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Expert Critique

FROM THE ASCO Reading Room

Justin B. Echouffo Tcheugui MD, PhD Johns Hopkins University

An estimated 1.4 million people, or 0.6% of the U.S. population identify as transgender. In order to transition, most transgender individuals undergo hormonal therapy, with transgender men receiving exogenous androgens for virilization.

Given the risks (bone loss and undesired cosmetic changes) associated with testosterone therapy for transgender men, historically, estrogen blockers have been viewed as a means of mitigating these risks. Hitherto, the findings on the need for estrogen blockers as a counterweight to testosterone therapy have been mixed. A recent study examined this important question based on retrospective data from electronic medical records for 34 transgender men (age 18 to 68 years) receiving testosterone therapy over a 6-year period, at a single medical center. In this group, the standard approach to transmasculine hormone therapy included weekly testosterone injections (testosterone cypionate or testosterone enanthate, typical maximum weekly dose of 125 mg) with no use of estrogen blockers. The peak serum testosterone levels were measured 24-48 hours after the weekly testosterone injection, with trough levels measured immediately before. The objective was to reach a testosterone level within the normal range for non-transgender men, with trough levels at 1 week > 300 ng/dL. Once the steady-state doses were achieved after about 9 months, peak testosterone levels remained constant at an average of 650 ng/dL. There was a substantially decrease in serum estradiol levels with increasing testosterone, from a baseline average of 81 pg/mL to an average of 54 pg/mL upon the initiation of therapy. At steady state, estradiol levels did not change over 6 years. Furthermore, estradiol levels were not significantly affected by body mass index. Overall, in these testosterone-creating transgender men, the estrogen levels over time were similar to or lower than levels prior to treatment. There was no evidence for elevated estradiol levels that would require mitigation with aromatase inhibitors.

These findings suggest that testosterone therapy is unlikely to suppress the hypothalamic-pituitary axis through aromatization, resulting in a reduction in estradiol. Consequently, there is also no need to worry about bone health with estrogen, an issue that has been controversial as previous evidence suggested that change from female to male increases the risk of bone resorption. There is also no ground for worrying about undesirable estrogenic effects such as gynecomastia in males.

The main clinical implication of the recent findings is that although antiestrogens or aromatase inhibitors have been viewed as a counterpoint to testosterone therapy, there is no need to block estrogen. In brief, giving testosterone treatment to a transgender man is the same as giving testosterone to any man.

Full Critique

Testosterone therapy for transgender men is no more risky or complex than testosterone therapy for any other man.

That's the essence of new study data published in the April issue of . Study authors arrived at their findings after examining the electronic medical records for 34 transgender men who received testosterone therapy at the Endocrinology Clinic at Boston Medical Center.

Scientists measured estradiol levels in transgender men over years of testosterone therapy. Some clinicians have historically viewed estrogen blockers as a means of mitigating risks related to testosterone therapy in this population, including bone loss and undesired cosmetic changes.

Findings have been mixed on the need for estrogen blockers as a counterweight to testosterone therapy. Authors of the new study, however, indicate that they are not necessary.

"There has historically been a misconception that the treatment is more complicated than it is. This simplifies things substantially," said study co-author Joshua Safer, MD, an endocrinologist and executive director of the Center for Transgender Medicine and Surgery at Mount Sinai Health System in New York. "Estrogen levels among testosterone-creating transgender men were about the same before they were treated, and sometimes a little bit lower."

Transgender individuals are defined as people with a gender identity different from his or her external sexual anatomy at birth. According to The Williams Institute at the UCLA School of Law, which compiles and releases data on transgender populations, 1.4 million adults or 0.6% of the U.S. adult population identify as transgender. Most transgender individuals undergo hormone therapy as part of their transitions, with most transgender men receiving exogenous androgens to virilize the individual.

Data on the 34 men studied in April's report came from EMR charts and went back through 6 years of testosterone therapy treatment. Ages ranged from 18-68 years, with a median age of 31 and an average age of 33.

At Boston Medical Center, the standard approach to transmasculine hormone treatment includes weekly testosterone injections, with testosterone cypionate and testosterone enanthate used interchangeably. The typical maximum dose is 125 mg each week. No estrogen blockers are used in treating transgender men.

Clinicians measured peak testosterone levels 24-48 hours after the weekly testosterone injection, with trough levels measured immediately before. The objective is reaching a serum testosterone level within the normal range for nontransgender men, with trough levels at 1 week kept above 300 ng/dL.

In the group of 34 patients, 22 started testosterone at the beginning of the investigated range, and 12 started testosterone prior to that. Researchers analyzed the groups separately and found no difference between them.

Testosterone levels rose among the patients from baseline (35 ng/dL) to several months after treatment was initiated (P<.0001). Over the longer term, once steady-state doses were achieved after about 9 months, peak testosterone levels did not significantly change, remaining constant at an average of 650 ng/dL.

A regression analysis of serum estradiol revealed a significant decrease in estradiol levels with respect to increasing testosterone (P<.02). A regression analysis of serum estradiol with respect to time revealed a decline in estradiol levels, from a baseline average of 81 pg/mL to an average of 54 pg/mL upon the initiation of therapy. At steady state, estradiol levels did not change over 6 years (P=.2).

Estradiol levels in transgender men also were not significantly affected by body mass index, as Safer and colleagues found no correlation between BMI and regression of estradiol (P=.96).

"Previous authors have reported a decrease in estradiol levels over shorter follow-up periods, suggesting that testosterone treatment can suppress the hypothalamic-pituitary axis with a resulting reduction in endogenous sex steroids, including estradiol," Safer and colleagues wrote. "We found that there was a significant decrease in estradiol levels with increasing testosterone treatment ....The key finding from our data is that it is extremely unlikely that there was an unappreciated rise in serum estradiol levels secondary to aromatization from exogenous testosterone."

Clinical Implications

For clinicians, the new findings could essentially result in a case of addition by subtraction.

"People should be reassured that there's no need to block estrogen," Safer said. "This is straightforward to do. It's not a complex regimen to keep track of over time. There is no need to worry about bone health with estrogen."

The issue has been a source of controversy, with findings on both sides. For example, a found that "those who underwent a change from female to male had increased bone resorption and decreased [bone mineral density]."

Although antiestrogens or aromatase inhibitors are sometimes viewed as a counterpoint to testosterone therapy, study authors said their data show that mitigating strategies are unnecessary.

"In non-transgender populations, there is reported concern for undesirable estrogenic effects in male-bodied individuals administered exogenous testosterone," Safer and colleagues wrote. "Reports have also associated increased serum estradiol levels with risk of gynecomastia in males in general .... Estradiol levels remain within the normal range in medically treated transgender men and do not rise. Thus, there is no evidence for elevated estradiol levels that may need to be mitigated with aromatase inhibitors."

As a result, simple testosterone therapy is sufficient for transgender men who choose to undergo it. Safer suggested that the finding could lead more clinicians to recommend or administer the treatment.

"The biggest takeaway for clinicians is that giving testosterone treatment to a transgender man is the same as giving testosterone to any man," Safer said. "Transgender men are not more complicated than any other man."