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Two Cases of Hypopituitarism Caused by Intrasellar Aneurysm

Giant internal carotid artery aneurysms sometimes extend into the sellar region, which rarely but occasionally results in hypopituitarism due to the compression of the normal pituitary gland or hypothalamus. Hyponatremia is a known complication of hypopituitarism. We herein report two cases of hypopituitarism caused by intrasellar aneurysm of different origins, resulting in hyponatremia. Untreated hypopituitarism may lead to lethargy, coma, cardiac arrhythmia, and death. Therefore, we must be alert for the occurrence of giant intrasellar aneurysm, as it causes hypopituitarism. The prompt diagnosis and treatment of hypopituitarism are necessary to prevent this fatal outcome.


Introduction
Hypopituitarism typically occurs because of the compression of the normal pituitary by pituitary adenomas or nonpituitary tumors. Giant internal carotid artery aneurysms sometimes extend into the sellar region and mimic pituitary tumors, resulting in hypopituitarism due to the compression of the normal pituitary or hypothalamus (1). Although it very rarely causes hypopituitarism, a previous study found that 7 (0.17%) of 4,087 patients with hypopituitarism were found to have hypopituitarism due to an intrasellar aneurysm (2). Hyponatremia is a known complication of hypopituitarism. Untreated hypopituitarism may lead to lethargy, coma, cardiac arrhythmia, and death due to hyponatremia or hypoglycemia. We must therefore be alert for the development of giant intrasellar aneurysm, as it causes hypopituitarism.
We herein report two cases of hypopituitarism caused by intrasellar aneurysm that resulted in hyponatremia.

Case 1
A 76-year-old woman was taken to a nearby hospital because of abdominal pain, appetite loss, and clouding of consciousness. A laboratory examination revealed hyponatremia (serum sodium: 108 mmol/L). She was referred to our department for the further evaluation and treatment of hyponatremia. Hormonal data on admission showed normal blood concentrations of adrenocorticotropic hormone (ACTH, 30 pg/mL), cortisol (7.8 μg/dL), and dehydroepiandrosterone sulfate (DHEA-S, 27 μg/dL) and low levels of growth hormone (GH, 0.07 ng/mL), insulin-like growth factor-1 (<10 ng/mL), luteinizing hormone (LH, 0.1 mIU/mL), and follicle-stimulating hormone (FSH, 0.3 mIU/mL) (Table 1A). The serum thyroid-stimulating hormone (TSH) level was not elevated, despite low free triiodothyronine (T3) and free thyroxine (T4) levels (  sponse of plasma ACTH levels (Table 2A). GH-releasing peptide-2 (GHRP-2) test demonstrated weak response of plasma cortisol and GH levels (Table 2B). Coronal magnetic resonance imaging (MRI) of the pituitary and aneurysm also revealed an aneurysm with heterogeneous enhancement that was compressing the left part of the pituitary gland (Fig. 1A). MR angiography of the pituitary and aneurysm revealed a giant aneurysm (37 mm) from the right cavernous sinus (Fig. 1B).
She was treated with hydrocortisone at 50 mg/day and 5% glucose acetated (Na 130 mEq/L) Ringer's solution of 1,500 mL by an intravenous drip for 3 days, followed by hydrocortisone and levothyroxine replacement at 15 mg/day and 25 μg/day orally, respectively. There was no recurrence.

Case 2
A 74-year-old woman was taken to a nearby hospital because of a low-grade fever, nausea, and appetite loss. A laboratory examination revealed hyponatremia (serum sodium: 124 mmol/L). She was referred to our department for the further evaluation and treatment of hyponatremia. Hormonal data on admission showed normal blood concentrations of ACTH (28 pg/mL), cortisol (6.0 μg/dL), and DHEA-S (23 μg/dL) and elevated levels of prolactin (PRL, 104.4 ng/mL) (Table 1B). In addition, the data also showed low levels of urinary free cortisol (7.8 μg/day) and serum insulin-like growth factor (IGF)-1 (41 ng/mL) (Table 1B). Endocrine examinations demonstrated a weak response of plasma cortisol levels and a delayed response of plasma ACTH levels in the hCRH test (Table 2C). Coronal MRI of the pituitary and aneurysm revealed an aneurysm enhanced heterogeneously and compression of the right part of the pituitary gland (Fig. 2A). MR angiography of the pituitary and aneurysm revealed the three-dimensional structure of a giant aneurysm (23 mm) from the left internal carotid artery (Fig. 2B).
She was treated with 5% glucose acetated (Na 130 mEq/ L) Ringer's solution of 500 mL and 10% NaCl of 20 mL for 6 days, followed by dexamethasone at 0.25 mg/day orally for 7 days. Finally, she was treated with hydrocortisone replacement at 10 mg/day. There was no recurrence.

Discussion
Aneurysms extending into the sellar region are rare and account for 1-2% of all intracranial aneurysms (2). In this report, two giant intrasellar aneurysms with different origins were found: from the right cavernous sinus and from the left internal carotid artery. Furthermore, the intrasellar aneurysms caused hypopituitarism. Therefore, we speculated that these two hypopituitarism cases were caused by the intrasel-lar aneurysm.
In case 1, the hCRH test results also suggested hypothalamic ACTH insufficiency. The LHRH test and GHRP-2 test suggested hypogonadism and severe GH deficiency. Hormonal data also indicated central hypothyroidism. Hanak et al. reported that ACTH deficiency and GH deficiency were detected in 70% and 33%, respectively, of the 32 patients with intrasellar aneurysms (3). Furthermore, they reported that endocrinopathy and hyponatremia were found in 57% and 21% of patients with intrasellar aneurysms, respectively (3).
In patients with hypopituitarism, hyponatremia tends to develop under stressful conditions. Severe hyponatremia is a frequent indicator of hypopituitarism after 60 years of age (4). The serum arginine vasopressin (AVP) levels were maintained in case 1, despite a low serum sodium level. Syndrome of inappropriate antidiuretic hormone (SIADH) has been associated with multiple disease states and conditions (5). Hyponatremia is frequently due to the SIADH (6). Inappropriate secretion of AVP/ADH can be caused by hypocortisolemia due to hypopituitarism even in patients with intrasellar aneurysms. Generally, hypovolemia and hypotension stimulate the release of AVP, resulting in a reduction in free water excretion in the kidney. An intravenous drip increases the circulating volume, resulting in volume-expanded hyponatremia.
In case 2, the results of the hCRH test suggested hypothalamic hypopituitarism. Hormonal data also indicated hypogonadism, GH deficiency, and hyperPRLnemia. The aneurysm compresses the hypothalamus or the pituitary stalk, likely leading to hyperPRLnemia. The thyroid function seems to have been maintained in this case. The thyroid function can sometimes worsen before the hypothalamicpituitary-adrenal axis in cases with hypopituitarism due to pituitary compression. However, hyperPRLnemia (90%), hypogonadism (82%), ACTH deficiency (70%), and TSH deficiency (60%) were noted in cases with infradiaphragmatic intrasellar aneurysms (3). Although the mechanism has not been determined, it may be related to the hypothalamic hypopituitarism due to the giant aneurysm or its position.
Giant internal carotid artery aneurysms sometimes mimic pituitary tumors, and recent imaging techniques, such as flow-related effects on standard MR angiography, have proven useful for the diagnosis of intrasellar aneurysms (7,8). Giant intrasellar aneurysms may rarely cause pituitary dysfunction, resulting in adrenal insufficiency (9). Two mechanisms have been suggested for the development of hypopituitarism due to giant intrasellar aneurysms (9). First, hypothalamic or pituitary stalk compression by aneurysms may cause pituitary dysfunction. In case 2, only the PRL levels were high, and other pituitary hormone levels were low, suggesting hypothalamic or pituitary stalk compression. Second, direct compression and destructive effects by an enlarging aneurysm may impair the normal pituitary function.
Most intrasellar aneurysms have a benign course (10). Aneurysm rupture has been considered rare, but 15% of cases were reported to present with acute aneurysm rupture (3). To prevent aneurysm rupture and reduce the mass effect on the pituitary, open surgery or endovascular treatment may be employed to treat aneurysms (1). Open surgery methods are hazardous and technically challenging (10). In addition, hypopituitarism is usually permanent, and improvement of the pituitary function is difficult to achieve, even after surgery (11,12). Therefore, hormone replacement therapy is required even after the operation. Thus, most recent cases have been followed without operation. However, the endovascular coil embolization has been developed and is now available for application. Good occlusion of the aneurysm and partial recovery of the pituitary function has been reported in some cases of middle-aged and elderly patients (13,14). The accumulation of more details on cases of hypopituitarism due to intrasellar aneurysms will be required in order to clarify the treatment and nature of this disease.
In summary, we reported two cases of hypopituitarism caused by intrasellar aneurysms of different origins. We have to closely monitor giant intrasellar aneurysm, as it causes hypopituitarism. The prompt diagnosis and treatment of hypopituitarism are necessary to prevent this fatal outcome.
Informed consent was obtained for endocrinological examinations.
The authors state that they have no Conflict of Interest (COI).