasts, are known to be up- and down-regulated, respectively, by glucocorticoids. The aim of this study was to determine whether a ratio between TSP1:OCN was altered by changes in glucocorticoid activity in humans. DESIGN: Prospective observational study. SETTING: Tertiary university hospital in Queensland, Australia. PATIENTS AND MEASUREMENTS: Patients with Cushing's syndrome (CS, n = 19), asthma or giant cell arteritis on chronic prednisolone treatment (PRED, n = 13), adrenal insufficiency (AI, n = 16) and healthy volunteers (HV, n = 20). Plasma TSP1 and serum total OCN were measured by immunoassay at 0800h, 1200h and 1600h in patients with CS, patients with AI taking replacement glucocorticoids, HV before and after 4 mg dexamethasone and PRED patients predose at 800 and 4 hours post-dose at 1200 hours. RESULTS: Plasma TSP1 in CS was higher (P < .0001), and serum OCN was lower (P < .0001) than HV. The TSP1:OCN ratio in HV increased significantly after 4 mg dexamethasone (P < .0001) and in AI after taking their hydrocortisone replacement therapy (P < .001). PRED patients had a higher TSP1:OCN ratio compared with HV at both 800 and 1200 hours (both P < .001), but no significant change occurred from pre- to post-dose. A TSP1:OCN ratio of >73 at 800 hours differentiated CS from HV with a sensitivity of 95% and a specificity of 100%. CONCLUSIONS: The TSP1:OCN ratio is elevated in patients on prednisolone and in patients with CS compared with healthy volunteers. It may be a useful biomarker of total body glucocorticoid activity in humans.