Research www AJOG.org REPRODUCTIVE ENDOCRINOLOGY AND INFERTILITY Breast cancer incidence after hormonal infertility treatment in Sweden: a cohort study Chantal C Orgéas, MPH; Karin Sanner, MD; Per Hall, MD, PhD; Peter Conner, MD, PhD; Jan Holte, MD, PhD; Staffan J Nilsson, MD; Karin Sundfeldt, MD, PhD; Ingemar Persson, MD, PhD; Kee Seng Chia, MD, PhD; Sara Wedren, MD, PhD; Paul W Dickman, PhD; Kamila Czene, PhD OBJECTIVE: To assess the impact of infertility treatment with causes of infertility on incidence of breast cancer STUDY DESIGN: Historical prospective cohort study of 1135 women attending major university clinics for treatment of infertility in Sweden, 1961-1976 Women were classified as users of clomiphene citrate or gonadotropins, or a combination of both therapies Standardized incidence ratios were calculated to estimate relative risk of breast cancer incidence ratio, 1.90; 95% confidence interval, 1.08-3.35) This association was more pronounced among women referred for nonovulatory factors, with 3-fold increased risk (standardized incidence ratio, 3.00; 95% confidence interval, 1.35-6.67) CONCLUSION: No overall increased risk for breast cancer was shown with infertility treatment Women with nonovulatory causes treated with high-dose clomiphene citrate therapy may have an elevated risk for breast cancer RESULTS: We observed 54 cases of breast cancer during 1961-2004, which did not significantly exceed those expected Users of high-dose clomiphene citrate had an almost 2-fold increased risk (standardized Key words: breast cancer, cohort, hormone infertility treatment, incidence, Sweden Cite this article as: Orgéas CC, Sanner K, Hall P, et al Breast cancer incidence after hormonal infertility treatment in Sweden: a cohort study Am J Obstet Gynecol 2009;200:72.e1-72.e7 T he role of female sex hormones in breast carcinogenesis is well established Recently, it has been shown that users of exogenous hormones, in particular menopausal hormone therapy, are at an increased risk of breast cancer; that risk increases with duration of use; and that risk is substantially greater for com- bined estrogen-progestin than for estrogen-only therapy.1-5 In addition, reproductive factors, such as parity and age at first birth, are vital in determining a woman’s lifetime risk of breast cancer.6 In contrast, the effects of infertility treatment on breast cancer risk remain uncertain In a large review, Venn et al7 From the Department of Medical Epidemiology and Biostatistics (Ms Orgéas, Drs Sanner, Hall, Persson, Wedren, Dickman, and Czene), Karolinska Institute, and the Department of Obstetrics and Gynecology (Dr Conner), Karolinska University Hospital, Stockholm, Sweden; the Department of Women’s and Children’s Health, Women’s Clinic-Obstetrics and Gynecology (Dr Sanner), Uppsala University Hospital, Carl von Linne Kliniken (Dr Holte), and Medical Products Agency (Dr Persson), Uppsala, Sweden; the Center for Clinical Research, Dalarna, and the Department of Women’s and Children’s Health, Women’s ClinicObstetrics and Gynecology (Dr Nilsson), Falun, Sweden; and the Department of Obstetrics and Gynecology (Dr Sundfeldt), Institute for Clinical Sciences, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden; and the Center for Molecular Epidemiology, Yong Loo Lin School of Medicine, National University of Singapore (Ms Orgéas and Dr Chia) and the Genome Institute of Singapore (Dr Chia), Republic of Singapore Received March 14, 2008; revised June 27, 2008; accepted Aug 29, 2008 Reprints: Chantal C Orgéas, MPH, Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Box 281, SE-17177, Stockholm, Sweden Chantal.Orgeas@ki.se This study was supported by the Swedish Cancer Society, Stockholm, Sweden Ms Orgéas is currently in the Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden 0002-9378/$36.00 • © 2009 Mosby, Inc All rights reserved • doi: 10.1016/j.ajog.2008.08.066 72.e1 American Journal of Obstetrics & Gynecology JANUARY 2009 found that a majority of studies investigating infertility, fertility drug treatments, and breast cancer risk revealed no excess risk compared with the general population Clomiphene citrate and gonadotropins, used commonly in infertility treatment, produce changes in intrinsic sex hormone levels, with possibly different effects on the breast However, not only the treatments but also the underlying causes of infertility are associated with alterations in hormonal profiles, thereby having the potential to influence breast cancer risk.8-11 Increased breast cancer risks have been recently reported among nulliparous users of gonadotropins;12 users of clomiphene citrate,13 with the association restricted to women with nonovulatory disorders;14 along with an inverse association between breast cancer and infertility because of ovulatory disorders only.15 Another study reported an increased risk of breast cancer among long-term users of gonadotropins but no increased risk among users of clomiphene, after accounting for underlying causes of in- www.AJOG.org Reproductive Endocrinology and Infertility Research related conditions as infertility All patients were either referred by their primary physician or attended the clinics independently FIGURE Schematic representation of construction of the study cohort and corresponding databases involved Exposure information Pharmaceutical drugs used for hormonal infertility treatment in this study cohort were as follows: clomiphene citrate (CC), human chorionic gonadotropin (hCG), human menopausal gonadotropin (hMG), and follicle-stimulating hormone (FSH) Other abstracted data included: reasons for referral to infertility treatment, age at registration, menstruating pattern, bleeding disorders, pregnancies, abdominal/pelvic surgeries and radiographs, and use of oral contraceptives Information on parity and age at first birth was obtained from the Fertility Register In red, all women seeking treatment for any type of menstrual disturbances, not necessarily only infertility, and attending of major clinics of obstetrics and gynecology; in yellow, women eventually desiring pregnancies with difficulty conceiving retained in the cohort; in green, cohort data sent to Statistics Sweden for record linkage with registers held by the bureau; in blue, final cohort of 1135 women with clinical and registry-based data Orgéas Breast cancer incidence after hormonal infertility treatment Am J Obstet Gynecol 2009 fertility, although the study relied on patients’ reports of drug exposures.16 Given the increase in number of women seeking hormonal infertility treatment, emerging information on the adverse effects of infertility treatment are of public health concern In this historical prospective cohort study, we assessed the impact of hormonal infertility treatment and reasons for referral to treatment on the incidence of breast cancer, while accounting for age, calendar period of breast cancer diagnosis, parity, and age at first birth M ATERIALS AND M ETHODS The study cohort The cohort comprised 1135 women treated for subfertility-associated disorders who attended the major clinics of obstetrics and gynecology in Stockholm, Gothenburg, and Uppsala in Sweden between 1961 and 1976 (Fig- ure 1) All women with any history of menstrual problems, irregular periods, or absence of periods during their lifetime were identified These women were not necessarily seeking treatment for infertility, however, sought medical help for any menstrual disturbances through their physicians Of all the women with menstrual problems, those who did eventually wish to conceive were retained in our cohort Record linkage was performed by Statistics Sweden in 2006, using the individual unique national registration number assigned to all Swedish residents The cohort was linked with the national Swedish Cancer Register, Population Migration Register, and the Fertility Register to comprise the final cohort Strictly speaking, a woman who eventually conceives and delivers is only subfertile; however, for simplicity, we will refer to all fertility- Classification of eposures In the analyses, we defined CC as an exclusive exposure group, whereas hCG, hMG, and FSH were combined as exposure to gonadotropins collectively In clinical practice, if FSH or hMG is prescribed, hCG is often given concurrently As the biologic potency varied between different gonadotropins used in the study cohort, we chose to state the number of menstrual cycles during the hormonal infertility treatment administered, as a measure of exposure dosage For exclusive users of CC or gonadotropins, we classified dosage as low, comprising 1-3 treatment cycles; and high, comprising or more treatment cycles The general composition of pharmaceutical treatment prescribed during the study period was evaluated from medical records The type and composition of gonadotropins used varied During the first half of the 1960s, the FSH used was extracted from human pituitary glands by using necropsy material The dosage was approximately 150-450 units, administered during 5-10 days in the preovulatory phase Ovulation was then induced by administering hCG during day or over several days The dose of hCG varied between 5000-10,000 units During the second half of the 1960s, hMG, extracted from the urine of post- JANUARY 2009 American Journal of Obstetrics & Gynecology 72.e2 Research Reproductive Endocrinology and Infertility menopausal women, was introduced The dosage of hMG was approximately the same as for FSH.17 Treatment was monitored by the assessment of cervical mucus and bimanual palpation of ovarian size until the late 1960s, when it became possible to determine levels of estrogen present in the urine on a daily basis.18 Ovulation was subsequently induced by administering hCG during day or over several days Stimulation of ovulation using CC was initiated during the 1960s Women who were treated with a combination of both CC and gonadotropins were mainly given a combination of various doses of CC and hCG.19 Causes of infertility were assessed by a gynecologic endocrinologist after a complete assessment of the patient’s medical history, full blood tests of sex hormones, temperature charts, sperm analyses, laparoscopy, and radiographs, if required Reasons for referral to the infertility clinics were categorized into the following: suspected ovulatory factors, mechanical factors, and other factors For simplicity, herein we will refer to all suspected ovulatory factors as ovulatory factors Ovulatory factors were defined as a diagnosis of anovulation or amenorrhea (Ͼ months between cycles), oligomenorrhea (35-90 days between cycles), polycystic ovary syndrome/SteinLeventhal syndrome, and hirsutism Mechanical factors included cervical competence factors and abnormalities of the fallopian tubes or uterus Other factors included endometriosis, habitual abortions, immunologic factors, and unexplained infertility Further, we dichotomized these into those presenting with ovulatory factors and those presenting with nonovulatory factors, comprised of mechanical and other factors combined, based on women with nonovulatory factors presenting with intrinsic baseline hormonal levels similar to the hormone levels in normally ovulating women Women could occasionally present with cause of ovulatory and cause of inovulatory; however, among these women, the cause was primarily listed as ovulatory Women who were grouped as having inovulatory factors had no coexisting ovulatory factors Women 72.e3 with nonovulatory causes of infertility were administered ovulation stimulation drugs for treating infertility as a second-line therapy when pregnancy had not been achieved All patient records and classifications of exposures were discussed by experienced gynecologists in our group (I.P., S.N.) Follow-up Follow-up commenced on the date of first hormonal treatment Information obtained from the Swedish Cancer Register used to ascertain all cases of breast cancer from Jan 1, 1961 through Dec 31, 2004, included the date of cancer diagnosis, with breast cancers coded according to the International Classification of Diseases (ICD) The reporting and registration of incident cancers is based on mandatory reporting from both public and private health care providers,20 and overall reporting to the registry is estimated to be 98% of all diagnosed cases.21 End of follow-up was recorded as the date of diagnosis of primary breast cancer, date of death, date of emigration, or Dec 31, 2004, whichever occurred first Information on parity and age at first birth was obtained from the Fertility Register, established in 1971 This register included information concerning women born in 1925 and later On the basis of the nationwide reporting of all births of women resident in Sweden, the data are of high quality.22 Statistical methods Standardized incidence ratios (SIRs)— the ratio of the observed number of breast cancer cases to the expected number of breast cancer cases, according to breast cancer rates observed in the total population of Swedish women—were calculated as an estimate of the relative risk Population breast cancer rates taking parity and maternal age at first birth into consideration were derived from the linkage between the Swedish Cancer Register and the Multi-Generation Register The Multi-Generation Register provides links to all parents of children born from 1932 onward and registered at any time since 1961 This register has been described in detail elsewhere.23 In- American Journal of Obstetrics & Gynecology JANUARY 2009 www.AJOG.org formation pertaining to age at first birth and parity from the Multi-Generation Register is identical to the Fertility Register, as these registers are constantly updated against each other in Sweden The expected number of breast cancer cases was derived by multiplying the observed number of person-years contributed by all individuals in the cohort with incidence rates dependent on age (5-year intervals), calendar periods (5-year intervals commencing in 1961-2004), parity (nulliparous, 1, 2, 3, and or more children), and age at first birth (5-year intervals) The SIRs and their corresponding 95% confidence intervals (CI) were based on the assumptions that the observed number of cancer cases follows a Poisson distribution.24 Written informed consent was obtained from all women who agreed to participate in the study after being contacted by their treating physicians in Uppsala, Göteborg, and Stockholm The institutional review board of the Karolinska Institute, Stockholm, Sweden, approved the study R ESULTS Of all 1135 women exposed to any hormonal treatment, 24% remained nulliparous and 76% were parous after the end of treatment (Table 1) A total of 67% of women presented with ovulatory dysfunction, 5% for mechanical factors, and 28% for other subfertility-related factors (Table 1) The median age at diagnosis was 53 years (Table 2) Overall, we observed 54 cases of breast cancer in the study cohort (5%), which did not statistically significantly exceed those expected numbers derived from the general population of Swedish women after adjustment for attained age, calendar period of breast cancer diagnosis, age at first birth and parity (SIR, 1.01; 95% CI, 0.77-1.31) (Table 3) All rates in which only attained age and calendar period of diagnosis were adjusted for yielded higher incidence ratio estimates in all groups compared with the fully adjusted rates for additional parity and age at first birth Predominantly, exclusive users of the CC-only therapy and users of combined CC and gonadotropin Reproductive Endocrinology and Infertility www.AJOG.org Research TABLE Characteristics of the study cohort comprising 1135 women attending infertility clinics in Sweden between 1961 and 1976, with follow-up to Dec 31, 2004, by reason for referral to treatment Reason for referral to treatment Background characteristics All women with infertility Mechanical factorsb Ovulatory factorsa Other factors,c median Age at menarche (y) 13 13 13 13 Age at first birth (y) 29 28 29 30 Age at start of treatment (follow-up) (y) 27 26 29 30 d Parity before start of treatment n (%) 733 (85) 533 (87) 30 (82) 170 (80) 101 (12) 67 (11) (16) 28 (13) 28 (3) 13 (2) (2) 14 (7) Ն children Final parity at the end of treatment 273 (24) 147 (19) 25 (40) 101 (32) 249 (22) 148 (19) 18 (29) 83 (26) Ն children 613 (54) 465 (62) 19 (31) 129 (42) Exposure characteristics Any exposure to hormonal treatment 1135 (100) 760 (67) 62 (5) 313 (28) CC only 390 (34) 245 (63) 43 (11) 102 (26) Gonadotropins only 311 (27) 209 (67) (2) 95 (31) Both (CC and gonadotropins) 434 (38) 306 (70) 12 (3) 116 (27) CC, clomiphene citrate a Ovulatory factors include: diagnosis of anovulation or amenhorrhea, oligomenorrhea or polycystic ovary syndrome/Stein-Leventhal syndrome, and hirsutism b Mechanical factors include: cervical factors and abnormalities in the fallopian tubes or uterus c Other factors include: endometriosis, habitual abortions, immunologic factors, and unexplained fertility d Among parous women Orgéas Breast cancer incidence after hormonal infertility treatment Am J Obstet Gynecol 2009 therapy had slightly elevated risks, albeit nonsignificantly (SIR, 1.15; 95% CI, 0.73-1.80; and SIR, 1.28; 95% CI, 0.871.88; respectively) Users of gonadotropins-only therapy had a 47% decreased risk of breast cancer, which was significant When investigating the effects of CC by dose, users of high-dose CC had an almost 2-fold increased risk of breast cancer (SIR, 1.90; 95% CI, 1.08-3.35) In women treated with any hormonal treatment, the absolute risk of developing breast cancer overall was 7.6% by age 70 years (data not shown) Overall, women referred for nonovulatory reasons had a 32% nonsignificant excess risk of breast cancer associated with any exposure to hormonal treatment, compared with an 18% nonsignificantly reduced risk among women referred for ovulatory reasons (Table 4) All estimates for type of hormonal treatment and dose cycles were consistently higher among women referred for nonovulatory factors compared with those referred for ovulatory factors Women referred for nonovulatory factors had a 3-fold increased risk of breast cancer after or more cycles of CC only (SIR, 3.00; 95% CI, 1.35-6.67) Women referred for ovulatory factors had a 64% reduced risk of breast cancer with exclusive treatment of gonadotropins (SIR, 0.36; 95% CI, 0.14-0.97) C OMMENT We observed no overall increased risk for breast cancer in the 1135 women exposed to hormone infertility treatment after adjusting for the important confounding reproductive factors of age at first birth and total parity However, we consistently observed significantly increased risks in breast cancer incidence among those women who were adminis- tered high doses of CC exclusively We were able to evaluate the effects of the drug itself by underlying causes of infertility, as indicated by reasons for referral, and only observed a significant excess risk among exclusive users of high-dose CC therapy referred for nonovulatory factors We additionally observed a reduced risk of breast cancer among those women who were exclusive users of gonadotropin therapy; however, these results had limited statistical power In addition to its nationwide population-based nature, our study has other strengths The historical prospective design of this study allowed for unbiased, detailed collection of exposure data on fertility drug therapies prescribed A long period of follow-up of more than 30 years resulted in the recruitment of a relatively large number of breast cancer cases In addition, we were able to obtain national population rates of breast can- JANUARY 2009 American Journal of Obstetrics & Gynecology 72.e4 Research Reproductive Endocrinology and Infertility cer for Swedish women by age at first birth and total parity through the linkage of registries, enabling adjustment for these factors Notably, we observed that risk estimates for infertility treatment decreased for all fertility drug exposures after adjustment for the confounding effects of parity and age at first birth Our study has a number of limitations First, in subgroup analyses, the small number of breast cancer events and the consequent large 95% CIs make our conclusions more hypotheses generating, rather than a true report of association with breast cancer Other cohort studies encountered similar issues when investigating underlying causes of infertility.25,26 Second, the majority of studies, including the present one, lack adjustment for the confounding effects of obesity, which limits conclusions drawn in studies of infertility and fertility drugs in relation to breast cancer risk.27 Third, we did not have the possibility to investigate hormone replacement therapy (HRT) use; however, we have no reason to believe that HRT use within the cohort would be significantly different from that of the general population of Swedish women Fourth, the interpretation of our results for use of oral contraceptives is limited, as data on the use of oral contraceptives were confined to the study period and not based on a woman’s lifetime exposure Finally, our findings among exclusive users of CC and gonadotropins therapy may not be directly generalizable to the currently used methods for treating infertility today, with advanced assisted reproductive technologies, with regard to the preparation, cumulative dosage, and timing of administration The effects of CC have been reported to increase serum estradiol and progesterone levels in stimulated menstrual cycles.28 Based on the finding of an excess risk of breast cancer with CC treatment in this and other studies,13,14,26 we hypothesize that high-dose CC has the potential to increase estrogen and ultimately, progesterone in normal ovulating women, resulting in a possible increased risk of breast cancer One study found this increased risk confined to users of CC therapy only when treated with 72.e5 www.AJOG.org TABLE Characteristics of the study cohort comprising 1135 women attending infertility clinics in Sweden between 1961 and 1976, with follow-up to Dec 31, 2004, by breast cancer status Women without breast cancer number (range) Characteristic Total number of patients Women with breast cancer number (range) 1081 54 35,092 1322 Total number of person-years of follow-up Median age at start of treatment (y) (IQR) 27 (6) 28 (6) Median age at breast cancer diagnosis (y) (IQR) — 53 (12) Median time from start of treatment to breast cancer diagnosis (y) (IQR) — 26 (10) IQR, interquartile range Orgéas Breast cancer incidence after hormonal infertility treatment Am J Obstet Gynecol 2009 low doses and few cycles;26 however, that study did not adjust the outcome with age at first birth or parity Our study, which evaluated fertility drug treatment by underlying reasons for infertility, supports the notion that fertility drugs and reasons for treatment are independent risk factors for breast cancer.7-10,16,29 The higher risks observed among women referred for nonovulatory reasons compared with ovula- tory reasons, indicates that the drug therapies may be acting on normal intrinsic hormone levels for women referred with nonovulatory factors Any elevation in estrogen and progesterone levels attributable to drug treatment could hypothetically further increase estrogen and progesterone proliferative action on breast tissue.30 On the other hand, women referred for ovulatory factors have had irregular or absent men- TABLE Standardized incidence ratios and 95% CI for breast cancer among women undergoing hormonal infertility treatment in Sweden between 1961 and 1976, for total follow-up period to Dec 31, 2004, by exposure to hormonal treatment Variable Observed cases (n) SIR (95% CI)a SIR (95% CI)b Any exposure to hormonal treatment 54 1.16 (0.89-1.52) 1.01 (0.77-1.31) Type CC only 19 1.31 (0.83-2.05) 1.15 (0.73-1.80) 0.63 (0.33-1.20) 0.53 (0.28-1.00) 26 1.48 (1.01-2.17) 1.28 (0.87-1.88) Gonadotropins only Both (CC and gonadotropins) Dose cycles (n) CC only, low (1-3) 0.91 (0.43-1.91) 0.80 (0.38-1.68) CC only, high (4ϩ) 12 2.15 (1.22-3.79) 1.90 (1.08-3.35) Gonadotropins only, low (1-3) 0.58 (0.22-1.55) 0.49 (0.18-1.32) Gonadotropins only, high (4ϩ) 0.73 (0.30-1.76) 0.63 (0.26-1.51) CC, clomiphene citrate; CI, confidence interval; SIR, standardized incidence ratios a Rates adjusted for attained age and calendar period of cancer diagnosis only b Rates adjusted for attained age, calendar period of breast cancer diagnosis, total parity, and age at first term birth Orgéas Breast cancer incidence after hormonal infertility treatment Am J Obstet Gynecol 2009 American Journal of Obstetrics & Gynecology JANUARY 2009 Reproductive Endocrinology and Infertility www.AJOG.org TABLE Breast cancer among women undergoing hormonal infertility treatment in Sweden between 1961 and 1976 Ovulatory factors Variable Any exposure to hormonal treatment Nonovulatory factors Observed Observed cases, na SIR (95% CI)a,b cases, nc SIR (95% CI)b,c 28 0.82 (0.57-1.19) 26 1.32 (0.90-1.94) Type CC only 0.96 (0.50-1.85) 10 1.38 (0.74-2.57) 15 0.36 (0.14-0.97) 0.85 (0.35-2.04) 1.10 (0.66-1.82) 11 1.68 (0.93-3.06) Gonadotropins only Both (CC and gonadotropins) Dose cycles (n) CC only, low (1-3) 0.70 (0.22-2.16) 0.90 (0.34-2.41) CC only, high (4ϩ) 1.39 (0.62-3.10) 3.00 (1.35-6.67) Gonadotropins only, low (1-3) 0.49 (0.12-1.96) 0.50 (0.12-1.99) Gonadotropins only, high (4ϩ) 0.31 (0.08-1.24) 1.99 (0.64-6.16) CC, clomiphene citrate; CI, confidence interval; SIR, standardized incidence ratios a Ovulatory factors include: diagnosis of anovulation or amenhorrhea, oligomenorrhea or polycystic ovary syndrome/SteinLeventhal syndrome, and hirsutism b Rates adjusted for attained age, calendar period of breast cancer diagnosis, total parity, and age at first term birth c Nonovulatory factors include: endometriosis, abnormalities in the fallopian tubes or uterus, habitual abortions, immunologic factors, and other cervical factors with unexplained fertility Orgéas Breast cancer incidence after hormonal infertility treatment Am J Obstet Gynecol 2009 strual cycles, and consequently reduced cumulative exposure of estrogen and progesterone on breast proliferation.30 Thus, any increase in estrogen and progesterone levels attributable to drug therapy in these women could possibly mimic normal breast proliferative activity Therefore, despite all women receiving similar hormonal treatment for infertility, it must be highlighted that not all women were similar endocrinologically, as women with ovulatory disturbances may have a hormonal milieu very different from that of women referred for nonovulatory factors We also observed a reduction in breast cancer risk among exclusive users of gonadotropins therapy (Tables and 4) This reduction was evident in almost all subgroups; however, possibly because of the limited numbers, we did not observe statistically significant findings in these groups These findings are consistent with those first reported by Russo et al31-33 in their series of studies on mammary carcinogenesis in rodents They established that a term pregnancy resulted in significant protection against chemi- cally carcinogenic-induced malignant transformation.34 Human chorionic gonadotropin, administered in virgin rats have shown a dose-dependent reduction in tumor incidence and number of tumors, leading to the authors’ implication of a protective role in mammary carcinogenesis and a hormonal approach to the prevention of breast cancer.35 In conclusion, our results provide no evidence of an overall increased risk of breast cancer among users of fertility drugs compared with the general population We observed that women treated for 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