Ketoconazole Effects on the Daily Cortisol Rhythm in Mild Autonomous Cortisol Secretion

Background: Cortisol is a hormone in the blood. Cortisol levels normally go down at night and up in the morning. Mild autonomous cortisol secretion (MACS) is a disease in which the body makes too much cortisol. MACS can cause high blood pressure, diabetes, and/or weight gain. Researchers think these problems may be caused by higher cortisol levels at night. Objective: To compare daily cortisol levels in people with MACS with those in healthy people. Also, to test a drug (ketoconazole) that may help lower cortisol levels in people with MACS. Eligibility: People aged 18 years and older with MACS. Healthy volunteers are also needed. Design: Participants with MACS will have a 2-night stay in the hospital. Day 1: A thin tube called a catheter will be inserted into a vein in the arm. Blood will be collected through the catheter every 2 hours starting at 8 PM. Participants will begin a 24-hour urine collection. Saliva will be collected every 6 hours for 24 hours. Day 2: Participants will take 2 tablets of the study drug ketoconazole with their evening meal. Blood will be collected via the catheter at regular intervals throughout the night. Day 3: Participants will leave the hospital in the morning. Healthy volunteers will be screened with a physical exam and blood tests. They will be tested to make sure they do not have MACS. To do this, they will take a drug (dexamethasone) at 11 PM on a day they choose; then they will return the next morning for a blood test. Healthy volunteers will have a 1-night stay in the hospital. They will have blood, urine, and saliva collected for 24 hours.

* INCLUSION CRITERIA: To be eligible to participate in this study, an individual must meet all of the following criteria: 1. Aged 18 years or older. 2. Stated willingness to comply with all study procedures and availability for the duration of the study. 3. Agreement to adhere to Lifestyle Considerations throughout the study. A. Subjects with Mild Autonomous Cortisol Secretion (MACS): 1. Co-enrollment in protocol 19DK0066. 2. Abnormal low-dose overnight dexamethasone suppression test (morning serum cortisol \>1.8 mcg/dL following 1 mg oral dexamethasone between 2300-0000h the evening prior) 3. One or more \>=1 cm adrenal nodule(s) on one or both adrenal glands on CT or MRI 4. One normal 24-hour urine free cortisol value (per the reference range of the assay used). 5. One morning plasma ACTH value \10 HU, per standard clinical care. 3. Known allergy or hypersensitivity to ketoconazole. 4. Significant liver disease or alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) \>3xULN, and/or total bilirubin \>1.5xULN during Screening. 5. Prolonged QTc interval (\>500 msec) on screening ECG. 6. Use of medications in the 2 weeks before inpatient admission that can: * Prolong QT when combined with ketoconazole (KTZ): \-- dofetilide, quinidine, pimozide, cisapride, methadone, disopyramide, dronedarone, ranolazine. * Cause toxicity from increased concentration due to KTZ-induced CYP3A4 inhibition: --methadone, disopyramide, dronedarone, ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine, methylergometrine, irinotecan, lurasidone, oral midazolam, alprazolam, triazolam, felodipine, nisoldipine, ranolazine, tolvaptan, eplerenone, lovastatin, simvastatin and colchicine. * Inhibit CYP3A4 and increase KTZ bioavailability: \-- ritonavir, darunavir, fosamprenavir. * Induce CYP3A4 and decrease KTZ bioavailability: * Isoniazid, rifabutin, rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine. 7. Inability to pause, for 24 hours, use of medication that reduces KTZ absorption: proton pump inhibitors (dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole) and H2 antagonists (cimetidine, famotidine, nizatidine). Inability to pause, for 3 hours, use of short-acting acid neutralizers that reduce KTZ absorption, e.g. aluminum hydroxide (acceptable if taken \>=1 hour before or \>=2 hours after KTZ).