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Prostate-specific antigen (PSA) testing may not accurately pinpoint levels at which transgender women on estrogen therapy may be at risk of developing prostate cancer, according to data from the Veterans Health Administration (VHA).

Among a group of more than 200 transgender women who were taking estrogen and were without prostate cancer, the median PSA value was 0.02 ng/mL -- 50-fold lower than the value reported in studies of similarly aged cisgender men without known prostate cancer, reported Farnoosh Nik-Ahd, MD, of the University of California San Francisco, and colleagues in a research letter published in .

Furthermore, more than a third of these transgender women receiving estrogen had undetectable PSA.

The extremely low PSA values for these transgender women receiving estrogen indicate "that the historic cut point of 4 ng/mL, often used as a threshold for further evaluation, is likely far too high a threshold for this population," Nik-Ahd and colleagues wrote.

Thus, they suggested that PSA values in transgender women should be interpreted cautiously. "Further studies are needed to understand the risks and benefits of PSA screening in this population and to establish ideal prostate cancer screening practices," they noted.

In a , co-author Stephen Freedland, MD, of Cedars-Sinai Medical Center in Los Angeles, said that "many transgender women take estrogen as a part of their gender-affirming care. This drastically lowers PSA levels, which could mean the threshold we are using as 'normal' is too high to detect early-stage cancer in these patients."

He added that while the best way to find prostate cancer early is through PSA testing, transgender women should "keep in mind that the test values are not calibrated for [them]" and that the results should be interpreted by a urologist.

The same research team published a study that indicated that the risk of prostate cancer among transgender women is greater than prior reports have suggested.

Moreover, that study showed that transgender women receiving estrogen at diagnosis had the most aggressive disease, with 25% of transgender women overall, and 35% receiving estrogen, having biopsy grade group 4 or 5 disease compared with only 16% of cisgender male veterans, suggesting potential delayed diagnosis.

"A possible reason for delayed diagnosis may be the absence of PSA reference ranges specific to transgender women receiving gender-affirming hormones," wrote Nik-Ahd and colleagues. "Due to the castrating effects of gender-affirming hormones, PSA, whose production is androgen-regulated, would be expected to be lowered."

Therefore, the researchers sought to determine PSA values among a nationwide cohort of transgender women receiving estrogen.

Using VHA records from January 2000 to August 2023, Nik-Ahd and colleagues identified 210 patients who met study criteria: confirmed identity as a transgender woman, no prostate cancer diagnosis, receiving estrogen (regardless of orchiectomy status/other gender-affirming hormone usage), and PSA test performed between ages 40 and 80 years while receiving estrogen for 6 or more consecutive months.

Of this group, 86% were white, and just 2% were Black or African-American. Mean age was 60 years, and median estrogen duration at time of PSA assessment was 4.7 years.

At the time of PSA measurement, 89% of patients had received spironolactone, 39% had received progesterone, 30% had received finasteride, 3% had received goserelin, and 5% had received leuprolide. About half of patients underwent bilateral orchiectomy prior to PSA measurement.

The authors noted that the low percentage of Black patients in the study was consistent with prior studies showing that fewer Black transgender women had prostate cancer. "Additional studies examining the experiences of minority transgender women and inequities in prostate cancer screening are needed," they suggested.

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