Perspectives

Commentary on:
Intracranial Meningiomas in Patients with
Uterine Sarcoma Treated with Long-Term
Megestrol Acetate Therapy
by Gruber et al. pp. 477.E16-477.E20.

Zvi Ram, M.D.

Professor and Chairman, Department of Neurosurgery
Tel Aviv Sourasky Medical Center

Hormonal Effect on Meningioma Growth

Tal Shahar1 and Zvi Ram1,2

he impact of growth-promoting hormones on meningioma formation and progression has been the subject of
discussions over many years. Isolated observations that
link hormonal surge, such as during pregnancy, to rapid growth of
meningiomas, and the identification of various hormonal receptors in meningioma prompted numerous investigations into this
area.

patients treated for a meningioma), thus highlighting the possible

association between hormonal therapy and the subsequent
meningioma presentation. Because baseline imaging studies
were not performed before the initiation of hormonal therapy,
there is no way to distinguish between a true tumor-inducing
effect of the drug from tumor progression, which may have been
facilitated by the therapy.

Meningiomas, which account for approximately 35% of all primary brain tumors, are mostly benign, slow-growing tumors with
a median age of 63 years at diagnosis. The incidence of meningiomas was found to be significantly higher in females than
males (8.87 vs. 3.91/100,000) (4).

Several studies have addressed the role of endogenous as well

as exogenous hormonal therapy on the risk of meningioma
formation. These studies were based on the finding of a substantially increased incidence of meningiomas in women compared
to men, the presence of hormonal receptors (progesterone,
estrogen, as well as androgen receptors) in some meningiomas
and an apparent concomitant occurrence of breast cancer with
meningiomas. In addition, meningiomas appear to grow at a
faster rate during pregnancy and menopause. Recent reports
have also described several cases where regression of multiple
meningiomas was observed following cessation of progesterone-agonist treatment (22, 24).

Several risk factors have been associated with the formation of

meningiomas. The most consistent factor is prior exposure to
ionizing radiation. Such linkage had been shown in patients
treated with radiation for tinea capitis (20, 21, 23), patients
exposed to diagnostic or therapeutic radiation (13, 14, 17, 19),
occupational exposure to radiation, and in atomic bomb survivors
in Japan (18). Other conditions hypothesized to be associated
with meningioma formation included exposure to endogenous or
exogenous hormones (5), breast cancer (6), head trauma (10),
use of cellular phones (11), occupational exposure to specific
chemicals, the use of hair dye (2), diet, and allergies (3). For most
of these factors no significant association with an increased risk
for meningioma has been found.
In this issue of WORLD NEUROSURGERY, Gruber et al. report on a
series of four patients treated for a uterine sarcoma with longterm use of the progesterone-agonist megestrol acetate. All four
patients had developed neurologic symptoms due to intracranial
meningiomas (usually multiple) years after suppressive treatment was initiated. Histopathologic studies of the meningiomas
demonstrated strong immunoreactivity for progesterone receptors (PRs). The identification of these cases was the result of a
search for patients diagnosed with uterine sarcoma (not selected

Key words
Epidemiology
Hormones
Meningioma
Risk factor

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A review of the English-language literature by Claus et al. (5)

examined the associated risk of meningioma with the use of
exogenous hormonal therapy, such as oral contraceptives or
hormonal replacement therapies. They did not find any statistical
evidence of an increased risk of meningiomas among users of
oral contraceptives. However, a suggested association was
found between the use of hormonal replacement therapy and
increased risk of developing a meningioma. A recently published
retrospective study in a cohort of 1.3 million middle-aged women
aimed to look into the effect of anthropometric and lifestyle
factors on the risk of developing gliomas or meningiomas (the
Million Women Study) found no association between oral contraceptives and the risk of meningioma with, RR 1.06 (95%
CI 0.811.38) for oral contraceptives use for less than 5 years
and RR 1.10 (95% CI 0.86 1.40) for oral contraceptives use
for more than 5 years (1). In contrast, a Swedish case control

From the 1Department of Neurosurgery, Tel Aviv Sourasky Medical Center, and
2
Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
To whom correspondence should be addressed: Zvi Ram, M.D. [E-mail: zviram@inter.net.il]
Citation: World Neurosurg. (2011) 76, 5:412-414.
DOI: 10.1016/j.wneu.2011.05.007

WORLD NEUROSURGERY, DOI:10.1016/j.wneu.2011.05.007

PERSPECTIVES

study by Wigertz et al. (26) looking at the possible association

between exogenous female steroid hormone exposure and the
risk for developing meningiomas and gliomas demonstrated an
increased risk for meningiomas among postmenopausal women
with any history of hormone replacement therapy, with an odds
ratio of 1.7 (95% CI 1.0 2.8). In addition, women who had
used long-acting hormonal contraceptives (subdermal implants,
injections, or hormonal intrauterine devices) had an increased risk
of meningioma; the odds ratio for at least 10 years of use was 2.7
(95% CI 0.9 7.5).
Additional studies assessed the risk of endogenous hormone
exposure and meningioma formation. Factors such as menopausal status, parity, ever being pregnant, and age at menarche
were investigated. A European population-based case control
study investigating such reproductive history covariates (25)
found that age at menarche, menopausal status, and age at
menopause had no impact on the risk for meningiomas. Similarly,
ever being pregnant, number of pregnancies, or number of
pregnancies leading to live births was also not associated with
increased risk for meningiomas. However, stratifying for woman
age revealed an increased risk for meningioma formation with
the number of live births. The investigators found an OR of 1.8
(95% CI 1.12.8) for women giving birth to three children in
comparison to nulliparous females. This was only demonstrated
in females younger than 50 years. Other conflicting results from
the Nurses Health Study cohort (12) observed that the relative
risk for meningioma in women whose menarche occurred at
ages 12 through 14 years was 1.29 (95% CI 0.86 1.92, P
0.21) and the relative risk for women whose menarche occurred
after age 14 years was 1.97 (95% CI 1.06 3.66, P 0.03). This
risk was compared to the relative risk for women whose menarche occurred before the age of 12 years. The authors had also
observed a nonsignificant trend for increased risk of meningiomas in parous as opposed to nulliparous women (multivariate
RR 2.39, 95% CI 0.76 7.53, P 0.14). No association was
found for past or current use of oral contraceptives.
The presence of progesterone and estrogen receptors in meningiomas and their possible growth-promoting role lead to further
investigation of these targets for hormonal therapy. Several in
vitro (15) and in vivo (16) studies supported the possible use of
the antiprogesterone agent mifepristone (RU486) as a treatment

REFERENCES
1. Benson VS, Pirie K, Green J, Casabonne D, Beral V:
Lifestyle factors and primary glioma and meningioma tumours in the Million Women Study cohort.
Br J Cancer 99:185-190, 2008.
2. Bluhm EC, Zahm SH, Fine HA, Black PM, Loefer
JS, Shapiro WR, Selker RG, Inskip PD: Personal hair
dye use and risks of glioma, meningioma, and
acoustic neuroma among adults. Am J Epidemiol
165:63-71, 2007.

option for meningioma by demonstrating inhibition of meningioma growth in cell cultures, as well as in animal models. In
clinical studies, Grunberg et al. (9) studied the effect of long-term
oral therapy of mifepristone (RU486) in 14 patients with unresectable meningiomas. The response rate was partial and minor
and was associated with fatigue, hot flashes, gynecomastia,
partial alopecia, and menstrual disturbances. In a recent study by
Grunberg et al. (8), 28 patients received daily oral mifepristone
(RU486) for a median duration of therapy of 35 months with a
minor response rate and with similar profile of side effects as
previously reported. However, in this group of longer treatment
duration, endometrial hyperplasia or polyps were documented in
three patients and peritoneal adenocarcinoma developed in one
patient 9 years after therapy. In another study, evaluating tamoxifen (7) (an antiestrogen agent) as a hormonal therapy for the
treatment of meningioma in 21 patients, only one patient demonstrated a partial response and two patients demonstrated
minor response on imaging. The other patients remained stable
(6 patients) or progressed (10 patients) over a median follow-up
of 31 months. The authors have concluded that a definite
recommendation for the use of tamoxifen as an anti-meningioma
therapy cannot be made from the study (7).
In conclusion, the current literature offers limited evidence for
the associated risk of developing meningiomas with the use of
exogenous female sex steroids. Although it appears that a subset
of women may be more sensitive to the effects of sex hormones
in either promoting meningiomas or enhancing their growth, no
unequivocal statistical evidence is present for an increased risk
for meningiomas among oral contraceptive users. A possible, but
inconclusive, increased risk for meningiomas may occur with
long-term hormonal replacement therapy. The current report by
Gruber et al. suggests a possible link between long-term treatment with megestrol acetate and meningioma development.
Their observation, along with the previously described data,
suggests that administration of long-term sex hormones, or their
agonists, to women who had been previously diagnosed with a
meningioma should be taken with care. However, the recommendation for screening patients who are treated with long-term
hormonal therapies by brain imaging appears to be premature
and unsubstantiated by the isolated cases reported so far.

nosed in the United States in 2004-2007. Chicago:

Central Brain Tumor Registry of the United States,
2011.
5. Claus EB, Black PM, Bondy ML, Calvocoressi L,
Schildkraut JM, Wiemels JL, Wrensch M: Exogenous hormone use and meningioma risk: what do
we tell our patients? Cancer 110:471-476, 2007.
6. Custer BS, Koepsell TD, Mueller BA: The association between breast carcinoma and meningioma in
women. Cancer 94:1626-1635, 2002.

3. Brenner AV, Linet MS, Fine HA, Shapiro WR, Selker

RG, Black PM, Inskip PD: History of allergies and
autoimmune diseases and risk of brain tumors in
adults. Int J Cancer 99:252-259, 2002.

7. Goodwin JW, Crowley J, Eyre HJ, Stafford B, Jaeckle

KA, Townsend JJ: A phase II evaluation of tamoxifen
in unresectable or refractory meningiomas: a
Southwest Oncology Group study. J Neurooncol 15:
75-77, 1993.

4. CBTRUS: 2011 CBTRUS Statistical Report. Primary

Brain and Central Nervous System Tumors Diag-

8. Grunberg SM, Weiss MH, Russell CA, Spitz IM,

Ahmadi J, Sadun A, Sitruk-Ware R: Long-term ad-

WORLD NEUROSURGERY 76 [5]: 412-414, NOVEMBER 2011

ministration of mifepristone (RU486): clinical

tolerance during extended treatment of meningioma. Cancer Invest 24:727-733, 2006.
9. Grunberg SM, Weiss MH, Spitz IM, Ahmadi J, Sadun A, Russell CA, Lucci L, Stevenson LL: Treatment
of unresectable meningiomas with the antiprogesterone agent mifepristone. J Neurosurg 74:861-866,
1991.
10. Inskip PD, Mellemkjaer L, Gridley G, Olsen JH: Incidence of intracranial tumors following hospitalization for head injuries (Denmark). Cancer Causes
Control 9:109-116, 1998.
11. INTERPHONE Study Group: Brain tumour risk in
relation to mobile telephone use: results of the
INTERPHONE international case-control study. Int J
Epidemiol 39:675-694, 2010.

www.WORLDNEUROSURGERY.org

413

PERSPECTIVES

12. Jhawar BS, Fuchs CS, Colditz GA, Stampfer MJ: Sex
steroid hormone exposures and risk for meningioma. J Neurosurg 99:848-853, 2003.
13. Karlsson P, Holmberg E, Lundell M, Mattsson A,
Holm LE, Wallgren A: Intracranial tumors after exposure to ionizing radiation during infancy: a
pooled analysis of two Swedish cohorts of 28,008
infants with skin hemangioma. Radiat Res 150:357364, 1998.
14. Longstreth WT Jr, Phillips LE, Drangsholt M, Koepsell TD, Custer BS, Gehrels JA, van Belle G: Dental
X-rays and the risk of intracranial meningioma: a
population-based case-control study. Cancer 100:
1026-1034, 2004.
15. Olson JJ, Beck DW, Schlechte J, Loh PM: Hormonal
manipulation of meningiomas in vitro. J Neurosurg
65:99-107, 1986.
16. Olson JJ, Beck DW, Schlechte JA, Loh PM: Effect of
the antiprogesterone RU-38486 on meningioma
implanted into nude mice. J Neurosurg 66:584-587,
1987.
17. Phillips LE, Frankenfeld CL, Drangsholt M, Koepsell TD, van Belle G, Longstreth WT Jr: Intracranial
meningioma and ionizing radiation in medical and

414

www.SCIENCEDIRECT.com

occupational settings. Neurology 64:350-352,

2005.
18. Preston DL, Ron E, Yonehara S, Kobuke T, Fujii H,
Kishikawa M, Tokunaga M, Tokuoka S, Mabuchi K:
Tumors of the nervous system and pituitary gland
associated with atomic bomb radiation exposure. J
Natl Cancer Inst 94:1555-1563, 2002.
19. Ron E, Modan B, Boice JD Jr, Alfandary E, Stovall M,
Chetrit A, Katz L: Tumors of the brain and nervous
system after radiotherapy in childhood. N Engl J
Med 319:1033-1039, 1988.
20. Rubinstein AB, Shalit MN, Cohen ML, Zandbank U,
Reichenthal E: Radiation-induced cerebral meningioma: a recognizable entity. J Neurosurg 61:966971, 1984.
21. Sadetzki S, Flint-Richter P, Ben-Tal T, Nass D: Radiation-induced meningioma: a descriptive study of
253 cases. J Neurosurg97:1078-1082, 2002.
22. Shimizu J, Matsumoto M, Yamazaki E, Yasue M:
Spontaneous regression of an asymptomatic meningioma associated with discontinuation of progesterone agonist administration. Neurol Med Chir
(Tokyo) 48:227-230, 2008.

23. Soffer D, Pittaluga S, Feiner M, Beller AJ: Intracranial meningiomas following low-dose irradiation to
the head. J Neurosurg 59:1048-1053, 1983.
24. Vadivelu S, Sharer L, Schulder M: Regression of
multiple intracranial meningiomas after cessation
of long-term progesterone agonist therapy. J Neurosurg 112:920-924, 2010.
25. Wigertz A, Lnn S, Hall P, Auvinen A, Christensen
HC, Johansen C, Klaeboe L, Salminen T, Schoemaker MJ, Swerdlow AJ, Tynes T, Feychting M:
Reproductive factors and risk of meningioma and
glioma. Cancer Epidemiol Biomarkers Prev 17:
2663-2670, 2008.
26. Wigertz A, Lnn S, Mathiesen T, Ahlbom A, Hall P,
Feychting M: Risk of brain tumors associated with
exposure to exogenous female sex hormones. Am J
Epidemiol 164:629-636, 2006.
Citation: World Neurosurg. (2011) 76, 5:412-414.
DOI: 10.1016/j.wneu.2011.05.007
Journal homepage: www.WORLDNEUROSURGERY.org
Available online: www.sciencedirect.com
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WORLD NEUROSURGERY, DOI:10.1016/j.wneu.2011.05.007