Challenges to Standard Prescribing Guidance for Gender-Affirming Hormone Therapy Require Future Research Endeavors

HRT. Hormone Replacement Therapy acronym on sticky notes. Office desk background
In this clinical practice review correspondence recently published in the Journal of Clinical Endocrine and Metabolism, physicians challenge some of the standard prescribing guidance for gender affirming hormone therapy.

Challenges to standard prescribing guidance for testosterone and estradiol in gender-affirming hormone therapy require future research to evaluate clinically desirable endpoints in the context of risk reduction. This is according to a review article published in the Journal of Clinical Endocrinology and Metabolism.1

A recent article published in the Journal of Clinical Endocrinology and Metabolism2 by India I. Pappas, MD, and colleagues, used new data to challenge the standard prescribing guidance for gender-affirming hormone therapy. Through a retrospective cohort study, investigators sought to determine first how often testosterone and estradiol therapy alone might effectively suppress gonadal function in male-to-female and female-to-male transgender patients, and second, the frequency and range of serum estradiol levels above the normal male range in female-to-make patients who were receiving testosterone therapy.

According to the authors of the response article,1 it is well-accepted that most transmasculine individuals only require exogenous testosterone therapy. Net serum estradiol levels typically fall following exogenous testosterone therapy, although these levels may, in some cases, remain “above the typical male physiologic range.” In the article by Dr Pappas and colleagues, estradiol levels in transmasculine patients fell into this latter category. It is not, however, clear if these levels should be checked routinely.

Estradiol dosing guidelines recommend a range of 2 to 6 mg daily for male-to-female transgender patients. In the original study, these patients required doses of up to 10 mg per day to achieve testosterone suppression—a reason worth, the authors wrote, revisiting the currently available suggestions in the literature.

They also noted that Dr Pappas’ research called into question the truth that “physiologic estrogen dosing alone is necessarily insufficient to suppress testosterone in the absence of adjunct therapy.”

Questions regarding the use of anti-androgen therapies to suppress gonadal function were also raised, hinging on the “technicality” of whether spironolactone is considered an anti-androgen therapy. The response authors call this answer complicated, writing that while spironolactone blocks androgen action at the receptor level, it may also reduce testosterone levels.

“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,” the authors noted.

“Achieving amenorrhea is a clear, attainable goal of hormone therapy for the transgender men,” the authors concluded. “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 in order to reduce excess risk.”

Disclosure: One study author declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


1.  Reisman T, Safer JD. New data to challenge gender affirming hormone therapy prescribing practice. Published online February 1, 2021. J Clin Endocrinol Metab. doi: 10.1210/clinem/dgab006

2.  Pappas II, Craig WY, Spratt LV, Spratt DI. Efficacy of sex steroid therapy without progestin or GnRH agonist for gonadal suppression in adult transgender patients. J Clin Endocrinol Metab. 2021;106(3):e1290-e1300.