By Sam | First published February 14, 2020 | Last modified October 5, 2020
Breast cancer is the most common invasive cancer in women. The worldwide incidence in this group is about 1 in 8 (Balasubramanian et al., 2019, McGuire et al., 2015). There are likely many genetic, hormonal and lifestyle factors that influence risk. For instance, breast cancer is strongly associated with age. Indeed, only 7% of breast cancer cases have been found to be in women under 40 years old (Anders et al., 2009).
Sex steroids have profound influences on the breast. Mammary gland development begins during embryogenesis and marked differentiation takes place in the adult female at puberty and during pregnancy as a consequence of such influences (Javed et al., 2013, Sun et al., 2018, Leitch et al., 2018). Estrogens such as estradiol, in tandem with growth factors, promote morphological breast development at puberty while androgens inhibit (Hynes et al., 2010, Dimitrakakis et al., 2009). Moreover, estradiol and progesterone act synergistically to induce lobuloalveolar development in preparation for lactation. Owing to the effect of sex steroids, there is a positive relationship between breast development and breast cancer (Folkerd et al., 2013, Rezvanpour et al., 2016). In accordance, it is well established in large epidemiological studies that use of estrogen medications are strongly associated with an increased risk of breast cancer relative to non-use (Kotsopoulos, 2019). Women with larger breasts and hence more breast tissue are also apparently at a greater risk for breast cancer (Jansen et al., 2014).
Some patients and clinicians believe that progesterone may have benefits to breast development or otherwise. However, the use of progesterone in transfeminine hormone therapy for these hypothetical benefits is controversial and not evidence-based (Hembree et al., 2017, Wierckx et al., 2014, Randolph, 2018). It is sometimes argued that because these benefits are unsupported and usage is associated with an increased risk of cancer, progestogens (and specifically progesterone) ought not to be indicated for therapy in transgender women (Coxon et al., 2018). I decided to evaluate the strength of this claim in a short literature review.
Oophorectomy (removal of the ovaries) can be used both as effective active treatment and prophylaxis against breast cancer (Singh, 2012, Moscucci et al., 2007). A large meta-analysis of over 100 epidemiological studies determined that both younger age at menarche and older age at menopause were associated with a greater risk of breast cancer (CGHFBC, 2012). While it is not clear how much this risk is attributable to estrogens vs progestogens, these findings are definitive evidence that breast cancer risk is linked to and enhanced by exposure to ovarian steroids.
High mammographic density is thought to be an important risk factor for breast cancer (Boyd et al., 2011, McCormack et al., 2006). Owing to this, it is interesting to note that use of hormone replacement therapy at the menopause is associated with both higher breast density and a higher incidence of breast cancer (Azam et al., 2018, CGHFBC, 2019). However, evidence suggesting association between sex hormones and breast cancer is conflicting. One study found no association between levels of free or total estradiol and breast density, but a positive association between levels of progesterone. (Sprague et al., 2010). Contrariwise, other studies reported no association between estradiol and progesterone and a negative association between estradiol and breast density, respectively (Jung et al., 2015, Tamimi et al., 2005). A review reported that in therapy with estrogens plus oral progesterone, breast density was increased significantly in three studies but unchanged in two other studies (Mirkin, 2018). Even though mammographic density is an important marker of breast cancer, the effects of sex steroids on this variable appear to be highly inconsistent between different studies. There may not be much to be learned from these findings.
The risk of breast cancer with different estrogen and progestogen medications in menopausal hormone therapy has also been directly assessed by high-quality meta-analysis and with large sample sizes in the E3N/E3N-EPIC studies (CGHFBC, 2019, Fournier et al., 2014). In these trials, women using estradiol in combination with the synthetic progestins such as medroxyprogesterone acetate and chlormadinone acetate, have been found to have significantly greater rates of breast cancer relative to estradiol alone (Fournier et al., 2008, Lambrinoudaki, 2014). Conversely, in these large observational studies, the use of estradiol in combination with oral micronised progesterone has not been associated with a higher risk of breast cancer in the short term.
On the basis of these findings, it has been claimed that micronized progesterone differs from synthetic progestins in that it is not associated with a higher risk of developing breast cancer (Regidor, 2014, Yang et al., 2016, Rymer et al., 2019). But this does not appear to be the case. In the E3N-EPIC cohort, the relative risks (RR) [95% confidence interval (CI)] of breast cancer with transdermal estrogens and oral micronised progesterone were 0.9 [0.6–1.4], 0.7 [0.4–1.2] and 1.2 [0.7–2.0] at less than 2 years, between 2 to 4 years and at over 4 years of use, respectively (Mirkin, 2018). However, in contrast to these short-term findings, long-term observational studies have consistently found the use of micronized oral progesterone to be associated with higher breast cancer risk. In the same cohort, the relative risks of estrogens plus oral progesterone were reported between 4 to 6 years and beyond 6 years as 1.26 [0.87–1.82] and 1.22 [0.89–1.67], respectively (Fournier et al., 2008). At the conclusion of this study, the relative risks for estrogen plus oral progesterone were determined to be 1.13 [0.99–1.29] and 1.31 [1.15–1.48] below 5 years and at and beyond 5 years (Fournier et al., 2014). A recent systematic review concluded, on the basis of these findings, that breast cancer risk is not increased in the short-term by oral progesterone in combination with estrogens, but that long-term exposure has greater risk (Stute et al., 2018). The more recent CGHFBC meta-analysis determined that relative risk for estrogens plus oral progesterone was 0.91 [0.47–1.78] at less 5 years of use (CGHFBC, 2019, Table). Yet, in the long term, after 5 to 14 years of exposure, the risk was increased to 2.05 [1.38–3.06] and hence as high as medroxyprogesterone acetate and other oral progestins (2.07 [1.96–2.19]). There is no adequately powered evidence to demonstrate that estrogens plus micronized progesterone is associated with a lower incidence of breast cancer.
The notion that micronized progesterone does not increase the risk of breast cancer had been criticised before the long-term follow up of the E3N cohort and CGHFBC meta-analysis (Kuhl et al., 2013). It is important to consider the pharmacology of oral progesterone. Unlike with the synthetic progestins, this route of administration is associated with rapid metabolism and marked inactivation of the active medication into metabolites of progesterone by the gastrointestinal tract (Lobo et al., 2019, Levine et al., 2001). As a result, bioavailability is very low and, in accordance, oral progesterone is considerably less potent than the oral progestins (Davey et al., 2018, Kuhl, 2005). Taking the fact that it is far less potent into consideration, it would seem logical to assume as a default null hypothesis that breast cancer takes longer to appear and may be less common with oral progesterone (Kuhl et al., 2013). It is difficult to rationalise why all these other progestins, in spite of their different structures and biochemistry, would increase the incidence of breast cancer while micronized progesterone would not or have even an opposing effect. Conversely, other parenteral routes of progesterone such as vaginal or rectal administration have considerably higher bioavailability and more potent systematic effects (Kuhl, 2005). These non-oral routes likely have a similar incidence of breast cancer to those of the synthetic progestins.
In the CGHFBC meta-analysis, it was found that bioidentical estradiol has a similar, if not greater, incidence to conjugated (and therefore non-bioidentical) estrogens (1.78 (1.58–1.99) vs 1.68 [1.57–1.80]) (CGHFBC, 2019). Therefore, the rate of breast cancer with bioidentical estrogen usage is not significantly lower than with non-bioidentical estrogen usage. This is of note because, unlike oral progesterone and its synthetic derivatives, oral estradiol can have similar potency to these conjugated estrogens at practical clinical doses (Kuhl, 2005). One might expect the same to be true of bioidentical and non-identical progestogens at comparable potencies. The ELITE trial reported that there were more cases of breast cancer in a group of women using estradiol and relatively low-dose vaginal progesterone (45 mg/day) versus controls (Hodis et al., 2016). However, as the sample sizes were not large enough, it is not possible to attribute the higher rate of breast cancer to parenteral progesterone (Stute et al., 2018). Higher quality evidence is necessary to confirm, beyond a shadow of a doubt, that parenteral progesterone does in fact have comparable breast cancer risk to oral progestins.
There is a positive association between breast cancer risk and a greater volume of breast tissue (Jansen et al., 2014, Eriksson et al., 2012). As transgender women develop breast tissue from hormone therapy, one might expect to find that their breast cancer rate would also increase. Surprisingly, however, the findings of epidemiological studies investigating the rate of breast cancer in transgender women are conflicting. Two large cohort studies (n = 2,307 and n = 1,259, respectively) reported no greater risk relative to cisgender men (Gooren et al., 2013a, Brown et al., 2014). However, another more recent study (n = 2,260) found a rate of breast cancer in transgender women that was between that of cisgender men and cisgender women (de Blok et al., 2019). The reason for this enormous difference in findings is unclear. A recent review found that there were just 20 cases of breast cancer in transgender women reported in the literature and hence almost as many as in transgender men (Hartley et al., 2018). It is of note that another review found only 7 reported cases of prostate cancer in transgender women (Gooren et al., 2013b). In accordance, prostate cancer seems to be an exceptionally rare diagnosis. One could argue on this basis, that the occurrence of breast cancer in transgender women is possibly also very rare.
Nonetheless, we should probably take the available evidence with some scepticism. It is well-known breast cancer takes many years to appear; after many decades of hormone exposure. Data from SEER in 2004 found that the incidences of breast cancer in women at 30, 40 and 50 years of age were only 1 in 1,523, 1 in 173 and 1 in 45, respectively (Anders et al., 2009). Given the secretion of ovarian steroid hormones begins at about 10-years-old in cisgender females, by the age of 50 these women have had about 40 years of exposure. But the follow-up times in these epidemiological studies of transgender women are very short in comparison (typically less than 20 years) and, following a similar timeframe of hormone exposure, breast cancer risk may be higher (Gooren et al., 2013a, Brown et al., 2014). This is particularly relevant because there appears to have been a recent surge in the number of transgender people commencing hormone therapy at a young age (MacGregor et al., 2019, Cartaya et al., 2018). Klinefelter syndrome affects about 1 in 600 men and, usually being accompanied by a state of mild hypoandrogenism and mild hyperestrogenism, these men develop gynecomastia (Høst et al., 2014). It is of note that the breast cancer risk for Klinefelter syndrome males is significantly higher (about 3% absolute risk) that the rest of the male population (Niewoehner et al., 2008). As transgender women effectively achieve a induced state of marked “hypoandrogenism” and “hyperestrogenism” with hormone therapy, their breast cancer risk may theoretically be at least as high, or higher, than these males with Klinefelter syndrome. A recent case report concluded that the risk of breast cancer in transgender women is “acceptably safe in the short term” but that “the safety and potential risks in the longer term are unknown at present” (Sattari, 2015). As the incidence appears to be low, breast cancer may not be an overwhelming concern for transgender women. It is not, at present, possible to be sure.
Based on all available evidence, as with estrogens, progestogen usage appears to be associated with a higher incidence of breast cancer. Longer and more intense exposure may exemplify risk. This is likely the case for both synthetic progestins and bioidentical progesterone (particularly with some parenteral routes). However, more rigorous and adequately powered studies on breast cancer risk with these routes of progesterone administration are necessary to confirm this.
Because breast cancer in transgender women may not be nearly as common as breast cancer in cisgender women, it could be argued that the increased risk associated with progestogen exposure is of far lesser significance. Contrariwise, it cannot be argued that progesterone has no effect on or reduces the incidence of breast cancer. Given the limited and conflicting evidence for the notion that breast cancer remains very low in transgender women with long-term therapy, it ought not to be dismissed that an increased risk of breast cancer may form the basis of contraindication for progesterone therapy. This may be a particularly important consideration for those with a family history of the disease. Nonetheless, based on the extremely low number of case reports of breast cancer in transgender women, progestogens and progesterone might be well tolerated in this respect; even over long periods of time. There are probably more convincing reasons for us not to add micronised progesterone to our regimens.