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Gender Affirming Hormone Treatment and the Risk of Cancer: A Literature Review

Breast cancer

The lifetime risk of breast cancer for cis women is approximately 12%, while the lifetime risk for cis men is approximately 0.1% (Sonnenblick et al., 2018).

Feminising hormone treatment

Research has shown that the lifetime risk of breast cancer for trans women on feminising hormone treatment is higher than the lifetime risk for cis men, but lower than the lifetime risk for cis women (de Blok et al., 2019).

This indicates that feminising hormone treatment with oestrogen is associated with an increased risk of breast cancer. Studies in postmenopausal cis women on hormone replacement therapy have suggested that the addition of synthetic progestin can increase the risk of breast cancer further (Beral, 2003; Colditz et al., 1995; Rossouw et al., 2002). However, there is no evidence that bioidentical progesterone is associated with any increased risk. Studies on hormone replacement therapy in postmenopausal cis women have shown that bioidentical progesterone is associated with a significantly lower risk of breast cancer than synthetic progestin (Asi et al., 2016; Fournier et al., 2008).

Research on trans women who developed breast cancer has shown that most of the tumours were positive for oestrogen and progesterone receptors (de Blok et al., 2019). Therefore, it is recommended that oestrogen and progesterone are not prescribed for people with active breast cancer, as there is a likelihood that the cancer will be sensitive to oestrogen and progesterone.

Masculinising hormone treatment

Research has shown that the lifetime risk of breast cancer for trans men is higher than the lifetime risk for cis men, but lower than the lifetime risk for cis women (de Blok et al., 2019).

There is currently no evidence that masculinising hormone treatment with testosterone increases the risk of breast cancer. While there has not been much research directly examining the connection between testosterone and breast cancer risk, testosterone in masculinising hormone treatment has been shown to decrease oestrogen levels (Defreyne et al., 2020). In turn, decreased oestrogen levels have been shown to be associated with decreased breast cancer risk (Folkerd and Dowsett, 2013).

Hence, the available evidence suggests that trans men who have a past history or family history of breast cancer can take testosterone without this affecting their subsequent risks of breast cancer. However, it is recommended that trans men who have breasts regularly examine themselves for any changes in breast tissue, seek medical attention if they notice any changes in breast tissue, and attend screening programmes for breast cancer.

BRCA genotypes

Special considerations are required for people who have BRCA1 or BRCA2 genotypes or family histories of breast cancer suggestive of BRCA1 or BRCA2 genotypes. BRCA1 and BRCA2 are genes which are associated with a substantially increased risk of breast cancer. The lifetime risk of breast cancer for cis women with BRCA1 or BRCA2 genotypes is estimated to be between 40% and 85%, while the lifetime risk for cis men with BRCA1 or BRCA2 genotypes is estimated to be between 1.2% to 6.8% (Pruthi et al., 2010; Tai et al., 2007).

Epidemiological evidence on the risk of breast cancer in trans people with BRCA1 or BRCA2 genotypes is lacking. However, a case report on a trans women with a BRCA1 genotype involved the continuation of feminising hormone treatment under informed consent (Colebunders et al., 2014). Given the potentially significant risk of breast cancer in people with BRCA1 or BRCA2 genotypes, it is strongly recommended that trans people with BRCA1 or BRCA2 genotypes receive genetic counselling and are fully informed of the risk before consenting to feminising hormone treatment. Trans women and transfeminine people with BRCA1 or BRCA2 genotypes on feminising hormone treatment are also advised to speak to their doctors about enhanced breast cancer screening programmes at younger ages and regular breast examinations.

Recommendations

  1. Trans women and transfeminine people who request feminising hormone treatment should be fully informed of the increased lifetime risk of breast cancer before they consent to treatment;
  2. If progesterone is requested, then bioidentical progesterone should be prescribed, rather than synthetic progestin;
  3. Trans women and transfeminine people on feminising hormone treatment, trans men who have breasts, and nonbinary people who have breasts should be offered the same screening programmes for breast cancer as cis women;
  4. All people who have strong family histories of breast cancer that are suggestive of BRCA1 or BRCA2 genotypes should be advised to consider genetic testing and genetic counselling;
  5. Trans women and transfeminine people with BRCA1 or BRCA2 genotypes who wish to commence feminising hormone treatment should be fully informed of the significant risk of breast cancer and should be advised to speak to their doctors about ways to mitigate this risk, such as enhanced screening programmes at younger ages and regular examinations;
  6. Oestrogen and progesterone should not be used in people who have active breast cancer.

Meningioma

A meningioma is a relatively rare tumour of the meninges which line the brain. It is usually benign and grows slowly.

There is evidence that the antiandrogen cyproterone acetate is associated with an increased risk of meningioma. In a study of 10,876 trans women, the risk of meningioma was 2.07 per 10,000 people per year in trans women who were taking cyproterone acetate, compared to 0 in trans women who were not taking cyproterone acetate. Further data on cis girls and cis women found that people who were taking cyproterone acetate were 5 times more likely to develop meningioma than people who were not taking cyproterone acetate. The risk of meningioma was greater with higher doses of cyproterone acetate (Weill et al., 2021).

Therefore, while the absolute risk of meningioma remains low, it is important to acknowledge that cyproterone acetate does increase the lifetime risk of developing meningioma. Apart from cyproterone acetate, there is no evidence that other antiandrogens or other hormonal treatments increase the risk of meningioma.

Recommendations

  1. Ensure that people are fully informed of the increased lifetime risk of meningioma before they consent to treatment with cyproterone acetate;
  2. Monitor testosterone levels so that the lowest possible dose of cyproterone acetate is used that successfully suppresses testosterone levels;
  3. Advise people who are taking cyproterone acetate to seek medical attention if they notice any neurological symptoms, including visual changes, headaches, drowsiness, loss of balance, muscle weakness, and seizures.

Prostate cancer

In people who have a prostate gland, there is a theoretical risk that exogenous testosterone could increase the risk and severity of prostate cancer (Michaud et al., 2015). However, this is inapplicable to people without prostates who are taking testosterone, such as trans men on masculinising hormone treatment.

There is no evidence that feminising hormone treatment in trans women is associated with an increased risk of prostate cancer. Recent studies have found that trans women on feminising hormone treatment have lower incidences of prostate cancer than cis men (Nash et al., 2018; Silverberg et al., 2017). And so, it can be concluded that feminising hormone treatment in trans women does not increase the risk of prostate cancer.

However, although feminising hormone treatment does not increase the risk of prostate cancer, it is important to recognise that trans women who have prostates can still get prostate cancer. The prostate is generally not removed in gender affirming surgery, and so the risk remains present in trans women who have had gender affirming surgery. Furthermore, there is some evidence that the diagnosis of prostate cancer may be more complicated in trans women who have had gender affirming surgery, because it may be more difficult to feel the prostate during a clinical examination (Tanaka et al., 2022).

Recommendations

  1. Trans women should be offered the same screening programmes for prostate cancer as cis men;
  2. Trans women who have had gender affirming surgery are advised to inform their doctors about the kinds of surgery they have had, in case further investigations are required to screen for or diagnose prostate cancer.

Endometrial cancer

To date, there is only one case report of endometrial cancer in a trans man (Urban et al., 2011). There is no evidence that masculinising hormone treatment increases the risk of endometrial cancer.

Recommendations

  1. The advice about endometrial cancer is the same for trans men as it is for cis women;
  2. Vaginal bleeding despite oestrogen levels being adequately suppressed and testosterone doses being optimal should be medically investigated;
  3. While hysterectomy may be offered as part of gender affirming surgery, it is not recommended solely for the prevention of endometrial cancer.

Ovarian cancer and testicular cancer

There have been some reported cases of ovarian cancer in trans men on masculinising hormone treatment (Dizon et al., 2006; Hage et al., 2000). However, there is no evidence that trans men on masculinising hormone treatment are at any increased risk of ovarian cancer compared to cis women.

A recent study found that trans women on feminising hormone treatment have similar incidences of testicular cancer to cis men (de Nie et al., 2022). Hence, there is no evidence that feminising hormone treatment increases the risk of testicular cancer.

Recommendations

  1. The advice about ovarian cancer and testicular cancer is the same for trans people as it is for cis people;
  2. While oopherectomy and orchidectomy may be offered as part of gender affirming surgery, they are not recommended solely for the prevention of ovarian cancer and testicular cancer respectively.

Cervical cancer, penile cancer, and anal cancer

Cervical cancer, penile cancer, and anal cancer tend to be caused by human papillomavirus infection, which is a sexually transmitted infection.

Gender affirming hormone treatment does not increase the risks of these cancers. Nonetheless, epidemiological evidence suggests that the trans population have higher incidences of these cancers than the cis population, due to disparities in social inclusion, healthcare access, economic stability, and support (Quinn et al., 2015).

Recommendations

  1. Encourage safe sex practices, including use of barrier contraception;
  2. Advise regular testing for sexually transmitted infections at a sexual health clinic;
  3. Advice vaccination against human papillomavirus infection.

Other cancers

Aside from what has been discussed above, there is no evidence that gender affirming hormone treatment increases the risks of other cancers (Braun et al., 2017).

References

Asi, N., Mohammed, K., Haydour, Q., Gionfriddo, M. R., Vargas, O. L., Prokop, L. J., Faubion, S. S., and Murad, M. H. (2016). “Progesterone vs. Synthetic Progestins and the Risk of Breast Cancer: A Systematic Review and Meta-Analysis”. Systematic Reviews, 5 (1): 121.

Beral, V. (2003). “Breast Cancer and Hormone Replacement Therapy in the Million Women Study”. Lancet, 362 (9382): 419–427.

Braun, H., Nash, R., Tangpricha, V., Brockman, J., Ward, K., and Goodman, M. (2017). “Cancer in Transgender People: Evidence and Methodological Considerations”. Epidemiologic Reviews, 39 (1): 93–107.

Colditz, G. A., Hankinson, S. E., Hunter, D. J., Willett, W. C., Manson, J. E., Stampfer, M. J., Hennekens, C., Rosner, B., and Speizer, F. E. (1995). “The Use of Estrogens and Progestins and the Risk of Breast Cancer in Postmenopausal Women”. New England Journal of Medicine, 332 (24): 1589–1593.

Colebunders, B., T’Sjoen, G., Weyers, S., and Monstrey, S. (2014) “Hormonal and Surgical Treatment in Trans-Women with BRCA1 Mutations: A Controversial Topic”. Journal of Sexual Medicine, 11 (10): 2496-2499.

de Blok, C. J. M., Wiepjes, C. M., Nota, N. M., van Engelen, K., Adank, M. A., Dreijerink, K. M. A., Barbé, E., Konings, I. R. H. M., and den Heijer, M. (2019). “Breast Cancer Risk in Transgender People Receiving Hormone Treatment: Nationwide Cohort Study in the Netherlands”. British Medical Journal, 365: 1652.

Defreyne, J., Aers, X. P., Collet, S. M., Wiepjes, C. M., Fisher, A. D., Schreiner, T., Den Heijer, M., Kaufman, J. M., and T’Sjoen, G. G. R. (2020) “Lower Serum Estradiol Levels in Assigned Female at Birth Transgender People with Initiation of Testosterone Therapy: Results from the European Network for the Investigation of Gender Incongruence”. LGBT Health, 7 (2): 71-81.

de Nie, I., Wiepjes, C. M., de Blok, C. J. M., van Moorselaar, R. J. A., Pigot, G. L. S., van der Sluis, T. M., Barbé, E., van der Voorn, P., van Mello, N. M., Huirne, J., and den Heijer, M. (2022). “Incidence of Testicular Cancer in Trans Women Using Gender-Affirming Hormonal Treatment: A Nationwide Cohort Study”. BJU international, 129 (4): 491–497.

Dizon, D. S., Tejada-Berges, T., Koelliker, S., Steinhoff, M., and Granai, C. O. (2006). “Ovarian Cancer Associated with Testosterone Supplementation in a Female-to-Male Transsexual Patient”. Gynecologic and Obstetric Investigation, 62 (4): 226-228.

Folkerd, E., and Dowsett, M. (2013). “Sex Hormones and Breast Cancer Risk and Prognosis”. Breast, 22 (S2): 38–43.

Fournier, A., Berrino, F., and Clavel-Chapelon, F. (2008). “Unequal Risks for Breast Cancer Associated with Different Hormone Replacement Therapies: Results from the E3N Cohort Study”. Breast Cancer Research and Treatment, 107 (1): 103–111.

Hage, J. J., Dekker, J. J., Karim, R. B., Verheijen, R. H., and Bloemena, E. (2000). “Ovarian Cancer in Female-to-Male Transsexuals: Report of Two Cases”. Gynecologic Oncology, 76 (3): 413-415.

Michaud, J. E., Billups, K. L., and Partin, A. W. (2015). “Testosterone and Prostate Cancer: An Evidence-Based Review of Pathogenesis and Oncologic Risk”. Therapeutic Advances in Urology, 7 (6): 378–387.

Nash, R., Ward, K. C., Jemal, A., Sandberg, D. E., Tangpricha, V., and Goodman, M. (2018). “Frequency and Distribution of Primary Site Among Gender Minority Cancer Patients: An Analysis of U.S. National Surveillance Data”. Cancer Epidemiology, 54: 1-6.

Pruthi, S., Gostout, B. S., and Lindor, N. M. (2010). “Identification and Management of Women With BRCA Mutations or Hereditary Predisposition for Breast and Ovarian Cancer”. Mayo Clinic proceedings, 85 (12): 1111–1120.

Quinn, G. P., Sanchez, J. A., Sutton, S. K., Vadaparampil, S. T., Nguyen, G. T., Green, B. L., Kanetsky, P. A., and Schabath, M. B. (2015). “Cancer and Lesbian, Gay, Bisexual, Transgender/Transsexual, and Queer/Questioning (LGBTQ) Populations”. CA: A Cancer Journal for Clinicians, 65 (5): 384–400.

Rossouw, J. E., Anderson, G. L., Prentice, R. L., LaCroix, A. Z., Kooperberg, C., Stefanick, M. L., Jackson, R. D., Beresford, S. A., Howard, B. V., Johnson, K. C., Kotchen, J. M., and Ockene, J. (2002). “Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results from the Women’s Health Initiative Randomized Controlled Trial”. Journal of the American Medical Association, 288 (3): 321–333.

Sonnenblick, E. B., Shah, A. D., Goldstein, Z., and Reisman, T. (2018). “Breast Imaging of Transgender Individuals: A Review”. Current Radiology Reports, 6: 1.

Silverberg, M. J., Nash, R., Becerra-Culqui, T. A., Cromwell, L., Getahun, D., Hunkeler, E., Lash, T. L., Millman, A., Quinn, V. P., Robinson, B., Roblin, D., Slovis, J., Tangpricha, V., and Goodman, M. (2017). “Cohort Study of Cancer Risk Among Insured Transgender People”. Annals of Epidemiology, 27(8): 499-501.

Tai, Y. C., Domchek, S., Parmigiani, G., and Chen, S. (2007). “Breast Cancer Risk Among Male BRCA1 and BRCA2 Mutation Carriers”. Journal of the National Cancer Institute, 99 (23): 1811–1814.

Tanaka, B. M., Sahota, K., Burn, J., Falconer, A., Winkler, M., Ahmed, H. U., and Rashid, T. G. (2022). “Prostate Cancer in Transgender Women: What Does a Urologist Need to Know?” BJU International, 129 (1): 113-122.

Urban, R. R., Teng, N. N. H., and Kapp, D. S. (2011). “Gynecologic Malignancies in Female-to-Male Transgender Patients: The Need of Original Gender Surveillance”. American Journal of Obstetrics and Gynecology, 204 (5): e9-e12.

Weill, A., Nguyen, P., Labidi, M., Cadier, B., Passeri, T., Duranteau, L., Bernat, A. L., Yoldjian, I., Fontanel, S., Froelich, S., and Coste, J. (2021). “Use of High Dose Cyproterone Acetate and Risk of Intracranial Meningioma in Women: Cohort Study”. British Medical Journal, 372: n37.

Updated on March 8, 2024

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