Cushing's disease (CD) is associated with increased morbidity and mortality. Until now, no medical treatment has been shown to be totally satisfactory when administrated alone. This study aimed to assess the effectiveness of cabergoline with added ketoconazole and of the same combination in reverse, using urinary free cortisol (UFC) and late night salivary cortisol (LNSC) levels as biochemical markers of the treatments' efficacy in CD patients. A prospective analysis conducted on 14 patients (f/m = 12/2; median age 52, range 33-70 years) divided into two groups: 6 patients initially treated with cabergoline for 4-6 months (rising from 0.5-1 mg/week up to 3.0 mg/week), after which ketoconazole was added (group A); and 8 patients first took ketoconazole alone for 4-6 months (rising from 200 mg/day to 600 mg/day), then cabergoline was added (group B). Patients were compared with 14 age-matched patients in prolonged remission after effective neurosurgery for CD. The combination therapy led to UFC normalization in 79 % of patients with no differences between the groups; only one patient failed to respond at all. Neither drug succeeded in controlling the disease when taken alone. LNSC dropped when compared to baseline levels, but not to a significant degree (p = 0.06), and it remained significantly higher than in controls (p = 0.0006). Associating cabergoline with ketoconazole may represent an effective second-line treatment, achieving a satisfactory reduction in UFC levels and clinical improvement. Although the combined treatment lowered patients' LNSC levels, they remained higher than normal, indicating a persistent subclinical hypercortisolism; the implications of this condition need to be considered. No differences emerged between the two treatment schedules.
When hypertension, a pathology that is frequently found in the general population, presents in a young patient, secondary causes such as Cushing's syndrome (CS), a rare disease characterized by long-term elevated cortisol levels, should be considered. Present in ~80% of CS patients independently of their age and sex, hypertension is one of the pathology's most prevalent, alarming features. Its severity is principally associated with the duration and intensity of elevated cortisol levels. Prompt diagnosis and rapid initiation of treatment are important for reducing/delaying the consequences of hypercortisolism. Glucocorticoid excess leads to hypertension via a variety of mechanisms including mineralocorticoid mimetic activity, alterations in peripheral and renovascular resistance, and vascular remodeling. As hypertension in CS patients is caused by cortisol excess, treating the underlying pathology generally contributes to reducing blood pressure (BP) levels, although hypertension tends to persist in approximately 30% of cured patients. Surgical removal of the pituitary tumor remains the first-line treatment for both adrenocorticotropin hormone (ACTH) dependent and independent forms of the syndrome. In light of the fact that surgery is not always successful in curing the underlying disease, it is essential that other treatments be considered and prescribed as needed. This article discusses the mechanisms involved in the pathogenesis of CS and the pros and the cons of the various antihypertensive agents that are presently available to treat these patients.
MET therapy is a rapid-onset, long-term effective, and safe medical treatment in CS patients, achieving UFC normalization (in 70% of patients) more than cortisol rhythm recovery (in 37% of subjects).
Objective: The Endocrine Society Clinical Guidelines recommend measuring 24-h urinary free cortisol (UFF) levels using a highly accurate method as one of the first-line screening tests for the diagnosis of Cushing's Syndrome (CS). We evaluated the performance of UFF, urinary free cortisone (UFE), and the UFF:UFE ratio, measured using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Subjects and methods: The LC-MS/MS was used to analyze UFF and UFE levels in 43 surgically confirmed CS patients: 26 with Cushing's disease (CD, 16 de novo and ten recurrences), 11 with adrenal CS and six with ectopic CS; 22 CD patients in remission; 14 eu-cortisolemic CD patients receiving medical therapy; 60 non-CS patients; and 70 healthy controls. Sensitivity and specificity were determined in the combined groups of non-CS patients, healthy controls, and CD in remission. Results: UFFO170 nmol/24 h showed 98.7% specificity and 100% sensitivity for de novo CS, while sensitivity was 80% for recurrent CD patients, who were characterized by lower UFF levels. The UFF:UFE and UFFCUFE showed lower sensitivity and specificity than UFF. Ectopic CS patients had the highest UFF and UFF:UFE levels, which were normal in the CD remission patients and in those receiving medical therapy. Conclusions: Our data suggest high diagnostic performance of UFF excretion measured using LC-MS/MS, in detecting de novo CS. UFF:UFE and UFFCUFE assessments are not useful in the first step of CS diagnosis, although high levels were found to be indicative of ectopic CS.
Patients with CD showed a stronger response to HDDST and CRH, and the adopted cut-offs showed a good SE and SP in discriminating them from patients with EAS. Concordant tests indicated CD when positive, whereas no response to either test was highly suggestive of EAS. The DDAVP test was of limited utility in the diagnostic phase. In conclusion, the choice of tests may play an important part in the differential diagnosis of ACTH-dependent CS.
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