Pituitary apoplexy after leuprolide injection for ovum donation

Case report 

A previously healthy, 22-year-old woman responded to an advertisement for cash payments for egg donation. She began taking daily injections of leuprolide, a GnRH analog, in preparation for egg donation. Vomiting and headaches began after the third injection and worsened after each subsequent dose. Five days after starting the medication, she presented with complaints of headache, fever, and vomiting.

Her past medical history was notable for irregular menstrual periods and a 6-month period of amenorrhea 4 years prior to admission. The menstrual irregularity had been attributed to anorexia nervosa and strenuous athletic activity, and she had since been on oral contraceptive pills.

On arrival in the emergency department, her temperature was 39.6°C, blood pressure 146/72 mmHg, heart rate 78/min, and respiratory rate 20/min. She had photophobia and neck stiffness but no visual, motor, or sensory deficits. A lumbar puncture demonstrated an opening pressure of 13 cm H2O, and clear, colorless cerebrospinal fluid with a protein concentration of 51 mg/dL and glucose of 44 mg/dL (serum level of 72 mg/dL). A gram stain demonstrated no micro-organisms. The cell count was 662 red blood cells per μL and 141 white blood cells per μL with 92% neutrophils. Her CBC had 10.7 × 109/L white blood cells with a normal differential. Her plasma sodium concentration was 126 mmol/L. She was started on antibiotic and antiviral therapy for presumed meningitis but continued to have severe headaches and fevers to 40°C. Cerebrospinal fluid (CSF) cultures were negative.

Her initial sodium concentration was 126 mmol/L but fell to 115 mmol/L on the morning of hospital Day 4. Despite initiation of therapy with 3% sodium chloride, her sodium continued to fall. She was lethargic, progressed rapidly to coma, and required endotracheal intubation. She developed left-sided hemiplegia, and her pupils were fixed and dilated. Her sodium concentration was 107 mmol/L at that time; it continued to decline to a low of 101 mmol/L (Figure 1). Head computerized tomography (CT) revealed an enlarged sella containing a mass with suprasellar extension. Magnetic resonance imaging confirmed a 1.5 × 2.5 × 2.7 cm mass with heterogeneous signal suggestive of hemorrhage and severe chiasmatic compression (Figure 2). Blood tests showed that the serum prolactin level was 5 ng/mL, LH was < 0.1 IU/L and follicle stimulating hormone (FSH) was 1.1 IU/L. She received stress dose glucocorticoids. More aggressive therapy with hypertonic saline and furosemide was required to correct her sodium concentration to 123 mmol/L. She then underwent urgent transphenoidal exploration of her sella. A hemorrhagic, necrotic pituitary macroadenoma was removed. Immunohistochemical studies showed positive staining for FSH and LH, establishing the diagnosis of gonadotropin-secreting adenoma.

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Figure 1. Changes in Serum Sodium During the First Week of Hospitalization.

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Figure 2. Magnetic resonance imaging (MRI) scan demonstrating a pituitary macroadenoma with hemorrhage and infarction. The high resolution images show an expanded sella with a 1.5 × 2.5 × 2.7 cm intrasellar and suprasellar mass. (a) Non-contrast sagittal image demonstrates a rim of high signal (arrow) consistent with hemorrhage. (b) Post-contrast sagittal image demonstrates low central signal intensity (arrow) suggestive of a necrotic center.

On the first post-operative day, her mental status improved, but she had persistent left hemiparesis. CT scan showed an infarction in the right anterior cerebral artery distribution. A follow-up MRI scan also showed a smaller infarction in the left anterior cerebral artery distribution. Angiography demonstrated severe vasospasm of the right supraclinoid internal carotid and anterior cerebral arteries. The vasospasm responded well to volume expansion, induced hypertension, and nimodipine.

The patient subsequently developed diabetes insipidus that was treated with desmopressin and fluid replacement. Her neurological status continued to improve and her sodium concentration stabilized. Her blood pressure was allowed to return to normal after repeat angiography demonstrated improvement of her vasospasm. Thyroid and steroid hormone replacement were continued. One month after her presentation, she was progressing well with rehabilitation for her left hemiparesis and cognitive impairment marked mostly by difficulties with short-term memory. One year later, she had almost normal cognitive functions and minimal differences in strength between her left and right sides.

Discussion 

Asymptomatic pituitary adenomas are common in the adult population (6%–23% in autopsy series) [30]. Pituitary apoplexy occurs in 1% to 17% of patients with known pituitary tumors 1, 31. Given the number of people at risk of developing apoplexy, physicians must be aware of drugs that may precipitate it.

To our knowledge, this is the first case of pituitary apoplexy after the use of leuprolide for pituitary down-regulation in conjunction with ovarian stimulation for oocyte donation. Pituitary testing with hypothalamic releasing hormones, including GnRH, has been linked with pituitary apoplexy in 30 patients 2, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25. Symptoms appeared within 30 minutes of administration of these hormones in 70% of cases and within 3 days in all cases. Five cases of pituitary apoplexy following administration of GnRH analogues for the treatment of prostate cancer have been reported 2, 26, 27, 28, 29. All patients had pituitary adenomas that were previously unrecognized.

The exact mechanism by which GnRH agonists precipitate pituitary apoplexy in patients with adenomas is unknown. LH and FSH levels increase during the first week after leuprolide administration before ultimately becoming suppressed; this hormonal hyperactivity may be related to pituitary apoplexy [2]. However, this does not explain the high incidence of nonfunctioning adenomas (50%–61%) in cases of apoplexy 4, 32. Some of these “non-functioning” adenomas may, however, have been gonadotropin-secreting tumors, since immunostaining for LH and FSH was not performed. Alternatively, GnRH agonists may induce tumor growth and/or increase metabolic activity, thus increasing local metabolic oxygen demand in excess of local oxygen delivery and causing hypoxia, infarction, and hemorrhage in the tumor 26, 28, 33. Given the rapid development of symptoms that can occur after leuprolide administration, others have proposed that a direct vascular event causes the hemorrhage [25]. Necrosis and hemorrhage may occur secondary to vessel compression following rapid tumor growth [3].

The variable clinical presentation of pituitary apoplexy reflects differing degrees to which tumor expansion, bleeding into the subarachnoid space, and pituitary destruction occur. Many cases of pituitary apoplexy are initially misdiagnosed as subarachnoid hemorrhage or meningitis. Sterile meningitis may be the only major clinical manifestation of pituitary necrosis and impending pituitary apoplexy [34].

Hyponatremia has been estimated to occur in 44% of patients with pituitary apoplexy [3]. It may result from release of preformed antidiuretic hormone and/or hypocortisolism, either of which may be life threatening if not treated promptly 35, 36. As this case demonstrates, unexplained hyponatremia should prompt a work-up for pituitary infarction or hemorrhage even in the absence of endocrinologic tests or ophthalmologic findings suggestive of pituitary apoplexy.

Conclusions 

The association of GnRH or GnRH agonists with pituitary apoplexy has already prompted the suggestion that this risk be added to the warning labels for these medications [26]. Based on our case and other cases in the literature, patients for whom treatment with these agents is planned should undergo careful screening for a possible pituitary adenoma. A thorough endocrine system review would reveal items such as amenorrhea or galactorrhea. A history of severe headaches or diplopia should also be elicited and confrontational visual field testing should be performed. Laboratory evaluation of serum prolactin levels would identify patients with prolactinomas. Gonadotroph adenomas, especially in patients on oral contraceptives, would be unlikely to be discovered with further laboratory testing. These and other non-prolactin secreting adenomas could only be identified based on the history or brain imaging. It is obviously impractical to image every patient, but any patient whose evaluation suggests pituitary hormonal abnormalities should have hypothalamic-pituitary imaging (a brain MRI) prior to administration of these agents.

Amenorrhea is the most common symptom of a pituitary tumor in women and a careful review of this patient’s history could have prompted a more thorough endocrinologic work-up and discovery of her pituitary adenoma. In conclusion, a thorough search to exclude underlying adenomas is clearly warranted in any patient receiving GnRH or GnRH agonists. In addition, the use of potentially harmful medications in healthy women who are donating ova deserves greater scrutiny.