Reproductive, menstrual, and other hormone-related factors and
risk of renal cell cancer
Antonella Zucchetto1*, Renato Talamini1, Luigino Dal Maso1, Eva Negri2, Jerry Polesel1, Valerio Ramazzotti3,
Maurizio Montella4, Vincenzo Canzonieri5, Diego Serraino1, Carlo La Vecchia2,6and Silvia Franceschi7
1SOC Epidemiologia e Biostatistica, IRCCS ‘‘Centro di Riferimento Oncologico’’, Aviano (PN), Italy
2Dipartimento di Epidemiologia, Istituto di Ricerche Farmacologiche ‘‘Mario Negri’’, Milan, Italy
3Servizio Integrato di Epidemiologia e Sistemi Informativi, Istituto Nazionale Tumori ‘‘Regina Elena’’, Rome, Italy
4Servizio di Epidemiologia, Istituto Nazionale Tumori ‘‘Fondazione G. Pascale’’, Naples, Italy
5SOC Anatomia Patologica, IRCCS ‘‘Centro di Riferimento Oncologico’’, Aviano (PN), Italy
6Istituto di Statistica Medica e Biometria, Universita ` degli Studi di Milano, Milan, Italy
7International Agency for Research on Cancer, Lyon, France
A role of hormone-related factors in renal cell cancer (RCC) etiol-
ogy has been hypothesized, but the epidemiological evidence is
inconsistent. The present study aimed at evaluating the effect of
reproductive, menstrual and other gender-specific variables on
RCC risk among women. This study is part of a larger hospital-
based, case-control study on RCC risk, conducted in northern,
central and southern Italy. Cases were 273 women, below age 80,
with histologically confirmed, incident RCC. Controls were 546
women hospitalized for acute, nonneoplastic conditions, fre-
quency-matched to cases by age and center. Odds ratios (OR) and
95% confidence intervals (CI) were computed using multiple logis-
tic regression models. RCC risk was inversely related to age at
first birth (OR 5 0.7, 95% CI 0.5–1.0, for ≥25 years vs. <25
years). Hysterectomy was found to double RCC risk (OR 5 2.3,
95% CI 1.3–4.2). A negative association of borderline-statistical
significance emerged for age at menarche, whereas, no associa-
tions were found between RCC risk and parity, menopausal sta-
tus, age at menopause and use of hormone replacement therapy or
oral contraceptives. Our findings give support to a role of hyster-
ectomy in increasing RCC risk without corroborating, however, a
major role of female hormone-related factors.
' 2008 Wiley-Liss, Inc.
Key words: kidney cancer; reproductive and menstrual factors;
hormones; hysterectomy; case-control study
The kidney is among the 10 most common cancer sites in more
developed countries. Worldwide, incidence rates are lower in women
than in men, with ?1:2 ratio. Such difference is recorded in Italy
also, where the world-standardized incidence rates per 100,000 per-
son-years are 11.5 and 4.6 among men and women, respectively.1
Cigarette smoking, obesity and hypertension are the only estab-
lished risk factors for renal cell cancer (RCC) (i.e., the most com-
mon type of kidney cancer) in both sexes.2–5Among potential risk
factors, a role of hormone-related dynamics on RCC development
has been hypothesized. To our knowledge, human studies have
never examined endogenous estrogens with RCC risk. However, ste-
roid hormone receptors have been found in normal and cancerous re-
nal cell tissue, indicating possible hormonal regulations6; this line of
reasoning is strengthened by the observation that polymorphisms of
the estrogen receptor gene were hypothesized to play a role in the
pathogenesis of RCC.7Animal studies have shown that estrogens
can promote or induce kidney cancer development.8In addition,
obesity, which is consistently associated to RCC, provides a major
source of estrogens in postmenopausal women.9
To evaluate the role of menstrual and reproductive history, ex-
ogenous hormone use, and gynecologic surgery in RCC etiology
in women, we conducted a multicentre, case-control study in Italy.
Material and methods
This study is part of a hospital-based, case-control study on
RCC risk in both sexes, which has been described in details else-
where.10,11The study was conducted between 1992 and 2004 in
4 Italian areas: the provinces of Pordenone and Gorizia, the
greater Milan area in the North, the province of Latina in the
Center, and the urban area of Naples in the South.
For the aim of this analysis, cases were 273 women (median
age 62, range 24–79 years) admitted with incident, histologically
confirmed cancer of the renal parenchyma (International Classifi-
cation of Diseases, Ninth Revision, code 189.0) to the main hospi-
tals of study areas. Histologic information on cases included can-
cer cell type classification, revised according to the 2004 WHO
Control subjects were 546 women (median age 62, range 22–79
years) admitted to the same network of hospitals of cases for
acute, non-neoplastic diseases that were not associated to hor-
mone-related disorders or genital tract conditions. Among these
women, 34% had nontraumatic orthopedic disorders, 30% trau-
mas, 8% surgical conditions and 28% miscellaneous diagnoses,
such as eye, ear, nose, throat, dental, or skin illnesses. Controls
were frequency-matched to cases by study center and quinquennia
of age, with a case-to-control ratio of 1:2.
Centrally trained staff members interviewed all eligible women,
during their hospital stay, using a structured questionnaire. Study
compliance was high (less than 5% of contacted cases and controls
refused the interview) and similar among study areas. The ques-
tionnaire collected information on socio-demographic characteris-
tics, anthropometric measures at different ages, lifestyle habits
(including physical activity, smoking, alcohol drinking, and diet),
and history of cancer in first-degree relatives. It also included a
problem-oriented medical section to assess the history of clinically
relevant diseases and medical procedures, including treated hyper-
tension, hysterectomy, mono/bilateral oophorectomy, and gyneco-
logic conditions (i.e., ovarian cysts, polycystic ovary syndrome,
endometriosis, uterine fibroids, pelvic infections and infertility).
In a detailed section of the questionnaire women were asked to
report their menstrual and reproductive histories, including age at
menarche, menopausal status (menopause was defined as lack of
menstruation for at least 12 months), type of menopause, age at
menopause, number of births and abortions, and the age at each
child delivery. Information was specifically collected on lifelong
use of oral contraceptives (OC) and hormone replacement therapy
(HRT), including age at start and duration of each episode of use.
Grant sponsor: Italian Association for Cancer Research.
*Correspondence to: SOC Epidemiologia e Biostatistica, IRCCS
‘‘Centro di Riferimento Oncologico—Aviano’’; Via F. Gallini no. 2;
33081Aviano (PN), Italy. Fax: 139-0434-659231.
Received 19 March 2008; Accepted after revision 21 May 2008
Int. J. Cancer: 123, 2213–2216 (2008)
' 2008 Wiley-Liss, Inc.
Publication of the International Union Against Cancer
Conditional logistic regression models provided odds ratios
(OR) and the corresponding 95% confidence intervals (CI) esti-
mates.13Analyses were conditioned on the matching variables
(i.e., study center and quinquennia of age), and adjusted for period
of interview (<1998, ?1998), years of education (<7, 7–11,
?12), smoking habits (never, former, current smoker of <20 or
?20 cigarettes/day), history of hypertension (No, Yes), family his-
tory of kidney cancer in first-degree relatives (No, Yes), and body
mass index (BMI: weight (kg)/height (cm)2) at age 30 years (<20,
20–<25, 25–<30, ?30 kg/m2) which was deemed a better indica-
tor of the role of overweight/obesity on RCC risk than current
BMI in our population.10
Table I reports the distribution of cases and controls according
to age, potential confounding variables and histologic type of
RCC. Cases were more educated, had been more frequently over-
weight/obese in young adulthood (i.e., BMI ? 25 kg/m2), and,
more often than controls, reported history of hypertension or of
kidney cancer in first-degree relatives. History of smoking did not
substantially vary between cases and controls.
Increasing age at menarche was nonsignificantly associated to a
decreasing risk of RCC, with an OR of 0.7 (95% CI 0.5–1.1) for
women who were aged 14 years or more at menarche, compared
to those aged below 12 years (Table II). No associations emerged
for menopausal status at diagnosis and age at natural menopause
Overall parity did not influence RCC risk (Table II). The OR
was 1.1 (95% CI 0.7–1.8) among parous women compared to nul-
liparae, with no trend in risk for number of deliveries. An inverse
association with RCC onset emerged for age at first birth, with an
almost 30% reduction in risk for giving birth to the first child at 25
years or more, compared to less than 25 years (Table II); this asso-
ciation was approximately linear, with an OR of 0.97 (95% CI
0.93–1.00) for each year of delay of age at first birth, starting from
age 15 years.
No relation was found between OC use and RCC risk (Table
II). In comparison with never use, the OR was 0.9 (95% CI 0.5–
1.7) among OC users and no association emerged with duration of
use (data not shown). HRT use among postmenopausal women
was nonsignificantly associated to RCC risk (OR 5 1.2, 95% CI
0.7–2.1, Table II), even if the ORs seemed to increase with dura-
tion of use, being 1.1 (95% CI 0.6–2.0) and 1.7 (95% CI 0.6–4.7)
for <5 years and ?5 years of use, respectively.
A 2-fold excess RCC risk (OR 5 2.3, 95% CI 1.3–4.2) was
found among hysterectomized women, as compared to those who
had never undergone any type of gynecologic surgery (Table II),
and the risk estimates did not substantially vary according to age
at, or years since hysterectomy (data not shown). Conversely, no
significant associations were observed for types of surgery (i.e.,
mono/bilateral oophorectomy with or without hysterectomy).
The associations between RCC risk and age at menarche, age at
first birth and gynecologic surgery were not significantly heteroge-
neous in different strata of cancer histologic type, smoking habit
and BMI at age 30 years (Table III).
The findings of the present study point to a reduced RCC risk
among women with late age at first birth and to an increased RCC
risk among those undergoing hysterectomy.
The borderline-significant inverse association between age at
menarche and RCC risk is in agreement with most of the previous
epidemiological studies. The International Renal Cell Study14
found a nonsignificant 30% risk reduction for age at menarche
over 14 years, as compared to less than 12 years. Nonsignificant
inverse associations were observed also by other studies,15,16but
some reported a lack of association.17,18By contrast, only 1 cohort
study found a nonsignificant direct association with age at men-
arche.19With regard to age at menopause or menopausal status,
our results confirm previous null findings.14–18,20
We do not confirm earlier suggestions of a relation between
parity and RCC risk. Several epidemiological studies reported
approximately doubled risks among women with 5 or more child-
births.14,17,20–23However, in the present study, only 8% of cases
and controls had 5 or more children. At this regard, it is also worth
noting that a previous study observed an effect of parity mainly
among overweight and hypertensive women, thus suggesting that
parity might affect RCC risk by interacting with these 2 known
RCC risk factors.17Because of the relatively low study power, we
could not examine the effect of parity by subgroups. Another
case-control study showed a nonsignificant positive association
with parity,24whereas others found no relation.15,16,18Findings
from the present study indicate a decreasing RCC risk for increas-
ing age at first birth, in agreement with previous studies that found
significant,14,15,21or nonsignificant inverse associations.17,19,23
Recent longitudinal studies conducted in the United States
among 37,440 women20and in Canada among 89,835 women19
did not find a statistical significant association between OC use
and RCC risk overall; however, when the analysis was stratified
according to smoking status, OC use appeared to confer a 45%
reduction in RCC risk among never smokers.19This reduction was
in agreement with findings of 2 case-control.14,23We did not find
any influence of OC use on RCC risk, neither considering smoking
status (data not shown). On the other hand, our results indicate a
slight increased RCC risk among HRT users, as already noted in
Italy,25while other studies found significant increased risks among
estrogenic-only HRT users.17,18,20As exogenous hormone use is
not common in Italy (8 and 11% of our study group reported OC
TABLE I – DISTRIBUTION OF 273 WOMEN WITH RENAL CELL CANCER
AND 546 CONTROLS, ACCORDING TO AGE AND OTHER
SELECTED VARIABLES. ITALY, 1992–2004
Body mass index at age 30 years2(kg/m2)
History of hypertension
Family history of kidney cancer3
Other known type
1Ex-smokers were women who had quit smoking for at least 4
years.–2The sum does not add up to the total, because of some missing
values (17 cases, 57 controls); current body mass index was used for
women aged less than 30 years.–3In first-degree relatives.
ZUCCHETTO ET AL.
and HRT use, respectively), we were unable to perform analyses
in sub-strata of different HRT types.
In our study a more-than-doubled RCC risk was observed
among women who had undergone hysterectomy, a relation that
has been inconsistently reported in the literature. A few previous
studies showed excess risks among hysterectomized women, or
among women who had undergone oophorectomy, or both surgi-
cal interventions.14,15,17,18,24Cases and controls enrolled in the
present study had no prior history of cancer in the pelvic region.
Furthermore, none of the gynecologic conditions, which could
TABLE II – DISTRIBUTION OF 273 WOMEN WITH RENAL CELL CANCER AND 546 CONTROLS, WITH
CORRESPONDING ODDS RATIOS (OR) AND 95% CONFIDENCE INTERVAL (CI), ACCORDING
TO MENSTRUAL AND REPRODUCTIVE HISTORY, EXOGENOUS HORMONES USE,
AND GYNECOLOGIC SURGERY.1ITALY, 1992–2004
Cases no. (%)Controls no. (%) OR2(95% CI)
Age at menarche (years)
v2for trend (p-value)
No. of deliveries
v2for trend (p-value)
Age at first birth (years)
Age at natural menopause4(years)
v2for trend (p-value)
2.70 (p 5 0.10)
0.44 (p 5 0.51)
0.05 (p 5 0.82)
OC: oral contraceptive; HRT: hormone replacement therapy.
1The sum may not add up to the total because of some missing values.–2Estimated from multiple logis-
tic regression models, conditioned on center and age, and adjusted for calendar year of interview, years
of education, smoking habits, body mass index at age 30 years, family history of kidney cancer in
first-degree relatives, and history of hypertension.–3Reference category.–4Post-menopausal women
only.–5Mono/bilateral oophorectomy with/without hysterectomy.
TABLE III – DISTRIBUTION OF 273 WOMEN WITH RENAL CELL CANCER AND 546 CONTROLS, WITH CORRESPONDING ODDS RATIOS1(OR) AND 95%
CONFIDENCE INTERVAL (CI), ACCORDING TO SELECTED VARIABLES IN STRATA OF HISTOLOGIC TYPE, SMOKING HABIT, AND BODY MASS
INDEX (BMI) AT AGE 30 YEARS. ITALY, 1992–2004
Histologic typeSmoking habit BMI at age 30 (kg/m2)2
Clear cell Other3
Never smokerEver smoker
OR (95% CI)OR (95% CI)OR (95% CI) OR (95% CI)OR (95% CI)OR (95% CI)
Age at menarche (years)
Age at first birth (years)
0.89 (0.58–1.36)0.42 (0.20–0.87) 0.61 (0.40–0.92)0.75 (0.37–1.52) 0.58 (0.38–0.89) 1.32 (0.56-3.07)
1Estimated from multiple logistic regression models, conditioned on center and age, and adjusted for calendar year of interview, years of
education, smoking habits, BMI at age 30 years, family history of kidney cancer in first-degree relatives, and history of hypertension, as appro-
priate.–2Current BMI was used for women aged less than 30 years.–3Unknown types were excluded.–4Reference category.–5Mono/bilateral
oophorectomy with or without hysterectomy.
HORMONE-RELATED FACTORS AND RENAL CELL CANCER RISK
have caused surgery (e.g., uterine fibroids, endometriosis, ovarian Download full-text
cysts, polycystic ovary syndrome, etc.), was found to increased
Several other potential hormone-related risk factors for RCC
were studied, including number of pregnancies, abortions, age at
last birth, years since last birth, and years of menstruation, but no
significant associations emerged.
Overall, our findings cannot be easily interpreted in biological
terms. Hormones, either directly or through growth factors, may
act as promoters of malignant changes by stimulating renal cell
proliferation.26Hysterectomy may cause hormonal alterations
that influence renal carcinogenesis,14and, as hypothesized by
Gago-Dominguez and colleagues,27its association with RCC
risk could be due to the lipid perioxidation mechanism. An alter-
native explanation could be related to possible damage to the
kidney, as a result of unintentional ureteral injury during the
With regard to the internal validity of our study, we cannot
exclude problems of reliability and recall bias. However, the inter-
viewer-administered questionnaire, employed in this study to col-
lect information on menstrual-reproductive factors and medical
conditions, had been previously tested for reliability.28Moreover,
the choice of hospital controls offers good reliability and validity
of information on drug use and medical procedures, given the sim-
ilar attention to medical history of cases and controls.29There was
also no evidence that reproductive, menstrual, exogenous hor-
mones use, or histories of gynecologic procedures should have
been differentially reported by cases and controls, as the general
population was unaware of the possible relationship between kid-
ney cancer and the analyzed variables, and given the similar hos-
Case-control studies, including hospital-based ones, may be
susceptible to selection bias.13However, in our study, cases and
controls were enrolled in the same catchment areas and participa-
tion was almost complete in the 2 groups. It is worth stressing that
women admitted for any condition related to exposures under
study were meticulously excluded from the control group. Further-
more, statistical analyses conducted using different subgroups of
controls did not alter the results. In addition, careful allowance
was made for potential confounding factors.
In conclusion, our findings give support to a role of hysterec-
tomy in increasing RCC risk and to an inverse association with
age at first birth. However, we could not corroborate a major role
of female hormone-related factors in RCC risk.
The authors thank Mrs. L. Mei and I. Calderan for editorial
assistance, Mrs. M. Volpato and Dr. M. Cozzi for study coordina-
tion, and Mrs. G. Bessega and L. Zaina, Drs. M. Grimaldi and O.
Manganelli for data collection. We are deeply thankful to Drs. A.
Garbeglio, A. Lenardon, and D. Maruzzi for their support in iden-
tifying cancer cases, and to Drs. G. Chiara, G. Tosolini, L. Forner,
A. Mele, E. Trevisanutto, P. Ascierto, R. Di Lauro, and R. Magri
for providing hospital control patients.
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