Short-Term Oral Contraceptive Use and the Risk of Epithelial Ovarian Cancer
Julia B. Greer,
Francesmary Modugno,
Glenn O. Allen and
Roberta B. Ness
From the Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA
Correspondence to Dr. Julia B. Greer, 3520 Fifth Avenue, Suite 510, Pittsburgh, PA 15213 (e-mail: juliabgreer{at}aol.com).
Received for publication December 15, 2004.
Accepted for publication March 31, 2005.
 |
ABSTRACT
|
---|
Oral contraceptive (OC) use has been consistently linked to a reduction in ovarian cancer in a dose-dependent fashion. Whether short-term OC use is protective remains controversial. In 19941998 in the Delaware Valley of Pennsylvania, the authors examined the association between short-term OC use and ovarian cancer in a population-based case-control study comparing 608 incident epithelial ovarian cancer cases with 926 community controls. Using unconditional logistic regression and adjusting for known confounders, they found a significant reduction in ovarian cancer risk for women who had used OCs for
6 months (odds ratio = 0.73, 95% confidence interval: 0.54, 0.99). This protective effect was observed in only that group who had used OCs for
6 months and stopped because of side effects (odds ratio = 0.59, 95% confidence interval: 0.40, 0.87 for side effects and odds ratio = 0.91, 95% confidence interval: 0.60, 1.37 for non-side-effects). Women who used OCs for >6 months were at a reduced risk independent of their reason for stopping. Results were similar when stratifying by parity and hormone therapy use. Thus, OC use for as little as 6 months provides significant protection against ovarian cancer risk, protection that appears limited to those women who stop using OCs because of side effects. Mediating factors may reflect endogenous hormone levels, OC metabolism, or OC bioactivity.
case-control studies; contraceptives, oral; ovarian neoplasms; risk factors
Abbreviations:
CI, confidence interval; OC, oral contraceptive; OR, odds ratio
 |
INTRODUCTION
|
---|
Ovarian cancer is the most fatal gynecologic cancer in the United States (1
). Oral contraceptives (OCs) have consistently been associated with a reduced risk of ovarian cancer, with increasing duration of use linked to greater risk reduction (2
5
). Some studies have shown a protective effect with as little as 6 months of OC use (6
9
). The Cancer and Steroid Hormone Study reported a 40 percent reduction in risk for women who had used OCs for as little as 36 consecutive months (7
). However, this protection appeared limited to those women who had stopped using OCs because of side effects, such as bloating and weight gain; there was little evidence of a protective effect for short-term users who had stopped for non-side-effect reasons, such as trying to conceive a child (6
). That study was limited by a small number of short-term users (41 cases, 412 controls), however. We therefore used data from a large, case-control study of epithelial ovarian cancer to determine whether short-term OC use is associated with decreased risk of ovarian cancer.
 |
MATERIALS AND METHODS
|
---|
Study subjects
Women in this study were selected from a case-control study of contraceptive and reproductive risk factors for epithelial ovarian cancer. Subject selection and data collection have been described elsewhere (2
). Briefly, cases 2069 years of age whose epithelial ovarian cancer was diagnosed within the 6 months prior to interview were ascertained from 39 hospitals in the Delaware Valley surrounding Philadelphia, Pennsylvania, between May 1994 and July 1998. A total of 1,253 potentially eligible women with incident borderline or invasive epithelial ovarian cancer were identified. After we excluded those who were diagnosed more than 6 months before interview (n = 296), were critically ill or dead (n = 69), or were untraceable (n = 15), 873 women remained eligible. Fourteen physicians did not consent to their patients' participation, and 92 women refused to participate. Thus, there were 767 completed case interviews (61 percent of potentially eligible cases and 88 percent of potentially eligible incident cases). For all cases, the diagnosis of epithelial ovarian cancer was confirmed by pathology.
Controls aged 65 years or younger were ascertained by random digit dialing and were frequency matched to cases by race, 5-year age groups, and three-digit telephone exchange. Of the 14,551 telephone numbers screened, 2,314 were for households with potentially eligible participants. Of these, 1,928 households (83 percent) included a potentially eligible woman who was willing to be screened further. Upon screening, 291 were found ineligible because of age, county of residence, or other factors. Of the remaining 1,637 potentially eligible controls, 1,215 (74 percent) completed interviews. Controls 6569 years of age were ascertained through Health Care Financing Administration lists. Four hundred twenty-three women, frequency matched to cases by county of residence, were initially identified, and 263 were potentially eligible. Of these women, 152 (58 percent) were interviewed. Therefore, of the 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) were interviewed.
Frequency-matched control selection was accomplished in intervals after ascertainment of each batch of cases and approximated the distribution of both telephone exchange (a surrogate measure of socioeconomic status) and age range. Interim analyses during the study ensured that age was relatively equally distributed between cases and controls. However, the large number of telephone exchanges made checking for the evenness of the distribution of this variable more difficult. Nonetheless, income was similarly distributed between cases and controls, suggesting successful frequency matching on telephone exchange, and adjustment for education, income, and race did not substantially impact our findings.
The analyses presented here were limited to women who had never used OCs or for whom complete OC information, including formulation, duration of use, and reason for stopping, was available. Complete data on duration of use of OCs were not available for 159 cases and 441 controls; thus, a total of 608 cases and 926 controls were included in the final analyses. All women who were never OC users were included; exclusion was based on inability to classify OC duration. Women included versus excluded in the analysis were compared by the known ovarian cancer risk factors of OC use, parity, tubal ligation, hysterectomy, and family history of ovarian cancer. The two groups were found to be equivalently distributed with regard to these risk factors (data not shown).
Data collection and exposure assessment
A standardized 1.5-hour in-person interview of cases and controls provided detailed demographic data as well as information on a subject's gynecologic and obstetric history, including menstrual history, pregnancy history, tubal ligation, lactation, hysterectomy, family history of breast and ovarian cancers, OC use, and hormone therapy use. A "life" calendar marked with important events that each participant recalled during her lifetime was used to enhance memory of distant events. The reference date was calculated as 6 months prior to diagnosis (cases) or interview (controls).
All contraceptive information was recorded, including the type, frequency of use, and duration of use. Additional details obtained for hormonal contraceptives included the brand, reason for use, and reason for stopping use. If women stopped using OCs because of side effects, they could specify the side effect(s) experienced as weight gain, water retention, acne/oily skin, excess hair growth, irritability, abnormal bleeding, headache, depression, amenorrhea, or other (specify). Nonmedical reasons for stopping OC use included attempting to conceive or because OCs were no longer needed. Four cases and three controls were not able to be classified according to their reason for stopping, and these women were dropped from the analyses. Picture books with photographs of OCs 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.
Statistical analyses
Odds ratios, with corresponding 95 percent confidence intervals, were calculated as the primary measure of effect size. Because the contraceptive and reproductive risk factors for epithelial ovarian cancer study used frequency rather than individual matching and matched on the basis of broad criteria, such as age within intervals of 510 years, we used unconditional logistic regression models to adjust for any additional effects of potential confounding variables. Included in the models were age and parity as continuous variables. Tests for trend (p value) were performed by coding OC duration of use as a grouped linear variable. Odds ratios for OC exposures were calculated from the estimated ß coefficients and their standard errors. All tests of statistical significance were two tailed and were considered significant at p < 0.05. All analyses were performed by using Stata software, release 8.0 (Stata Corporation, College Station, Texas).
 |
RESULTS
|
---|
A total of 176 controls and 94 cases used a single OC in a single episode (i.e., continuously) for less than 6 months. In comparison to never use, OC use in a single episode of less than 6 months' duration was associated with a significant reduction in ovarian cancer risk (odds ratio (OR) = 0.73, 95 percent confidence interval (CI): 0.54, 0.99 adjusted for age and parity) (table 1). Women who reported a total of less than 6 months of OC use (one or more episodes) also experienced a decrease in risk (adjusted OR = 0.75, 95 percent CI: 0.56, 1.00). Results were similar when we limited analyses to hormone therapy ever users (adjusted OR = 0.78, 95 percent CI: 0.47, 1.28), hormone therapy never users (adjusted OR = 0.74, 95 percent CI: 0.50, 1.09), and parous women (adjusted OR = 0.71, 95 percent CI: 0.50, 0.99) who had used OCs in a single episode of 6 months or less and to those who had used OCs for a total of less than 6 months in one or more episodes (adjusted OR = 0.71, 95 percent CI: 0.51, 0.99).
View this table:
[in this window]
[in a new window]
|
TABLE 1. Duration of OC* use and risk of epithelial ovarian cancer for women in the Delaware Valley of Pennsylvania, 19941998
|
|
When we stratified by reason for stopping OC use (table 2), a significant reduction in ovarian cancer risk was observed for short-term (<6 months), single-episode users who stopped because of side effects (adjusted OR = 0.59, 95 percent CI: 0.40, 0.87) but not for those who stopped for non-side-effect reasons (adjusted OR = 0.91, 95 percent CI: 0.60, 1.37). Similar results were found when stratifying by parity and hormone therapy use (table 2).
View this table:
[in this window]
[in a new window]
|
TABLE 2. Adjusted odds ratios for epithelial ovarian cancer, stratified by reason for stopping use of OCs,* associated with a single episode of use only, Delaware Valley of Pennsylvania, 19941998
|
|
Women who reported multiple episodes of OC use could have reported stopping use for both medical and nonmedical reasons. Therefore, we categorized women who reported more than one episode of OC use according to ever, never, and only stopping for medical reasons (table 3). Again, short-term OC users (regardless of the number of episodes) who ever or only stopped because of side effects had a significant reduction in risk, while short-term OC users who never stopped because of side effects had no such reduction (adjusted ORs = 0.57, 0.56, and 0.95, respectively). In contrast, women who used OCs for more than 6 months had a reduced risk of ovarian cancer, regardless of their reason for stopping (adjusted ORs = 0.62, 0.60, and 0.62 for ever, never, and only stopping because of side effects, respectively).
View this table:
[in this window]
[in a new window]
|
TABLE 3. Adjusted odds ratios for epithelial ovarian cancer, by duration of use and reason for stopping use of OCs,* for women with one or more episode of use, Delaware Valley of Pennsylvania, 19941998
|
|
Finally, we stratified OC users who had used either high- or low-dose estrogen or progestin OCs by whether they had stopped OC use because of side effects. No association with side effects was noted (
2 = 0.000479, p = 0.98 for high vs. low estrogen dosage;
2 = 2.174, p = 0.14 for high vs. low progestin dosage) (data not shown).
 |
DISCUSSION
|
---|
As previously reported (6
, 7
, 10
), short-term (<6 months) use of OCs is associated with a significant reduction in ovarian cancer risk. However, this protection appears limited to only those women who stopped using OCs because of side effects. Women who use OCs for more than 6 months have a reduced risk regardless of their reason for stopping. The data were consistent for parous women as well as for hormone therapy users and nonusers. Additionally, side effects did not appear to be related to the dosage of estrogen or progestin in the OC used.
A 1998 nationwide prospective study of 1,657 women initiating or switching to the use of a new contraceptive (11
) found that, 6 months after they received a new OC prescription, 68 percent of new starters were still using OCs. Of women who discontinued use, 46 percent did so because of side effects, including depression, headache, irritability, bloating, breast tenderness, loss of libido, irritability, anxiety, and weight gain (12
14
). A 1995 study analyzed a convenience sample of almost 6,700 current or former users of OCs aged 1530 years from Denmark, France, Italy, Portugal, and the United Kingdom and noted that even the perception of side effects can lead to cessation of use of OCs (15
, 16
).
One plausible hypothesis for these findings is that the side effects themselves were manifestations of greater OC bioactivity in this particular group of women. Women who suffer significant side effects with a brief duration of OC use may have altered liver enzyme activity (17
, 18
). Slower metabolizers may initially have decreased levels of hormonal metabolites because of a slower rate of biotransformation and maintain a low level, but longer duration, of exogenous hormones in their bloodstream. For them, the OC might be more effective at suppressing ovulation and lowering follicle-stimulating hormone and luteinizing hormone levels and at reducing stromal cell reactivity, all of which are hypothesized to reduce the risk of developing epithelial ovarian cancer (19
).
Another hypothesis is that endogenous estrogen and progesterone levels might have been higher in the group that experienced medical side effects. Progestins appear to protect against ovarian cancer (20
23
). Conversely, the group that experienced side effects might have had lower-than-normal endogenous hormone levels, and OCs may have been particularly potent in these women. OCs with higher progestin activity, in particular, have been associated with depression and loss of libido (24
27
).
Suppression of ovulation, even for a brief period, may protect against ovarian cancer, as evidenced by the fact that any incomplete pregnancy provides some degree of protection (28
). However, it is unlikely that the degree of ovulation suppression would have differed substantially between short-term users who stopped for medical reasons and those who stopped for other reasons.
The strengths of our study include the population-based ascertainment of participants; the large number of incident ovarian cancer cases; and the use of life-events calendars, comprehensive picture books, and structured interviews to enhance recollection of medical and contraceptive information. Methodological features limited the potential for selection bias and information bias. Moreover, because both participants and interviewers were unaware of the research question being addressed, recall bias or interviewer bias should not account for our results. While previous studies found that ovarian cancer risk reduction in short-term users (
6 months) was limited to women who stopped OC use because of side effects, we are not aware of any other study of this magnitude (a total of 608 cases and 926 controls were included in the final analyses) and no other study that posited why this finding may have occurred in this particular group of women. Additionally, our study was large enough to create comparisons among subgroups, such as hormone therapy users and nonusers.
Limitations of our analysis include possible misclassification of OC use among ovarian cancer cases and controls, particularly in terms of the retrospective reporting of specific OC formulations that the study subjects had used in their lifetime. Other studies that have attempted to assess the relation between OC formulations and ovarian cancer have also suffered from this limitation (29
, 30
). Given that the analysis included only 608 of the 873 potentially eligible cases (70 percent) and 926 of the 1,637 potentially eligible controls (57 percent), a bias may have occurred because of nonparticipation. However, it is unlikely that women's initial choice to participate in the study would hinge upon whether they had suffered side effects because of OC use. Additionally, for those interviews completed, cases and controls included versus excluded from the study were compared, and no differences in the previously established risk factors for ovarian cancer of OC use, parity, hysterectomy, tubal ligation, or family history of ovarian cancer were observed.
In conclusion, women who use OCs for as little as 16 months can achieve a reduction in the risk of ovarian cancer, but only if they stop use because of side effects. Mediating factors might reflect endogenous hormone levels, OC metabolism, or OC bioactivity.
 |
ACKNOWLEDGMENTS
|
---|
This work was supported in part by National Cancer Institute grants R01CA61095, R25 CA57703, and K07-CA80668.
Conflict of interest: none declared.
 |
References
|
---|
- Cancer facts and figures 2003. Washington, DC: American Cancer Society, 2003. (http://www.cancer.org/docroot/STT/stt_0_2003.asp?sitearea=STT&level=1).
- Ness RB, Grisso JA, Vergona R, et al. Oral contraceptives, other methods of contraception, and risk reduction for ovarian cancer. Epidemiology 2001;12:30712.[CrossRef][ISI][Medline]
- Ness RB, Cramer DW, Goodman MT, et al. Infertility, fertility drugs, and ovarian cancer: a pooled analysis of case-control studies. Am J Epidemiol 2002;155:21724.[Abstract/Free Full Text]
- Stanford JL. Oral contraceptives and neoplasia of the ovary. Contraception 1991;43:54356.[CrossRef][ISI][Medline]
- Rosenberg L, Palmer JR, Zauber AG, et al. A case-control study of oral contraceptive use and invasive epithelial ovarian cancer. Am J Epidemiol 1994;139:65461.[Abstract]
- Gross TP, Schlesselman JJ, Stadel BV, et al. The risk of epithelial ovarian cancer in short-term users of oral contraceptives. Am J Epidemiol 1992;136:4653.[Abstract]
- 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;316:6505.[Abstract]
- Cramer DW, Hutchison GB, Welch WR, et al. Determinants of ovarian cancer risk. I. Reproductive experiences and family history. J Natl Cancer Inst 1983;71:71116.[ISI][Medline]
- Risch HA. Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone. J Natl Cancer Inst 1998;90:177486.[Abstract/Free Full Text]
- Oral contraceptive use and the risk of ovarian cancer. The Centers for Disease Control Cancer and Steroid Hormone Study. JAMA 1983;249:15969.[Abstract]
- Crosby RA, Yarber WL, Meyerson B. Prevention strategies other than male condoms employed by low-income women to prevent HIV infection. Public Health Nurs 2000;17:5360.[CrossRef][ISI][Medline]
- Trussell J, Vaughan B. Contraceptive failure, method-related discontinuation and resumption of use: results from the 1995 National Survey of Family Growth. Fam Plann Perspect 1999;31:6472, 93.[ISI][Medline]
- Henshaw SK. Unintended pregnancy in the United States. Fam Plann Perspect 1998;30:249, 46.[ISI][Medline]
- Forman SF, Emans SJ, Kelly L, et al. Attitudes of female college students toward over-the-counter availability of oral contraceptives. J Pediatr Adolesc Gynecol 1997;10:2037.[Medline]
- Fu H, Darroch JE, Haas T, et al. Contraceptive failure rates: new estimates from the 1995 National Survey of Family Growth. Fam Plann Perspect 1999;31:5663.[ISI][Medline]
- Rosenberg MJ, Waugh MS, Burnhill MS. Compliance, counseling and satisfaction with oral contraceptives: a prospective evaluation. Fam Plann Perspect 1998;30:8992, 104.[ISI][Medline]
- Fotherby K. Interactions with oral contraceptives. Am J Obstet Gynecol 1990;163:21539.[ISI][Medline]
- Thurmann PA, Hompesch BC. Influence of gender on the pharmacokinetics and pharmacodynamics of drugs. Int J Clin Pharmacol Ther 1998;36:58690.[ISI][Medline]
- Modugno F. Ovarian cancer and high-risk womenimplications for prevention, screening, and early detection. Gynecol Oncol 2003;91:1531.[CrossRef][ISI][Medline]
- Rodriguez GC, Walmer DK, Cline M, et al. Effect of progestin on the ovarian epithelium of macaques: cancer prevention through apoptosis? J Soc Gynecol Investig 1998;5:2716.[CrossRef][ISI][Medline]
- Rodriguez GC, Nagarsheth NP, Lee KL, et al. Progestin-induced apoptosis in the Macaque ovarian epithelium: differential regulation of transforming growth factor-beta. J Natl Cancer Inst 2002;94:5060.[Abstract/Free Full Text]
- Modugno F. Ovarian cancer and polymorphisms in the androgen and progesterone receptor genes: a HuGE review. Am J Epidemiol 2004;159:31935.[Abstract/Free Full Text]
- Fraser IS, Kovacs GT. The efficacy of non-contraceptive uses for hormonal contraceptives. Med J Aust 2003;178:6213.[ISI][Medline]
- Kane FJ. Clinical psychiatric symptoms accompanying oral contraceptive use. Comments Contemp Psychiatry 1971;1:716.
- Farias da Silva W. Neurological disturbances associated with anovulatory treatment. Neurobiologia 1976;39:26576.
- Grant EC, Pryse-Davies J. Effect of oral contraceptives on depressive mood changes and on endometrial monoamine oxidase and phosphatases. Br Med J 1968;3:77780.[Medline]
- Herzberg BN, Draper KC, Johnson AL, et al. Oral contraceptives, depression, and libido. Br Med J 1971;3:495500.[Medline]
- Gierach GL, Modugno F, Ness RB. Relations of gestational length and timing and type of incomplete pregnancy to ovarian cancer risk. Am J Epidemiol 2005;161:45261.[Abstract/Free Full Text]
- Schildkraut JM, Calingaert B, Marchbanks PA, et al. Impact of progestin and estrogen potency in oral contraceptives on ovarian cancer risk. J Natl Cancer Inst 2002;94:328.[Abstract/Free Full Text]
- 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:18726.[CrossRef][ISI][Medline]