Cushing Syndrome in Pregnancy: When to Suspect and How to Treat

cushing syndrome
cushing syndrome
Despite the preponderance of CS in women of childbearing age and the likelihood of pregnancy triggering CS, the condition is often overlooked because of the overlap of pregnancy and hypercortisolism symptoms.

Cushing syndrome (CS), a rare disorder of the adrenal gland, is even more challenging to detect in pregnant individuals.1 Even in normal pregnancies, plasma and urinary free cortisol can be 2 to 3 times their normal levels.1 High levels of cortisol can lead to maternal hypertension, preeclampsia, diabetes, cardiac failure, and even death. Fetal complications include prematurity, growth retardation, hypoadrenalism, and intrauterine death.1 Fortunately, given the high risks for both mother and fetus, fewer than 200 cases of pregnancy-related CS have been reported in literature.1

Diagnostic Considerations in Pregnancy

Despite the preponderance of CS in women of childbearing age and the likelihood of pregnancy triggering CS, the condition is often overlooked because of the overlap of pregnancy and hypercortisolism symptoms — fatigue, weight gain, hirsutism, emotional lability, and acne.1-3 The common triad of symptoms including hypertension, ecchymosis, and muscle weakness, however, may heighten suspicion for CS.1

Pregnancy activates the renin-angiotensin-aldosterone system, which can lead to higher aldosterone and deoxycorticosterone levels that can trigger hypokalemia.1 As such, the traditional biochemical markers of CS, such as urinary free cortisol, may be difficult to discern in pregnant women. Recent evidence suggests that salivary cortisol may be a more accurate indicator during the first 2 trimesters.1

Other diagnostic considerations include adrenal ultrasound and magnetic resonance imaging of the pituitary or adrenal glands. There is insufficient evidence to recommend testing adrenocorticotropic hormone and corticotropin-releasing hormone levels or to perform the desmopressin test or high-dose dexamethasone suppression test in pregnant women with suspected CS.1

Differential diagnoses for CS consist of pheochromocytoma, primary aldosteronism, and gestational hypertension.1 Pheochromocytoma diagnosed during pregnancy, which is confirmed by urinary free metanephrines, does not usually include weight gain or proteinuria, depending on hypertension levels.1 Low renin levels may indicate primary aldosteronism, which does not include the usual signs of hypercortisolism such as ecchymosis, purple striae, weight gain, and muscle weakness.1 If hypertension is diagnosed in the first trimester, it is considered a preexisting condition, commonly caused by kidney disease.1

“Cushing syndrome during pregnancy is such a rare event that even most endocrinologists will have difficulty in seeing any such patient, especially as most pregnant patients are seen by obstetricians, who probably are even less aware of this differential diagnosis,” noted Professor Dr Ursula Plöckinger, head of metabolic diseases at the Interdisciplinary Center of Metabolism at Charité University Berlin in Germany.

Hair: An Alternative to Biochemical Cortisol Testing

Testing hair for long-term exposure to hypercortisolism may be one overlooked diagnostic tool in women who are pregnant.4 A pencil-width sample of hair from the vertex of the scalp can detect cortisol levels that have been present for several months.4 Further, the 93% sensitivity and 90% specificity of hair cortisol correspond with the sensitivity and specificity of urinary free, salivary, and serum cortisol testing and of dexamethasone suppression testing in pregnant and nonpregnant patients.4 Hair cortisol also has the benefit of detecting periodic or cyclical CS and may reduce the need for repeated tests.4

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“Patients with CS frequently have confusing biochemical results. Most of the current tests (salivary cortisol, urinary cortisol) provide a reflection of a limited window of cortisol exposure (up to 24 hours),” said Mihail Zilbermint, MD, from the section on endocrinology and genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. “Hair cortisol may detect months-long exposure to elevated cortisol. We suggest hair cortisol should be used in patients with cyclical or periodic hypercortisolemia.”

How Pregnancy Complicates Treatment

Clinicians can treat the comorbidities of pregnant patients with mild CS; however, for women with moderate to severe CS, second-trimester pituitary or adrenal surgery is recommended.1 After surgery, women will need to be treated for adrenal insufficiency with hydrocortisone for the rest of their pregnancy.1

For patients whose CS is not diagnosed until the third trimester, clinicians can control comorbidities such as hypertension and diabetes.1 Case reports and expert opinion guide medical management of hypercortisolism in later pregnancy.1 Pharmacologic agents such as metyrapone and cabergoline have been cited in the literature, but robust evidence is lacking.1

Adrenal Insufficiency Is Also Challenging in Pregnancy

On the flip side, low glucocorticoid, mineralocorticoid, and androgen levels can also imperil maternal and fetal outcomes.5 Like CS, adrenal insufficiency is difficult to detect in pregnancy because many symptoms overlap: nausea, vomiting, dizziness, and fatigue.5 Adrenal insufficiency is diagnosed when the symptoms do not correspond with the gestational status, such as weight loss, hypoglycemia, or hyponatremia.5 Morning cortisol of <3 µg/dL or an abnormal response to cosyntropin stimulation can confirm adrenal insufficiency.5

“After successful conception, with appropriate hormonal replacement, pregnancy outcomes are not usually affected in patients with both primary and secondary adrenal insufficiency,” said Maria Fleseriu, MD, FACE, professor of medicine (endocrinology) and neurological surgery at Oregon Health & Science University in Portland, Oregon.

“Preconception counseling is essential; thyroid function and other pituitary hormone axes, including growth hormone, should be assessed and deficiencies appropriately addressed in patients with secondary adrenal insufficiency,” said Dr Fleseriu. “Under and over glucocorticoid replacement during pregnancy should be avoided. In addition to maternal effects (edema, gestational hypertension, and exacerbation of preeclampsia), excessive glucocorticoid may lead to fetal adverse effects, including low birth weight and premature delivery, long-term effects on the hypothalamic-pituitary-adrenal axis, and possible susceptibility to cardiometabolic disease.”

Summary & Clinical Applicability

Cushing syndrome during pregnancy is challenging to diagnose because so many women without CS have abnormal readings of hypokalemia and plasma, salivary, and urinary cortisol levels. High cortisol levels can indicate adrenal adenoma, which can cause serious maternal and fetal morbidity, and in rare cases, mortality.

Limitations & Disclosures


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1. Brue T, Amodru V, Castinetti F. Management of Cushing’s syndrome during pregnancy: solved and unsolved questions. Eur J Endocrinol. 2018;178(6):R259-R266.

2. Palejwala SK, Conger AR, Eisenberg AA, et al. Pregnancy-associated Cushing’s disease? An exploratory retrospective study. Pituitary. 2018;21(6):584-592.

3. Plöckinger U, Chrusciel M, Doroszko M, et al. Functional implications of LH/hCG receptors in pregnancy-induced Cushing syndrome. J Endocr Soc. 2017;1(1):57-71.

4. Hodes A, Meyer J, Lodish MB, Stratakis CA, Zilbermint M. Mini-review of hair cortisol concentration for evaluation of Cushing syndrome. Expert Rev Endocrinol Metab. 2018;13(5):225-231.

5. Langlois F, Lim DST, Fleseriu M. Update on adrenal insufficiency: diagnosis and management in pregnancy. Curr Opin Endocrinol Diabetes Obes. 2017;24(3):184-192.