Oral Contraceptives and Benign Ovarian Tumors

Carolyn Westhoff1, Julie A. Britton2, Marilie D. Gammon3, Tom Wright4 and Jennifer L. Kelsey5

1 Department of Obstetrics and Gynecology, and School of Public Health, College of Physicians and Surgeons, Columbia University, New York, NY.
2 Department of Preventive Medicine, Mount Sinai School of Medicine, New York, NY.
3 Department of Epidemiology, University of North Carolina, Chapel Hill, NC.
4 Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY.
5 Department of Health Research and Policy, Stanford University, Stanford, CA.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Whether use of combined oral contraceptives (OC) protects against benign ovarian tumors is unknown. A case-control study of pathologically confirmed benign ovarian tumors was conducted in the New York City area and included cases diagnosed from January 1, 1992, to December 31, 1993, and controls identified by random digit dialing. There were 196 cases with serous adenomas, 176 with teratomas, 311 with endometriomas, and 65 with mucinous adenomas. Interview data were used to determine contraceptive use. Ever use of OC was associated with a decreased risk of these benign tumors (age- and hospital-adjusted odds ratio = 0.79, 95% confidence interval: 0.60, 1.05). In histologic subgroup analyses, the risk of ovarian tumors was reduced for both current and past OC users. Among tumor subtypes, the risk reduction was greatest for women who had endometriotic lesions. The risk reduction also was greater for women who had used OC for more than 24 months. Protection against benign ovarian tumors may be an additional noncontraceptive benefit of OC use. Am J Epidemiol 2000;152:242–6.

adenoma; contraceptives; oral; endometriosis; ovarian neoplasms; teratoma

Abbreviations: OC, combined oral contraceptives.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The reduced risk of ovarian malignancies for oral contraceptive users is strong, increases with duration of use of combined oral contraceptives (OC), and has been found in many studies (1Go, 2Go). Because most ovarian cancer occurs later in life, reduced risk has been related to OC use many years earlier. The risk for surgically diagnosed functional ovarian cysts, which occur mainly during the reproductive years, is reduced by current use of OC (3GoGoGo–6Go). These decreased risks are generally thought to be a result of the inhibitory effect of the oral contraceptive on aspects of ovarian activity, particularly ovulation. In contrast, several studies have found no consistent effect of OC use on the risk of benign ovarian neoplasms (7GoGoGoGo–11Go). It is surprising that use of OC appears to protect against both functional ovarian cysts and malignant ovarian tumors without protecting against benign tumors.

Most previous studies of OC and benign ovarian tumors have been small, thus limiting their ability to explore this association. In this paper, we present results from a case-control study of the association between OC use and benign ovarian tumors that, to our knowledge, included a larger number of cases than assessed previously.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Cases who had surgically confirmed benign ovarian tumors were identified from six New York metropolitan area hospitals between January 1, 1992, and December 31, 1993. Eligible tumors included serous cystadenomas, mucinous cystadenomas, endometriomas (or ovarian endometriosis), teratomas, Brenner tumors, and fibroma-thecomas. Pathology reports that included information on an ovary or portion of an ovary were reviewed by the study pathologist (T. W.), followed by a review of all relevant slides. We identified 1,259 women who had 1,460 confirmed benign tumors (some women had more than one). Tumors were classified on the basis of histopathology criteria recommended by both the World Health Organization and the international Federation of Gynecology and Obstetrics (12Go). The endometriotic lesions classification includes both endometriosis of the ovary and endometriomas and, for brevity, are subsequently referred to in this paper as endometriomas. Teratomas were ascertained for only 18 months; all other tumor types were ascertained for 24 months.

To be eligible, a woman was required to be aged 18–74 years, live within 50 miles (80 km) of New York City, have a telephone, and speak English. Women with a concurrent diagnosis of cancer were excluded. Written approval to approach cases was obtained from the operating physician. Controls were selected by using a modified Waksberg method of random digit dialing (13Go). Telephone prefixes for women admitted to the participating hospitals for gynecologic care formed the sampling frame for selection of random digit dialing controls. Controls were approximately frequency matched to cases by 10-year age groups (18–24, 25–34, 35–44, 45–54, 55–64, 65–74) and by hospital. Within each age group, the number of controls exceeded the number of cases in any histologic subgroup. The participation rate for controls does not account for any women in households that never answered the telephone during the screening process (table 1); the screener response rate was 82.4 percent.


View this table:
[in this window]
[in a new window]
 
TABLE 1. Participation rates and distribution of histology types for women studied to determine the relation between use of oral contraceptives and benign ovarian tumors, New York City, 1992–1993

 
Subjects were contacted by a letter from their physicians and then by telephone. After informed consent was obtained, a structured questionnaire was administered in person, usually at the subject's home, to 88 percent of the subjects. A telephone interview was used when necessary. Cases and controls were assigned a reference date: the diagnosis date for cases and 3 months prior to the telephone screening interview for controls (so the time frame for recalling events was similar for cases and controls).

The interview included sociodemographic descriptors, medical and reproductive history, use of contraceptives and other hormones, diet, and family history. Details of contraceptive and reproductive history were obtained by using a monthly calendar from menarche until the interview date. Identification of each oral contraceptive brand or other hormone was attempted by using a book of photographs to aid recall. Twenty percent of subjects underwent partial telephone reinterviews for quality control purposes and whenever needed for clarification.

Odds ratios from unconditional logistic regression analysis, and their corresponding 95 percent confidence intervals, are reported in this paper (14Go). All models were adjusted for the two frequency-matching factors: age in 10-year bands and hospital. Including age as a continuous variable had no additional effect on the results. Case-control analyses were performed by comparing all cases with all controls as well as by histologic subgroups. Because of small numbers, Brenner tumors and fibroma-thecomas were included in the analysis for ever-never OC use only. Cases who had more than one tumor were included in each appropriate subtype analysis. Analyses restricted to subjects who had only one tumor yielded similar results (data not shown).

Variables examined as possible confounders included medical insurance, race, education, marital status, gravidity, parity, age at first full-term pregnancy, abortions, miscarriages, breastfeeding, fertility, age at menarche, menopausal status, primary dysmenorrhea, other contraceptive use (besides OC), hormone replacement therapy, other exogenous hormone use, past medical conditions, body mass index (weight in kilograms/height in meters squared), alcohol consumption, exercise, and vitamin use. Covariates that caused a 10 percent change in the OC beta coefficient when entered individually into the model were included together in a full regression model; then, backward elimination techniques were used to create the most parsimonious model that provided an odds ratio and 95 percent confidence interval similar to that for the full model. Models were created separately for each tumor type since, a priori, we did not expect the same risk factors. The data also were evaluated by using polychotomous logistic models, which yielded similar results.

Analyses focused on the use of OC. Few subjects reported use of any progestin-only contraceptive methods; therefore, these contraceptives were not included in the analysis. Ever use of OC included any use of 1 month or more. Duration of use was considered both as a continuous variable and in categories of 1–24, 25–60, and more than 60 months. Duration of use refers to lifetime duration and often includes discontinuous episodes. In our study, a woman was considered a current user if any use occurred within 6 months of the reference date. Recent-past users reported OC use that ceased 6 months to 5 years prior to the reference date. Distant-past users had discontinued OC use more than 5 years prior to the reference date. These intervals were selected for their compatibility with previous studies; however, a sensitivity analysis indicated that none of the findings presented here changed when the boundaries of these definitions were changed by a few months in either direction. Analyses defining duration of use and recency of use in quartiles were also undertaken (data not shown) and did not yield any results different from those presented below. OC were collapsed into subgroups according to estrogen dose (>50, 50, and <50 µg of ethinyl estradiol) and type of progestin.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Table 1 shows the distribution of histology types of benign ovarian tumors for cases included in this study; the distribution of tumor types for nonparticipants was similar to that for participants. Cases and controls were similar with regard to age and ethnicity/race (table 2). Most subjects reported receiving gynecologic care from a private physician, but lack of any health insurance among those without a private physician was more frequent for controls (8.4 percent) than cases (1.7 percent).


View this table:
[in this window]
[in a new window]
 
TABLE 2. Characteristics of cases and controls studied to determine the relation between use of oral contraceptives and benign ovarian tumors, New York City, 1992–1993

 
Ever use of oral contraceptives was associated with a modest decrease in the risk of benign ovarian tumors (odds ratio 5 0.79, 95 percent confidence interval: 0.60, 1.05) (table 3). The odds ratios were below 1.0 for both statistical models and for all tumor subgroups except for analyses limited to the small group of mucinous adenomas. However, all 95 percent confidence intervals were wide. Odds ratios changed little after adjustment for confounding factors; therefore, because of the small numbers of subjects in subgroups, subsequent analyses were adjusted for age and hospital only.


View this table:
[in this window]
[in a new window]
 
TABLE 3. Association of benign ovarian tumors with ever versus never use of oral contraceptives, New York City, 1992–1993

 
Among OC users, the average duration of use was 4 years. About three quarters of OC use had occurred at least 5 years earlier; conversely, only a few subjects were current or recent OC users. Recency and duration of OC use were examined separately for each group of tumors (tables 4 and 5), keeping in mind the small numbers in some categories. These analyses also were carried out by using polychotomous regression models; for ever-never and for past OC use, none of the odds ratios for the tumor subtypes was different from each other. In analyses of current OC use, the estimates from the polychotomous regression models were markedly unstable because of the small number of subjects (data not shown).


View this table:
[in this window]
[in a new window]
 
TABLE 4. Association of benign ovarian tumors with current use of combined oral contraceptives, by total duration of use (months),* New York City, 1992–1993

 

View this table:
[in this window]
[in a new window]
 
TABLE 5. Association of benign ovarian tumors with past use of combined oral contraceptives (more than 5 years ago), by total duration of use (months),* New York City, 1992–1993

 
We found no suggestion of reduced risk associated with OC for short-term (1–24 months) current users (table 4). For current users who used OC for a longer period of time, there was the suggestion of a reduced risk. A strong trend of decreasing risk with duration of use was found for all tumor types (p = 0.006 for months of OC use evaluated as a continuous variable); all of this trend appeared to be due to the decreased risk we observed for women with endometriomas (p = 0.001). Excluding episodes of OC use that began within 6 months of the reference date had no effect on these results. Too few women had discontinued OC use within 5 years to enable meaningful analysis by duration of use or tumor subtype. The odds ratios calculated for this group tended to be close to 1.0, but all had very wide confidence intervals (data not shown).

Most OC users had discontinued use at least 5 years prior to the reference date (table 5). These women had a decreased risk of all benign tumor subtypes. The risk was decreased particularly for cases with a longer duration of OC use, but little difference was found between cases with a medium (25–60 months) and a long (>60 months) duration of use. Similar to the findings for current use, when duration of use was evaluated as a continuous variable in months, the trend toward decreasing risk with increasing OC use essentially was limited to the subjects with endometriomas.

Practically all recent users had been exposed to only low-estrogen-dose OC (<=35 µg of ethinyl estradiol). It was not feasible to separate the effects of recency of use and dose except for distant-past users who reported using a wide range of different formulations. We found no difference in the odds ratios according to estrogen dose of the OC (data not shown); in particular, there was no evidence of greater decreases in risk for women who had ever used or only used high- or medium-estrogen-dose OC (>50 or 50 µg, respectively, of ethinyl estradiol). Insufficient numbers of women were exposed to any particular progestins or particular combinations to enable more detailed subgroup analysis by type of OC.


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
This study was not population based; however, the distribution of tumor histology types for cases was similar to that found in population-based series of benign ovarian tumors (15Go, 16Go). The patterns of OC use reported by controls were similar to use patterns reported by women throughout the United States (17Go). This study may have included a different spectrum of cases than found in previous European studies because of higher US rates of surgery for benign ovarian cysts and tumors (18Go). This study was larger than previous studies of benign ovarian tumors, but the numbers of subjects available for analysis were nonetheless too small to enable precise effect estimates to be determined.

Four previous studies evaluated the association between OC use and teratomas: 116 cases (7Go), 47 cases (4Go), and 20 cases (8Go) all from the United Kingdom and 77 cases from Italy (9Go). None of these studies found a decreased risk of teratomas associated with OC use. In contrast, the present study, with 176 cases, identified a small decrease in risk for both current OC users with more than 24 months of use and past OC users. No duration-response effect was found in the present study. Overall, any effect of OC use on teratomas seems to be small.

Three previous studies of adenomas (4Go, 8Go, 10Go) were also small, with 61, 41, and 88 cases, respectively. Earlier analyses combined serous and mucinous adenomas and found either no association or a slightly increased risk; however, combining serous and mucinous tumors may be inappropriate. In ovarian cancer studies that separated cancers by histologic type (19Go, 20Go), OC use protected against serous but not mucinous cancers. We found a modest negative association between OC use and serous adenomas (with 196 cases) for current long-term users and distant-past users and a similar negative association for the few mucinous adenomas.

The endometriomas included in this study represented a subset that was surgically diagnosed and excised for pathologic examination. Women with medically managed endometriosis or solely extraovarian endometriosis were not included. Other studies included such women and found a negative association with OC use for current users only (11Go, 21Go). Both Vessey et al. (21Go) and Parazzini et al. (11Go) concluded that OC use does not offer long-term protection against endometriosis. In contrast, the present study found, among 311 cases, a decreased risk of endometriosis for both current and past OC users as well as decreasing risk with increasing duration of use. Ovarian endometriotic lesions were the most common tumor type included in this study, reflecting their importance in the participating hospitals and also throughout the United States. While theories about the pathogenesis of endometriosis would predict OC use to be protective (22Go), this study is probably the first to provide support for a long-term protective effect.

Medical surveillance often increases with the onset and discontinuation of OC use. In the United States, periodic pelvic examinations typically are associated with prescription of OC (23Go). These examinations may increase the opportunity for diagnosis of benign ovarian tumors in OC users compared with nonusers and, in the short run, may distort the relation between OC use and diagnosis of benign ovarian tumors. In particular, increased surveillance of OC users may increase detection of prevalent tumors when women first use OC.

Women who discontinued OC use in the more distant past no longer receive intensive surveillance specifically because of their OC use. They also are most comparable to OC users in studies of ovarian cancer in which, because of the age of the cases, current or recent use is rare. In the present study, past use of OC was associated with a decreased risk of benign ovarian tumors overall, particularly for long-term users and for women with endometriomas. The magnitude of the reduced risk we found was similar to that reported in studies of OC use and ovarian cancer (1Go, 2Go), even though the effect associated with duration of use was reduced.

In conclusion, oral contraceptive use was associated with a modest and long-lasting decreased risk of benign ovarian tumors. Current and past OC users had fewer benign ovarian tumors than never users. When compared with short-term users, long-term OC users had a lower risk. The decreased risks observed were greatest for women with endometriomas. These findings held for users of both low- and high-estrogen-dose OC. Because surgical excision of benign ovarian tumors is common in the United States, with at least 60,000 cases per year, this effect may substantially reduce the burden of this condition.


    ACKNOWLEDGMENTS
 
This project was supported in part by grant CA50658 from the National Cancer Institute, Bethesda, Maryland.


    NOTES
 
Correspondence to Dr. Carolyn Westhoff, Department of Obstetrics and Gynecology, College of Physicians and Surgeons, 630 West 168 Street, New York, NY 10032 (e-mail: clw3{at}columbia.edu).


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Whittemore AS, Harris R, Itnyre J. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Am J Epidemiol 1992;136:1184–203.[Abstract]
  2. Hankinson S, Colditz G, Hunter D, et al. A quantitative assessment of oral contraceptive use and risk of ovarian cancer. Obstet Gynecol 1992;80:708–14.[Abstract]
  3. Functional ovarian cysts and oral contraceptives. Negative association confirmed surgically. A cooperative study. JAMA 1974;228:68–9.[ISI][Medline]
  4. Vessey M, Metcalfe A, Wells C, et al. Ovarian neoplasms, functional ovarian cysts, and oral contraceptives. BMJ 1987;297:1518–20.[ISI]
  5. Holt VL, Daling JR, McKnight B, et al. Functional ovarian cysts in relation to the use of monophasic and triphasic oral contraceptives. Obstet Gynecol 1992;79:529–33.[Abstract]
  6. Lanes SF, Birmann B, Walker AM, et al. Oral contraceptive type and functional ovarian cysts. Am J Obstet Gynecol 1992;166:956–61.[ISI][Medline]
  7. Westhoff C, Pike M, Vessey M. Benign ovarian teratomas: a population-based case-control study. Br J Cancer 1988;58:93–8.[Medline]
  8. Booth M, Beral V, Maconochie N, et al. A case-control study of benign ovarian tumours. J Epidemiol Community Health 1992;46:528–31.[Abstract]
  9. Parazzini F, La Vecchia C, Negri E, et al. Risk factors for benign ovarian teratomas. Br J Cancer 1995;71:644–6.[ISI][Medline]
  10. Parazzini F, La Vecchia C, Franceschi S, et al. Risk factors for endometrioid, mucinous and serous benign ovarian cysts. Int J Epidemiol 1989;18:108–12.[Abstract]
  11. Parazzini F, Ferraroni M, Bocciolone L, et al. Contraceptive methods and risk of pelvic endometriosis. Contraception 1994;49:47–55.[ISI][Medline]
  12. Russel P, Ballatyne P, eds. Surgical pathology of the ovary. Edinburgh, Scotland: Churchill Livingston, 1989.
  13. Hartge P, Brinton LA, Rosenthal JF, et al. Random digit dialing in selecting a population-based control group. Am J Epidemiol 1984;120:825–33.[Abstract]
  14. Hosmer DW, Lemeshow S. Applied logistic regression. New York, NY: John Wiley & Sons, Inc, 1989.
  15. Bennington J, Ferguson B, Haber S. Incidence and relative frequency of benign and malignant ovarian neoplasms. Am J Obstet Gynecol 1968;32:627–32.
  16. Katsube Y, Berg J, Silverberg S. A histopathological review of primary ovarian neoplasms diagnosed in the Denver SMSA 1 July–31 December 1969 and 1 July–31 December 1979. Int J Gynecol Pathol 1982;1:3–16.[ISI][Medline]
  17. Abma JC, Chandra A, Mosher WD, et al. Fertility, family planning, and women's health: new data from the 1995 National Survey of Family Growth. Vital Health Stat 23 1997;May:1–114.
  18. Westhoff C, Clark C. Benign ovarian cysts in England and Wales and in the United States. Br J Obstet Gynecol 1992;99:329–32.[ISI][Medline]
  19. Risch HA, Marrett LD, Jain M, et al. Differences in risk factors for epithelial ovarian cancer by histologic type: results of a case-control study. Am J Epidemiol 1996;144:363–72.[Abstract]
  20. Epithelial ovarian cancer and combined oral contraceptives. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Int J Epidemiol 1989;18:538–45.[Abstract]
  21. Vessey MP, Villard-Mackintosh L, Painter R. Epidemiology of endometriosis in women attending family planning clinics. BMJ 1993;306:182–4.[ISI][Medline]
  22. Olive D, Schwartz L. Endometriosis. N Engl J Med 1993;328:1759–69.[Free Full Text]
  23. Speroff L, Darney P. A clinical guide for contraception. 2nd ed. Baltimore, MD: Williams & Wilkins, 1996:79–80.
Received for publication May 7, 1999. Accepted for publication September 7, 1999.