Doi:10.1016/s0015-0282(02)04950-6

FERTILITY AND STERILITY௡
Copyright 2003 American Society for Reproductive Medicine Printed on acid-free paper in U.S.A.
Infertility drugs and the risk of breast
cancer: findings from the National Institute
Received July 2, 2002;revised and accepted of Child Health and Human Development
September 24, 2002.
Supported by contractsfrom the Contraception Women’s Contraceptive and Reproductive
and Reproductive HealthBranch, Center for Experiences Study
Population Research,National Institute of ChildHealth and Human Ronald T. Burkman, M.D.,a Mei-Tzu C. Tang, Ph.D.,b Kathleen E. Malone, Ph.D.,b Development, NationalInstitutes of Health, Polly A. Marchbanks, Ph.D.,c Jill A. McDonald, Ph.D.,c and Suzanne G. Folger, Ph.D.c National Cancer Institute Surveillance, Epidemiology, and End Results Registries, Atlanta, Georgia, Detroit, Michigan, Los Angeles, California, and Seattle, Washington; University of Pennsylvania, Philadelphia, Pennsylvania; Centers for Disease Control and Prevention, Atlanta, Georgia; and National Institute of Child 3-3174, N01 HD 3-3176,and N01 HD 3-3175), an Health and Human Development, Bethesda, Maryland Objective: To determine the association between infertility drug use and invasive breast cancer in a
the Centers for DiseaseControl and Prevention population-based case– control study.
Design: Multicenter case– control study.
Setting: Women aged 35 to 64 years in metropolitan Atlanta, Detroit, Los Angeles, Philadelphia, and Seattle.
by the Surveillance,Epidemiology, and End Patient(s): The 4,575 case patients had histologically confirmed primary invasive breast cancer. The 4,682
control subjects were women without breast cancer identified in the same geographic locations using N01 CN-65064, N01 PC-57010, and N01 PC-67006).
Intervention(s): A standardized questionnaire focusing on reproductive health and family history as well as
use of oral contraceptives and other hormones and infertility drugs was administered to all subjects. Data on the type of breast cancer were also obtained.
Main Outcome Measure(s): Odds ratios examining the association between use of various infertility drugs
Health, Centers for DiseaseControl and Prevention, or Result(s): Overall, a history of infertility drug use was not associated with the risk of developing breast
cancer. Compared with women who never used any fertility medication, however, women using human menopausal gonadotropin (hMG) for Ն6 months or for at least six cycles had a relative risk of breast cancer Conclusion(s): Long-term use of certain infertility drugs could adversely affect risk of breast cancer.
Additional confirmatory studies are needed. (Fertil Steril௡ 2003;79:844 –51. 2003 by American Society for to: Ronald T. Burkman,M.D., Department of Key Words: Breast cancer, infertility, infertility drugs, human menopausal gonadotropins (hMG)
Gynecology, BaystateMedical Center, 759Chestnut Street,Springfield, Massachusetts Other authors include: Sandra A. Norman, Ph.D., and Brian L. Strom, M.D., Center for Clinical Epidemiology and Bio- have regarding breast cancer, investigators are statistics, Department of Biostatistics and Epidemiology, continuing their efforts to identify risk factors University of Pennsylvania, Philadelphia, Pennsylvania; Le- slie Bernstein, Ph.D., and Giske Ursin, M.D., Department of for the disease, especially those that are poten- Preventive Medicine, Keck School of Medicine of the Uni- tially modifiable. Toward this end, the relation- versity of Southern California, Los Angeles, California; Linda K. Weiss, Ph.D., Karmanos Cancer Institute at WayneState University, Population Studies and Prevention Pro- Research Center, Seattle,Washington.
gram, Detroit, Michigan (now at the National Cancer Insti- tute, Organ Systems Branch, Bethesda, Maryland); Janet cycle characteristics and infertility, including R. Daling, Ph.D., Fred Hutchinson Cancer Research Center, various treatment approaches, have also been Seattle, Washington; Michael S. Simon, M.D., Division ofHematology and Oncology, Karmanos Cancer Institute at Wayne State University, Detroit, Michigan; and Robert Spir- studies indicate that increased numbers of ovu- tas, Dr.P.H., Contraception and Reproductive Health latory menstrual cycles may increase the risk of Branch, Center for Population Research, National Institute of Child Health and Human Development, Bethesda, Maryland.
ings that elevated risk of breast cancer is associated with match case interview frequencies within the strata of study early menarche and late menopause, occurrences that prob- center, race, and age group. Interviews were completed on ably increase the lifetime number of ovulatory menstrual 4,575 of 5,982 eligible cases (76.5%) and 4,682 of 5,956 cycles In addition, studies indicate that peak mitotic activity occurs in breast cells during the luteal phase of the All study subjects were interviewed in person using a menstrual cycle Thus, increasing the number of ovula- detailed questionnaire. Sections dealing with hormone use tory cycles would extend periods of increased mitotic activ- were modeled after instruments used in prior studies to obtain detailed histories on use of oral contraceptives, hor- Women with infertility due at least in part to ovulatory mone replacement therapy, and other hormones. The ques- dysfunction may undergo various drug treatments that stim- tionnaire also obtained detailed information on demograph- ulate ovulation and alter levels of endogenous reproductive ics; pregnancy and reproductive history; exercise, health, hormones. Although some prior studies failed to demonstrate and family history of cancer; smoking and alcohol use; and an association between pharmacologic therapy for infertility other factors. In addition, we collected information on his- and breast cancer risk others have shown an tory of infertility and infertility drug use.
association As part of a multicenter, population- Women were asked if they had ever visited a doctor, based, case– control study, the National Institute of Child clinic, or hospital because of a problem becoming pregnant, Health and Human Development (NICHD) Women’s Con- or to seek help in becoming pregnant. For women who traceptive and Reproductive Experiences (CARE) Study, we reported that they had sought medical help for becoming elected to analyze the relationship between use of various pregnant, information was collected on whether they or their drug therapies for infertility treatment and the risk of breast partner had tests performed for possible infertility, on the causes of the infertility, on whether they had been prescribedinfertility drugs, and on the types and duration of use of such MATERIALS AND METHODS
drugs if prescribed. Information on use of IVF or GIFTtechniques was also obtained. The interviews were con- The design and conduct of this study have been presented ducted in a standardized manner using extensively trained in detail elsewhere The study was conducted in five interviewers. Data on tumor characteristics including Inter- geographic regions: Atlanta, Detroit, Philadelphia, and Se- national Classification of Disease for Oncology (ICD-O) attle, as well as Los Angeles County. The protocol was codes, histologic type, extent of disease, laterality, and es- approved by institutional review boards at the field centers trogen and progesterone receptor status were collected on and by a Data Coordinating Center at the Centers for Disease Control and Prevention, Atlanta, Georgia. Case patients were Data Analysis
women newly diagnosed with breast cancer between July A multiple logistic regression model was used to deter- 1994 and April 1998. Except for Philadelphia, where case mine odds ratios (ORs) and confidence intervals (CI) as patients were identified by field staff, case patients were estimates of relative risks for breast cancer associated with ascertained by the National Cancer Institute’s Surveillance, infertility drug use Analyses involved adjustment for Epidemiology, and End Results (SEER) registry program age (in 5-year age groups), race (white, black), and study site using rapid-reporting systems. Younger case subjects and (5 study sites). The reference date for analyses was the date black women who were cases or controls were oversampled of breast cancer diagnosis for cases and the date of telephone to achieve a more uniform distribution across six age groups screening for controls. Evaluation by a health professional was required for a subject to be defined as being infertile.
Eligibility criteria for cases included the following: age Women were considered to have been diagnosed with infer- 35 to 64 years; presence of histologically confirmed, primary tility if they reported having had testing because of a prob- invasive breast cancer with no prior invasive or in situ breast lem becoming pregnant and if these tests detected a probable cancer history; US birth with residence at date of diagnosis cause. The causes included the following: problems with in a study region; white or black race (including Hispanic cervical mucus; other abnormalities of the cervix, uterus, ethnicity); a working telephone at the individual’s residence fallopian tubes, or ovaries; endometriosis; and endocrinolog- at date of diagnosis; ability to be interviewed in English; and ical dysfunction. Variables including first-degree family his- physical and mental capability to undergo the interview tory of breast cancer, body mass index, age at first full-term process. Other than the case-defining event (invasive breast pregnancy (Ͼ26 weeks of gestation), age at menarche, cancer), eligibility criteria for cases and controls were iden- smoking status, alcohol consumption, screening mammo- tical. Controls were identified from the same counties as gram in the past 2 years, income, education, and use of oral were the cases, through random-digit dialing using unclus- contraceptives and hormone replacement therapy did not tered sampling, with automated elimination of nonworking change the OR by Ն10% and therefore were not included in numbers. Control subject selection rates were designed to FERTILITY & STERILITY௡
Characteristics of cases and controls.
Alcohol use (number of drinks per week at Burkman et al.
Continued.
a Percentages calculated with nonmissing values.
b First-degree family history in mother, full sister, or daughter.
c Indicates whether women received test for fertility problem.
d Among women who were tested for infertility problem; some women were diagnosed with more than one infertility problem. For cases, n ϭ 416; forcontrols, n ϭ 467.
Burkman. Infertility drugs and breast cancer risk. Fertil Steril 2003. We examined whether there was an association between lobular), menopausal status, parity, and family history of infertility drug use and risk of breast cancer. We also exam- ined whether any association of infertility history or infer-tility drug use and breast cancer varied by the total durationor actual cycles (usually treatment within a 1-month interval) of each infertility drug use. In addition, we evaluated the When compared with controls, women with breast cancer possible modification of any association between breast can- were more likely to have had fewer full-term pregnancies, cer and infertility medication by histologic type (ductal vs.
their first full-term pregnancy at a later age, an earlier men- FERTILITY & STERILITY௡
arche, and a family history of breast cancer population-based case and control ascertainment through the Among 1,193 women who ever sought medical care for help SEER registries, and detailed data on a large number of becoming pregnant (576 cases and 617 controls), 71% (416 potential variables and effect modifiers. However, there are cases and 432 controls) had been tested for infertility, and weaknesses that pertain to the current analysis. The number 42% (229 cases and 269 controls) reported that a cause for of women reporting a history of infertility treatment includ- their infertility had been identified. Three hundred thirty- ing use of infertility drugs was small. The Women’s CARE seven women (179 cases and 158 controls) had had infertil- study was not primarily designed to extensively evaluate the ity testing, but no specific etiology had been identified. A association between infertility or use of fertility drugs and total of 184 cases (4.0%) and 200 controls (4.3%) reported breast cancer. The study, except for the breast cancer case ever using infertility drugs This included 79 cases ascertainment, did not survey or verify information from and 82 controls who, based on our definition of infertility, medical records. Finally, as is true in many case– control were never diagnosed with infertility but were prescribed studies, recall bias potentially could influence the risk esti- Overall, as shown in women who had ever used Another potential problem in our analysis is the difficulty infertility drugs had the same risk of breast cancer as did of distinguishing the effect of infertility from that of treat- women who had never used such medication (OR, 0.9; 95% ment for infertility. Among women who never used infertil- CI, 0.8 –1.2). Among women who had been diagnosed with ity medications, we found no association between a history infertility, use of infertility drugs was not associated with an of infertility and risk of breast cancer (OR, 0.9; 95% CI, overall increase in risk of breast cancer (OR, 1.2; 95% CI, 0.7–1.1; adjusted for age, race, and study site). To eliminate 0.8 –1.7). The OR did not vary substantially according to age the potential role of infertility, the analysis was confined to women who had been diagnosed with a specific infertility Within subgroups of women who used specific types of problem. The latter analysis was limited by the small number fertility drugs, an association was observed among women of women remaining after exclusion of 337 women with no who had used hMG (Pergonal; Serono Laboratories, Inc., specific infertility diagnosis. The results, however, were Norwell, MA) for Ն6 months or for at least six treatment similar if the analyses included these 337 women in the cycles (for all women: Ն6 months of use, OR, 2.1; 95% CI, infertility group. Among 384 women who used infertility 1.0 – 4.4; Ն6 cycles of use, OR, 2.7; 95% CI, 1.0 – 6.9; for drugs, 108 women (59 cases and 49 controls) had used two women with an infertility diagnosis: Ն6 months of use, OR, or more types of infertility medications. For these women, 2.8; 95% CI, 1.1– 6.8; Ն6 cycles of use, OR, 3.8; 95% CI, the main effect of each type of infertility drug may be 1.2–11.8). There was a suggestion of increased risk of breast difficult to differentiate. When we restricted our analyses to cancer for women with a prior diagnosis of infertility who women using only one infertility drug, the results were not had used clomiphene citrate (Clomid; Aventis Pharmaceuti- statistically significant because of small numbers of women.
cal Company, Bridgewater, NJ) for Ͻ6 months or for fewer Other investigators have evaluated the relationship be- than six treatment cycles (OR, 1.7; 95% CI, 0.9 –3.2 and OR, tween use of fertility drugs and breast cancer with mixed 1.7; 95% CI, 0.9 –3.0, respectively).
results. Brzezinski et al. identified 16 women in their Overall, a history of taking infertility drugs was not center in Israel between 1982 and 1991 who were treated associated with an increased risk of either invasive ductal or with either clomiphene citrate alone (2 cases) or in combi- invasive lobular breast cancer. However, compared with the nation with hMG (14 cases) and who subsequently were case of women who had never taken any infertility medica- diagnosed with breast cancer. Of interest to the current study tion, a greater risk of ductal carcinoma appeared to be is that 12 of the 14 women undergoing treatment with hMG associated with use of hMG (OR, 1.6; 95% CI, 1.0 –2.7; had been treated for at least six cycles, with a mean number Further, results were similar in strata of meno- of treatment cycles of 12.7. On the basis of an age-adjusted pausal status, parity, and family history of breast cancer estimate of expected cases of breast cancer using data from the Israel Cancer Registry, they noted that the observed rateof breast cancer in these women was about double that of the DISCUSSION
general population. However, this study is limited by the Overall, a history of infertility drug use was not associ- small number of cases and the use of a historical cohort ated with an increased risk of breast cancer. However, our study, based on a small number of women, did suggest that Braga and co-workers conducted a case– control study women who used hMG for Ն6 months or who used hMG for of breast cancer and potential risk factors in Italian women, at least six treatment cycles had a risk of breast cancer that and detected an OR of 1.43 (95% CI, 0.9 –2.3) for breast was two to three times greater than that of other women.
cancer in women who received drug therapy for infertility These results should be interpreted with caution. The compared with women who had never received such treat- particular strengths of the Women’s CARE study include the ment. However, this study was hampered by the small num- Burkman et al.
Risk of breast cancer and use of fertility medications.
Note: Excludes women with unknown history of fertility drug use. Data missing for women who cannot recall the duration/actual cycles of use.
a Odds ratio was relative to never taking any fertility medication; adjusted for age, race, and study site.
b The confidence interval does not include 1.0.
c Includes Danazol, Lupron Depot, Metrodin, and so on.
d Includes hormonal contraceptives and other hormones for infertility treatment.
Burkman. Infertility drugs and breast cancer risk. Fertil Steril 2003. FERTILITY & STERILITY௡
Risk of invasive breast cancer in relation to fertility medication use, according to histologic type.
Note: Excludes women with unknown history of fertility drug use. The tumors were grouped into their histologic types: [1] ductal, ICD-O code 8500; [2]lobular, ICD-O code 8520, or mixed lobular, ICD-O code 8522; and [3] other specific histologies including papillary, ICD-O code 8050, 8260, or 5603;tubular, ICD-O 8211; mucinous, ICD-O 8480 or 8481; and medullary, ICD-O 8510 or 8512.
a In each histologic group, odds ratio was relative to never taking any fertility drug; adjusted for age, race, and study site.
b The confidence interval does not include 1.0.
c Includes Danazol, Lupron Depot, Metrodin, and so on.
d Includes hormonal contraceptives and other hormones used for infertility treatment.
Burkman. Infertility drugs and breast cancer risk. Fertil Steril 2003. ber of subjects with a history of infertility. Potashnik et al.
whether duration effects were examined is unclear. Finally, also evaluated the role of fertility drugs using a historical in a case– control study of breast cancer in the greater Milan, cohort design among 1,197 women receiving infertility treat- Italy area that was conducted between 1983 and 1991, no ment in Israel between 1960 and 1984. When compared with association between fertility drug therapy and breast cancer the expected rate of breast cancer in the Israel Cancer Reg- was found However, the total number of cases and istry, the standardized incidence ratio for breast cancer was controls in the analysis relating to fertility drug use was increased only in patients undergoing one or two clomiphene citrate cycles (relative risk, 2.6; 95% CI, 1.2–5.0) and a total When Rossing and colleagues compared the number dose of the drug of Յ1,000 mg (relative risk, 2.5; 95% CI, of breast cancer cases in 3,837 women treated for infertility 1.2– 4.6). Of the 780 women receiving fertility drug therapy, in Seattle, Washington to that expected from population- only 177 received hMG in some form. Further, because only based data, they did not detect an elevated risk for breast 16 cases of breast cancer occurred in the 780 women under- cancer. In fact, the investigators found that the risk of breast going fertility drug therapy, one must be cautious about cancer was reduced (adjusted relative risk, 0.5; 95% CI attributing too much significance to the results of this study.
0.2–1.2) among users of clomiphene citrate, compared with Other studies have failed to show an association between women who had not used the drug, although this result was fertility drug treatment and breast cancer. Ron and co-work- not statistically significant. Because only 4.4% of women in ers evaluated the incidence of breast and female repro- this study had been exposed to hMG and the overall number ductive cancers through 1981 in a cohort of 2,632 Israeli of women receiving infertility drug treatment was low, the women treated for infertility between 1964 and 1974. Al- role of hMG in modifying the risk of breast cancer could not though they observed an excess of breast cancer cases in their cohort compared with that expected using data from the The potential mechanisms for the associations observed Israel Cancer Registry, the increase did not achieve statisti- in the current study are unclear. Fertility drugs have varying cal significance. Further, use of hMG or clomiphene citrate effects on hormonal output. The drug hMG consists of a alone or in combination did not affect this risk. However, mixture of follicle-stimulating hormone and luteinizing hor- these authors reported no data regarding the number of mone. Through stimulation of the ovary, the medication treatment cycles or duration of treatment.
produces plasma estradiol levels of 1,000 to 1,500 pg/mL Modan et al. continued follow-up of this same cohort daily and midluteal phase plasma progesterone levels of through 1991. Again, no association was reported between around 29 ng/mL In comparison, during natural use of clomiphene citrate or hMG and breast cancer, and menstrual cycles, peak estradiol levels infrequently exceed Burkman et al.
600 pg/mL, whereas luteal phase progesterone levels usually 6. Meirow D, Schenker JG. The link between female infertility and cancer: epidemiology and possible aetiologies. Hum Reprod Update do not rise above 20 ng/mL Thus, hMG may mediate risk of breast cancer through its effects on either of these two 7. Modan B, Ron E, Lerner-Geva L, Blumstein T, Menczer J, Rabinovici hormones. Although estrogen is reasonably accepted as a J, et al. Cancer incidence in a cohort of infertile women. Am JEpidemiol 1998;147:1038 –42.
promoter of breast cell proliferation and the development 8. Potashnik G, Lerner-Geva L, Genkin L, Chetrit A, Lunenfeld E, Porath and growth of some forms of breast cancer, the role of A. Fertility drugs and the risk of breast and ovarian cancers: results ofa long-term follow-up study. Fertil Steril 1999;71:853–9.
progesterone is still being debated Clomiphene citrate 9. Ricci E, Parazzini F, Negri E, Marsico S, La Vecchia C. Fertility drugs structurally resembles selective estrogen receptor modula- and the risk of breast cancer. Hum Reprod 1999;14:1653–5.
10. Ron E, Lunenfeld B, Menczer J, Blumstein T, Katz L, Oelsner G, et al.
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