Cancer Epidemiology 36 (2012) 198205

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Cancer Epidemiology
The International Journal of Cancer Epidemiology, Detection, and Prevention
journal homepage: www.cancerepidemiology.net

Hormonal therapies and meningioma: Is there a link?

Luca Cea-Soriano a,*, Tilo Blenk b, Mari-Ann Wallander b,c, Luis A. Garca Rodrguez a
a

Spanish Centre for Pharmacoepidemiologic Research (CEIFE), C/Almirante 28, 28, 28004 Madrid, Spain
Global Epidemiology, Bayer HealthCare Pharmaceuticals, Berlin, Germany
c
Department of Public Health and Caring Science, Uppsala University, Sweden
b

A R T I C L E I N F O

A B S T R A C T

Article history:
Received 22 December 2010
Received in revised form 25 July 2011
Accepted 17 August 2011
Available online 22 September 2011

Background: The aetiology of meningiomas is largely unknown although hormones have been suggested
to play a role. Methods: A cohort study was performed to evaluate hormone-related factors associated
with meningioma. Patients (1289 years) with a rst diagnosis of meningioma (January 1996June
2008) were identied from The Health Improvement Network UK primary care database and age- and
sex-matched to controls (n = 10 000) from the same cohort. Odds ratios (ORs) were calculated following
a nested case control analysis using unconditional logistic regression. Results: In total, 745 patients with
meningioma were identied from a study population of 2 171 287. No signicantly increased risk of
meningioma was found among female users of oral contraceptives (OR: 1.15; CI: 0.671.98), hormone
replacement therapy (OR: 0.99; CI: 0.731.35) or low-dose cyproterone acetate (CPA; OR: 1.51; CI: 0.33
6.86) compared with non-users. There was a signicantly increased risk of meningioma among male
users of androgen analogues (OR: 19.09; CI: 2.81129.74) and among users of high-dose CPA (OR: 6.30;
CI: 1.3728.94) compared with non-users, however there were only three cases currently using these
drugs. No signicant association was found between meningioma and prostate, breast, or genital
cancers. Conclusions: Our results do not support a role for exogenous hormone use by females in
meningioma development. The risk in males was only observed with high-dose, short-term (<1 year)
therapy. Impact: While hormonal cancers and therapies are not associated with meningioma in females,
the risk in males requires further investigation.
2011 Elsevier Ltd. All rights reserved.

Keywords:
Meningioma
Nested casecontrol
Exogenous hormones
Cancer
Oral contraceptives
Hormonal replacement therapy
Cyproterone

1. Introduction
Meningiomas are typically benign tumours arising from the
meningothelial cells of the arachnoid membrane covering the
brain and spinal cord. The majority of meningiomas (around 90%)
are intracranial [1,2], and they account for approximately 20% of all
intracranial tumours [3,4]. Because the majority of meningiomas
progress slowly [5], most remain asymptomatic and are discovered
only at autopsy or during neuroimaging studies [6]. A metaanalysis of studies reporting incidental ndings from neuroimaging suggested that 0.3% of the general population has unknown
meningioma [7], and this is likely to increase with age; the
prevalence of previously unknown meningioma was 3% in a study
of women aged 75 years [8]. When symptoms arise from a
meningioma they are usually the result of raised intracranial
pressure and vary according to the size and location of the tumour.
Such symptoms include headache, vomiting, hemiparesis, seizures,
changes in personality and mood, and problems with speech, sight,
coordination, and memory [911]. Meningiomas are primarily

* Corresponding author. Tel.: +34 91 531 62 42; fax: +34 91 531 28 71.
E-mail address: luciaceife@telefonica.net (L. Cea-Soriano).
1877-7821/$ see front matter 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.canep.2011.08.003

treated surgically, with radiotherapy being reserved for residual

tumour remaining or recurring after surgery [12]. In approximately 2% of cases, meningiomas are malignant and are associated with
poor outcomes [4].
The aetiology of meningiomas is largely unknown. Risk factors
such as exposure to ionising radiation [13] and chromosomal
deletions [14] are well established, and others, for example mobile
phone use [1517], head trauma [1820], and family history
[21,22], have been proposed but remain uncertain. There is
evidence to suggest that hormones may play a role in the
development of meningiomas, including the observation that
these tumours occur more commonly in women, with a female-tomale ratio of up to 3.5:1 in some age groups [23]. Further evidence
for a possible role for hormones in brain tumour aetiology
includes: the presence of progesterone, oestrogen, and androgen
receptors in some meningiomas [2426]; the suggested association between breast cancer and meningioma [27]; a possible link
between use of exogenous hormones and meningioma development [2831]; and the documented changes in meningioma
biology during the menstrual cycle, pregnancy, and breastfeeding
[32]. In addition, hormonal therapies currently used to treat
prostate cancer, such as luteinising hormone-releasing hormone
(LHRH) agonists and cyproterone acetate (CPA), a progestin with

L. Cea-Soriano et al. / Cancer Epidemiology 36 (2012) 198205

anti-androgenic properties, could be involved in the growth of

existing meningiomas [3335].
This study was carried out to explore the possible association
between hormonal therapies and the risk of developing meningioma in a large primary care-based population.
2. Methods
2.1. Patients and study design
A retrospective cohort study with a nested casecontrol
analysis was conducted using individuals identied from The
Health Improvement Network (THIN) UK primary care database.
Validation studies have shown THIN to be appropriate for use in
pharmacoepidemiology research and to give similar results to the
currently more widely used General Practice Research Database
(GPRD) [36]. The database contains anonymised computerised
information on over 3 million patients, which is entered by
primary care physicians (PCPs) for use in research projects [37].
The computerised information includes patient demographics,
details from PCP visits, diagnoses from specialist referrals and
hospital admissions, results of laboratory tests, and a free-text
section. Prescriptions issued by the PCP are generated directly from

the computer and an indication can be assigned on the basis of

associated diagnostic information. Diagnoses are recorded using
Read codes, which were developed in UK primary care and which
form a comprehensive coded clinical language [38,39]. Drugs are
coded based on data from the Multi-function Standardised Lexicon
for European Community Languages (MULTILEX) classication
[40].
All individuals in the THIN database who were 1289 years old
between January 1996 and June 2008 and who had a current
registration status of permanent or died were identied. Patients
became members of the source population on the rst day within
the study period that they met the criteria of at least 2 years
enrolment with the PCP and 1 year of computerised prescription
history. That date was considered their start date. Patients with a
recorded code for meningioma before the start date were excluded
from the source population. Individuals aged 70 years or older at
the start date and for whom either no data were recorded or there
was only one record during their whole period of follow-up were
excluded. This ensured that patients for whom insufcient data
were available were not included.
All members of the source population were followed up until
the rst of the following endpoints were reached: meningioma
diagnosis, reaching the age of 90 years, death, or the end of the

Study population
2171287 patients
14059934 person-years

Search by Read code

Potential incident meningioma cases

798

Case validation by PCP

521 cases

Questionnaire returned
500 cases

Cases (validated)
453

No case validation by PCP

277 cases

No questionnaire returned
21 cases

Manual review of
returned questionnaires
and documents

Non-cases (validated)
47

199

Manual review of THIN

free-text comments

Cases (ascertained)
292

Non-cases (ascertained)
6

Total number of cases

745
Fig. 1. Study design and case ascertainment. PCP, primary care physician.

200

L. Cea-Soriano et al. / Cancer Epidemiology 36 (2012) 198205

study period (June 2008). The nal source population included

2 171 287 patients who contributed 14 059 934 person-years to
the study over an average follow-up period of 6.5 years.
2.2. Identication of cases
Meningioma cases were identied initially by an automatic
computer search, which found 798 patients with a rst ever
recorded code of meningioma during the study period. Free-text
comments were obtained for all 798 individuals and their patient
proles were reviewed manually.
In order to validate cases, questionnaires were sent to all 521
PCPs (covering 65.3% of patients) who were willing to participate
in this phase of the study. PCPs were asked to conrm the
diagnosis of meningioma and to provide copies of all medical
records related to the diagnosis, including hospital discharge
letters and reports of test procedures (i.e. computed tomography
scans, magnetic resonance imaging, radiography, cerebral angiography, or others as specied by the PCP). The investigators had
no direct contact with the practices; Additional Information
Services (AIS) acted as an intermediary between the practices and
investigators. In total, responses were received to 500 (96.0%)
questionnaires. From these, 453 cases of incident meningiomas
were conrmed (90.6% conrmation rate) using both free-text
comments and questionnaires. A manual review of the patient
proles was conducted (including free-text comments) for the
277 individuals for whom questionnaires were not sent and the 21
for whom no responses were received. This helped to conrm a
further 292 incident cases of meningioma, and six non-cases were
identied.
Thus, 745 cases of incident meningioma were used for the
nested casecontrol analysis (Fig. 1). The index date was dened as
the date of the rst diagnosis of meningioma ascertained by the
PCP or by the rst indication of a meningioma diagnosis found in
the manual review. All patients with incident meningioma were
used as cases in the nested casecontrol analysis.
2.3. Selection of controls
Density sampling was used to select 10 000 controls at random.
A random date within the study period was generated for each
member of the study population and if this date was within his or
her eligible person time (follow-up period), the individual was
selected as a control. The same inclusion and exclusion criteria
were applied to both controls and cases. Controls were frequencymatched to cases by age (within 1 year), sex, and index year (year
of newly diagnosed meningioma). The random date generated for
each control was used as their index date in the nested case
control analysis.

Patients receiving cyproterone acetate (CPA) were allocated

into two groups: high dose, when the daily dose was 50 mg or
higher, and low dose, comprising all daily doses under 50 mg. All
female patients receiving a combination of 2 mg/day CPA with an
oestrogen were also identied.
2.5. Hormone-related comorbidities
Information on comorbidities (such as some breast, genital and
prostate cancers) and lifestyle characteristics recorded at any time
before the index date was collected from THIN. The numbers of PCP
visits, referrals, and hospitalisations were ascertained for the year
prior to the index date.
2.6. Statistical analysis
In this sampling design, the odds ratio (OR) is an unbiased
estimator of the incidence ratio. Unconditional logistic regression
was therefore used to estimate ORs and 95% condence intervals
(CIs) of meningioma associated with each variable of interest.
Statistical analyses were performed using the Stata1 package
version 11.0. Lag-time analyses were conducted to account for the
potential latency that can occur between the time of drug
exposure and the clinical onset of meningioma by advancing the
index date by 1 and 2 years sequentially. Additionally Fishers
exact test was used for variables with less than 5 individuals in any
category.
3. Results
3.1. Cases and controls: main characteristics
In total, 745 incident cases of meningioma were validated
through a combination of PCP conrmation and manual review of
patient les. The overall incidence of meningioma was 5.30 (95%
CI: 4.935.69) per 100 000 person-years. The incidence was higher
in female patients (7.19 [95% CI: 6.627.82] per 100 000 personyears) than in male patients (3.05 [95% CI: 2.653.51] per 100 000
person-years), which corresponds to a female: male ratio of 2.36:1.
Table 1 summarises the baseline characteristics of the cases and
controls studied, contact with the healthcare system, and the
associated risk of meningioma diagnosis. The mean age at
meningioma diagnosis was 62.6 years (95% CI: 61.463.9) for
female patients and 62.2 years (95% CI: 60.064.4) for male
patients. A graded effect was observed for the three healthcare
contact variables studied (PCP visits, referrals, and number of
hospitalisations; respective p value for trend <0.001 for each
variable). We found no association with socioeconomic status
(using the Townsend index which measures deprivation by area)
or with urban/rural living (data not shown).

2.4. Exposure to hormonal therapies

3.2. Exposure to hormonal therapies and meningioma risk
The use of oral contraceptives (OCs) and hormone replacement
therapy (HRT) was evaluated in female patients, and the use of
LHRH agonists, antiandrogens, and other hormones was studied in
male patients. Exposure to drugs was classied as: (1) current use,
where the most recent prescription lasted until the index date or
ended in the year before the index date; (2) past use, when the
most recent use was more than 1 year before the index date; and
(3) non-use, when there was no recorded use of the drug at any
point before the index date. The duration of treatment was also
calculated by summing the time of consecutive prescriptions
(allowing for a free interval gap no greater than 60 days). Current
users were then categorised into two mutually exclusive groups
based on their length of treatment: less than 1 year (short term) or
more than 1 year (long term).

Table 2 presents the risk of developing meningioma associated

with exogenous hormonal treatment in females. Those currently
taking OCs were not at signicantly increased risk of developing
meningioma (OR: 1.15; 95% CI: 0.671.98). A similar result was
observed when the analysis was restricted to women below 50
years of age (OR: 1.04; 95% CI: 0.601.79). Among current users,
61.8% of controls and 55.0% of cases were using progesterone in
combination with oestrogens, and the remainder were using
progesterone alone. Neither therapy was signicantly associated
with meningioma (Table 2).
The association was then analysed according to the time since
OC treatment was initiated. There was no signicant increased risk
of developing meningioma in individuals who had a treatment

L. Cea-Soriano et al. / Cancer Epidemiology 36 (2012) 198205

201

Table 1
Baseline characteristics of individuals in the casecontrol study, contact with the healthcare system, and the presence of meningioma.

Sex
Male
Female
Age (years)
1339
4049
5059
6069
7079
8089
Index date (calendar year)
19961999
20002002
20032005
20062008
PCP visits
04
59
1019
20
Referrals
0
14
510
>10
Hospitalisations
0
1
2

Odds ratio (95% CI)a

Cases with meningioma

(n = 745) number (%)

Controls without meningioma

(n = 10 000) number (%)

Characteristics

Male patients

Female patients

2653 (26.5)
7347 (73.5)

196 (26.3)
549 (73.7)

NA
NA

NA
NA

862
1200
2043
2270
2454
1171

(8.6)
(12.0)
(20.4)
(22.7)
(24.5)
(11.7)

57
89
152
170
184
93

(7.7)
(11.9)
(20.4)
(22.8)
(24.7)
(12.5)

NA
NA
NA
NA
NA
NA

NA
NA
NA
NA
NA
NA

1326
2183
3314
3177

(13.3)
(21.8)
(33.1)
(31.8)

99
164
247
235

(13.3)
(22.0)
(33.2)
(31.5)

NA
NA
NA

NA
NA
NA

3970
2772
2367
891

(39.7)
(27.7)
(23.7)
(8.9)

138
183
277
147

(18.5)
(24.6)
(37.2)
(19.7)

1.00
2.36 (1.523.67)
4.79 (3.117.38)
6.27 (3.7810.37)

1.00
2.02 (1.542.65)
3.80 (2.934.93)
5.97 (4.408.09)

4945
3871
909
275

(49.5)
(38.7)
(9.1)
(2.8)

148
368
150
79

(19.9)
(49.4)
(20.1)
(10.6)

1.00
3.01 (1.984.58)
5.85 (3.4110.03)
11.57 (5.9622.45)

1.00
2.59 (2.033.30)
3.94 (2.885.39)
6.29 (4.179.49)

1.00
1.52 (0.942.46)
1.80 (1.043.10)

1.00
1.36 (1.011.83)
1.59 (1.082.35)

9085 (90.9)
618 (6.2)
297 (3.0)

610 (81.9)
81 (10.9)
54 (7.2)

a
Adjusted for sex, age, calendar year, and the number of PCP visits.
CI, condence interval; NA, not applicable; PCP, primary care physician.

duration of less than 1 year (OR: 1.38; 95% CI: 0.772.48) or who
had a treatment duration of greater than 1 year (OR: 0.60; 95% CI:
0.181.98) compared with non-users.
Current users of HRT were not at increased risk of developing
meningioma (OR: 0.99; 95% CI: 0.731.35). Among current users, a
total of 87.3% of controls and 84.5% of cases were aged 50 years or
more; the corresponding OR was 1.10 (95% CI: 0.801.52) when the

analysis was restricted to this group. A similar proportion of

current users took oestrogens alone (controls, 48.2%; cases, 50.0%)
and oestrogens in combination with progesterone (controls, 43.1%;
cases, 44.8%). Neither treatment was signicantly associated with
meningioma (Table 2).
As expected, among current users of HRT, 67% of controls and
62% of cases had a duration of HRT use greater than 1 year. No

Table 2
Risk of developing meningioma in female patients receiving hormonal therapy.
Exposurea

Odds ratiob (95% CI)

Female controls without

meningioma (n = 7347)

Female cases with

meningioma (n = 549)

Number (%)

Number (%)

6485
262
100
162
600

(88.3)
(3.6)
(1.4)
(2.2)
(8.2)

482
20
9
11
47

(87.8)
(3.6)
(1.6)
(2.0)
(8.6)

1.00
1.15
1.32
1.01
1.17

(0.671.98)
(0.642.76)
(0.502.03)
(0.811.69)

5706
708
341
62
305
933

(77.7)
(9.6)
(4.6)
(0.8)
(4.2)
(12.7)

408
58
29
3
26
83

(74.3)
(10.6)
(5.3)
(0.5)
(4.7)
(15.1)

1.00
0.99
1.01
0.53
1.08
1.10

(0.731.35)
(0.671.52)
(0.171.73)
(0.701.67)
(0.841.44)

7295
52
17
35

(99.3)
(0.7)
(0.2)
(0.5)

545
4
2
2

(99.3)
(0.7)
(0.4)
(0.4)

1.00
1.03 (0.362.95)
1.51 (0.336.86)
0.78 (0.183.35)

Oral contraceptives
Non-use
Current use
Current use of progesterone
Current use of progesterone and oestrogens
Past use
Hormone replacement therapy
Non-use
Current use
Current use of oestrogens
Current use of steroids (tibolone)
Current use of oestrogens and progesterone
Past use
Cyproterone acetate and oestrogen combination
Non-use
Ever use
Current use
Past use

a
Ever use: any use before the index date; current use: when the most recent prescription lasted until the index date or ended in the year before the index date; past use:
when the most recent prescription ended more than 1 year before the index date.
b
Adjusted for age, index year, and number of primary care physician visits.
c
Excludes cyproterone acetatae in combination with oestrogen.
CI, condence interval.

L. Cea-Soriano et al. / Cancer Epidemiology 36 (2012) 198205

202

Table 3
Risk of developing meningioma in male patients receiving hormonal therapy.
Exposurea

LHRH agonists
Non-use
Current use
Past use
Antiandrogensc
Non-use
Current use
Past use
Androgen analoguesd
Non-use
Current use
Past use
Cyproterone acetate
Non-use
Ever use
Current use
Past use

Odds ratiob (95% CI)

Male controls without meningioma (n = 2653)

Male cases with meningioma (n = 196)

Number (%)

Number (%)

2623 (98.9)
26 (1.0)
4 (0.2)

191 (97.4)
4 (2.0)
1 (0.5)

1.00
1.33 (0.453.94)
2.89 (0.3027.64)

2644 (99.7)
7 (0.3)
2 (0.1)

195 (99.5)
1 (0.5)
0

1.00
1.16 (0.149.62)

2642 (99.6)
2 (0.1)
9 (0.3)

192 (98.0)
3 (1.5)
1 (0.5)

2641
12
4
8

192
4
3
1

(99.5)
(0.5)
(0.2)
(0.3)

(98.0)
(2.0)
(1.5)
(0.5)

1.00
19.09 (2.81129.74)
1.25 (0.1510.21)
1.00
3.28 (1.0110.64)
6.30 (1.3728.94)
1.37 (0.1611.42)

a
Ever use: any use before the index date; current use: when the most recent prescription lasted until the index date or ended in the year before the index date; past use:
when the most recent prescription ended more than 1 year before the index date.
b
Adjusted for age, index year, and number of primary care physician visits.
c
Antiandrogens include bicalutamide and utamide.
d
Androgen analogues include testosterone, mesterolone, and uoxymesterone.
CI, condence interval; LHRH, luteinising hormone-releasing hormone.

Table 4
Risk of meningioma associated with hormone-related comorbidities.
Comorbidity

Female patients
Breast cancer
Genital cancer
Male patients
Prostate cancer

Controls without meningioma

Cases with meningioma

Number (%)

Number (%)

n = 7347
252 (3.4)
95 (1.3)
n = 2653
42 (1.6)

n = 549
26 (4.7)
3 (0.6)
n = 196
8 (4.1)

Odds ratioa (95% CI)

1.26 (0.831.91)
0.38 (0.121.20)
1.84 (0.834.07)

Adjusted for age, index year, and number of primary care physician visits.
CI, condence interval.
Genital cancer includes cancer of the cervix, uterus, endometrium, ovary, fallopian tube vagina, labia, vulva and clitoris.

association was found between duration of HRT use and

development of meningioma (data not shown).
All CPA exposure in females was at a dose of 2 mg/day in
combination with oestrogens. Current use of low-dose CPA was not
associated with a signicantly increased risk of meningioma.
When current and past users were pooled into one category (ever
use), no signicant risk of developing meningioma was found with
low-dose CPA use compared with non-use.
Table 3 shows the risk of developing meningioma associated
with male use of exogenous hormones. There was no signicant
increase in risk of meningioma associated with current use of
LHRH agonists and anti-androgens. Current users of male
hormones such as testosterone, mesterolone, and uoxymesterone
had a signicantly increased risk of developing meningioma
compared with non-users, but there were only 3 current users
among the cases which conferred a wide condence interval (OR:
19.09; 95% CI: 2.81129.74; p value in Fishers exact test: 0.004).
Based on small numbers the evaluation of treatment duration was
not possible.
All patients receiving CPA were taking doses higher than 50 mg/
day and all had a recorded diagnosis of prostate cancer. Current use
of high-dose CPA among male patients was associated with an
increased meningioma risk compared with non-users (OR: 6.30;
95% CI: 1.3728.94; p value in Fishers exact test: 0.008). No
association was observed with past use of high-dose CPA. The
corresponding risk of meningioma associated with ever use of
high-dose CPA was 3.28 (95% CI: 1.0110.64). Of the three male

patients receiving high-dose CPA in the year prior to the

occurrence of meningioma, only one had treatment duration of
longer than 1 year, whereas all four control individuals had
received therapy for less than 1 year.
Additionally, in a lag-time analysis, current use of low-dose
CPA in female patients resulted in very similar estimates of risk
when the index date was advanced by 1 year (OR: 1.33; 95% CI:
0.305.85) or 2 years (OR: 1.68; 95% CI: 0.387.45). Among male
patients the risk of developing meningioma associated with highdose CPA use reduced with advancing index date (OR: 3.39; 95%
CI: 0.3433.84 for 1 years time lag; OR: 2.90; 95% CI: 0.3126.84
for 2 years lag time). We did not nd any difference in the
estimate of risk for the other hormonal therapies among women
and men separately.
3.3. Hormone-related comorbidities and meningioma risk
Meningioma risk was assessed for several conditions that could
inuence endogenous hormonal levels and consequently play a
role in the development of this tumour (Table 4).
No signicant increase in the risk of developing meningioma
was found among female patients with breast cancer or genital
cancer compared with those who did not have these conditions.
The risk estimates remained unchanged when analysis was
restricted to female patients with a recorded diagnosis within
the 5 years preceding the index date (OR: 1.24; 95% CI: 0.692.23
for breast cancer; OR: 0.88; 95% CI: 0.272.89 for genital cancer).

L. Cea-Soriano et al. / Cancer Epidemiology 36 (2012) 198205

A diagnosis of prostate cancer any time before the index date

was not signicantly associated with an increased risk of
developing meningioma. No signicant difference in risk was
found when the multivariable model was further adjusted by
prostate cancer therapy (which included CPA, antiandrogens, and
LHRH agonists separately; OR: 2.33; 95% CI: 0.678.03). Furthermore, there was no signicant increase in risk when the analysis
was restricted to individuals with a recorded diagnosis of prostate
cancer within the 5 years preceding the index date (OR: 1.26; 95%
CI: 0.483.32).
4. Discussion
This large, controlled, population-based study evaluated
2 171 287 patients contributing 14 059 934 person-years over
an average follow-up period of 6.5 years, and identied a total of
745 individuals with an incident case of meningioma. There was
no signicant association between meningioma development
and the use of OCs, low-dose CPA, or HRT in female patients. Use
of androgen analogues conferred an increased risk of meningioma in male patients; those taking high-dose CPA also had an
increased risk of meningioma, but this was limited to short-term
use.
Our data do not support the presence of a signicant association
between meningioma and HRT or OC use in female patients. These
ndings are in agreement with other studies [31,4145]. For
example, a large, population-based study that examined risk factors
for meningioma in 143 women with meningioma and 286 agematched controls from a population of approximately 2.8 million
found that there was no signicant association between meningioma risk and past or current use of HRT [41]. In addition, casecontrol
studies have showed no increased risk associated with HRT [31,42].
However, the role of HRT and OCs remains controversial; several
cohort studies have shown a positive relationship between HRT and
meningioma [29,30,46]. Some studies have also reported an
increased risk of meningioma associated with HRT use [43,44].
Furthermore, a protective association of factors known to inuence
endogenous hormones was reported in a small study that relied on
self-reported data [47], although these data do not appear to support
an aetiologic role of OCs or HRT in meningioma development. An
increased risk in current users of OCs compared with those who had
never used OC, was reported by Michaud et al., although they
concluded that their ndings could be due to diagnostic bias and
require conrmation [30].
Our data showed that male exposure to androgen analogues
(testosterone, mesterolone, and uoxymesterone) was signicantly associated with an increased risk of meningioma, albeit
with a very wide condence interval because of the small
number of exposed cases (four) identied in the study
population. While this result should be interpreted cautiously,
it helps to reinforce a possible role for androgens in meningioma
development, as suggested by the presence of androgen
receptors in samples of meningioma tissue [48,49]. The present
study provided little evidence for an increased risk associated
with the use of LHRH agonists, the standard hormonal therapy
for prostate cancer [50]. However, a previous case report
described an individual who had undergone prostatectomy
and then developed meningioma following LHRH agonist
treatment [51]. We found a signicantly increased risk of
meningioma in male patients taking high-dose CPA, but no
signicant association between meningioma and low-dose CPA
use in female patients. However, the estimates of risk in male
individuals are based on only four cases of meningioma in
patients treated with CPA. While high-dose CPA (50300 mg/
day) is used therapeutically in cases of inoperable prostate
cancer [52], lower doses (25100 mg/day) are used to treat

203

sexual aggression in male individuals [53], and severe signs of

androgenisation in female patients [54], as well as to treat maleto-female transsexuals (in conjunction with oestrogens) [55].
Very low doses (12 mg/day) are used as treatment for
androgen-dependent diseases, and as OCs and HRT in female
individuals [56]. There is some evidence from small studies in
the literature to suggest an association between meningiomas
and CPA therapy [34,57]. The present study included only one
male patient receiving high-dose CPA in the year prior to the
occurrence of meningioma who had a treatment period lasting
longer than 1 year while for the remaining 15 patients exposed
to CPA none had a duration greater then 180 days. Long latency
periods between the stimulus and the development of meningioma are well known, particularly in the case of radiation [13]. It
is therefore unlikely that CPA is having a causal effect on
meningioma in the period we studied, and alternatively it may
be acting as a late tumour promoter.
While a trend was observed in the present study towards an
increased risk of meningioma development among patients with
hormonal cancers such as those of the prostate and breast, the risk
estimates were not statistically signicant. Some previous studies
have supported an association between breast cancer and the risk
of meningioma [5860]. However, the ndings of our study do not
support such an association, and are in line with those of other
previous studies that found no statistically signicant association
[27,61].
We also observed a trend according to healthcare utilization.
The reasons for this trend are uncertain; it could be due to
meningioma symptoms prompting the individual to consult
their PCP, but it could also reect an increased prevalence of
comorbidities among individuals who go on to develop
meningioma.
Our study has several strengths and limitations. An important strength is that the records of potential cases (including
free-text comments) were manually reviewed and the case
status was validated by the PCP with a conrmation rate of 91%.
A limitation is the lack of consistent recording in THIN of race
and education (making it impossible to isolate the relationship
of these factors with meningioma), and of reproductive factors,
such as the number of live births, age at menarche, and whether
or not a woman has breastfed. In addition, prescriptions for OCs
issued by family planning clinics will not be recorded in THIN as
they are issued outside the patients GP practice. For this reason,
the numbers in this primary care database may be underrepresented. However, the use of family planning clinics is in
decline and increasingly patients consult their GP for contraceptive needs. This is the case for combined and single component
OCs. Despite the large cohort, another limitation of this study is
the small number of meningioma cases with recorded exposure
to exogenous hormonal treatments. This results in broad CIs, in
particular for dose and duration response analyses. Although the
present study includes data for 14 059 934 person-years, it
appears that a greater number of exposed patients need to be
identied to increase the precision of the risk estimates and to
assess whether hormonal exposure can lead to the development
of meningioma. To our knowledge this is the rst primary
care study reporting the role of cyproterone in meningioma
onset.
In summary, this study in contrast with previous cohort studies
found no association between development of meningioma and
the use of hormonal replacement therapy in female patients. A link
between meningioma and OC use in women was also not observed.
An increased risk of meningioma was found in male patients using
high-dose CPA, but this was restricted to short-term CPA use and
should be interpreted with caution because only four cases were
exposed to CPA.

204

L. Cea-Soriano et al. / Cancer Epidemiology 36 (2012) 198205

Conict of interest statement

LCS and LGR work for the Spanish Centre for Pharmacoepidemiologic Research (CEIFE), which has received unrestricted research
grants from Bayer HealthCare Pharmaceuticals. TB was an employee
of Bayer HealthCare Pharmaceuticals, Berlin, Germany at the time of
the study and M-AW is an employee of Bayer AB, Solna, Sweden.
Acknowledgements
The authors thank Dr Catriona Turnbull and Dr Catherine Hill of
Oxford PharmaGenesisTM Ltd who provided editorial assistance
and Bayer Schering Pharma AG for funding.
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