scholarly journals Long-Term Control of Urinary Free Cortisol With Osilodrostat in Patients With Cushing’s Disease: Final Results From the LINC 2 Study

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A521-A522
Author(s):  
Maria Fleseriu ◽  
Beverly M K Biller ◽  
Jerome Bertherat ◽  
Jacques Young ◽  
Giorgio Arnaldi ◽  
...  
Keyword(s):  
Adrenal Insufficiency ◽  
Cushing’S Disease ◽  
Clinical Signs ◽  
Urinary Free Cortisol ◽  
Cushing's Disease ◽  
Efficacy And Safety ◽  
Entire Treatment Period ◽  
Free Cortisol ◽  
Long Term Treatment

Abstract Introduction: During the 22-week core LINC 2 study, the oral 11β-hydroxylase inhibitor osilodrostat normalized mean urinary free cortisol (mUFC) in 79% (15/19) of patients with Cushing’s disease. This report describes long-term LINC 2 efficacy and safety results following an optional extension. Methods: Patients receiving clinical benefit at week 22 could enter the extension (that ran until Oct 22, 2019), continuing the same osilodrostat dose; dose adjustments were permitted based on efficacy and safety. Response rate (mUFC ≤ULN [controlled] or mUFC >ULN but ≥50% decrease from baseline [BL; partially controlled]) was assessed over time. Efficacy/safety were assessed for all patients from core BL until study end. Results: Of 19 enrolled patients (female:male 14:5; mean [SD] age 36.8 years [8.4]), 16 entered the optional extension and 8 of them remained on treatment until study end. Median (range) osilodrostat exposure was 282 weeks (2-351). Mean mUFC decreased from BL (9.9 x ULN) to ≤ULN by week 4 and remained stable throughout the study. All 19 patients achieved mUFC ≤ULN at least once during the study. At each assessment up to month 70 of the extension phase, 50-88% of ongoing patients were controlled, and up to 18% were partially controlled. Mean percentage change in clinical signs from BL (mean [SD]) to last assessment were: fasting plasma glucose, -10.8% (22.1) (from BL: 105.6 mg/dL [49.2]); HbA1c, -2.1% (9.0) (from BL: 5.7% [0.7]); systolic BP, -3.3% (12.6) (from BL: 132.6 mmHg [11.6]); diastolic BP, -2.0% (10.4) (from BL: 85.0 mmHg [6.5]); BMI, -5.9% (8.8) (from BL: 30.7 kg/m2 [7.0]). Overall, 9 patients discontinued treatment (n=2 core and n=7 extension), mostly because of AEs or no longer requiring treatment (n=3 each). The most common AEs during the entire treatment period were nausea (n=10), adrenal insufficiency, and headache (both n=9). AEs related to hypocortisolism and adrenal hormone precursor accumulation occurred in 11 (mostly adrenal insufficiency, n=9) and 12 patients (mostly hypertension, n=4), respectively; most were grade 1/2 and managed with dose adjustment/interruption and/or concomitant medication. Mean (SD) plasma ACTH increased from 1.8 x ULN (0.9) at BL to 7.1 x ULN (12.3) at week 22 and 6.9 x ULN (12.6) at last assessment. Mean (SD) 11-deoxycortisol increased from 1.2 x ULN (1.3) at BL to 13.6 x ULN (12.2) at week 22 and 3.6 x ULN (4.2) at last assessment. In females, mean (SD) testosterone increased from 0.8 x ULN (0.4) at BL to 2.4 x ULN (2.1) at week 22 and 1.0 x ULN (0.9) at last assessment. Two patients, both female, reported an AE of hirsutism. Conclusions: Rapid reductions in mUFC were sustained for up to 6 years of osilodrostat treatment and were accompanied by improvements in clinical signs of hypercortisolism. Osilodrostat was well tolerated, with no new safety signals during long-term treatment.

scholarly journals Cabergoline for Cushing’s disease: a large retrospective multicenter study

2017 ◽  
Vol 176 (3) ◽  
pp. 305-314 ◽  
Author(s):  
A Ferriere ◽  
C Cortet ◽  
P Chanson ◽  
B Delemer ◽  
P Caron ◽  
...  
Keyword(s):  
Multicenter Study ◽  
Cushing’S Disease ◽  
Urinary Free Cortisol ◽  
Cushing's Disease ◽  
Plasma Prolactin ◽  
University Hospitals ◽  
Free Cortisol ◽  
Long Term Treatment ◽  
Retrospective Multicenter Study

Objective The efficacy of cabergoline in Cushing’s disease (CD) is controversial. The aim of this study was to assess the efficacy and tolerability of cabergoline in a large contemporary cohort of patients with CD. Design We conducted a retrospective multicenter study from thirteen French and Belgian university hospitals. Methods Sixty-two patients with CD received cabergoline monotherapy or add-on therapy. Symptom score, biological markers of hypercortisolism and adverse effects were recorded. Results Twenty-one (40%) of 53 patients who received cabergoline monotherapy had normal urinary free cortisol (UFC) values within 12 months (complete responders), and five of these patients developed corticotropic insufficiency. The fall in UFC was associated with significant reductions in midnight cortisol and plasma ACTH, and with clinical improvement. Compared to other patients, complete responders had similar median baseline UFC (2.0 vs 2.5xULN) and plasma prolactin concentrations but received lower doses of cabergoline (1.5 vs 3.5 mg/week, P < 0.05). During long-term treatment (>12 months), cabergoline was withdrawn in 28% of complete responders because of treatment escape or intolerance. Overall, sustained control of hypercortisolism was obtained in 23% of patients for 32.5 months (19–105). Nine patients on steroidogenesis inhibitors received cabergoline add-on therapy for 19 months (1–240). Hypercortisolism was controlled in 56% of these patients during the first year of treatment with cabergoline at 1.0 mg/week (0.5–3.5). Conclusions About 20–25% of CD patients are good responders to cabergoline therapy allowing long-term control of hypercortisolism at relatively low dosages and with acceptable tolerability. No single parameter, including the baseline UFC and prolactin levels, predicted the response to cabergoline.

scholarly journals Use of late-night salivary cortisol to monitor response to medical treatment in Cushing’s disease

2020 ◽  
Vol 182 (2) ◽  
pp. 207-217 ◽  
Author(s):  
John Newell-Price ◽  
Rosario Pivonello ◽  
Antoine Tabarin ◽  
Maria Fleseriu ◽  
Przemysław Witek ◽  
...  
Keyword(s):  
Cushing’S Disease ◽  
Salivary Cortisol ◽  
Clinical Signs ◽  
Urinary Free Cortisol ◽  
Phase Iii ◽  
Cushing's Disease ◽  
Late Night ◽  
Late Night Salivary Cortisol ◽  
Free Cortisol ◽  
Two Samples

Objective Monitoring of patients with Cushing’s disease on cortisol-lowering drugs is usually performed with urinary free cortisol (UFC). Late-night salivary cortisol (LNSC) has an established role in screening for hypercortisolism and can help to detect the loss of cortisol circadian rhythm. Less evidence exists regarding the usefulness of LNSC in monitoring pharmacological response in Cushing’s disease. Design Exploratory analysis evaluating LNSC during a Phase III study of long-acting pasireotide in Cushing’s disease (clinicaltrials.gov: NCT01374906). Methods Mean LNSC (mLNSC) was calculated from two samples, collected on the same days as the first two of three 24-h urine samples (used to calculate mean UFC [mUFC]). Clinical signs of hypercortisolism were evaluated over time. Results At baseline, 137 patients had evaluable mLNSC measurements; 91.2% had mLNSC exceeding the upper limit of normal (ULN; 3.2 nmol/L). Of patients with evaluable assessments at month 12 (n = 92), 17.4% had both mLNSC ≤ULN and mUFC ≤ULN; 22.8% had mLNSC ≤ULN, and 45.7% had mUFC ≤ULN. There was high variability in LNSC (intra-patient coefficient of variation (CV): 49.4%) and UFC (intra-patient CV: 39.2%). mLNSC levels decreased over 12 months of treatment and paralleled changes in mUFC. Moderate correlation was seen between mLNSC and mUFC (Spearman’s correlation: ρ = 0.50 [all time points pooled]). Greater improvements in systolic/diastolic blood pressure and weight were seen in patients with both mLNSC ≤ULN and mUFC ≤ULN. Conclusion mUFC and mLNSC are complementary measurements for monitoring treatment response in Cushing’s disease, with better clinical outcomes seen for patients in whom both mUFC and mLNSC are controlled.

scholarly journals Cabergoline monotherapy in the long-term treatment of Cushing's disease

2010 ◽  
Vol 163 (5) ◽  
pp. 709-716 ◽  
Author(s):  
Ariane Godbout ◽  
Marcos Manavela ◽  
Karina Danilowicz ◽  
Hugues Beauregard ◽  
Oscar Domingo Bruno ◽  
...  
Keyword(s):  
Partial Response ◽  
Cushing’S Disease ◽  
Complete Response ◽  
Cushing's Disease ◽  
Term Therapy ◽  
Dopamine Receptor Agonist ◽  
Ectopic Acth ◽  
Free Cortisol ◽  
Long Term Treatment

BackgroundCabergoline is a long-acting dopamine receptor agonist used to treat prolactinomas. Identification of D2 receptors in corticotroph tumors led to clinical trials of cabergoline therapy in limited cases of Nelson's syndrome, ectopic ACTH-secreting tumors, and recently Cushing's disease (CD).ObjectiveTo evaluate the long-term efficacy of cabergoline monotherapy in patients with CD.MethodsRetrospective analysis of non-randomized clinical therapy with cabergoline in 30 patients with CD treated in academic centers of Buenos Aires and Montreal. Cabergoline was initiated at 0.5–1.0 mg/week and adjusted up to a maximal dose of 6 mg/week based on urinary free cortisol (UFC) levels. Complete response to cabergoline was defined as a sustained normalization of UFC with at least two normal values measured at 1–3 months interval; partial response was defined as a decrease of UFC to <125% of the upper limit of normal, and treatment failure as UFC ≥125% of it.ResultsWithin 3–6 months, complete response was achieved in 11 patients (36.6%) and partial response in 4 patients (13.3%). After long-term therapy, nine patients (30%) remain with a complete response after a mean of 37 months (range from 12 to 60 months) with a mean dose of 2.1 mg/week of cabergoline. Two patients escaped after 2 and 5 years of complete response, but one patient transiently renormalized UFC after an increase in cabergoline dosage. No long-term response was maintained in four initial partial responders.ConclusionsCabergoline monotherapy can provide an effective long-term medical therapy for selected patients with CD, but requires close follow-up for dose adjustments.

scholarly journals Ketoconazole revisited: a preoperative or postoperative treatment in Cushing's disease

2008 ◽  
Vol 158 (1) ◽  
pp. 91-99 ◽  
Author(s):  
F Castinetti ◽  
I Morange ◽  
P Jaquet ◽  
B Conte-Devolx ◽  
T Brue
Keyword(s):  
Cushing’S Disease ◽  
Transsphenoidal Surgery ◽  
Urinary Free Cortisol ◽  
Postoperative Treatment ◽  
Cushing's Disease ◽  
Intention To Treat ◽  
Free Cortisol ◽  
In Series

ContextAlthough transsphenoidal surgery remains the first-line treatment in Cushing's disease (CD), recurrence is observed in about 20% of cases. Adjunctive treatments each have specific drawbacks. Despite its inhibitory effects on steroidogenesis, the antifungal drug ketoconazole was only evaluated in series with few patients and/or short-term follow-up.ObjectiveAnalysis of long-term hormonal effects and tolerance of ketoconazole in CD.DesignA total of 38 patients were retrospectively studied with a mean follow-up of 23 months (6–72).SettingAll patients were treated at the same Department of Endocrinology in Marseille, France.PatientsThe 38 patients with CD, of whom 17 had previous transsphenoidal surgery.InterventionKetoconazole was begun at 200–400 mg/day and titrated up to 1200 mg/day until biochemical remission.Main outcome measuresPatients were considered controlled if 24-h urinary free cortisol was normalized.ResultsFive patients stopped ketoconazole during the first week because of clinical or biological intolerance. On an intention to treat basis, 45% of the patients were controlled as were 51% of those treated long term. Initial hormonal levels were not statistically different between patients controlled or uncontrolled. Ketoconazole was similarly efficacious as a primary or postoperative treatment. Among 15 patients without visible adenoma at initial evaluation, subsequent follow-up allowed identification of the lesion in five cases. No adrenal insufficiency was observed. Adverse effects were rare in patients treated long term.ConclusionsKetoconazole is a safe and efficacious treatment in CD, particularly in patients for whom surgery is contraindicated, or delayed because of the absence of image of adenoma on magnetic resonance imaging.

scholarly journals The Role of Isotretinoin Therapy for Cushing’s Disease: Results of a Prospective Study

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Lucio Vilar ◽  
José Luciano Albuquerque ◽  
Ruy Lyra ◽  
Erik Trovão Diniz ◽  
Frederico Rangel Filho ◽  
...  
Keyword(s):  
Cushing’S Disease ◽  
Transsphenoidal Surgery ◽  
Urinary Free Cortisol ◽  
Cushing's Disease ◽  
Efficacy And Safety ◽  
Upper Limit ◽  
Free Cortisol ◽  
A Prospective Study ◽  
Isotretinoin Therapy

Objective. This prospective open trial aimed to evaluate the efficacy and safety of isotretinoin (13-cis-retinoic acid) in patients with Cushing’s disease (CD).Methods. Sixteen patients with CD and persistent or recurrent hypercortisolism after transsphenoidal surgery were given isotretinoin orally for 6–12 months. The drug was started on 20 mg daily and the dosage was increased up to 80 mg daily if needed and tolerated. Clinical, biochemical, and hormonal parameters were evaluated at baseline and monthly for 6–12 months.Results. Of the 16 subjects, 4% (25%) persisted with normal urinary free cortisol (UFC) levels at the end of the study. UFC reductions of up to 52.1% were found in the rest. Only patients with UFC levels below 2.5-fold of the upper limit of normal achieved sustained UFC normalization. Improvements of clinical and biochemical parameters were also noted mostly in responsive patients. Typical isotretinoin side-effects were experienced by 7 patients (43.7%), though they were mild and mostly transient. We also observed that the combination of isotretinoin with cabergoline, in relatively low doses, may occasionally be more effective than either drug alone.Conclusions. Isotretinoin may be an effective and safe therapy for some CD patients, particularly those with mild hypercortisolism.

Long-distance and long-term follow-up of a patient with intermittent Cushing's disease by salivary cortisol measurements

1995 ◽  
Vol 133 (3) ◽  
pp. 313-316 ◽  
Author(s):  
H Mosnier-Pudar ◽  
P Thomopoulos ◽  
X Bertagna ◽  
C Fournier ◽  
D Guiban ◽  
...  
Keyword(s):  
North Africa ◽  
Cushing’S Disease ◽  
Salivary Cortisol ◽  
Clinical Signs ◽  
Cushing's Disease ◽  
Long Distance ◽  
Free Cortisol ◽  
Long Term Follow Up

Mosnier-Pudar H, Thomopoulos P, Bertagna X, Fournier C, Guiban D, Luton JP. Long-distance and long-term follow-up of a patient with intermittent Cushing's disease by salivary cortisol measurements. Eur J Endocrinol 1995;133:313–6. ISSN 0804–4643 Salivary cortisol is an excellent indicator of the plasma free cortisol concentration in normal and pathological situations. We took advantage of its ease of sampling, allowing multiple collections at home, to follow the course of a patient with Cushing's disease living in North Africa. This 48-year-old woman presented with a clinically moderate hypercortisolism caused by a large basophilic pituitary adenoma. Bilateral extension to the cavernous sinuses precluded surgical therapy. She went into spontaneous remission based on clinical signs as well as biochemical findings. During the following 2 years she demonstrated intermittent relapses that were treated by radiotherapy (50 Gy), followed by ketoconazole and then o-paraprime-dichloro-diphenyl-dichloroethane (Op′DDD). After a prolonged clinical remission, Cushing's syndrome again became active. Bromocriptine was started without effect and a new treatment with Op′DDD was began. Evaluation and follow-up were performed during hospitalizations and mainly through the measurements of salivary cortisol in more than 100 samples sent from North Africa by air mail to our department in Paris. Thus we were able to demonstrate intermittent overproduction of cortisol before any treatment, with periods of normal and even low values, and to follow the efficacy of therapy and to detect the relapses. We conclude that measurement of salivary cortisol is a valuable tool in difficult clinical situations such as intermittent hypercortisolism and remoteness between the patient and hospital. H Mosnier-Pudar, Clinique des Maladies Endocriniennes et Metaboliques, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, 75014 Paris, France

scholarly journals Assessment of Vitamin D Metabolism in Patients with Cushing’s Disease in Response to 150,000 IU Cholecalciferol Treatment

Nutrients ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 4329
Author(s):  
Alexandra Povaliaeva ◽  
Viktor Bogdanov ◽  
Ekaterina Pigarova ◽  
Artem Zhukov ◽  
Larisa Dzeranova ◽  
...  
Keyword(s):  
Vitamin D ◽  
Cushing’S Disease ◽  
Serum Vitamin ◽  
Urinary Free Cortisol ◽  
Cushing's Disease ◽  
Control Group ◽  
Vitamin D Metabolites ◽  
Vitamin D Metabolism ◽  
Serum Vitamin D ◽  
Free Cortisol

In this study we aimed to assess vitamin D metabolism in patients with Cushing’s disease (CD) compared to healthy individuals in the setting of bolus cholecalciferol treatment. The study group included 30 adults with active CD and the control group included 30 apparently healthy adults with similar age, sex and BMI. All participants received a single dose (150,000 IU) of cholecalciferol aqueous solution orally. Laboratory assessments including serum vitamin D metabolites (25(OH)D3, 25(OH)D2, 1,25(OH)2D3, 3-epi-25(OH)D3 and 24,25(OH)2D3), free 25(OH)D, vitamin D-binding protein (DBP) and parathyroid hormone (PTH) as well as serum and urine biochemical parameters were performed before the intake and on Days 1, 3 and 7 after the administration. All data were analyzed with non-parametric statistics. Patients with CD had similar to healthy controls 25(OH)D3 levels (p > 0.05) and higher 25(OH)D3/24,25(OH)2D3 ratios (p < 0.05) throughout the study. They also had lower baseline free 25(OH)D levels (p < 0.05) despite similar DBP levels (p > 0.05) and lower albumin levels (p < 0.05); 24-h urinary free cortisol showed significant correlation with baseline 25(OH)D3/24,25(OH)2D3 ratio (r = 0.36, p < 0.05). The increase in 25(OH)D3 after cholecalciferol intake was similar in obese and non-obese states and lacked correlation with BMI (p > 0.05) among patients with CD, as opposed to the control group. Overall, patients with CD have a consistently lower 25(OH)D3/24,25(OH)2D3 ratio, which is indicative of a decrease in 24-hydroxylase activity. This altered activity of the principal vitamin D catabolism might influence the effectiveness of cholecalciferol treatment. The observed difference in baseline free 25(OH)D levels is not entirely clear and requires further study.

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