New Data to Challenge Gender-Affirming Hormone Therapy Prescribing Practice

Tamar Reisman; Joshua D. Safer


J Clin Endocrinol Metab. 2021;106(5):e2365-e2366. 

Transgender people often use gender-affirming hormone therapy to better align their bodies with their gender identities. Because of a paucity of rigorous data for optimal hormone prescribing, guidelines and reviews often default to physiologic levels in surrogate populations along with expert opinion.[1,2]

In this issue of the Journal of Clinical Endocrine and Metabolism,[3] Pappas et al challenge some standard prescribing guidance with data gleaned from a retrospective review of their clinic experience. The intention of the authors was to determine the degree to which gender-affirming goals could be achieved with hormone therapy alone in the absence of adjunctive agents. Specifically, how often either trans masculine individuals or trans feminine individuals could achieve treatment goals without either progestins or GnRH agonists.

With masculinizing therapy, it is already well accepted that the only treatment most trans masculine individuals require is exogenous testosterone. It is not surprising that the median total testosterone level for the patients reviewed by Pappas et al was 712 ng/dL and that 91% of the patients evaluated ceased menstruating. It is possible that menstrual suppression would be achieved in the remainder with modest testosterone dose increases, leaving them with levels still inside the usual physiologic male range.

Without always knowing the estrogen source, we and others have found that net serum estradiol levels fall with exogenous testosterone administration,[4] albeit to levels that are sometimes above the typical male physiologic range. Although estradiol levels among the trans masculine patients in the study by Pappas et al were higher than the typical male physiologic range, consistent with either aromatization of exogenous testosterone, remaining endogenous estrogen production, or some combination, it is not clear if there is a concern that merits checking these levels routinely. For now, the data from Pappas et al reinforce the current guidance regarding gender-affirming hormone treatment for transgender men.

With feminizing therapy, the findings of Pappas et al raise more questions. Although guidelines posit estradiol dose ranges of 2 to 6 mg daily for feminizing treatment, Pappas et al observed that they and others required estradiol doses up to 10 mg daily to achieve testosterone suppression into the typical female physiologic range, a possible reason to revisit the dosing suggestions in the literature.

Notably, Pappas et al found that testosterone levels were suppressed to the typical female range in 84% of their patients, calling into question whether it is always true that physiologic estrogen dosing alone is necessarily insufficient to suppress testosterone in the absence of adjunct therapy. Weakening the authors' argument, Pappas et al claim that spironolactone should have no testosterone-suppressing impact. The authors are so confident that virtually their entire cohort of transgender women ostensibly on estrogen therapy alone were actually also taking spironolactone.

The argument that most transgender women do not need an antiandrogen to suppress gonadal function thus hinges on the technicality of whether we consider spironolactone to be an antiandrogen. The answer is complicated. Spironolactone blocks the action of androgens at the receptor level, but also may reduce testosterone levels. Spironolactone has been reported to prevent testosterone secretion in rats, guinea pigs, dogs, and goats.[5–7] Several older studies describe similar decreases in testosterone level among human cisgender men.[8] Although the degree to which spironolactone suppresses testosterone levels is the subject of debate, the definitive study of the power of estradiol alone remains for the future.

Pappas et al also observed that the serum estradiol levels they measured were more modest than stated in guidelines. The authors chose to limit the estradiol dose to the minimum necessary to suppress testosterone. There is logic for such an approach: hypogonadism in cisgender men results in gynecomastia. Thus, Pappas et al were able to observe that on some occasions their patients achieved testosterone levels at goal with estradiol levels lower than the ranges noted in the guidelines. As the authors suggest, if venous thromboembolism risk from exogenous estrogens correlates with dose, perhaps the goal for feminizing hormone therapy should be the lowest estrogen dose that achieves the goal testosterone level.

The fallibility of estradiol levels as a surrogate for estrogen action was also observed. The authors found that suppression of menses in their trans masculine patients did not correlate with measured estradiol levels. Even more striking, as we and others have noted, higher administered doses of exogenous estradiol did not always correlate with higher serum estradiol levels. Conversion of exogenous estrogens to metabolites including estrone may be a significant component of metabolism and action which will await better assays to be understood.

Finally, in this study, achieving amenorrhea is a clear, attainable goal of hormone therapy for the transgender men. There is no analogous clinical endpoint for the study's transgender women. Future studies should investigate the degree to which clinically desirable endpoints, such as breast size or patient satisfaction, can be achieved with lower estradiol levels to reduce excess risk.