Cancer Causes & Control

, Volume 25, Issue 8, pp 1007–1013 | Cite as

A pooled multisite analysis of the effects of female reproductive hormones on glioma risk

  • Bhuma KrishnamachariEmail author
  • Dora Il’yasova
  • Michael E. Scheurer
  • Melissa L. Bondy
  • Margaret Wrensch
  • Faith G. Davis
Original Paper



The association between female reproductive factors and glioma risk is unclear, but most published studies have been limited by small sample size. We conducted a pooled multisite study of pre- and postmenopausal women, investigating the effect of female reproductive factors, including hormonal medications.


Unconditional logistic regression was used to calculate odds ratios (ORs) and 95 % confidence intervals (95 % CIs) assessing the effects of female reproductive factors and female hormonal medications in glioma cases and unrelated controls.


Menarche over the age of 15 as compared to under 12 was associated with a statistically significant risk for glioma (OR 2.00, 95 % CI 1.47–2.71). Use of oral contraceptive pills (OCP) was inversely associated with risk of glioma (OR 0.61, 95 % CI 0.50–0.74), and there was an inverse trend with longer duration of OCP use (p for trend <0.0001). Use of hormone replacement therapy (HRT) was also inversely associated with risk of glioma (OR 0.55, 95 % CI 0.44–0.68), and there was an inverse trend with longer duration of use (p for trend <0.0001). Compared to those reporting neither OCP use nor HRT use, those who reported using both were less likely to have a diagnosis of glioma (OR 0.34, 95 % CI 0.24–0.48).


Female reproductive hormones may decrease the risk for glioma. The association appears to be strongest with greater length of use and use of both HRT and OCP.


HRT Hormones Females Contraceptives Glioma 



The Brain Tumor Epidemiology Consortium (BTEC) was instrumental in facilitating the collaboration and data sharing necessary for this study. In addition, the following individuals are acknowledged for their contributions: MD Anderson: Phyllis Adatto; University of Illinois at Chicago/Duke Study: Candace Zahora, Kristin Rankin, North Shore University Health System: Pat Lada, and Nicholas Vick; University of California at San Francisco: Lucie McCoy and Terri Rice. Research at the University of Illinois at Chicago was conducted under a Brain Tumor SPORE grant project (NIH Specialized Programs of Research Excellence grant 5P50 CA108786-4), directed by Dr. Faith Davis, Dr. Darell Bigner and Dr. Francis Ali-Osman. Funding was also received from the American Brain Tumor Association. Data from MD Anderson Cancer Center were collected under NIH grant R01CA070917 (M. Bondy, PI). M. E. Scheurer was funded by NIH grant K07CA131505. Data from UCSF were collected with funding from R01CA52689 and P50CA097257.


  1. 1.
    Ostrom QT, Gittleman H, Farah P et al (2013) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States 2006–2010. Neuro-Oncol 15(Suppl 2):ii1–ii56PubMedCrossRefGoogle Scholar
  2. 2.
    Preston DL, Ron E, Yonehara S, Kobuke T, Fujii H, Kishikawa M et al (2002) Tumors of the nervous system and pituitary gland associated with atomic bomb radiation exposure. J Natl Cancer Inst 94:1555–1563PubMedCrossRefGoogle Scholar
  3. 3.
    Yonehara S, Brenner AV, Kishikawa M, Inskip PD, Preston DL, Ron E et al (2004) Clinical and epidemiologic characteristics of first primary tumors of the central nervous system and related organs among atomic bomb survivors in Hiroshima and Nagasaki, 1958–1995. Cancer 101:1644–1654PubMedCrossRefGoogle Scholar
  4. 4.
    Garcia-Segura LM, Azocoitia I, DonCarlos LL (2001) Neuroprotection by estradiol. Prog Neurobiol 63:29–60PubMedCrossRefGoogle Scholar
  5. 5.
    Santagati S, Melcangi RC, Celotti F, Martini L, Maggi A (1994) Estrogen receptor is expressed in different types of glial cells in culture. J Neurochem 63:2058–2064PubMedCrossRefGoogle Scholar
  6. 6.
    Carroll RS, Zhang J, Dashner K, Sar M, Black PM (1995) Steroid hormone receptors in astrocytic neoplasms. Neurosurgery 37:496–503PubMedCrossRefGoogle Scholar
  7. 7.
    Khalid MH, Shibata S, Furukawa K, Nadel A, Ammerman MD, Caputy AJ (2004) Role of estrogen receptor-related antigen in initiating the growth of human glioma cells. J Neurosurg 100:923–930PubMedCrossRefGoogle Scholar
  8. 8.
    Hatch EE, Linet MS, Zhang J, Fine HA, Shapiro WR, Selker RG et al (2005) Reproductive and hormonal factors and risk of brain tumors in adult females. Int J Cancer 114:797–805PubMedCrossRefGoogle Scholar
  9. 9.
    Silvera SA, Miller AB, Rohan TE (2006) Hormonal and reproductive factors and risk of glioma: a prospective cohort study. Int J Cancer 118:1321–1324PubMedCrossRefGoogle Scholar
  10. 10.
    Hochberg F, Toniolo P, Cole P (1990) Nonoccupational risk indicators of glioblastoma in adults. J Neuro-Oncol 8:55–60CrossRefGoogle Scholar
  11. 11.
    Cantor KP, Lynch CF, Johnson D (1993) Reproductive factors and risk of brain, colon, and other malignancies in Iowa (United States). Cancer Causes Control 4:505–511PubMedCrossRefGoogle Scholar
  12. 12.
    Lambe M, Coogan P, Baron J (1997) Reproductive factors and the risk of brain tumors: a population-based study in Sweden. Int J Cancer 72:389–393PubMedCrossRefGoogle Scholar
  13. 13.
    Schlehofer B, Blettner M, Preston-Martin S, Niehoff D, Wahrendorf J, Arslan A, Ahlbom A, Choi WN, Giles GG, Howe GR, Little J, Ménégoz F et al (1999) Role of medical history in brain tumor development. Results from the International Adult Brain Tumor Study. Int J Cancer 82:155–160PubMedCrossRefGoogle Scholar
  14. 14.
    Huang K, Whelan EA, Ruder AM, Ward EM, Deddens JA, Davis-King KE et al (2004) Reproductive factors and risk of glioma in women. Cancer Epidemiol Biomarkers Prev 13:1583–1588PubMedGoogle Scholar
  15. 15.
    Felini MJ, Olshan AF, Schroeder JC, Carozza SE, Miike R, Rice T, Wrensch M (2009) Reproductive factors and hormone use and risk of adult glioma. Cancer Causes Control 20:87–96PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Wigertz A, Lönn S, Mathiesen T, Ahlbom A, Hall P, Feychting M et al (2006) Risk of brain tumors associated with exposure to exogenous female sex hormones. Am J Epidemiol 164:629–636PubMedCrossRefGoogle Scholar
  17. 17.
    Benson VS, Pirie K, Green J, Casabonne D, Beral V, Million Women Study Collaborators (2008) Lifestyle factors and primary glioma and meningioma tumors in the Million Women Study cohort. Br J Cancer 99:185–190PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Wigertz A, Lönn S, Hall P, Auvinen A, Christensen HC, Johansen C, Klaeboe L, Salminen T, Schoemaker MJ, Swerdlow AJ, Tynes T, Feychting M (2008) Reproductive factors and risk of meningioma and glioma. Cancer Epidemiol Biomarkers Prev 17:2663–2670PubMedCrossRefGoogle Scholar
  19. 19.
    Schlehofer B, Blettner M, Wahrendorf J (1992) Association between brain tumors and menopausal status. J Natl Cancer Inst 84:1346–1349PubMedCrossRefGoogle Scholar
  20. 20.
    Qi Z, Shao C, Zhang X, Hui G, Zhong W (2013) Exogenous and endogenour hormones in relation to glioma in women: a meta-analysis of 11 case–control studies. PLoS ONE 8(7):e68695PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    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. doi: 10.1002/ijc.25413 PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Amirian E, Scheurer ME, Bondy ML (2010) The association between birth order, sibship size and glioma development in adulthood. Int J Cancer 126:2752–2756PubMedCentralPubMedGoogle Scholar
  23. 23.
    Wiemels JL, Wiencke JK, Kelsey KT, Moghadassi M, Rice T, Urayama KY et al (2007) Allergy-related polymorphisms influence glioma status and serum IgE levels. Cancer Epidemiol Biomarkers Prev 16:1229–1235PubMedCrossRefGoogle Scholar
  24. 24.
    Wrensch M, McMillan A, Wiencke J, Wiemels J, Kelsey K, Patoka J et al (2007) Nonsynonymous coding single-nucleotide polymorphisms spanning the genome in relation to glioblastoma survival and age at diagnosis. Clin Cancer Res 13:197–205PubMedCrossRefGoogle Scholar
  25. 25.
    Zisakis A, Piperi C, Themistocleous MS, Korkolopoulou P, Boviatsis EI, Sakas DE et al (2007) Comparative analysis of peripheral and localised cytokine secretion in glioblastoma patients. Cytokine 39:99–105PubMedCrossRefGoogle Scholar
  26. 26.
    Berger A (2000) Th1 and Th2 responses: what are they? BMJ 321:424PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Brandacher G, Winkler C, Schroecksnadel K, Margreiter R, Fuchs D (2006) Antitumoral activity of interferon-gamma involved in impaired immune function in cancer patients. Curr Drug Metab 7:599–612PubMedCrossRefGoogle Scholar
  28. 28.
    Schwartzbaum J, Jonsson F, Ahlbom A, Preston-Martin S, Lönn S, Söderberg KC et al (2003) Cohort studies of association between self-reported allergic conditions, immune-related diagnoses and glioma and meningioma risk. Int J Cancer 106:423–428PubMedCrossRefGoogle Scholar
  29. 29.
    Girón-González JA, Moral FJ, Elvira J, García-Gil D, Guerrero F, Gavilán I et al (2000) Consistent production of a higher TH1:TH2 cytokine ratio by stimulated T cells in men compared with women. Eur J Endocrinol 143:31–36PubMedCrossRefGoogle Scholar
  30. 30.
    Subramanian S, Matejuk A, Zamora A, Vandenbark AA, Offner H (2003) Oral feeding with ethinyl estradiol suppresses and treats experimental autoimmune encephalomyelitis in SJL mice and inhibits the recruitment of inflammatory cells into the central nervous system. J Immunol 170:1548–1555PubMedCrossRefGoogle Scholar
  31. 31.
    Vural P, Akgul C, Canbaz M (2006) Effects of hormone replacement therapy on plasma pro-inflammatory and anti-inflammatory cytokines and some bone turnover markers in postmenopausal women. Pharmacol Res 54:298–302PubMedCrossRefGoogle Scholar
  32. 32.
    Kamada M, Irahara M, Maegawa M, Ohmoto Y, Murata K, Yasui T et al (2001) Transient increase in the levels of T-helper 1 cytokines in postmenopausal women and the effects of hormone replacement therapy. Gynecol Obstet Invest 52:82–88PubMedCrossRefGoogle Scholar
  33. 33.
    Kumru S, Yildiz FM, Godekmerdan A, Kutlu S, Yilmaz B, Gurates B (2008) Effects of raloxifene and hormone replacement therapy on serum Th2 and Th3 type cytokine concentrations in healthy postmenopausal women: a randomised controlled trial. Arch Gynecol Obstet 277:489–493PubMedCrossRefGoogle Scholar
  34. 34.
    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 130:405–410PubMedCrossRefGoogle Scholar
  35. 35.
    Batistatou A, Kyzas PA, Goussia A, Arkoumani E, Voulgaris S, Polyzoidis K et al (2006) Estrogen receptor beta (ERbeta) protein expression correlates with BAG-1 and prognosis in brain glial tumours. J Neurooncol 77:17–23PubMedCrossRefGoogle Scholar
  36. 36.
    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 56:43–48PubMedCrossRefGoogle Scholar
  37. 37.
    Inoue T, Akahira J, Suzuki T, Darnel AD, Kaneko C, Takahashi K et al (2002) Progesterone production and actions in the human central nervous system and neurogenic tumors. J Clin Endocrinol Metab 87:5325PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Bhuma Krishnamachari
    • 1
    Email author
  • Dora Il’yasova
    • 2
  • Michael E. Scheurer
    • 3
  • Melissa L. Bondy
    • 3
  • Margaret Wrensch
    • 4
  • Faith G. Davis
    • 5
  1. 1.Department of MedicineNew York Institute of Technology College of Osteopathic MedicineOld WestburyUSA
  2. 2.Duke Cancer InstituteDuke University Medical CenterDurhamUSA
  3. 3.Department of Pediatrics and Dan L. Duncan Cancer CenterBaylor College of MedicineHoustonUSA
  4. 4.Department of Neurological SurgeryUniversity of California, San FranciscoSan FranciscoUSA
  5. 5.Division of Epidemiology and BiostatisticsUniversity of Illinois at ChicagoChicagoUSA

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