Exogenous sex hormones and risk of breast cancer

Introduction

Breast cancer is the most commonly diagnosed noncutaneous cancer in women in the United States and all over the world and accounts for the second highest number of deaths because of cancer. The etiology of breast cancer is multifactorial and cannot be directly linked to any single factor, including estrogen. The epidemiological literature supports a highly complex interplay between different exposures and host characteristics and between exogenous and endogenous hormones and an individual's genetic makeup.

Oral contraceptives and risk of breast cancer

Combined oral contraceptives (COCs) are among the most widely used effective and reversible means of family planning. Their beneficial effects are well documented, but many questions are still raised concerning a possible association between the use of COCs and the development of cancer.

Many epidemiological studies have not demonstrated an association between the use of oral contraceptives (OCs) and the risk of breast cancer [1,3]. One case-control study found a relative risk of 4 1,4 (95% CI, 0.8–2.4) in women who took OCs for more than 12 years compared with non-users [1]. This increase in risk was consistent with the results of an earlier large pooled analysis which had also shown a small but significant increase in the relative risk of breast cancer [2,3] in current OC users [4]. The increase in risk returned to baseline 10 years after discontinuation of OC use. Criticisms about this analysis have been raised because a low percentage of women had never used OCs (40%), and it lacked the follow-up necessary to determine whether there were long-term effects of OC use.

Exogenous estrogen does not seem to increase the risk of breast cancer by a positive family history of breast cancer, but OC use may increase risk to a greater extent in carriers of BRCA ½ mutations than in the general population [5], though this point of view was not confirmed in a latter study by Lee et al. [6].

There are no reassuring data from two large studies that OCs do not increase breast cancer risk later in life [6,7]. Key findings included no breast cancer risk among current (OR, 1.0; 95% CI, 0.8–1.3) or former (OR, 0.9; 95% CI, 0.8–1.0) OC users and no risk associated with the duration of use or dose of estrogen.

In most women, the benefits of OCs overweigh the absolute minimal increased risk of breast cancer that may occur among young women [8,9]. Later, Lech and Ostrowska also provided a broad and up-to-date review of the literature regarding the relation between COC use and carcinogenesis in different organs. Studies have not unequivocally confirmed that such a relation exists with regard to breast cancer [10].

In the United States, Gill et al. conducted a population-based case–control study of incident breast cancer in situ among black and white women aged 35–64 years residing in Los Angeles County. Case patients (n = 567) were newly diagnosed with breast cancer in situ and control participants (n = 614) were identified by random digit dialing between March 1, 1995 and May 31, 1998. All subjects were required to have had a mammogram in the 2 years before case diagnosis or control recruitment. OC use was not associated with the risk of breast cancer in situ (OR, 1.04; 95% CI, 0.76–1.42). Risk did not increase with longer periods of use. No associations with breast cancer in situ risk were observed for OC use before first term pregnancy, age at first OC use, or for time since last use. Risk was not modified by estrogen dose, age, race, or parity [11].

A qualitative age-interaction is defined as the reversal of relative risks or rates according to age at onset. Once thought rare, qualitative age-interactions are commonly reported in studies that examine the etiology, prognosis, and treatment of breast cancer. Thus, nulliparity, obesity, and OCs decrease breast cancer risk in younger women but increase risk in older women [12].

The report by Vessey and Yeates is an update of findings, first reported in 1981, on the relationship between OCs and benign breast disease with special reference to OCs containing <50 μg estrogen. The Oxford-Family Planning Association study includes 17,032 women using different methods of contraception recruited at 17 family planning clinics between 1968 and 1974. These women were subsequently followed up until mid-1994. Among other items, information about contraceptive method changes and morbidity as measured by hospital referrals was collected during follow-up. The findings in the present analysis were based on large number of cases (fibroadenoma 185 cases; chronic cystic disease 1361 cases; breast lump with no specific diagnosis 650 cases). Hospital referral rates for fibroadenoma and chronic cystic disease declined with increasing duration of OC use, with the effect being strongest among recent users. The apparent protective effect was present for women using OCs containing >50 μg, 50 μg and <50 μg estrogen but not for progestagen-only OCs [13].

Ovulation induction and risk of breast cancer

Breast cancer is a classic model of a hormone-dependent malignancy. As the drugs used for ovulation induction as part of in vitro fertilization (IVF) treatment increase the levels of endogenous gonadal hormones, concerns have arisen regarding a possible association between IVF and the risk of developing breast cancer.

Salhab et al. presented a review of 11 cohort studies and 4 case–control studies to examine a possible association between IVF and breast cancer risk. None of the individual studies showed an overall significant association between IVF and breast cancer and, in fact, one study showed that treatment with human chorionic gonadotropin (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 treated with ovulation induction/IVF showed no significant association between these treatments and increased the 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 expected, 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 fertility treatment and breast cancer risk. Overall, there is no clear evidence that ovulation induction or IVF increases the risk of breast cancer [14].

Hormone replacement therapy and risk of breast cancer

Hormone replacement therapy is the most efficacious intervention for the relief of climacteric symptoms. Controversies surrounding HRT have left many women puzzled and afraid. Gynecologists are faced with long-standing beneficial assumptions challenged by an abundance of robust detrimental new data, with little guidance on how to interpret these findings. One of the greatest concerns of women who are considering HRT is its relationship with breast cancer. Initial results of the Women's Health Initiative (WHI) trial showed a modest increased risk of breast cancer in the estrogen–progestin group. This made many physicians and patients to refuse HRT. But reanalysis of large clinical trials was going on and resulted in position statements of International Menopause Society, European Menopause and Andropause Society, and North American Menopause Society, all published in 2008. The main message was that risk of breast cancer depends on women's age and menopause duration, benefits of HRT with minimal risks can be achieved when starting HRT in 50–59-year-old woman with menopause duration less than 10 years.

WHI reanalysis showed that after 5 years' use of combined estrogen and progestogen, in WHI cohort there was a small increase in the risk of breast cancer of about eight extra cases per 10,000 women per year. Risk was not increased in first-time hormone users (RR, 1.09; 95% CI, 0.86–1.39) [15–19].

In the WHI estrogen-only arm, there was no increase in breast cancer risk for up to 7 years with six fewer cases of invasive breast cancer per 10,000 women per year of estrogen monotherapy (ET) use (RR, 0.77; 95% CI, 0.59–1.01). However, the risk of invasive breast cancer was significantly lower in first-time users of estrogen [2,19]. In observational studies, a small increase in risk during estrogen-alone therapy was recorded only after long-term use [20,16].

In the E3N cohort study, the association of estrogen–progestagen combinations with breast cancer risk varied significantly according to the type of progestagen: the relative risk was 1.00 (0.83–1.22) for estrogen–progesterone, 1.16 (0.94–1.43) for estrogen–dydrogesterone, and 1.69 (1.50–1.91) for estrogen combined with other progestagens. This study found no evidence of an association with risk according to the route of estrogen administration (oral or transdermal/percutaneous). These findings suggest that the choice of the progestagen component in combined hormone replacement therapy (HRT) is of importance regarding breast cancer risk [21].

In the open prospective randomized trial conducted by Heikkinen et al., the risk of breast cancer during 10 years of different HRT regimens did not increase and was lower than that in the general population [22].

Women using combined HRT before a diagnosis of breast cancer have a reduced mortality [17,23].

We can conclude that most of the exogenous estrogens do not increase the risk of breast cancer if they were indicated individually to a woman at an appropriate time.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.