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From the Clinical Research Centers |
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
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.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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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 were higher in patients with hypopituitarism than in those with normal pituitary function (P = 4.6013 x 10-6). Patients presenting with HAs had higher MISP than those who did not (P = 5.44 x 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.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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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, 4, 5, 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, 2, 3, 4, 5, 6). Likewise, patients with large pituitary adenomas often present with similar clinical and biochemical features consisting of hypopituitarism and mild hyperpro-lactinemia (3, 7). Based on detailed endocrine dynamic studies, 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.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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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 µg/L) was not considered as a manifestation of hypopituitarism. Testing procedures and definitions used at our institution in the evaluation of hypothalamic-pituitary 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 diet-controlled 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 one-way 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).
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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. 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.
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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 x 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.
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, 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).
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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 x 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.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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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.
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, 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.
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Acknowledgments |
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Footnotes |
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Received October 18, 1999.
Revised January 31, 2000.
Accepted February 10, 2000.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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, 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.