1 Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, WA.
2 Department of Epidemiology, University of Washington, Seattle, WA.
3 Division of General Medicine, School of Medicine, Emory University, Atlanta, GA.
4 US National Cancer Institute, Bethesda, MD.
Received for publication March 22, 2004; accepted for publication August 23, 2004.
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ABSTRACT |
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Infertility; ovarian neoplasms
Abbreviations: Abbreviations: CARE, Womens Contraceptive and Reproductive Experiences; CI, confidence interval; OR, odds ratio; SEER, Surveillance, Epidemiology, and End Results.
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INTRODUCTION |
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We conducted a population-based, multicenter, case-control study among women aged 3554 years to assess the influence of infertility and use of ovulation-inducing drugs on risk of ovarian cancer. The limited age range of partipants reflected the availability of ovulation-inducing drugs during the reproductive ages of women during the years in which the study was conducted: clomiphene citrate was first approved for use in the United States in 1967 (5), and other regimens of ovulation induction came into use even more recently.
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MATERIALS AND METHODS |
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Women eligible to be interviewed as cases for this study included English-speaking, White or Black female residents of King County, Washington; Wayne, Oakland, or Macomb counties, Michigan; or Fulton, Cobb, or Dekalb counties, Georgia, who were 3554 years of age when diagnosed with a SEER Program-reportable, first primary borderline ovarian tumor from July 1994 or first primary invasive ovarian cancer from July 1995 through June 1998. Women without a residential telephone at the time of diagnosis were considered ineligible, because random digit telephone dialing was used to select controls. Eligible case women were identified through the population-based SEER Program tumor registries in each area. The registries supplied information regarding the histologic type of cancer and the degree of invasiveness (i.e., borderline or invasive). Borderline ovarian tumors (also referred to as tumors of low malignant potential) considered reportable to the SEER Program during the years in which the study was conducted were those with International Classification of Diseases for Oncology, Second Edition (7), codes of 8442/3 (serous cystadenoma, borderline), 8451/3 (papillary cystadenoma, borderline), 8462/3 (papillary serous cystadenoma, borderline), 8472/3 (mucinous cystadenoma, borderline), or 8473/3 (papillary mucinous cystadenoma, borderline).
A total of 406 cases were interviewed of the 547 women eligible for interview (74.2 percent). Thirty-two women were not contacted because their physician declined permission for their contact, 63 chose not to participate, 22 were not located by the study staff, and 24 died before they could be interviewed. Because controls were women without a previous diagnosis of breast cancer and were required to be born in the United States, we excluded from these analyses interviewed case women who reported a prior history of breast cancer (n = 16) or who were foreign-born (n = 12), resulting in 378 cases available for analysis. Based on the tumor histologies recorded by the SEER Program registries and a published histologic grouping system (8), 355 (93.9 percent) cases had epithelial ovarian tumors, and of these, 213 (60.0 percent) were invasive. Serous tumors were the most common histologic subtype of epithelial tumors (n = 201; 56.6 percent), and 65 (18.3 percent of epithelial tumors) were mucinous.
Only those CARE Study controls who were residents of the Seattle, Atlanta, or Detroit metropolitan area counties listed above and were aged 3554 years at reference were considered potentially eligible (n = 2,228). Of those women, interviews were obtained from 1,828 (82.0 percent). After the exclusion of interviewed women who reported having had a bilateral oophorectomy (n = 176) or ovarian cancer (n = 6) prior to the reference date and nine women who were uncertain whether they retained at least one ovary at that date, 1,637 women were included in this study as controls.
Cases and controls received a letter of approach that described the study and invited their participation. The letter was followed by telephone contact with an interviewer who scheduled an in-person interview with the subject if she was willing. All participants signed a consent form prior to interview. Information collected at interview pertained to the period of time before ovarian cancer diagnosis (for cases) or before an assigned, comparable reference date (for controls) and covered the following: demographic and lifestyle characteristics; medical history; family history of cancer; and detailed reproductive history, including menstrual, pregnancy, and contraceptive history, use of noncontraceptive hormones, and testing and treatment for infertility. To aid recall, interviewers used a calendar to record major life events as well as time intervals of pregnancy, breastfeeding, and use of various contraceptive methods. In addition, interviewers provided lists and photographs of commonly used oral contraceptive and hormone replacement preparations and lists of fertility medications. Cases and controls were administered nearly identical questionnaires, except for the addition of questions regarding the circumstances that led to the diagnosis of ovarian cancer and deletion of questions regarding detailed mammographic history among cases. Control interviews were conducted from September 1994 through December 1998; because of later availability of funding for case interviews, these were conducted from January 1996 through July 1999.
To identify women with possible fertility problems, interviewers examined the life-events calendar for time periods at least 12 months long (after menarche and before the first occurrence of tubal ligation, hysterectomy, or last reported menstrual period) when the study participant was not pregnant, breastfeeding, or using birth control (including male contraceptive methods) or noncontraceptive hormones. For each of these intervals, women were asked whether they were at risk of becoming pregnant, that is, having regular sexual intercourse (three or more times per month) with a male partner. The dates of all such intervals were recorded. Moreover, women were asked if they had ever visited a physician, clinic, or hospital because of a problem becoming pregnant or to seek help in becoming pregnant. For women who reported that they had sought such medical attention, information was collected on whether they or their partner had had infertility testing performed, the basis for their infertility, and the types and durations of infertility medications received. Information regarding use of assisted reproductive technologies, such as artificial insemination, in vitro fertilization, and gamete intrafallopian transfer, was also collected. At interview, female causes of infertility were classified into the following types of abnormalities: cervical mucous; fallopian tube; ovarian, including cysts or anovulation; hormonal, including luteal phase defect; uterine; endometriosis; or other.
Unconditional logistic regression was used to calculate odds ratios as estimates of the relative risk of ovarian cancer associated with the exposures of interest while controlling for the confounding effects of other variables. Parameter estimates were computed by maximum likelihood techniques, and 95 percent confidence intervals were based on the standard error of the coefficients and the normal approximation (9). We assessed the odds ratio of ovarian cancer associated with various definitions and aspects of infertility separately among nulliparous and parous women. All analyses were adjusted for the CARE Study frequency-matching variables of age (5-year groups), race (White or Black), and study site. Analyses among nulliparous women were additionally adjusted for duration of oral contraceptive use and, among parous women, for duration of oral contraceptive use and number of full-term births. Other characteristics examined as potentially confounding or modifying the associations of interest included education, marital status, diagnosis/reference year, number of pregnancies, duration of breastfeeding, body mass index, tubal ligation, hysterectomy, family history of breast cancer, and family history of ovarian cancer. None of these latter variables importantly influenced relative risk estimates.
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RESULTS |
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Among nulliparous women, the risk of ovarian cancer associated with a history of infertility was most apparent among women who had had one or more incomplete pregnancies (for infertility and infertility first identified at 30 years of age: adjusted ORs = 3.0 (95 percent CI: 1.3, 7.2) and 3.6 (95 percent CI: 1.3, 10.4), respectively). This elevation in risk was similar regardless of whether the termination of pregnancy was spontaneous or induced, or whether a pregnancy occurred before or after the last infertility episode. Among parous women, risk was not elevated among women who did or did not give birth after the last infertility episode.
We also assessed risk associated with alternative definitions of infertility, including the following: seeking medical care related to a problem in becoming pregnant; having medical testing related to infertility; diagnosis of female infertility (i.e., excluding infertility due only to a problem of the male partner); and diagnosis of specific types of female infertility. Among cases and controls who had never experienced infertility according to our initial definition of this condition (i.e., an interval of greater than 12 months during which a woman at risk of pregnancy reported engaging in regular intercourse without contraception or conception), 6 percent of each group reported seeking care for fertility problems. Among women who had experienced such infertility, 41.3 percent of cases and 31.1 percent of controls sought care. Among nulliparous women only, risk was somewhat elevated among women who had ever sought care for a fertility problem (OR = 1.5, 95 percent CI: 0.9, 2.8). However, risk of ovarian cancer was not associated with a womans receipt of testing for infertility, the diagnosis of female infertility, or the diagnosis of any specific type of female abnormality leading to infertility (table 3). Similar results were obtained in analyses that compared women who had sought care for infertility with the subgroup of women who had neither sought care for infertility nor had had a greater than 12-month interval at risk of pregnancy. In addition, results were similar when analyses were conducted separately for borderline and invasive tumors and in analyses restricted to nonmucinous epithelial tumors. When the analyses shown in table 3 were conducted among the subgroup of women who had experienced infertility (again, defined as a >12-month interval at risk of pregnancy), the adjusted odds ratio among nulliparous women who sought care for infertility was 1.0 (95 percent CI: 0.4, 2.3), suggesting that nulliparous women who seek care for infertility are at no greater risk than nulliparous, infertile women who do not seek such care.
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DISCUSSION |
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Many prior ovarian cancer studies have been restricted to epithelial types, which accounted for over 90 percent of our case group. Because this study was designed to assess risk associated with infertility and use of ovulation-inducing drugs, and because some previous studies suggested an association of fertility drug use with the occurrence of both epithelial and nonepithelial ovarian tumors (2, 11, 12), we included all histologic types of ovarian cancer. Our results were similar when restricted to epithelial tumors.
Infertility has been variously defined (13), and we analyzed risk according to multiple definitions of this condition. Based on the occurrence of one or more intervals of infertility, 37.4 percent of controls in the current study had a history of this condition, while 15.1 percent reported having sought care for fertility-related problems; 6.5 percent were diagnosed with a specific female-derived basis for infertility while, for 1.7 percent of women, a male abnormality was the only diagnosed cause. These proportions are similar to those reported in a prior population-based study of women aged 2054 years (13).
Prior studies that have adjusted for confounding by oral contraceptive use and other factors have generally not found a strong overall association of infertility with risk of ovarian cancer. However, several studies have reported an increased risk among a subgroup of nulliparous or nulligravid women. In a combined analysis of case-control data, Whittemore et al. (2) suggested that a subgroup of infertile women with long periods of unprotected intercourse and/or prior use of infertility medications may be at increased risk. Ness et al. (4), in a subsequent combined analysis of case-control studies (including data from Risch et al. (1) discussed separately below), also reported an increased risk among women with a long lifetime duration of years of attempted conception. In both studies, the increased risk was more apparent among nulligravid than gravid women. In a prospective cohort study of women who were unlikely to have been exposed to ovulation-inducing drugs, Rodriguez et al. (3) reported an increased risk of fatal ovarian cancer in nulligravid women who reported that their infertility was related to a female, rather than male, abnormality, while no increase in risk associated with infertility was observed in gravid women. Risch et al. (1) observed an increased risk associated with a late age at recognition of infertility among nulliparous, but not parous, women, in a population in which no cases and only two controls reported use of an ovulation-inducing drug.
Similar to other researchers, we observed an increased risk associated with infertility among nulliparous, but not parous, women. Among nulliparous women, risk associated with infertility was particularly evident among women whose infertility was first recognized at an older age and among women who had conceived but had not given birth. We observed no association with a particular type of female abnormality leading to infertility or with receipt of fertility drugs, among either nulliparous or parous women. While some prior studies have reported associations with infertility due to the female, but not male, partner (3) or with particular subtypes of female infertility (most studies reviewed by Klip et al. (14); see also Ness et al. (4)), these associations have been inconsistently observed. The results of studies examining the relation of fertility drug use with ovarian cancer have also been inconsistent (most studies reviewed by Glud et al. (15); see also Ness et al. (4)). In a prior cohort study (16), we observed an increased risk of developing a borderline or invasive ovarian tumor among women with long-term use of clomiphene (12 cycles), although this association was statistically imprecise (relative risk = 11.1, 95 percent CI: 1.5, 82.3). Most studies, including the current one, have had a very limited ability to assess the effect of long-term use of clomiphene or other ovulation-inducing drugs.
Nieto et al. (17) hypothesized that infertility and ovarian cancer might both be consequences of a common underlying genetic abnormality, particularly among nulliparous women. The suggestion in our data that risk was greatest among nulliparous women whose first infertility episode occurred relatively late in reproductive life does not readily support this hypothesis, as it seems unlikely that an inherited basis for infertility (that also increased ovarian cancer risk) would become manifest only at an older age. Further, a first-degree family history of ovarian or breast cancer was reported by similar proportions of cases with (2.1 percent and 7.9 percent, respectively) or without (3.6 percent and 9.3 percent) a history of infertility.
Low levels of progesterone during a womans reproductive years have been proposed to increase the risk of ovarian cancer (18), and inability to carry a pregnancy to term late in reproductive life has been proposed as a marker of progesterone deficiency (19). Conceivably, the increased risk we observed in nulliparous women who experienced an infertility episode relatively late in reproductive life may reflect the occurrence or onset of a progesterone deficiency. However, while progesterone deficiency may in part account for the relatively greater increase in risk we observed among infertile nulliparous women who had been pregnant at least once, such women were at a similar risk regardless of whether their pregnancies ended in spontaneous or induced abortion.
The current study adds support to the hypothesis that a subset of women who experience infertility may be at increased risk of ovarian cancer. As in other studies, the proportion of women at increased risk appears to be fairly low. In this study, 6.0 percent of controls and 11.1 percent of cases were nulliparous women who were classified as infertile on the basis of a joint consideration of their reproductive, contraceptive, and sexual histories; even lower percentages of women elected to seek medical care for infertility. Although this study and other studies have attempted to determine whether the observed increase in risk of ovarian cancer among nulliparous, infertile women is related to the pathologic basis for the infertility, the use of ovulation-inducing drugs, shared genetic susceptibility to infertility and ovarian cancer, or some other unrecognized factor, the reason for this increase in risk remains unclear.
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NOTES |
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REFERENCES |
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