Diagnosis and Treatment > Signs and Symptoms
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Summary
Cushing’s syndrome is an endocrine disorder that causes anovulatory infertility secondary to hypercortisolism; therefore, pregnancy rarely occurs during its course. We present the case of a 24-year-old, 16-week pregnant female with a 10-month history of unintentional weight gain, dorsal gibbus, nonpruritic comedones, hirsutism and hair loss. Initial biochemical, hormonal and ultrasound investigations revealed hypokalemia, increased nocturnal cortisolemia and a right adrenal mass. The patient had persistent high blood pressure, hyperglycemia and hypercortisolemia. She was initially treated with antihypertensive medications and insulin therapy. Endogenous Cushing’s syndrome was confirmed by an abdominal MRI that demonstrated a right adrenal adenoma. The patient underwent right laparoscopic adrenalectomy and anatomopathological examination revealed an adrenal adenoma with areas of oncocytic changes. Finally, antihypertensive medication was progressively reduced and glycemic control and hypokalemia reversal were achieved. Long-term therapy consisted of low-dose daily prednisone. During follow-up, despite favorable outcomes regarding the patient’s Cushing’s syndrome, stillbirth was confirmed at 28 weeks of pregnancy. We discuss the importance of early diagnosis and treatment of Cushing’s syndrome to prevent severe maternal and fetal complications.
Learning points:
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Pregnancy can occur, though rarely, during the course of Cushing’s syndrome.
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Pregnancy is a transient physiological state of hypercortisolism and it must be differentiated from Cushing’s syndrome based on clinical manifestations and laboratory tests.
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The diagnosis of Cushing’s syndrome during pregnancy may be challenging, particularly in the second and third trimesters because of the changes in the maternal hypothalamic-pituitary-adrenal axis.
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Pregnancy during the course of Cushing’s syndrome is associated with severe maternal and fetal complications; therefore, its early diagnosis and treatment is critical.
Faculty of Medicine, Westmead Hospital, University of Sydney, Sydney, 2145, Australia
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Department of Endocrinology, Royal North Shore Hospital, St Leonards, 2065, Australia
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Faculty of Medicine, Westmead Hospital, University of Sydney, Sydney, 2145, Australia
St Vincent's Clinical School, University of New South Wales, Sydney, 2010, Australia
Diabetes and Transcription Factors Group, Garvan Institute of Medical Research (GIMR), Sydney, 2010, Australia
Department of Diabetes, Obesity and Endocrinology, The Westmead Institute for Medical Research, The University of Sydney, Sydney, 2045, Australia
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Summary
Ketoconazole was a first-line agent for suppressing steroidogenesis in Cushing's disease. It now has limited availability. Fluconazole, another azole antifungal, is an alternative, although its in vivo efficacy is unclear. A 61-year-old female presented with weight gain, abdominal striae and worsening depression. HbA1c increased to 76 mmol/mol despite increasing insulin. Investigations confirmed cortisol excess; afternoon serum cortisol was 552 nmol/l with an inappropriate ACTH of 9.3 pmol/l. In total, 24-h urinary free cortisol (UFC):creatinine ratio was 150 nmol/mmol with failure to suppress after 48 h of low-dose dexamethasone. Pituitary MRI revealed a 4-mm microadenoma. Inferior petrosal sinus sampling confirmed Cushing's disease. Transsphenoidal resection was performed and symptoms improved. However, disease recurred 6 months later with elevated 24-h UFC >2200 nmol/day. Metyrapone was commenced at 750 mg tds. Ketoconazole was later added at 400 mg daily, with dose reduction in metyrapone. When ketoconazole became unavailable, fluconazole 200 mg daily was substituted. Urine cortisol:creatinine ratio rose, and the dose was increased to 400 mg daily with normalisation of urine hormone levels. Serum cortisol and urine cortisol:creatinine ratios remain normal on this regimen at 6 months. In conclusion, to our knowledge, this is the first case demonstrating prolonged in vivo efficacy of fluconazole in combination with low-dose metyrapone for the treatment of Cushing's disease. Fluconazole has a more favourable toxicity profile, and we suggest that it is a potential alternative for medical management of Cushing's disease.
Learning points
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Surgery remains first line for the management of Cushing's disease with pharmacotherapy used where surgery is unsuccessful or there is persistence of cortisol excess.
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Ketoconazole has previously been used to treat cortisol excess through inhibition of CYP450 enzymes 11-β-hydroxylase and 17-α-hydroxylase, though its availability is limited in many countries.
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Fluconazole shares similar properties to ketoconazole, although it has less associated toxicity.
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Fluconazole represents a suitable alternative for the medical management of Cushing's disease and proved an effective addition to metyrapone in the management of this case.
