Original Article PITUITARY APOPLEXY IN NONFUNCTIONING PITUITARY MACROADENOMAS: A CASE-CONTROL STUDY Guadalupe Vargas, MD1; Baldomero Gonzalez, MD1,3; Gerardo Guinto, MD2,3; Victoria Mendoza, MD1; Blas López-Félix, MD2; Erick Zepeda, MD2; Moisés Mercado, MD1,3 ABSTRACT Objective: Pituitary apoplexy (PA) is an endocrinologic emergency characterized by headache, visual abnormalities, and hemodynamic instability in the context of hemorragic infarction of a pituitary adenoma. Our goal was to estimate the incidence, precipitating factors, clinical characteristics, and outcome of PA in a cohort of patients with nonfunctioning pituitary macroadenomas (NFPMAs). Methods: A retrospective, case-control study of 46 patients with PA and 47 controls matched for age, gender, and tumor invasiveness. Clinical, hormonal, and tumoral charactersitics, as well as the presence of potential precipitating factors and long-term outcome were evaluated using both bivariate and multivariate analysis. Results: The prevalence of PA was 8%. Cases and controls were similar in regards to the prevalence of diabetes, hypertension, use of antiplatelet agents, and the presence of headaches and visual field defects. Oculomotor paralysis was present in 18% of cases and in none of the controls (P = .001). Prior use of dopamine agonists was significantly more frequent among cases than in controls on both bivariate and multivariate analysis. Pituitary hormone deficiencies were more common among cases than in
Submitted for publication March 23, 2014 Accepted for publication June 8, 2014 From the 1Endocrinology Service/Experimental Endocrinology Unit and 2Neurosurgery Service, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, IMSS, and 3Neurological Center, American British Cowdray Medical Center, Mexico City, Mexico. Address correspondence to Dr. Moisés Mercado, Aristóteles 68, Polanco 11560, Mexico City, Mexico. E-mail: [email protected] or moises.mercado@endocrinología.org.mx. Published as a Rapid Electronic Article in Press at http://www.endocrine practice.org on August 6, 2014. DOI:10.4158/EP14120.OR To purchase reprints of this article, please visit: www.aace.com/reprints. Copyright © 2014 AACE.
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controls on bivariate but not on multivariate analysis. Early and late surgical treatment was carried out in 11 and 25 patients, respectively; 11 patients were managed conservatively. Visual and endocrine outcomes were similar among the 3 groups. Conclusion: PA represents a life-threatening medical emergency. Prior use of dopamine agonists and the presence of oculomotor abnormalities clearly distinguished patients with NFPMA who developed PA from those who did not. (Endocr Pract. 2014;20:1274-1280) Abbreviations: DA = dopamine agonist; MRI = magnetic resonance imaging; NFPMA = nonfunctioning pituitary macroadenoma; PA = pituitary apoplexy; PRL = prolactin INTRODUCTION Pituitary apoplexy (PA) is an acute syndrome characterized by sudden development of headache, vomiting, altered consciousness, visual abnormalities, and hemodynamic instability in the context of hemorrhagic infarction of a pituitary adenoma (1). Although isolated postmortem reports of pituitary hemorrhagic necrosis go back to the late 19th century, it was not until 1950 that the term pituitary apoplexy was coined by Brougham, alluding to 5 patients who presented with the full clinical syndrome (2). The exact prevalence of PA is difficult to establish, since published reports have used different criteria to define this condition. It is thought to occur in 5 to 20% of all pituitary tumors and appears to be more common among nonfunctioning pituitary macroadenomas (NFPMAs) than in hormonally active lesions (1). The clinical, biological, and biochemical risk factors for the development of this endocrine emergency have not been clearly established, although there are some wellknown precipitating causes, such as dynamic testing with hypothalamic hormones and the use of dopamine agonists, as well as concurrent treatment with anticoagulant
Pituitary Apoplexy in Nonfunctioning Pituitary Adenomas, Endocr Pract. 2014;20(No. 12) 1275
or antiplatelet drugs (1,3,4). The present study was specifically designed to evaluate if there are any distinctive features that would differentiate patients with NFPMA that develop PA from those who do not. METHODS All cases presenting with PA and their respective matched controls were selected from a large database of 600 patients with clinical NFPMAs diagnosed and treated at our center between January 1999 and December 2013. Our scientific and ethics committees approved the study, and both cases and controls signed the corresponding informed consent. The diagnosis of PA was based on the abrupt onset of headache, hypotension, and visual abnormalities, along with the presence of a pituitary adenoma with evidence of recent hemorrhage. Patients with PA were matched for age, gender, and cavernous sinus invasion to a group of NFPMA controls without apoplexy. Magnetic resonance imaging (MRI) of the sellar region was available in all patients and controls; in the controls, we evaluated the initial MRI on which the diagnosis of NFPA was established, whereas in the PA cases, we evaluated the first imaging study that showed evidence of pituitary hemorrhage. Hypocortisolism was defined by a morning serum cortisol level below 3 µg/dL; central hypothyroidism was defined by a free thyroxine level below 0.5 ng/dL, irrespective of the thyroid-stimulating hormone level. The diagnosis of central hypogonadism was established when the serum estradiol concentration was below 10 pg/mL in females and the serum total testosterone level was below 300 ng/dL in males, along with low or inappropriately normal gonadotropin levels. Panhypopituitarism was diagnosed when three or more hormone deficiencies could be documented. All hormones were measured on a commercially available automated immunoassay platform (Immulite [Diagnostic Systems Laboratory, Webster, Texas] from 2000 to 2007 and Diasorin [Liaison, Salugia, Italy] from 2007 to 2012). Quantitative variables are presented either as means and SD or as medians with interquartile ranges, according to their distribution. Data distribution was determined
by means of the Shapiro-Wilks test. Quantitative variables were analyzed using the Student t, Mann-Whitney U, or Wilcoxon tests, whereas for qualitative variables we used either chi-square or Fisher exact tests. A step-wise, multiple regression analysis was carried out to determine which of the analyzed variables was significantly and independently associated with the development of PA. A P value 3.5 cm (%)
Cases (n = 47)
Controls (n = 46)
P value
50.9 ± 13.3 44 21 50 34
50.4 ± 12.5 52 15 54 41
.52 .47 .45 .83 .38
1276 Pituitary Apoplexy in Nonfunctioning Pituitary Adenomas, Endocr Pract. 2014;20(No. 12)
50 and 54%, respectively, had evidence of cavernous sinus invasion at diagnosis (P = .47). Neither the cases nor the controls harbored cystic lesions. Nine of the patients (19%) were being treated with dopamine agonists (DAs) when they presented with PA, whereas only one of the control subjects (2%) was receiving cabergoline upon diagnosis of the NFPMA. In 8 of the patients, cabergoline had been used at a mean weekly dose of 3.6 ± 2.6 mg weekly (range, 0.5 to 7.5 mg) during the 1 to 6 months prior to the diagnosis of PA; the only patient on bromocriptine had been treated with daily doses of 2.5 mg. Mean prolactin (PRL) levels in these DA-treated subjects were 29.6 ± 16 ng/mL upon diagnosis of NFPMA and 22 ± 17 ng/mL when they presented with PA. In most instances, the referring endocrinologist had initiated DA therapy as a temporary measure while waiting for pituitary surgery to take place and/or because of minor elevations in PRL concentrations. Neither the cases nor the controls were on anticoagulant therapy. The use of antithrombotic therapy (low-dose aspirin) was found in 14 and 22% of patients with apoplexy and controls, respectively (P = .34). The prevalence of diabetes (cases 20% vs. controls 11%; P = .20) and hypertension (cases 20% vs. controls 33%; P = .19) was similar among cases and controls. Previous history of dyslipidemia was more frequent among cases than controls (33% vs. 9%; P = .004). Table 2 depicts the bivariate analysis of all these features. Pituitary hormone deficiencies were more frequent among cases than among controls (Table 2). Central hypothyroidism was present in 53% of patients with
pituitary apoplexy and 33% of controls (P = .05); hypocortisolism was found in 53% of cases and 24% of controls (P = .024); hypogonadotrophic hypogonadism occurred in 49% of cases and 32% of controls (P = .09); and panhypopituitarism was found in 35% of cases and 9% of controls (P = .04). No cases of diabetes insipidus were documented prior to surgery. Postoperative diabetes insipidus was found in 5 patients with PA and none of the controls; in only one of these did the condition prove to be permanent. Upon multivariate analysis, only the previous use of a DA remained significantly associated with the development of PA (odds ratio, 8.82; 95% confidence interval, 1 to 77.4; P = .04). As the presence of oculomotor palsy was associated with pituitary apoplexy in 23% of the cases but none of the controls, this variable was not included in the logistic regression. Of the 47 patients with PA, 11 (23%) underwent emergency surgery (within 2 weeks of presentation), whereas 25 (53%) were operated on electively for the removal of their pituitary adenomas after stabilization of their condition (more than 2 weeks after presentation). In the remaining 11 patients, PA resulted in significant tumor necrosis and eventual disappearance; therefore, surgery was no longer required. The surgical decision was usually made based on the severity of visual impairment, because in most instances, hemodynamic instability was successfully managed with intravenous fluids and glucocorticoids. Histopathology revealed severe hemorrhagic necrosis, and no tissue was available for immunohistochemistry. Table 3 compares the long-term outcome of these patients. Neither
Table 2 Frequency of Predisposing Conditions, Symptoms and Signs, and Pituitary Hormone Deficiencies Among Cases and Controls (Bivariate Analysis) Precipitating conditions • Diabetes (%) • Hypertension (%) • Dyslipidemia (%) • Antithrombotic (%) • Dopamine agonists (%) Symptoms and signs • Headache (%) • Visual field defect (%) • Oculomotor palsy (%) Hormone deficiencies • Hypothyroidism (%) • Hypogonadism (%) • Hypocortisolism (%) • Panhypopituitarism (%)
Cases (n = 47)
Controls (n = 46)
P value
20 20 33 14 18
11 33 9 22 2
.20 .19 .004 .34 .01
75 73 23
63 85 0
.21 .16 .001
53 49 53 35
33 32 24 9
.05 .09 .024 .04
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Table 3 Long-Term Visual, Endocrine, and Tumor Outcomes Stratified by Type of Treatment
Age Male/female Follow-up (years) Persistent visual field defect Persistent oculomotor palsy Hypothyroidism Hypocortisolism Hypogonadism Panhypopituitarism Tumor outcome
Nonsurgical treatment (n = 11)
Early surgery (n = 11)
Late surgery (n = 25)
52.7 ± 11.7 3/8 4.7 ± 1.5 4.7 (3.5-5.4) 3 (27%) 2 (18%) 6 (54%) 6 (54%) 5 (45%) 3 (27%) 6 No tumor 2 Stable remnant 3 Recurrences
56.2 ± 12.4 8/3 9.9 ± 3.1 10.5 (6-12) 8 (73%) 3 (27%) 7 (63%) 7 (63%) 7 (63%) 5 (45%) 3 No tumor 6 Stable remnant 2 Recurrences
51.5 ± 13.1 16/10 8.8 ± 4.38 7 (5-13) 24 (92%) 6 (23%) 11 (42%) 11 (42% 10 (38%) 8 (31%) 4 No tumor 11 Stable remnant 10 Recurrences
the recovery rate of oculomotor abnormalities nor the final hormonal outcome differed significantly among the 3 groups. Persistent visual field defects were significantly more common among patients treated surgically (early surgery 73% and late surgery 92%) than among those managed conservatively without surgery (23%) (P = .001). Of the 11 patients treated conservatively, whose lesions had apparently disappeared due to the PA, 6 remained without evidence of tumor, whereas in 5 patients the adenoma recurred and 3 patients eventually required surgery. Of those treated with late elective surgery, 4 have remained tumor free, 10 eventually presented with tumoral recurrences requiring surgery, and 12 have a stable, small tumor remnant that is being observed. Of the 11 subjects who were operated on early, 3 are tumor free upon their last evaluation, 6 have a stable remnant, and 2 developed a significant recurrence requiring surgical reintervention. DISCUSSION This is the largest series of patients with PA occurring in the context of NFPMA, managed at a single center. As with all published studies dealing with PA, our study was retrospective; however, we used a case-control design to strengthen the power of our observations. Using a definition that included not only the finding of hemorrhage on imaging studies but also the clinical features of this neuroendocrinologic emergency, we found an 8% prevalence of PA, which is consistent with previously published data. Most published studies have confirmed that the prevalence of PA varies between 3 and 20% and indeed depends on the tumor type (5-14). In a recent metaanalysis evaluating the natural history of NFPMA, PA was found to be a
P value .91 .07
.001 .87 .28 .28 .23 .56
rather uncommon event (15). Although the event rate per 100 person-years was only 0.6, the analysis was associated with significant heterogeneity, and the prevalence of PA among the analyzed studies ranged from 4 to 14% (15). Because most cases of PA do occur in macroadenomas (1012), it has been postulated that a large tumor size is a risk factor; however, PA does occur in microadenomas (16). All of our patients with PA harbored macroadenomas, yet both tumor size and the presence of cavernous sinus invasion were similar among cases and controls. Möller-Goede et al (12) reported an incidence of 16.5% in NFPMA, 5.5% in prolactinomas, 3.1% in somatotropinomas, and 4% in corticotropinomas. Although patients with NFPMA appear to have a higher incidence of PA than subjects harboring functioning tumors (12,14), this remains controversial, because in many instances, the tissue available for pathologic evaluation is so necrotic that immunostaining for anterior pituitary hormones is not possible (17). Although it is well established that pituitary adenomas bleed more frequently than any other intracranial tumor, there is still controversy regarding whether PA is the result of a primary hemorrhage or represents hemorrhagic infarction (1,5,6). The most popular theory is that PA occurs when the adenoma outgrows its blood supply; yet, hemorrhage can occur in small microadenomas, making this mechanism unlikely to explain the phenomenon in all cases (6). Another potential mechanism is that the expanding pituitary mass compresses the superior hypophyseal vessels, resulting in ischemia; however, most of the adenoma blood supply comes from the inferior arteries (1). Some authors have suggested that pituitary tumors have an intrinsic vasculopathy that renders them more susceptible to hemorrhage and infarction (18).
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Although PA can occur spontaneously, conditions potentially associated with PA include pregnancy, postpartum heart surgery, orthopedic surgery, and urologic surgery (3,4,12,19-21). In these situations, the common denominator is an abnormal coagulation state, and the use of both anticoagulants and antithrombotic medications has also been found to increase the risk of developing PA (22,23). Head trauma (24), systemic hypertension (7), and diabetes mellitus (3,7) have also been implicated, although with questionable statistical significance. In our series, the prevalence of hypertension, diabetes, and the number of patients on antithrombotic medications (mostly low-dose aspirin) was similar among patients and controls. None of the subjects we studied were on anticoagulant therapy or had a recent history of surgery, pregnancy, or head trauma. Pituitary dynamic testing with gonadotropin-releasing hormone, thyrotropin-releasing hormone, corticotropinreleasing hormone, and insulin, and prior estrogen or clomiphene treatment are all reportedly associated with PA, usually as isolated cases (1,3,4). In our study, recent use of cabergoline was the most striking potential precipitating factor of PA, as it was recorded in 18% of cases but only 2% of controls. These medications have been considered potential triggers of PA since the early 1980s. In most instances, the reports allude to bromocriptine in patients harboring macroprolactinomas (25,26), although there are recent publications implicating cabergoline as well in the same scenario (27,28). To our knowledge, there have not been any reports of cabergoline as a precipitating factor of PA in NFPMA. Although DAs are not routinely used in the management of NFPMA, a proportion of these tumors do express the dopamine 2A receptor (29), and cabergoline is increasingly gaining popularity as treatment for residual or persistent nonfunctioning tumors (30). Although it is unclear how DA use leads to PA, bromocriptine is known to produce perivascular fibrosis and hemorrhagic necrosis in PRL-secreting adenomas (31). The cellular morphologic changes resulting from cabergoline treatment have not been evaluated. Patients presenting with acute headache, signs of meningeal irritation, visual abnormalities, impairment of consciousness, and hemodynamic instability require a complex differential diagnosis that includes conditions such as subarachnoid hemorrhage, central nervous system infections, cavernous sinus thrombosis, hypertensive encephalopathy, basilar artery occlusion, and even complicated migraine. Therefore, a high index of suspicion is indispensable in order to indicate a brain MRI or computed tomography scan early on, avoiding procedures such as spinal tap for cerebrospinal fluid analysis or angiography, which may be dangerous to the patient. In the majority of series of PA cases published between 1999 and 2013, 75 to 100% of the patients had been unaware of the presence of pituitary adenoma (3,4,7-10). A remarkable exception is the series by Möller-Goede et al (12), in which 41 of the 42 patients
with PA had a known diagnosis of an adenoma. PA was the first manifestation of a pituitary adenoma in 54% of our patients, a figure similar to that reported by Bujawansa et al (13). This variability in the awareness of the presence of a pituitary mass in patients presenting with PA stems from a referral bias and also likely from the retrospective nature of all the published studies. Cranial nerve involvement is known to be extremely rare in patients with pituitary adenomas. In fact, the presence of oculomotor paralysis in a patient with a pituitary adenoma, even in the presence of cavernous sinus extension, should prompt a search for alternative diagnoses, including metastasis to the sellar region and infiltrative disorders. However, in the context of PA, ophthalmoplegia due to involvement of the III, IV, or VI cranial nerves has been reported in 26 to 70% of cases (3,4,7,8,10,12-14). In this regard, although the incidence of oculomotor paralysis found in our patients was somewhat lower than in previous series, its presence was clearly distinctive of patients with PA, as it did not occur in any of the control subjects. No other clinical finding was found to differentiate patients from controls. Although pituitary hormone deficiencies seemed to be more common among cases than in controls upon bivariate analysis, upon multivariate analysis, only the presence of panhypopituitarism was marginally associated with the development of PA; thus, hypopituitarism was not a distinctive feature of patients with apoplexy. The proper management of PA relies on good clinical judgment. The decision to proceed with emergency surgery is usually based on the severity of visual abnormalities and the presence of ominous neurologic symptoms and signs, such as an altered mental status. In general, a conservative approach is reserved for patients who stabilize hemodynamically and neuro-ophtalmologically with initial management that includes intravenous fluids and glucocorticoids (7,8,12-14). Therefore, an objective outcome comparison of patients treated surgically with those managed conservatively is probably not appropriate. Another relevant characteristic of our study is that patients were followed up in a systematic way for at least 3.5 years and up to 12 years, allowing us to evaluate long-term outcome. Although the majority of our patients underwent surgical treatment (37 of 48), in only 23% did this occur within the first 2 weeks after presentation; the remaining patients underwent surgery on an elective basis as the treatment of their pituitary adenoma. In agreement with the largest published series of PA (3,4,7,8,12-14), whereas the oculomotor paralysis and visual field defects resolved in a significant number of our patients, the endocrine deficiencies did not. The proportion of patients who remained with persistent oculomotor abnormalities was similar among patients treated surgically and among those managed conservatively. Surgically treated subjects had a significantly higher frequency of persistent visual field defects, perhaps due to the fact that a progressive campimetric abnormality
Pituitary Apoplexy in Nonfunctioning Pituitary Adenomas, Endocr Pract. 2014;20(No. 12) 1279
was by itself a criterion to operate on a patient with PA. Interestingly, 11 of our patients were not referred to surgery because the PA had resulted in significant necrosis and disappearance of the initial mass; yet, in 5 of these 11 patients, the adenoma recurred, and 3 of these patients required surgical treatment over 1 year after they presented with PA. This finding underscores the need for long-term surveillance of patients with NFPMA, in view of the high recurrence rate even after PA-induced necrosis of the initial lesion (32). CONCLUSION PA constitutes an endocrine emergency that should be managed in a multidisciplinary way, regardless whether it occurs in the setting of a functionining or a nonfunctioning adenoma. A timely diagnosis, based on a high index of suspicion derived from the presence of oculomotor abnormalities and the presence of precipitating factors is of paramount importance in order to decide what therapeutic intervention is the most appropriate for each individual patient. Initial management should always consist of hemodynamic stabilization and administration of stress doses of glucocorticoids. Some patients can be treated conservatively; however, rapidly progressive visual abnormalities are by themselves an indication of emergency decompressing surgery, which in most instances can be done via the transsphenoidal approach. ACKNOWLEDGMENT Guadalupe Vargas and Bladomero Gonzalez contributed equally to this study. DISCLOSURE
The authors have no multiplicity of interest to disclose.
REFERENCES 1. Ranabir S, Baruah MP. Pituitary apoplexy. Indian J Endocrinol Metab. 2011;15(suppl 3):S188-S196. 2. Brougham M, Heusner AP, Adams RD. Acute degenerative changes in adenomas of the pituitary body-with special reference to pituitary apoplexy. J Neurosurg. 1950;7: 421-439. 3. Biousse V, Newman NJ, Oyesiku NM. Precipitating factors in pituitary apoplexy. J Neurol Neurosurg Psychiatry. 2001;71:542-545. 4. Semple PL, Jane JA Jr, Laws ER Jr. Clinical relevance of precipitating factors in pituitary apoplexy. Neurosurgery. 2007;61:956-962. 5. Wakai S, Fukushima T, Teramoto A, Sano K. Pituitary apoplexy: its incidence and clinical significance. J Neurosurg. 1981;55:187-193. 6. Mohr G, Hardy J. Hemorrhage, necrosis, and apoplexy in pituitary adenomas. Surg Neurol. 1982;18:181-189.
7. Randeva HS, Schoebel J, Byrne J, Esiri M, Adams CB, Wass JA. Classical pituitary apoplexy: clinical features, management and outcome. Clin Endocrinol (Oxf). 1999; 51:181-188. 8. Ayuk J, McGregor EJ, Mitchell RD, Gittoes NJ. Acute management of pituitary apoplexy-surgery or conservative management? Clin Endocrinol (Oxf). 2004;61:747-752. 9. Sibal L, Ball SG, Connolly V, et al. Pituitary apoplexy: a review of clinical presentation, management and outcome in 45 cases. Pituitary. 2004;7:157-163. 10. Dubuisson AS, Beckers A, Stevenaert AD. Classical pituitary tumor apoplexy: clinical features, management and outcomes in a series of 24 patients. Clin Neurol Neurosurg. 2007;109:63-70. 11. Liu ZH, Chang CN, Pai PC, et al. Clinical features and surgical outcome of clinical and subclinical pituitary apoplexy. J Clin Neurosci. 2010;17:694-699. 12. Möller-Goede DI, Brändle M, Landau K, Bernays RL, Schmid C. Pituitary apoplexy: re-evaluation of risk factors for bleeding into pituitary adenomas and impact on outcome. Eur J Endocrinol. 2011;164:39-43. 13. Bujawansa S, Thondam SK, Steele C, et al. Presentation, management and outcomes in acute pituitary apoplexy: a large, single-center experience from the United Kingdom. Clin Endocrinol (Oxf). 2014;80:419-424. 14. Nielsen EH, Lindholm J, Bjerre P, et al. Frequent occurrence of pituitary apoplexy in patients with non-functioning pituitary adenoma. Clin Endocrinol (Oxf). 2006;64: 319-322. 15. Fernández-Balsells MM, Murad MH, Barwise A, et al. Natural history of nonfunctioning pituitary adenomas and incidentalomas: a systematic review and metaanalysis. J Clin Endocrinol Metab. 2011;96:905-912. 16. Jeffcoat WJ, Birch CR. Pituitary apoplexy in small pituitary tumors. J Neurol Neurosurg Psychiatry. 1986;49: 1077-1078. 17. Mou C, Han T, Zhao H, Wang S, Qu Y. Clinical features and immunohistochemical changes in pituitary apoplexy. J Clin Neurosci. 2009;16:64-68. 18. Cardoso ER, Peterson EW. Pituitary apoplexy: A review. Neurosurgery. 1984;14:363-373. 19. de Heide LJ, van Tol KM, Doorenbos B. Pituitary apoplexy presenting during pregnancy. Neth J Med. 2004;62: 393-396. 20. Battacharyya A, Tymms DJ, Naqvi M. Asymptomatic pituitary apoplexy during aortocoronary bypass surgery. Int J Clin Pract. 1999;53:394-395. 21. Khandelwal M, Chhabra A, Krishnan S. Pituitary apoplexy following bilateral total knee arthroplasty. J Postgrad Med. 2005;51:155-156. 22. Oo MM, Krishna AY, Bonavita GJ, Rutecki GW. Heparin therapy for myocardial infarction: an unusual trigger for pituitary apoplexy. Am J Med Sci. 1997;314:351-353. 23. Fuchs S, Beeri R, Hasin Y, Weiss AT, Gotsman MS, Zahger D. Pituitary apoplexy as the first manifestation of pituitary adenomas following thrombolytic and antithrombotic therapy. Am J Cardiol. 1998;81:110-111. 24. Uchiyama H, Nishizawa S, Satoh A, Yokoyama T, Uemura K. Post-traumatic pituitary apoplexy: two case reports. Neurol Med Chir (Tokyo). 1999;39:36-39. 25. Sobrinho LG, Nunes MC, Calhaz-Jorge C, Mauricio JC, Santos MA. Effect of treatment with bromocriptine on the size and activity of prolactin-producing pituitary tumors. Acta Endocrinol (Copenh). 1981;96:24-29.
1280 Pituitary Apoplexy in Nonfunctioning Pituitary Adenomas, Endocr Pract. 2014;20(No. 12) 26. Pinto G, Zerah M, Trivin C, Brauner R. Pituitary apoplexy in an adolescent with prolactin-secreting adenoma. Horm Res. 1998;50:38-41. 27. Knoepfelmacher M, Gomes MC, Melo ME, Mendonca BB. Pituitary apoplexy during therapy with cabergoline in an adolescent male with prolactin-secreting macroadenoma. Pituitary. 2004;7:83-87. 28. Balarini Lima GA, Machado Ede O, Dos Santos Silva MC, Filho PN, Gadelha MR. Pituitary apoplexy during treatment of cystic macroprolactinomas with cabergoline. Pituitary. 2008;11:287-292. 29. Pivonello R, Matrone C, Filippella M, et al. Dopamine receptor expression and function in clinically non-functioning pituitary tumors: comparison with the effectiveness of
cabergoline treatment. J Clin Endocrinol Metab. 2004;89: 1674-1683. 30. García EC, Naves LA, Silva AO, de Castro LF, Casulari LA, Azevedo MF. Short-term treatment with cabergoline can lead to tumor shrinkage in patients with nonfunctioning pituitary adenomas. Pituitary. 2013;16:189-194. 31. Kontogeorgos G, Horvath E, Kovacs K, et al. Morphologic changes of prolactin-producing pituitary adenomas after short treatment with dopamine agonists. Acta Neuropathol. 2006;111:46-52. 32. Pal A, Capatina C, Tenreiro AP, et al. Pituitary apoplexy in non-functioning pituitary adenomas: long-term follow up is important because of significant numbers of tumor recurrences. Clin Endocrinol (Oxf). 2011;75:501-504.
Submitted for publication March 23, 2014 Accepted for publication June 8, 2014 From the 1Endocrinology Service/Experimental Endocrinology Unit and 2Neurosurgery Service, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, IMSS, and 3Neurological Center, American British Cowdray Medical Center, Mexico City, Mexico. Address correspondence to Dr. Moisés Mercado, Aristóteles 68, Polanco 11560, Mexico City, Mexico. E-mail: [email protected] or moises.mercado@endocrinología.org.mx. Published as a Rapid Electronic Article in Press at http://www.endocrine practice.org on August 6, 2014. DOI:10.4158/EP14120.OR To purchase reprints of this article, please visit: www.aace.com/reprints. Copyright © 2014 AACE.
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controls on bivariate but not on multivariate analysis. Early and late surgical treatment was carried out in 11 and 25 patients, respectively; 11 patients were managed conservatively. Visual and endocrine outcomes were similar among the 3 groups. Conclusion: PA represents a life-threatening medical emergency. Prior use of dopamine agonists and the presence of oculomotor abnormalities clearly distinguished patients with NFPMA who developed PA from those who did not. (Endocr Pract. 2014;20:1274-1280) Abbreviations: DA = dopamine agonist; MRI = magnetic resonance imaging; NFPMA = nonfunctioning pituitary macroadenoma; PA = pituitary apoplexy; PRL = prolactin INTRODUCTION Pituitary apoplexy (PA) is an acute syndrome characterized by sudden development of headache, vomiting, altered consciousness, visual abnormalities, and hemodynamic instability in the context of hemorrhagic infarction of a pituitary adenoma (1). Although isolated postmortem reports of pituitary hemorrhagic necrosis go back to the late 19th century, it was not until 1950 that the term pituitary apoplexy was coined by Brougham, alluding to 5 patients who presented with the full clinical syndrome (2). The exact prevalence of PA is difficult to establish, since published reports have used different criteria to define this condition. It is thought to occur in 5 to 20% of all pituitary tumors and appears to be more common among nonfunctioning pituitary macroadenomas (NFPMAs) than in hormonally active lesions (1). The clinical, biological, and biochemical risk factors for the development of this endocrine emergency have not been clearly established, although there are some wellknown precipitating causes, such as dynamic testing with hypothalamic hormones and the use of dopamine agonists, as well as concurrent treatment with anticoagulant
Pituitary Apoplexy in Nonfunctioning Pituitary Adenomas, Endocr Pract. 2014;20(No. 12) 1275
or antiplatelet drugs (1,3,4). The present study was specifically designed to evaluate if there are any distinctive features that would differentiate patients with NFPMA that develop PA from those who do not. METHODS All cases presenting with PA and their respective matched controls were selected from a large database of 600 patients with clinical NFPMAs diagnosed and treated at our center between January 1999 and December 2013. Our scientific and ethics committees approved the study, and both cases and controls signed the corresponding informed consent. The diagnosis of PA was based on the abrupt onset of headache, hypotension, and visual abnormalities, along with the presence of a pituitary adenoma with evidence of recent hemorrhage. Patients with PA were matched for age, gender, and cavernous sinus invasion to a group of NFPMA controls without apoplexy. Magnetic resonance imaging (MRI) of the sellar region was available in all patients and controls; in the controls, we evaluated the initial MRI on which the diagnosis of NFPA was established, whereas in the PA cases, we evaluated the first imaging study that showed evidence of pituitary hemorrhage. Hypocortisolism was defined by a morning serum cortisol level below 3 µg/dL; central hypothyroidism was defined by a free thyroxine level below 0.5 ng/dL, irrespective of the thyroid-stimulating hormone level. The diagnosis of central hypogonadism was established when the serum estradiol concentration was below 10 pg/mL in females and the serum total testosterone level was below 300 ng/dL in males, along with low or inappropriately normal gonadotropin levels. Panhypopituitarism was diagnosed when three or more hormone deficiencies could be documented. All hormones were measured on a commercially available automated immunoassay platform (Immulite [Diagnostic Systems Laboratory, Webster, Texas] from 2000 to 2007 and Diasorin [Liaison, Salugia, Italy] from 2007 to 2012). Quantitative variables are presented either as means and SD or as medians with interquartile ranges, according to their distribution. Data distribution was determined
by means of the Shapiro-Wilks test. Quantitative variables were analyzed using the Student t, Mann-Whitney U, or Wilcoxon tests, whereas for qualitative variables we used either chi-square or Fisher exact tests. A step-wise, multiple regression analysis was carried out to determine which of the analyzed variables was significantly and independently associated with the development of PA. A P value 3.5 cm (%)
Cases (n = 47)
Controls (n = 46)
P value
50.9 ± 13.3 44 21 50 34
50.4 ± 12.5 52 15 54 41
.52 .47 .45 .83 .38
1276 Pituitary Apoplexy in Nonfunctioning Pituitary Adenomas, Endocr Pract. 2014;20(No. 12)
50 and 54%, respectively, had evidence of cavernous sinus invasion at diagnosis (P = .47). Neither the cases nor the controls harbored cystic lesions. Nine of the patients (19%) were being treated with dopamine agonists (DAs) when they presented with PA, whereas only one of the control subjects (2%) was receiving cabergoline upon diagnosis of the NFPMA. In 8 of the patients, cabergoline had been used at a mean weekly dose of 3.6 ± 2.6 mg weekly (range, 0.5 to 7.5 mg) during the 1 to 6 months prior to the diagnosis of PA; the only patient on bromocriptine had been treated with daily doses of 2.5 mg. Mean prolactin (PRL) levels in these DA-treated subjects were 29.6 ± 16 ng/mL upon diagnosis of NFPMA and 22 ± 17 ng/mL when they presented with PA. In most instances, the referring endocrinologist had initiated DA therapy as a temporary measure while waiting for pituitary surgery to take place and/or because of minor elevations in PRL concentrations. Neither the cases nor the controls were on anticoagulant therapy. The use of antithrombotic therapy (low-dose aspirin) was found in 14 and 22% of patients with apoplexy and controls, respectively (P = .34). The prevalence of diabetes (cases 20% vs. controls 11%; P = .20) and hypertension (cases 20% vs. controls 33%; P = .19) was similar among cases and controls. Previous history of dyslipidemia was more frequent among cases than controls (33% vs. 9%; P = .004). Table 2 depicts the bivariate analysis of all these features. Pituitary hormone deficiencies were more frequent among cases than among controls (Table 2). Central hypothyroidism was present in 53% of patients with
pituitary apoplexy and 33% of controls (P = .05); hypocortisolism was found in 53% of cases and 24% of controls (P = .024); hypogonadotrophic hypogonadism occurred in 49% of cases and 32% of controls (P = .09); and panhypopituitarism was found in 35% of cases and 9% of controls (P = .04). No cases of diabetes insipidus were documented prior to surgery. Postoperative diabetes insipidus was found in 5 patients with PA and none of the controls; in only one of these did the condition prove to be permanent. Upon multivariate analysis, only the previous use of a DA remained significantly associated with the development of PA (odds ratio, 8.82; 95% confidence interval, 1 to 77.4; P = .04). As the presence of oculomotor palsy was associated with pituitary apoplexy in 23% of the cases but none of the controls, this variable was not included in the logistic regression. Of the 47 patients with PA, 11 (23%) underwent emergency surgery (within 2 weeks of presentation), whereas 25 (53%) were operated on electively for the removal of their pituitary adenomas after stabilization of their condition (more than 2 weeks after presentation). In the remaining 11 patients, PA resulted in significant tumor necrosis and eventual disappearance; therefore, surgery was no longer required. The surgical decision was usually made based on the severity of visual impairment, because in most instances, hemodynamic instability was successfully managed with intravenous fluids and glucocorticoids. Histopathology revealed severe hemorrhagic necrosis, and no tissue was available for immunohistochemistry. Table 3 compares the long-term outcome of these patients. Neither
Table 2 Frequency of Predisposing Conditions, Symptoms and Signs, and Pituitary Hormone Deficiencies Among Cases and Controls (Bivariate Analysis) Precipitating conditions • Diabetes (%) • Hypertension (%) • Dyslipidemia (%) • Antithrombotic (%) • Dopamine agonists (%) Symptoms and signs • Headache (%) • Visual field defect (%) • Oculomotor palsy (%) Hormone deficiencies • Hypothyroidism (%) • Hypogonadism (%) • Hypocortisolism (%) • Panhypopituitarism (%)
Cases (n = 47)
Controls (n = 46)
P value
20 20 33 14 18
11 33 9 22 2
.20 .19 .004 .34 .01
75 73 23
63 85 0
.21 .16 .001
53 49 53 35
33 32 24 9
.05 .09 .024 .04
Pituitary Apoplexy in Nonfunctioning Pituitary Adenomas, Endocr Pract. 2014;20(No. 12) 1277
Table 3 Long-Term Visual, Endocrine, and Tumor Outcomes Stratified by Type of Treatment
Age Male/female Follow-up (years) Persistent visual field defect Persistent oculomotor palsy Hypothyroidism Hypocortisolism Hypogonadism Panhypopituitarism Tumor outcome
Nonsurgical treatment (n = 11)
Early surgery (n = 11)
Late surgery (n = 25)
52.7 ± 11.7 3/8 4.7 ± 1.5 4.7 (3.5-5.4) 3 (27%) 2 (18%) 6 (54%) 6 (54%) 5 (45%) 3 (27%) 6 No tumor 2 Stable remnant 3 Recurrences
56.2 ± 12.4 8/3 9.9 ± 3.1 10.5 (6-12) 8 (73%) 3 (27%) 7 (63%) 7 (63%) 7 (63%) 5 (45%) 3 No tumor 6 Stable remnant 2 Recurrences
51.5 ± 13.1 16/10 8.8 ± 4.38 7 (5-13) 24 (92%) 6 (23%) 11 (42%) 11 (42% 10 (38%) 8 (31%) 4 No tumor 11 Stable remnant 10 Recurrences
the recovery rate of oculomotor abnormalities nor the final hormonal outcome differed significantly among the 3 groups. Persistent visual field defects were significantly more common among patients treated surgically (early surgery 73% and late surgery 92%) than among those managed conservatively without surgery (23%) (P = .001). Of the 11 patients treated conservatively, whose lesions had apparently disappeared due to the PA, 6 remained without evidence of tumor, whereas in 5 patients the adenoma recurred and 3 patients eventually required surgery. Of those treated with late elective surgery, 4 have remained tumor free, 10 eventually presented with tumoral recurrences requiring surgery, and 12 have a stable, small tumor remnant that is being observed. Of the 11 subjects who were operated on early, 3 are tumor free upon their last evaluation, 6 have a stable remnant, and 2 developed a significant recurrence requiring surgical reintervention. DISCUSSION This is the largest series of patients with PA occurring in the context of NFPMA, managed at a single center. As with all published studies dealing with PA, our study was retrospective; however, we used a case-control design to strengthen the power of our observations. Using a definition that included not only the finding of hemorrhage on imaging studies but also the clinical features of this neuroendocrinologic emergency, we found an 8% prevalence of PA, which is consistent with previously published data. Most published studies have confirmed that the prevalence of PA varies between 3 and 20% and indeed depends on the tumor type (5-14). In a recent metaanalysis evaluating the natural history of NFPMA, PA was found to be a
P value .91 .07
.001 .87 .28 .28 .23 .56
rather uncommon event (15). Although the event rate per 100 person-years was only 0.6, the analysis was associated with significant heterogeneity, and the prevalence of PA among the analyzed studies ranged from 4 to 14% (15). Because most cases of PA do occur in macroadenomas (1012), it has been postulated that a large tumor size is a risk factor; however, PA does occur in microadenomas (16). All of our patients with PA harbored macroadenomas, yet both tumor size and the presence of cavernous sinus invasion were similar among cases and controls. Möller-Goede et al (12) reported an incidence of 16.5% in NFPMA, 5.5% in prolactinomas, 3.1% in somatotropinomas, and 4% in corticotropinomas. Although patients with NFPMA appear to have a higher incidence of PA than subjects harboring functioning tumors (12,14), this remains controversial, because in many instances, the tissue available for pathologic evaluation is so necrotic that immunostaining for anterior pituitary hormones is not possible (17). Although it is well established that pituitary adenomas bleed more frequently than any other intracranial tumor, there is still controversy regarding whether PA is the result of a primary hemorrhage or represents hemorrhagic infarction (1,5,6). The most popular theory is that PA occurs when the adenoma outgrows its blood supply; yet, hemorrhage can occur in small microadenomas, making this mechanism unlikely to explain the phenomenon in all cases (6). Another potential mechanism is that the expanding pituitary mass compresses the superior hypophyseal vessels, resulting in ischemia; however, most of the adenoma blood supply comes from the inferior arteries (1). Some authors have suggested that pituitary tumors have an intrinsic vasculopathy that renders them more susceptible to hemorrhage and infarction (18).
1278 Pituitary Apoplexy in Nonfunctioning Pituitary Adenomas, Endocr Pract. 2014;20(No. 12)
Although PA can occur spontaneously, conditions potentially associated with PA include pregnancy, postpartum heart surgery, orthopedic surgery, and urologic surgery (3,4,12,19-21). In these situations, the common denominator is an abnormal coagulation state, and the use of both anticoagulants and antithrombotic medications has also been found to increase the risk of developing PA (22,23). Head trauma (24), systemic hypertension (7), and diabetes mellitus (3,7) have also been implicated, although with questionable statistical significance. In our series, the prevalence of hypertension, diabetes, and the number of patients on antithrombotic medications (mostly low-dose aspirin) was similar among patients and controls. None of the subjects we studied were on anticoagulant therapy or had a recent history of surgery, pregnancy, or head trauma. Pituitary dynamic testing with gonadotropin-releasing hormone, thyrotropin-releasing hormone, corticotropinreleasing hormone, and insulin, and prior estrogen or clomiphene treatment are all reportedly associated with PA, usually as isolated cases (1,3,4). In our study, recent use of cabergoline was the most striking potential precipitating factor of PA, as it was recorded in 18% of cases but only 2% of controls. These medications have been considered potential triggers of PA since the early 1980s. In most instances, the reports allude to bromocriptine in patients harboring macroprolactinomas (25,26), although there are recent publications implicating cabergoline as well in the same scenario (27,28). To our knowledge, there have not been any reports of cabergoline as a precipitating factor of PA in NFPMA. Although DAs are not routinely used in the management of NFPMA, a proportion of these tumors do express the dopamine 2A receptor (29), and cabergoline is increasingly gaining popularity as treatment for residual or persistent nonfunctioning tumors (30). Although it is unclear how DA use leads to PA, bromocriptine is known to produce perivascular fibrosis and hemorrhagic necrosis in PRL-secreting adenomas (31). The cellular morphologic changes resulting from cabergoline treatment have not been evaluated. Patients presenting with acute headache, signs of meningeal irritation, visual abnormalities, impairment of consciousness, and hemodynamic instability require a complex differential diagnosis that includes conditions such as subarachnoid hemorrhage, central nervous system infections, cavernous sinus thrombosis, hypertensive encephalopathy, basilar artery occlusion, and even complicated migraine. Therefore, a high index of suspicion is indispensable in order to indicate a brain MRI or computed tomography scan early on, avoiding procedures such as spinal tap for cerebrospinal fluid analysis or angiography, which may be dangerous to the patient. In the majority of series of PA cases published between 1999 and 2013, 75 to 100% of the patients had been unaware of the presence of pituitary adenoma (3,4,7-10). A remarkable exception is the series by Möller-Goede et al (12), in which 41 of the 42 patients
with PA had a known diagnosis of an adenoma. PA was the first manifestation of a pituitary adenoma in 54% of our patients, a figure similar to that reported by Bujawansa et al (13). This variability in the awareness of the presence of a pituitary mass in patients presenting with PA stems from a referral bias and also likely from the retrospective nature of all the published studies. Cranial nerve involvement is known to be extremely rare in patients with pituitary adenomas. In fact, the presence of oculomotor paralysis in a patient with a pituitary adenoma, even in the presence of cavernous sinus extension, should prompt a search for alternative diagnoses, including metastasis to the sellar region and infiltrative disorders. However, in the context of PA, ophthalmoplegia due to involvement of the III, IV, or VI cranial nerves has been reported in 26 to 70% of cases (3,4,7,8,10,12-14). In this regard, although the incidence of oculomotor paralysis found in our patients was somewhat lower than in previous series, its presence was clearly distinctive of patients with PA, as it did not occur in any of the control subjects. No other clinical finding was found to differentiate patients from controls. Although pituitary hormone deficiencies seemed to be more common among cases than in controls upon bivariate analysis, upon multivariate analysis, only the presence of panhypopituitarism was marginally associated with the development of PA; thus, hypopituitarism was not a distinctive feature of patients with apoplexy. The proper management of PA relies on good clinical judgment. The decision to proceed with emergency surgery is usually based on the severity of visual abnormalities and the presence of ominous neurologic symptoms and signs, such as an altered mental status. In general, a conservative approach is reserved for patients who stabilize hemodynamically and neuro-ophtalmologically with initial management that includes intravenous fluids and glucocorticoids (7,8,12-14). Therefore, an objective outcome comparison of patients treated surgically with those managed conservatively is probably not appropriate. Another relevant characteristic of our study is that patients were followed up in a systematic way for at least 3.5 years and up to 12 years, allowing us to evaluate long-term outcome. Although the majority of our patients underwent surgical treatment (37 of 48), in only 23% did this occur within the first 2 weeks after presentation; the remaining patients underwent surgery on an elective basis as the treatment of their pituitary adenoma. In agreement with the largest published series of PA (3,4,7,8,12-14), whereas the oculomotor paralysis and visual field defects resolved in a significant number of our patients, the endocrine deficiencies did not. The proportion of patients who remained with persistent oculomotor abnormalities was similar among patients treated surgically and among those managed conservatively. Surgically treated subjects had a significantly higher frequency of persistent visual field defects, perhaps due to the fact that a progressive campimetric abnormality
Pituitary Apoplexy in Nonfunctioning Pituitary Adenomas, Endocr Pract. 2014;20(No. 12) 1279
was by itself a criterion to operate on a patient with PA. Interestingly, 11 of our patients were not referred to surgery because the PA had resulted in significant necrosis and disappearance of the initial mass; yet, in 5 of these 11 patients, the adenoma recurred, and 3 of these patients required surgical treatment over 1 year after they presented with PA. This finding underscores the need for long-term surveillance of patients with NFPMA, in view of the high recurrence rate even after PA-induced necrosis of the initial lesion (32). CONCLUSION PA constitutes an endocrine emergency that should be managed in a multidisciplinary way, regardless whether it occurs in the setting of a functionining or a nonfunctioning adenoma. A timely diagnosis, based on a high index of suspicion derived from the presence of oculomotor abnormalities and the presence of precipitating factors is of paramount importance in order to decide what therapeutic intervention is the most appropriate for each individual patient. Initial management should always consist of hemodynamic stabilization and administration of stress doses of glucocorticoids. Some patients can be treated conservatively; however, rapidly progressive visual abnormalities are by themselves an indication of emergency decompressing surgery, which in most instances can be done via the transsphenoidal approach. ACKNOWLEDGMENT Guadalupe Vargas and Bladomero Gonzalez contributed equally to this study. DISCLOSURE
The authors have no multiplicity of interest to disclose.
REFERENCES 1. Ranabir S, Baruah MP. Pituitary apoplexy. Indian J Endocrinol Metab. 2011;15(suppl 3):S188-S196. 2. Brougham M, Heusner AP, Adams RD. Acute degenerative changes in adenomas of the pituitary body-with special reference to pituitary apoplexy. J Neurosurg. 1950;7: 421-439. 3. Biousse V, Newman NJ, Oyesiku NM. Precipitating factors in pituitary apoplexy. J Neurol Neurosurg Psychiatry. 2001;71:542-545. 4. Semple PL, Jane JA Jr, Laws ER Jr. Clinical relevance of precipitating factors in pituitary apoplexy. Neurosurgery. 2007;61:956-962. 5. Wakai S, Fukushima T, Teramoto A, Sano K. Pituitary apoplexy: its incidence and clinical significance. J Neurosurg. 1981;55:187-193. 6. Mohr G, Hardy J. Hemorrhage, necrosis, and apoplexy in pituitary adenomas. Surg Neurol. 1982;18:181-189.
7. Randeva HS, Schoebel J, Byrne J, Esiri M, Adams CB, Wass JA. Classical pituitary apoplexy: clinical features, management and outcome. Clin Endocrinol (Oxf). 1999; 51:181-188. 8. Ayuk J, McGregor EJ, Mitchell RD, Gittoes NJ. Acute management of pituitary apoplexy-surgery or conservative management? Clin Endocrinol (Oxf). 2004;61:747-752. 9. Sibal L, Ball SG, Connolly V, et al. Pituitary apoplexy: a review of clinical presentation, management and outcome in 45 cases. Pituitary. 2004;7:157-163. 10. Dubuisson AS, Beckers A, Stevenaert AD. Classical pituitary tumor apoplexy: clinical features, management and outcomes in a series of 24 patients. Clin Neurol Neurosurg. 2007;109:63-70. 11. Liu ZH, Chang CN, Pai PC, et al. Clinical features and surgical outcome of clinical and subclinical pituitary apoplexy. J Clin Neurosci. 2010;17:694-699. 12. Möller-Goede DI, Brändle M, Landau K, Bernays RL, Schmid C. Pituitary apoplexy: re-evaluation of risk factors for bleeding into pituitary adenomas and impact on outcome. Eur J Endocrinol. 2011;164:39-43. 13. Bujawansa S, Thondam SK, Steele C, et al. Presentation, management and outcomes in acute pituitary apoplexy: a large, single-center experience from the United Kingdom. Clin Endocrinol (Oxf). 2014;80:419-424. 14. Nielsen EH, Lindholm J, Bjerre P, et al. Frequent occurrence of pituitary apoplexy in patients with non-functioning pituitary adenoma. Clin Endocrinol (Oxf). 2006;64: 319-322. 15. Fernández-Balsells MM, Murad MH, Barwise A, et al. Natural history of nonfunctioning pituitary adenomas and incidentalomas: a systematic review and metaanalysis. J Clin Endocrinol Metab. 2011;96:905-912. 16. Jeffcoat WJ, Birch CR. Pituitary apoplexy in small pituitary tumors. J Neurol Neurosurg Psychiatry. 1986;49: 1077-1078. 17. Mou C, Han T, Zhao H, Wang S, Qu Y. Clinical features and immunohistochemical changes in pituitary apoplexy. J Clin Neurosci. 2009;16:64-68. 18. Cardoso ER, Peterson EW. Pituitary apoplexy: A review. Neurosurgery. 1984;14:363-373. 19. de Heide LJ, van Tol KM, Doorenbos B. Pituitary apoplexy presenting during pregnancy. Neth J Med. 2004;62: 393-396. 20. Battacharyya A, Tymms DJ, Naqvi M. Asymptomatic pituitary apoplexy during aortocoronary bypass surgery. Int J Clin Pract. 1999;53:394-395. 21. Khandelwal M, Chhabra A, Krishnan S. Pituitary apoplexy following bilateral total knee arthroplasty. J Postgrad Med. 2005;51:155-156. 22. Oo MM, Krishna AY, Bonavita GJ, Rutecki GW. Heparin therapy for myocardial infarction: an unusual trigger for pituitary apoplexy. Am J Med Sci. 1997;314:351-353. 23. Fuchs S, Beeri R, Hasin Y, Weiss AT, Gotsman MS, Zahger D. Pituitary apoplexy as the first manifestation of pituitary adenomas following thrombolytic and antithrombotic therapy. Am J Cardiol. 1998;81:110-111. 24. Uchiyama H, Nishizawa S, Satoh A, Yokoyama T, Uemura K. Post-traumatic pituitary apoplexy: two case reports. Neurol Med Chir (Tokyo). 1999;39:36-39. 25. Sobrinho LG, Nunes MC, Calhaz-Jorge C, Mauricio JC, Santos MA. Effect of treatment with bromocriptine on the size and activity of prolactin-producing pituitary tumors. Acta Endocrinol (Copenh). 1981;96:24-29.
1280 Pituitary Apoplexy in Nonfunctioning Pituitary Adenomas, Endocr Pract. 2014;20(No. 12) 26. Pinto G, Zerah M, Trivin C, Brauner R. Pituitary apoplexy in an adolescent with prolactin-secreting adenoma. Horm Res. 1998;50:38-41. 27. Knoepfelmacher M, Gomes MC, Melo ME, Mendonca BB. Pituitary apoplexy during therapy with cabergoline in an adolescent male with prolactin-secreting macroadenoma. Pituitary. 2004;7:83-87. 28. Balarini Lima GA, Machado Ede O, Dos Santos Silva MC, Filho PN, Gadelha MR. Pituitary apoplexy during treatment of cystic macroprolactinomas with cabergoline. Pituitary. 2008;11:287-292. 29. Pivonello R, Matrone C, Filippella M, et al. Dopamine receptor expression and function in clinically non-functioning pituitary tumors: comparison with the effectiveness of
cabergoline treatment. J Clin Endocrinol Metab. 2004;89: 1674-1683. 30. García EC, Naves LA, Silva AO, de Castro LF, Casulari LA, Azevedo MF. Short-term treatment with cabergoline can lead to tumor shrinkage in patients with nonfunctioning pituitary adenomas. Pituitary. 2013;16:189-194. 31. Kontogeorgos G, Horvath E, Kovacs K, et al. Morphologic changes of prolactin-producing pituitary adenomas after short treatment with dopamine agonists. Acta Neuropathol. 2006;111:46-52. 32. Pal A, Capatina C, Tenreiro AP, et al. Pituitary apoplexy in non-functioning pituitary adenomas: long-term follow up is important because of significant numbers of tumor recurrences. Clin Endocrinol (Oxf). 2011;75:501-504.
