Gender dysphoria describes the distress associated with having a gender identity that differs from one’s birth-assigned sex. To relieve this distress, transgender, and gender diverse (henceforth, trans) individuals commonly undergo medical transition involving hormonal treatments. Current hormonal treatment guidelines cater almost exclusively for those who wish to transition from male to female or vice versa. In contrast, there is a dearth of hormonal options for those trans individuals who identify as non-binary and seek an androgynous appearance that is neither overtly male nor female. Though prolonged puberty suppression with gonadotrophin releasing hormone agonists (GnRHa) could in theory be gender-affirming by preventing the development of unwanted secondary sex characteristics, this treatment option would be limited to pre- or peri-pubertal adolescents and likely have harmful effects. Here, we discuss the theoretical use of Selective Estrogen Receptor Modulators (SERMs) for non-binary people assigned male at birth (AMAB) who are seeking an androgynous appearance through partial feminization without breast growth. Given their unique range of pharmacodynamic effects, SERMs may represent a potential gender-affirming treatment for this population, but there is a lack of knowledge regarding their use and potentially adverse effects in this context.
Given their tissue-specific antagonistic and agonistic effects, SERMs could potentially be suitable either as an independent or combined treatment modality for the gender-affirming care of non-binary individuals AMAB who desire partial feminization without breast growth. Specific SERMs (Table 1) have been shown to inhibit breast and endometrial tissue growth, while exhibiting beneficial estrogenic effects on bones in pre- and post-menopausal cisgender women (35, 43). These effects are not well-studied in people AMAB. Theoretically, a SERM with anti-estrogenic effects on breast but estrogenic effects on bone, fat composition, and skin might offer appeal as a hormone treatment for a non-binary person AMAB who desires an androgynous body.
While SERMs could be used independently for non-binary adults AMAB to induce partial feminization, SERMs alone would not be expected to block unwanted pubertal masculinization in non-binary adolescents AMAB. Androgen blockade would still be required in this younger population. In the following sections, we explore the theoretical use of SERMs in this context, extrapolating from what is known about their use in other situations.
Whilst SERMs should not be routinely recommended as treatment options, clinicians may encounter scenarios where SERMs may be requested by patients AMAB who desire feminization of skin or fat distribution without breast growth. Indeed, we are aware of SERMs already being used anecdotally by adults in this context. For patients wanting to use SERMs to affirm their gender, the lack of evidence for efficacy or safety must be highlighted, and there should be a clear explanation that treatment is experimental. To provide informed consent, individuals need to understand the selective differential effects of SERMs, their potential lack of benefit, and the risk of adverse effects. If a shared decision between patient and doctor is made to trial the use of a SERM, then clear goals of treatment (e.g., fat redistribution) over a pre-specified timeline (e.g., 3-6 months) should be determined. If treatment goals are not achieved, treatment should be ceased. Given Raloxifene is the only SERM with evidence for agonistic effects on fat and body composition (40, 41), it would appear to be the most suitable choice at present and would ideally be used in the context of a prospective research study. Consistent with this, clinical trials – ideally across multiple centers to aid in patient recruitment – are required to provide greater evidence regarding the potential benefits and harms of using SERMs in non-binary individuals.
In the clinical setting, increasing numbers of non-binary individuals are seeking gender-affirming hormone therapy, and some desire androgynous physical characteristics to align with their gender identity. This can pose challenges in tailoring treatment options, and a lack of well-defined therapeutic pathways leaves non-binary people at risk of persistent GD and ongoing vulnerability to adverse mental health outcomes. SERMs may be a theoretically attractive option for non-binary people AMAB who desire partial feminization without breast growth. However, there is a dearth of evidence regarding the safety and efficacy of SERMs in this context. An individualised, shared decision-making approach to care is therefore needed when considering the use of SERMs in non-binary people, with acknowledgement of their experimental nature, significant potential risk and need for further research.
Xu, J. Y., O’Connell, M. A., Notini, L., Cheung, A. S., Zwickl, S., & Pang, K. C. (2021). Selective estrogen receptor modulators: A potential option for non-binary gender-affirming hormonal care? Frontiers in Endocrinology, 12, Article 701364. https://doi.org/10.3389/fendo.2021.701364
― 18 Jun 2021