Ketoconazole: Therapy for Cushing’s syndrome

Surgical vs. Medical Treatment for Cushing’s Syndrome

Dr. Friedman often recommends surgical treatment for Cushing’s syndrome and, specifically, pituitary surgery for those with pituitary Cushing’s disease. However, many patients are not good surgical candidates for their Cushing’s disease. This can occur if they do not have a tumor clearly seen on their pituitary or if their tests are equivocal for Cushing’s. There are several medical treatments for Cushing’s syndrome available including Korlym, Recorlev, Pasireotide, Cabergoline, and Isturisa. Please see Dr. Friedman’s guide to medications for Cushing’s syndrome. However, Dr. Friedman has found that ketoconazole is the most effective medicine for treating Cushing’s syndrome. Ketoconazole (not FDA approved in the US, but approved in Europe) works by blocking several enzymes in the adrenals that are involved in glucocorticoid synthesis. There is a new drug called Recorlev (levoketoconazole) that is recently FDA-approved, but it is  expensive and unlikely to have advantages over ketoconazole, which is low cost and usually doesn’t need insurance approval.

Advantages of Ketoconazole

There are several advantages of ketoconazole over the other cortisol-lowering medicines. One of them is that it has a fairly short half-life of about 6 hours. That means it only stays in the blood for a short time. Cushing’s syndrome is a disease of high cortisol at night and not during the day, so Dr. Friedman prefers to give ketoconazole in the late evening to lower the nighttime cortisol. It usually does not affect the daytime cortisol, which is good because high daytime cortisol is usually not a problem. Dr. Friedman usually starts with a dose of 200 mg of ketoconazole at 8 PM and 10 PM, assuming the patient goes to bed at about 11 PM, and may increase it up to a total of 800 mg per night. The highest dose he usually uses is 1200 mg. This is usually quite effective at lowering cortisol at night, and the patient usually sleeps better, has more energy during the day, and loses weight. Occasionally (about 10% of the time), patients have low cortisol in the morning on ketoconazole, and Dr. Friedman sometimes gives a low dose of hydrocortisone, such as 5 mg in the morning, to prevent adrenal insufficiency in the morning. 

The Main Side Effect of Ketoconazole Are:

1. It can give adrenal insufficiency that can be remedied with a low dose of hydrocortisone in the morning. If the patient develops severe adrenal insufficiency, the ketoconazole should be stopped. 
2. A transient increase in liver function tests. This is rare at the doses of ketoconazole that Dr. Friedman uses, although in the literature, it is described as about 15%. These increases in liver function tests are completely reversible, and Dr. Friedman usually does not worry unless the AST and ALT are 3 times normal, in which case he would stop the ketoconazole. If they are 2 times normal, he may reduce the dose. Some people can go to a lower dose of ketoconazole and have their liver function tests return to normal. 
3. Ketoconazole should be used cautiously with several medicines, including some of the antidepressants and statins but, in general, most medicines can be used with it. There is also a concern about benzodiazepines, such as Xanax, which is also called alprazolam, and ketoconazole. If that is the case, the patient should probably stop taking the alprazolam. 
4. It was thought that ketoconazole can prolong part of the EKG called the QT Interval, however Dr. Friedman found an article showing that ketoconazole does not do that. Since finding that article, he is not suggesting that EKG be performed on patients using ketoconazole.

Dr. Friedman usually checks liver function tests and a morning cortisol and ACTH in about 2 months after starting the ketoconazole. In general, because ketoconazole blocks steroid synthesis, the cortisol level should go down a little bit and the ACTH should go up. However, because of feedback, there is usually not too much change. In general, Dr. Friedman finds that if the ACTH goes up above 50 pg/mL, it is a good sign the ketoconazole is working.

Dr. Friedman recommends all patients on ketoconazole to take vitamin E, 400 iU a day and milk thistle with 1000 mg silymarin (the active ingredient) a day. Both of these help protect the liver and are available on Amazon and health food stores.

Reasons to Use Ketoconazole before Surgery

There are 5 reasons Dr, Friedman use ketoconazole in all patients suspected of having Cushing’s syndrome before surgery.

1. It helps determine if the patient’s symptoms are due to high cortisol.
2. It helps the patient feel better right away
3. By normalizing cortisol levels before surgery, the surgical risk is less. 
4. It is less invasive then surgery
5. It reduces cortisol withdrawal symptoms after surgery and patients may need less hydrocortisone and for a shorter duration after surgery.

The one disadvantage of using ketoconazole before surgery, is that it may make determining a cure hard, which is hard anyways in episodic patients.

Long-Term Use of Ketoconazole

Dr. Friedman frequently uses ketoconazole to help determine how much of a patient’s symptoms are due to high cortisol. If the patient’s symptoms get a lot better with the ketoconazole, this would indicate that the patient’s symptoms are due to high cortisol, and they would benefit from surgery. On the other hand, Dr. Friedman also finds that the ketoconazole works so well that many patients want to stay on it for long term. Dr. Friedman has used ketoconazole for up to 12 years in a couple of his patients and finds that if the patient tolerates it, it does work well and is often a better option than surgery, as not all of the time is the surgery successful, and surgery can lead to other complications.

To make an appointment to see Dr. Friedman visit Dr. Friedman’s website at goodhormonehealth.com.