Diagnosis and selective cure of Cushing's disease during pregnancy by transsphenoidal surgery

Abstract

The diagnosis of Cushing's Disease during pregnancy is complex because the biochemical features are obscured by changes in the normal hypothalamo-pituitary-adrenal axis that occur during gestation. To date, treatment has not been successful and there is a high incidence of maternal and fetal complications. We report the case of a 24-year-old woman with Cushing's disease who presented during her 16th week of pregnancy. Diagnosis was confirmed by the finding of elevated serum and urinary free cortisol levels with loss of the normal circadian rhythm of serum cortisol. Cortisol levels failed to suppress after a low-dose dexamethasone test but suppressed after a high-dose test. There was an exaggerated serum cortisol and plasma adrenocorticotrophin (ACTH) response to corticotrophin-releasing hormone (CRH). Magnetic resonance (MR) scanning demonstrated a pituitary tumour and cure was effected by transsphenoidal surgery where tumour immunostaining for ACTH was removed. Postoperatively the patient made an uncomplicated recovery; serum cortisol and plasma ACTH levels were undetectable at 9 days following surgery and recovery of the hypothalamo-pituitary axis occurred at 99 days after surgery. Caesarean section was performed at 38 weeks of pregnancy and a healthy but small female infant was delivered. This case illustrates the biochemical features of Cushing's disease during pregnancy and is the first report of the use of CRH testing and MR scanning in this clinical situation. The cure by surgery and successful outcome for mother and infant, with preservation of normal anterior pituitary function, suggest that transsphenoidal surgery may be the treatment of choice.

Periodic Secretion of Adrenocorticotropin in a Patient with Cushing's Disease Manifested during Pregnancy

“…One of the most helpful means to distinguish Cushing's syndrome from hypercortisolism of normal pregnancy is to uncover loss of normal circadian variation in increased cortisol levels [15]. Furthermore, Ross et al reported the significance of exaggerated ACTH response to CRH in a pregnant woman with Cushing's disease [16]. Unfortunately we could not assess the endocrine condition of our patient before delivery; however, the combination of CRH test and daily profile of circulating ACTH and cortisol would have been a safe and beneficial method for the early recognition of Cushing's syndrome.…”

“…Although the experience of other drugs, such as aminoglutethimide [18], mitotane [10,19], bromocriptine [9] and cyproheptadine [20][21][22][23][24], was also reported, aminoglutethimide and mitotane should be avoided as much as possible because of their potential toxicity to fetus. Transsphenoidal surgery of pituitary ACTH-secreting adenoma was carried out successfully in five patients during pregnancy [11,16,[25][26][27]. Even radiation therapy was performed in a case of Cushing's disease during pregnancy [6].…”

Cushing's Disease and Pregnancy

“…In fact, urinary free cortisol secretion increases in normal pregnancy and modestly elevated levels (≈100-300 µg/24 h) are compatible with pregnancy per se [17,21]. Conversely, urinary free cortisol levels in pregnant patients with Cushing's syndrome are reportedly extremely high [22,23] and most often do not overlap with levels observed in normal pregnant women. Resistance to cortisol feedback in pregnancy calls for higher cortisol cut-off values after low dose dexamethasone (1 mg overnight).…”

“…Most patients with Cushing's disease diagnosed during pregnancy present ACTH levels in the upper half of the normal range or even higher [23,25,26]. Conversely, out of nearly 30 reported cases with adrenal Cushing's syndrome diagnosed during pregnancy, the majority displayed undetectable or subnormal ACTH levels, 10 and 15 patients, respectively, while ACTH levels were in the normal range only in 4 patients.…”

“…In fact, 8 mg dexamethasone suppression correctly identified almost all reported cases using the 50% cortisol decrease threshold [25,26] and stimulation with 100 µg CRH evoked marked ACTH and cortisol responses in patients tested so far [23,27,28]. Inferior petrosal sinus sampling has been carried out in a few pregnant women with suspected Cushing's disease [25,[27][28][29] but should be employed sparingly in order to avoid unnecessary radiation and possible thrombotic events.…”