Occasionally, cortisol production in CS may not be constantly increased but may fluctuate in a "periodic" pattern, ranging in length from days to months. This relatively rare phenomenon of periodic, cyclic, or episodic hormonogenesis has been described in patients with CD, ectopic ACTH syndrome (bronchial carcinoids were involved in 50% of the reported cases), and cortisol-secreting adrenal tumors or micronodular adrenal disease (20-32).
Biochemically, patients with periodic hormonogenesis may have consistently normal 24-h UFC and paradoxically "normal" responses to dexamethasone (stimulation of cortisol) in the presence of CS clinical stigmata. In such patients, several weekly 24-h UFC determinations for a period of 3 to 6 mo may be necessary to establish the diagnosis.
Cushing's Syndrome in Pregnancy
In normal pregnancy, a small progressive rise in plasma ACTH and a twofold to threefold increase in plasma total and free cortisol occur. UFC is also elevated above normal, especially between the 34th and 40th wk of gestation (90 to 350 ^g/d; 248-966 nmol/d). In the latter part of pregnancy, immunoreactive CRH (irCRH) IR-CRH of placental origin is detected in plasma, with levels reaching up to 10,000 pg/mL (2200 pmol/L) (83). Because plasma cortisol is poorly suppressed in response to dexamethasone in normal pregnancy, the diagnosis of mild or early CS may be difficult to ascertain (84). Transient pregnancy-related and pregnancy-limited CS has been described. Its etiology is unknown.
Glucocorticoid resistance in humans is characterized by spontaneous hypercortisolism without CS features, owing to an apparent end-organ insensi-tivity to cortisol usually as a result of genomic defects of the glucocorticoid receptor (85). In addition to increased plasma ACTH and serum and urinary cortisol and decreased cortisol suppression by dexamethasone administration, these patients frequently have elevated plasma and urinary adrenal androgens and mineralocorticoids. Plasma Cortisol has a circadian rhythm similar to that of normal subjects, albeit at elevated concentrations, and responds normally to stress tests such as insulin-induced hypoglycemia. The most frequent manifestation of glucocorticoid resistance is adrenal hyperandrogenism in women and children and mild hypertension in both genders.
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