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Journal of Clinical Oncology, Vol 26, No 2 (January 10), 2008: pp. 279-282 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.2133 Is There an Association Between Meningioma and Hormone Replacement Therapy?
From the Department of Neurology and Biostatistics Unit, Mayo Clinic, Jacksonville, FL Corresponding author: Kurt A. Jaeckle, MD, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224; e-mail: Jaeckle.Kurt{at}mayo.edu
Purpose Molecular and clinical observations suggest a role of sex steroid hormones in the occurrence of meningioma. However, there is limited and often conflicting data on the use of hormone replacement therapy (HRT) as a possible risk factor for meningioma. The goal of this study was to investigate whether there is an association between a diagnosis of meningioma and either current or past HRT use in women. Methods We retrospectively reviewed records in the Mayo Clinic Jacksonville electronic patient database between 1993 and 2003 to identify women with a diagnosis of either symptomatic or incidentally discovered, clinically silent meningioma. Records were also searched to identify women with a documented history of either current or past HRT use. Results Of the 355,318 women, ages 26 to 86, evaluated for any medical issue, 18,037 (5%) were documented as current or past HRT users. A total of 1,390 women with a history of symptomatic or incidentally discovered meningiomas were identified, 156 (11%) of whom were either current or past HRT users. A logistic regression analysis, adjusted for age, demonstrated a positive association between a diagnosis of meningioma and HRT use, with an odds ratio of 2.2 (95% CI, 1.9 to 2.6; P < .0001). The frequency of meningioma in women with either current or past HRT use was 865 in 100,000, whereas the frequency of meningioma in women without the history of HRT use was 366 in 100,000. Conclusion The study provides evidence of a positive association between HRT use and diagnosis of meningioma, and therefore, HRT use may be a risk factor for meningioma.
The sex difference in the incidence of meningioma is widely established, with the frequency of meningioma twice as high in women as in men.1 Clinical findings suggest that meningiomas may be influenced by estrogen and progesterone based on the observation of a positive association with breast cancer2 and tumor growth during pregnancy and menstruation.3 Molecular and immunohistochemical studies confirm that meningioma is a hormone-sensitive tumor, with approximately 70% of meningiomas expressing progesterone receptors and approximately 30% expressing estrogen receptors.4,5 Proliferation of human meningioma cell lines after exposure to estrogen and progesterone has also been observed.6 On the basis of these observations, there has been much speculation by patients and physicians that hormone replacement therapy (HRT) may be a risk factor for meningioma. This concern has been further highlighted by recent data from the Women's Health Initiative trial, which identified increased risk of breast cancer, coronary heart disease, ischemic stroke, and venous thrombosis with prolonged HRT use.7 Several studies have tried to elucidate the risk of meningioma in relation to endogenous and exogenous sex hormones,8-14 but the results have been conflicting, especially with respect to HRT. Therefore, the relationship between the risk of meningioma and the use of hormonal supplementation in women remains unclear. The current study was undertaken to investigate whether an association exists between a diagnosis of meningioma and either current or past HRT use in women.
We retrospectively reviewed records in the Mayo Clinic Jacksonville electronic patient database between 1993 and 2003. During this period, a total of 355,318 female patients, age 26 to 86 years, were evaluated as outpatients. The records of these patients were searched with the following key phrases: "meningioma," "meningioma and hormone replacement therapy," and "hormone replacement therapy." Women were then defined as HRT users if they had a documented history of either current or past use of HRT in their records. Documentation of HRT use was obtained from medication lists, medical evaluations, and obstetric/gynecologic evaluations. HRT use was defined to include all forms of hormone replacement, including estrogen and progestin in combination or estrogen alone. The patients were defined as having a diagnosis of meningioma if they had a documented lesion consistent with meningioma on magnetic resonance imaging of the brain. A histologic diagnosis was not required, but the lesion on neuroimaging had to be interpreted as consistent with meningioma in the official report by the neuroradiologist. All patients with meningioma (n = 1,390) were confirmed to have a history of either symptomatic meningioma or clinically silent, incidentally discovered meningioma, as confirmed by the official neuroradiology report. A logistic regression analysis, adjusted for age, was used to investigate evidence for an association between a diagnosis of meningioma and the use of HRT. The frequency of meningioma in women with or without the use of HRT was calculated in raw proportions and per 100,000 women. The study was approved by the Mayo Clinic Institutional Review Board.
Of the 355,318 female patients evaluated between 1993 and 2003 for any medical issue at the Mayo Clinic Jacksonville, 18,037 (5%) were documented current or past users of HRT. A total of 1,390 women with a history of symptomatic or incidentally discovered meningiomas were identified; 156 of these women (11%) were either current or past HRT users, whereas the remaining 1,234 women with meningioma had no historical evidence of HRT use (Table 1). The rates of meningioma in women with and without HRT use according to age group are listed in Table 1. Overall, the proportion of meningiomas in HRT users was 156 in 18,037 users, corresponding to a calculated prevalence of 865 in 100,000, whereas the proportion of meningiomas in non-HRT users was 1,234 in 337,281 nonusers, corresponding to a calculated prevalence of 366 in 100,000 (Table 1).
A logistic regression analysis, adjusted for age, demonstrated a positive association between a diagnosis of meningioma and HRT use, with an odds ratio (OR) of 2.2 (95% CI, 1.9 to 2.6; P < .0001). When the association between meningioma and HRT use was analyzed according to the age groups, the estimated OR was consistently between 1.7 and 2.1 for women greater than 56 years of age (Fig 1). In women aged 26 to 55 years, the association seemed stronger, with an OR of 4.1 (95% CI, 2.7 to 6.4). The overall frequency of meningioma, regardless of the HRT use, increased with age, with the highest prevalence (677 in 100,000) observed in women age 76 years and older.
Meningiomas account for approximately 25% of primary intracranial tumors in the United States15 and are twice as common in women as in men.1 In vitro studies suggest that meningioma is a hormone-sensitive tumor that often contains both progesterone and estrogen receptors.4,5 This finding plus the observation that meningioma cell lines proliferate after exposure to progesterone and estrogen6 provide molecular and physiologic evidence for a potential role of sex steroid hormones in the development and growth of meningioma. Clinical evidence suggesting that meningioma might be a hormone-sensitive tumor is based on observations of higher incidence in women than in men,1 an observed increased growth of meningioma during pregnancy and menses,3 increased incidence of meningioma in women with breast cancer,2 and a higher prevalence in women with lymphangioleiomyomatosis, a cystic lung disease that is commonly treated long term with progesterone and other hormonal agents.16 In this retrospective study, we found a positive association between a diagnosis of meningioma and HRT use (OR = 2.2; 95% CI, 1.9 to 2.6; P < .0001). The prevalence of meningioma in women with either current or past HRT use was 865 in 100,000, whereas the prevalence of meningioma in women without a history of HRT use was 366 in 100,000. To our knowledge, this is the largest sample size study that assesses the relationship of exogenous hormone use and meningioma. Two prior studies also found a positive association between HRT and meningioma.10,11 In the Nurses' Health Study, the relative risk of meningioma was found to be 1.01 (95% CI, 0.49 to 2.1; P = .98) in postmenopausal women who were past users of HRT and 1.86 (95% CI, 1.07 to 3.24; P = .03) in current HRT users.10 Of the 125 women with meningioma in the Nurses' Health Study, which relied on mailed questionnaires, only 11 women identified themselves as past HRT users, whereas 33 women responded as current HRT users. More recently, Wigertz et al11 examined 178 women with meningioma, 68 of whom responded in interviews as ever using HRT. This study found an increased relative risk of meningioma in postmenopausal women with a history of ever using HRT, with an OR of 1.7 (95% CI, 1.0 to 2.8). Several other studies have attempted to assess the relationship between HRT use and meningioma, but the results were either inconclusive as a result of low statistical power or showed a nonsignificant protective effect of HRT use on meningioma.12-14 When the association between meningioma and HRT use was analyzed according to the age groups, we found that the estimated OR consistently approximated 2 for women older than 56 years. However, for women ages 26 to 55 years, the association was stronger, with an estimated OR of 4.1. This raises the provocative possibility that, in younger women, there may be a stronger effect of HRT on the occurrence of meningioma. We were unable to extract enough information in this retrospective analysis regarding pre- or postmenopausal status or the timing of the first HRT exposure to draw conclusions about a possible relationship. As expected, we found that the total prevalence of meningiomas in female patients at our institution increased with age, with the highest prevalence (677 in 100,000) being in women age 76 years and older. This finding is consistent with previous reports, which showed an increase in prevalence of meningioma with age.17,18 Our study has several limitations that need to be considered. We recognize the limitations inherent to a retrospective chart review, including a possibility that some women who were current or past HRT users were not documented as such in the medical records. Additionally, there may be a more accurate historical documentation of HRT exposure in women with meningioma compared with women evaluated for other medical issues. Self-reporting of oral contraceptives has been validated in other studies,19,20 but self-reporting of HRT use has not been previously validated. A number of important questions were raised by our study regarding the impact of HRT exposure, including the type, dosage, duration, and timing, on the development and growth rate of meningioma. These data could not be extracted from the medical chart documentation because they were not often detailed and would be best obtained in the context of a prospective analysis. Finally, in this study, we did not separate symptomatic meningiomas from those that are clinically silent and discovered incidentally via neuroimaging. As such, it is impossible to determine at this time whether HRT use is associated with symptomatic or radiographic progression of clinically silent meningiomas. In summary, this is the largest sample size study providing evidence of a positive association between HRT use and a diagnosis of symptomatic or incidentally discovered, clinically silent meningioma. Our findings suggest that HRT use may be a risk factor for meningioma, and future confirmation of these results is needed in the context of prospective studies. Until then, however, clinicians and patients alike should be aware of these data when considering the risks and benefits of HRT.
The author(s) indicated no potential conflicts of interest.
Conception and design: Svetlana Blitshteyn, Kurt A. Jaeckle Provision of study materials or patients: Svetlana Blitshteyn, Kurt A. Jaeckle Collection and assembly of data: Svetlana Blitshteyn Data analysis and interpretation: Svetlana Blitshteyn, Julia E. Crook, Kurt A. Jaeckle Manuscript writing: Svetlana Blitshteyn Final approval of manuscript: Svetlana Blitshteyn, Julia E. Crook, Kurt A. Jaeckle
Presented in part at the 9th Annual Meeting of the Society for Neuro-Oncology, November 18-21, 2004, Toronto, Ontario, Canada. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Central Brain Tumor Registry of the United States: Statistical report: Primary brain tumors in the United States, 1995-1999. http://www.cbtrus.org/2002/2002report.pdf 2. Schoenberg BS, Christine BW, Whisnant JP: Nervous system neoplasms and primary malignancies of other sites: The unique association between meningiomas and breast cancer. Neurology 25:705-712, 1975 3. Roelvink NC, Kamphorst W, van Alphen HA, et al: Pregnancy-related primary brain and spinal tumors. Arch Neurol 44:209-215, 1987 4. Carroll RS, Zhang J, Black PM: Expression of estrogen receptors alpha and beta in human meningiomas. J Neurooncol 42:109-116, 1999[CrossRef][Medline] 5. Hsu DW, Efird JT, Hedley-Whyte ET: Progesterone and estrogen receptors in meningiomas: Prognostic considerations. J Neurosurg 86:113-120, 1997[Medline] 6. Speirs V, Boyle-Walsh E, Fraser WD: Constitutive co-expression of estrogen and progesterone receptor mRNA in human meningiomas by RT-PCR and response of in vitro cell cultures to steroid hormones. Int J Cancer 72:714-719, 1997[CrossRef][Medline] 7. Rossouw JE, Anderson GL, Prentice RL, et al: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA 288:321-333, 2002 8. Schlehofer B, Blettner M, Wahrendorf J: Association between brain tumors and menopausal status. J Natl Cancer Inst 84:1346-1349, 1992 9. Ryan P, Lee MW, North B, et al: Risk factors for tumors of the brain and meninges: Results from the Adelaide Adult Brain Tumor Study. Int J Cancer 51:20-27, 1992[Medline] 10. Jhawar BS, Fuchs CS, Golditz GA, et al: Sex steroid hormone exposures and risk for meningioma. J Neurosurg 99:848-853, 2003[Medline] 11. Wigertz A, Lonn S, Mathiesen T, et al: Risk of brain tumors associated with exposure to exogenous female sex hormones. Am J Epidemiol 164:629-636, 2006 12. Hatch E, Linet M, Zhang J, et al: Reproductive and hormonal factors and risk of brain tumors in adult females. Int J Cancer 114:797-805, 2005[CrossRef][Medline] 13. Custer B, Longstreth WT Jr, Phillips LE, et al: Hormonal exposure and the risk of intracranial meningioma in women: A population-based case-control study. BMC Cancer 6:152, 2006[CrossRef][Medline] 14. Lee E, Grutsch J, Persky V, et al: Association of meningioma with reproductive factors. Int J Cancer 119:1152-1157, 2006[CrossRef][Medline] 15. Claus EB, Bondy ML, Schildkraut JM, et al: Epidemiology and of intracranial meningioma. Neurosurgery 57:1088-1095, 2005[Medline] 16. Moss J, DeCastro R, Patronas N, et al: Meningiomas in lymphangioleiomyomatosis. JAMA 286:1879-1881, 2001 17. Staneczek W, Janisch W: Epidemiologic data on meningiomas in East Germany 1961-1986: Incidence, localization, age and sex distribution. Clin Neuropathol 11:135-141, 1992[Medline] 18. Krampla W, Newrkla S, Pfistere W, et al: Frequency and risk factors for meningioma in clinically healthy 75-year-old patients. Cancer 100:1208-1212, 2004[CrossRef][Medline] 19. Chasan-Taber L, Willett WC, Stampfer MJ, et al: A prospective study of oral contraceptives and NIDDM among U. S. women. Diabetes Care 20:330-335, 1997[Abstract] 20. Norell SE, Boethius G, Persson I: Oral contraceptive use: Interview data versus pharmacy records. Int J Epidemiol 27:1033-1037, 1998 Submitted August 28, 2007; accepted October 12, 2007.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
