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Review
. 2022 Dec;7(12):1268-1279.
doi: 10.1016/j.bpsc.2022.07.002. Epub 2022 Jul 18.

Centering the Needs of Transgender, Nonbinary, and Gender-Diverse Populations in Neuroendocrine Models of Gender-Affirming Hormone Therapy

Krisha Aghi  1 , Teddy G Goetz  2 , Daniel R Pfau  3 , Simón E D Sun  4 , Troy A Roepke  5 , Eartha Mae Guthman  6
Affiliations
Review

Centering the Needs of Transgender, Nonbinary, and Gender-Diverse Populations in Neuroendocrine Models of Gender-Affirming Hormone Therapy

Krisha Aghi et al. Biol Psychiatry Cogn Neurosci Neuroimaging. 2022 Dec.

Abstract

Most studies attempting to address the health care needs of the millions of transgender, nonbinary, and/or gender-diverse (TNG) individuals rely on human subjects, overlooking the benefits of translational research in animal models. Researchers have identified many ways in which gonadal steroid hormones regulate neuronal gene expression, connectivity, activity, and function across the brain to control behavior. However, these discoveries primarily benefit cisgender populations. Research into the effects of exogenous hormones such as estradiol, testosterone, and progesterone has a direct translational benefit for TNG individuals on gender-affirming hormone therapies (GAHTs). Despite this potential, endocrinological health care for TNG individuals remains largely unimproved. Here, we outline important areas of translational research that could address the unique health care needs of TNG individuals on GAHT. We highlight key biomedical questions regarding GAHT that can be investigated using animal models. We discuss how contemporary research fails to address the needs of GAHT users and identify equitable practices for cisgender scientists engaging with this work. We conclude that if necessary and important steps are taken to address these issues, translational research on GAHTs will greatly benefit the health care outcomes of TNG people.

Keywords: Hormones; Metabolism; Mood; Social behavior; Stress; Transgender.

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Conflict of interest statement

The authors reported no biomedical financial interests or potential conflicts of interest.

Figures

Figure 1.
Figure 1.
Recommendations for rodent models of GAHT. (A) Classic endocrinology studies use GDX and hormone replacement to study the role of individual hormones. Researchers should take care to best model the human condition. GAHT in trans men and transmasculine people typically involves exogenous T treatment, GAHT in trans women and transfeminine people typically involves exogenous E2 and antiandrogen treatment, sometimes combined with P4, and transgender people who have their gonads removed do so later in life after the initiation of GAHT (3,15). Therefore, better models of GAHT should use intact animals at pubertal, adult, and aged time points. In adults and aged animals, untreated, intact animals with ovaries and testes should be compared with intact animals with ovaries treated with T and intact animals with testes treated with antiandrogens, E2, and/or P4. Commonly used antiandrogens include spironolactone, cyproterone acetate, and finasteride; all 3 antiandrogens have distinct mechanisms of action and off-target effects (3). Models using all 3 should be tested in translational studies. In peripubertal animals, untreated intact mice should be compared with intact mice treated with a GnRH agonist, such as leuprolide. (B) Owing to the high levels of chronic stress faced by transgender, nonbinary, and/or gender diverse populations, researchers should strive to assess both the effect of GAHT on stress systems in the brain and periphery and the effect of various stressors on the efficacy of GAHT relative to particular experimental end points. Care should be taken to assess the effects of stressors occurring prior to, during, and after the onset of exogenous hormone treatment. (C) Relevant timelines for rodent models of GAHT. E2, estradiol; GAHT, gender-affirming hormone therapy; GDX, gonadectomy; GnRH, gonadotropin hormone-releasing hormone; P4, progesterone; T, testosterone.
Figure 2.
Figure 2.
Key neuroanatomical regions to consider in gender-affirming hormone therapy studies in both rodent animal models and humans. Certain brain regions are especially relevant to the study of gender-affirming hormone therapies, indicated in (A) murine and (B) human central nervous systems. Broad anatomical regions are indicated by uppercase abbreviations, with key subregions indicated in lowercase. (C) Schematic summarizing the relative expression levels of canonical nuclear hormone receptors in the murine brain, with darker shades indicating higher expression. Data represented includes both immunolocalization of receptor protein and receptor messenger RNA in adult rodent models. This summary does not include membrane or other hormone receptors (Table 1) and does not account for known isoform, developmental, and sex variability. [Visualizations based on data presented in (,,–92)]. a, anterior; ah, anterior hypothalamus; AMY, amygdala; AR, androgen receptor; arc, arcuate nucleus; avpv, anteroventral periventricular nucleus; BNST, bed nucleus of the stria terminalis; CBL, cerebellum; cin, cingulate; CTX, cortex; dr, dorsal raphe; ER, estrogen receptor; HPF, hippocampal formation; HYP, hypothalamus; lc, locus coeruleus; mea, medial amygdala; MID, midbrain neuromodulatory centers; mpoa, medial preoptic area; nac, nucleus accumbens; OLF, olfactory bulb; p, posterior; pa, posterior amygdala; pag, periaqueductal gray; pfc, prefrontal cortex; pmv, ventral premammillary nucleus; poa, preoptic area; PR, progesterone receptor; SA, septal area, includes medial and lateral septal nuclei; sn, substantia nigra; STR, striatum; vmhvl, ventromedial hypothalamus ventrolateral division; vta, ventral tegmental area.
Figure 3.
Figure 3.
Questions and considerations for effective biomedical research on GAHTs. Summary for research questions and considerations presented in this review. Understanding GAHT requires understanding how GAHT affects certain brain functions (research question 1) and what factors affect GAHT to achieve beneficial outcomes for TNG individuals (research question 2). For researchers engaging in TNG-relevant research, it is important to properly engage with TNG communities in several ways: learning about TNG people outside of the immediate biological question, involving TNG individuals who are interested in participating, and supporting TNG people who wish to contribute. E2, estradiol; GAHT, gender-affirming hormone therapy; P4, progesterone; T, testosterone; TNG, transgender, nonbinary, and/or gender diverse.
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