Response to Letter to the Editor: “Progesterone Is Important for Transgender Women’s Therapy—Applying Evidence for the Benefits of Progesterone in Ciswomen”

Thank you for reading my recent Perspective article, suggesting that progesterone would be an important addition to transgender women’s gender-affirming hormone therapy (GAHT) that now usually consists of high-dose estradiol, with or without an antiandrogen (1). I appreciate the commitment that we all share to the practice of GAHT, as it evolves from physiology to evidence-supported clinical practice. Surely, physicians and endocrinology specialists believe that women’s reproduction requires both estradiol and progesterone. The development of secondary sexual characteristics is also positively affected by both of these ovarian hormones. We know that estradiol interacts with receptors in multiple tissues and influences numerous physiological systems (hence, the Women’s Health Initiative’s hypothesis that estrogen would protect against women’s cardiovascular disease). Evidence from multiple tissues and in many species has shown further that estradiol and progesterone are part of a unified system in which estradiol primarily causes cellular proliferation, and progesterone stimulates cellular maturation while counterbalancing overproliferation (2). It is therefore reasonable that transgender women should have access to both important hormones in a physiological reproductive system. I appreciate that we currently have no systematic assessments of transgender women’s lobular breast maturation, as likely reflected by differences in areolar size. A testable hypothesis is that that the areola will enlarge with estrogen–progesterone therapy; we showed this in early photo-documented clinical observations (3). The quoted Wierckx et al. (4) paper did not measure areolar diameter. It is clear from many studies and a meta-analysis in cisgender women that breast cancer risks are lower on estrogen–progesterone than on estrogen–progestin (5). That makes it even more important that authors not extrapolate, as they did in their letter, from Women’s Health Initiative data that tested medroxyprogesterone and did not study the physiological actions of progesterone. Randomized controlled trial data are required to assess whether the addition of progesterone to transgender women’s GAHT causes positive areal bone mineral density (BMD) and bone strength changes. The quoted Wiepjes et al. (6) 2018 paper suffers from limitations consistent with its retrospective nature (only 33% had any follow-up) but does suggest that the lower BMD may precede GAHT. They would have learned much more by inquiring about the development of fractures in their many participants. A more thoughtful and likely accurate approach to evaluation of BMD in transgender people is to use the strategy of Hammond et al. (7): to analyze and report the BMD data using the age-specific reference ranges for both the natal sex and the chosen gender. To be clear, I have written nothing in my Perspective article about “cardiovascular benefits with progestins.” I only discussed progesterone. Conflating progesterone and progestins is not accurate nor scientific—progesterone is a unique and foundational steroid near the top of the steroid cascade, as well as an ovarian hormone. The progestins, by contrast, are varied, created from different steroid species and without even a class effect. The term “progestins” only applies to drugs that mimic the endometrial and pregnancy-preserving effects of progesterone. Progestins have numerous (largely unexplored) effects on myriad other physiological systems, and many of these differ from those of progesterone. Evidence suggests that progesterone, as well as estradiol, is needed to preserve ciswomen’s “cardiovascular protection” compared with men (8). That is supported by data from a 3-month, placebo-controlled randomized controlled trial in which there were no negative cardiovascular markers or anthropometry effects of oral micronized progesterone (300 mg at bedtime) in healthy postmenopausal women (9). As far as I could find, there are no endothelial function data on progesterone in cisgender men or transgender women. This letter raised the issue of my Perspective being “premature and potentially dangerous.” I agree that it may seem early in the thought processes of some providers of transgender health care. However, I challenge the authors to show evidence that the addition of progesterone to transgender women’s GAHT is harmful. Progesterone would be beneficial if it allowed even a 25% reduction in the usually double physiological estradiol doses (10). Meanwhile, I also look forward to the systematic review on progesterone promised by the World Professional Association for Transgender Health. What I do know is that transgender women are asking for progesterone therapy. This is a physiologically sensible intervention that is desired by our patients. As a goal of transgender women’s GAHT is to “maintain hormone levels within the normal range for individuals of the person’s chosen gender” (11), as the Endocrine Society guidelines advocate, then progesterone therapy becomes necessary. It is up to those of us who care about transgender health to do the science that proves or disproves that transgender women deserve the benefits we are now learning that progesterone is providing for ciswomen. bone mineral density gender-affirming hormone therapy

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