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Cushing's syndrome, a condition resulting from an excess of the hormone cortisol, is often difficult to diagnosis; both diagnosis and treatment are more difficult during pregnancy. It is important to make the diagnosis as soon as possible as the high cortisol levels have a very harmful effect on both the mother and the developing fetus. The clinical symptoms present may overlap with normal pregnancy in some respects as described below. In addition, tests used to diagnose Cushing's may be more difficult to interpret because of the hormone changes that normally occur during pregnancy. Finally, any surgical and/or medical management must take into account the side effects of surgery and medical therapy given to a pregnant woman.

Questions about Pregnancy and Cushing's Syndrome

1. I'm pregnant and they think I have Cushing's. How do the symptoms of Cushing's differ if a woman is pregnant?

Many of the clinical features that raise suspicion for Cushing's syndrome can also occur in normal pregnancy. For example, weight gain, loss of menstrual periods, stretch marks, fatigue, back pain, mood changes, facial roundness and redness are common in pregnancy but can be symptoms of Cushing's. In addition, the development of elevated glucoses or blood pressure increases occur often in Cushing's but may occur during pregnancy as well. Sometimes the degree of these changes may be helpful. Signs favoring a diagnosis of Cushing's syndrome, as they are not likely to occur in a normal pregnancy are the following: weakness, particularly proximal weakness such as involving the thigh muscles causing difficulty climbing stairs, spontaneous and significant bruising, and wide striae (purple stretch marks). A laboratory finding that is particularly worrisome in a woman not taking a water pill is a low blood level of potassium. If you are pregnant and the possibility of Cushing's has been raised, it is important that you be evaluated by an endocrinologist.

2. What causes Cushing's during pregnancy?

Cushing's syndrome is usually caused by a tumor in the pituitary or adrenal gland, or less commonly from an ectopic source (a tumor elsewhere in the body that stimulates the adrenal glands to make too much cortisol). The most common cause is a small pituitary tumor. In the pregnant woman, a benign pituitary tumor is still the most common source. However, the percent of patients with Cushing's with adrenal tumors is higher than in men or in women who are not pregnant. An adrenal source accounts for 40 to 50% of cases of Cushing's in pregnant women.

3. What tests can be done to diagnosis Cushing's Syndrome in Pregnancy?

Tests done to diagnose Cushing's syndrome which rely on measuring cortisol are complicated by two factors. First, during normal pregnancy the adrenal glands make much more cortisol and the levels of urine free cortisol (a commonly used screening test for Cushing's) may overlap with levels seen in Cushing's syndrome, especially in the second and third trimester. Second, levels of ACTH, the pituitary hormone controlling the adrenal glands, may also increase. Therefore, unless cortisol levels are markedly elevated, the results of these tests may be difficult to interpret. Dexamethasone suppression testing can be used to diagnose Cushing's syndrome in the non-pregnant state, however, during pregnancy, this test may be positive in patients without Cushing's because high levels of estrogen which are produced during pregnancy affect cortisol measurements.

4. What tests are safe and valid to do during pregnancy?

A 24 hour urinary free cortisol level is typically done and may be useful if very high. If the ACTH level is low in the setting of very high cortisol levels, then an adrenal source becomes more likely. The use of a midnight salivary cortisol is under investigation. As mentioned, dexamthasone suppression testing is of very limited use and not typically done. Once the diagnosis of Cushing's syndrome is confirmed, imaging studies are used to locate the source of the hormone production such as an MRI of the pituitary or a scan of the adrenal glands. Specific tests should be discussed with both the endocrinologist and the obstetrician. Typically, the use of radiology tests and imaging contrast material is limited as much as possible to protect the fetus yet still be able to enable a correct diagnosis to be made.

5. What happens if I'm not treated?

It is imperative to treat Cushing's syndrome in pregnancy. The complications of pregnancy in women with Cushing's syndrome include high blood pressure, diabetes, preeclampsia, infection and psychiatric disorders. In terms of the fetus, complications include premature birth and intrauterine growth retardation Therefore, the best outcome for both the mother and the baby is to treat the disease promptly.

6. What treatments can be used for Cushing's during pregnancy?

If there are metabolic problems such as diabetes or low potassium, immediate correction of these problems must take place. Treatment of high blood pressure is very important. Once the source of the disease is found, surgery should be discussed with an experienced surgeon and anesthesiologist as a cure should provide the best outcome. If surgery cannot be performed, the use of medical therapy to block cortisol production is considered. Metyrapone, a drug that blocks the production of cortisol can be considered (although it has not been approved by the FDA for use in pregnancy) and has been reported in the medical literature in a few cases. However, definitive surgery usually should not be delayed until the cortisol level is normalized. Other drugs more commonly used to treat Cushing's, such as ketoconazole are not considered safe to use during pregnancy. It crosses the placenta, inhibits production of the hormone progesterone and may cause birth defects or miscarriage.

7. Can pregnancy be attained after cure of Cushing's and how long should someone wait before attempting a pregnancy?

Once a cure is established, patients are typically hypoadrenal (their own hormones have been suppressed by the Cushing's and need to recover). A cured Cushing's patient will take replacement cortisol (glucocorticoids) for many months and in some cases over a year before normal function returns and the medication can be stopped. In some patients with pituitary disease, the surgery has damaged the part of the gland that makes ACTH so that cortisol replacement is life long. In terms of reproductive function, if the source of the Cushing's is adrenal, return of reproductive function should be expected unless there are other problems. If the problem is a pituitary tumor, the same is expected unless the part of the normal pituitary gland that controls reproductive function has been damaged. Patients should discuss with their endocrinologists when they are stable and pregnancy should be sought. Patients taking chronic cortisol replacement may need to increase their doses during pregnancy. Even patients whose pituitary gland no longer functions can be evaluated for ovulation induction to stimulate the ovaries. Many women with a history of cured Cushing's have gone on to deliver healthy babies.

Editor's Note: Dr. Anne Klibanski, M.D. is Professor of Medicine at Harvard Medical School and Chief of the Neuroendocrine Unit at Massachusetts General Hospital in Boston. Dr. Klibanski has many years of experience with Cushing's.

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