INCLUSION CRITERIA:
Subjects will be included if they have ALL of the three following criteria:
1. Hypercortisolism from Cushing's syndrome caused by ACTH ectopic secretion confirmed by:
- Inferior petrosal sinus sampling (IPSS) with a central to peripheral ACTH ratio of less than 2.0 before CRH administration and less than 3.0 after CRH administration
- or biopsy with ACTH immunoreactivity
- or presence of a tumor evidenced by imaging combined with both a negative CRH test and a negative 8-mg dexamethasone suppression test.
No major change in tumor status/anti-tumor therapy should be expected during the study
AND
2. Glucose intolerance AND/OR hypertension that is considered to be caused or worsened by the hypercortisolism:
Diabetes defined by
- fasting plasma glucose level greater than or equal to 7.0 mmol/l (126 mg/dl)
- or 2-hour glucose plasma level after 75 g OGTT greater than or equal to 11.0 mmol/l (200 mg/dl)
- or treated diabetes. In addition, treatment should be stable, i.e. for thiazolidinediones, patients must have been on stable therapy for at least four months prior to study entry; for all other diabetes treatments, including insulin, patients must have been on stable therapy for at least two weeks prior to study entry.
- or glucose intolerance defined by:
- fasting plasma glucose values between 5.5 mmol/l (100 mg/dl) and 7.0 mmol/l (126 mg/dl) or 2-hour glucose plasma level after 75 g OGTT greater than or equal to 7.8 mmol/l (140 mg/dl) and less than 11.1 mmol/(200 mg/dl)
- Prior to study entry, fasting blood sugar must be less than 11.1 mmol/l (200 mg/dl) for at least two weeks
Hypertension defined by
- systolic BP greater than or equal to 140 mm Hg and/or diastolic BP greater than or equal to 90 mm Hg
- Prior to study entry, BP must be less than 180/110 mm Hg for at least two weeks
- or treated hypertension: patients must have been on stable anti-hypertensive therapy for at least four weeks prior to study entry.
AND
3. At least one of the following symptoms attributable to the Cushing's syndrome:
- Body weight increase or truncal obesity
- Depression or treated depression or psychiatric disorder
- Fatigue
- Proximal muscle weakness
- Hirsutism
- Hypokalemia
- Bruising
- Violaceous striae
- In men, gynecomastia or libido decrease
- Impaired cognition or memory
- Hyperpigmentation
- Amenorrhea
- Osteopenia or osteoporosis
In addition, the following criteria should be met:
- Written informed consent to participate in the study
- Female subjects should be sterilized, post-menopausal, sexually inactive or willing to use barrier methods of contraception throughout the study.
- Subject willing to return to investigational site during the full course of the study
- Age in the range of 18 to 75 years inclusive
EXCLUSION CRITERIA:
- Evidence for Cushing's disease as judged by positive inferior petrosal sinus sampling or a lesion on pituitary MRI with positive CRH test
- Suspected or known adrenocortical cancer or adenomas, as judged by ACTH values less than 10 pg/ml and adrenal mass
- Subjects with cyclic Cushing's syndrome defined by at least 3 measurements of urinary free cortisol over the previous two months without normal values.
- Children (age less than 18) and subject of more than 75 years of age
- Pregnant or lactating women. A urinary pregnancy test will be performed in women of childbearing potential unless they have a history of menopause prior to Cushing's syndrome or hysterectomy
- Life expectancy less than three months
- Severe and/or uncontrolled diabetes (plasma glucose greater than 11.0 mmol/L)
- Severe and/or uncontrolled hypertension (blood pressure greater than 160/100 mmHg)
- Recent (less than two weeks prior to inclusion) initiation of corrective treatments for depression
- Clinically significantly impaired cardiovascular function (e.g. stage IV cardiac failure)
- Severe liver disease (liver enzymes greater than or equal to 3 x the institutional upper limit of normal range)
- Severe renal impairment (serum creatinine greater than or equal to 2.2 mg/dl or creatinine clearance less than 30 ml/min)
- Severe hypokalemia (plasma K below 3.0 mmol/L)
- Uncontrolled severe active infection
- In women, known endometrial cancer, history of endometrial hyperplasia or vaginal bleeding of unknown cause
- Recent (less than two weeks prior to inclusion) initiation of or significant change in dose of anti-tumor therapy
- Premenopausal women with hemorrhagic disorders or on anticoagulants
- Previous treatment with approved or experimental steroidogenesis inhibitors, adrenolytic agents or somatostatin analogues within four weeks of admission (eight weeks for patients on octreotide LAR or on lanreotide autogel)
- Plasma mitotane concentration greater than 5 microliter (g)/ml
- Impaired mental capacity or markedly abnormal psychiatric evaluation that precludes informed consent
- Body weight over 136 kg, which is the limit for the tables used in the scanning areas
- Inherited porphyria
- Positive pregnancy test at inclusion
- Use of antiretroviral agents, midazolam, cabergoline, ketoconazole, intraconazole, erythromycin, or grapefruit juice within two weeks of the study