Understanding the role of sex hormones in cancer for the transgender community

Abstract

Sex hormones are crucial for the body’s development and function. Therefore many transgender people seek hormone therapy as part of their transition. However, sex hormones modulate cancer risk. Studying sex hormones in cisgender and transgender populations will improve our knowledge of their biological role in cancer and reduce health disparities.

Transgender (trans) people, those identifying as a gender that differs from their sex assigned at birth (SAAB), make up ^~0.4% of the population[I]. The current medical model creates myriad interpersonal and system-based faults, negatively impacting the patient experience. Trans patients therefore tend to avoid healthcare and present less frequently for routine screening. As we move towards a personalised and equitable care, clinicians should understand the factors that may drive cancer risk in this population and both clinicians and researchers should work with the community to address them.

Among the factors that may drive cancer risk is the use of gender affirming hormone therapy (GAHT) (Box 1). Research suggests that hormonal exposure affects the risk of many cancers in cisgender (cis) populations, those whose gender identity aligns with their SAAB. For some cancer types there are sex-based differences in risk which are not yet fully explained. This lack of clarity leads to challenges in understanding cancer risk in trans people accessing GAHT (Box 1).

Box 1. Gender Affirming Hormone Therapy (GAHT).

The principles of GAHT are twofold: firstly, to reduce endogenous sex steroid production and reduce secondary sexual characteristics associated with the sex assigned at birth; and secondly to replace sex hormones to as closely as possible reflect the physiological characteristics of that individual’s affirmed gender.[15]

Masculinising hormone therapy with exogenous testosterone causes changes including increased body and facial hair, deepening of the voice, menstrual suppression, and increased muscle development. Testosterone levels in the male physiological range typically exert sufficient suppression of the pituitary – gonadal axis to reduce endogenous sex hormones although in some cases additional therapy using progestogens or gonadotrophin releasing hormone analogues (GnRHa) may be needed.[15]

Feminising hormone therapy, such as exogenous oestradiol causes changes including breast growth, softening of the skin, reduction in body hair, and a change in body shape and composition. In the majority of cases, anti-androgen therapy is needed, and may take the form of non-specific androgen receptor antagonists, specific androgen receptor antagonists, or GnRHa that suppress the hypothalamic-pituitary-gonadal axis.[15] In some cases, progesterone is also used for GAHT for its effects on breast development.[15]

We outline the literature on sex hormones and cancer risk in cis populations for 4 cancer types, how this might apply to GAHT for trans people and the evidence for effects on cancer incidence in this population (summarized in Figure 1). Finally, we discuss how we can improve the evidence base for the biological role of sex hormones in cancer and reduce healthcare inequality.

Figure 1 -.

Summary of the evidence for effects on risk of the 4 featured cancers for trans people, according to the sex that the individual was assigned at birth.

Sex Hormones in Cancer Incidence

Oestrogen, progesterone and androgen signalling play key roles in stem cell renewal, epigenetics, and immune response, each of which contributes to oncogenesis. [1] Understanding the mechanisms by which sex hormones modulate cancer progression in both cis and trans people can improve treatments and reduce cancer incidence.

Breast Cancer

Oestrogen raises breast cancer risk primarily by stimulation of proliferation of breast epithelium. Increased circulating oestradiol levels are associated with cancer risk in post-menopausal cis women,[2] as is higher lifetime exposure to endogenous oestrogens.[2] Use of exogenous oestrogen (e.g. hormone replacement therapy) results in excess cancer risk that reduces with time after cessation.[2]

Both endogenous and exogenous progesterone have been linked to increased breast cancer risk [2] but different progestins appear to stimulate breast epithelial hyperproliferation to different degrees. [2] Breast tumours may also express the androgen receptor (AR) and a UK Biobank study found a positive correlation between testosterone and breast cancer risk in post-menopausal but not pre-menopausal women.[3] ARs may act as growth suppressors in luminal tumours, driving cell proliferation in oestrogen receptor (ER)-negative tumours.

In the largest cohort of trans people in Europe, trans women on GAHT were observed to have a higher risk of breast cancer than cis men (standardized incidence ratio [SIR]: 46.7) but a lower risk compared to cis women (SIR: 0.3).[4] Trans men on testosterone therapy had a decreased risk of breast cancer compared to cis women (SIR: 0.2), no doubt in part related to tendency to undergo bilateral mastectomy with male chest reconstruction. However, their risk for breast cancer was elevated when compared to cis men (SIR: 58.9).[4] Further, the age at cancer diagnosis was significantly younger in both trans groups.[4] The authors postulated that this could be related to undiagnosed genetic predisposition. In trans women they also hypothesise that the progestogenic effects of cyproterone acetate further increased cancer risk while anti-androgens reduced the usually suppressive effects of androgens on luminal cancer development,[2] which was the predominant subtype in this study. The low numbers of reported breast cancers in trans men make it difficult to ascertain subtype specific incidence and determine the role of testosterone or its aromatisation to oestrogen in breast cancer development. Answering these questions will require the initiation of large-scale, longitudinal cohorts, as well as inclusion of trans status in cancer registries, to study the effects of hormones on benign and malignant breast tissue in trans people.

Prostate Cancer

Testosterone drives the growth and development of both benign and malignant prostate cancer cells. However, while low levels of testosterone in cis men are linked to reduced prostate cancer incidence, meta-analysis supports a ‘saturation hypothesis’ where high levels beyond a threshold fail to further increase risk.[5] Prostate cancer is typically treated with hormone therapy to reduce testosterone levels, including androgen-suppressing drugs, or luteinizing hormone-releasing hormone (LHRH) agonists and antagonists, in addition to orchiectomy (surgical castration). Similar therapies have also been used by trans women to reduce testosterone levels; therefore, it has been hypothesized that the risk is decreased for trans women. Indeed, a lower prostate cancer risk in trans women on GAHT is found compared to the Dutch cis male population (SIR 0.20).[6] Oestrogens were also historically used in prostate cancer treatment of cis men due to their ability to suppress testosterone via the pituitary axis, though their role has reduced due to side effects and the advent of gonadotrophin releasing hormone analogues. Therefore, exogenous oestrogen could also reduce the incidence of prostate cancer. However, as oestrogens can stimulate carcinogenesis, there is concern that tumours forming in the presence of high levels of oestrogen may be more aggressive. Its role in prostate cancer is further complicated depending on which ER isoform is activated. Activation of ER-alpha has protumourigenic effects in prostate cancer, while activation of ER-beta has a tumour suppressive role in the prostate.[7]

Testicular Cancer

Testicular cancer is the most common malignancy in young cis men aged 15–40 years, with increasing incidence over the past 40 years.[8] Some suggest that exposure to oestrogens either in utero (e.g. diethylstilbestrol) or post-natal (e.g. pesticides) may play a role in the development of testicular cancer.[8] However, the long-term effects of GAHT on testicular cancer among trans women are largely unknown. One prospective cohort study of Dutch trans women on GAHT found that the incidence of testicular cancer is similar to that of cis men.[9] Further, because no cancers occurred among long-term GAHT users, the researchers concluded long-term hormonal treatment does not increase the risk for testicular cancer.[9]

Endometrial Cancer

In cis women, endometrial cancer risk is positively correlated with unopposed oestrogen exposure with progestogens having a protective effect. Increased serum androgens are also associated with increased endometrial cancer risk in postmenopausal women. Women with polycystic ovary syndrome (PCOS), who have elevated circulating androgen concentrations, also have increased rates of both endometrial hyperplasia and cancer.[10] These effects may relate to the ability of testosterone to be aromatized to oestrogen and to suppress the progesterone axis, though testosterone can also be metabolized to dihydrotestosterone, which suppresses endometrial proliferation. As such there is a theoretical risk of endometrial hyperplasia and cancer in trans men and non-binary people on testosterone therapy who do not opt for hysterectomy, but increased incidence has not yet been demonstrated [11] and further data is required to confirm this hypothesis.

Increasing research to reduce cancer care disparities

Cancer among trans individuals is understudied and poorly understood due to a paucity of data collection and rigorous research. Trans-specific screening guidelines cannot be developed without appropriate estimates of risk. This lack of research may lead to worse cancer outcomes for trans persons.[12] We outline how to improve cancer research for trans communities.

Data collection

Trans status is not collected on most population-based surveys, cancer registries, or death registries. Clinical intake forms and electronic health records (EHR) often conflate SAAB and gender identity and fail to acknowledge that the latter may change over the life course. Best practice guidelines recommend allowing patients to self-report gender identity on medical forms. Early education of all healthcare staff in cultural humility is also essential to increase trans patients’ comfort in reporting gender identity.

Experimental methods

We cannot answer key questions regarding the contribution of hormones to cancer risk unless their levels are longitudinally measured in both cis and trans patients as part of clinical studies. Biobanking of normal and cancer tissues (with appropriate ethical measures in place) along with paired data on hormone exposures is needed for trans populations.[13] Finally, experimental models that consider both karyotype and hormonal sex are of utility.

Co-production in studies

Collaboration is key to inclusive research and should be with organisations already engaged with the trans community, such as third sector groups, to share knowledge, expand recruitment and be guided in best practice. Advisory panels of patients can be recruited to oversee our process and help design and steer the research most salient to their community. Participant recruitment should also be intersectional [14] given the paucity of data on people who are ‘multiple minorities’.

Concluding Remarks

GAHT is a requisite component of medical care for many trans individuals, improving their quality of life. It is therefore essential to understand how its use may alter cancer risk. Studies suggest that hormone therapy may increase the risk of breast, endometrial, and testicular cancers, while it may lower the risk of prostate cancer. However, the evidence for cancer risk and outcomes among trans persons is based on a handful of studies necessitating the initiation of large-scale prospective cohort studies to better understand cancer in this population, particularly as GAHT prescribing patterns change and trans persons transition earlier in life. The collection of trans status and GAHT use in cancer registries, surveys, and EHR data will greatly contribute vital knowledge to reduce cancer health disparities in this community.