As more transgender people openly identify as such, research is needed to understand best practices for cancer screening of birth organs. One such area is in prostate cancer screening in transgender women (assigned male sex at birth but identify as women). A key fact that is not universally appreciated is that the prostate is not removed in any form of gender-affirmation surgery; thus, transgender women remain at risk of prostate cancer.

Historically, prostate cancer was thought to rarely occur in transgender women as only limited case series had been published. However, last year in JAMA, our group showed that prostate cancer is not as rare in this population as previously thought.¹ More concerning, transgender women on estrogen had more aggressive prostate cancer at diagnosis, including in comparison to transgender women formerly or never on estrogen and compared to cisgender men.¹ This suggests potentially delayed diagnoses of clinically significant prostate cancer. Although there are likely multiple reasons for delayed diagnosis, an important and potentially preventable reason is that the traditional PSA upper limit of 4 ng/mL, which is for better or worse often still used as a threshold for referral to urology, is an inappropriate cutoff for those on gender-affirming hormones due to the castrating effects of those hormones. The physiological effects of estrogen are to cause castration and, subsequently, very low testosterone levels. Given testosterone is needed for PSA production, it is intuitive that PSA levels would be lower, but exactly how low are they in transgender women on estrogen? To clarify, while the risks and benefits of prostate cancer screening in cisgender men are well established, the benefits and risks in transgender women are unknown. Nonetheless, anecdotal data suggest PSA testing is occurring in these patients. As such, if one is going to screen transgender women for prostate cancer, what are the appropriate PSA cutoffs to use?

To address this, in a paper recently published in JAMA,² we determined the range of PSA values in transgender women ages 40 to 80 with no known prostate cancer using records from the Veterans Health Administration between 2000 and 2023.

In total, from the entire Veterans Health Administration medical records, we identified 14,915 patients with an International Classification of Diseases code related to transgender identity.² Among these, we performed detailed chart review on 1000 patients to confirm transgender identity, estrogen usage for at least 6 consecutive months, a lack of prostate cancer diagnosis, and the presence of at least 1 PSA test between ages 40 and 80 years after being on estrogen for at least 6 months. In total, 210 patients met inclusion criteria and had a total of 852 PSA tests. The median age was 60 years, and the majority (86%) of patients were White, with only 2% Black. The median estrogen duration at the time of PSA testing was 4.7 years. Approximately 49% had undergone bilateral orchiectomy prior to PSA testing.

The overall median PSA value in this cohort was 0.02 ng/mL—50-fold lower than the median PSA in similarly aged cisgender men.³ Furthermore, the 95th percentile and the overall highest PSA in this cohort were 0.6 ng/mL and 2.2 ng/mL, respectively. We performed additional sensitivity analyses using only the first PSA test between ages 40 and 80 years and a median of all PSA values obtained for each patient; PSA distributions were similar. In short, PSA values among transgender women on estrogen are far lower than those in cisgender men, and care must be taken when interpreting PSA values. Specifically, “normal” values as defined by historic PSA cutoffs may not be normal in this population and may, indeed, be cause for concern among those on gender-affirming hormones. While the optimal cut point to define abnormal in this population is not yet known, we are hopeful that awareness of transgender-specific normal values could lead to earlier identification of aggressive disease in transgender women to improve outcomes and hopefully save lives.

Ultimately, this study serves as an important first step in establishing baseline PSA values among transgender women on gender-affirming hormones and sheds light on an important reason for delays in diagnosing prostate cancer in transgender women. However, much work remains. Further research should aim to establish proper PSA cutoffs, create tools to guide how best to perform screening in this population, and understand additional barriers that may impact transgender women of color. Although much work remains, this is an important and impactful area to help create inclusive and patient-centered practices to better care for transgender patients.

Funding

R38AG070171, 2023 Urology Care Foundation™ Residency Research Award.