Cushing’s Syndrome (CS) is an endocrine disorder resulting from prolonged exposure to excessively high levels of the hormone cortisol. While pregnancy involves a substantial and necessary increase in cortisol production, it does not typically cause the pathological condition of CS. True endogenous CS during gestation is extremely rare, with fewer than 200 cases reported globally. The challenge lies in distinguishing the normal, regulated hormonal changes of pregnancy from the unregulated, disease-causing hypercortisolism of the syndrome.
Hormonal Changes and the Causal Question
Normal pregnancy naturally induces a state of physiological hypercortisolism, a regulated rise in cortisol necessary for proper fetal development and maternal metabolic adjustments. As gestation progresses, the concentration of cortisol can increase to two or even three times the levels found in non-pregnant individuals. This elevation is driven by rising estrogen, which stimulates the liver to produce more corticosteroid-binding globulin (CBG), a protein that binds and carries cortisol.
Pathological CS is typically caused by a tumor, such as a pituitary adenoma (Cushing’s Disease) or a cortisol-secreting adrenal adenoma, the most common cause found in pregnant women. In these cases, the excess cortisol production is unregulated and autonomous. While pregnancy is not the underlying cause of CS, the existing hormonal environment can sometimes unmask a pre-existing, subclinical case of the syndrome.
Overlapping Symptoms of Pregnancy and Cushing’s
The diagnosis of Cushing’s Syndrome is complicated because many of its symptoms mimic the common physical changes experienced during a healthy pregnancy. Weight gain, facial rounding, and the development of stretch marks are frequently observed in both conditions. Both CS and pregnancy can also lead to metabolic changes like hypertension and impaired glucose tolerance, which may manifest as gestational diabetes.
However, certain physical signs suggest true pathology rather than normal gestation. The stretch marks associated with CS, known as striae, are often wider, deeper, and purplish, contrasting with the pinker striae of pregnancy. Other findings include proximal muscle weakness, easy bruising, and thin skin, none of which are typical features of a normal pregnancy.
Diagnostic Challenges During Gestation
Diagnosing Cushing’s Syndrome during pregnancy is a significant challenge because standard biochemical tests are frequently unreliable due to the physiological changes of gestation. The 24-hour urinary free cortisol (UFC) test is naturally elevated in pregnancy, making it difficult to set a clear cutoff for pathology. Similarly, the low-dose dexamethasone suppression test is often misleading because cortisol suppression is attenuated in healthy pregnant women.
To overcome these obstacles, clinicians rely on tests that assess the body’s cortisol rhythm rather than just the overall level. The measurement of late-night salivary cortisol (LNSC) is a preferred method, as it detects the loss of the normal circadian cortisol variation seen in CS. Midnight serum cortisol has also been noted to have better sensitivity for diagnosing hypercortisolism than the UFC test during pregnancy.
For localizing the cause, magnetic resonance imaging (MRI) without contrast is used cautiously to identify pituitary or adrenal tumors. Adrenal ultrasound can also be helpful. The desmopressin stimulation test can also be used to help differentiate Cushing’s Disease from other forms of CS.
Treatment Considerations and Pregnancy Outcomes
Once a diagnosis of true Cushing’s Syndrome is confirmed, treatment is necessary to reduce the significant risks posed to both the mother and the fetus. Untreated CS is associated with a high incidence of maternal complications, including severe hypertension, preeclampsia, and gestational diabetes. Fetal outcomes are also negatively affected, with increased risks of prematurity, intrauterine growth restriction, and fetal loss.
The preferred treatment option is typically surgery to remove the tumor, either a transsphenoidal surgery for a pituitary adenoma or an adrenalectomy for an adrenal tumor. This procedure is ideally performed between the late first trimester and the early second trimester, as this period is associated with lower risks of spontaneous abortion and premature labor. Medical therapy with agents that suppress cortisol production, such as metyrapone or ketoconazole, is considered a second option when surgery is delayed or contraindicated. Management requires a collaborative approach involving endocrinologists, high-risk obstetricians, and surgeons to balance maternal hypercortisolism control with fetal safety.