Cerebrospinal Fluid Hormone Concentration in the Evaluation of Pituitary Tumors RICHARD M. JORDAN,

M.D.; JOHN W. KENDALL,

M.D.; J. LAIRD SEAICH,

M.D.;

JOHN P. ALLEN, M.D.; C. ALVIN PAULSEN, M.D., F.A.C.P.; CHARLES W. KERBER, M.D.;

and

WILLARD P. VANDERLAAN, M.D.; Portland, Oregon; and Seattle, Washington

Cerebrospinal fluid (CSF) concentrations of corticotropin, growth hormone, thyrotropin, prolactin, luteinizing hormone, and follicle stimulating hormone were measured in 28 patients with various neurologic disorders, in 49 patients with pituitary tumors of whom 22 had suprasellar extension, and in 6 patients with craniopharyngiomas. With the exception of 1 patient with pseudotumor cerebri, CSF adenohypophyseal hormone concentrations were low in patients with neurologic disease and in patients with pituitary tumor without suprasellar extension. In marked contrast, 21 of 22 patients with suprasellar extension of a pituitary tumor and 2 of 6 patients with a craniopharyngioma had elevations of one or more CSF adenohypophyseal hormones. Posttreatment CSF adenohypophyseal hormone levels fell from previously elevated levels in 4 of 5 patients. These data suggest that an elevated CSF adenohypophyseal hormone concentration is a sensitive indicator of suprasellar extension of a pituitary tumor, and posttreatment measurements are useful in determining efficacy of therapy.

INFORMATION concerning the size of a pituitary tumor is critical for selecting an appropriate treatment modality. Suprasellar extension of a pituitary tumor, in general, precludes treatment with heavy particle irradiation ( 1 , 2 ) , stereotactic isotope implantation ( 3 ) , and cryohypophysectomy ( 4 ) . In addition, the presence of suprasellar extension can modify the surgical approach chosen for tumor removal (5, 6 ) . The inaccessability of the pituitary gland, however, has limited the means of detecting suprasellar extension to pneumoencephalography and visual field examination. At present, the pneumoencephalogram is the most accurate and sensitive means to diagnose suprasellar extension; however, the patient is exposed to a painful and potentially dangerous procedure ( 7 ) . Visual field examination, although painless and noninvasive, can be normal in the presence of significant suprasellar extension ( 8 ) . Plasma hormone levels do not distinguish patients with • From the Research Service, Portland Veterans Administration Hospital; and the Departments of Medicine and Radiology, University of Oregon Health Sciences Center; Portland, Oregon; and the U.S. Public Health Service Hospital, University of Washington School of Medicine; Seattle, Washineton.

suprasellar extension from those without suprasellar extension; however, recent reports of a small number of patients have suggested that cerebrospinal fluid (CSF) adenohypophyseal hormone concentrations are unusually high when there is coexisting suprasellar extension of a pituitary tumor (9-13). These observations encouraged us to explore the possible diagnostic significance of adenohypophyseal hormones in the CSF of patients with pituitary tumors. We have measured CSF concentrations of anterior pituitary hormones in patients with pituitary tumors, craniopharyngiomas, and neurologic disorders. The findings indicate that only when a pituitary tumor extends beyond the diaphragma sellae are elevated levels of adenohypophyseal hormones found in the CSF. In addition, successful therapy of a pituitary tumor with suprasellar extension results in a fall of previously elevated CSF adenohypophyseal hormone concentrations. Patients Eighty-three patients undergoing a pneumoencephalographic examination for pituitary or neurologic disease were studied. Of these, 28 had suspected neurologic disease without known endocrine dysfunction. Forty-nine of the patients were studied because of a suspected pituitary tumor, and all except 2 had enlargement of the sella turcica. Twenty-seven of the patients with a suspected pituitary mass lesion had pituitary tumors without suprasellar extension. The presence of a pituitary tumor in these 27 patients was determined either by surgery, clinical and hormonal evidence of pituitary hormone hypersecretion (acromegaly and Nelson's syndrome), or adenohypophyseal hormone deficiencies. Twenty-two patients had suprasellar extension of a pituitary tumor, and all except 2 were verified surgically. Six patients had craniopharnygiomas, all of which were verified by surgery. Methods and Materials CSF HORMONE MEASUREMENT

Virtually all CSF specimens were obtained as a byproduct of a pneumoencephalographic examination. Specimens were obtained at the beginning of the pneumoencephalogram with a plastic syringe and aspirated through polyethylene tubing. All samples studied were clear and colorless. Microscopic examination of CSF specimens from all patients with suprasellar extension were found to be virtually free of erythrocytes. Both CSF and blood specimens were immediately chilled in an ice bath. The blood was centrifuged at 4 °C within 1 hour of collection; the plasma was separated, and both plasma and CSF were frozen until the time of radioimmunoassay.

Annals of Internal Medicine 85:49-55, 1976

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49

Figure 1. CSF adenohypophyseal hormone concentrations in patients with various neurologic disorders (A) are compared to patients with pituitary tumor without suprasellar extension ( O ) . No difference between the two groups is evident. A patient with pseudotumor cerebri, hyperprolactinemia, and elevated levels of CSF prolactin and luteinizing hormone (LH) ( • ) is shown with patients with nonendocrine disease, although an endocrine disorder and a possible suprasellar tumor are present. TSH = thyroid stimulating hormone; LH = luteinizing hormone; FSH = follicle stimulating hormone; 2nd IRP = The Second International Reference Preparation. LER 907 is the designation given to the crude pituitary extract distributed for standardization by the National Pituitary Agency.

Corticotropin (ACTH), growth hormone, prolactin, thyrotropin (TSH), luteinizing hormone (LH), and follicle stimulating hormone (FSH) levels were determined by radioimmunoassay. The method of ACTH determination has been previously described (14). The sensitivity limit of this assay was 10 pg/ml. Growth hormone was determined with a double antibody system modified from the method of Roth and co-workers (15). The sensitivity limit was 0.2 ng/ml. The TSH value was determined by double antibody modified from the method of Odell, Wilber, and Paul (16). The sensitivity limit was 0.25 fiU/mh Prolactin was measured by the double antibody method of Sinha and co-workers (17). The sensitivity limit was 2 ng/ml. The LH value was measured by the double antibody radioimmunoassay of Morgan and Lazarow as adapted by Midgely for LH (18). The sensitivity limit was 1.0 mlU 2nd IRP/ml. The Second International Reference Preparation (2nd IRP) was used as a standard. The FSH value was measured by the radioimmunoassay technique of Midgely (19). The sensitivity limit was 25 rn/xg LER 907/ml. LER 907 is the designation given to the crude pituitary extract distributed by the National Pituitary Agency. The LH and FSH determinations were done by Dr. Alvin Paulsen without knowledge of the patients' diagnoses after plasma and CSF specimens were shipped on dry ice to his laboratory. RECOVERY OF ADENOHYPOPHYSEAL HORMONES FROM CSF

The radioimmunoassays used were initially established for plasma rather than CSF; therefore, the validity of using the assays for CSF hormones was examined. Recovery of hormones added to CSF was checked for all six adenohypophyseal hormones and was expressed as the percent of recovery relative to the recovery from plasma. The findings were as follows: ACTH, 100%; growth hormone, 94%; prolactin, 108%; TSH, 102%; LH, 100%; and FSH, 100%. PNEUMOENCEPHALOGRAPHY

The extent of pituitary enlargement in patients with pituitary tumors was assessed by pneumoencephalogram. A neuroradiologist with no knowledge of hormone assay results diagnosed suprasellar extension of a pituitary tumor. Suprasellar extension was defined as extension of a pituitary tumor above a line connecting the superior aspect of the posterior clinoid processes with the posterior ridge of sphenoid. PREPARATION OF

125

I-ACTH

A patient with an ACTH-secreting chromophobe adenoma that developed after bilateral adrenalectomy (Nelson's syndrome) received 125I-ACTH intravenously. Informed consent was obtained in accordance with the Helsinki conference. The ahACTH (donated by the National Pituitary Agency, Bethesda, Maryland) was iodinated and purified as previously described (14). One microcurie of 125I-ACTH was reconstituted in 3 ml of saline and autoclaved at 132.2 °C [270 °F] for 30 minutes. 50

An aliquot of the labeled hormone was adsorbed with charcoal and yielded 95% recovery of radioactivity, providing evidence that the 125I was still bound to the ACTH. Previous data have shown that ACTH remains biologically and immunologically stable after similar treatment (20, 21). The preparation was injected intravenously for 1 minute with a plastic syringe approximately 2 hours after preparation, and samples of plasma and CSF were taken every 10 to 15 minutes for 60 minutes. Results CSF HORMONE CONCENTRATIONS IN NONENDOCRINE PATIENTS

The CSF adenohypophyseal hormone concentrations of 27 patients without known endocrine disease (control population) who underwent pneumoencephalography are shown in Figure 1. All CSF hormone levels were found to be low. Brain tumors were diagnosed in 3 patients, headaches in 2, polyarteritis in 2, seizure disorder in 2, hydrocephalus in 2, idiopathic cerebral atrophy in 2, multiple sclerosis in 2, metastatic carcinoma to brain in 2, Alzheimer's disease in 2, and neurofibromatosis, cerebrovascular disease, subdural hematoma, ataxia, and others in 4. CSF ADENOHYPOPHYSEAL

HORMONE CONCENTRATION

IN

PATIENTS WITH PITUITARY TUMORS

The CSF adenohypophyseal hormone concentrations were determined in 49 patients with pituitary tumors. The CSF adenohypophyseal hormone levels in 27 patients without suprasellar extension of a pituitary tumor are compared with the levels in the 27 patients of the control population in Figure 1. The CSF hormone concentrations of patients without suprasellar extension did not differ significantly from the control population. One acromegalic patient with a chromophobe adenoma without suprasellar extension had a coexisting "empty sella." Adenohypophyseal hormone levels in this patient were also low, although CSF LH and CSF FSH concentrations were not measured. A patient with pseudotumor cerebri had a plasma prolactin of 89 ng/ml with a CSF prolactin of 17 ng/ml. The CSF LH was also elevated to 4 mlU 2nd IRP/ml. The significance of elevated CSF prolactin and LH in this patient is not known; however, suprasellar calcifications were noted on skull films, raising the possibility that the patient could have a suprasellar tumor not detected by pneumoencephalography.

July 1976 • Annals of Internal Medicine • Volume 85 • Number 1

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Twenty-two patients had suprasellar extension of a pituitary tumor. Clinical and endocrine data of these patients are included in Table 1. The CSF adenohypophyseal hormone concentrations of the 22 patients are shown in Figure 2, with the range of CSF adenohypophyseal hormones in the control population and in patients without suprasellar extension of a pituitary tumor represented by the shaded area. All except 1 of the patients with suprasellar extension had definite elevations of one or more CSF adenohypophyseal hormone concentrations when compared with the control population and patients with pituitary tumors without suprasellar extension. Thirteen patients had more than one hormone present in CSF in elevated concentrations, and 3 patients had four hormones in elevated CSF concentrations. Prolactin, LH, and FSH were the most commonly elevated hormones in the CSF. Increased

LH CSF and FSH CSF concentrations occurred together in 9 patients. Markedly elevated CSF prolactin concentrations were seen in 7 patients with suprasellar extension of a chromophobe adenoma. All 3 patients with Nelson's syndrome and suprasellar extension had strikingly elevated CSF ACTH levels. The patient without a clear elevation of any CSF adenohypophyseal hormone level had suprasellar extension of a cystic pituitary tumor and panhypopituitarism. Considered separately are six patients with craniopharyngiomas and suprasellar extension. The CSF adenohypophyseal hormone concentrations were elevated in only two patients, one with an elevated CSF prolactin concentration and the other with a slightly elevated CSF FSH level (Figure 2 ) . Although no systematic study of CSF protein concentra-

Table 1. Clinical and Pathologic Date of 22 Patients with Pituitary Tumor with Suprasellar Extension*

Patient

Age

Sex

Pathology

A

yrs 67

F

B

65

F

C

24

F

D

51

F

E F

28 39

F M

G

25

F

Chromophobe adenoma Advanced field constriction without localization Chromophobe adenoma Bitemporal hemianopia (Nelson's syndrome) Chromophobe adenoma Early bitemporal (Nelson's syndrome) hemianopia Chromophobe adenoma Bitemporal hemianopia (Nelson's syndrome) Chromophobe adenoma Bitemporal hemianopia Peripituitary epidermoid Bitemporal hemianopia cyst Chromophobe adenoma Normal visual fields

H

19

M

Chromophobe adenoma Normal visual fields

Prolactin, LH, FSH

I J

36 67

F F

Bitemporal hemianopia Normal visual fields

Prolactin, LH, FSH LH, FSH

K L

39 58

F M

Chromophobe adenoma Eosinophilic adenoma (acromegaly) Chromophobe adenoma Chromophobe adenoma

Bitemporal hemianopia Bitemporal hemianopia

Prolactin, LH, FSH Prolactin

M

59

M

Bitemporal hemianopia

N

15

M

Eosinophilic adenoma (acromegaly) Embryonal cell carcinoma

Growth hormone, LH, FSH, TSH LH, ACTH, prolactin

O

62

F

P

46

F

Q

81

M

R

26

M

S T

26 65

F M

U

55

V

38

Pituitary epidermoid cyst Presumed chromophobe adenoma Presumed chromophobe adenoma Chromophobe adenoma

Visual Fields

Bitemporal field hemianopia

Elevated CSF Hormone

Endocrine Data

FSH

Postmenopausal with low plasma LH

ACTH

Bilateral adrenalectomy

ACTH, FSH, LH, prolactin Bilateral adrenalectomy ACTH

Bilateral adrenalectomy

Prolactin, LH, FSH, TSH TSH, LH, FSH

Amenorrhea 1° Hypothyroidism, 2° hypocortisolism Galactorrhea, amenorrhea with low LH, FSH 2° Hypogonadism, normal pneumoencephalogram Amenorrhea with low LH, FSH No deficiencies!

Prolactin, growth hormone

No deficiencies f Previous radiation therapy, no deficiencies t Low testosterone level, low LH, FSH 2° Hypothyroidism, 2° hypocortisolism, elevated urinary estrogens, galactorrhea Panhypopituitarism

Normal visual field

Borderline elevated LH, FSH Prolactin

Normal visual field

Prolactin, LH, FSH

No deficiencies f

Bitemporal hemianopia

Prolactin, LH LH Prolactin, LH

M

Chromophobe adenoma Normal visual field Chromophobe adenoma Blind right eye, temporal hemianopia in left eye Chromophobe adenoma Bitemporal hemianopia

LH

F

Chromophobe adenoma Bitemporal hemianopia

Prolactin

No deficiencies t, testosterone determination not performed Amenorrhea 2° Hypothyroidism, 2° hypocortisolism, 2° hypogonadism No deficiencies, testosterone determination not performed Amenorrhea, galactorrhea

Bitemporal hemianopia

No deficiencies f

t Patients without deficiencies had normal circulating levels of thyroid hormone, normal basal levels of urinary 17-hydroxy corticosteroids, and normal testosterone levels or normal menstrual periods. Patient J had LH and FSH concentrations in the postmenopausal range. Not all patients with an elevated plasma prolactin level had galactorrhea. * LH = luteinizing hormone; FSH = follicle stimulating hormone; TSH = thyroid stimulating hormone. Jordan et al. • Pituitary Tumors

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51

Figure 2. CSF adenohypophyseal hormone concentrations in patients with pituitary tumor with suprasellar extension (O) and craniopharyngiomas (A). Range of CSF adenohypophyseal hormones in patients with neurologic disorders (control population) and pituitary tumor patients without suprasellar extension are represented by the shaded area. TSH = thyroid stimulating hormone; LH = luteinizing hormone; FSH = foMicle stimulating hormone; 2nd IRP = The Second International Reference Preparation. LER 907 is the designation given to the crude pituitary extract distributed for standardization by the National Pituitary Agency.

tion was made, several patients with suprasellar extension had values within the normal range (15 to 45 m g / d l ) . The observation that CSF protein is an unreliable indicator of suprasellar extension has been previously reported by Linfoot and co-workers ( 9 ) . MECHANISM OF HORMONE ENTRY INTO CSF

Plasma and CSF hormone levels were compared in selected patients with pituitary tumor with and without suprasellar extension (Figure 3). Patients with markedly elevated plasma hormone levels but without suprasellar extension had low CSF hormone concentrations. This was true of all six adenohypophyseal hormones. This finding suggests that the blood-CSF barrier is intact in patients without suprasellar extension. The CSF hormone concentrations in patients with suprasellar extension were not absolutely dependent on plasma hormone levels and were found in concentrations high, approximately equal, or lower than plasma hormone levels. High CSF hormone concentrations were, however, frequently associated with high plasma hormone levels; therefore, a direct test of the integrity of the blood-CSF barrier in the presence of suprasellar extension was conducted in a patient with Nelson's syndrome. This patient had suprasellar extension of an ACTH-secreting chromophobe adenoma, and the CSF ACTH level was 3100 pg/ml. One microcurie of 125 I was given intravenously for 1 minute, and simultaneous

blood and CSF specimens were obtained at 10- and 15minute intervals for 60 minutes and measured for radioactivity (Figure 4 ) . Despite high blood levels of radioactivity, no radioactivity appeared in the CSF by the end of 1 hour, suggesting that the blood-CSF barrier is intact even with suprasellar extension. This laboratory has previously shown that CSF ACTH concentration in a normal person was low after a 48-hour ACTH infusion that produced a plasma ACTH concentration of greater than 10 000 pg/ml (14). The apparent stabilization of plasma radioactivity at 20 minutes after injection of 125 I-ACTH could reflect the fact that fragments of ACTH both biologically and immunologically inactive exist in plasma up to 60 minutes after administration. POSTTREATMENT CSF HORMONE CONCENTRATIONS

Posttreatment CSF hormone concentrations have been measured in five patients with suprasellar extension (Table 2 ) . The CSF specimens for hormone determination were obtained 3 months to 2 years after therapy. In each case, treatment consisted of surgery and postoperative irradiation. Previously elevated levels of prolactin and TSH became undetectable in Patients E and F. The CSF hormone levels in Patients M and N, although not normal, have decreased, suggesting partial improvement. The CSF ACTH levels in Patient B were not significantly lowered. Although this patient is clinically stable without further

Figure 3. A comparison of plasma and CSF adenohypophyseal hormone concentrations in patients with and without suprasellar extension. The lines connect CSF and plasma values of individual patients with suprasellar extension. Shaded area shows normal plasma hormone concentrations. TSH = thyroid stimulating hormone; LH = luteinizing hormone; FSH = follicle stimulating hormone; 2nd IRP = The Second International Reference Preparation. LER 907 is the designation given to the crude pituitary extract distributed for standardization by the National Pituitary Agency. 52

July 1976 • Annals of Internal Medicine • Volume 85 • Number 1

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visual field deficit, she presumably still has tumor above the diaphragma sellae. Discussion

The results show that, in the normal person, there is a blood-CSF barrier and a "pituitary-CSF" barrier for adenohypophyseal hormones. Low concentrations of anterior pituitary hormones were found in CSF in various neurologic disorders and pituitary tumors without suprasellar extension (Figure 1). Even in conditions with markedly elevated plasma adenohypophyseal hormone levels such as Nelson's syndrome, acromegaly, hyperprolactinemia, primary hypothyroidism, and postmenopausal hypergonadotropinism, the CSF adenohypophyseal hormone levels were low if there was no suprasellar extension of a pituitary tumor. Low CSF pituitary hormone concentrations are not surprising in view of the large size and lipid-insoluble nature of these molecules, since, in general, such characteristics favor exclusion from CSF (22). In marked contrast, patients with suprasellar extension of a pituitary tumor almost always have an elevated CSF concentration of one or more adenohypophyseal hormones (Figure 2 ) . The explanation for the presence of adenohypophyseal hormones in CSF when a pituitary tumor has extended beyond the diaphragma sellae is uncertain, but a breakdown in the blood-CSF barrier seems unlikely. Evidence against this means of entry is the low CSF hormone levels with elevated plasma hormone levels in patients with pituitary tumors without suprasellar extension (Figure 3). In patients with suprasellar extension, the CSF hormone levels are not closely correlated with plasma hormone concentrations; however, a high CSF hormone level is not unusual with a high plasma hormone level. Because of these findings, a direct test of the blood-CSF barrier was conducted with intravenous administration of radiolabeled ACTH to

Figure 4. Plasma and CSF radioactivity after intravenous administration of 125I-ACTH to a patient with suprasellar extension of an ACTHsecreting chromophobe adenoma. Radioactivity was present in plasma but not detectable in CSF throughout the study.

Table 2. Pretreatment and Posttreatment CSF Adenohypophyseal Hormone Concentrations in Patients with Suprasellar Extension*

Patient

Hormone

Pretreatment

Posttreatment

E

Prolactin TSH TSH Growth hormone LH ACTH

35 ng/ml 8 /zU/ml 10 ,uU/ml 12 ng/ml

Cerebrospinal fluid hormone concentration in the evaluation of pituitary tumors.

Cerebrospinal Fluid Hormone Concentration in the Evaluation of Pituitary Tumors RICHARD M. JORDAN, M.D.; JOHN W. KENDALL, M.D.; J. LAIRD SEAICH, M...
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