Cushing's syndrome and pregnancy: Clinical presentation and diagnosis

Cushing's syndrome (CS) during pregnancy is an exceptionally rare but high-risk condition that poses major diagnostic and therapeutic challenges. Its low prevalence is mainly due to cortisol-induced infertility. Although its low prevalence stems primarily from cortisol-induced infertility, an increasing number of cases are being recognized due to enhanced clinical awareness and expanded use of assisted reproductive technologies. In contrast to the general population where pituitary adenomas predominate, pregnancy-associated CS demonstrates a distinct etiology pattern, with ACTH-independent causes accounting for the majority of cases, particularly benign adrenal adenomas. The physiological hypercortisolism of gestation complicates diagnostic testing, as urinary free cortisol and late-night salivary cortisol rise up to threefold, although circadian rhythmicity is usually preserved. Clinical features overlapping with normal pregnancy delay recognition, but specific signs such as wide violaceous striae, proximal myopathy, and easy bruising should raise suspicion. Untreated CS carries a markedly increased risk of maternal morbidity, including preeclampsia, diabetes, infections, and thromboembolic events, and adverse fetal outcomes such as prematurity, growth restriction, and fetal loss. Management requires a multidisciplinary team. Surgery in the second trimester, remains the treatment of choice. Medical therapy, mainly with metyrapone, may be considered in selected severe cases, whereas ketoconazole and cabergoline have more limited roles. Drugs such as mitotane and mifepristone are contraindicated during pregnancy, while osilodrostat lacks clinical evidence. In summary, early recognition and individualized management are essential to optimize maternal and fetal outcomes in this rare but high-risk condition.