Affiliations of authors: R. B. Ness, Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, University of Pittsburgh Cancer Institute, and Magee-Womens Research Institute, Pittsburgh, PA; C. Cottreau, Department of Epidemiology, University of Pittsburgh Graduate School of Public Health.
Correspondence to: Roberta B. Ness, M.D., M.P.H., University of Pittsburgh Graduate School of Public Health, 130 DeSoto St., Rm. 513, Parran Hall, Pittsburgh, PA 15261 (e-mail: repro{at}vms.cis.pitt.edu).
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ABSTRACT |
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INTRODUCTION |
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Studies were identified for this review by searching the English language literature in the MEDLINE® database and by an extensive review of bibliographies from articles found through that search.
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EVIDENCE SUPPORTING THE PITUITARY GONADOTROPIN AND OVULATION HYPOTHESES |
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If fertility drugs were found to influence the development of ovarian cancer, this influence would also potentially support both the ovulation and gonadotropin hypotheses, since these drugs both elevate gonadotropin levels and cause superovulation. However, the literature (49,50) is conflicting regarding the association between the use of fertility drugs and ovarian cancer.
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SCRUTINIZING THE PITUITARY GONADOTROPIN HYPOTHESIS |
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Furthermore, in the only prospective study to examine this question directly (54), gonadotropin levels measured from serum stored many years prior to outcome were not associated with the occurrence of ovarian cancer. Helzlsouer et al. (54) analyzed levels of LH, FSH, and other hormones among case patients with ovarian cancer and control subjects arising from a prospective population-based serum bank study. Of 20 305 participants from whom serum had been collected and frozen, 31 who were not taking hormone replacement therapy (HRT) at baseline developed ovarian cancer a mean of 8 years after blood collection. These case patients were matched to 62 control subjects on age, menopausal status, and, for premenopausal women, number of days from the beginning of the last menstrual period. Mean levels of FSH, LH, and estrogens were somewhat lower among case patients with ovarian cancer than among control subjects, whereas the androgens androstenedione, dihydroepiandosterone, and dihydroepiandosterone sulfate were associated with an increased risk. These results do not support the hypothesis that elevated pituitary gonadotropin levels increase ovarian cancer risk. However, limitations of the study were the measurement of hormones at a single point in time, the inclusion of premenopausal women without precise determination of timing of blood collection within the menstrual cycle, the small number of cases of ovarian cancer, and the limited adjustment for confounding factors.
A more complex issue that is somewhat difficult to reconcile with the gonadotropin hypothesis is that postmenopausal estrogen use has been modestly, albeit inconsistently, associated with increased risk for ovarian cancer (7,8,11,12,14,18,24,36,55-62). A recent meta-analysis (63), including 11 articles with data from 21 studies, did show a small increase in overall risk with HRT use (relative risk [RR] = 1.15; 95% confidence interval [CI] = 1.05-1.27) with a somewhat higher risk, albeit of borderline significance, among users for more than 10 years' duration (RR = 1.27; 95% CI = 1.00-1.61). Rodriguez et al. (62) in the prospective Nurses Health Study found 18 cases in 5000 person-years among long-term users (>11 years), for an RR of 1.7 (95% CI = 1.1-2.8). Postmenopausal estrogens reduce gonadotropins and increase estrogen levels. To the degree that the gonadotropin hypothesis predicted that excess LH and FSH stimulate mutagenesis, these findings would seem to counter the predictions of the hypothesis. However, if the hormonal mechanism more relevant to the thesis of the gonadotropin hypothesis were that of estrogen elevation, then these findings would indeed fit the data. Taken together, the literature reviewed above does not fully support the gonadotropin hypothesis, although it is quite possible that steroid hormones do play some role in pathogenesis.
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SCRUTINIZING THE OVULATION HYPOTHESIS |
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Factors that reduce ovulation do not proportionally reduce the risk of ovarian cancer (24,46). First proposed by Risch et al. (24) and later demonstrated by Whittemore et al. (46), 1 year of delayed menarche or of early menopause was associated with a much less marked reduction in ovarian cancer risk than was 1 year of term pregnancy, 1 year of breast-feeding, or 1 year of oral contraceptive use. Were the ovulation hypothesis to hold, there is no reason to imagine that various sources of ovulation cessation would differentially impact risk. However, age at menarche and age at menopause may less accurately reflect ovulatory function than does pregnancy or oral contraceptive use; the initiation and cessation of menses do not reflect the initiation and cessation of ovulation (70). Nevertheless, suppression of ovulation cannot fully account for the risk reductions observed in epidemiologic studies. Assuming that ovulations occur over a period of at least 20 years, a full-term pregnancy would be expected to reduce ovarian cancer risk by 5%, whereas Whittemore et al. (46) observed about a 15% reduction in risk for each pregnancy after the first.
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EPIDEMIOLOGIC DATA SUPPORTING THE ROLE OF LOCAL INFLAMMATION IN OVARIAN CANCER RISK |
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TALC AND ASBESTOS EXPOSURE |
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Although household-related asbestos exposure may be related to dust on the clothing, with those who launder the clothing at increased risk of cancer, it is also possible that exposure occurs through sexual intercourse with particles traveling from the lower to the upper genital tract. Traffic of endogenous cells and pathogens from the lower to the upper genital tract has been shown to be common (79). This fact links cervicitis, i.e., sexually transmitted infection of the lower genital tract epithelium, to PID. It may also link asbestos exposure and talc use to ovarian epithelial inflammation.
Talc, which is structurally similar to asbestos, has repeatedly been related to ovarian cancer. Prior to 1976, talc was commonly contaminated with asbestos, so that the early studies relating talc to ovarian cancer may have been confounded by the asbestos-ovarian cancer relationship (80). More recent findings are less likely to be solely driven by the asbestos relationship.
At least 12 epidemiologic studies (8,81-91) have evaluated the use of talc in relationship to ovarian cancer. Eight of these studies (81-87,90) reported an elevated cancer risk among women whose powder exposure was described as a "dusting of the perineum," with ORs ranging from 1.3 to 3.9. Two other studies (8,88) found a very small elevation in risk with the use of a more general exposure definition, and one study (89) found no association. In the most extensive and focused analysis to date, Cook et al. (81) interviewed 313 case patients with ovarian cancer and 422 control subjects regarding exposure to a variety of powder products used in a series of ways (e.g., perineal dusting, diaphragm storage, powder on sanitary napkins, and genital deodorant spray). Both talc-containing and non-talc-containing baby or bath powder products were associated with an elevated risk of ovarian cancer; each way of using it, with the exception of diaphragm storage, was also associated with an elevated risk of ovarian cancer. A limited number of studies (8,81,90,92) have examined the potential for a dose-response relationship. Some studies have shown some increase in risk with more frequent exposure (83,86), longer exposure (86), and greater total number of lifetime applications (86). However, other studies (8,81,90) have not shown any dose-response relationship. The link between talc exposure and ovarian cancer is limited by a lack of supportive animal data and an inconsistency in the detection of talc in the ovarian tissue of women who reported heavy use (91). Nevertheless, the consistency of an association between talc use and ovarian cancer in a series of well-conducted studies of varying design suggests that talc use may represent another environmental exposure that enhances epithelial inflammation and thereby either initiates or promotes ovarian carcinogenesis.
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ENDOMETRIOSIS |
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Ovarian tumors arise out of ovarian endometriosis in 0.3%-0.8% of case patients who are followed clinically (93,94). In the most extensive epidemiologic study to date, Brinton et al. (95) assessed cancer outcomes among 20 686 women with endometriosis who were hospitalized in Sweden. Hospitalizations were identified through the nationwide Swedish Inpatient Registrar, and outcomes were identified through the National Swedish Cancer Registry after a mean of 11.4 years of follow-up. The risk of ovarian cancer was elevated 2.5-fold for women followed for 10 or more years, and the risk rose to more than fourfold among women whose endometriosis was located in the ovaries. Unfortunately, this study did not control for parity or oral contraceptive use, which might have led to an inflated estimate of risk. However, there is also substantial clinical support for an association between endometriosis and ovarian cancer.
Several case series (93,96-101) have demonstrated cancer tumorigenesis that arises from endometriosis. Sampson (102), who documented the first case, outlined a set of criteria for establishing the existence of such a cancerous transformation. These criteria include the following: 1) demonstration of both cancerous and benign endometrial tissues in the same ovary, 2) demonstration of cancer arising in the tissue and not invading from another source, and 3) demonstration of a histologic relationship between invasive and benign components. Reviewing the literature, Heaps et al. (93) noted that 165 cases have been published that meet these criteria. Almost 80% of these malignant transformations arose from ovarian endometriosis, and the rest came from extragonadal sites. Endometrioid adenocarcinomas accounted for 69% of lesions, followed by clear-cell carcinomas (13.5%) and sarcomas (11.6%). This is a far higher proportion of endometrioid and clear-cell tumors than is found among ovarian cancers in general (10%-20% and 3%-10%, respectively), which again points to a possible transformation from endometriosis to specific types of endometrial cancer (103). One case report (99) documented the experience of a woman who, on biopsy, first showed atypia within ovarian endometriosis and then 3 years later had a clear-cell ovarian carcinoma arising from the same ovary. Finally, Sainz de la Cuesta et al. (96) found endometriosis among about 40% of women with stage I endometrioid or clear-cell ovarian carcinoma, about one third of which were carcinomas arising out of endometriosis. Czernobilsky and Morris (104) also showed that mild cytologic atypia occurred in about 20% of endometriosis lesions and that severe atypia, a probable precursor of ovarian cancer, occurred in 3.6%. Taken as a whole, these data strongly support a temporal pattern of transition from simple endometriosis to atypical endometriosis to ovarian cancer.
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HYSTERECTOMY AND BILATERAL TUBAL LIGATION |
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PELVIC INFLAMMATORY DISEASE |
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ANTI-INFLAMMATORY MEDICATIONS |
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BIOLOGIC RATIONALE FOR THE ROLE OF INFLAMMATION IN OVARIAN CANCER RISK |
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Inflammation, by its nature, produces toxic oxidants meant to kill pathogens. These oxidants cause direct damage to DNA, proteins, and lipids and may, therefore, play a direct role in carcinogenesis (121). At the same time, chronic inflammation is associated with increased cell division. Rapid cell division gives rise to the potential for replication errors with resultant DNA repair; aberrant DNA repair, particularly at key regulatory sites (e.g., tumor suppressor DNA regions), may increase the risk for mutagenesis (119). Finally, bioactive substances, such as cytokines, growth factors, and prostaglandins, that are synonymous with inflammation may play an important role in ovarian mutagenesis. Ovarian epithelial cells secrete cytokines, including interleukin 1, interleukin 6, and macrophage colony-stimulating factor, among others (122). Auersperg et al. (123) pointed out that these same factors are also produced by ovarian cancer cells and suggested that the recruitment of normally secreted cytokines into disregulated autocrine loops may be important in neoplastic progression. Prostaglandins have multiple effects that favor tumorigenesis (124). For example, prostaglandins are more common in ovarian malignant tumors than in normal cells (125), overexpression of prostaglandins increases the invasiveness of tumor cells, and inhibitors of cyclooxygenase activity (and therefore prostaglandin formation) protect against a variety of cancers in animals (124). Epidemiologic studies have shown that long-term use of nonsteroidal anti-inflammatory medications generally reduces the risk of colon cancer in both men and women (118,126,127) and breast cancer in women (128).
Ovulation may be mutagenic. The process of ovulation requires disruption of the ovarian epithelium (129,130). Degenerative epithelial cells adjacent to the site of follicular rupture are shed from the ovarian surface, presumably through apoptosis (i.e., programmed cell death). The wound that ensues from cell loss and follicular extrusion is repaired by the proliferation of epithelial cells from the perimeter of the ruptured follicle. In the process, inclusion cysts are formed as surface epithelial cells become entrapped in the ovarian wound created during ovulation. There has been speculation that inclusion cysts are among the ovarian surface changes that represent a path of differentiation that is less plastic than the relatively pleuripotential normal ovarian epithelium and more likely to proceed to ovarian carcinogenesis (130). This suggestion comes from two observations. First, women with ovarian cancer are more likely to have inclusion cysts in the contralateral ovary (131); however, this finding was not confirmed in another study (132). Second, in an unblinded study (133), ovaries of women at high familial risk of developing ovarian cancer, compared with ovaries of normal women, were more likely to have multiple inclusion cysts as well as papillomatosis, deep invaginations, epithelial pseudostratification, and/or hyperactive stroma. Women with a genetic predisposition to ovarian cancer may thus have ovarian epithelium that is already committed to ovarian carcinogenesis, a feature of which is an excess of inclusion cysts.
There are also data from animal studies and limited human studies to support the hypothesis that ovulation may trigger cellular events that result in carcinogenesis. Hyperovulatory hens have a markedly increased likelihood of developing ovarian adenocarcinomas, as do rats with hyperproliferating ovarian epithelial cells (134,135). In women, mutations of the p53 tumor suppressor gene were associated with an increased number of lifetime ovulations in a study by Schildkraut et al. (120). Mutations of the p53 gene are the most common molecular alterations in ovarian cancer and are thought to result from spontaneous errors of DNA synthesis during cell proliferation (136). Risch (137) questioned the validity of these results on the basis that case patients with p53 mutations were older, had poorer tumor differentiation, and had disease of distant rather than of local or regional stage at diagnosis, perhaps indicating that p53-positive tumors are diagnosed later in the neoplastic process. Schildkraut et al. (138) reanalyzed the data matching on age and then on stage and replicated the original findings. However, a more recent case-control study (139) was unable to confirm the association between lifetime ovulations and p53 mutations.
Mutagenicity induced by ovulation may be mediated by inflammation. Ovulation is associated with a marked inflammatory process at the level of ovulatory follicles (140). Many inflammatory mediators, including vasoactive agents such as bradykinin and inflammatory and anti-inflammatory substances such as prostaglandins and leukotrienes, are locally elevated during ovulation. Epithelium in the neighborhood of inclusion cysts is brought in closer proximity to these substances. Follicle rupture probably involves tissue remodeling, with high cell turnover, that is also characteristic of inflammatory reactions. Thus, the process of ovulation is intimately related to inflammation. In particular, epithelium in and around the site of ovulation may replicate more actively, come into contact with cytokines and prostaglandins, and may be subject to oxidative stress, thereby enhancing the risk of mutagenesis.
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PREDICTIONS FROM THE INFLAMMATION HYPOTHESIS AND SUGGESTIONS FOR FUTURE RESEARCH |
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Experimentally induced inflammation of the epithelial ovarian surface should be studied to see whether such manipulation will result in epithelial inclusion cysts. Furthermore, demonstration of markers of mutagenicity within inclusion cysts should be sought to suggest movement along a pathway toward ovarian cancer. For example, known markers of mutagenesis, such as mutations in tumor suppressor genes, if they are more common in inflammation-induced inclusion cysts, would provide evidence supporting the role of inflammation in ovarian cancer pathogenesis. Animal experiments could also examine whether suppression of ovarian epithelial inflammation with anti-inflammatory medications would reduce the number of inclusion cysts and the rate of cancer-associated mutations. Antioxidants may also lower ovarian cancer risk, and evaluation of such an effect in both animals and humans would be helpful in testing the inflammation hypothesis.
Susceptibility to the effects of ovarian epithelial inflammation may be modulated by DNA excision and repair potential; i.e., individuals with more precise or active DNA repair capabilities may be relatively spared from the effects of local inflammation. The prevalence of such DNA polymorphisms within women with ovarian cancer and control subjects could be tested. All of these are testable hypotheses that could help in our understanding of the biologic mechanisms underlying ovarian cancer.
It is likely that hypotheses regarding ovulation, gonadotropins, and inflammation are not mutually exclusive but are instead interactive. The occurrence of inflammation during ovulation has been discussed. Steroid hormones may also mediate inflammation. Estrogens, according to the gonadotropin hypothesis, elevate ovarian cancer risk and they may also stimulate the immune response (142). In particular, estrogens have been demonstrated in vitro to stimulate B-cell response and decrease suppressor T-cell reactivity, resulting in elevations in antibodies and autoantibodies. Moreover, oral contraceptives elevate the concentrations of local immunoglobulin G and immunoglobulin A in the female genital tract (143). Elevated LH may also enhance oxidative stress. The principal bioassay for LH is the ovarian ascorbic acid depletion assay. Ascorbic acid is an antioxidant, and it is possible that LH depletes ascorbic acid by generating the production of free radicals (144). This observationthat a gonadotropin and estrogen may stimulate inflammation and oxidationprovides a link between steroid hormone excess and the physiologic events involved in inflammation. Thus, it is not necessary to argue as to whether the data fit one hypothesis better than another, but rather it is necessary to develop a more comprehensive model of pathogenesis that may incorporate a role for steroid hormones, ovulation, and inflammation in ovarian cancer. Such a model would account for epidemiologic data suggesting associations between reproductive factors and ovarian cancer and also between PID, endometriosis, talc and asbestos exposure, tubal ligation, and hysterectomy and ovarian cancer.
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SUMMARY |
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REFERENCES |
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1
Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics,
1998 [published erratum appears in CA Cancer J Clin 1998;48:192 and 1998;48:329]. CA Cancer J Clin 1998;48:6-29.
2 Fathalla MF. Incessant ovulationa factor in ovarian neoplasia? Lancet 1971;2:163.[Medline]
3 Russell SE, Hickey GI, Lowry WS, White P, Atkinson RJ. Allele loss from chromosome 17 in ovarian cancer. Oncogene 1990;5:1581-3.[Medline]
4 Eccles DM, Cranston G, Steele CM, Nakamura Y, Leonard RC. Allele losses on chromosome 17 in human epithelial ovarian carcinoma. Oncogene 1990;5:1599-601.[Medline]
5 Cramer DW, Welch WR. Determinants of ovarian cancer risk. II. Inferences regarding pathogenesis. J Natl Cancer Inst 1983;71:717-21.[Medline]
6 Risch HA, Marrett LD, Howe GR. Parity, contraception, infertility, and the risk of epithelial ovarian cancer. Am J Epidemiol 1994;140:585-97.[Abstract]
7 Risch HA. Estrogen replacement therapy and risk of epithelial ovarian cancer. Gynecol Oncol 1996;63:254-7.[Medline]
8 Booth M, Beral V, Smith P. Risk factors for ovarian cancer: a case-control study. Br J Cancer 1989;60:592-598.[Medline]
9 McGowan L, Parent L, Lednar W, Norris HJ. The women at risk for developing ovarian cancer. Gynecol Oncol 1979;7:325-44.[Medline]
10 Gwinn ML, Lee NC, Rhodes PH, Layde PM, Rubin GL. Pregnancy, breast feeding, and oral contraceptives and the risk of epithelial ovarian cancer. J Clin Epidemiol 1990;43:559-68.[Medline]
11 Tzonou A, Day NE, Trichopoulos D, Walker A, Saliaraki M, Papapostolou M, et al. The epidemiology of ovarian cancer in Greece. A case-control study. Eur J Cancer Clin Oncol 1984;20:1045-52.[Medline]
12 Hildreth NG, Kelsey JL, LiVolsi VA, Fischer DB, Holford TR, Mostow ED, et al. An epidemiologic study of epithelial carcinoma of the ovary. Am J Epidemiol 1981;114:398-405.[Abstract]
13 Newhouse ML, Pearson RM, Fullerton JM, Boesen EA, Shannon HS. A case control study of the ovary. Br J Prev Soc Med 1977;31: 148-53.[Medline]
14 Wu ML, Whittemore AS, Paffenbarger RS Jr, Sarles DL, Kampert JB, Grosser S, et al. Personal and environmental characteristics related to epithelial ovarian cancer. I. Reproductive and menstrual events and oral contraceptive use. Am J Epidemiol 1988; 128:1216-27.[Abstract]
15 Casagrande JT, Louie EW, Pike MC, Roy S, Ross RK, Henderson BE. "Incessant ovulation" and ovarian cancer. Lancet 1979;2:170-3.[Medline]
16 Rosenberg L, Shapiro S, Slone D, Kaufman DW, Helmrich SP, Miettinen OS, et al. Epithelial ovarian cancer and combination oral contraceptives. JAMA 1982;247:3210-2.[Abstract]
17 Mori M, Harabuchi I, Miyake H, Casagrande JT, Henderson BE, Ross RK. Reproductive, genetic, and dietary risk factors for ovarian cancer. Am J Epidemiol 1988;128:771-7.[Abstract]
18 Cramer DW, Hutchison GB, Welch WR, Scully RE, Ryan KJ. Determinants of ovarian cancer risk. I. Reproductive experiences and family history. J Natl Cancer Inst 1983;1:711-6.
19 Kvale G, Heuch I, Nilssen S, Beral V. Reproductive factors and risk of ovarian cancer: a prospective study. Int J Cancer 1988;42:246-51.[Medline]
20 Joly DJ, Lilienfeld AM, Diamond EL, Bross ID. An epidemiologic study of the relationship of reproductive experience to cancer of the ovary. Am J Epidemiol 1974;99:190-209.[Medline]
21 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.[Abstract]
22 Franceschi S, La Vecchia C, Helmrich SP, Mangioni C, Tognoni G. Risk factors for epithelial ovarian cancer in Italy. Am J Epidemiol 1982;115:714-9.[Abstract]
23 La Vecchia C, Decarli A, Franceschi S, Regallo M, Tognoni G. Age at first birth and the risk of epithelial ovarian cancer. J Natl Cancer Inst 1984;73:663-6.[Medline]
24 Risch HA, Weiss NS, Lyon JL, Daling JR, Liff JM. Events of reproductive life and the incidence of epithelial ovarian cancer. Am J Epidemiol 1983;117:128-39.[Abstract]
25 Voigt LF, Harlow BL, Weiss NS. The influence of age at first birth and parity on ovarian cancer risk. Am J Epidemiol 1986;124:490-1.[Medline]
26 Mori M, Kiyosawa H, Miyake H. Case-control study of ovarian cancer in Japan. Cancer 1984;53:2746-52.[Medline]
27 Wynder EL, Dodo H, Barber HR. Epidemiology of cancer of the ovary. Cancer 1969;23:352-70.[Medline]
28 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]
29 Adami HO, Hsieh CC, Lambe M, Trichopoulos D, Leon D, Persson I, et al. Parity, age at first childbirth, and risk of ovarian cancer. Lancet 1944;344:1250-4.
30 Chen MT, Cook LS, Daling JR, Weiss NS. Incomplete pregnancies and risk of ovarian cancer (Washington, United States). Cancer Causes Control 1996;7:415-20.[Medline]
31 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. Collaborative Ovarian Cancer Group. Am J Epidemiol 1992;136:1184-203.[Abstract]
32 Purdie D, Green A, Bain C, Siskind V, Ward B, Hacker N, et al. Reproductive and other factors and risk of epithelial ovarian cancer: an Australian case-control study. Survey of Women's Health Study Group. Int J Cancer 1995;62:678-84.[Medline]
33 Hartge P, Schiffman MH, Hoover R, McGowan L, Lesher L, Norris HJ. A case-control study of epithelial ovarian cancer. Am J Obstet Gynecol 1989;161:10-6.[Medline]
34 Shu XO, Brinton LA, Gao YT, Yuan JM. Population-based case-control study of ovarian cancer in Shanghai. Cancer Res 1989;49:3670-4.[Abstract]
35 Vessey M, Metcalfe A, Wells C, McPherson K, Westhoff C, Yeates D. Ovarian neoplasms, functional ovarian cysts, and oral contraceptives. Br Med J (Clin Res Ed) 1987;294:1518-20.[Medline]
36 Harlow BL, Weiss NS, Roth GJ, Chu J, Daling JR. Case-control study of borderline ovarian tumors: reproductive history and exposure to exogenous female hormones. Cancer Res 1988;48:5849-52.[Abstract]
37 The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. The reduction in risk of ovarian cancer associated with oral-contraceptive use. N Engl J Med 1987;316:650-5.[Abstract]
38 The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Epithelial ovarian cancer and combined oral contraceptives. Int J Epidemiol 1989;18:538-45.[Abstract]
39 Beral V, Hannaford P, Kay C. Oral contraceptive use and malignancies of the genital tract. Results from the Royal College of General Practitioners' Oral Contraceptive Study. Lancet 1988;2:1331-5.[Medline]
40 Willett WC, Bain C, Hennekens CH, Rosner B, Speizer FE. Oral contraceptives and risk of ovarian cancer. Cancer 1981;48:1684-7.[Medline]
41 Cramer DW, Hutchison GB, Welch WR, Scully RE, Knapp RC. Factors affecting the association of oral contraceptives and ovarian cancer. N Engl J Med 1982;307:1047-51.[Abstract]
42 Weiss NS, Lyon JL, Liff JM, Vollmer WM, Daling JR. Incidence of ovarian cancer in relation to the use of oral contraceptives. Int J Cancer 1981;28:669-71.[Medline]
43 La Vecchia C, Franceschi S, Decarli A. Oral contraceptives and the risk of epithelial ovarian cancer. Br J Cancer 1984;50:31-4.[Medline]
44 Parazzini F, La Vecchia C, Negri E, Bocciolone L, Fedele L, Franceschi S. Oral contraceptive use and the risk of ovarian cancer: an Italian case-control study. Eur J Cancer 1991;27:594-8.[Medline]
45 Stanford JL. Oral contraceptives and neoplasia of the ovary. Contraception 1991;43:543-56.[Medline]
46 Whittemore AS, Harris R, Itnyre J. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. IV. The pathogenesis of epithelial ovarian cancer. Collaborative Ovarian Cancer Group. Am J Epidemiol 1992;136:1212-20.[Abstract]
47 Liu J, Rebar RW, Yen SS. Neuroendocrine control of the postpartum period. Clin Perinatol 1983;10:723-36.[Medline]
48
Risch HA. Hormonal etiology of epithelial ovarian cancer, with a
hypothesis concerning the role of androgens and progesterone. J Natl Cancer Inst 1998;90:1774-86.
49 Glud E, Kjaer SK, Troisi R, Brinton LA. Fertility drugs and ovarian cancer. Epidemiol Rev 1998;20:237-57.[Medline]
50 Bristow RE, Karlan BY. Ovulation induction, infertility, and ovarian cancer risk. Fertil Steril 1996;66:499-507.[Medline]
51 Zeimet AG, Muller-Holzner E, Marth C, Daxenbichler G. Immunocytochemical versus biochemical receptor determination in normal and tumorous tissues of the female reproductive tract and the breast. J Steroid Biochem Mol Biol 1994;49:365-72.[Medline]
52 Cramer DW, Harlow BL, Titus-Ernstoff L, Bohlke K, Welch WR, Greenberg ER. Over-the-counter analgesics and risk of ovarian cancer. Lancet1998 ;351:104-7.[Medline]
53 Cramer DW. Epidemiologic aspects of early menopause and ovarian cancer. Ann N Y Acad Sci 1990;592:363-75.[Abstract]
54 Helzlsouer KJ, Alberg AJ, Gordon GB, Longcope C, Bush TL, Hoffman SC, et al. Serum gonadotropins and steroid hormones and the development of ovarian cancer. JAMA 1995;274:1926-30.[Abstract]
55 Hoover R, Gray LA Sr, Fraumeni JF Jr. Stilboestrol (diethylstilbestrol) and the risk of ovarian cancer. Lancet 1977;2:533-4.[Medline]
56 Annegers JF, Strom H, Decker DG, Dockerty MB, O'Fallon WM. Ovarian cancer: incidence and case-control study. Cancer 1979;43:723-9.[Medline]
57 Hartge P, Hoover R, McGowan L, Lesher L, Norris HJ. Menopause and ovarian cancer. Am J Epidemiol 1988;127:990-8.[Abstract]
58 Weiss NS, Lyon JL, Krishnamurthy S, Dietert SE, Liff JM, Daling JR. Noncontraceptive estrogen use and the occurrence of ovarian cancer. J Natl Cancer Inst 1982;68:95-8.[Medline]
59 Kaufman DW, Kelly JP, Welch WR, Rosenberg L, Stolley PD, Warshauer ME, et al. Noncontraceptive estrogen use and epithelial ovarian cancer. Am J Epidemiol 1989;130:1142-51.[Abstract]
60 La Vecchia C, Liberati A, Franceschi S. Noncontraceptive estrogen use and the occurrence of ovarian cancer [letter]. J Natl Cancer Inst 1982;69:1207.[Medline]
61
Hempling RE, Wong C, Piver MS, Natarajan N, Mettlin CJ.
Hormone replacement therapy as a risk factor for epithelial ovarian cancer: results of a
case-control study. Obstet Gynecol 1997;89:1012-6.
62 Rodriguez C, Calle EE, Coates RJ, Miracle-McMahill HL, Thurn MJ, Heath CW Jr. Estrogen replacement therapy and fatal ovarian cancer. Am J Epidemiol 1995;141:828-35.[Abstract]
63
Garg PP, Kerlikowske K, Subak L, Grady D. Hormone
replacement therapy and the risk of epithelial ovarian carcinoma: a meta-analysis. Obstet
Gynecol 1998;92:472-9.
64
Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG.
Ovarian tumors in a cohort of infertile women. N Engl J Med 1994;331:771-6.
65 Venn A, Watson L, Lumley J, Giles G, King C, Healy D. Breast and ovarian cancer incidence after infertility and in vitro fertilisation. Lancet 1995;346:995-1000.[Medline]
66 Bristow RE, Karlan BY. Ovulation induction, infertility, and ovarian cancer risk. Fertil Steril 1996;66:499-507.[Medline]
67 Mosgaard BJ, Lidegaard O, Kjaer SK, Schou G, Andersen AN. Infertility, fertility drugs, and invasive ovarian cancer: a case-control study. Fertil Steril 1997;67:1005-12.[Medline]
68 Modan B, Ron E, Lerner-Geva L, Blumstein T, Menczer J, Rabinovici J, et al. Cancer incidence in a cohort of infertile women. Am J Epidemiol1998 ;147:1038-42.[Abstract]
69 Shushan A, Paltiel O, Iscovich J, Elchalal U, Peretz T, Schenker JG. Human menopausal gonadotropin and the risk of epithelial ovarian cancer. Fertil Steril 1996;65:13-8.[Medline]
70 Harlow SD, Ephross SA. Epidemiology of menstruation and its relevance to women's health. Epidemiol Rev 1995;17:265-86.[Medline]
71 Graham J, Graham R. Ovarian cancer and asbestos. Environ Res 1967;1:115-28.[Medline]
72 Keal EE. Asbestosis and abdominal neoplasma. Lancet 1960;2:1211-6.[Medline]
73 Acheson ED, Gardner MJ, Pippard EC, Grime LP. Mortality of two groups of women who manufactured gas masks from chrysotile and crocidolite asbestos: a 40-year follow-up. Br J Ind Med 1982;39:344-8.[Medline]
74 Newhouse ML, Berry G, Wagner JC, Turok ME. A study of the mortality of female asbestos workers. Br J Ind Med 1972;29:134-41.[Medline]
75 Newhouse ML, Berry G, Wagner JC. Mortality of factory workers in East London 1933-80. Br J Ind Med 1985;42:4-11.[Medline]
76 Heller DS, Gordon RE, Westhoff C, Gerber S. Asbestos exposure and ovarian fiber burden. Am J Ind Med 1996;29:435-9.[Medline]
77 Kelsey JL, Hildreth NG. Breast and gynecologic cancer epidemiology. Boca Raton (FL): CRC press; 1983.
78 Neugut AI, Eisenberg D, Silverstein M, Pulkrabek P, Weinstein IB. Effects of asbestos on epithelioid cell lines. Environ Res 1978;17:256-65.[Medline]
79 Rice PA, Schachter J. Pathogenesis of pelvic inflammatory disease. What are the questions? JAMA 1991;266:2587-93.[Abstract]
80 Harlow BL, Hartge PA. A review of perineal talc exposure and risk of ovarian cancer. Regul Toxicol Pharmacol 1995;21:254-60.[Medline]
81 Cook LS, Kamb ML, Weiss NS. Perineal powder exposure and the risk of ovarian cancer [published erratum appears in Am J Epidemiol 1998;148:410]. Am J Epidemiol 1997;145:459-65.[Abstract]
82 Cramer DW, Welch WR, Scully Re, Wojciechowski CA. Ovarian cancer and talc: a case-control study. Cancer 1982;50:372-6.[Medline]
83 Whittemore AS, Wu ML, Paffenbarger PS Jr, Sarles DL, Kampert JB, Grosser S, et al. Personal and environmental characteristics related to epithelial ovarian cancer. II. Exposures to talcum powder, tobacco, alcohol, and coffee. Am J Epidemiol 1988;128:1228-40.[Abstract]
84 Harlow BL, Weiss NS. A case-control study of borderline ovarian tumors: the influence of perineal exposure to talc. Am J Epidemiol 1989;130:390-4.[Abstract]
85 Chen Y, Wu PC, Lang JH, Ge WJ, Hartge P, Brinton LA. Risk factors for epithelial ovarian cancer in Beijing, China. Int J Epidemiol 1992;21:23-9.[Abstract]
86 Harlow BL, Cramer DW, Bell DA, Welch WR. Perineal exposure to talc and ovarian cancer risk. Obstet Gynecol 1992;80:19-26.[Abstract]
87 Rosenblatt KA, Szklo M, Rosenshein NB. Mineral fiber exposure and the development of ovarian cancer. Gynecol Oncol 1992;45:20-5.[Medline]
88 Hartge P, Hoover R, Lesher LP, McGowan L. Talc and ovarian cancer [letter]. JAMA 1988;250:1844.
89 Tzonou A, Polychronopoulou A, Hsieh CC, Rebelakos A, Karakatsani A, Trichopoulos D. Hair dyes, analgesics, tranquilizers and perineal talc application as risk factors for ovarian cancer. Int J Cancer 1993;55:408-10.[Medline]
90 Chang S, Risch HA. Perineal talc exposure and risk of ovarian carcinoma. Cancer 1997;79:2396-401.[Medline]
91 Heller DS, Westhoff C, Gordon RE, Katz N. The relationship between perineal cosmetic talc usage and ovarian talc particle burden. Am J Obstet Gynecol 1996;174:1507-10.[Medline]
92 Harlow BL, Hartge PA. A review of perineal talc exposure and risk of ovarian cancer. Regul Toxicol Pharmacol 1995;21:254-60.[Medline]
93 Heaps JM, Nieberg RK, Berek JS. Malignant neoplasms arising in endometriosis. Obstet Gynecol 1990;75:1023-8.[Abstract]
94 Hitti IF, Glasberg SS, Lubicz S. Clear cell carcinoma arising in extra-ovarian endometriosis: report of three cases and review of the literature. Gynecol Oncol 1990;39:314-20.[Medline]
95 Brinton LA, Gridley G, Persson I, Baron J, Bergqvist A. Cancer risk after a hospital discharge diagnosis of endometriosis. Am J Obstet Gynecol 1997;176:572-9.[Medline]
96 Sainz de la Cuesta R, Eichhorn JH, Rice LW, Fuller AF Jr, Mikrui N, Goff BA. Histologic transformation of benign endometriosis to early epithelial ovarian cancer. Gynecol Oncol 1996;60:238-44.[Medline]
97 Vercellini P, Parazzini F, Bolis G, Carinelli S, Dindelli M, Vendola N, et al. Endometriosis and ovarian cancer. Am J Obstet Gynecol 1993;169:181-2.[Medline]
98 LaGrenade A, Silverberg SG. Ovarian tumors associated with atypical endometriosis. Hum Pathol 1988;19:1080-4.[Medline]
99 Moll UM, Chumas JC, Chalas E, Mann WJ. Ovarian carcinoma arising in atypical endometriosis. Obstet Gynecol 1990;75:537-9.[Abstract]
100 Jimbo H, Yoshikawa H, Onda T, Yasugi T, Sakamoto A, Taketani Y. Prevalence of ovarian endometriosis in epithelial ovarian cancer. Int J Gynecol Obstet 1997;59:245-50.[Medline]
101 DePriest PD, Banks ER, Powell DE, van Nagell JR Jr, Gallion HH, Puls SE, et al. Endometrioid carcinoma of the ovary and endometriosis: the association in postmenopausal women. Gynecol Oncol 1992;47:71-5.[Medline]
102 Sampson JA. Endometrial carcinoma of the ovary arising in endometrial tissue in that organ. Arch Surg 1925;10:1-72.
103 Friedlander ML. Prognostic factors in ovarian cancer. Semin Oncol 1998;25:305-14.[Medline]
104 Czernobilsky B, Morris WJ. A histologic study of ovarian endometriosis with emphasis on hyperplastic and atypical changes. Obstet Gynecol 1979;53:311-23.
105 Weiss NS, Harlow BL. Why does hysterectomy without bilateral oophorectomy influence the subsequent incidence of ovarian cancer? Am J Epidemiol 1986;124:856-8.[Medline]
106 Whittemore AS, Wu ML, Paffenbarger RS Jr, Sarles DL, Kampert JB, Grosser S, et al. Epithelial ovarian cancer and the ability to conceive. Cancer Res 1989;49:4047-52.[Abstract]
107 Irwin KL, Weiss NS, Lee NC, Peterson HB. Tubal sterilization, hysterectomy, and the subsequent occurrence of epithelial ovarian cancer. Am J Epidemiol 1991;134:362-9.[Abstract]
108 Cramer DW, Xu H. Epidemiologic evidence for uterine growth factors in the pathogenesis of ovarian cancer. Ann Epidemiol 1995;5:310-4.[Medline]
109 Hankinson SE, Hunter DJ, Colditz GA, Willett WC, Stampfer MJ, Rosner B, et al. Tubal ligation, hysterectomy, and risk of ovarian cancer. A prospective study. JAMA 1993;270:2813-8.[Abstract]
110 Miracle-McMahill HL, Calle EE, Kosinski AS, Rodriguez C, Wingo PA, Thun MJ, et al. Tubal ligation and fatal ovarian cancer in a large prospective cohort study. Am J Epidemiol 1997;145:349-57.[Abstract]
111 Loft A, Lidegaard O, Tabor A. Incidence of ovarian cancer after hysterectomy: a nationwide controlled follow up. Br J Obstet Gynaecol 1997;104:1296-301.[Medline]
112 Kreiger N, Sloan M, Cotterchio M, Parsons P. Surgical procedures associated with risk of ovarian cancer. Int J Epidemiol 1997;26:710-5.[Abstract]
113 Cornelison TL, Natarajan N, Piver MS, Mettlin CJ. Tubal ligation and the risk of ovarian carcinoma. Cancer Detect Prev 1997;21:1-6.[Medline]
114 Green A, Purdie D, Bain C, Siskind V, Russell P, Quinn M, et al. Tubal sterilisation, hysterectomy and decreased risk of ovarian cancer. Survey of Women's Health Study Group. Int J Cancer 1997;71:948-51.[Medline]
115 Rosenblatt KA, Thomas DB. Reduced risk of ovarian cancer in women with a tubal ligation or hysterectomy. The World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives. Cancer Epidemiol Biomarkers Prev1996 ;5:933-5.[Abstract]
116 Risch HA, Howe GR. Pelvic inflammatory disease and the risk of epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev 1995;4:447-51.[Abstract]
117 Parazzini F, La Vecchia C, Negri E, Moroni S, dal Pino D, Fedele L. Pelvic inflammatory disease and risk of ovarian cancer. Cancer Epidemiol Biomarkers Prev 1996;5:667-9.[Abstract]
118
Giovannucci E, Rimm EB, Stampfer MJ, Colditz GA, Ascherio
A, Willett WC. Aspirin use and the risk for colorectal cancer and adenoma in male health
professionals. Ann Intern Med 1994;121:241-6.
119 Ames BN, Gold LS, Willett WC. The causes and prevention of cancer. Proc Natl Acad Sci U S A 1995;92:5258-65.[Abstract]
120
Schildkraut JM, Bastos E, Berchuck A. Relationship between
lifetime ovulatory cycles and overexpression of mutant p53 in epithelial ovarian cancer. J
Natl Cancer Inst 1997;89:932-8.
121 Dreher D, Junod AF. Role of oxygen free radicals in cancer development. Eur J Cancer 1996;32A:30-8.
122 Ziltener HJ, Maines-Bandiera S, Schrader JW, Auersperg N. Secretion of bioactive interleukin-1, interleukin-6, and colony-stimulating factors by human ovarian surface epithelium. Biol Reprod 1993;49:635-41.[Abstract]
123 Auersperg N, Edelson MI, Mok SC, Johnson SW, Hamilton TC. The biology of ovarian cancer. Semin Oncol 1998;25:281-304.[Medline]
124 Subbaramaiah K, Zakim D, Weksler BB, Dannenberg AJ. Inhibition of cyclooxygenase: a novel approach to cancer prevention. Proc Soc Exp Biol Med 1997;216:201-10.[Abstract]
125 Aitokallio-Tallberg AM, Viinikka LU, Ylikorkala RO. Increased synthesis of prostacyclin and thromboxane in human ovarian malignancy. Cancer Res 1988;48:2396-8.[Abstract]
126
Giovannucci E, Egan KM, Hunter DJ, Stampfer MJ, Colditz
GA, Willett WC, et al. Aspirin and the risk of colorectal cancer in women. N Engl J Med 1995;333:609-14.
127
Giardiello FM, Hamilton SR, Krush AJ, Piantadosi S, Hylind
LM, Celano P, et al. Treatment of colonic and rectal adenomas with sulindac in familial
adenomatous polyposis. N Engl J Med 1993;328:1313-6.
128 Harris RE, Namboodiri KK, Farrar WB. Nonsteroidal antiinflammatory drugs and breast cancer. Epidemiolgy 1996;7:203-5.
129 Murdoch WJ. Ovarian surface epithelium, ovulation and carcinogenesis. Biol Rev Camb Philos Soc 1996;71:529-43.[Medline]
130 Auersperg N, Maines-Bandiera SL, Dyck HG. Ovarian carcinogenesis and the biology of ovarian surface epithelium. J Cell Physiol 1997;173:261-5.[Medline]
131 Mittal KR, Zeleniuch-Jacquotte A, Cooper JL, Demopoulos RI. Contralateral ovary in unilateral ovarian carcinoma: a search for preneoplastic lesions. Int J Gynecol Pathol 1993;12:59-63.[Medline]
132 Westhoff C, Murphy P, Heller D, Halim A. Is ovarian cancer associated with an increased frequency of germinal inclusion cysts? Am J Epidemiol1993 ;138:90-3.[Abstract]
133
Salazar H, Godwin AK, Daly MB, Laub PB, Hogan WM,
Rosenblum N, et al. Microscopic benign and invasive malignant neoplasms and a cancer-prone
phenotype in prophylactic oophorectomies. J Natl Cancer Inst 1996;88:1810-20.
134 Wilson JE. Adenocarcinomata in hens kept in a constant environment. Poultry Sci 1958;37:1253.
135 Godwin AK, Testa JR, Handel LM, Liu Z, Vanderveer LA, Tracey PA, et al. Spontaneous transformation of rat ovarian surface epithelial cells: association with cytogenetic changes and implications of repeated ovulation in the etiology of ovarian cancer. J Natl Cancer Inst 1992;84:592-601.[Abstract]
136 Jones PA, Buckley JD, Henderson BE, Ross RK, Pike MC. From gene to carcinogen: a rapidly evolving field in molecular epidemiology. Cancer Res 1991;51:3617-20.[Abstract]
137
Risch HA. Relationship between lifetime ovulatory cycles and
overexpression of mutant p53 in epithelial ovarian cancer [letter]. J Natl Cancer
Inst 1997;89:1726-7.
138
Schildkraut JM, Bastos E, Halabi S, Berchuck A. Relationship
between lifetime ovulatory cycles and overexpression of mutant p53 in epithelial ovarian cancer. J Natl Cancer Inst 1997;89:932-8.
139
Webb PM, Green A, Cummings MC, Purdie DM, Walsh MD,
Chenevix-Trench G. Relationship between number of ovulatory cycles and accumulation of
mutant p53 in epithelial ovarian cancer. J Natl Cancer Inst 1998;90:1729-34.
140 Espey LL. Current status of the hypothesis that mammalian ovulation is comparable to an inflammatory reaction. Biol Reprod 1994;50:233-8.[Abstract]
141 Cibere J, Sibley J, Haga M. Rheumatoid arthritis and the risk of malignancy. Arthritis Rheum 1997;40:1580-6.[Medline]
142 Manzi S, Ramsey-Goldman R. Autoimmune diseases. In: Ness RB, Kuller LH, editors. Health and disease among women. Biological and environmental influences. New York (NY): Oxford University Press; 1998. p. 342-72.
143 Crowley-Nowick PA. Basic principles of immunology and genital tract immunity. In: Ness RB, Kuller LH, editors. Health and disease among women. Biological and environmental influences. New York (NY): Oxford University Press; 1998. p. 273-96.
144 Kolodecik TR, Aten RF, Behrman HR. Ascorbic acid-dependent cytoprotection of ovarian cells by leukocyte and nonleukocyte peroxidases. Biochem Pharmacol 1998;9:1497-503.
Manuscript received December 14, 1998; revised June 24, 1999; accepted July 6, 1999.
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