Pituitary Apoplexy Associated with Endocrine Stimulation Test: Endocrine Stimulation Test, Treatment, and Outcome

Pituitary apoplexy is a rare clinical syndrome attributable to hemorrhage or hemorrhagic infarction of pituitary tumors or pituitary glands. The features of pituitary apoplexy associated with the endocrine stimulation test remain to be elucidated and the importance of surgical treatment has not been discussed enough. We report two rare patients who were treated successfully by endoscopic endonasal transsphenoidal surgery within several hours after onset of pituitary apoplexy associated with the endocrine stimulation test. Their postoperative course was uneventful. We reviewed earlier reports on this clinical entity, document its features especially as related to the endocrine stimulation test, discuss the significance of immediate surgical treatment, and present our treatment outcomes. Performing only conservative treatment is not recommended. We suggest that the necessity of endocrine stimulation test should be assessed on a case-by-case basis and in patients subjected to the test, and neurosurgical support should be sought.


Introduction
Pituitary apoplexy is a life-threatening clinical syndrome thought to be attributable to hemorrhage or hemorrhagic infarction of pituitary tumors or pituitary glands [1]. Suggested precipitating factors are hypertension, anticoagulation, and bromocriptine therapy, and pregnancy . There are few reports on the occurrence of pituitary apoplexy as a complication of the endocrine stimulation test, and its features remain to be elucidated. We report two rare patients with pituitary apoplexy associated with the endocrine stimulation test who were treated successfully by surgery and present a review of the literature. We also discussed about the necessity of neurosurgical support.

Case 1.
A 56-year-old woman with a one-year history of visual disturbance was admitted to our hospital for the evaluation of a suprasellar tumor. Physical examination at admission revealed visual disturbance (temporal hemianopia on the left side) but no other neurological disorders or endocrinological symptoms. Her baseline levels of pituitary hormones were normal. Computed tomography (CT) and magnetic resonance imaging (MRI) studies demonstrated a pituitary adenoma with suprasellar extension and superior displacement of the optic chiasm. To evaluate her hormonal responses we performed combined endocrine stimulation tests with growth-hormone-releasing hormone (GRH, 100 μg), thyrotropin-releasing hormone (TRH, 250 μg), luteinizing hormone-releasing hormone (LH-RH, 100 μg), and corticotrophin-releasing hormone (CRH, 100 μg). Fifteen minutes after the intravenous bolus injection she complained of severe headache, and this was followed by vomiting, progressive visual disturbance, and left oculomotor paralysis. She was alert but her symptoms gradually worsened. Emergency CT and MRI revealed intratumoral hemorrhage (Figures 1(a)-1(d)). Four hours after onset, her 2 Case Reports in Endocrinology left visual acuity was reduced to total blindness; there was temporal hemianopia in the right visual field. At emergency endoscopic endonasal transsphenoidal surgery was (ETSS) performed 5 hr after onset. Partially, tumor was solid and reddish-brown, different from the typical feature of pituitary adenoma. The tumor was totally removed. Pathological examination revealed hemorrhagic and necrotic area in nonnecrotic papillary-patterned tumor tissue (Figure 1(e)). Postoperatively, her headache, nausea and left oculomotor paralysis resolved, and her vision returned to the preonset level. Because of her diabetes insipidus (DI) she received transient desmopressin replacement therapy. She was able to resume her normal life.

Case 2.
A 73-year-old man with an 8-month history of visual disturbance was referred to our hospital. Five years earlier, when he was diagnosed with suprasellar tumor, he was asymptomatic and without visual disturbance. In the intervening five years, his tumor gradually enlarged and became symptomatic. At admission to our hospital, visual field examination revealed temporal hemianopia on the left side.
He had no other neurological disorders or endocrinological symptoms. His baseline pituitary hormone levels were normal. CT and MRI demonstrated a pituitary adenoma with suprasellar extension and superior displacement of the optic chiasm. For preoperative endocrine evaluation we performed combined endocrine stimulation tests with growth hormone releasing peptide-2 (GHRP2, 100 μg), TRH (250 μg), LH-RH (100 μg), and CRH (100 μg). Twenty minutes after the intravenous bolus injection he complained of progressive visual disturbance. He was alert and experienced neither headache nor nausea. Emergency CT and MRI performed one hr after onset showed no evidence of intratumoral hemorrhage (Figures 2(a)-2(c)), two hr after onset his left visual acuity was reduced to total blindness. There was no visual disturbance on the right side. He underwent ETSS 5 hr after onset, and the tumor was totally removed. Same as Case 1, tumor was partially solid and reddish-brown. Pathological examination revealed papillary-patterned adenoma with diffuse hemorrhage and necrosis ( Figure 2(d)). His postoperative course was uneventful. One month after the operation his visual disturbance resolved completely, and he required no hormone replacement therapy.
Case Reports in Endocrinology

Discussion
Pituitary apoplexy is a rare clinical syndrome thought to be attributable to hemorrhage or hemorrhagic infarction of pituitary tumors or pituitary glands. It is characterized by the sudden onset of headache, vomiting, visual impairment, and decreased consciousness. Reported precipitating factors of pituitary apoplexy are hypertension, anticoagulation and bromocriptine therapy, pregnancy, and angiography [1,22]. Although pituitary apoplexy associated with the endocrine stimulation test has been reported (  [3, 4, 7, 8, 11, 13-15, 17-23, 26, 27, 29]. Of the latter, all experienced symptom exacerbation after suffering pituitary apoplexy [7,8,14,21,26]. Among the 20 surgically treated patients, in 14 the symptoms worsened after the occurrence of pituitary apoplexy while in the other six they were unchanged or improved [3, 4, 11, 13, 15, 17-20, 22, 23, 27, 29]. In three patients who underwent tumor removal on the day of onset of pituitary apoplexy, the symptoms were worse after than before onset while in another four they were improved or unchanged [3,11,15,18,29]. In our cases, the patients underwent surgery within 5 hr of apoplexy onset, the symptoms attributable to pituitary apoplexy were improved. Because pituitary apoplexy associated with the above-cited precipitating factors is rare, controversy continues to surround the standard treatment [1]. In some instances the symptoms associated with precipitating factors improved when surgery was performed within 7-8 days of apoplexy onset [1,30].
Our review of the literature suggests that patients with pituitary apoplexy elicited by the endocrine stimulation test should be operated within several hours after its onset, that is, sooner than patients with pituitary apoplexy associated with the other precipitating factors. Performing only conservative treatment is not recommended. We recommend that the necessity for endocrine stimulation tests should be considered carefully and that they be performed with neurosurgical support.