0021-972X/00/$03.00/0 Vol. 85, No. 5 The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright 2000 by The Endocrine Society The Dominant Role of Increased Intrasellar Pressure in the Pathogenesis of Hypopituitarism, Hyperprolactinemia, and Headaches in Patients with Pituitary Adenomas* BAHA M. ARAFAH, DANIELLE PRUNTY, JUAN YBARRA, MARY L. HLAVIN, AND WARREN R. SELMAN Division of Clinical and Molecular Endocrinology (B.M.A., J.Y.) and Department of Neurological Surgery (D.P., M.L.H., W.R.S.), Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio 44106 ABSTRACT Mild hyperprolactinemia frequently accompanies the hypopituitarism seen in patients with pituitary macroadenomas that do not secrete PRL. Recent data suggested that the hypopituitarism and mild hyperprolactinemia in this setting are largely due to compression of pituitary stalk and portal vessels. Headaches (HAs) are frequently seen in patients with large adenomas and at times in those with microadenomas. Because the walls of the sella turcica are relatively rigid, we postulate that tumor growth within the sella increases intrasellar pressure (ISP), which in turn impairs portal blood flow, resulting in mild hyperprolactinemia and hypopituitarism. We also postulate that increased mean ISP (MISP) contributes to the development of HAs. Normal MISP is not known but is unlikely to exceed normal intracranial pressure of less than 10 15 mm Hg. We determined MISP in 49 patients who had transsphenoidal surgery for pituitary adenomas. MISP was measured using a commonly available intracranial monitoring kit where a fiberoptic transducer was inserted through a 2-mm dural incision at the time of adenomectomy. Patients with deficient FSH, LH, ACTH, or TSH secretion were considered hypopituitary. Data on serum PRL levels were included for analysis only in patients whose adenomas had negative immunostaining for the hormone. MISP measurements ranged from 7 56 mm Hg, with a mean ( SD) of 28.8 13.5 and a median of 26 mm Hg. The pressure measurements PHYSIOLOGIC secretion of pituitary hormones depends on the integrity of the hypothalamus, portal vessels, and the hormone-secreting cells of the anterior hypophysis. Portal vessels have a profound influence on pituitary hormone secretion. Neurohormones synthesized and secreted by the hypothalamus are released and transported to the anterior pituitary primarily through the portal vessels. In addition to their role in transporting hypothalamic-releasing and -inhibitory factors, portal vessels are also important in providing blood supply to anterior pituitary cells. Studies Received October 18, 1999. Revision received January 31, 2000. Accepted February 10, 2000. Address correspondence and requests for reprints to: Baha M. Arafah, M.D., Division of Clinical and Molecular Endocrinology, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, Ohio 44106. * This work was conducted in part on the Clinical Research Center and was supported by a grant to the Clinical Research Center from the General Clinical Research Center. were higher in patients with hypopituitarism than in those with normal pituitary function (P 4.6013 10 6 ). Patients presenting with HAs had higher MISP than those who did not (P 5.44 10 7 ), regardless of their pituitary function or tumor sizes. PRL levels correlated positively with MISP values (r 0.715, P 0.0001). Tumor size did not correlate with MISP or PRL levels. The findings of increased MISP in hypopituitary patients and the documented correlation with PRL levels, suggest that ISP is a major mechanism involved in the pathogenesis of hypopituitarism and hyperprolactinemia. Similarly, the increased MISP in patients with HAs, irrespective of tumor size or pituitary function, suggest that increased ISP is a major mechanism involved in the pathogenesis of this symptom. The data support the hypothesis that in patients with pituitary adenomas increased ISP is a major mechanism contributing to the development of hyperprolactinemia, hypopituitarism, and HAs. Increased ISP in these patients leads to compression of the portal vessels and the associated interruption of the delivery of hypothalamic hormones to the anterior pituitary. This would explain the reversibility of pituitary function observed in most patients after adenomectomy. However, increased ISP may also lead to decreased blood supply, resulting in ischemic necrosis in some regions of the pituitary. The latter could limit potential recovery of pituitary function after adenomectomy. (J Clin Endocrinol Metab 85: 1789 1793, 2000) have documented that, under physiologic conditions, the majority of blood supply to the anterior pituitary comes through the portal vessels. Interruption of the pituitary stalk or mechanical compression of the portal vessels would cause diminished hypothalamic control over pituitary hormone secretion, leading to hyperprolactinemia and deficiency in the secretion of all other pituitary hormones. Studies conducted in experimental animals (1, 2), as well as in humans (3 6), have demonstrated a classical pattern of change in pituitary hormone secretion when the pituitary stalk is sectioned or compressed by mass lesions such as a large pituitary adenoma (3), a carotid artery aneurysm (4), a meningioma (5), or a craniopharyngioma (6). Patients with pituitary stalk compression demonstrate mild hyperprolactinemia and loss of other pituitary hormone secretion (1 6). Likewise, patients with large pituitary adenomas often present with similar clinical and biochemical features consisting of hypopituitarism and mild hyperprolactinemia (3, 7). Based on detailed endocrine dynamic stud- 1789
1790 ARAFAH ET AL. JCE&M 2000 Vol 85 No 5 ies, we postulated that mechanical compression of the pituitary stalk and portal vessels by the expanding tumor was the predominant mechanism causing pituitary dysfunction in this setting (3, 8, 9). Studies done in primates using a Doppler probe showed that blood flow through portal vessels was significantly reduced by transient elevations in venous pressure (10). Similar measurements are not available in humans. Perfusion pressure to anterior pituitary cells depends on portal venous pressure, as well as the local tissue pressure within the sella or intrasellar pressure (ISP). Because the lateral walls of the sella are relatively rigid, it is anticipated that tumor growth within the sella is likely to result in increased ISP over a period of time. Furthermore, because normal anterior pituitary cells depend on portal vessels as a source of blood supply and also as a transport mechanism for hypothalamic regulatory hormones, it would be reasonable to postulate that alterations in ISP would influence pituitary hormone secretion. One particular setting in which this hypothesis can be tested is that of patients with pituitary macroadenomas and hypopituitarism. Earlier studies showed that ISP in patients with adenomas is increased (11, 12). Published studies, however, failed to thoroughly investigate the relationship of increased pressure to pituitary function. Headache (HA) is a frequent additional clinical manifestation of pituitary macroadenomas. The cause of HAs in this setting is not clear, although it has been postulated to be secondary to stretching of the meninges by the expanding tumor. The role of increased ISP in the pathogenesis of HAs in these patients has not been previously investigated. The current study investigates the role of ISP in the pathogenesis of HAs, hypopituitarism, and the associated mild hyperprolactinemia in patients with pituitary adenomas. We postulate that continued pituitary tumor growth leads to gradual increase in ISP. The rise in ISP decreases blood flow in portal vessels and causes diminished delivery of hypothalamic-releasing factors to anterior pituitary cells, which in turn results in mild to moderate hyperprolactinemia and hypopituitarism. We also postulate that increased ISP is commonly associated with the development of HAs and hypopituitarism in patients with adenomas. The study provides data supporting the central role of increased ISP in these processes. Patients and Methods The study included 49 consecutive patients with pituitary adenomas who had transsphenoidal surgery at our institution between 1993 and 1997 and in whom measurement of ISP was performed. The 49 patients had transsphenoidal surgery for functioning or nonfunctioning adenomas of various sizes and variable degrees of associated impairment in pituitary function. Some of the 49 patients presented in the current study were included in two recent reports that addressed PRL dynamics and the recovery of pituitary-adrenal function following adenomectomy (8, 9). The present report focuses on ISP measurements in patients at the time of surgery, and, therefore, data pertinent to pituitary function will be presented only briefly. Hypopituitarism was defined as partial or complete loss of any of the following hypothalamic-pituitary axes: gonadal, adrenal, and thyroidal (3, 8, 9). For the purposes of this report, the hypogonadism seen in patients with significant hyperprolactinemia ( 50 g/l) was not considered as a manifestation of hypopituitarism. Testing procedures and definitions used at our institution in the evaluation of hypothalamicpituitary function have been described in detail (3, 8, 9). All patients were ambulatory and, except for those with hypopituitarism, had no chronic diseases or illnesses. Two patients had dietcontrolled diabetes mellitus, and four patients had mild and uncomplicated hypertension. At presentation, none of the patients was on hormone replacement or was receiving medications known to influence PRL levels or pituitary-thyroidal, adrenal, or gonadal functions. Patients were specifically questioned as to whether they had new onset HAs over the 5 yr preceding the diagnosis of pituitary adenoma. For the purposes of this study, patients were considered to have HAs when they had more than two episodes per week requiring analgesics for relief. As reported previously (8, 13), patients with normal preoperative pituitary-adrenal function (n 38) were not given glucocorticoids at any time before, during, or after surgery. The latter group included 16 patients without hypopituitarism and 22 of the 33 patients with partial hypopituitarism, in whom adrenal function was normal. The study was approved by the Institutional Review Board, and informed consent was obtained from each patient. Statistical analysis of the data was performed using oneway ANOVA, followed by the Student-Newman Keuls test and the t test. Data are shown as mean sd, unless otherwise stated. Measurement of ISP We used The OLM-Intracranial Pressure Monitoring Kit (Camino Laboratories, San Diego, CA) to determine ISP. The kit uses a fiberoptic transducer connected to a pressure monitor. The transducer is located at the tip of a catheter that is 1.3 mm in diameter. At transsphenoidal surgery, a portion of the floor of the sella was removed and an approximately 2-mm dural opening was made to allow placement of the catheter without extravasation of intrasellar contents. The tip of the transducer was then inserted into the tissues of the pituitary fossa. Thirty to 60 sec later, and after a stable waveform was obtained, mean ISP (MISP) was recorded and the transducer removed. In 15 patients measurements of MISP were repeated within a few minutes and were noted to be 2 mm Hg of the original recordings. Surgical adenomectomy was then performed using standard procedures. The wave form resembles that of an arterial pressure recording and is similar to that observed by others (11, 12). Surgical/pathological findings All 49 patients had histologically documented adenomas measuring 0.8 4.5 cm in longest dimension. Patients whose tumors were demonstrated to have PRL-positive cells on immunostaining (n 7) were included in the ISP measurement data, but were excluded from the correlation analysis of ISP and serum PRL levels. Multiple sections of adenomas resected from 16 patients included in the current study were demonstrated on immunostaining to be negative for all hormones tested (PRL, GH, TSH, FSH, LH, subunit, and ACTH). In the remaining 33 patients, some cells stained positively for PRL (n 7), GH (n 8), gonadotropin (LH, FSH, or subunit; n 14), mixed GH, and gonadotropin (n 2) and TSH (n 2). Results The characteristics of patients included in the study are shown in Table 1. Eight patients had microadenomas ( 1 cm), and the rest had large ( 1 cm) tumors. Of the 49 patients, 33 had deficiency in one to three axes, whereas 16 had no hormone deficits. TABLE 1. Characteristics of 49 patients included in the study Total number 49 Age (mean SD) 53.7 9 Sex (F/M) 25/24 No. without hormone deficit 16/49 No. with hypopituitarism 33/49 No. with one axis deficit 19/33 No. with two axes deficits 6/33 No. with three axes deficits 8/33 No. of patients with microadenomas/total 8/49
ISP, HEADACHES, AND PITUITARY TUMORS 1791 ISP measurements MISP measurements in the 49 patients ranged from 7 56 mm Hg, with a mean ( sd) of 28.8 13.5 and a median of 26 mm Hg. Although the number of patients with microadenomas (n 8) was relatively small, the latter group had statistically similar MISP measurements (18 35; 25.4 6.7 mm Hg) to those with macroadenomas (7 56; 28 14 mm Hg). As shown in Table 2, MISP measurements were significantly higher in patients with hypopituitarism (33.6 13.3 mm Hg) than in those without (19 7.3 mm Hg) pituitary hormone deficiency (P 4.6103 10 6 ). As expected, patients with hypopituitarism as a group had higher serum PRL levels, as well as larger tumor sizes, than those with intact pituitary function. Seven patients whose adenomas showed positive PRL immunostaining were excluded from the analysis of the correlation between serum PRL and MISP measurements. Serum PRL levels in the remaining 42 patients ranged from 4 41 g/l, with mean of 22.2 9.1 and a median of 22.9 g/l. As shown in Fig. 1, when data on all patients were included there was a strong positive correlation between serum PRL levels and MISP measurements (r 0.715, P 0.0001). Of interest was the fact that similar degrees of positive correlation between serum PRL levels and MISP measurements were noted when data in patients with hypopituitarism (r 0.603, P 0.001) and also in those without hypopituitarism (r 0.559, P 0.01) were analyzed separately. That is, if one looks at the data in patients without hypopituitarism, one would still appreciate a positive correlation between serum PRL levels and MISP measurements. As shown in Fig. 1, there was no significant statistical correlation between tumor size and MISP measurements in our patients, even when separated on the basis of pituitary function (i.e. with or without hypopituitarism). Of the 49 patients included in the series, 25 had HAs at presentation, whereas 24 did not. As shown in Table 3, patients who presented with HAs had higher MISP measurements than those who did not (37 12.6 vs. 19.8 7.4 mm Hg, P 5.44 10 7 ), regardless of their respective tumor sizes. Similarly significant differences in MISP measurements between patients who complained of HA and those who did not were observed when the data on hypopituitary patients were analyzed separately from those with normal pituitary function (Table 4). That is, patients who presented with HAs had higher MISP measurements than their respective counterpart, irrespective of tumor sizes or pituitary function. Furthermore, six patients had a MISP of less than 15 mm Hg and all did not have HAs on presentation. As reported previously, many patients with pituitary adenomas and hypopituitarism recover pituitary function after adenomectomy (3, 8). In the current series, 18 of the 33 patients with hypopituitarism recovered partially or completely after adenomectomy. MISP measurements were slightly, but not significantly higher in the 18 patients who recovered pituitary function than in the 15 with persistent hypopituitarism (37 13.6 vs. 28.7 13.2 mm Hg, P 0.075). The current study confirms previous reports (3, 8) demonstrating that hypopituitary patients who recovered pituitary function had higher preoperative serum PRL levels than those who did not (33.5 4.9 vs. 19.8 3.8, P 8.5 10 7 ). Tumor sizes in the subgroup of patients recovering function (n 18) were similar to those who did not (2.11 0.5 vs. 2.33 0.35; P 0.248). Discussion The normal MISP in humans is not known, but is unlikely to exceed that of the intracranial pressure of less than 10 15 FIG. 1.Top, Correlation between serum PRL levels ( g/dl) and MISP (mm Hg) measurements in 42 patients with non-prl-secreting adenomas who had transsphenoidal surgery and whose adenomas stained negatively for PRL., Individual patients with hypopituitarism; asterisk, individual patients without hypopituitarism. The line drawn is the best fit for the relationship between the two with an r of 0.715 and a P 0.0001. Bottom, Correlation between tumor size (cm) and MISP (mm Hg) in 49 patients with pituitary adenomas who had transsphenoidal surgery., Patients with hypopituitarism; asterisk, patients without hypopituitarism. The line drawn is the best fit for the relationship between the two with an r of 0.08 and a P 0.5, indicating the absence of any statistical significance in the relation. TABLE 2. The range and mean SD of the MISP, serum PRL, as well as tumor sizes, in 33 patients with hypopituitarism and 16 others without deficiency who had transsphenoidal adenomectomy Patients with hypopituitarism (n 33) Patients without hypopituitarism (n 16) P value a Range Mean SD Range Mean SD MISP (mm Hg) 12 56 33.6 13.4 7 32 19 7.3 4.6013 10 6 PRL (ug/l) 13 41 25.9 8 4 20 16.6 8.1 3.11 10 5 Tumor size (cm) 1.3 4.5 2.18 0.59 0.8 3.5 1.66 0.69 0.00012 a Respective statistical differences between data of patients with and those without hypopituitarism.
1792 ARAFAH ET AL. JCE&M 2000 Vol 85 No 5 mm Hg. Although there are no specific data in the literature to demonstrate that, there are published data to support that estimate (12, 14). A study by Lees et al. (12) showed that when MISP was measured in patients with microadenomas and empty sella by inserting a needle through the dura before it was opened, the recorded ISP readings were 13.5 3mmHg. In one patient with an empty sella, a Valsalva maneuver resulted in an increase in ISP from 7 mm Hg to 14 mm Hg. Furthermore, portal vessels are under intracranial pressure before they enter the confines of the sella turcica. Collectively, these data suggest that, under normal circumstances, MISP is lower or similar to intracranial pressure. The data presented here show that MISP is generally increased in patients with pituitary adenomas. Only three of our patients had MISP measurements of less than 10 mm Hg, and all had normal pituitary function. The observed MISP measurements in our patient population are similar to those reported in previous publications, using slightly different techniques (11, 12, 14). Specifically, the median MISP in these studies ranged from 27 30 mm Hg, which is very similar to our patients median of 26 mm Hg. Even though some reports suggested that patients with hypopituitarism had higher MISP, the authors did not provide sufficiently detailed data to document that. Furthermore, in one of their studies addressing serum PRL levels (11), the authors included all patients, even those with prolactinomas and others on dopamine agonist therapy. Our study separated patients with prolactinomas from those with hyperprolactinemia seen in patients with hypopituitarism on the basis of immunocytochemistry. Our data are the first to demonstrate a powerful positive correlation between serum PRL levels and measured MISP in these patients. TABLE 3. MISP, serum PRL levels, and tumor sizes in 49 patients with pituitary adenomas who had transsphenoidal adenomectomy Patients with (n 25) Patients without (n 24) P value a No. of patients with 18/25 15/24 0.713 hypopituitarism/total MISP (mm Hg) Mean SD 37 12.6 19.8 7.4 5.44 10 7 Range 20 56 7 31 N/A Tumor size (cm) 1.94 0.59 2.1 0.76 0.23 a Statistical differences between respective data of patients with and those without. The findings of increased MISP in patients with hypopituitarism and the strong correlation with preoperative serum PRL levels suggest that high MISP is involved in the pathogenesis of hypopituitarism. Doppler measurements of portal blood flow in monkeys demonstrated that increased venous pressure resulted in decreased blood flow to the anterior pituitary (10). Similarly, a sudden rise in ISP induced during pituitary surgery in humans resulted in profound diminution of blood flow to the pituitary (14). Thus, it is reasonable to suggest that persistent increase in MISP results in decreased blood flow through portal vessels and consequently diminished delivery of hypothalamic hormones to pituitary cells. Considering the unique mechanism regulating PRL secretion relative to other pituitary hormones, it is easy to appreciate the finding of increased MISP in patients with hypopituitarism and the strong positive correlation observed between MISP and serum PRL levels. Increased MISP can also diminish perfusion pressure to the normal pituitary. The data indicate that most patients with large adenomas have MISP that were higher than systemic venous pressure. Considering the fact that portal vessels are similar in structure to peripheral veins, it is reasonable to suggest that even a minor elevation in MISP would diminish blood flow to the pituitary. In fact, it is surprising to note that with the high MISP, there was blood flowing to the pituitary tissue and there was viable pituitary tissue. The latter argument indicates that there must be additional arterial blood supply to the anterior pituitary, as was recently suggested (15). The presence of arterial blood supply can explain how viability of pituitary cells can be maintained when portal vessels are obstructed as a result of increased MISP. Thus, the increase in MISP explains the development of hypopituitarism in patients with macroadenomas and its reversibility in most, but not all individuals (8, 16). The data also explain the fact that some patients with very large adenomas had relatively low MISP and also had no significant compromise in pituitary function. It is likely that the direction in which the adenoma expands influences the potential development of changes in MISP. For example, patients with infrasellar extension have lower MISP measurements than those with parasellar extension (14). Another important factor that is likely to be involved in determining MISP is the rate of tumor growth and the ability of the walls of the sella to modulate as fast. In general, patients with rapidly growing mass lesions within the confines of the sella (e.g. apoplexy, TABLE 4. MISP (mm Hg) and tumor sizes in 33 patients with hypopituitarism and 16 others without hypopituitarism. The data on patients presenting with are shown separately and compared to that of patients without With (n 18) Patients with hypopituitarism (n 33) Without (n 15) P value a With (n 7) Patients without hypopituitarism (n 16) Without (n 9) P value b MISP (mm Hg) Mean SD 41.9 11.2 21.9 6.3 1.1 10 6 24.4 5 13.6 5.9 0.0003 Median 43 25 N/A 22 18 N/A Range 21 56 12 31 N/A 20 32 7 23 N/A Tumor size (cm) 2.18 0.42 2.23 0.7 0.406 1.82 0.7 1.3 0.5 0.062 a Statistical differences between respective data in patients with hypopituitarism (those with vs. those without ). b Statistical differences between respective data in patients without hypopituitarism (those with vs. those without ).
ISP, HEADACHES, AND PITUITARY TUMORS 1793 metastatic cancer) are more likely to have hypopituitarism than others with slowly growing tumors. The presence of mild to moderate hyperprolactinemia in most patients with macroadenomas who also had other pituitary hormone deficits clearly suggests impairment of hypothalamic regulation of normal pituitary hormones secretion. Furthermore, the observed hormonal responses to the administration of exogenous hypothalamic-releasing hormones suggest that pituitary cells are, for the most part, viable and capable of responding to natural stimuli (3, 8, 9). The changes in serum PRL levels, as well as the associated recovery of other pituitary function immediately after surgical decompression, support the postulated mechanism for hypopituitarism (8, 9). It was in these patients with hypopituitarism where the MISP measurements were high. By decompressing the sella and alleviating the increased MISP, we postulate that portal blood flow is resumed and hypothalamic control over pituitary function is regained. It was postulated that compromised blood flow to the pituitary leading to ischemic necrosis is an additional significant mechanism contributing to the pathophysiology of hypopituitarism in patients with pituitary adenomas (3, 8). It is reasonable to speculate that some patients fail to induce adequate adaptive changes to provide an increasing source of blood supply, perhaps because of rapid increase in ISP. Examples of such processes can be seen in patients with pituitary tumor apoplexy and those with metastatic cancer. The postulated decrease in blood flow could cause partial ischemic necrosis of anterior pituitary cells, particularly when MISP measurements are very high. The latter would explain why some with pituitary functions recover and others do not. HA is a common symptom reported in most, but not all, patients with pituitary macroadenomas. Although the exact pathophysiology of HAs in this setting is still poorly understood, it is felt that stretching of the meninges represents a major mechanism. The HAs reported in some patients with pituitary microadenomas are more difficult to explain. The findings of our study suggest that increased ISP plays a major role in the pathogenesis of HAs in this setting. Patients who presented with HAs were demonstrated to have higher MISP than those who did not have the symptom, regardless of their tumor size. If one looks at the data in patients with hypopituitarism alone (Table 4), one would appreciate the role of MISP in mediating HA. The MISP in patients with hypopituitarism and HAs was twice as high as those recorded in patients without HAs, despite having identical tumor sizes as well as similar degrees of hypopituitarism. Similarly, if one looks at the data in patients without hypopituitarism, one would still observe the modulating influence of increased ISP on the presence or absence of HAs. It was interesting to note that all six patients who had a MISP of less than 15 mm Hg did not have HAs on presentation. Thus, the data presented here suggest that the increased MISP is a major contributing mechanism in the pathogenesis of HAs in this patient population. In summary, the data presented here show that ISP is increased in patients with pituitary adenomas, particularly those with macroadenomas, hypopituitarism, and/or HAs. The strong correlation between serum PRL levels and ISP, regardless of the tumor size support the hypothesis that elevation of ISP is the dominant mechanism contributing to the development of mild hyperprolactinemia, hypopituitarism, and HAs in patients with pituitary adenomas. Portal blood flow is likely to be diminished in these patients, accounting for the decreased delivery of hypothalamic-releasing hormones to the anterior pituitary. Cell viability, however, is likely to be maintained in the majority of patients through increased blood supply from the arterial circulation. The availability of viable pituitary cells at the time of adenomectomy can limit the potential recovery of pituitary function postoperatively. Acknowledgments We thank all referring physicians, the staff of the Clinical Research Center, and the Neuroscience Intensive Care Unit for their efforts in caring for the patients and conducting the study. We also thank Paul Hartman and Beth Smith for their technical assistance and Robert Meyers for his help in preparing the manuscript. References 1. Vaughan L, Carmel PW, Dyrenfurth I, Frantz AG, Antunes JL, Ferin M. 1980 Section of the pituitary stalk in the Rhesus monkey. Neuroendocrinology. 30:70 75. 2. 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Lees PD, Falhbusch R, Zrinzo A, Pickard JD. 1994 Intra-sellar pituitary tissue pressure, tumor size, and endocrine status-an international comparison in 107 patients. Br J Neurosurg. 8:313 318. 13. Hout WM, Arafah BM, Salazar R, Selman WR. 1988 Evaluation of the hypothalamic-pituitary adrenal axis immediately after pituitary adenomectomy: is peri-operative steroid therapy necessary? J Clin Endocrinol Metab. 66:1208 1212. 14. Kruse A, Astrup J, Cold GE, Hansen HH. 1992 Pressure and blood flow in pituitary adenomas measured during transsphenoidal surgery. Br J Neurosurg. 6:333 342. 15. Gorczyca W, Hardy J. 1987 Arterial supply of the human anterior pituitary gland. Neurosurgery. 20:369 378. 16. Anonymous. 1991 Reversible hypopituitarism (Editorial). Lancet 337:276.