J Neurosurg 60:985-993, 1984

Estrogen and progesterone receptors in meningiomas

DAVID W.CAHILL~M.D., NASIR BASHIRELAHI, PH.D., LOUIS W. SOLOMON, M.D.,

THOMAS DALTON, M.S., MICHAEL SALCMAN, M.D., AND THOMAS B. DUCKER, M . D .
Division of Neurological Surgery, Department of Surgery, and Department of Biochemistry, School of
Dentistry. University of Maryland Hospital Baltimore, Maryland

L,- Two-thirds of all meningiomas and four-fifths of intraspinal and sphenoidal meningiomas occur in women.
Meningiomas frequently enlarge or become symptomatic during pregnancy or during the luteal phase of the
menstrual cycle. There is an increased incidence of meningiomas in women with breast carcinoma.
In a series of 23 patients with meningiomas, the authors assayed biopsy specimens of the tumor for the
presence of estrogen (ER) and progesterone (PR) receptors, using glycerol density gradient centrifugation and
dextran-coated charcoal techniques, Significant levels of ER were found in only 17% of the patients, while
significant PR levels were detected in 39%. Only one of the 16 tumors from female patients had significant
ER levels, whereas three of the seven tumors from men had significant ER levels. Eight of the 16 tumors in
women had significant PR levels, whereas only one of the seven tumors in men had a significant PR level.
Thus, three out of four tumors with definite ER were from men, whereas eight of nine tumors with definite
PR were from women. Of the eight women whose tumors contained PR, three were premenopausal and five
postmenopausal. The single tumor with high levels of PR in the male patient was histologically atypical.
The results of this series were compared with six published series of sex steroid assays in meningiomas,
These seven series were divided into two groups: one group included two reports from the same laboratories
in France, and the other the remaining five reports. Much higher percentages of both ER- and PR-positive
tumors were reported from the French group. The authors suggest that this discrepancy may be due to the use
of preoperative glucocorticoid therapy in the series from the United States.
Since meningiomas are known to enlarge during periods when levels of circulating progestins are high, the
presence of significant quantities of PR in a high percentage of tumors may have therapeutic implications for
recurrent, malignant, or incompletely excised tumors, or for medically fragile patients. Conversely, since
meningiomas are not known to enlarge during the proliferative phase of the menstrual cycle or with exogenous
estrogen therapy, the small number of tumors positive for ER may indicate that ER lacks clinical significance.
High levels of PR found in a small group of histologically aggressive tumors in several series may indicate that
hormonal therapy may be especially useful in this difficult subset of patients.

KEY WORDS 9 nervous system tumor 9 meningioma 9 neurochemistry 9

hormone receptors estrogen 9 progesterone

T
WO-TrtmDS o f all meningiomas are reported in
women, t~ and fourth-fifths o f meningiomas
located along the sphenoid wing or within the
spinal canal are found in women. 3~'3v More than 50
years ago, Cushing and EisenhardP ~ observed that me-
ningiomas frequently become symptomatic during
pregnancy. Since that time, m a n y authors have reported
that intracranial as well as intraspinal meningiomas
frequently enlarge or become symptomatic during preg-
nancy or during the luteal phase o f the menstrual
cycle.2,4,~4,~9,24,37,38,45,48,58
Since Rand and Andler 45 first postulated in 1950 that
the symptomatic enlargement o f meningiomas during
periods of h o r m o n a l flux is secondary to engorgement
of the intratumoral vasculature, m a n y authors have
reported a similar conclusion. Others, beginning with
Weyand, et al., in 1951, 58 believed that h o r m o n a l fluc-
tuation leads to intracellular fluid retention and thus
enlargement o f the t u m o r secondary to increasing cel-
lular dimensions. Whatever the mechanism, there is no
question that pathologically verifiable enlargement does
occur during periods of hormonal flux.
Schoenberg, et al., s~ found an increased incidence o f
meningiomas a m o n g w o m e n with breast carcinoma.
Based on statistical analysis in a large group of patients,
they found that this was fhe only significant association
between a nervous system neoplasm and a primary
malignancy in another site. For almost 100 years, it has

J. Neurosurg. / Volume 60/May. 1984 985

 D. W. Cahill, et al.

TABLE 1 to endocrine therapy. 23"35 There are two predominant

Clinical data and assay results in 23 patients with hypotheses to explain the failure o f the remaining one-
meningioma* third o f receptor-rich tumors to respond. The first
proposes that some tumors are composed o f heteroge-
Case Age (yrs) Location of Assay Resultst neous cell populations and are in m a n y cases multi-
No. & Sex Tumor ER PR clonal. 7'~1'35 The assayed portion o f the mass may not
1 79, M parasagittal 0 (-) 78 (+) reflect the predominant cell type. A t u m o r in which
2 65, M parasagittal 0 (-) 6.4 (-) only a minority o f the cells are receptor-positive m a y
3 40, M parasagittal 0 (-) 0 (-) fail to respond to manipulation. Alternatively, the ER
4 72, M convexity 33.2 (+) 0 (-)
5 38, M parasagittal 19.1 (+) 0 (-) assayed in some tumors m a y be nonfunctional. In an
6 56, M convexity 11.4 (+) 0 (-) effort to establish which receptors are functional, Hor-
7 55, M convexity 0 (-) 5.9 (-) witz, et al., 20'21'36A7 proposed the concomitant assay of
8 36, F basal 0 (-) 110 (+) progesterone receptor (PR) protein. They believed that
9 46, F basal 0 (-) 31.1 (+)
10 29, F retro-orbital 0 (-) 0 (-) in the reproductive tracts o f animals "few if any pro-
11 46, F intraspinal 0 (-) 32.3 (+) gesterone effects are seen in tissues which have not first
12 77, F basal 0 (-) 129.4 (+) been prepared by estradiol. ''2~ These authors suggested
13 77, F basal 0 (-) 0 (-) that a significant a m o u n t o f assayable P R within a
14 58, F parasagittal 0 (-) 0 (-) tissue implies that the concomitantly assayed ER is
15 74, F convexity 0 (-) 0 (-)
16 56, F basal 0 (-) 0 (-) functional. In a series of 36 ER-positive tumors, Hor-
17 74, F convexity 0 (-) 1.1 (-) witz and McGuire 2~ found a 37% response to h o r m o n e
18 66, F convexity 5.9 (-) 13.1 (+) therapy a m o n g those that were PR-negative but a 70%
19 55, F basal 0 (-) 0 (-) response for those that were PR-positive.
20 58, F posteriorfossa 2.9 (-) 13.1 (+)
Receptors for androgen, estrogen, and progesterone
21 67, F parasagittal 0 (-) 72.2 (+)
22 68, F parasagittal 12.4 (+) 0 (-) have also been detected in h u m a n prostate carcinoma,
23 75, F posteriorfossa 3.4 (-) 75.1 (+) and therapy with orchiectomy, estrogens, progester-
* Cases 8 to 11 were premenopausal women, and Cases 12 to 23 ones, and anti-androgens has been successful in a ma-
were postmenopausal. jority of patients? 5 Certain forms o f leukemia have
t ER = estrogenreceptor; PR = progesteronereceptor. Assayresults cells with glucocorticoid receptors and may respond to
are given in fM/mg of cytosolic protein. An ER or PR level greater glucocorticoid therapy. 26 Estrogen receptors are fre-
than 10 fM/mg of cytosolic protein was considered to be significant
(+), while a receptor level equal to or less than that value was not sig- quently detected not only in endometrial carci-
nificant (-). noma, 13'17'18'43'44carcinoma of the cervix, 32 and carci-
n o m a of the ovary, 55 but also in tumors not limited to
women, such as renal cell carcinoma, 8 colon carci-
noma, 34 and malignant melanoma. ~5'55 A wide variety
of other benign and malignant tumors have been found
been known that some w o m e n with metastatic breast to have receptor proteins in isolated cases. 55
carcinoma m a y respond dramatically to castration. 22 Sex steroid receptors are also present in m a n y normal
However, of all w o m e n with breast carcinoma, only tissues, including brain. 3~ Magdelenat, eta[., 31 have
one-third will respond to hormonal manipulation o f demonstrated both ER and PR in a single biopsy of
any k i n d . 2223 normal h u m a n leptomeninges, from which tissue me-
In an effort to distinguish those breast tumors that ningiomas are thought to arise.
might respond to endocrine therapy from those that In this paper, we present a series o f 23 meningiomas
would not, Jensen, et al., 22 assayed the estrogen receptor assayed for both ER and P R proteins, and correlate our
(ER) protein in malignant breast tissue in 1967. Steroid results with those of other investigators.
receptors are intracytoplasmic proteins with a high
binding affinity for specific circulating hormones. The Materials and Methods
h o r m o n e diffuses or is transported into the cytoplasm
of the cell and binds to the receptor, after which the Clinical a n d B i o p s y D a t a
complex is translocated into the nucleus where it in- Twenty-three t u m o r biopsy specimens were obtained
duces the production o f specific messenger ribonucleic at surgery from 23 patients with meningiomas. The
acid molecules, which are thought to cause the observed epidemiological characteristics of the patients, as well
effect. 4~ The ER assay has become widely accepted and as the locations and histopathology of the tumors, were
is in general use throughout the United States and typical o f a large series of meningiomas. There were 16
Europe.~ 1~27.35 w o m e n and seven men in the series (Table 1). O f the
O f all primary and metastatic breast t u m o r tissues 16 women, four were premenopausal and 12 postmen-
assayed, 30% to 40% have significant amounts of ER. opausal. O f the total 23 patients, only six were under
O f these, about two-thirds will respond to hormonal 50 years of age.
manipulation. O f the 60% to 70% of tumors without O f the 23 tumors, 21 were intracranial, one was
significant a m o u n t s of ER, almost none will respond retro-orbital, and one was intraspinal (Table 2). Both

986 J. Neurosurg. / Volume 6 0 / M a y , 1984

Estrogen and progesterone receptors in meningiomas
extracranial tumors were in premenopausal women.
Among the 21 intracranial tumors, two were in the
posterior fossa. Of the 19 supratentorial tumors, six
were basal and 13 were either located at the convexity
or were parasagittal. Basal lesions included sphenoid
wing, tentorial, and olfactory groove tumors. There
were three recurrent tumors, all in males. Only one of
the three was histologically malignant. In the whole
series, 21 of the 23 tumors were typical benign menin-
giomas of the endotheliomatous, fibroblastic, or tran-
sitional type. There were no angioblastic tumors. The
remaining two lesions were both in males: one was re-
current and frankly malignant on histological grounds;
the other was primary and histologically atypical, with
mild nuclear pleomorphism and occasional mitotic
figures.
All 23 patients received 10 mg of intravenous dexa-
methasone at surgery, prior to tumor removal. In ad-
dition, 21 (91%) of the 23 patients received dexameth-
asone preoperatively, 16 to 40 mg/day for 2 to 13 days
before surgery.
Assay Procedure
Tissue Handling. Meningioma tissue obtained at
surgery was placed immediately in containers with ice-
cold normal saline. Tissue was kept at 1~ to 4~ and
any dark, burned tissue or blood clots were discarded.
The specimen was weighed and either processed im-
mediately or placed in a vial, then quick-frozen in liquid
nitrogen and stored at -70~
Buffer Preparation. Water was deionized, then dis-
tilled in glass vials. All pH values were determined using
a Coming No. 476050 combination electrode with a
Beckman No. 566002 buffer as a standard, and a Corn-
ing Model 12 pH meter.* Buffered TED (10 m M Tris,
1.5 m M EDTA (ethylenediaminetetraacetic acid), and
0.5 m M dithiothreitol); buffered T E D G 10% (TED and
10% glycerol, v/v): buffered T E D G 30% (TED and
30% glycerol, v/v) were all adjusted to a pH of 7.4 at
0~ The percentage of glycerol in each buffer solution
was checked with a Bausch and L o m b refractometer.t
Measurement of Radioactivity. A wetting agent,
Triton X-100,~ was purchased as a semireagent and
required gravity filtration through silica gel. The Triton
X-100 was mixed with scintillation-grade PPO (2,5-
diphenyloxazole), bis-MSB (p-bis-(o-methylstyryl)-ben-
zene), toluene, and double-distilled water. Tissue sam-
ples were mixed with 4 ml of scintillation cocktail and
measured in a Packard liquid scintillation spectrome-
*Corning electrode and Corning pH meter manufactured
by Corning Glass Works, Science Products, Corning, New
York: and Beckman buffer manufactured by Beckman Instru-
ments, Fullerton, California.
t Refractometer manufactured by Bausch and Lomb,
Rochester, New York.
Triton X-IO0 obtained from Peerless Chemical Co., Bal-
timore, Maryland.
J. Neurosurg. / Volume 60/May, 1984
TABLE 2
Tumor location and histological diagnosis in 23 cases of
meningioma*
Tumor Location & Histology No. of Tumors
location
retro-orbital 1
intraspinal 1
intracranial 21
posterior fossa 2
basal 6
convexityor parasagittal 13
histological diagnosis
benign fibroblastic,endotheliomatous, or 21
transitional
atypical 1
malignant 1
* Three tumors were recurrent.
ter.w Each sample was measured for 4 minutes and
allowed to equilibrate to the instrument temperature at
least 1 hour prior to measurement.
Cytosol Preparation. All procedures were per-
formed at 0 to 2~ unless otherwise stated. Fresh tissue
was minced with surgical scissors. Frozen tissue was
refrozen in liquid nitrogen, facilitating pulverization
with a h a m m e r between sheets of aluminum foil.
Buffered T E D G was added to the pulverized or minced
tissue in a ratio of about 2:1, volume to tissue weight.
Using a Polytron PT 10-35 homogenizer with a PT 10
probe, II the tissue was homogenized three times at high
speed for 5 seconds, allowing a 60-second cooling time
between each period of homogenization. The homog-
enate was centrifuged at 100,000 G for 1 hour in a
Beckman T50.1 rotor.* The supernatant fraction,
termed ~'cytosol," was carefully decanted off the pellet.
The protein content of the cytosol was determined
according to the method of Lowry, et al., 29using bovine
serum albumin as a standard.
Glycerol Density Gradient Centrifugation. Linear
10% to 30% glycerol gradients were prepared in 5-ml
cellulose nitrate tubes using a gradient-former of our
own design and a peristaltic p u m p . t A portion of the
cytosol (0.3 ml) was carefully layered over the gradients.
The gradients were centrifuged either in a Beckman
Type SW50.1 swinging-bucket rotor for 16 hours at
149,000 G or in a Sorvall Type TV865 vertical-angle
rotor for 2 hours at 365,000 G.~ Both methods gave
wPackard Model 2425 automatic Tri-Carb liquid scintilla-
tion spectrometer manufactured by Packard Instrument Co.,
Downers Grove, Illinois.
l[ Polytron homogenizer manufactured by Brinkman In-
strument Co., Westbury, New York.
* Beckman rotor manufactured by Beckman Instruments,
Fullerton, California.
"~Peristaltic pump manufactured by Technicon Instrument
Corp., Tarrytown, New York.
z~Beckman rotor manufactured by Beckman Instruments,
Fullerton, California; and Sorvall vertical-angle rotor manu-
factured by Ivan Sorvall, Inc., Newtown, Connecticut.
987
 D. W. Cahill, et al.
130
Single Saturation Dose Assay. All assays were per-
formed in duplicate. Cytosol (0.25 ml) was incubated
Male
120
<~ :
with a final concentration of 1 • 10-8 M labeled ste-
: Female roid (3H-estradiol (2,4,6,7-3H(N), 90.0 Ci/mmol); or
110
3H-R5020 (6,7-3H)- 17,21-dimethyl- 19-nor-4,9-pregna -
diene-3,20-dione, 87 Ci/mmol)) to determine total
bound steroid. Cytosol (0.25 ml) was also incubated
10(~
with 1 • 10-8 M labeled steroid in the presence of 100-
fold excess unlabeled steroid (diethylstilbesterol (DES)
90 or radioinert R5020) to determine nonspecific bound
steroid. 46'59 In order to stabilize the 8S form of the
8G O steroid receptor, 20 mM sodium molybdate was in-
cluded in all assays) The R5020 assays were incubated
= 70
2 hours at 00 to 40C, while estradiol assays were incu-
o bated overnight (24 hours) at 0 ~ to 4~ Each reaction
mixture was treated with dextran-coated charcoal to
60
E
remove free steroid. Dextran-coated charcoal, 0.1 ml,
m
(0.25 gm% Norit A and 0.0025 gm% dextran in
_-- 5E Tris buffer) was formed into pellets by centrifugation at
2500 G for 15 minutes. The reaction mixture was
E
40 pipetted onto the charcoal pellet and briefly mixed with
o a vortex mixer. After 10 minutes' incubation, the mix-
E

=" 30
20 0
10 ,----------------------------------------------------------,
Estrogen Receptor
FIG. 1. Graph showing the numbers of tumors from male
and female patients with detectable levels of either estrogen
or progesterone receptors. Symbols above the broken line
indicate tumors that were positive for receptor (> 10 fM/mg
of protein).
similar results. Sedimentation values were determined
from patterns of known standards (that is, carbon-14
(t4C)-labeled bovine serum albumin, '4C-ovalbumin,
~4C-globulin, or catalase) run simultaneously with sam-
ples in parallel gradients. Radioactive standards were
prepared by acetylation of the proteins with t4C-acetic
anhydride, according to the method of Siiteri, et aL 52
Catalase solution was prepared by dissolving 100 mg in
0.1 ml of TED buffer, and layering 0.1 ml of the
solution on the surface of the gradient. After centrifu-
gation, absorbance of each fraction was determined at
405 nm. Fractions were collected by inserting a thin
steel tube to the bottom of the gradient and removing
the contents by a peristaltic pump. Three drop fractions
(about 0.2 ml each) were collected into scintillation
vials using an LKB fraction collector.w Scintillation
cocktail (4 ml) was added to each tube and mixed with
a vortex mixer. 4]
wLKB fraction collector manufactured by LKB Instru-
ments, Inc., Stockholm, Sweden.
ture was again centrifuged at 2500 G for 10 minutes. A
portion (0.3 ml) of the supernatant was layered on
gradients, and another portion (0.1 ml) was removed
for measurement. Specific binding was determined by
Xc~ subtracting nonspecific binding from total binding. A
o
second single-point assay was performed following a
o
similar experimental procedure. Again, duplicate (0.25
Progestm Receptor
ml) samples of cytosol were prepared and incubated in
either 3H-estradiol (1 • 10-8 M), in the presence or
absence of a 100-fold excess radioinert DES, or 3H-
R5020 (5 • 10-9 M), in the presence or absence of a
100-fold excess radioinert R5020.
Results
There was detectable ER in seven (30%) of the 23
tumors. However, only four tumors (17%) had receptor
concentrations above the minimum value considered
significant in our laboratory (10 femtomoles (fM)/mg
of cytosolic protein). Twelve (52%) of the 23 tumors
had detectable PR, nine (39%) with significant levels.
Only one tumor from a female patient (6%) had an ER
level in the significant range (Fig. 1 and Table 1). Three
of four tumors with definitely positive ER values were
from men. Therefore, 43% of males had ER-positive
tumors. Of the nine tumors with definite PR, eight
(89%) were from women. The single man whose tumor
was positive for PR was the oldest patient in the series
(79 years of age). Of the eight women with PR-positive
tumors, three were premenopausal and five were post-
menopausal.
Three of the 23 tumors had detectable levels of both
ER and PR. However, in all three cases, ER was below
10 fM/mg of protein (Table 1). Thus, no tumors had
both ER and PR levels in the significant range, but
there were seven tumors in the series with no detectable
levels of either ER or PR. If the cases with insignificant
as well as undetectable levels of both receptors are

988 J. Neurosurg. / Volume 6 0 / M a y , 1984

Estrogen and progesterone receptors in meningiomas
included, then l0 of 23 cases (44%) were negative for
both receptors.
Of the three recurrent tumors, none had definitely
positive PR but one had significant ER. Of the two
tumors that were not histologically benign, neither had
detectable ER. The recurrent and malignant tumor
exhibited neither receptor, but the primary and atypical
tumor had PR.
The retro-orbital tumor from a premenopausal
woman had neither ER nor PR. The intraspinal tumor
from another premenopausal woman showed only PR.
Both posterior fossa tumors had definitely positive PR
and detectable but insignificant ER levels. Three of six
basal tumors were positive for PR, but none had de-
tectable ER. All four tumors with definitely positive ER
were located at the convexity or the parasagittal area.
Discussion
Although most meningiomas are benign and can
often be completely excised, this is not always true. A
small percentage of meningiomas are malignant and
are rarely cured by surgical excision alone. 49 A larger
percentage of tumors, although histologically benign,
cannot be completely excised, j~ As many as 20% of all
meningiomas recur following surgery. Of the tumors
known to be incompletely removed, three-fourths recur
symptomatically.~'5"9"53"57'6"-Finally, a small but signifi-
cant proportion of meningiomas occur in elderly, med-
ically fragile patients whose condition may preclude
complicated and lengthy neurosurgical procedures.
Since meningiomas account for 13% to 18% of all
intracranial tumors and 25% of all intraspinal tumors, 49
the total number of patients who may benefit from
adjunctive therapeutic measures is epidemiologically
significant. It is postulated that the presence of cytosolic
receptor proteins for estrogens and progestins indicates
that these tumors may be hormone-sensitive in a man-
ner analogous to carcinoma of the breast and pros-
t a t e . t~-'3~33"425~ However, the results of the six pub-
lished meningioma series in which ER's and/or PR's
were assayed are conflicting and difficult to interpret.
Part of the problem lies in differences in the units of
measurement in which various laboratories report their
results. Our series and those of Tilzer, et al., 56 and
Schnegg, et al., 5~ are reported in units of femtomoles
per milligram of cytosolic protein. However, the results
of other s t u d i e s 12"31"33"42 a r e expressed in units of fem-
tomoles per gram of tumor tissue. Obviously, the
amount of receptor protein per gram of tissue will be
considerably greater than the amount of receptor pro-
tein per milligram of total protein.
Second, what is considered a positive result varies
from one laboratory to the next. In the series of Mag-
delenat, et al., 3~ and Poisson, el al., 42 receptor values
of less than I00 fM/gm of tumor are reported as
negative. In the series of Tilzer, et al., 56 the receptor
value must be above 8 fM/mg of protein and the
dissociation constant (Kd value) must be less than 3 x
J. Neurosurg. / V o l u m e 6 0 / M a y , 1984
10-9 M to be considered positive. In the other se-
ties,~2'33'5~no minimum significant values are used. This
is important in the interpretation of both false-positives
and false-negatives. Donnell, et al., ~2 reported detecta-
ble ER in five of six meningiomas. However, only two
of those tumors had ER values greater than 100 fM/
gm of tumor. (Only one tumor can be included if only
the 8S form of the receptor is counted.) Martuza, et
al.? 3 reported ER in seven of 10 meningiomas tested;
however, only two had ER greater than 100 fM/gm of
tumor. Similarly, these authors reported PR in two of
three tumors tested, but only one had a level of more
than 100 fM/gm of tumor. In contrast, Tilzer, et al., 56
reported ER in none of six meningiomas tested, al-
though the protein was detected in four of the six, in
one case with a level of 12 fM/mg of protein. This was
because a maximum Kd had been arbitrarily defined
in their laboratory, and none of the tumors tested fit
this criterion. In the majority of the tumors assayed in
other series, Kd was not determined, since Scatchard
plots 6 were performed in only a few cases.
In our series, seven (30%) of 23 cases had detectable
ER, and 12 (52%) of 23 had detectable PR. However,
if the arbitrary minimum criterion applied to breast
and prostate tumors in our laboratory (10 fM/mg of
protein) is applied to meningiomas, the results drop to
four (17%) and nine (39%), respectively, of the total 23
cases.
In the six other series, two groups report ER in none
of the tumors tested) ~ The other four report ER in
59% to 79% of tumors) z'31'33"42 Positive results were
obtained in all five series in which PR was assayed,
ranging from 40% to 100% of tumors tested. 31'33"42"5~
The series of Poisson, et al., 42 and Magdelenat, et al., 3~
are from the same group of workers in France, If one
combines the results of these two groups, in which
identical surgical and biochemical techniques were
used, then their results show 43 (72%) of 60 meningi-
omas tested positive for ER, and 61 (95%) of 64 were
positive for PR. All tumors classified as positive had
levels greater than 100 fM/gm of tumor. If one com-
bines our results with the remaining four series from
unrelated laboratories? 2"~3"5~ and applies the same ar-
bitrary minimum criteria (100 fM/gm tumor or 10 fM/
mg protein) to the data in all series, then nine (16%) of
55 tumors tested positive for ER and 18 (43%) of 42
tested positive for PR (Table 3). The results from the
French laboratories 3~'42 (Group 2) are in clear contrast
to our results and those from the remaining laboratories
in the United States and Switzerland ~2'33"5~ (Group 1)
(Table 3).
How might this discrepancy in results be explained?
The techniques of biopsy, freezing of tissue in liquid
nitrogen, duration of tissue storage, and methods of
homogenization did not differ in any of the series
reported. The epidemiological characteristics of the
patients and the histological characteristics of the tu-
mors were also comparable. The biochemical tech-
niques used in each series were quite similar. [n each
989

TABLE 3
S u m m a o ' o f published series o f E R and P R in meningiomas*
Significant Receptor Levelst
Authors & Year
ER PR
Group 1
Donnell, et al., 1979 2/6 not tested
Martuza, et al., 1981 2/10 1/3
Schnegg, et al., 1981 0/10 4/10
Tilzer, et al., 1982 1/6 4/6
Cahill, et al., 1984 4/23 9/23
total cases 9/55 (16%) 18/42 (43%)
Group 2
Poisson, et al., 1980 13/22 22/22
Magdelenat, et al., 1982 30/38 39/42
total cases 43/60 (72%) 61/64 (95%)
* ER = estrogen receptor; PR = progesterone receptor. For a
description of groups see text.
t Only significant concentrations of receptor (> 100 fM/gm of
tumor or > 10 fM/mg of protein) are included. Numbers indicate
ER- or PR-positivetumors compared to total tumors.
series in Group l, tritiated estradiol was used in the
radioassay for ER. Dextran-coated charcoal techniques
were used in all five Group 1 series. Sucrose or glycerol
density gradient centrifugation was used by Donnell, et
al., 12 Tilzer, et aL, 56 and in our series. Scatchard plots
were performed on the data in all six cases of Tilzer, et
al., s6 one of Martuza, et al., 33 and four of Schnegg, et
a l ) ~ R502046"59 was used as the progesterone analog in
each series except that of Schnegg, et al., 5~ who used
promegestone.
In the Group 2 series 31'42 dextran-coated charcoal
assays were also used in all cases and sucrose density
gradient centrifugation and Scatchard plots were per-
formed in some cases. These authors also used R5020
as the progesterone analog. However, R2858 (11/3 meth-
oxy, 17/3 ethynylestradiol) was used as the estrogen
analog. Raynaud, et al., 47 described the use of R2858
instead of estradiol in the measurement of ER concen-
tration. They believed that it might offer a more accu-
rate assay since it does not bind to human sex steroid-
binding protein in serum. They suggested that this
binding to serum proteins may lead to artifactually high
results if estradiol is used in the assay. Despite the use
of R2858 (which should produce lower results) in
Group 2 series, ER was found in 72% of meningiomas
tested as compared to 16% in Group 1. Progesterone
receptor was found in 95% of cases in Group 2, com-
pared with 43% of cases in Group 1.
A possible explanation for this discrepancy between
groups is suggested in the work of Magdelenat, et al. 3t
Of the 42 patients in their series, 13 were treated
preoperatively with glucocorticoids. Ten of these 13
patients had lower PR concentrations than the mean
of the series. In a specificity experiment in which a 100-
or 500-fold excess of dexamethasone and aldosterone
was added to the progesterone analog in the assay, a
50% reduction in the concentration of PR was noted.
990
D. W. Cahill, et al.
Magdelenat, et al., found that this phenomenon does
not occur in high salt conditions, and they suggested
that, since their assays were performed in high salt
conditions, the effect would not apply. However, su-
crose density gradient centrifugation revealed that the
standard 8S peak expected for the hormonally active
forms of ER and PR was shifted to the 4S region in
high salt conditions. Hence, the 4S form of the receptors
was assayed in their series. Wittliff and Savlov 6~ have
shown that the 4S form of ER in human breast carci-
noma does not correlate with hormonal responsiveness.
In our series, 21 (91%) of the 23 tumors were from
patients who had received preoperative glucocorticoid
therapy. All 23 patients had received intraoperative
glucocorticoid therapy. Glucocorticoid receptors were
demonstrated in all of the six meningiomas reported
by Yu, e t al. 63 The efficacy of glucocorticoid treatment
in the reduction of peritumoral edema in meningioma
patients is well known. 6j Even though no other reported
series mentions the use of preoperative glucocorticoid
therapy, it is quite likely that the majority of patients
in series from the United States were so treated.
In an average-weight (70-kg) adult with normal renal
and hepatic function, the equilibrium concentration of
glucocorticoid in tissue may be calculated from the
dosage and molecular weight of the particular steroid.
If, as in our series, the steroid dexamethasone is admin-
istered in doses of 16 to 40 mg/day, the whole body
concentration is in the order of 1 to 2 • 10-6 M.
Circulating concentrations of estrogens and progestins
and the established Kd for ER and PR are approxi-
mately 10 -9 M. Therefore, in tumors so treated, there
is a 1000-fold excess of circulating glucocorticoid at the
time of biopsy.
Lippman, et al.fl 8 have found that, in tissue cultures
of human MCF-7 breast carcinoma, dexamethasone
competes for the PR when an excess of 1000 to
2000 M is reached, at which time there is a 50%
reduction in assayable receptor. Wittliff, et al., 59 have
found that, in lactating rat m a m m a r y gland, a 250-fold
excess of dexamethasone inhibits receptor detection by
77%. Since the concentration of dexamethasone in our
patients was in the order of a 1000-fold molar excess,
the low percentage of positive results in Group 1 as
compared with Group 2 may be related to preoperative
glucocorticoid therapy. To test this hypothesis we are
presently attempting to obtain tissue from a menin-
gioma that has not been pretreated with glucocorticoids,
in order to perform competition and specificity exper-
iments.
In Group 1, 24% of tumors from men and 11% of
tumors from women were ER-positive (Table 4). Con-
versely, 29% of tumors from men and 50% of tumors
from women were PR-positive. Even in Group 2 series,
the authors noted that PR levels were quantitatively
higher in tumors from women than in those from men,
and that PR levels were quantitatively higher in tumors
from both men and women than were ER levels.
Considering our series alone, three (43%) of seven
J. Neurosurg. / V o l u m e 6 0 / M a y , 1984
Estrogen and progesterone receptors in meningiomas
Results of receptor assay according to sex of patients*
Estrogen Receptor
Series
Males
Cahill, et al. 3/7 (43%)
Group 1 4/17 (24%)
Group 2 10/18 (56%)
* Only significantconcentrationsof receptor(> 100 fM/gm of tumor or > 10 fM/mg of protein)are included. The number of estrogen-or
progesterone-positivetumors are comparedto the total numberof tumors. For a descriptionof groupssee text.
tumors from males but only one (6%) of 16 tumors
from females were ER-positive; that is, had significant
levels of ER. In comparison, only one (14%) of seven
tumors from men but eight (50%) of 16 tumors from
women were PR-positive. In every series, PR has been
more frequently demonstrated than ER, and PR levels
have been quantitatively higher in women. Also, in
every series, ER levels have been frequently near the
level of significance and well below the levels that have
been found to correlate with hormonal responsiveness
in breast carcinoma.
In human breast carcinoma, the ER concentration is
virtually always higher in postmenopausal than in pre-
menopausal women. Jensen 22 has found that, in post-
menopausal women, ER levels of less than 750 fM/gm
of tumor do not correlate with response to endocrine
therapy, whereas in premenopausal women ER levels
equal to or more than 250 fM/gm of tumor correlate
well. It is thought that higher levels of circulating estro-
gen in premenopausal women block a portion of avail-
able receptors, leading to lower assay results. Not
enough breast carcinomas from male patients have been
assayed to draw valid conclusions as to whether ER
levels would be still higher in men. 25 Surprisingly, Mag-
delenat, et al., 3~ found no significant differences be-
tween ER levels in meningiomas from premenopausal
women, postmenopausal women, or even men. They
also found no differences in PR levels in meningiomas
from pre- or postmenopausal women, although both
were higher than in tumors from men. It is nonetheless
tempting to speculate that the higher percentage of
males with ER-positive tumors in Group 1 may reflect
lower levels of circulating estrogen in men and a con-
comitantly higher percentage of unbound receptors
available for assay, rather than a greater number of
total receptors.
In carcinoma of the breast, prostate, or endome-
trium, PR is responsive to other hormonal receptors. 36
The assayed level of PR in breast or endometrial car-
cinoma tissues is directly proportional to the level of
circulating estrogens. In prostate carcinoma, the PR
level is controlled by circulating androgens. Grmez, et
al.J 6 have found that the levels of PR and ER in normal
endometrium vary_during the menstrual cycle. The ER
level is highest and the PR level lowest during the
proliferative phase, while the opposite is true during the
J. Neurosurg. / Volume 6 0 / M a y , 1984
TABLE 4
Progesterone Receptor
Females Males Females
1/16 (6%) 1/7 (14%) 8/16 (50%)
4/38 (11%) 4/14 (29%) 14/28 (50%)
32/42 (76%) 7/19 (90%) 44/45 (98%)
luteal phase. Since human meningiomas are known to
enlarge symptomatically during the luteal phase of the
menstrual cycle and during pregnancy, the finding of
high levels of PR in all major series may be significant.
Conversely, since meningiomas are not known to en-
large during the proliferative phase of the menstrual
cycle or with exogenous estrogen therapy, the finding
of low levels of ER may reflect this receptor's lack of
clinical significance.
Pollow, et aL, 43"44 have found that, in human endo-
metrial carcinoma, ER and PR concentrations vary
directly with the degree of differentiation of the tumor.
The more histologically malignant the tumor, the higher
the ER concentration and the lower the PR concentra-
tion. Similar results were noted by McClendon, et al., 34
in carcinoma of the colon. Magdelenat, et al., 31 found
high levels of PR in all four malignant meningiomas in
their series. Poisson, et al., 42 found high levels of PR in
six "proliferative" meningiomas. In our series, one
"atypical" meningioma had PR. The malignant men-
ingioma had neither receptor. This combined series of
12 atypical or malignant meningiomas with significant
PR levels is too small to allow firm conclusions, but if
a high PR concentration can be documented in a larger
series of histologically aggressive tumors, there would
be clear therapeutic implications.
Conclusions
1. There is a wide discrepancy in results reported
from ER and PR assays in meningioma series, The
seven reported series may be divided into two groups:
this present series and four others ~2"33"5~ comprise
Group 1, and two series from the same laboratories in
France make up Group 2. 31"42A much lower percentage
of positive results has been reported by Group 1 inves-
tigators. This discrepancy between the groups may be
related to the use of preoperative glucocorticoid therapy
in Group 1, since high molar concentrations of gluco-
corticoid may competitively block a portion of sex
steroid receptors.
2. Since meningiomas are known to enlarge symp-
tomatically during pregnancy and during the luteal
phase of the menstrual cycle, when levels of circulating
progestins are high, the finding of high levels of PR in
all series, particularly among tumors from women,
991

suggests that anti-progestin therapy may be of clini-
cal use.
3. Conversely, since meningiomas are not known to
enlarge during the proliferative phase of the menstrual
cycle or with exogenous estrogen therapy, the finding
of small numbers of ER-positive tumors and low con-
centrations of ER may reflect this receptor's lack of
clinical significance.
4. High levels of PR found in a small group of
histologically aggressive meningiomas may indicate that
hormonal therapy may be especially useful in this dif-
ficult subset of patients.
5. The epidemiology and clinical history of menin-
giomas in pregnant and menstruating women suggests
that the study of sex steroid receptors may play a role
in the development of a theory of ontogenesis of this
tumor.
Addendum
Since submission of this manuscript, another paper
reporting hormone binding on various brain tumors
has been published (Glick RP, Molteni A, Fors EM:
Hormone binding in brain tumors. Neurosurgery
13:513-519, 1983). These authors found "significant"
ER levels in 13 of 21 meningiomas tested and "signifi-
cant" PR levels in three of four meningiomas tested.
However, if the same minimum criteria (10 f M / m g
protein) are applied to their data as to the other series
summarized above, the results drop to four ( 19 %) of 21
ER-positive tumors (three of 21, if only the 8S form of
the receptor is counted), making their data comparable
to ours and to the other series of Group 1.
References
1. Adegbite AB, Khan MI, Paine KWE, et al: The recurrence
of intracranial meningiomas after surgical treatment. J
Neurosurg 58:51-56, 1983
2. Bailey P, Bucy PC: Tumors of the spinal canal. Surg Clin
North Am 10:233-257, 1930
3. Bevins CL, Bashirelahi N: Stabilization of 8S progester-
one receptor from human prostate in the presence of
molybdate ion. Cancer Res 40:2234-2239, 1980
4. Bickerstaff ER, Small JM, Guest IA: The relapsing course
of certain meningiomas in relation to pregnancy and
menstruation. J Neurol Neurosurg Psychiatry 21:89-91,
1958
5. Carella RJ, Ransohoff J, Newall J: Role of radiation
therapy in the management of meningioma. Neurosur-
gery 10:332-339, 1982
6. Chamness GC, McGuire WL: Scatchard plots: common
errors in correction and interpretation. Steroids 26:
538-542, 1975
7. Chamness GC, Mercer WD, McGuire WL: Are histo-
chemical methods for estrogen receptor valid? J Histo-
chem Cytochem 28:792-798, 1980
8. Concolino G, Marocchi A, Conti C, et al: Human renal
cell carcinoma as a hormone dependent tumor. Cancer
Res 38:4340-4344, 1978
9. Crompton MR, Gautier-Smith PC: The prediction of
recurrence in meningiomas. J Neurol Neurosnrg Psychia-
try 33:80-87, 1970
10. Cushing H, Eisenhardt L: Meningiomas: Their Classifi-
cation, Regional Behavior, Life History, and Surgical End
992
D. W. Cahill, et al.
Results. Springfield, Ill: Charles C Thomas, 1938, 785 pp
11. DeSombre ER, Carbone PP, Jensen EV, et al: Steroid
receptors in breast cancer. N Engl J Med 301:1011-1012,
1979
12. Donnell MS, Meyer GA, Donegan WL: Estrogen-receptor
protein in intracranial meningiomas. J Neurosurg 50:
499-502, 1979
13. Ehrlich CE, Young PCM, Cleary RE: Progesterone recep-
tor (PR) as a marker of progestin responsive human
endometrial cancer, in Wittliff JL, Dapunt O (eds): Ste-
roid Receptors and Hormone-Dependent Neoplasia. New
York: Masson, 1980, pp 95-99
14. Fischer F: 15bet die Ursachen bitemporaler Hemianopsie
bei Schwangerschaft. Z Augenh 85:88-108, 1935
15. Fisher RI, Neifeld JP, Lippman ME: Oestrogen receptors
in human malignant melanoma. Lancet 23:337-338,
1976
16. G6mez F, Bohnet HG, Friesen HG: Changes in proges-
terone and estrogen receptors in the rat uterus during the
estrous cycle and the puerperium, in McGuire WL, Ray-
naud JP, Baulieu EE (eds): Progesterone Receptors in
Normal and Neoplastic Tissues. New York: Raven Press,
1977, pp 245-259
17. Gurpide E: Endometrial cancer in postmenopausal estro-
gen users: a rationale for uterine protection with proges-
tins, in Wittliff JL, Dapunt O (eds): Steroid Receptors
and Hormone-Dependent Neoplasia. New York: Masson,
1980, pp 29-35
18. Gurpide E, Tseng L: Estrogens in normal human endo-
metrium, in Pasqualini JR (ed): Receptors and Mecha-
nism of Action of Steroid Hormones. New York: Marcel
Dekker, 1976, pp 109-158
19. Hagedoorn A: The chiasmal syndrome and retrobulbar
neuritis in pregnancy. Am J Ophthalmol 20:690-699,
1937
20. Horwitz KB, McGuire WL: Estrogen and progesterone:
their relationship in hormone-dependent breast cancer,
in McGuire WL, Raynaud JP, Baulieu EE (eds): Proges-
terone Receptors in Normal and Neoplastic Tissues. New
York: Raven Press, 1977, pp 103-124
21. Horwitz KB, McGuire WL, Pearson OH, et al: Predicting
response to endocrine therapy in human breast cancer: a
hypothesis. Science 189:726-727, 1975
22. Jensen EV: Hormone dependency of breast cancer. Can-
cer 47:2319-2326, 1981
23. Jensen EV, Polley TZ, Smith S, et al: Prediction of
hormone dependency in human breast cancer, in Mc-
Guire WL, Carbone PP, Vollmer EP (eds): Estrogen
Receptors in Human Breast Cancer. New York: Raven
Press, 1975, pp 37-56
24. King AB: Neurologic conditions occurring as complica-
tions of pregnancy. Arch Neurol Psychiatry 63:611-644,
1950
25. Leclerq G, Verhest A, Deboel M, et al: Oestrogen recep-
tors in male breast cancer. Biomedicine 25:327-330, 1976
26. Lippman M: Glucocorticoid receptors in human leuke-
mia, in Witliff JL, Dapunt O (eds): Steroid Receptors and
Hormone-Dependent Neoplasia. New York: Masson,
1980, pp 167-176
27. Lippman M, Allegra JC: Estrogen receptor and endocrine
therapy of breast cancer. N Engl J Med 299:930-933,
1978
28. Lippman M, Huff K, Bolan G, et al: Interactions of
R5020 with progesterone and glucocorticoid receptors in
human breast cancer and peripheral blood lymphocytes
in vitro, in McGuire WE, Raynaud JP, Baulieu EE (eds):
Progesterone Receptors in Normal and Neoplastic Tis-
sues. New York: Raven Press, 1977, pp 193-210
J. Neurosurg. / Volume 60/May, 1984
Estrogen and progesterone receptors in meningiomas
29. Lowry OH, Rosebrough N J, Farr AL, et al: Protein mea-
surement with the Folin phenol reagent. J Biol Chem
193:265-275, 1951
30. MacLusky NJ, McEwen BS: Oestrogen modulates pro-
gestin receptor concentrations in some rat brain regions
but not in others. Nature 274:276-278, 1978
31. Magdelenat H, Pertuiset BF, Poisson M, et al: Progestin
and oestrogen receptors in meningiomas. Biochemical
characterization, clinical and pathological correlations in
42 cases. Acta Neurochir 64:199-213, 1982
32. Martin JD, H~ihnel R, McCartney AJ, et al: Prognostic
value of estrogen receptors in cancer of the uterine cervix.
N Engl J Med 306:485, 1982 (Letter)
33. Martuza RL, MacLaughlin DT, Ojemann RG: Specific
estradiol binding in schwannomas, meningiomas, and
neurofibromas. Neurosurgery 9:665-671, 1981
34. McClendon JE, Appleby D, Claudon DB, et al: Colonic
neoplasms. Tissue estrogen receptor and carcinoembry-
onic antigen. Arch Surg 112:240-241, 1977
35. McGuire WL, Carbone PP, Sears ME, et al: Estrogen
receptors in human breast cancer: an overview, in Mc-
Guire WL, Carbone PP, Vollmer EP (eds): Estrogen
Receptors in Human Breast Cancer. New York: Raven
Press, 1975, pp 1-7
36. McGuire WL, Raynaud JP, Baulieu EE: Progesterone
receptors: introduction and overview, in McGuire WL,
Raynaud JP, Baulieu EE (eds): Progesterone Receptors in
Normal and Neoplastic Tissues. New York: Raven Press,
1977, pp 1-8
37. Mealey J Jr, Carter JE: Spinal cord tumor during preg-
nancy. Obstet Gynecoi 32:204-209, 1968
38. Michelson J J, New PFJ: Brain tumour and pregnancy. J
Neurol Neurosurg Psychiatry 32:305-307, 1969
39. Moguilewsky M, Raynaud JP: Estrogen-sensitive proges-
tin-binding sites in the female rat brain and pituitary.
Brain Res 164:165-175, 1979
40. Munck A: General aspects of steroid hormone-receptor
interactions, in Pasqualini JR (ed): Receptors and Mech-
anism of Action of Steroid Hormones. New York: Marcel
Dekker, 1976, pp 1-40
41. Patterson M, Greene RC: Measurement of low-energy
beta-emitters in aqueous solution by liquid scintillation
counting of emulsions. Anal Chem 37:854-857, 1965
42. Poisson M, Magdelenat H, Foncin JF, et al: Rreepteurs
d'oestrog~nes et de progestrrone dans les mrningiomes.
Etude de 22 cas. Rev Neurol 136:193-203, 1980
43. Pollow K, Liibbert H, Boquoi E, et al: Characterization
and comparison of receptors for 17~-estradiol and pro-
gesterone in human proliferative endometrium and en-
dometrial carcinoma. Endocrinology 96:319-328, 1975
44. Pollow K, Schmidt-Gollwitzer M, Nevinny-Stickel J: Pro-
gesterone receptors in normal human endometrium and
endometrial carcinoma, in McGuire WL, Raynaud JP,
Baulieu EE (eds): Progesterone Receptors in Normal and
Neoplastic Tissues. New York: Raven Press, 1977, pp
313-338
45. Rand CW, Andler M: Tumors of the brain complicating
pregnancy. Arch Neurol Psychiatry 63:1-41, 1950
46. Raynaud JP: R5020, a tag for the progestin receptor, in
McGuire WL, Raynaud JP, Baulieu EE (eds): Progester-
one Receptors in Normal and Neoplastic Tissues. New
York: Raven Press, 1977, pp 9-21
47. Raynaud JP, Ojasoo T, Delarue JC, et al: Estrogen and
J. Neurosurg. / Volume 60/May, 1984
progestin receptors in human breast cancer, in McGuire
WL, Raynaud JP, Baulieu EE (eds): Progesterone Recep-
tors in Normal and Neoplastic Tissues. New York: Raven
Press, 1977, pp 171-191
48. Rucker CW, Kearns TP: Mistaken diagnoses in some
cases of meningioma. Clinics in Perimetry No. 5. Am J
Ophthalmol 51:15-19,1961
49. Russell DS, Rubinstein LJ: Pathology of Tumors of the
Nervous System. Baltimore: Williams & Wilkins, 1977,
pp 65-100
50. Schnegg JF, Gomez F, LeMarchand-Beraud T, et al:
Presence of sex steroid hormone receptors in meningioma
tissue. Surg Neuroi 15:415-418, 1981
51. Schoenberg BS, Christine BW, Whisnant JP: Nervous
system neoplasms and primary malignancies of other
sites. The unique association between meningiomas and
breast cancer. Neurology 25:705-712, 1975
52. Siiteri PK, Schwarz BE, Moriyama I, et al: Estrogen
binding in the rat and human. Adv Exp Med Biol 36:
97-112, 1973
53. Simpson D: The recurrence of intracranial meningiomas
after surgical treatment. J Neurol Neurosurg Psychiatry
20:22-39, 1957
54. Spelsberg TC, Toft DO: The mechanism of action of
progesterone, in Pasqualini JR (ed): Receptors and Mech-
anism of Action of Steroid Hormones. New York: Marcel
Dekker, 1976, pp 261-309
55. Stedman KE, Moore GE, Morgan RT: Estrogen receptor
proteins in diverse human tumors. Arch Surg 115:
244-248, 1980
56. Tilzer LL, Plapp FV, Evans JP, et al: Steroid receptor
proteins in human meningiomas. Cancer 49:633-636,
1982
57. Wara WM, Sheline GE, Newman H, et al: Radiation
therapy of meningiomas. AJR 123:453-458, 1975
58. Weyand RD, MacCarty CS, Wilson RB: The effect of
pregnancy on intracranial meningiomas occurring about
the optic chasm. Surg Clin North Am 31:1225-1233, 1951
59. Wittliff JL, Mehta RG, Kute TE: Interaction of R5020
with binding sites in normal and neoplastic mammary
tissues, in McGuire WL, Raynaud JP, Baulieu EE (eds):
Progesterone Receptors in Normal and Neoplastic Tis-
sues. New York: Raven Press, 1977, pp 39-57
60. Wittliff JL, Savlov ED: Estrogen-binding capacity of cy-
toplasmic forms of the estrogen receptors in human breast
cancer, in McGuire WL, Carbone PP, Vollmer EP (eds):
Estrogen Receptors in Human Breast Cancer. New York:
Raven Press, 1975, pp 73-91
61. Yamada K, Bremer AM, West CR: Effects of dexameth-
asone on tumor-induced brain edema and its distribution
in the brain of monkeys. J Neurosurg 50:361-367, 1979
62. Yamashita J, Handa H, Iwaki K, et al: Recurrence of
intracranial meningiomas, with special reference to radio-
therapy. Surg Neuroi 14:33-40, 1980
63. Yu ZY, Wrange O, Bo6thius J, et al: A study of gluco-
corticoid receptors in intracranial tumors. J Neurosurg
55:757-760, 1981
Manuscript received May 31, 1983.
Address reprint requests to." David W. Cahill, M.D., Di-
vision of Neurosurgery, University of South Florida College
of Medicine, Box 16, Tampa, Florida 33612.
993