Abstract
Objective
To assess the influence of infertility and fertility drugs on risk of ovarian tumors.
Design
Case-control study (Mayo Clinic Ovarian Cancer Study).
Setting
Ongoing academic study of ovarian cancer.
Patient(s)
A total of 1900 women (1028 with ovarian tumors and 872 controls, frequency matched on age and region of residence) who had provided complete information in a self-report questionnaire about history of infertility and fertility drug use.
Intervention(s)
None
Main outcome measure(s)
Effect of infertility history, use of fertility drugs and oral contraception and gravidity on the risk of ovarian tumor development, after controlling for potential confounders.
Result(s)
Among women who had a history of infertility, use of fertility drugs was reported by 24% (44/182) of controls and 17% (38/226) of cases. Infertile women who used fertility drugs were not at increased risk of developing ovarian tumors compared to infertile women who did not use fertility drugs, adjusted odds ratio was 0.64 (95% CI 0.37, 1.11). Findings were similar when stratified by gravidity and when analyzed separately for borderline versus invasive tumors.
Conclusion(s)
We did not find any significant association between fertility drug use and risk of ovarian tumors. Further larger, prospective studies are needed to confirm this observation.
Keywords: Fertility drugs, ovarian tumors, borderline tumors, case-control, primary infertility
INTRODUCTION
Infertility, nulliparity and late-onset of menopause are some of the factors known to be associated with an increased risk for ovarian cancer (1–4). Several studies have been done to assess the association between fertility drug use and risk of ovarian tumors; however, the available data is conflicting. While early studies reported an association between exposure to fertility drugs and the development of ovarian tumors (5–7), subsequent studies did not find any statistically significant association (8–15). In contrast, other recent studies (16, 17) have reported an increased risk among a subgroup of nulliparous women, especially regarding risk of borderline ovarian tumors.
Fertility drug use has increased markedly in the U.S. and is expected to continue to rise as the percentage of women who postpone attempting pregnancy until after age 35 increases (23). The association, if any, between fertility drug use and risk of ovarian tumors should therefore be an integral part of preconception counseling.
Establishing the relationship between fertility drug use and risk of development of ovarian tumors is complicated by the fact that infertility itself is associated with an increased risk of ovarian tumors (18, 19). Two theories have been proposed to explain the mechanisms by which fertility drug use may increase the risk of ovarian tumor development. The “Incessant Ovulation Hypothesis” theorizes that the repeated damage and subsequent repair cycles that occur during ovulation on the epithelial surface of the ovary contributes to DNA damage and increases the risk of developing ovarian tumors (20). The increased risk of ovarian cancer in chickens, a species of incessant ovulators, supports this hypothesis (21). The “Gonadotropin Hypothesis” postulates that exposure to high levels of circulating pituitary gonadotropins, which stimulates the ovarian surface epithelium, plays a role in the development of ovarian tumors (22). The protective effect of oral contraceptive pills is consistent with this hypothesis. Both of these theories suggest that fertility drugs, which also stimulate ovulation by transiently increasing gonadotropins, may increase the risk of ovarian tumors. Separation of the effects of underlying infertility and other important confounding factors from those of fertility drug use is essential if the true relationship between fertility drug use and ovarian tumor risk can be established. This requires for studies assessing the relationship to have large sample sizes.
Interpreting the available data on fertility drugs and ovarian tumors for the average U.S. woman undergoing fertility treatment is complicated by a number of factors among which is the fact that most of the studies have been conducted outside of the U.S., and the few conducted in the U.S. have used very small sample sizes (5, 6). Our goal was to use a large on-going U.S. case-control study of epithelial ovarian tumors to assess the long-term effects of infertility and use of fertility drugs on the risk of ovarian tumors among U.S. women, incorporating important confounding factors such as use of oral contraceptives, parity, gravidity, and family history of ovarian cancer.
MATERIALS AND METHODS
Study Design and Patient Population
We used data from an ongoing case-control study of prevalent and incident epithelial ovarian tumors initiated in December 1999 at Mayo Clinic (Rochester, MN). Written informed consent was obtained from all participants. For this analysis, we included participants enrolled during the period December 14, 1999 through May 10, 2012. The Institutional Review Board at the Mayo Clinic approved the study protocol.
Clinic attendance formed the sampling frame for the cases and controls. Eligible women were at least 19 years old. All cases had histologically confirmed epithelial ovarian tumor (borderline or invasive) and most of them were enrolled in the study within 1 year of date of initial diagnosis. Cases lived in the six-state region that defines the primary service population of Mayo Clinic (Minnesota, Iowa, Wisconsin, Illinois, North Dakota, and South Dakota).
Controls were selected from women without ovarian tumors, and with at least one ovary intact, who had presented to the clinic for general medical examination. These women were frequency matched on age (5-year age categories), and region of residence to cases. A total of 2253 women (1157 cases and 1096 controls) were enrolled as of May 10, 2012. Of these, 1900 women (1028 cases and 872 controls) provided complete information in the self-report questionnaire about history of infertility and fertility medication use and were included in our study.
Risk Factor Data Collection
Information on known and suspected ovarian cancer risk factors and demographic data were collected. These included race/ethnicity, height and weight 1 year before the interview, use of tobacco, education level, medical and surgical history, use of exogenous hormones, and family history of breast or ovarian cancer in first and second-degree relatives.
Detailed menstrual and reproductive history including age at menarche, pregnancies, live births, age at first birth, infertility diagnosis, use and duration of use of oral contraceptives, surgical sterilization, age at menopause, and hormone replacement therapy were self-reported by the patients via a questionnaire. Infertility was defined as the inability to achieve a pregnancy over an interval of at least 12 months in a woman who desired to get pregnant and engaged in regular intercourse without contraception. Information about specific fertility treatment provided by the study participants included type of fertility medication used and duration of treatment.
Statistical Analyses
Unconditional logistic regression models were fit to compare patient characteristics and risk factors between cases and controls. Models were adjusted for potential confounders including age, race, gravidity, parity, oral contraceptive use, and family history of ovarian cancer. Associations were summarized by calculating odds ratios (OR) and 95% confidence intervals (CI) based on the parameter estimates obtained from the univariable and multivariable models. All calculated p-values were two-sided and p-values less than 0.05 were considered statistically significant. Analyses were performed using SAS version 9.2 software package (SAS Institute, Inc., Cary, NC).
RESULTS
Baseline characteristics of the study population are presented in Table 1. Women with ovarian tumors were less likely to have post-high school education compared to controls. Also, women with ovarian tumors were almost twice as likely to be current smokers (vs. never smoked) compared to controls. As summarized in Table 2, women with ovarian tumors were significantly less likely to have used OCs for 60 months or greater and, less likely to have two or more live births or pregnancies compared to controls.
Table 1.
Characteristics of the study population
| Characteristic | Controls (N=872) |
Cases (N=1028) |
Unadjusted OR (95% CI) |
P-value |
|---|---|---|---|---|
| Age (years)*, mean (SD) | 60.5 (13.2) | 61.3 (12.8) | 1.05 (0.98, 1.13)‡ | 0.17 |
| Marital status, N (%) | <0.001 | |||
| Missing/unknown | 7 | 29 | - | |
| Married | 698 (80.7) | 736 (73.7) | Reference | |
| Not married | 167 (19.3) | 263 (26.3) | 1.49 (1.20, 1.86) | |
| Race, N (%) | 0.05 | |||
| Missing/unknown | 35 | 120 | - | |
| White | 825 (98.6) | 882 (97.1) | Reference | |
| Other | 12 (1.4) | 26 (2.9) | 2.03 (1.02, 4.04) | |
| Education, N (%) | <0.001 | |||
| Missing | 4 | 83 | - | |
| No high school | 25 (2.9) | 71 (7.5) | 1.95 (1.21, 3.16) | |
| High school | 270 (31.1) | 393 (41.6) | Reference | |
| Some college | 256 (29.5) | 272 (28.8) | 0.73 (0.58, 0.92) | |
| College graduate | 189 (21.8) | 109 (11.5) | 0.40 (0.30, 0.53) | |
| Graduate school | 128 (14.7) | 100 (10.6) | 0.54 (0.40, 0.73) | |
| Smoking status, N (%) | <0.001 | |||
| Missing/unknown | 9 | 84 | - | |
| Never smoked | 552 (64.0) | 583 (61.8) | Reference | |
| Former smoker | 269 (31.2) | 269 (28.5) | 0.95 (0.77, 1.16) | |
| Current smoker | 42 (4.9) | 92 (9.7) | 2.07 (1.41, 3.04) | |
| Age at menarche (years), mean (SD) | 13.0 (1.6) | 12.8 (1.6) | 0.47 (0.26, 0.86)‡ | 0.01 |
| Age at first live birth (years), mean (SD) | 24.1 (4.5) | 23.0 (4.4) | 0.57 (0.46, 0.71)‡ | <0.001 |
| Family history of OVCA, N (%) | 0.01 | |||
| No | 801 (91.9) | 906 (88.1) | Reference | |
| Yes | 71 (8.1) | 122 (11.9) | 1.52 (1.12, 2.07) |
Abbreviations: OR, odds ratio; CI, confidence interval
Age for controls is age at study consent and age for cases is age at ovarian tumor diagnosis
Odds ratio is per 10-year increment
Table 2.
Gravidity, parity, OCP use and risk of ovarian tumors
| Variable | Controls (N=872) |
Cases (N=1028) |
Unadjusted OR (95% CI) |
Adjusted* OR (95% CI) |
|---|---|---|---|---|
| N (%)† | N (%)† | |||
| Ever pregnant | ||||
| No | 49 (5.7) | 105 (10.2) | Reference | Reference |
| Yes | 817 (94.3) | 923 (89.8) | 0.53 (0.37, 0.75) | 0.58 (0.39, 0.88) |
| Number of pregnancies | ||||
| 0 | 49 (5.7) | 105 (10.2) | Reference | Reference |
| 1 | 62 (7.2) | 90 (8.8) | 0.68 (0.42, 1.08) | 0.69 (0.42, 1.13) |
| 2 | 232 (26.8) | 262 (25.5) | 0.53 (0.36, 0.77) | 0.49 (0.32, 0.77) |
| 3 | 228 (26.3) | 252 (24.5) | 0.52 (0.35, 0.76) | 0.46 (0.28, 0.74) |
| ≥4 | 295 (34.1) | 319 (31.0) | 0.51 (0.35, 0.73) | 0.35 (0.20, 0.62) |
| Ever delivered a live birth | ||||
| No | 64 (7.4) | 126 (12.3) | Reference | Reference |
| Yes | 800 (92.6) | 902 (87.7) | 0.57 (0.42, 0.79) | 0.68 (0.47, 0.98) |
| Number of live births | ||||
| 0 | 64 (7.4) | 126 (12.3) | Reference | Reference |
| 1 | 86 (9.9) | 109 (10.6) | 0.64 (0.43, 0.97) | 0.73 (0.47, 1.13) |
| 2 | 279 (32.3) | 314 (30.5) | 0.57 (0.41, 0.80) | 0.66 (0.45, 0.96) |
| ≥3 | 435 (50.4) | 479 (46.6) | 0.56 (0.40, 0.78) | 0.61 (0.38, 0.95) |
| Use of OCPs (months) | ||||
| Never | 254 (30.1) | 414 (41.5) | Reference | Reference |
| <6 | 10 (1.2) | 19 (1.9) | 1.17 (0.53, 2.55) | 1.23 (0.55, 2.72) |
| 6–59 | 194 (23.0) | 265 (26.5) | 0.84 (0.66, 1.07) | 0.83 (0.63, 1.08) |
| ≥60 | 387 (45.8) | 300 (30.1) | 0.48 (0.38, 0.59) | 0.47 (0.37, 0.60) |
Abbreviations: OR, odds ratio; CI, confidence interval
Each of the variables in this table was evaluated in a separate logistic regression model adjusted for age, race, duration of OCP use, number of pregnancies, number of live births, and family history of ovarian cancer (OVCA) when not the factor of interest
Percentage of the women with non-missing data.
A history of infertility was reported by 182 (21%) of the 872 of controls and 226 (22%) of the 1028 cases. Overall, there was no significant association between infertility and ovarian tumor risk (adjusted OR 0.99; 95% CI 0.78, 1.26). Because risk of ovarian tumor is generally influenced by gravidity, we stratified by gravidity, and noted that among the subgroup of women who had never been pregnant, the adjusted odds ratio (OR) for ovarian tumors among those who reported a history of infertility was 1.65(95% CI 0.80, 3.43) compared to those who did not have a history of infertility, suggesting no statistically significant association between history of infertility and risk of ovarian tumors among nulligravid women (Table 3). Similarly, among women who had been pregnant, there was no statistically significant association between a history of infertility and risk of developing ovarian tumors (adjusted OR 0.90; 95% CI 0.69, 1.16). Analyses were repeated separately for borderline and invasive ovarian tumors and no significant association was found between infertility and type of tumor histology (data not shown).
Table 3.
Association between history of infertility and ovarian tumor, stratified by gravidity
|
Subgroups defined by gravidity† |
History of infertility |
Controls N (%) |
Cases N (%) |
Unadjusted OR (95% CI) |
Adjusted OR (95% CI) |
|---|---|---|---|---|---|
| All women | No | 690 (79.1) | 802 (78.0) | Reference | Reference |
| Yes | 182 (20.9) | 226 (22.0) | 1.07 (0.86, 1.33) | 0.99 (0.78, 1.26)* | |
| Nulligravid women | No | 29 (59.2) | 49 (46.7) | Reference | Reference |
| Yes | 20 (40.8) | 56 (53.3) | 1.66 (0.83, 3.29) | 1.65 (0.80, 3.43)** | |
| Gravid women | No | 656 (80.3) | 753 (81.6) | Reference | Reference |
| Yes | 161 (19.7) | 170 (18.4) | 0.92 (0.72, 1.17) | 0.90 (0.69, 1.16)* |
Abbreviations: OR, odds ratio; CI, confidence interval
Adjusted for age, race, duration of OCP use, number of pregnancies, number of live births, and family history of OVCA
Adjusted for age, race, duration of OCP use, and family history of OVCA
Information on gravidity was not provided by 6 controls
Among women who had a history of infertility, use of fertility drugs was reported by 24% (44/182) of controls and 17% (38/226) of cases. Among infertile women, ever use of fertility drugs was not significantly associated with ovarian tumor risk (Table 4) and remained non-significant after additional adjustment for potential confounders (adjusted OR 0.64; 95% CI 0.37,1.11). When we stratified by tumor histology (data not shown), we had a small number of women with borderline ovarian tumors (32 borderline cases and 194 invasive cases, with a history of infertility), and observed no significant association between fertility drug use and borderline ovarian tumor (adjusted OR 0.61; 95% CI 0.23; 1.61) or with invasive ovarian cancer (adjusted OR 0.66; 95% CI 0.37, 1.16). We also examined the association of ovarian tumor risk and fertility drug use separately among women with a history of infertility who had been pregnant (gravids) versus those who had never been pregnant (nulligravids). We observed that among both nulligravids and gravids who had a history of infertility, there was no statistically significant difference between the odds of exposure to fertility drugs among cases compared to controls.
Table 4.
Odds ratios for ovarian tumor associated with use of fertility drugs among women with a history of infertility, stratified by gravidity
|
Subgroups defined by gravidity† |
Fertility drug use |
Controls N (%) |
Cases N (%) |
Unadjusted OR (95% CI) |
Adjusted OR (95% CI) |
|---|---|---|---|---|---|
| All | No | 138 (75.8) | 188 (83.2) | Reference | Reference |
| Yes | 44 (24.2) | 38 (16.8) | 0.63 (0.39, 1.03) | 0.64 (0.37, 1.11)* | |
| Nulligravid women | No | 16 (80.0) | 49 (87.5) | Reference | Reference |
| Yes | 4 (20.0) | 7 (12.5) | 0.57 (0.15, 2.21) | 0.59 (0.14, 2.52)**h | |
| Gravid women | No | 122 (75.8) | 139 (81.8) | Reference | Reference |
| Yes | 39 (24.2) | 31 (18.2) | 0.70 (0.41, 1.19) | 0.69 (0.37, 1.26)* |
Abbreviations: OR, odds ratio; CI, confidence interval
Adjusted for age, race, duration of OCP use, number of pregnancies, number of live births, and family history of OVCA
Adjusted for age, race, duration of OCP use, and family history of OVCA
Information on gravidity was not provided by 1 control
Among all cases and controls with a history of infertility who reported using fertility drugs (n=82), 31 (38%) used them for less than 6 months, 34 (41%) used them for 6 to 12 months, 9 (11%) used them for >12 months, and the duration was unknown for 8 (10%). We did not observe any association between duration of fertility drug use and risk of ovarian cancer (data not shown). Approximately 65% of patients did not provide information on specific types of fertility drugs used; we therefore did not assess the association between specific types of fertility drugs and ovarian cancer risk.
DISCUSSION
The results from our study are consistent with results from previous studies (1–4, 6, 24), which showed that OC use, gravidity, and parity are associated with decreased risk for development of ovarian tumors. We did not find any statistically significant increased risk of ovarian tumors among women with primary infertility (women with infertility who had never been pregnant); this observation is inconsistent with findings from previous studies (1–4, 6, 24). Given our large sample size (1900 women) and the observation that 20.9% of the controls had a history of infertility, the study had 80% power to detect an odds ratio of 1.36 and above. Even though our study was sufficiently powered to detect odds ratios consistent with previous studies, we only observed a slightly higher exposure rate among the ovarian cancer cases yielding an unadjusted odds ratio of 1.07. However, among the subset of 408 women with a history of infertility, given that 24% of the controls used fertility drugs the study was potentially underpowered as there was 80% power to only detect odds ratios of 1.85 and above.
Ever use of fertility drugs was not significantly associated with development of ovarian tumors; this did not change when we stratified by gravidity. We conducted the analyses separately for borderline tumors and invasive cancers, and, similar to previous reports (15, 25); we found no significant association between fertility drug use and borderline ovarian tumors.
Our finding that fertility drug use does not significantly contribute to ovarian tumor risk among infertile women is in line with results from other, recent studies (8–15; 24, 26). However there are also several reports, mostly from studies conducted in the 1990s, which have reported increased risk for ovarian cancer with fertility drug use (5–7). The contradictory findings may stem from the fact that these earlier studies had small sample sizes, and were unable to adjust for important confounding factors known to impact ovarian tumor risk. Also, fertility drugs have been used in the U.S. since 1967 (23); it is possible that there have been significant changes in the fertility drugs of choice and doses over the past 5 decades, which could account for the differences observed between the earlier studies and most recent ones, however there is no reliable data to support this argument.
The strengths of our study include a large sample size and availability of important reproductive and medical histories of women included in the study. By being able to adjust for important factors linked to ovarian cancer risk, risks of ovarian cancer associated with these factors were separated clearly from risk associated with fertility drug use. By comparing with an unexposed group of infertile women, we were able to better assess the risk of fertility drugs vs. infertility itself and also evaluate the importance of other known confounders. We were therefore able to determine whether fertility drug use is an independent risk factor for ovarian tumors.
A limitation of our study is that we did not review the medical records and therefore could not verify the self-reported reproductive and medical history provided by the study participants. Also, we were unable to assess the effect of specific fertility drugs on ovarian tumor risk, as this information was not provided by approximately 65% of our patients. Another limitation of our study is related to errors in recall of important fertility-related information. However, the associations we observed of ovarian tumors with other factors generally known to influence ovarian tumor risk including OC use, gravidity, and parity are consistent with those previously reported (1, 3, 4), suggesting that the extent of recall or selection bias in our study is not likely to be significantly different from that of previous research.
Overall, our findings do not support the null hypothesis that fertility drug use significantly increases the risk of ovarian tumor development, when known confounding factors are adjusted for (adjusted OR 0.64; 95% CI 0.37, 1.11). We also did not find any statistically significant association between history of infertility and risk of ovarian tumors among nulligravids.
In conclusion, our case-control study provides modest evidence that fertility drugs do not increase risk of ovarian tumor development. Further larger, prospective studies are needed to confirm this observation.
ACKNOWLEDGEMENTS
We are indebted to Michaela E McGree at the Biomedical Statistics and Informatics Division (Mayo Clinic, Rochester MN) for data support and analysis and Kimberly R Kalli, PhD, of the Women’s Cancer Program at the Mayo Clinic Cancer Center for study outcomes ascertainment and management.
Grant Support: This research was supported by National Institutes of Health grants R01 CA122443, P50 CA136393 and Mayo Foundation
Footnotes
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REFERENCES
- 1.McGowan L, Parent L, Lednar W, Norris HJ. The woman at risk for developing ovarian cancer. Gynecol Oncol. 1979;7:325–344. doi: 10.1016/0090-8258(79)90111-2. [DOI] [PubMed] [Google Scholar]
- 2.Hartge P, Schiffman MH, Hoover R, McGowan L, Lesher L, Norris HJ. A case-control study of epithelial ovarian cancer. Am J Obstet Gynecol. 1989;161:10–16. doi: 10.1016/0002-9378(89)90221-4. [DOI] [PubMed] [Google Scholar]
- 3.Risch HA, Marrett LD, Howe GR. Parity, contraception, infertility, and the risk of epithelial ovarian cancer. Am J Epidemiol. 1994;140:585–597. doi: 10.1093/oxfordjournals.aje.a117296. [DOI] [PubMed] [Google Scholar]
- 4.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;344:1250–1254. doi: 10.1016/s0140-6736(94)90749-8. [DOI] [PubMed] [Google Scholar]
- 5.Whittemore AS, Harris R, Itnyre J. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Collaborative Ovarian Cancer Group. Am J Epidemiol. 1992;136:1184–1203. doi: 10.1093/oxfordjournals.aje.a116427. [DOI] [PubMed] [Google Scholar]
- 6.Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian tumors in a cohort of infertile women. N Engl J Med. 1994;331:771–776. doi: 10.1056/NEJM199409223311204. [DOI] [PubMed] [Google Scholar]
- 7.Shushan A, Paltiel O, Iscovich J, Elchalal U, Peretz T, Schenker JG. Human menopausal gonadotropin and the risk of epithelial ovarian cancer. Fertil Steril. 1996;65:13–18. [PubMed] [Google Scholar]
- 8.Mosgaard BJ, Lidegaard O, Kjaer SK, Schou G, Andersen AN. Infertility, fertility drugs, and invasive ovarian cancer: a case-control study. Fertil Steril. 1997;67:1005–1012. doi: 10.1016/s0015-0282(97)81431-8. [DOI] [PubMed] [Google Scholar]
- 9.Modan B, Ron E, Lerner-Geva L, Blumstein T, Menczer J, Rabinovici J, et al. Cancer incidence in a cohort of infertile women. Am J Epidemiol. 1998;147:1038–1042. doi: 10.1093/oxfordjournals.aje.a009397. [DOI] [PubMed] [Google Scholar]
- 10.Doyle P, Maconochie N, Beral V, Swerdlow AJ, Tan SL. Cancer incidence following treatment for infertility at a clinic in the UK. Hum Reprod. 2002;17:2209–2213. doi: 10.1093/humrep/17.8.2209. [DOI] [PubMed] [Google Scholar]
- 11.Rossing MA, Tang MT, Flagg EW, Weiss LK, Wicklund KG. A case-control study of ovarian cancer in relation to infertility and the use of ovulation-inducing drugs. Am J Epidemiol. 2004;160:1070–1078. doi: 10.1093/aje/kwh315. [DOI] [PubMed] [Google Scholar]
- 12.Jensen A, Sharif H, Frederiksen K, Kjaer SK. Use of fertility drugs and risk of ovarian cancer: Danish Population Based Cohort Study. BMJ. 2009;338:b249. doi: 10.1136/bmj.b249. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Brinton LA, Lamb EJ, Moghissi KS, Scoccia B, Althuis MD, Mabie JE, et al. Ovarian cancer risk after the use of ovulation-stimulating drugs. Obstet Gynecol. 2004;103:1194–1203. doi: 10.1097/01.AOG.0000128139.92313.74. [DOI] [PubMed] [Google Scholar]
- 14.Harris R, Whittemore AS, Itnyre J. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. III. Epithelial tumors of low malignant potential in white women. Collaborative Ovarian Cancer Group. Am J Epidemiol. 1992;136:1204–1211. doi: 10.1093/oxfordjournals.aje.a116428. [DOI] [PubMed] [Google Scholar]
- 15.Mosgaard BJ, Lidegaard O, Kjaer SK, Schou G, Andersen AN. Ovarian stimulation and borderline ovarian tumors: a case-control study. Fertil Steril. 1998;70:1049–1055. doi: 10.1016/s0015-0282(98)00337-9. [DOI] [PubMed] [Google Scholar]
- 16.Sanner K, Conner P, Bergfeldt K, Dickman P, Sundfeldt K, Bergh T, et al. Ovarian epithelial neoplasia after hormonal infertility treatment: long-term follow-up of a historical cohort in Sweden. Fertil Steril. 2009;91:1152–1158. doi: 10.1016/j.fertnstert.2008.01.073. [DOI] [PubMed] [Google Scholar]
- 17.Källén B, Finnström O, Lindam A, Nilsson E, Nygren KG, Olausson PO. Malignancies among women who gave birth after in vitro fertilization. Hum Reprod. 2011;26:253–258. doi: 10.1093/humrep/deq307. [DOI] [PubMed] [Google Scholar]
- 18.Mosgaard BJ, Lidegaard O, Andersen AN. The impact of parity, infertility and treatment with fertility drugs on the risk of ovarian cancer. A survey. Acta Obstet Gynecol Scand. 1997;76:89–95. doi: 10.3109/00016349709050061. [DOI] [PubMed] [Google Scholar]
- 19.Brinton LA, Lamb EJ, Moghissi KS, Scoccia B, Althuis MD, Mabie JE, et al. Ovarian cancer risk associated with varying causes of infertility. Fertil Steril. 2004;82:405–414. doi: 10.1016/j.fertnstert.2004.02.109. [DOI] [PubMed] [Google Scholar]
- 20.Tung KH, Wilkens LR, Wu AH, McDuffie K, Nomura AM, Kolonel LN, et al. Effect of anovulation factors on pre- and postmenopausal ovarian cancer risk: revisiting the incessant ovulation hypothesis. Am J Epidemiol. 2005;161:321–329. doi: 10.1093/aje/kwi046. [DOI] [PubMed] [Google Scholar]
- 21.Giles JR, Elkin RG, Trevino LS, Urick ME, Ramachandran R, Johnson PA. The restricted ovulator chicken: a unique animal model for investigating the etiology of ovarian cancer. Int J Gynecol Cancer. 2010;20:738–744. doi: 10.1111/igc.0b013e3181da2c49. [DOI] [PubMed] [Google Scholar]
- 22.Mohle J, Whittemore A, Pike M, Darby S. Gonadotrophins and ovarian cancer risk. J Natl Cancer Inst. 1985;75:178–180. [PubMed] [Google Scholar]
- 23.Wysowski DK. Use of fertility drugs in the United States, 1973 through 1991. Fertil Steril. 1993;60:1096–1098. doi: 10.1016/s0015-0282(16)56417-6. [DOI] [PubMed] [Google Scholar]
- 24.Ness RB, Cramer DW, Goodman MT, Kjaer SK, Mallin K, Mosgaard BJ, et al. Infertility, fertility drugs, and ovarian cancer: a pooled analysis of case-control studies. Am J Epidemiol. 2002;155:217–224. doi: 10.1093/aje/155.3.217. [DOI] [PubMed] [Google Scholar]
- 25.Cusido M, Fabregas R, Pere BS, Escayola C, Barri PN. Ovulation induction treatment and risk of borderline ovarian tumors. Gynecol Endocrinol. 2007;23:373–376. doi: 10.1080/09513590701350341. [DOI] [PubMed] [Google Scholar]
- 26.Kurta ML, Moysich KB, Weissfeld JL, Youk AO, Bunker CH, Edwards RP, Modugno F, Ness RB, Diergaarde B. Use of fertility drugs and risk of ovarian cancer: results from a u.s.-Based case-control study. Cancer Epidemiol Biomarkers Prev. 2012;21:1282–1292. doi: 10.1158/1055-9965.EPI-12-0426. [DOI] [PMC free article] [PubMed] [Google Scholar]