To be eligible to participate in this study, an individual must meet all of the following criteria:
- Aged 18-70 years
- Agreement to adhere to Lifestyle Considerations throughout the study.
- Evidence of acceptable laboratory testing results within four weeks of the first test day, as shown by medical record review:
- Hematocrit at entry >=33 %
- Plasma sodium 136-145 mmol/L (unless taking a drug that can cause hyponatremia, see below) eGFR >=60 ml/min/1.73 sq.m, calculated based on serum creatinine
- For subjects taking any drug that could worsen hyponatremia, a normal plasma sodium (136-145 mmol/L) must have been obtained within seven days of the first test day.
In addition, an individual must meet all the criteria listed for their diagnostic group below, based on medical record review:
A. Patients with possible ACTH-dependent Cushing Syndrome (where the results of further work up will classify the patient as having CD, EAS or pseudo-CS):
1. A. Hypercortisolemia as evidenced by physician note or laboratory report: at least one screening modality (1 mg dexamethasone suppression test, 24-hour urinary free cortisol (UFC), bedtime or late night (2200h - 2359h) salivary or serum cortisol) within 4 weeks of screening. In patients suspected to have cyclic CS any previous abnormal result will suffice.
2. A. Normal or increased plasma ACTH (>20 pg/mL) as evidenced by physician note or laboratory report.
B. Patients with recurrent ACTH-dependent Cushing Syndrome (previous CD or EAS):
1B. Evidence of previous remission of CD or EAS after resection of a causative pituitary or ectopic tumor, evidence of current ACTH-dependent hypercortisolism, and willingness to undergo repeat surgery.
C. Healthy volunteers:
C1. In good general health as evidenced by medical history and physical examination; and in a stable state of health without ongoing acute/temporary illness per the clinical judgement of the investigator.
EXCLUSION CRITERIA:
An individual who meets any of the following criteria will be excluded from participation in this study, based on medical record review (possible Cushing syndrome patients) or a screening visit (healthy volunteers).
1. Inability to comply with all study procedures and visits
2. Inability of subject to understand or to sign a written informed consent document.
3. Known allergy/hypersensitivity to desmopressin.
4. Pregnancy or lactation, due to alterations in measured serum cortisol and lack of data on desmopressin safety.
5. A history of angina, significant coronary artery disease, congestive heart failure, or syndrome of inappropriate antidiuretic hormone secretion (SIADH), due to risk of fluid overload and/or hyponatremia.
6. Uncontrolled hypertension (blood pressure >150/95 mmHg) at screening and before desmopressin administration, due to risk of further increase if fluid overload occurs
7. Any condition that in the opinion of the Investigator would jeopardize the participant s appropriate participation in this study.
8. Current daily use of any of the following medications:
- Drug used for the stimulation tests: Desmopressin.
- Drugs that can suppress ACTH and cortisol test responses: Systemic glucocorticoids, including inhaled or topical formulations.
- Vasopressors: phenylephrine, dopamine and vasopressin.
- Drugs that interfere with desmopressin duration of action or potency: carbamazepine, lamotrigine, tolvaptan
9. Strong inducers of CYP3A4 (e.g. barbiturates, phenytoin, rifampin, rifabutin, rifapentine, carbamazepine, eslicarbazepine, primidone, cenobamate, Modafinil). Use of St John's wort or nafcillin within 14 days.
10. Initiation or dose increase within the past 14 days of drugs that can worsen hyponatremia: non-steroidal anti-inflammatory drugs (NSAIDs), loop diuretics (bumetanide, ethacrynic acid, furosemide, torsemide), chlorpromazine, chlorpropamide, cisplatin, monoamine oxidase inhibitors (MAOI), opiate agonists, oxybutynin, selective serotonin reuptake inhibitors (SSRI), vincristine, tricyclic antidepressants (TCAs)
11. Chronic enhanced hydration (estimated as >4 liters) to supplement mealtime fluid intake.
12. Any contraindication to intravenous catheter use.
13. Previous participation in this protocol.
14. History of hemophilia of any type.
15. Any hematology or chemistry screening laboratory value drawn at screening that the Investigator determines is clinically significant for exclusion.
Condition-specific exclusions will also apply to each subject group as follows:
A.Patients with possible ACTH-dependent Cushing Syndrome:
1. A. Use of medications that block glucocorticoid production (ketoconazole, levoketoconazole, metyrapone, osilodrostat) within the past two weeks, if normal cortisol is achieved. If hypercortisolism persists despite the use of these medications, as evidenced by an elevated 24-hour urinary free cortisol (UFC) or late night (2200h - 2359h) salivary or serum cortisol within two weeks of the first desmopressin test, the medication(s) may be continued until 48 hours before the first desmopressin test.
2. A. Use of the adrenolytic mitotane at any point, due to its prolonged half-life.
3. A. Use of medications that block glucocorticoid action or ACTH release within the past two weeks - mifepristone, cabergoline, octreotide (subcutaneous), pasireotide (subcutaneous), megestrol acetate, other synthetic glucocorticoids (except for topical or inhaled agents and single doses of oral dexamethasone for diagnostic testing within the past 48 hours)
4. A. Use of intramuscular long-acting forms of octreotide or pasireotide within the past 4 months.
5. A. Treatment of diabetes insipidus.
B. Healthy volunteers:
1. B. Use of oral, injectable, or inhaled glucocorticoids (unless intermittent, for symptomatic asthma) within the last year. Use of topical non-hydrocortisone containing potent glucocorticoids on more than 36 square inches in the last six months.
2. B. Hemoglobin A1c >= 6.5% on screening labs.