We describe two patients who developed adrenal insufficiency and subsequently Cushing disease after hemorrhage into adrenocorticotropin hormone (ACTH)-secreting pituitary microadenomas. To our knowledge, this has not been reported previously.

Case Reports

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Patient 1, a 23-year-old white woman, developed the Cushing syndrome in 1984. She was first evaluated at the National Institutes of Health (NIH) in 1985. During the initial endocrine assessment, she had cushingoid features but low basal 0800-h plasma cortisol levels (range, <11 to 88 nmol/L; normal range, 166 to 717 nmol/L) and 24-h urinary free cortisol levels (range, 14 to 72 nmol/d; normal range, 25 to 262 nmol/d). Thirty minutes after cosyntropin was administered (250 µg intravenously), the cortisol level increased from 55 nmol/L to 441 nmol/L. This response was also below normal (normal level at 30 minutes, >497 nmol/L). Thyroid and gonadal axes were intact. Table 1 shows other endocrine data. Computed tomography of the sella turcica was normal. The patient became pregnant 8 months later but terminated the pregnancy with elective abortion.

When the patient was re-evaluated 1 year later, 24-h urinary free cortisol levels were elevated (range, 1655 to 1931 nmol/d). Inferior petrosal sinus sampling with corticotropin-releasing hormone stimulation showed a central to peripheral ACTH gradient (Table 1). The patient had trans-sphenoidal excision of a 6-mm pituitary microadenoma; surgical and histopathologic findings are shown in Table 1. Subsequent endocrine assessment showed resolution of hypercortisolism (24-h urinary free cortisol level, 61 nmol/d), and the patient remained in remission for more than 7 years.

Patient 2, a 36-year old white woman, had acute onset of headache, vomiting, and loss of consciousness in 1984. Plasma ACTH, plasma cortisol, and urinary cortisol levels were low (<3.3 pmol/L, 55 nmol/L, and <2.7 nmol/d, respectively). She was treated with prednisone (5 to 7.5 mg/d) for 1 year. In 1986, computed tomography showed an empty sella. One year later, the Cushing syndrome developed. Endocrine evaluation showed elevated plasma ACTH (53 pmol/L) and 24-h urinary free cortisol levels (range, 276 to 497 nmol/d). Magnetic resonance imaging of the pituitary gland was normal.

The patient was first evaluated at NIH in 1988. She presented with unequivocal cushingoid features. Her 24-h urinary free cortisol levels were mildly elevated (375 nmol/d), and thyroid and gonadal axes were intact. Other endocrine data are shown in Table 1. Inferior petrosal sinus sampling with corticotropin-releasing hormone stimulation showed a central to peripheral ACTH gradient (Table 1). The patient had a transsphenoidal excision of a 3-mm semiliquid pituitary microadenoma that was partially embedded in the thickened medial wall of the left cavernous sinus. Surgical and histopathologic findings are shown in Table 1. The 24-h urinary free cortisol level remained elevated after the operation (593 nmol/d), but it did return to normal (201 nmol/d) 3 years after the pituitary gland was irradiated.

Neither patient had been receiving estrogen, bromocriptine, or anticoagulant agents [8].

Discussion

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Pituitary tumor hemorrhage may be clinically silent (patient 1) or may have neurologic manifestations (patient 2). The spectrum of the clinical presentation of pituitary apoplexy has previously been shown to be related to the vascular supply of the pituitary gland and to the involvement of parasellar structures [9, 10]. The expanding tumor may compromise the blood supply of the gland, thus causing tumoral ischemia that leads to necrosis and hemorrhage.

The recovery of pituitary function after an apoplectic attack, either spontaneously [4, 5] or after surgical decompression [6, 7], suggests reversible damage to the normal pituitary gland. However, as shown by our patients, spontaneous recovery may include recurrence of tumor activity. In one patient, Cushing disease recurred 1 year after silent pituitary tumor hemorrhage; in the other, the disease developed 3 years after an apoplectic attack. A similar course was previously observed in a patient with prolactinoma [11].

Results of endocrine assessment may be misleading in patients who have had a pituitary hemorrhage. Both patient 1 and patient 2 showed secondary adrenal insufficiency after pituitary apoplexy, although patient 1 had clinical evidence of the Cushing syndrome. This suggests that the apoplectic attack had been recent. Thus, hemorrhage into pituitary ACTH-secreting microadenomas may transiently destroy the function of the tumor and lead to a delayed diagnosis. Subsequently, hypercortisolism and clinical signs of Cushing disease developed in both patients.