| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
ORIGINAL RESEARCH |
From the Program for Prevention, Detection, and Control Research, Duke Comprehensive Cancer Center, Durham, North Carolina; Epidemiology Branch, National Institute of Environmental Health Sciences, Cancer Center Biostatistics, Duke Comprehensive Cancer Center, Durham, North Carolina; Epidemiology and Biostatistics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute and Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California.
Address reprint requests to: Joellen M. Schildkraut, PhD, Program for Prevention, Detection, and Control Research, Duke Comprehensive Cancer Center, Room 238, Hanes House, PO Box 2949, Durham, NC 27710; E-mail: schil001{at}mc.duke.edu
 |
ABSTRACT |
|---|
TOP
 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
METHODS: Using data from six population-based, case-control studies conducted in the United States, age at natural menopause among 1411 women with epithelial ovarian cancer and 6380 control subjects were analyzed using survival analysis methods, including Kaplan-Meier and proportional hazards models. Subjects ranged from 20 to 81 years of age.
RESULTS: The median age at natural menopause was 50 years among cases compared with 51 years among controls, a difference of borderline statistical significance (P = .06). The hazard ratio for the relationship between case-control status and age at natural menopause was 1.09 (95% confidence interval 0.99, 1.20). Controlling for potential confounders including parity, oral contraceptive use, tubal ligation, smoking, and body mass index did not appreciably change this association. There was little evidence of an association between early age at natural menopause and early onset ovarian cancer (diagnosis age under 48 years).
CONCLUSION: We observed a weak association between ovarian cancer risk and age at natural menopause and, among women with early onset disease, there was little evidence to suggest that early menopause is related to ovarian cancer. Thus, there seems little need for increased surveillance or screening for ovarian cancer among women with early natural menopause.
It has been postulated that early menopause may be associated with an increased risk of developing ovarian cancer.1 This idea was based on the gonadotropin hypothesis for ovarian cancer pathogenesis that predicts that the higher concentrations of FSH and LH that accompany ovarian senescence increase the risk of developing ovarian cancer. If gonadotropins act as tumor promotors, early age at natural menopause may be more directly linked to early onset ovarian cancer (eg, under age 45 or 50 years) than to later onset disease. In contrast, the "incessant ovulation" hypothesis proposes that ovarian cancer may arise from DNA damage that occurs from the ovulation-induced rupture and subsequent repair of epithelial tissue. Under this model, ovarian cancer risk would be expected to increase with a later age of menopause because older age at menopause would provide greater exposure to ovulatory cycles.2–4 However, ovarian cancer is most likely a heterogeneous disease with various underlying causes. It is also plausible that the "incessant ovulation" and the "gonadotropin" hypotheses may be interconnected and complementary rather than competing theories.
The epidemiologic literature concerning the relationship between age at natural menopause and ovarian cancer has been inconsistent.1,5–11 In this report, we examined the relationship between age at natural menopause and risk of developing epithelial ovarian cancer using data from six population-based, case-control studies conducted in the United States. A previous analysis of a portion of these data did not detect an association5 but was limited to women 55 years and older at diagnosis. By including women under age 55 in the current analysis, we are able to more fully evaluate the relationship between an early age at menopause and ovarian cancer and to specifically focus on early-onset disease.
|
MATERIALS AND METHODS |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
). We excluded the six studies with hospital-based control groups because some of the leading causes of morbidity and hospitalization in women (eg, heart disease, breast cancer) may be associated with age at natural menopause. The resulting sample consisted of 1431 women diagnosed with invasive epithelial ovarian cancer. We restricted our analyses to women with invasive tumors because there is some evidence suggesting that invasive epithelial ovarian cancer may be distinct from low malignant potential tumors. For example, tumors of low malignant potential have earlier age at diagnosis and better prognosis compared to invasive tumors.6–8 After excluding 20 cases and 40 controls who had a missing age at natural menopausal, 1411 women diagnosed with invasive epithelial ovarian cancer and 6380 control subjects were included in the analysis.
|
Menopausal status was determined by an algorithm reported by Whittemore et al.5 Regardless of reference age, a woman was classified as having had surgical menopause if the age at hysterectomy was the same age or within 1 year after the age at last menstrual period. A woman was classified as premenopausal if her reference age was at most 55 years and her age at last menstrual period was at least that of her reference age. A woman was classified as natural menopausal if: 1) she had a hysterectomy at least 1 year after her age at last menstrual period; or 2) her reference age was greater than 55 and she had not had a hysterectomy by age 55; or 3) her reference age was less than 55, her age at last menstrual period was at least 1 year before her reference age, and she had not had a hysterectomy. Age at natural menopause was defined as age at last menstrual period for postmenopausal women who had either natural or surgical menopause. Women with unknown menopausal status were excluded from the analysis (23 ovarian cancer cases and 40 controls).
Subject characteristics available for all studies included age, race, ever married (yes, no), parity defined as the number of births of 20 or more weeks’ gestation (0, 1, 2–3, 4+), and ever use of oral contraceptives (OC) (yes, no). Additional variables that were available for some but not all of the studies included education (some college versus no college), tubal ligation (yes, no), family history of breast or ovarian cancer in a mother or sister (yes, no), infertility defined as having seen a doctor about problems getting pregnant (yes, no), body mass index (BMI) (kg/m2) as an adult, and smoking history (never smoked, current smoker, or ex-smoker).
The Kaplan-Meier method was used to estimate the age at natural menopause for ovarian cancer cases and controls. By using the Kaplan-Meier method and the proportional hazards model, we were able to study the occurrence and timing of natural menopause. In these analyses, women who were classified as premenopausal or surgically menopausal were censored at reference age/age at surgery, respectively. Stratified analyses were performed to examine possible effect modification by factors that may affect the risk of ovarian cancer (age, race, parity, family history, tubal ligation, OC use) or factors that may affect age at natural menopause (smoking, BMI). The proportional hazards model was used to assess the association, estimated as the hazard ratio and 95% confidence intervals (CI), between case-control status and age at natural menopause. The hazard ratio is the ratio of the probability of experiencing natural menopause at a given time for an ovarian cancer case compared with a control. If the hazard ratio is greater than 1.0, cases are more likely than controls to have experienced earlier natural menopause, adjusting for the other variables in the model. Tests of interaction between case-control status and study site were conducted using proportional hazards analysis.
|
RESULTS |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
. Women with ovarian cancer were more likely to have known or suspected risk factors for ovarian cancer compared with control subjects. These factors included higher median age, a greater frequency of breast or ovarian cancers in a mother or sister, lower parity, higher median BMI, lower likelihood of using OC, and lower likelihood of having had a tubal ligation. Additionally, women with ovarian cancer were less likely to be premenopausal or to have had surgical menopause compared with control women.
|
The cumulative distribution of age at natural menopause by case-control status is presented in Figure 1. Age at natural menopause was somewhat younger, and of borderline significance, among ovarian cancer cases compared with controls with a median age at natural menopause equal to 50 years among women with ovarian cancer compared with 51 years among controls (log rank = 3.60, P = .06, Table 3). No association was observed between age at natural menopause and early age at diagnosis when the analysis was limited to women whose age at diagnosis was less than 48 years (Table 3).
|
|
. These results indicate somewhat stronger associations between age at natural menopause and ovarian cancer risk in specific subgroups. For example, among parous women, the median age at natural menopause was 50 years for ovarian cases compared with 51 years for controls (log rank = 4.45, P = .04), but there was no difference between cases and controls in the distribution of age at natural menopause among nulliparous women. A similar pattern in the distribution of age at natural menopause was seen in the analyses stratified by family history of breast or ovarian cancer. The association between early menopause and ovarian cancer risk was seen among women with a family history (log rank = 3.82, P = .05). However, there was no evidence for effect modification of any of the factors in Table 3 when testing for interaction in a proportional hazards model (P > .10). The hazard ratio for age at natural menopause, adjusting for study, was 1.09 (95% CI 0.99, 1.20) for ovarian cancer cases compared with controls. We performed additional multivariable analyses to adjust for potential confounders with risk factors for ovarian cancer or age at natural menopause. There was little change in the hazard ratio with further adjustment for marital status, parity, OC use, infertility, BMI, and education. Because data were not available from all six case-control studies for smoking, family history, and tubal ligation, evaluation of potential confounding by these factors was limited to a subset of approximately 75% of the total sample. There was no evidence, in terms of a change in the hazard ratio, of confounding by these factors in these analyses.
|
DISCUSSION |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
The results of our combined analysis of data from six population-based, case-control studies suggest a weak association between early age at natural menopause and ovarian cancer risk, with a hazard ratio of 1.09. There was little evidence that early onset ovarian cancer (under age 48) was associated with early menopause. However, an association was seen within other subgroups of women, including parous women and women with a family history of breast or ovarian cancer.
Although this is a large study (1411 ovarian cancer cases), there was limited power to establish effect modification among subgroups in the analysis. There was also limited power to detect an association between age at natural menopause in women with early onset (under age 48) ovarian cancer because only 5% of subjects had experienced menopause by this age.
One explanation for not finding a stronger association between age at natural menopause is the possibility that ovarian cancer is a heterogeneous disease with several distinct etiologic pathways.6,21 Thus, if incessant ovulation and high gonadotropin levels each independently contribute to the risk of developing ovarian cancer, it is possible that an effect could be nullified by our inability to distinguish between cancers that arise through either of these two pathways.
A limitation of our analysis is that menopausal status and age at natural menopause were based on self-reported data. Recall error is possible, but previous studies have reported fairly high levels of accuracy or reliability for interview or questionnaire-based data on age at natural menopause17,18,22 and oophorectomy history.23 Because it is not possible to use cessation of menses to determine age at ovarian senescence (menopause) among women with a surgical menopause (hysterectomy without bilateral oophorectomy), these women could not contribute to the analysis of age at menopause, and the resulting selection bias could have affected our results. However, the analytic methods we used allowed us to include these women in the analysis up to the time of their surgery. Age at natural menopause was truncated at 55 because of concerns about the accuracy of the data. This affected less that 1% of the total sample of cases and controls in our study. Alternatively, when we used reported age of the last menstrual period as the age at natural menopause, the hazard ratio for the relationship between age at natural menopause and case-control status was 1.12 (95% CI 1.01, 1.23, P = .02). This is slightly higher than the hazard ratio calculated when age at natural menopause was truncated at 55 years. Thus, truncating age at natural menopause was a conservative approach for estimating the relationship with ovarian cancer.
Controlling for potential confounders in a proportional hazards model did not alter the relationship between age at natural menopause and ovarian cancer. We were able to control for the factors that have been most consistently reported to be associated with age at natural menopause: smoking24–26 and parity.25,27 Information on other potential confounders, such as irregularity of menstrual cycles before age 25, and family history of early menopause27,28 were not available in our data. Thus, although the possibility of residual confounding exists, the unmeasured factor would have to be strongly related to both age at natural menopause and ovarian cancer risk to have an effect on our results and the conclusions drawn.
Our analyses do not support that age at natural menopause is an important factor in predicting ovarian cancer risk. There was also no evidence that early menopause is related to ovarian cancer among women who had an early age at diagnosis of ovarian cancer. Therefore, there is no indication for increased surveillance among women with early menopause.
|
Footnotes |
|---|
The authors wish to thank Drs. Andrew Berchuck, Patricia Moorman, Matthew Longnecker, and Dale Sandler for their critical review of the manuscript.
Received November 29, 2000. Received in revised form February 5, 2001. Accepted March 8, 2001.
|
REFERENCES |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
2. Fathalla MF. Incessant ovulation: A factor in ovarian neoplasia? Lancet 1971;2:163.[Medline]
3. Ames BN, Gold LS. Too many rodent carcinogens: Mitogenesis increases mutagenesis. Science 1990;249:970–97.
4. Preston-Martin S, Pike ML, Ross RK, Jones PA, Henderson BE. Increased cell division as a cause of human cancer. Cancer Res 1990;50:7415–21.
5. Whittemore AS, Harris R, Itnyre J. Characteristics relating to ovarian cancer risk: Collaborative analysis of 12 US case-control studies II. Invasive epithelial ovarian cancers in white women. Am J Epidemiol 1992;136:1184–203.
6. Schildkraut JM, Bastos E, Berchuck A. Relationship between lifetime ovulatory cycles of mutant p53 in epithelial ovarian cancer. J Natl Cancer Inst 1997;89:932–8.
7. Ozols RF, Rubin SC, Dembo AJ, Robboy SJ. Epithelial ovarian cancer. In: Hoskins WJ, Perez CA, Young RC, eds. Principles and practice of gynecologic oncology. Philadelphia: JB Lippincott, 1992:731–81.
8. Morrow CP. Malignant and borderline epithelial tumors of the ovary: Clinical features, staging, diagnosis, intraoperative assessment and review of management. In: Coppleson M, ed. Gynecologic oncology: Fundamental principles and clinical practice. 2nd ed. Edinburgh: Churchill Livingston, 1992:889–915.
9. Casagrande JT, Louie EW, Pike MC, Roy S, Ross RK, Henderson BE. "Incessant ovulation" and ovarian cancer. Lancet 1979;2:170–3.[Medline]
10. Cramer DW, Hutchinson GB, Welch WR, Scully RE, Ryan KJ. Determinants of ovarian cancer risk. I. Reproductive experiences and family history. J Natl Cancer Inst 1983;71:711–6.
11. CASH. The reduction in risk of ovarian cancer associated with oral-contraceptive use. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. N Engl J Med 1987;316:650–5.[Abstract]
12. Whittemore AS, Harris R, Itnyre J, Halpern J. Characteristics relating to ovarian cancer risk: Collaborative analysis of 12 US case-control studies. I. Methods. Collaborative Ovarian Cancer Group. Am J Epidemiol 1992;136: 1175–83.
13. Nasca PC, Greenwald P, Chorost S, Richart R, Caputo T. An epidemiologic case-control study of ovarian cancer and reproductive factors. Am J Epidemiol 1984;119:705–13.
14. Weiss NS, Lyon JL, Liff JM, Vollmer WM, Daling JR. Incidence of ovarian cancer in relation to the use of oral contraceptives. Intl J Cancer 1981;28:669–71.[Medline]
15. Wu ML, Whittemore AS, Paffenbarger RS Jr, Sarles DL, Kampert JB, Grosser S, et al. Personal and environmental characteristics related to epithelial cancer. I. Reproductive and menstrual events and oral contraceptive use. Am J Epidemiol 1988;128:1216–27.
16. Franceschi S, La Vecchia C, Booth M, Tzonou A, Negri E, Parazzini F, et al. Pooled analysis of 3 European case-control studies of ovarian cancer: II. Age at menarche and at menopause [see comments]. Intl J Cancer 1991;49: 57–60.[Medline]
17. Bean JA, Leeper JD, Wallace RB, Sherman BM, Jagger H. Variations in the reporting of menstrual histories. Am J Epidemiol 1979;109:181–5.
18. Colditz GA, Stampfer MJ, Willett WC, Stason WB, Rosner B, Hennekens CH, et al. Reproducibility and validity of self-reported menopausal status in a prospective cohort study. Am J Epidemiol 1987;126:319–25.
19. Wynder EL, Dodo H, Barber HRK. Epidemiology of cancer of the ovary. Cancer 1969;23:352–70.[Medline]
20. Hildreth NG, Kelsey JL, Livolsi VA. An epidemiologic study of epithelial carcinoma of the ovary. Am J Epidemiol 1981;114:398–405.
21. Hankinson SE, Colditz GA, Hunter DJ, Willett WC, Stampfer MJ, Rosner B, et al. A prospective study of reproductive factors and risk of epithelial ovarian cancer. Cancer 1995;76:284–90.[Medline]
22. Horwitz RI, Yu EC. Problems and proposals for interview data in epidemiological research. Intl J Epidemiol 1985;14: 463–7.
23. Irwin KL, Wingo PA, Lee NC. Agreement of self-reported ovarian number following gynecologic surgery with medical record reports. J Clin Epidemiol 1990;43:181–7.[Medline]
24. Midgette AS, Baron JA. Cigarette smoking and the risk of natural menopause. Epidemiology 1990;1:474–80.[Medline]
25. Bromberger JT, Matthews KA, Kuller LH, Wing RR, Meilahn EN, Plantinga P. Prospective study of the determinants of age at menopause. Am J Epidemiol 1997;145: 124–33.
26. Cooper GS, Sandler DP, Bohlig M. Active and passive smoking and the occurrence of natural menopause. Epidemiology 1999;10:771–3.[Medline]
27. Stanford JL, Hartge P, Brinton LA, Hoover RN, Brookmeyer R. Factors influencing the age at natural menopause. J Chronic Dis 1987;40:995–1002.[Medline]
28. Cramer DW, Xu H. Predicting age at menopause. Maturitas 1996;23:319–26.[Medline]
This article has been cited by other articles:
|
|
 |
|
  A. Lukanova and R. Kaaks Endogenous Hormones and Ovarian Cancer: Epidemiology and Current Hypotheses Cancer Epidemiol. Biomarkers Prev., January 1, 2005; 14(1): 98 - 107. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E Allsworth, S. Zierler, K. L Lapane, N. Krieger, J. W Hogan, and B. L Harlow Longitudinal study of the inception of perimenopause in relation to lifetime history of sexual or physical violence J. Epidemiol. Community Health, November 1, 2004; 58(11): 938 - 943. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Arslan, A. Zeleniuch-Jacquotte, E. Lundin, A. Micheli, A. Lukanova, Y. Afanasyeva, P. Lenner, V. Krogh, P. Muti, S. Rinaldi, et al. Serum Follicle-Stimulating Hormone and Risk of Epithelial Ovarian Cancer in Postmenopausal Women Cancer Epidemiol. Biomarkers Prev., December 1, 2003; 12(12): 1531 - 1535. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
