1 Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA.
2 Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA.
3 Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL.
4 Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA.
5 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA.
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ABSTRACT |
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contraceptives; oral; estrogens; ovarian neoplasms; progestational hormones
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INTRODUCTION |
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Until now, few women taking the newer, lower-dose preparations had passed through the critical age window during which the incidence of ovarian cancer rises. Three previous studies evaluated ovarian cancer risk associated with specific oral contraceptive formulations, but all included a limited number of women who used lower-dose formulations (1113
). One reported somewhat less risk reduction for low- versus high-dose estrogen formulations (
). The other studies showed that various formulations of oral contraceptives (vs. nonuse) reduced the risk of ovarian cancer to various degrees, but did not directly assess whether lower-dose formulations were equivalent to higher-dose formulations in lowering ovarian cancer risk (12
, 13
). We report the results of a population-based, case-control investigation designed to address further the impact of dose of oral contraception on its association with ovarian cancer.
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MATERIALS AND METHODS |
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Controls aged 65 years or younger were ascertained by random digit dialing and were frequency matched by 5-year age groups and three-digit telephone exchanges to cases. Of the 14,551 telephone numbers screened for this purpose, 6,597 were businesses or were not in service, and 5,640 had no female of eligible age in the household, leaving 2,314 households with potentially eligible participants. Of these, 1,928 (83 percent) households had a potentially eligible woman who was willing to be screened further. Upon screening, a further 291 had no eligible resident woman on the basis of age (n = 5), residence outside of the target counties (n = 11), prior diagnosis of ovarian cancer (n = 9), a prior bilateral oophorectomy (n = 187), not speaking English or being mentally incompetence (n = 22), being critically ill or deceased (n = 6), or being untraceable (n = 51). Of the 1,637 screened and potentially eligible controls, 422 declined to be interviewed, and 1,215 (74 percent) completed interviews. Controls aged 6569 were ascertained through Health Care Financing Administration lists. A total of 423 women, frequency matched to cases by county of residence, were identified initially. Of these, 160 were ineligible for the reasons given above. Of the 263 potentially eligible women from Heath Care Financing Administration lists, 111 refused to participate, and 152 (58 percent) were interviewed. Therefore, of the total 1,900 screened and potentially eligible controls (1,637 from random digit dialing and 263 from Health Care Financing Administration lists), 1,367 (72 percent) are included in our analyses.
Cases included 616 women with invasive epithelial ovarian tumors and 151 with borderline epithelial ovarian tumors. The diagnosis of ovarian cancer was confirmed by pathology in all cases. Central pathologic review was conducted on a random sample of 120 cases. The reference pathologist agreed with the original pathologic review for invasiveness in 95 percent of cases and for cell type in 82 percent. The original pathologic diagnosis was then used for all cases.
Oral contraceptive use
Standardized 1.5-hour interviews were conducted by trained interviewers in the homes of participating women. A "life" calendar marked with important events that each participant recalled during her life was used to enhance memory of distant information. On the calendar, sexual activity, use of contraceptives, and reproductive events were coded for every month from sexual debut until a reference date. The reference date was calculated as 6 months prior to the interview (for both cases and controls). Picture books with photographs of oral contraceptives available in the United States (courtesy of Dr. Ruth Peters, University of Southern California, Los Angeles, California) were used to help women specify the formulations used.
All contraceptive use was recorded, including the type of contraception, frequency of use, and duration of use. Additional details obtained for hormonal contraceptives included the brand, reason for use, and reason for stopping use. For each combined oral contraceptive preparation, we obtained information on active ingredients and doses (14) by using a variety of existing databases and reference books; for discontinued medications, we made inquiries to pharmaceutical manufacturers. Ethinyl estradiol and mestranol were the estrogens used in all combined oral contraceptives. Mestranol (100 µg) is approximately equipotent to estradiol (50 µg) (15, 16). Therefore, pills containing less than 100 µg of mestranol or less than 50 µg of ethinyl estradiol were categorized as low-estrogen dose formulations, and those containing 100 µg or more of mestranol or 50 µg or more of ethinyl estradiol were categorized as high dose.
There are no universally recognized standards for potency of progestins (). Therefore, we used two alternative potency estimates, one based on the delay-of-menses test and the other based on the ability to induce subnuclear vacuolization, consistent with secretory function, in an estrogen-primed endometrium (18
). Dickey and Stone (18
) summarized potency data from two sources for each of these two assays. To obtain a potency ranking for a given oral contraceptive preparation on the subnuclear vacuolization test, we multiplied the mean of the two potency estimates on the subnuclear vacuolization test for 1.0 mg of the progestin contained in that pill by the dose of progestin. Progestins were classified as low dose if their relative potency was less than 0.5 mg norgestrel. Alternatively, a mean potency estimate for each progestin was obtained from the delay-of-menses test. Again, the dose of the progestin was multiplied by the mean potency of 1.0 mg of each progestin. Progestins with a relative potency of 0.5 mg or more norgestrel were categorized as high dose. A relative potency of 0.30.4 mg norgestrel was considered intermediate, and a relative potency of 0.2 mg or less norgestrel was considered low dose.
Covariates
Detailed demographic and reproductive information was obtained by interview. Demographic information included age, race, and education. Participants were asked about menstrual onset, regularity, and cessation. Each pregnancy, its length and outcome, as well as the length of breastfeeding, were recorded on the life calendar. Hysterectomy and its timing were recorded, as were women's reported weight and height. Detailed cancer histories for first-degree family members were also obtained.
Statistical analysis
Odds ratios, with corresponding 95 percent confidence intervals, were calculated as the primary measure of effect size. Because matching was based on frequencies for only two broad criteria, age within 5-year intervals and three-digit telephone exchange (or county of residence), we did not preserve the "match" in the analyses. Odd ratios were adjusted for any residual effect of age and for gravidity (each as continuous variables), race (White/Black/other), and history of ovarian cancer in any first-degree relative (yes/no) in unconditional logistic regression models (19). Duration of oral contraceptive use was added to multivariable models in examining the relation between the risk of ovarian cancer and the following indicators of oral contraceptive use: time since last use, age at first use, year of first use, and dose. Statistical tests for trend in time since last oral contraceptive use, age at first use, calendar year of first use, and dose variables were based on evaluation of a continuous function for the use characteristic of interest among ever users; the model also contained all relevant adjustment covariates (age, gravidity, race, family history, and duration).
For analyses of combined oral contraceptive estrogen and progestin dose, only women who were taking combined oral contraceptive preparations with known estrogen and progestin content (n = 758) compared with women who never took oral contraceptives (n = 341) were included. We classified women's exposure to oral contraceptive formulations on the basis of the longest episode of use. Of the 1,366 women who ever used oral contraceptives, 78 used a triphasic or progestin-only preparation and so were excluded from these analyses. Among combined oral contraceptive users, 756 (59 percent) reported the brand name used for the longest episode, and 533 (41 percent) could not recall the brand name used. Of the 756 who recalled the brand name, 521 knew the specific formulation from which dose could be classified, and 235 used an unknown formulation of either Ortho-Novum (Ortho Pharmaceutical Corp, Raritan, New Jersey) or Norinyl (G. D. Searle & Co., Chicago, Illinois). Of the known Ortho-Novum and Norinyl formulations used by study participants, 68 percent were low estrogen/low progestin, and the remainder were high estrogen/low progestin. We analyzed the data, considering these unknown Ortho-Novum/Norinyl users first as low estrogen/low progestin and then as high estrogen/low progestin, and it had no substantive effect on the interpretation of results. This report codes women using unknown Ortho-Novum/Norinyl preparations as low estrogen/low progestin in the analyses of oral contraceptive dose.
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RESULTS |
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The impact of oral contraceptive use was not particularly variable by invasiveness of tumor (invasive vs. borderline) or by histologic type (serous, mucinous, endometrioid, clear cell, or other) as shown in table 4. In these subanalyses, the number of cases was smaller and confidence intervals were broader, but for all invasiveness/histologic types, the odds ratio among oral contraceptive users declined with longer duration of use. In addition, later age at initiation and lower-dose oral contraceptive formulations did not strongly reduce the protective effect of oral contraception in any invasiveness/histologic type. However, within broad confidence intervals, there was some suggestion that more than 10 years since oral contraceptive cessation was less protective for endometrioid and clear cell tumors.
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DISCUSSION |
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The effect of oral contraceptives in studies published prior to the mid-1980s has been primarily assessed in two meta-analyses, with summary odds ratios of 0.6 and 0.7 (2, 3
). More recent case-control studies, in which a larger proportion of participants would have used lower-dose oral contraceptive preparations, generally support these estimates (20
, 21
), with the exception of one report by Hartge et al. (22
).
To our knowledge, only three reports have specifically compared the effects on ovarian cancer risk of low-estrogen (<50 µg ethinyl estradiol) with high-estrogen dose (50 µg ethinyl estradiol) combined oral contraceptives (11
13
). In a World Health Organization-sponsored case-control study, Rosenblatt et al. (11
) compared 393 cases with 2,561 controls and found that the odds ratio for ovarian cancer was only slightly higher for low-dose combined oral contraceptive preparations (odds ratio = 0.81) than for high-dose preparations (odds ratio = 0.68), a difference compatible with chance. A relatively small proportion of cases and controls used oral contraceptives: 30 cases used high-dose estrogen formulations, and 27 cases used low-dose formulations. The Cancer and Steroid Hormone Study evaluated a series of specific formulations, all of which were associated with relative risks of less than 1.0, some statistically significant and some not. The odds ratios associated with specific formulations ranged from 0.3 to 0.9. The relative reduction in ovarian cancer risk for higher- versus lower-dose formulations was not tested (12
). Finally, Rosenberg et al. (13
) showed odds ratios ranging from 0.4 to 1.3 for various formulations among women who used oral contraceptives for 3 or more years compared with controls. Given the small numbers of women using any given formulation, it was not possible to formally compare use of high- versus low-dose preparations.
In our study, oral contraceptives were protective long after stopping use (30 or more years) and were protective after relatively short durations of exposure (14 years). The long-term protection afforded by oral contraceptives has been shown in previous reports (1, 2
, 23
), although previous studies did not have the opportunity to observe as long a time interval between oral contraception cessation and incident ovarian cancer as did ours. These features (protection after short-duration use and long after cessation) enhance the attractiveness of oral contraception as a potential chemopreventative for ovarian cancer. Recent evidence suggests that for women at elevated genetic risk for ovarian cancer, oral contraceptives may be protective (24
). Further studies will be needed to evaluate the full benefit versus risk equation for such women, taking into account not only cancer at other sites but thrombotic risk as well (25
27
).
Strengths of our study include the population-based ascertainment of cases and controls; the large number of newly diagnosed cases; and the use of life-events calendars, comprehensive picture books, and structured interviews to enhance the recollection of medical information and contraceptive preparations used. All of these methodological features limited the potential for selection bias and information bias.
A weakness of our study was somewhat low participation rates among controls and cases. For cases, this was strongly influenced by whether women with prevalent ovarian cancer (diagnosed >6 months prior to interview) were included in the denominator when the response was calculated. In our design, we excluded such women to avoid survival bias. Excluding them from the denominator resulted in an 88 percent response rate; however, to the extent that the oral contraceptive use characteristics of these women may differ from those of women with ovarian cancer overall, we report the 61 percent response rate with them included in the denominator.
Another weakness is that, despite efforts to determine oral contraceptive preparations used over a lifetime, many women simply could not recall the exact formulation used. Nevertheless, we were able to classify estrogen and progestin dose for nearly 60 percent of users of combination oral contraceptives. Furthermore, we assumed unknown Ortho-Novum/Norinyl preparations to be low estrogen/low progestin. This resulted in confidence intervals that may have overestimated the precision of our estimates. Previous studies examining the relation between specific oral contraceptive formulations and ovarian cancer have also suffered from this limitation (11). Although validation studies have found that recall of use and timing of use of oral contraceptives is quite accurate, recall for specific formulations is less so (28
30
). Because of this concern, we conducted an additional analysis using a surrogate measure of dose, i.e., year of initiation of oral contraceptive use. We nevertheless realize that this analysis may be influenced by cohort effects and time since last use.
In summary, our findings indicate that oral contraceptive formulations in common use today protect against ovarian cancer and that this effect continues long after use has stopped.
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ACKNOWLEDGMENTS |
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Members of the Steroid Hormones and Reproduction (SHARE) Study Group: Abington Memorial Hospital, Dr. Parviz Hanjani; Albert Einstein Medical Center, Dr. Richard Belch; St. Luke's Hospital-Allentown Campus, Dr. David Lezinsky; Bryn Mawr Hospital, Dr. Robert Carr; Memorial Hospital of Burlington County, Dr. Allen Weinstein; Chester County Hospital, Dr. Morrie Gold; Chestnut Hill Hospital, Dr. Terry Kriedman; Cooper Hospital/University Medical Center, Dr. Thomas Rocereto; Crozer-Chester Medical Center, Dr. Joel Noumoff; Delaware County Memorial Hospital, Dr. Joel Noumoff; Doylestown Hospital, Dr. Nestor Sendzik; Hospital of the Fox Chase Cancer Center, Drs. Michael Hogan and Matthew Boente; Frankford Hospital of the City of Philadelphia, Dr. Allan Terzian; Graduate Hospital, Dr. Thomas Sedlacek; Grand View Hospital, Dr. Patricia Stephenson; Hahneman University Hospital, Drs. Lisa Anderson and Antoine Jahshan; Holy Redeemer Hospital and Medical Center, Dr. Charles Mangan; Hospital of the University of Pennsylvania, Dr. Mark Morgan; Thomas Jefferson University Hospital, Dr. Charles Dunton; Kennedy Memorial Hospital-University Medical Center, Drs. Nathan Freed, Dr. M. Grossman, and Paul Krueger; Lankenau Hospital, Dr. Michael Hogan; Lehigh Valley Hospital, Drs. Gazi Abdulhay and Sergio Perticucci; Medical Center of Delaware, Dr. Charles Whitney; Medical College Hospitals-Bucks County Campus, Dr. David Podrasky; Mercer Medical Center, Dr. Ronald Burbella; Mercy Fitzgerald Hospital, Drs. Enrique Hernandez, Sherman Everlof, and Charles Dunton; Methodist Hospital, Dr. David Iddenden; Montgomery Hospital, Dr. John Bennett; Northeastern Hospital of Philadelphia, Dr. Myung Shin; Our Lady of Lourdes Medical Center, Dr. Howard Saul; Pennsylvania Hospital, Dr. Charles Mangan; Medical Center of Princeton, Dr. Daniel Shapiro; Reading Hospital and Medical Center, Dr. Norman Rosenblum; Sacred Heart Hospital, (Allentown), Drs. Gazi Abdulhay and Bruce Viechnicki; St. Luke's Hospital, Dr. Gazi Abdulhay; Suburban General Hospital/Norristown Regional Cancer Center, Dr. Carl Sharer; Temple University Hospital, Drs. William Helm and Desmond Barton; West Jersey Hospital-Marlton, Dr. Thomas Rocereto.
The authors thank and acknowledge the efforts of interviewers who recruited and interviewed study participants, in particular, Kristin Pedemonti, lead interviewer. They also gratefully acknowledge technical assistance from Barbara Kolodziej and Lori Burleigh.
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NOTES |
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REFERENCES |
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