ARTICLE

Impact of Progestin and Estrogen Potency in Oral Contraceptives on Ovarian Cancer Risk

Joellen M. Schildkraut, Brian Calingaert, Polly A. Marchbanks, Patricia G. Moorman, Gustavo C. Rodriguez

Affiliations of authors: J. M. Schildkraut, B. Calingaert, P. G. Moorman (Department of Community and Family Medicine and the Duke Comprehensive Cancer Center), G. C. Rodriguez (Department of Obstetrics and Gynecology/Division of Gynecologic Oncology), Duke University Medical Center, Durham, NC; P. A. Marchbanks, Division of Reproduction Health, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Atlanta, GA.

Correspondence to: Joellen M. Schildkraut, Ph.D., Program of Cancer Prevention, Detection and Control Research, Duke University Medical Center, Box 2949, Durham, NC 27710 (e-mail: schil001{at}mc.duke.edu).


    ABSTRACT
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Oral contraceptive (OC) use is associated with a reduced risk of developing ovarian cancer, but the mechanism for the risk reduction has not been well defined. In this study, we investigate the relationship between the progestin and estrogen potency in combination OCs and the risk of developing ovarian cancer. Methods: The study included 390 case subjects with epithelial ovarian cancer and 2865 control subjects, between 20 and 54 years of age, identified from the Cancer and Steroid Hormone Study. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between ovarian cancer risk and combination OC formulations while controlling for potential confounders. All statistical tests were two-sided. Results: With users of high-progestin/high-estrogen potency OC as the referent group, users of low-progestin/high-estrogen potency formulations (adjusted OR = 2.1; 95% CI = 1.2 to 3.7) and low-progestin/low-estrogen potency formulations (adjusted OR = 1.6; 95% CI = 0.9 to 3.0) had a higher risk of ovarian cancer than users of high-progestin/high-estrogen potency formulation. Low-progestin potency OC formulations were associated with a statistically significant higher risk than high-progestin potency formulations (adjusted OR = 2.2; 95% CI = 1.3 to 3.9). This association was seen even among users of short duration. Conclusion: The combination OC formulations with high-progestin potency appear to be associated with a greater reduction in ovarian cancer risk than those with low-progestin potency. Mechanisms underlying this reduction may include inhibition of ovulation and/or some direct biologic effects of the progestin.



    INTRODUCTION
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Along with parity, oral contraceptive (OC) use has consistently been associated with a decreased risk of ovarian cancer (1,2). Three or more years of OC use reduces the risk of developing epithelial ovarian cancer by 30%–50% (1,35). The association increases with the duration of use and appears to be independent of inherent ovarian cancer risk(1,6,7).

The mechanisms underlying this marked reduction have not been well defined. However, it is commonly believed that ovulation, with its associated disruption and subsequent repair of the ovarian epithelium, can lead to the acquisition of genetic damage in ovarian epithelial cells and, in turn, to ovarian cancer in susceptible individuals (810). The "incessant ovulation" hypothesis for ovarian cancer is supported by a large volume of epidemiologic evidence linking ovulation with ovarian cancer risk (1,5,6,8,1116) and by the finding that spontaneous ovarian cancers arise frequently in poultry hens, which ovulate daily (17).

Under the incessant ovulation model, reproductive and hormonal factors, such as OC use and pregnancy, have been presumed to alter ovarian cancer risk mainly via their impact on ovulation. Although this hypothesis is attractive, it fails to completely explain the observed differences in the degree of ovarian cancer risk reduction associated with various factors, such as pregnancy, OC use, breast-feeding, and age at menarche, that would be expected simply on the basis of the number of ovulatory cycles that are inhibited (1,6). In addition, pregnancy is associated with a reduced risk of ovarian cancer, even in women who are known to have ovulatory dysfunction and among those for whom the pregnant state has little impact on the number of lifetime ovulatory cycles (18). Some studies (19,20) have reported a relationship between increasing risk of epithelial ovarian cancer and increasing time since last birth. These data support the hypothesis that hormonal factors impact ovarian cancer risk through additional biologic mechanisms unrelated to ovulation inhibition (21).

Recently, a 3-year study in primates demonstrated that the progestin component of an OC has a potent apoptotic effect on the ovarian epithelium, providing support for the hypothesis that OCs may lower ovarian cancer risk via induction of cancer-preventive molecular pathways in the ovary (22). Eighty cynomolgus macaques were randomly allocated into one of four groups, including a control group, a group treated with the OC Triphasil (which contains the estrogen ethinyl estradiol and the progestin levonorgestrel), and one group each treated either with ethinyl estradiol or levonorgestrel alone on the same dosage and schedule as those animals receiving Triphasil. At trial completion, examination of the ovaries revealed a striking and statistically significant increase in the percentage of apoptotic ovarian epithelial cells of monkeys treated with Triphasil (14.5%) or levonorgestrel (24.9%) as compared with controls (3.8%) or with monkeys treated with estrogen alone (1.8%). The apoptosis pathway is one of the most important in vivo mechanisms for eliminating cells that have sustained DNA damage and are thus prone to malignant transformation (23). In addition, induction of apoptosis is a biologic effect associated with many known chemopreventive agents (2431). The finding that progestins activate this critical pathway in the ovarian epithelium raises the possibility that progestin-mediated apoptotic effects, and not solely ovulation inhibition as has been previously assumed, may underlie the reduction in ovarian cancer associated with routine OC use. Consistent with these findings, a review and reanalysis of the literature by Risch (32) supported the theory that progesterone may render a protective effect on ovarian cancer risk. If this hypothesis is correct, then it is possible that OC formulations that have greater progestin potency may confer greater ovarian cancer protection than OC formulations containing weak progestins.

Only a few case–control studies (3,5,33,34) have attempted to examine the relationship between use of specific OC hormonal formulations and ovarian cancer risk. Overall, these studies have shown that combination estrogen–progestin OCs are associated with a reduced risk of ovarian cancer. However, none was able to demonstrate that there was a relationship between hormone potency and this protective effect. Each of these studies has had methodologic limitations, which may have affected their ability to detect meaningful differences in protective efficacy between different OC formulations. An initial analysis of the Cancer and Steroid Hormone (CASH) Study attempted to characterize the protective effect of specific OC formulations on ovarian cancer risk (5). All of the formulations examined appeared to be associated with a reduced risk. However, OC formulations were not categorized according to the potency, or dosages, of estrogen and progestin and there were too few cases of each formulation to detect differences. Similarly, Rosenberg et al. (3) suggested a protective effect of progestogen-only contraceptives but did not calculate odds ratios (ORs) for different OC formulations because of the small number of women taking any given formulation. Rosenblatt et al. (33) reported a somewhat lower risk reduction associated with low- versus high-potency OC formulations, but the differences were small and could have occurred by chance. In addition, OC formulations were ranked as low versus high potency solely on the basis of the estrogen component, with no consideration of the progestin component. Finally, a recent study by Ness et al. (34) suggested that there were no differences in the risk reduction associated with OCs of varying estrogenic and progestin potencies. To our knowledge, this was the largest study, to date, for which hormone potency was taken into account (34).

In this study, we examine the relationship between progestin and estrogen potency and the risk of epithelial ovarian cancer in a reanalysis of the CASH Study data. In this article, consideration is given to the associations with combined estrogen and progestin OCs according to the relative potency of each formulation's subcomponents. Unlike the prior analysis of the CASH Study data, formulations have been categorized and combined according to hormonal potency to have sufficient power to permit the detection of differences in various OC formulations and their association with a reduction in ovarian cancer risk.


    MATERIALS AND METHODS
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study Subjects

Details of the CASH Study have been described previously (35). The ovarian cancer case subjects in this article include patients, 20–54 years of age, diagnosed with epithelial ovarian cancer from December 1, 1980, through December 31, 1982, who participated in the CASH Study. Incident cases of histologically confirmed ovarian cancer were identified from eight population-based tumor registries of the Surveillance, Epidemiology, and End Results (SEER)1 Program, including the metropolitan areas of Atlanta, GA, Detroit, MI, San Francisco, CA, and Seattle, WA; the states of Connecticut, New Mexico, and Iowa; and four urban counties of Utah. Of the 816 women who were identified as eligible ovarian cancer subjects, 579 (71%) were interviewed. Because of known epidemiologic differences in epithelial versus nonepithelial ovarian cancer, the current analysis was restricted to women classified as having epithelial tumors. At the time of patient accrual for the CASH Study, an expert panel of three pathologists reviewed histologic material from 449 of the epithelial ovarian cancer subjects. Because the classification of tumors as epithelial versus nonepithelial by the panel agreed closely with the original classification by the local pathologists at the time of diagnosis, the classification by the local pathologists was used whenever histologic materials were not available to the panel. Women diagnosed with ovarian cancers of low malignant potential were included in the current study. Previous reports have shown that OC use is associated with a risk reduction for both invasive cancers and tumors of low malignant potential (36,37). Information on the subject's tumor behavior, invasive versus low malignant potential, was available for only the 449 subjects who were reviewed by the three study pathologists. Thus, 324 women with invasive ovarian cancer, 123 with tumors of low malignant potential, two with carcinoma in situ, and 44 for whom tumor behavior was unknown were considered for inclusion in the analysis, for a total of 493 women diagnosed with epithelial ovarian cancer available in the CASH Study.

Control subjects were aged 20–54 years, had resided in the same eight geographic locations as the case subjects, and were recruited through random-digit telephone dialing. Of the 5698 women selected as control subjects, 4754 (83%) agreed to participate. The control group was restricted to women who were at risk for a first primary ovarian cancer at the time of the interview. Thus, 711 women were excluded because of a history of bilateral oophorectomy, a prior history of ovarian cancer, or uncertainty regarding prior oophorectomy, leaving 4043 control subjects.

In this study, we limited OC users to women who used combination OC pills (containing both an estrogen and a progestin for 21 days each month). Excluded from the analysis were women who did not know if they had ever used OCs for 3 or more consecutive months (two ovarian cancer case subjects and 10 control subjects), those who had used an unknown type of OC pill (51 ovarian cancer case subjects and 473 control subjects), those who did not know the dose of an OC that they had used (12 ovarian cancer case subjects and 193 control subjects), and those who used a sequential OC (estrogen-only formulation for the first 14–16 days, followed by combination of estrogen and progestin for 5–6 days) (seven ovarian cancer case subjects and 111 control subjects). Women taking sequential OCs were excluded, since the hormone schedule of these formulations is much different than that of combination OCs. In addition, we excluded women who used progestin-only OCs (one case subject and seven control subjects).

Up to seven OC episodes were recorded among subjects classified as users. Each OC episode was categorized according to progestin and estrogen potency, either low or high, according to the scheme described below. Among those who were classified as OC users, only subjects who had a single OC episode or multiple episodes with all OC episodes being from the same hormone-potency category were retained for analysis purposes. In other words, women who used OCs from more than one potency category were excluded. Altogether, there were 390 epithelial ovarian cancer case subjects and 2865 control subjects available for the analysis.

Data Collection and Analysis Variables

A standardized questionnaire was administered in the home of each study participant. Women who reported three or more consecutive months of OC use were categorized as ever users and women who used OCs for less than 3 months were classified as nonusers. Detailed information on the formulations used was collected from all of the women who reported having used OCs for 3 or more consecutive months. A life calendar (a calendar on which to record major life events around which contraceptive use might be better remembered) and color photographs of OC packages were used to help women recall their contraceptive use up to the time of diagnosis (for case subjects) or the date of the interview (for control subjects).

Additional questionnaire items included socioeconomic information, age at menarche and menopause, use of other hormones, infertility (defined as failure to conceive after 2 years that was determined by a physician to be because of a problem in the woman or both the woman and her partner), number of pregnancies 6 or more months in duration, history of breast-feeding, medical history, and family history of cancer. Reference age was defined as age at diagnosis for women diagnosed with ovarian cancer and age at interview for control subjects.

Strategy for Classifying OC Hormonal Potency

Each OC used by the study participants was classified according to estrogen and progestin potency. Using the categorization described in a standard pharmacy reference text, progestin potency was based on delay of menses and glycogen incorporation in human endometrial vacuoles tests (38,39). For our analyses, OCs classified by the standard text in the low- and intermediate-progestin potency categories were combined into the low-progestin potency category, and the remainder were classified as high potency. For estrogen potency, it was assumed that ethinyl estradiol is twice as potent as mestranol (40). OC formulations containing 35 µg or less of ethinyl estradiol or its equivalent were categorized as low-estrogen potency, and the remainder were classified as high potency. Therefore, each OC formulation was placed in one of four categories: high progestin/high estrogen, high progestin/low estrogen, low progestin/high estrogen, or low progestin/low estrogen (Table 1Go). The high-potency progestin formulations reported by subjects in Table 1Go were first released on the market between 1960 and 1970, with the majority from the period 1966 through 1970 (Demulen; Ovulen; Ovral; Enovid, 10 mg; and Provest) (41). Similarly, among the low-potency progestin formulations, the year of release on the market ranged from the period 1962 through 1975, the majority of which were released from the period 1962 through 1968 (i.e., Enovid, 5 mg; Enovid-E; Norinyl 1 + 80; Ortho-Novum 1/80; Norinyl, 2 mg; Ortho-Novum, 2 mg; Norlestrin, 1 mg; Norlestrin, 2.5 mg; Norinyl 1 + 50; Ovral var brown; and Ovral var blue) (41).


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Table 1. Oral contraceptive (OC) formulation classifications and frequency distributions of episodes of OC use in the Cancer and Steroid Hormone Study*
 
Statistical Analysis

Pearson chi-square tests were used to identify statistical differences between case and control groups for dichotomous variables and nonordinal categorical variables. The extended Mantel– Haenszel chi-square test was used to identify differences between case and control groups for ordinal categoric variables. Student's t tests were used to compare differences between groups for continuous variables. Unconditional logistic regression was used to calculate ORs and 95% confidence intervals (CIs). When assessing the impact of various potency categories of OC formulations relative to nonusers, the potential confounders (reference age, total months or duration of OC use, time since first use or latency of OC use, diabetes, number of pregnancies >6 months, race, infertility, and years of education) were included one at a time in the logistic model and tested to see if they had an impact on the point estimates of the ORs. Those variables causing a 10% change in any of the ORs were included in the final models. In addition, duration of OC use was added to logistic models when comparing various categories of OC formulations with each other. All statistical tests were two-sided.


    RESULTS
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The frequency distribution of the episodes of use among the various OC formulation categories for the women in the study is shown in Table 1Go. Although the analysis was limited to those women who used OCs from one potency category, individual subjects included in this analysis used up to five different types or brands within the same potency category of OCs.

No significant differences were found in the reference age or the age at menarche between case and control subjects (Table 2Go). The mean age at diagnosis for women with ovarian cancer was 43.8 years (standard deviation [SD] = 8.9 years), while the mean age at interview for the control subjects was 44.1 years (SD = 8.2 years). The mean age of menarche was 12.7 years for both the case and control groups, respectively. However, compared with control women, women with epithelial ovarian cancer were more likely to be white, to have 12 or fewer years of education, to have undergone natural menopause versus surgical menopause, and to report having infertility. In addition, the women diagnosed with ovarian cancer had fewer pregnancies and were more likely to report a family history of breast or ovarian cancer in a first-degree relative.


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Table 2. Comparison of characteristics of 390 case subjects with ovarian cancer and 2865 control subjects participating in the Cancer and Steroid Hormone Study
 
Crude and adjusted ORs for the relationship between ovarian cancer risk and use of OCs according to each potency category as well as any prior use of OCs are presented in Table 3Go. Using high-progestin/high-estrogen potency OC users as the referent group and controlling for the effect of age, number of pregnancies, and duration and latency period of OC use, the associations suggested that low-progestin/high-estrogen potency formulations (adjusted OR = 2.1; 95% CI = 1.2 to 3.7) and low-progestin/low-estrogen potency formulations (adjusted OR = 1.6; 95% CI = 0.9 to 3.0) are less protective than high-progestin/high-estrogen potency formulations. Nonusers of OCs were more likely to develop ovarian cancer than high-progestin/high-estrogen potency OC users (OR = 2.9; 95% CI = 1.8 to 4.5) controlling for age and number of pregnancies. In addition, nonusers of OCs were more likely to develop ovarian cancer compared with any potency category of OC users.


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Table 3. Crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for ovarian cancer according to oral contraceptive (OC) hormone potency, with the high-potency group as a referent group in the Cancer and Steroid Hormone Study
 
Collapsing the data over estrogen potency category and controlling for the effect of estrogen potency, age, the number of pregnancies, and duration and latency period of OC use, low-progestin potency OC formulations were associated with a significantly lower protective effect than high-progestin formulations (adjusted OR = 2.2; 95% CI = 1.3 to 3.9) (Table 3Go). The relative protective effect of high-potency progestin OCs compared with low-potency progestin OCs remained consistent when the data were stratified according to parity (parous versus nulliparous), menopausal status (premenopausal versus postmenopausal), and tumor behavior (borderline versus malignant) (data not shown). However, the number of subjects in these subcategories who used high-potency progestins was small, producing unstable estimates. Comparison of the relationship between high- and low-estrogen potency formulations and the risk of ovarian cancer, while controlling for progestin potency, age, number of pregnancies, and duration and latency period of OC use, suggested no effect of estrogen potency on ovarian cancer risk, with the risk reduction due to low-potency estrogen formulations similar to that of high-estrogen potency formulations (adjusted OR = 0.7; 95% CI = 0.4 to 1.2) (Table 3Go).

Further analysis of the association between progestin and estrogen potency and ovarian cancer risk, according to the duration of OC use (3–18 months, 19–59 months, and >=60 months versus nonusers as the referent), is reported in Table 4Go. For both high- and low-progestin potency formulations, there was a trend toward an increased protective association with increased duration of use. The results revealed that the protective association of high-potency progestin formulation was greater than low-potency formulations within each category for duration of use, although the CIs overlapped. Among users of high-potency progestin formulations, a statistically significant and markedly reduced risk of ovarian cancer was observed among all categories of duration of use, even among women reporting 3–18 months of OC use (OR = 0.4; 95% CI = 0.2 to 0.8). For the low-potency group, a marked reduced risk was apparent only for users for at least 60 months. With regard to estrogen-formulation potency, a similar but weaker trend was observed among high-estrogen potency users compared with high-progestin potency users. There was no consistent relationship among low-estrogen potency users.


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Table 4. Odds ratios (ORs)* and 95% confidence intervals (CIs) for ovarian cancer according to oral contraceptive (OC) hormone potency, by duration of OC use, with adjustment for age and nonusers group used as a referent in the Cancer and Steroid Hormone Study

 

    DISCUSSION
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Our analyses of data from the CASH Study identified an association consistent with a reduced risk of ovarian cancer among users of all formulations of combination OCs, regardless of the hormonal content or potency. When comparing OCs categorized by estrogen and progestin potency, our results provide evidence that OC formulations with higher progestin potency confer a greater reduction in risk of ovarian cancer than those with lower progestin potency, irrespective of the estrogen content, duration of use, and latency. Analyses examining duration of use demonstrate a statistically significant reduction in risk associated with use of high-progestin OCs, even among women who used them for a relatively short duration. Because all of the OC formulations included in the analyses contained both progestin and estrogen, it is not possible to completely separate the effects of the two hormones on ovarian cancer risk. The finding that the degree of protection associated with OC use is related to progestin potency is consistent with the hypothesis that direct biologic effects related to the progestin component may be a mechanism underlying the reduction in ovarian cancer risk associated with OC use.

Since some previously published data support that there is a latency effect of OCs on the decreased risk of ovarian cancer (3,33), one might hypothesize that our results were driven by a greater latency period among high-potency progestin users compared with low-potency progestin users. In fact, we found that, in our data high-potency users had a shorter latent period of OC use (age-adjusted mean = 13.4 years; SD = 3.9 years) than that of low-progestin potency users (age-adjusted mean = 14.3 years; SD = 3.9) (P<.001). In addition, controlling for latency did not appear to explain the differences we detected.

It has long been hypothesized that the protective association between OC use and ovarian cancer is related to OC suppression of ovulation, thereby reducing the amount of genetic damage to the ovarian epithelium associated with ovulation. If this hypothesis is correct, all combination estrogen/progestin OCs should be equally protective against ovarian cancer, since they are all potent inhibitors of ovulation. In addition, it might be anticipated that the risk reduction afforded by a short course of OC use would be low, but that it would increase in proportion to the duration of use, as more ovulations are prevented. The results of this study are inconsistent with the hypothesis that OC use is associated with a risk reduction solely through ovulation inhibition, in that we found that the protective association is influenced by the progestin potency of the formulation. Moreover, we found a protective association with use of high-progestin potency OCs, even when used for only a short interval during which few ovulatory cycles are inhibited. The findings supported the conclusions derived from a previous primate study in which the progestin component of OCs was specifically noted to activate chemopreventive molecular pathways in the ovarian epithelium leading the authors to hypothesize that progestins may be effective ovarian cancer preventives (22).

The results of a recent study by Ness et al. (34) are not consistent with those of this article. In the former study (34), which included 767 ovarian cancer case subjects and 1367 control subjects, the risk reduction associated with use of low-estrogen/low-progestin pills was identical to that associated with use of high-estrogen/high-progestin pills, with ORs of 0.5 for the risk reduction associated with the use of OCs of each potency class compared with nonuse. Despite similarities between this study and the study by Ness et al. (34), including that both were population-based studies of newly diagnosed ovarian cancer patients and that both used in-person structured interviews, life-events calendars, and pictorial views of OC preparations, there are several aspects of the study design by Ness et al. that suggest why different findings may have arisen. The current study involved younger women, there were temporal differences in the OCs available, and the classification schemes for defining potency were not identical. It is not clear if these differences could explain the variations in findings between the two studies.

Despite some significant strengths in the design of the CASH Study, limitations of our analysis include the possible misclassification of OC use among ovarian cancer case and control subjects, particularly in terms of the retrospective reporting of specific OC formulations that the study subjects had used in their lifetime. In addition, we did not have formulation and dosage information on all OC users in the CASH Study and did not have an adequate number of women who used progestin-only OCs to examine their effect. The women who participated in the CASH Study were relatively young compared with women in the general population who develop ovarian cancer, and we do not know whether our results apply to menopausal women who develop ovarian cancer. Since the CASH Study was conducted more than 20 years ago, we were unable to evaluate more recent OC formulations. However, the newer formulations have had lower potencies and, therefore, are likely to have a reduced effect on the risk of ovarian cancer.

Despite these limitations, these data provide further support for the hypothesis that biologic effects related to the progestin component in OCs may be a mechanism underlying their protective effect independent of inhibition of ovulation. It is hoped that further research in the field of ovarian cancer prevention will lead to the identification of promising agents, in addition to progestins, which activate cancer-prevention pathways in the ovarian epithelium, and that can then be formulated into a pharmacologic strategy that achieves maximum protection against ovarian cancer, while minimizing side effects.


    NOTES
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
1 Editor's note: SEER is a set of geographically defined, population-based, central cancer registries in the United States, operated by local nonprofit organizations under contract to the National Cancer Institute (NCI). Registry data are submitted electronically without personal identifiers to the NCI on a biannual basis, and the NCI makes the data available to the public for scientific research. Back

Supported by Public Health Service grant CA76016 from the National Cancer Institute (NCI), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), and by grant DAMD 17-98-1-8656 from the Department of Defense. The Cancer and Steroid Hormone Study was supported by interagency agreement 3-01 HD-8-1037 between the Centers for Disease Control and Prevention and the National Institute of Child Health and Human Development, NIH, DHHS, with additional support from the NCI.

We acknowledge the contributions of Drs. Kathryn Curtis (Centers for Disease Control and Prevention, Atlanta, GA) and Andrew Berchuck (Duke University Medical Center, Durham, NC).


    REFERENCES
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 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

1 Whittemore AS, Harris R, Intyre 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]

2 Weiss NS, Cook LS, Farrow DC, Rosenblatt KA. Ovarian cancer. In: Schottenfeld D, Fraumeni JF Jr, editors. Cancer epidemiology and prevention. New York (NY): Oxford University Press; 1996. p. 1040–57.

3 Rosenberg L, Palmer JR, Zauber AG, Warshauer ME, Lewis JL, Strom BL, et al. A case–control study of oral contraceptive use and invasive ovarian cancer. Am J Epidemiol 1994;139:654–61.[Abstract]

4 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]

5 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]

6 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]

7 Narod SA, Risch H, Moslehi R, Dorum A, Neuhausen S, Olsson H, et al. Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary Ovarian Cancer Clinical Study Group. N Engl J Med 1998;339:424–8.[Abstract/Free Full Text]

8 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.[Abstract/Free Full Text]

9 Ames BN, Gold LS. Too many rodent carcinogens: mitogenesis increases mutagenesis. Science 1990;249:970–1.[Medline]

10 Preston-Martin S, Pike MC, Ross RK, Jones PA, Henderson BE. Increased cell division as a cause of human cancer. Cancer Res 1990;50:7415–21.[Abstract]

11 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.[Medline]

12 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]

13 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]

14 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]

15 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]

16 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.[Abstract]

17 Fredrickson TN. Ovarian tumors of the hen. Environ Health Perspect 1987;73:35–51.[Medline]

18 Mosgaard BJ, Lidegaard O, Andersen AN. The impact of parity, infertility and treatment with fertility drugs on the risk of ovarian cancer. Acta Obstet Gynecol Scand 1997;76:89–95.[Medline]

19 Cooper GS, Schildkraut JM, Whittemore AS, Marchbanks PA. Pregnancy recency and risk of ovarian cancer. Cancer Causes Control 1999;10:397–402.[Medline]

20 Albrektsen G, Heuch I, Kvale G. Reproductive factors and incidence of epithelial ovarian cancer: a Norwegian prospective study. Cancer Causes Control 1996;7:421–7.[Medline]

21 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 1994;344:1250–4.[Medline]

22 Rodriguez GC, Walmer DK, Cline M, Krigman H, Lessey BA, Whitaker RS, et al. Effect of progestin on the ovarian epithelium of macaques: cancer prevention through apoptosis? J Soc Gynecol Investig 1998;5:271–6.[Medline]

23 Canman CE, Chen CY, Lee MH, Kastan MB. DNA damage responses: p53 induction, cell cycle perturbations, and apoptosis. Cold Spring Harb Symp Quant Biol 1994;59:277–86.[Medline]

24 Ponzoni M, Bocca P, Chiesa V, Decensi A, Pistoia V, Raffaghello L, et al. Differential effects of N-(4-hydroxyphenyl)retinamide and retinoic acid on neuroblastoma cells: apoptosis versus differentiation. Cancer Res 1995;55:853–61.[Abstract]

25 Delia D, Aiello A, Lombardi L, Pelicci PG, Grignani F, Formelli F, et al. N-(4-Hydroxyphenyl)retinamide induces apoptosis of malignant hemopoietic cell lines including those unresponsive to retinoic acid. Cancer Res 1993;53:6036–41.[Abstract]

26 Lotan R. Retinoids in cancer chemoprevention. FASEB J 1996;10:1031–9.[Abstract/Free Full Text]

27 Kuo SM. Antiproliferative potency of structurally distinct dietary flavonoids on human colon cancer cells. Cancer Lett 1996;110:41–8.[Medline]

28 Thompson HJ, Jiang C, Lu J, Mehta RG, Piazza GA, Paranka NS, et al. Sulfone metabolite of sulindac inhibits mammary carcinogenesis. Cancer Res 1997;57:267–71.[Abstract]

29 Gould MN. Cancer chemoprevention and therapy by monoterpenes. Environ Health Perspect 1997;105 Suppl 4:977–9.[Medline]

30 Pascale RM, Simile MM, De Miglio MR, Nufris A, Daino L, Seddaiu MA, et al. Chemoprevention by S-adenosyl-L-methionine of rat liver carcinogenesis initiated by 1,2-dimethylhydrazine and promoted by orotic acid. Carcinogenesis 1995;16:427–30.[Abstract]

31 el-Bayoumy K, Upadhyaya P, Chae YH, Sohn OS, Rao CV, Fiala E, et al. Chemoprevention of cancer by organoselenium compounds. J Cell Biochem Suppl 1995;22:92–100.

32 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.[Abstract/Free Full Text]

33 Rosenblatt KA, Thomas DB, Noonan EA. High-dose and low-dose combined oral contraceptives: protection against epithelial ovarian cancer and the length of the protective effect. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Eur J Cancer 1992;28A:1872–6.

34 Ness RB, Grisso JA, Klapper J, Schlesselman JJ, Silberzweig S, Vergona R, et al. Risk of ovarian cancer in relation to estrogen and progestin dose and use characteristics of oral contraceptives. SHARE Study Group. Steroid Hormones and Reproductions. Am J Epidemiol 2000;152:233–41.[Abstract/Free Full Text]

35 Wingo PA, Ory HW, Layde PM, Lee NC. The evaluation of the data collection process for a multicenter, population-based, case–control design. Am J Epidemiol 1988;128:206–17.[Abstract]

36 Risch HA, Marrett LD, Jain M, Howe GR. Differences in risk factors for epithelial ovarian cancer by histologic type. Am J Epidemiol 1996;144:363–72.[Abstract]

37 Parazzini F, Restelli C, La Vecchia C, Negri E, Chiari S, Maggi R, et al. Risk factors for epithelial ovarian tumours of borderline malignancy. Int J Epidemiol 1991;20:871–7.[Abstract]

38 Covington TR, Dipalma JR, Hussar DA, Lasagna L, Tatro DS, Whitsett TL, editors. Hormones. In: Drug facts and comparisons. St. Louis (MO): J. B. Lippincott Co.; 1986.

39 Piper JM, Kennedy DL. Oral contraceptives in the United States: trends in content and potency. Int J Epidemiol 1987;16:215–21.[Abstract]

40 Bolt HM, Bolt WH. Pharmacokinetics of mestranol in man in relation to its oestrogenic activity. Eur J Clin Pharmacol 1974;7:295–305.[Medline]

41 Hatcher RA, Stewart GK, Guest F, Finkelstein R, Godwin C. Contraceptive technology, 1976–1977. 8th ed. New York (NY): Irvington; 1976. p. 42–3.

Manuscript received January 29, 2001; revised October 3, 2001; accepted October 15, 2001.


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