Abstract
Gender-specific incidence patterns and the presence of hormonal receptors on tumor cells suggest that sex hormones may play a role in the onset of primary brain tumors. However, epidemiological studies on the relation of hormonal risk factors to the risk of brain tumors have been inconsistent. We examined the role of reproductive factors in the onset of glioma and meningioma in a case–control study conducted in the Southeastern US that included 507 glioma cases, 247 meningioma cases, and 695 community-based and friend controls. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95 % confidence intervals (CI) adjusting for age, race, US state of residence, and education. An older age at menarche was associated with an increased risk of glioma (≥15 vs. ≤12 years: OR 1.65; 95 % CI 1.11–2.45), with a stronger association observed in pre-menopausal (OR 2.22; 95 % CI 1.12–4.39) than post-menopausal (OR 1.55; 95 % CI 0.93–2.58) women. When compared to controls, meningioma cases were more likely to have undergone natural menopause (OR 1.52; 95 % CI 1.04–2.21) whereas glioma cases were less likely to be long term users of oral contraceptives (OR 0.47; 95 % CI 0.33–0.68). Increasing parity was not related to the risk of either tumor. Current findings are consistent with a limited role for hormones in the onset of brain tumors in women. Results contribute to a growing body of evidence that a later age at menarche increases the risk of glioma in women.
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Ostrom QT, Gittleman H, Farah P, Ondracek A, Chen Y, Wolinsky Y, Stroup NE, Kruchko C, Barnholtz-Sloan JS (2013) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2006–2010. Neuro Oncol 15(Suppl 2):1–56
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114(2):97–109
Krex D, Klink B, Hartmann C, von Deimling A, Pietsch T, Simon M, Sabel M, Steinbach JP, Heese O, Reifenberger G et al (2007) Long-term survival with glioblastoma multiforme. Brain 130(Pt 10):2596–2606
Preston DL, Ron E, Yonehara S, Kobuke T, Fujii H, Kishikawa M, Tokunaga M, Tokuoka S, Mabuchi K (2002) Tumors of the nervous system and pituitary gland associated with atomic bomb radiation exposure. J Natl Cancer Inst 94(20):1555–1563
Ron E, Modan B, Boice JD Jr, Alfandary E, Stovall M, Chetrit A, Katz L (1988) Tumors of the brain and nervous system after radiotherapy in childhood. N Engl J Med 319(16):1033–1039
Shete S, Hosking FJ, Robertson LB, Dobbins SE, Sanson M, Malmer B, Simon M, Marie Y, Boisselier B, Delattre JY et al (2009) Genome-wide association study identifies five susceptibility loci for glioma. Nat Genet 41(8):899–904
Wrensch M, Jenkins RB, Chang JS, Yeh RF, Xiao Y, Decker PA, Ballman KV, Berger M, Buckner JC, Chang S et al (2009) Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility. Nat Genet 41(8):905–908
Dobbins SE, Broderick P, Melin B, Feychting M, Johansen C, Andersson U, Brannstrom T, Schramm J, Olver B, Lloyd A et al (2011) Common variation at 10p12.31 near MLLT10 influences meningioma risk. Nat Genet 43(9):825–827
Gu J, Liu Y, Kyritsis AP, Bondy ML (2009) Molecular epidemiology of primary brain tumors. Neurotherapeutics 6(3):427–435
CBTRUS (2011) Statistical report: primary brain tumors in the United States, 2004–2007. Central Brain Tumor Registry of the United States. Available at http://www.cbtrus.org/2011-NPCR-SEER/WEB-0407-Report-3-3-2011.pdf
Deorah S, Lynch CF, Sibenaller ZA, Ryken TC (2006) Trends in brain cancer incidence and survival in the United States: surveillance, epidemiology, and end results program, 1973 to 2001. Neurosurg Focus 20(4):E1
McKinley BP, Michalek AM, Fenstermaker RA, Plunkett RJ (2000) The impact of age and sex on the incidence of glial tumors in New York state from 1976 to 1995. J Neurosurg 93(6):932–939
De Nicola AF, Brocca ME, Pietranera L, Garcia-Segura LM (2012) Neuroprotection and sex steroid hormones: evidence of estradiol-mediated protection in hypertensive encephalopathy. Mini Rev Med Chem 12(11):1081–1089
Garcia-Segura LM, Azcoitia I, DonCarlos LL (2001) Neuroprotection by estradiol. Prog Neurobiol 63(1):29–60
Kirches E, Warich-Kirches M (2009) 2-methoxyestradiol as a potential cytostatic drug in gliomas? Anticancer Agents Med Chem 9(1):55–65
Kang SH, Cho HT, Devi S, Zhang Z, Escuin D, Liang Z, Mao H, Brat DJ, Olson JJ, Simons JW et al (2006) Antitumor effect of 2-methoxyestradiol in a rat orthotopic brain tumor model. Cancer Res 66(24):11991–11997
Lis A, Ciesielski MJ, Barone TA, Scott BE, Fenstermaker RA, Plunkett RJ (2004) 2-Methoxyestradiol inhibits proliferation of normal and neoplastic glial cells, and induces cell death, in vitro. Cancer Lett 213(1):57–65
Chamaon K, Stojek J, Kanakis D, Braeuninger S, Kirches E, Krause G, Mawrin C, Dietzmann K (2005) Micromolar concentrations of 2-methoxyestradiol kill glioma cells by an apoptotic mechanism, without destroying their microtubule cytoskeleton. J Neurooncol 72(1):11–16
Jay JR, MacLaughlin DT, Riley KR, Martuza RL (1985) Modulation of meningioma cell growth by sex steroid hormones in vitro. J Neurosurg 62(5):757–762
Batistatou A, Stefanou D, Goussia A, Arkoumani E, Papavassiliou AG, Agnantis NJ (2004) Estrogen receptor beta (ERbeta) is expressed in brain astrocytic tumors and declines with dedifferentiation of the neoplasm. J Cancer Res Clin Oncol 130(7):405–410
Gonzalez-Aguero G, Ondarza R, Gamboa-Dominguez A, Cerbon MA, Camacho-Arroyo I (2001) Progesterone receptor isoforms expression pattern in human astrocytomas. Brain Res Bull 56(1):43–48
Khalid H, Shibata S, Kishikawa M, Yasunaga A, Iseki M, Hiura T (1997) Immunohistochemical analysis of progesterone receptor and Ki-67 labeling index in astrocytic tumors. Cancer 80(11):2133–2140
Korhonen K, Salminen T, Raitanen J, Auvinen A, Isola J, Haapasalo H (2006) Female predominance in meningiomas can not be explained by differences in progesterone, estrogen, or androgen receptor expression. J Neurooncol 80(1):1–7
Blankenstein MA, Verheijen FM, Jacobs JM, Donker TH, van Duijnhoven MW, Thijssen JH (2000) Occurrence, regulation, and significance of progesterone receptors in human meningioma. Steroids 65(10–11):795–800
Khalid H (1994) Immunohistochemical study of estrogen receptor-related antigen, progesterone and estrogen receptors in human intracranial meningiomas. Cancer 74(2):679–685
Claus EB, Calvocoressi L, Bondy ML, Schildkraut JM, Wiemels JL, Wrensch M (2011) Family and personal medical history and risk of meningioma. J Neurosurg 115(6):1072–1077
Rao G, Giordano SH, Liu J, McCutcheon IE (2009) The association of breast cancer and meningioma in men and women. Neurosurgery 65(3):483–489 discussion 489
Custer BS, Koepsell TD, Mueller BA (2002) The association between breast carcinoma and meningioma in women. Cancer 94(6):1626–1635
Cowppli-Bony A, Bouvier G, Rue M, Loiseau H, Vital A, Lebailly P, Fabbro-Peray P, Baldi I (2011) Brain tumors and hormonal factors: review of the epidemiological literature. Cancer Causes Control 22(5):697–714
Little RB, Madden MH, Thompson RC, Olson JJ, Larocca RV, Pan E, Browning JE, Egan KM, Nabors LB (2013) Anthropometric factors in relation to risk of glioma. Cancer Causes Control 24(5):1025–1031
Qi ZY, Shao C, Zhang X, Hui GZ, Wang Z (2013) Exogenous and endogenous hormones in relation to glioma in women: a meta-analysis of 11 case-control studies. PLoS ONE 8(7):e68695
Kabat GC, Park Y, Hollenbeck AR, Schatzkin A, Rohan TE (2011) Reproductive factors and exogenous hormone use and risk of adult glioma in women in the NIH-AARP Diet and Health Study. Int J Cancer 128(4):944–950
Silvera SA, Miller AB, Rohan TE (2006) Hormonal and reproductive factors and risk of glioma: a prospective cohort study. Int J Cancer 118(5):1321–1324
Onland-Moret NC, Peeters PH, van Gils CH, Clavel-Chapelon F, Key T, Tjonneland A, Trichopoulou A, Kaaks R, Manjer J, Panico S et al (2005) Age at menarche in relation to adult height: the EPIC study. Am J Epidemiol 162(7):623–632
Juul A, Bang P, Hertel NT, Main K, Dalgaard P, Jorgensen K, Muller J, Hall K, Skakkebaek NE (1994) Serum insulin-like growth factor-I in 1030 healthy children, adolescents, and adults: relation to age, sex, stage of puberty, testicular size, and body mass index. J Clin Endocrinol Metab 78(3):744–752
Kitahara CM, Wang SS, Melin BS, Wang Z, Braganza M, Inskip PD, Albanes D, Andersson U, Beane Freeman LE, Buring JE, et al (2012) Association between adult height, genetic susceptibility and risk of glioma. Int J Epidemiol 41(4):1075–1085
Jhawar BS, Fuchs CS, Colditz GA, Stampfer MJ (2003) Sex steroid hormone exposures and risk for meningioma. J Neurosurg 99(5):848–853
Claus EB, Calvocoressi L, Bondy ML, Wrensch M, Wiemels JL, Schildkraut JM (2013) Exogenous hormone use, reproductive factors, and risk of intracranial meningioma in females. J Neurosurg 118(3):649–656
Korhonen K, Raitanen J, Isola J, Haapasalo H, Salminen T, Auvinen A (2010) Exogenous sex hormone use and risk of meningioma: a population-based case-control study in Finland. Cancer Causes Control 21(12):2149–2156
Johnson DR, Olson JE, Vierkant RA, Hammack JE, Wang AH, Folsom AR, Virnig BA, Cerhan JR (2011) Risk factors for meningioma in postmenopausal women: results from the Iowa women’s health study. Neuro Oncol 13(9):1011–1019
Michaud DS, Gallo V, Schlehofer B, Tjonneland A, Olsen A, Overvad K, Dahm CC, Kaaks R, Lukanova A, Boeing H et al (2010) Reproductive factors and exogenous hormone use in relation to risk of glioma and meningioma in a large European cohort study. Cancer Epidemiol Biomarkers Prev 19(10):2562–2569
Wigertz A, Lonn S, Hall P, Auvinen A, Christensen HC, Johansen C, Klaeboe L, Salminen T, Schoemaker MJ, Swerdlow AJ et al (2008) Reproductive factors and risk of meningioma and glioma. Cancer Epidemiol Biomarkers Prev 17(10):2663–2670
Custer B, Longstreth WT Jr, Phillips LE, Koepsell TD, Van Belle G (2006) Hormonal exposures and the risk of intracranial meningioma in women: a population-based case-control study. BMC Cancer 6:152
Lee E, Grutsch J, Persky V, Glick R, Mendes J, Davis F (2006) Association of meningioma with reproductive factors. Int J Cancer 119(5):1152–1157
Hatch EE, Linet MS, Zhang J, Fine HA, Shapiro WR, Selker RG, Black PM, Inskip PD (2005) Reproductive and hormonal factors and risk of brain tumors in adult females. Int J Cancer 114(5):797–805
Schlehofer B, Blettner M, Preston-Martin S, Niehoff D, Wahrendorf J, Arslan A, Ahlbom A, Choi WN, Giles GG, Howe GR et al (1999) Role of medical history in brain tumour development. Results from the international adult brain tumour study. Int J Cancer 82(2):155–160
Felini MJ, Olshan AF, Schroeder JC, Carozza SE, Miike R, Rice T, Wrensch M (2009) Reproductive factors and hormone use and risk of adult gliomas. Cancer Causes Control 20(1):87–96
Schlehofer B, Blettner M, Becker N, Martinsohn C, Wahrendorf J (1992) Medical risk factors and the development of brain tumors. Cancer 69(10):2541–2547
Cicuttini FM, Hurley SF, Forbes A, Donnan GA, Salzberg M, Giles GG, McNeil JJ (1997) Association of adult glioma with medical conditions, family and reproductive history. Int J Cancer 71(2):203–207
Huang K, Whelan EA, Ruder AM, Ward EM, Deddens JA, Davis-King KE, Carreon T, Waters MA, Butler MA, Calvert GM et al (2004) Reproductive factors and risk of glioma in women. Cancer Epidemiol Biomarkers Prev 13(10):1583–1588
Benson VS, Pirie K, Green J, Casabonne D, Beral V (2008) Lifestyle factors and primary glioma and meningioma tumours in the million women study cohort. Br J Cancer 99(1):185–190
Schlehofer B, Blettner M, Wahrendorf J (1992) Association between brain tumors and menopausal status. J Natl Cancer Inst 84(17):1346–1349
Lambe M, Coogan P, Baron J (1997) Reproductive factors and the risk of brain tumors: a population-based study in Sweden. Int J Cancer 72(3):389–393
Wang SS, Hartge P, Yeager M, Carreon T, Ruder AM, Linet M, Inskip PD, Black A, Hsing AW, Alavanja M et al (2011) Joint associations between genetic variants and reproductive factors in glioma risk among women. Am J Epidemiol 174(8):901–908
Wigertz A, Lonn S, Mathiesen T, Ahlbom A, Hall P, Feychting M (2006) Risk of brain tumors associated with exposure to exogenous female sex hormones. Am J Epidemiol 164(7):629–636
Cea-Soriano L, Blenk T, Wallander MA, Rodriguez LA (2012) Hormonal therapies and meningioma: is there a link? Cancer Epidemiol 36(2):198–205
Michels KB, Manson JE (2003) Postmenopausal hormone therapy: a reversal of fortune. Circulation 107(14):1830–1833
Wacholder S, Silverman DT, McLaughlin JK, Mandel JS (1992) Selection of controls in case-control studies. II. Types of controls. Am J Epidemiol 135(9):1029–1041
Acknowledgments
The authors wish to acknowledge our study participants and their families. We further wish to thank the clinicians and research staffs at participating medical centers for their contributions. In addition, we acknowledge Dr. Sajeel A. Chowdhary at the Florida Hospital Cancer Institute in Orlando, FL, as well as Harold Colbassani, MD; Dean Gobo, MD; and Christopher Mickler, DO at Morton Plant Mease Healthcare and Baycare Health System in Clearwater, Fl for their efforts recruiting subjects to the study. The project was supported by the National Institutes of Health (R01CA116174) and institutional funding provided by the Moffitt Cancer Center (Tampa, FL) and the Vanderbilt-Ingram Comprehensive Cancer Center (Nashville, TN). Development of this manuscript was supported in part through a National Cancer Institute postdoctoral fellowship training grant (R25CA147832).
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Anic, G.M., Madden, M.H., Nabors, L.B. et al. Reproductive factors and risk of primary brain tumors in women. J Neurooncol 118, 297–304 (2014). https://doi.org/10.1007/s11060-014-1427-0
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DOI: https://doi.org/10.1007/s11060-014-1427-0