2 women with Cushing’s disease use metyrapone throughout pregnancy
Both declined to have surgery to remove their adrenal glands
Two women with Cushing’s disease successfully used the cortisol-lowering medication metyrapone during their pregnancy, a case study shows.
“Metyrapone represents a viable option for managing [Cushing’s disease] throughout pregnancy when surgical intervention is contraindicated or declined, although careful monitoring and dose optimization are essential,” the researchers wrote. The cases were detailed in the study, “Successful Medical Management of Cushing Disease With Metyrapone Throughout Pregnancy: A Report of 2 Cases,” published in JCEM Case Reports.
Cushing’s disease is caused by a tumor in the pituitary gland, which produces and releases abnormally high levels of adrenocorticotropic hormone (ACTH). This triggers the adrenal glands, on top of the kidneys, to produce too much cortisol, leading to Cushing’s symptoms.
During pregnancy, excess cortisol poses significant risks for the mother and fetus, including high blood pressure, gestational diabetes, restricted fetal growth, and premature delivery.
The first line of treatment for Cushing’s disease is the removal of the pituitary tumor through a procedure called transsphenoidal pituitary surgery. When surgery is contraindicated or declined, medications are used instead.
Metyrapone, which is sold as Metopirone, is approved in the U.S. for use alongside other diagnostic tests to diagnose adrenal insufficiency, a condition wherein the adrenal glands don’t produce enough hormones. While metyrapone has been used off-label to treat excess cortisol associated with Cushing’s, including during pregnancy, continuously administering it before, during, and after pregnancy hasn’t been previously reported.
Metyrapone throughout pregnancy
The women, both diagnosed with Cushing’s disease before their pregnancy, declined to undergo surgery to remove their adrenal glands and were managed instead with metyrapone. Surgery is recommended for women with medically managed Cushing’s who are planning to become pregnant.
The first woman, 31 was diagnosed with Cushing’s disease in 2011 based on laboratory tests that showed high cortisol and ACTH, and an MRI scan that revealed a pituitary tumor. The woman achieved remission after undergoing transsphenoidal pituitary surgery.
Tests in 2017 revealed elevated cortisol in the urine and saliva, even though repeat MRI scans failed to detect a pituitary tumor, however. She began treatment with ketoconazole, which is sometimes used off-label for Cushing’s in the U.S., but was discontinued due to liver toxicity. She was then stated on metyrapone. The woman said she wanted to conceive, but declined surgery to remove the adrenal glands.
She underwent in vitro fertilization while on metyrapone and metformin, which is mainly used for type 2 diabetes. She remained on metyrapone during pregnancy and was monitored for high blood pressure, gestational diabetes, asnd changes in ACTH and cortisol levels.
In 2022, she delivered two healthy infants, a boy and a girl, via cesarean section, without signs of adrenal insufficiency. She continued taking metyrapone postpartum and nifedipine was added to treat high blood pressure, but eventually stopped.
Since then, the woman has maintained clinical stability on metyrapone, with stable weight, regular menses, and normal blood sugar levels. The twins are healthy and thriving at 2.5 years of age.
The woman, 29, had lived with recurrent Cushing’s disease since she was 12. She’d had two transsphenoidal pituitary surgeries in 1997 and 2000 and gamma knife radiosurgery, a type of radiation therapy that uses gamma rays to eliminate tumor cells, due to recurrence. The woman was managed with ketoconazole for several years before stopping and had remained asymptomatic without treatment for about 14 years.
In 2016, her urinary cortisol levels began to rise, but there were no significant new findings on MRI scans. She restarted ketoconazole, which normalized her cortisol levels, and also wanted to conceive a child, but declined adrenal surgery.
Based on previous case reports, she was switched to daily metyrapone and conceived naturally. Her cortisol and ACTH were also monitored throughout pregnancy, with no signs of complications due to metyrapone. She stopped metyrapone 36 hours before delivery and gave birth to a healthy baby girl via cesarean section without evidence of adrenal insufficiency.
The woman resumed metyrapone four days after giving birth. The dose was increased and blood-pressure lowering medications were successfully discontinued. Due to a temporary metyrapone shortage, ketoconazole was added and metyrapone was decreased until her urinary cortisol levels were well controlled. The patient has been doing well and is currently on ketoconazole. Her 5-year-old child is developing normally.
“We describe, for the first time, [two] patients with [Cushing’s disease] treated preconception and throughout pregnancy with the cortisol synthesis inhibitor metyrapone,” the authors wrote. “Metyrapone therapy requires careful monitoring and dose adjustments due to its potential hypertensive effects, highlighting the importance of regular blood pressure monitoring.”
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