Int J Fertil, 50(5), 2005 p. 00–00 2005 Controversies in Obstetrics and Gynecology, Polish Society of Perinatal Medicine, the International Society of Reproductive Medicine, the World Foundation for Medical Studies in Female Health and the Center for the Study of Cryopreservation of Oocytes and Spermatozoa In Vitro Fertilization and
Breast Cancer Risk:
W. Al Sarakbi
M. Salhab
Kefah Mokbel, M.S.
ABSTRACT: Introduction—Breast cancer is a classic model of a hormone-dependent malignancy. Since the
drugs used for ovulation induction as part of in vitro fertilization (IVF) treatment increase the levels of endoge-
nous gonadal hormones, concerns have arisen regarding a possible association between IVF and the risk of developing breast cancer. The aim of this paper was to review the literature and examine the potential effects of IVF treatment on breast cancer risk. Methods—Medline search was conducted using the key words below
in English-language articles. Further papers were obtained using the bibliographies of relevant articles.
Furthermore, a combined analysis of retrieved data was performed. Results—Fifteen studies were identified;
of these, 11 were cohort studies and 4 were case-control studies. None of the individual studies showed an overall significant association between IVF and breast cancer and, in fact, one study showed that treatment with hCG significantly reduced the risk of breast cancer in women whose maximum nonpregnant body mass index was less than 27.5. A combined analysis of the cohort studies including a total of 60,050 women treat- ed with ovulation induction/IVF showed no significant association between these treatments and increased risk of breast cancer (observed vs. expected: 601 vs. 568, pooled relative risk [RR] = 1.06, P = 0.337). The case- control studies included a total of 11,303 women in the breast cancer groups and 10,930 controls. Women in the breast cancer groups were slightly less likely to have received IVF (2.2% vs. 2.5%, pooled RR = 0.88, P = 0.231). However, one study showed that infertility treatment was associated with an increased risk of breast cancer of borderline significance among women with a family history of the disease. Another study showed that the incidence of breast cancer within the first year of exposure to fertility drugs was higher than expect- ed, possibly due to the promotion of preexisting cancer lesions caused by superovulation or due to the early diagnosis made in the course of IVF treatment. Conflicting results were reported regarding the type of fertili- ty treatment and breast cancer risk. Conclusion—Overall, there is no clear evidence that ovulation induction
or IVF increases the risk of breast cancer. However, there may be a transient increase in the incidence of breast cancer in the first year due to earlier diagnosis. Furthermore, the risk may be increased in women with a pos- itive family history. Future research should focus on the type of fertility treatment used and breast cancer risk.
Aromatase inhibitors should be evaluated further as an alternative to standard ovulation-inducing drugs. Int KEY WORDS: breast cancer, IVF, ovulation induction, fertility drugs, epidemiology
Breast cancer is a classic model of a hormone- dependent malignancy, whereby overwhelming BREAST CANCER REMAINS THE MOST evidence points to an association between breast
common malignancy in the Western world.
cancer and prolonged exposure to female sex hor- The lifetime risk of developing breast cancer mones [2]. Early menarche and late menopause, both of which imply a longer exposure to menstrual W. Al Sarakbi
Summary of cohort studies.

RR = relative risk; SIR = standardized incidence ratio; CI = confidence interval; NA = not applicable; NS = not specified; CC = clomiphene citrate; HCG = human chorionic gonadotropin; HMG = human menopausal gonadotropin; GnRH = gonadotropin-releasing hormone IVF and Breast Cancer Risk
after CC use ≥20 years RR 1.39(95% CI 0.9–2.1) W. Al Sarakbi
Summary of case–control studies.

OR = odds ratio; hMG = human menopausal gonadotropin; hCG = human chorionic gonadotropin; RR = relative risk;CC = clomiphene citrate; NS = not specified cycles, are recognized risk factors for developing the threefold increase in estradiol levels as well as an increase in progesterone levels [6–8]. Human In the United States, the proportion of women menopausal gonadotropin (hMG), which contains aged 15 to 44 years reporting some form of fertility FSH and LH, also is used commonly in IVF and problems increased from 8% in 1982 to 10% in increases the serum levels of estradiol and proges- 1995 [4]. Furthermore, the number of women (per terone as well as the number of ovulations to about year) treated with fertility drugs nearly doubled 6 to 9 times that of untreated women [9]. Other between 1973 and 1991 [5]. Such agents are used drugs used in IVF include human chorionic routinely in in vitro fertilization (IVF) treatment to gonadotropin (hCG), which is given to support the induce a state of superovulation in order to increase luteal phase of the menstrual cycle by stimulating the chances of pregnancy in a given treatment cycle ovulation and progesterone secretion.
and allow the freezing of excess embryos for subse- The aim of this paper is to review the literature, beginning with a case report from 1977 [10], and Because the drugs used for ovulation induction in examine the potential effects of IVF treatment on IVF increase the levels of endogenous gonadal hor- mones, which are known to play a role in the etiol- ogy of breast cancer, concerns have arisen regarding a possible association between IVF and the risk of developing breast cancer. Given the increasing num- We conducted a Medline search using the listed key ber of women undergoing IVF treatment and the ris- words in English-language articles. Additional ing incidence of breast cancer among young women, papers were obtained using the bibliographies of rel- this issue is of public health importance.
evant articles. These studies are summarized in Clomiphene citrate (CC) is the most commonly Table I and Table II. We also performed a pooled used drug in IVF. It is a selective estrogen receptor modulator (SERM), which acts as a direct antiestro- gen on the hypothalamus. CC suppresses the natu- rally circulating estrogens and stimulates the pitu- itary gland to produce higher levels of follicle-stim- ulating hormone (FSH) and luteinizing hormone Fifteen studies were identified. Of these, 11 were (LH), which, in turn, stimulate the ovaries to mature cohort studies [11–21], and 4 were case–control stud- a follicle. The use of CC is associated with a two- to ies [22–25]. None of these studies showed an overall IVF and Breast Cancer Risk
≥6 months or for ≥6 cycles RR 2.7–3.8 For treatment with HMG: ≥6 cyclesOR 3.8 (CI 1.2–11.8) association between IVF treatment and breast can- In a prospective cohort study, Gauthier et al reported that infertility treatment was associated In the cohort studies, a total of 60,050 patients with an increased risk of breast cancer of borderline were treated with ovulation induction agents and significance among women with a family history of IVF. After a follow-up period ranging from 0.5 to 34 years, 601 patients were observed to develop breast Four studies raised concerns about a possible link cancer, compared with 567.91 expected. The pooled between specific drugs and the development of relative risk (RR) was 1.06 (P = 0.337).
breast malignancy [12,19,22,23]. In one case–control The four case control studies compared a total of study, CC was found to cause a nonsignificant 11,303 patients with established breast cancer with reduction in the risk of breast cancer in infertile 10,930 patients in the control groups. The pooled women, compared with infertile women who had analysis showed that 253 patients were exposed to not used this drug [19]. This finding was attributed ovulation-inducing drugs in the case groups, com- to the fact that CC is a SERM similar to tamoxifen.
pared with 273 patients in the control groups. The Such a reduction in risk did not increase with dura- pooled RR was 0.88 (P = 0.224).
Overall, 14 studies demonstrated no overall sig- On the contrary, although Brinton et al observed nificant association between ovulation induction no overall association between breast cancer and the and IVF treatment and increased risk of breast can- use of ovulation-inducing drugs, they reported a sig- cer [11–21,23–25] and one study showed a decreased nificant association between the risk of developing risk [22]. However, in a large case series of 27,900 invasive breast cancer and the use of CC [12]. There women who had been referred for IVF treatment, also was a slight and nonsignificant elevation in risk Venn et al found no increased risk of breast cancer seen for CC and gonadotropin after 20 years of after a long follow-up period. Nevertheless, they observed that the incidence of breast cancer within Similar to the majority of the studies, no associa- the first year of exposure to fertility drugs was high- tion was observed in a long-term historic prospec- er than expected, possibly due to the promotion of tive case–control study by Potashnik et al [17].
preexisting cancer lesions caused by superovulation However, the SIR for breast cancer was increased or due to the early diagnosis made in the course of significantly only in patients with one or two CC IVF treatment [16]. They observed 17 cases of breast treatments and a dose of ≤1000 mg [17].
cancer, compared with 8.7 expected (standardized Additionally, Burkman et al showed that the long- incidence ratio [SIR] = 1.96: 95% CI: 1.22–3.15).
term use of certain infertility drugs such as hMG for W. Al Sarakbi
≥6 months or for at least 6 cycles was associated tion induction and IVF treatment [19]; this was due with a relative risk of breast cancer ranging between to its similarity to tamoxifen, which is a recognized Finally, only one case-control study conducted One study found that treatment with hCG was by Bernstein et al showed that treatment with associated with a reduced risk of developing hCG significantly reduced the risk of breast cancer breast cancer [22]. This reduction in breast cancer risk after hCG treatment was comparable to that of mass index was less than 27.5; no such reduction in full-term pregnancy and was supported by animal risk was observed in more obese women [22].
studies [35]. Despite the fact that neither con- Although the odds ratios were reduced for both stituent of hMG such as FSH nor LH (both con- nulliparous and parous women with a maximum stituents of hMG) is thought to influence breast tis- nonpregnant weight mass index of 27.5, only the sue, Burkman et al reported a relative increase in results for the nulliparous women were statistically breast cancer risk with hMG treatment for at least 6 In a large epidemiological Australian study, Venn and colleagues reviewed and followed up a cohort of DISCUSSION
29,700 patients who underwent IVF treatment [16].
Although they found no overall association between Attention was first drawn to a possible association the different ovulation-inducing drugs and breast between breast cancer risk and ovulation-inducing cancer risk, they observed a twofold increase in drugs in a case report published in the Lancet in breast cancer risk within the first year after treat- 1977 [10]. Since then, several additional case reports ment. This prompted the suggestion that ovulation- have been published [26–28]. However, case reports stimulating drugs might promote the rapid develop- have limited value, in view of the fact that breast ment of preexisting tumors, similar to the short- cancer is a common neoplasm. In general, the asso- term transient increase in breast cancer risk follow- ciation between female gonadal hormones and the ing a recent pregnancy [35]. The other possible development of breast cancer is still not fully under- explanation is that early diagnosis was made in the stood, and several possible explanations have been course of management of infertility or other related health problems due to extensive screening in these In this review, we found no significant overall women. Other studies have not reported such find- association between IVF treatment and breast can- ings [12]. Therefore, this hypothesis requires further cer risk. All individual studies identified by our evaluation in prospective studies with larger num- research had limitations; therefore, a definite con- bers of patients and longer follow-up. Despite the clusion could not be drawn from a single study.
conflicting results, breast cancer screening in These limitations include the small numbers of women undergoing IVF treatment should be consid- breast cancer cases or incomplete ability to control ered. Women with a family history of breast cancer for other correlates of risk, including a variety of are particularly at risk [11]; therefore, this group of well-recognized familial and other risk factors.
women should be considered for breast cancer Hence, we performed a combined analysis of all screening that includes MRI [36]. Furthermore, studies identified and found no significant link tamoxifen stimulation appears to result in a higher number of embryos and may provide a safe method Some studies supported the notion that fertility of IVF and fertility preservation in breast cancer medication and IVF treatment may affect the breast patients. Therefore, it should be considered in high- cancer risk. In those studies that suggested that fer- risk women, such as those with a strong family his- tility drugs may increase [12,23] or reduce the risk tory, BRCA-1 or BRCA-2 mutations, or a recent his- [19,22] , the findings were conflicting and were based on a small number of events. For instance, CC was Further research is required to examine the rela- observed to increase the risk as well as reduce the tionship between the different fertility drug types risk of breast cancer in two different studies [12,19].
and breast cancer risk, so that the safest drugs can be Brinton et al showed that CC increased breast can- used. Moreover, the issue of whether breast cancer cer risk [12]. On the other hand, CC was found by in patients who had IVF treatment is associated with Rossing et al to be a chemopreventive agent for poor prognostic features also requires further evalu- breast cancer in infertile women undergoing ovula- IVF and Breast Cancer Risk
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