TL;DR The statement is MISLEADING. The experiments use mice to analyze the impact of sex hormones when it comes to multiple health-related issues, including the immune response to the HIV vaccine, breast cancer, and asthma prevalence, among other things.
Mice are given sex hormones to study their effects on these cases. The goal is not to turn them into Transgender animals. As far as we know, transgenderism itself is a concept specific to humans.
Note: Most of these researches are still underway, no results are publicized yet.
The White House Article is available here.
Experiment 1: A Mouse Model to Test the Effects of Gender-affirming Hormone Therapy on HIV Vaccine-induced Immune Responses
This experiment is funded by NIH and is reported here.
The abstract of the paper is as follows:
Biological sex impacts the immune system, as evidenced by differences between men and women in vaccine- induced humoral responses. There is a considerable gap in knowledge, however, surrounding the immunological responsiveness of transgender people, a population at considerably higher risk for HIV and other STIs. To address this gap, we propose to develop an animal model of feminizing hormone therapy to study the effects of estrogen/anti-testosterone therapy on HIV vaccine-induced immune responses. Cross-sex hormone therapy (XHT) is the most common approach for transition-related care, but immunological studies of transgender individuals are generally limited to case studies. Animal models of gonadectomy and/or supranormal hormone treatment have implicated sex hormones as potent modulators of the immune system, with estrogens generally appearing to enhance immune responses and testosterone inhibiting them. However, ambiguous (and sometimes paradoxical) observations have obscured an overarching consensus for sex hormone effects on immunity. In recent years, mouse models of XHT have provided important insights into effects of prolonged hormone therapy on bone physiology, reproductive function etc., but information on the effects of sex hormone therapy on immune responsiveness is scarce. For this project, we will develop a mouse model of XHT that recapitulates clinical hormone therapy for male-to-female transition in humans. We hypothesize that mice and humans share sets of immune-related genes that are impacted by a feminizing hormone regimen, and that mice undergoing XHT will exhibit altered immune responses to a HIV vaccine compared to control male mice. To test these hypotheses, we will define the relevance of this mouse model to human transition-related care through a single-cell transcriptomics approach to define differentially expressed genes in control and XHT mice, and then compare these cell-type specific sets of differentially expressed genes to those obtained from the same analyses of people undergoing feminizing hormone therapy (pre and two years post-initiation of hormone therapy) (Specific Aim 1). To test the effects of hormone therapy on in vivo vaccine responses, we will immunize control male mice and XHT mice with a HIV vaccine regimen that is highly sensitive to sex-dependent factors (Specific Aim 2). Should this study reveal an immunoregulatory effect of feminizing hormone therapy on HIV vaccine responsiveness in mice, it will provide a new platform for assessing the effects of sex hormones on vaccine responses. Moreover, this animal model could then be used to test various vaccination parameters (adjuvant, dose, interval, etc.) for sex hormone-dependent effects, with the ultimate goal of designing an HIV vaccine that maximizes efficacy but minimizes adverse outcomes.
Explanation:
- Previous studies have found that sex hormone plays a huge role in how an individual’s immune system works.
- The effects of some vaccines are dependent on these hormones.
- Specifically, this research focuses on how hormone therapy affects the effectiveness (and adverse outcomes) of the HIV vaccine.
- Note that hormone therapy isn’t only used for Transgender individuals. Hormone therapy is a treatment that includes both menopausal hormone therapy and testosterone replacement therapy.
- The market for testosterone replacement therapy alone in the US is valued at $848 million in 2023 (Read more here).
Conclusion:
Labeling this study as “transgender experiments” ignores the broader medical importance of hormone therapy. The research aims to enhance vaccine effectiveness for people undergoing hormone treatments such as menopausal therapy, TRT, or gender-affirming care.
Experiment 2: Reproductive Consequences of Steroid Hormone Administration
Experiment report here. The abstract is as follows:
Recent data estimates 1.4 million transgender adults and 150,000 transgender adolescents live in the United States, many of whom are on cross-sex hormone therapy with estradiol or testosterone (T). National and international medical organizations recommend fertility preservation counseling prior to initiation of cross-sex hormone therapy, based on an assumption of fertility loss. However, the impact of long-term cross-sex hormone therapy on reproductive health is largely unknown, particularly in transgender men (female-to- male or FTM). The available human studies suggest ovarian changes from cross-sex T therapy, but are observational studies, with conflicting results. Moreover, there is a lack of data on the fecundity of T-treated transgender men, and there have been no studies that address the reversibility of T-induced changes after cessation of T for reproductive purposes. There are also no studies on future reproductive consequences of the treatment paradigm for transgender adolescents, in which GnRHa is initiated in the early peripubertal period to suppress further pubertal progression prior to transitioning directly to T therapy (GnRHa-T). None of the existing animal models that address the effect of androgens on reproductive function in females are directly applicable to the clinical paradigm of cross-sex T therapy in transgender men or GnRHa-T therapy in transgender adolescents. To address this knowledge gap, we have developed a mouse model to mimic T treatment for FTM gender transition. These mice manifest defects in ovarian architecture and have altered folliculogenesis. This model provides a powerful tool to clarify the effects of T therapy on reproductive phenotype and function, in a manner not possible in humans. The objective of the proposed studies is to use the FTM mouse model to investigate the effects of cross-sex T treatment on reproductive phenotype and function, and determine the reversibility of these effects following cessation of T. Our central hypothesis is that T therapy will adversely affect ovarian architecture and fertility, but that fertility can be recovered with cessation of T, without adverse reproductive effects in offspring. To test this hypothesis, we will examine the reversibility of postpubertal T administration in female mice, mimicking FTM gender transition, on reproductive phenotype (AIM 1), and examine fertility during and after cessation of long-term testosterone therapy, including reproductive phenotype in offspring (AIM 2). In an exploratory aim, we will examine the reproductive consequences of testosterone administration after pretreatment with peripubertal GnRHa, mimicking FTM cross-sex hormone therapy in adolescents, on reproductive phenotype and fertility (AIM 3). This proposal challenges the status quo of recommending fertility preservation prior to cross-sex T therapy, and will lay the foundation for further translational studies. Our long-term goal is to provide the necessary data for evidence-based fertility counseling of transgender men. Clarifying the effects and reversibility of cross-sex T therapy on the reproductive tract could lead to future paradigm shifts in clinical fertility care of transgender men.
Explanation:
- Previously, it was believed that transgender men would face permanent reproductive issues.
- This, of course, is an issue any would-be transgender men have to weigh into consideration before transition.
- This research aims to see if this reproductive issues are permanent of not if cross-sex hormone are halted.
Conclusion:
Mice were used to model transgender men to assess whether cross-sex hormone therapy leads to permanent reproductive issues. This work provides a foundation for future clinical studies that could improve fertility counseling and care for transgender individuals.
Experiment 3: Gender-Affirming Testosterone Therapy on Breast Cancer Risk and Treatment Outcomes
Experiment report here. The abstract is as follows:
This proposal will undertake preclinical studies to address breast cancer (BC) risk and treatment concerns of transmasculine people (female-to-male transition). This proposal will also elucidate the interplay of miRNAs and testosterone in mammary gland development, carcinogenesis, and response to BC treatment. Most transmasculine individuals pursue testosterone therapy (TT) to treat their gender dysphoria. The breast is a sex hormone-sensitive organ. Transmasculine individuals who receive TT are now a subject of concern – very little is known about how such high levels of testosterone affect the breast and subsequently risk of developing BC. Prospective human studies will take decades. Mouse aging is accelerated by a factor of 70 compared to humans, and the hormone regulation of breast development is similar in mice and humans. Aim 1 will use two mouse models to clarify the extent to which TT affects the risk of developing estrogen receptor positive (ER+) and negative (ER-) BC. We will compare the incidences and tumor specific survival in female mice (intact) and oophorectomized female mice receiving TT with their respective counterparts that do not receive TT (Aim 1.1). On the other end of the spectrum, for transmasculine patients diagnosed with BC, there are neither clinical guidelines nor risk-benefit studies on whether they can continue TT while being treated for BC. There is a gap in knowledge about whether testosterone affects the efficacy of BC treatment. The discontinuation of TT is undesirable as it affects these patients’ emotional wellbeing and body image, and compounds their cancer- induced emotional distress. Aim 2 will address the clinical treatment issue of whether continuing testosterone affects BC treatment outcomes. Aim 2 will use the same two mouse models to investigate whether continuing testosterone affects alpelisib (FDA approved therapy for ER+ tumors harboring a PIK3CA mutation) or olaparib (FDA approved therapy for ER- tumors harboring a BRCA1 mutation) treatment outcomes (Aim 2.1). We will leverage Aims 1.1 and 2.1 to conduct molecular investigations about the effect of TT on androgen receptor and ER mediated transcriptional programs—mRNA and miRNA expression—on regulating mammary gland development and carcinogenesis (Aim 1.2), and response to BC treatment (Aim 2.2). Transgender people are the fastest growing group in the LGBTQ community. We need to start understanding their cancer risk and the long-term health outcomes of TT. Our proposal will be the first to lead to fundamentally new insights to understand BC risk and develop clincial treatment guidelines to improve BC outcome in the medically underserved transmasculine population. The increased understanding of the role of sex hormones in BC risk and treatment, as well as the miRNA landscape in regulating androgen expression in BC, are not only important to improve transmasculine health and reduce their healthcare disparities. These knowledge will have direct implications for understanding BC risk and open up new avenues of treatment for cisgender men and women as well.
Explanation:
- The breast is a hormone-dependent organ in the human body, raising concerns as to whether or not testosterone may cause breast cancer or not.
- Researching on transgender men would take too long. Instead, they use mice as they age approximately 70x faster than humans.
- This work aims to see the impact of testosterone on breast cancer survival rate, and how it affects the efficacy of breast cancer treatment.
Conclusion:
Understanding how testosterone impacts breast cancer (whether it induces or reduces the cancer) will be an important step towards understanding and developing breast cancer treatment for both transgender men and cis women.
Experiment 4: Microbiome mediated effects of gender affirming hormone therapy in mice
Experiment report here. The abstract is as follows:
Gender affirming hormone therapy (GAHT) is used by transgender (TG) people to alleviate gender dysphoria. GAHT for male to female TG subjects (transwomen) consists of a gonadotropin-releasing hormone agonist (GnRHa) to block testosterone production and cross-sex hormone treatment (CSHT) with estrogen. GAHT for female to male TG subjects (transmen) is based on testosterone CSHT without a GnRHa. CSHT is often started at 12-16 years of age, before the pubertal surge in bone mass and the completion of skeletal maturation. In addition, male and female adolescents with gender dysphoria are sometime treated temporarily with a GnRHa without CSHT to suppress puberty. The effects of puberty blockade followed by CSHT and those of CSHT without prior puberty blockade on skeletal maturation are mostly unknown. The gut microbiome is pivotal regulator of skeleton postnatal maturation, bone health, and bone responsiveness to GnRHa and sex steroids. Moreover, the composition of the microbiome is regulated by sex steroids. Thus, modifications to the gut microbiome composition may mediate the effects of GnRHa and CSHT on the skeleton. Supporting this hypothesis, our preliminary metagenomic analysis revealed that CSHT induced differences in the composition of the gut microbiome. Preliminary studies also showed that CSHT impacts gut permeability, which can lead to further changes in the gut microbiome composition. We further show that CSHT-induced modifications to the composition of the gut microbiome alters indices of bone volume and structure, and the frequency of intestinal and bone marrow (BM) T regulatory cells (Tregs), which is a T cell lineage expanded by estrogen and testosterone. Tregs are essential in the regulation of bone formation and bone resorption. Based on our preliminary data and on published reports, we hypothesize that GnRHa treatment and CSHT affect skeletal maturation, and that these effects are mediated, in part, by modifications in gut microbiome composition and changes in gut permeability. Aim 1a will investigate the extent to which microbiome depletion by antibiotic treatment alters the skeletal effects of the GnRHa Leuprolide with and without subsequent CSHT in young male and female mice. Aim 1b will utilize fecal material transfers (FMTs) to directly determine the extent to which stool microbiome contributes to the skeletal effects of GnRHa treatment with and without subsequent CSHT in young male and female mice. Aim 2a will determine the contribution of microbiome dependent expansion and migration of gut Tregs to the skeletal effects of GnRHa treatment with and without subsequent CSHT. Aim 2b will determine the contribution of increased gut permeability to the skeletal effects of GnRHa treatment with and without subsequent CSHT, and Aim 2c will investigate if colonization of GF mice with bacteria mediating the skeletal effects of Leuprolide with and without subsequent CSHT restores effects that are absent in GF mice. This project will determine the effects of GnRHa treatment with and without ensuing CSHT on skeletal maturation, and whether such effects are mediated by modifications to the microbiome.
Explanation:
- Cross-sex hormone treatment has been shown to cause differences in skeletal growth.
- Skeletal growth is also affected by the gut’s microbiome, which in turn is affected by gonadotropin-releasing hormone agonist.
- The output of this research would help transgender adolescents to avoid skeletal growth issues.
Conclusion:
By investigating how hormone therapy and puberty blockers interact with the gut microbiome and bone health, this research could help optimize treatment guidelines for transgender adolescents.
Experiment 5: Androgen effects on the reproductive neuroendocrine axis
Experiment report here. The abstract is as follows:
This R01 proposal responds to “Notice of Special Interest in Research on the Health of Sexual and Gender Minority (SGM) Populations” (NOT-MD-19-001) which calls for research describing “clinical, behavioral, and social processes affecting the health of SGM individuals and their families” that will promote development of appropriate interventions to improve SGM health and fertility care. This proposal includes clinical studies of transgender individuals and the effects of androgen treatment on their reproductive health. Androgens can have significant inhibitory effects on neuroendocrine reproductive hormone secretion in both sexes, yet the mechanisms and cell types by which androgens suppress GnRH and LH pulsatile and surge secretion in females are poorly studied and remain unknown. Indeed, high levels of exogenous androgens fundamentally contribute to reproductive disruption seen in otherwise healthy women and transgender men (female sex individuals taking high levels of androgens), but the mechanisms, time course, and target neuroendocrine site(s) of action for these inhibitory androgen effects are poorly understood. Our overall hypothesis is that male levels of exogenous androgens can inhibit the female reproductive neuroendocrine axis by acting through androgen receptor (AR) in hypothalamic kisspeptin neurons to modulate endogenous LH pulse secretion and impede generation of the estrogen-generated preovulatory LH surge. We test this hypothesis in two complementary Aims that study the role of high exogenous androgens in both a clinical setting in transgender male (female sex) human subjects and corresponding transgenic female mouse models. Aim 1 investigates the effects of exogenous androgens in a clinical setting, studying transgender men taking gender affirming testosterone therapy. This clinical Aim assess the inhibitory effects and time-course of androgen treatment on a wide suite of reproductive neuroendocrine parameters, with a focus on in vivo LH pulse and LH surge secretion, coupled with analyses of menstrual cyclicity and ovarian measures. Aim 2 utilizes transgenic mice to test whether male-level androgens acting via AR specifically in kisspeptin neurons are necessary and/or sufficient for androgen inhibition of in vivo LH pulse parameters, including pulse frequency, and the estrogen-induced LH surge. This Aim also elucidates whether elevated androgen action directly in kisspeptin cells is necessary for AR inhibition of reproductive gene expression in the female brain, and uses innovative methodology to analyze androgen-induced changes in the transcriptome of specific kisspeptin neural populations in females, identifying how exogenous androgens impact these neurons to impede LH secretion. Together, these two complementary Aims will elucidate the cellular, molecular, and physiological mechanisms of androgen inhibition on female neuroendocrine reproductive hormones. This project will advance our understanding of fundamental mechanisms of androgen action in neuroendocrine control of reproduction and inform upon future clinical interventions for rescuing reproductive function in females or currently understudied SGM transgender males exposed to exogenous androgens.
Explanation:
- Androgen is a hormone that inhibits the effect of neuroendocrine reproductive hormone secretion. (Sorry, I’m not a biologist, I’m as confused as you are here)
- Exogenous (external-source) androgens have been linked to cause reproductive disruption in transgender men, but why this happens is unclear.
- The research will help us understand how Androgen impacts neuroendocrine control (nerve cells and glands that produce hormones) on female reproduction.
Conclusion:
Androgen is shown to decrease reproductive functions in females and transgender men. Learning how Androgen acts can help researchers to counteract its effect, potentially rescuing reproductive functions in affected individuals.
Experiment 6: Gonadal hormones as mediators of sex and gender influences in asthma
Experiment report here. The abstract is as follows:
Asthma is a lung disease caused by exaggerated lung inflammation leading to airway obstruction and compromised airflow. Despite significant advances in its diagnosis and treatment, asthma continues to be a significant health problem affecting more than 25 million patients in the US, and over 300 million around the world. Well-characterized sex and gender differences in asthma have been reported, with changes in morbidity throughout life. Starting around puberty and peaking during mid-life, women have increased asthma prevalence and higher rates of asthma exacerbations than men. Causes of these disparities remain unclear; however, studies have shown that sex-specific inflammatory mechanisms controlled by hormones contribute to differences in airway reactivity in response to environmental stimuli. Despite this, experimental models of asthma have not explored the contributions of sex hormones to inflammatory mechanisms in the female and male lung, and no studies have explored the effects of feminizing hormone therapy with estrogen in the lungs of trans women. Prior studies from our laboratory using mouse models have reported sex differences and influences of the estrous cycle and circulating sex hormones in the inflammatory response to environmental exposures. Based on these findings, we hypothesized that female sex hormones, specifically estrogens, contribute to asthma phenotypes in the lung via activation of inflammatory mechanisms mediated by estrogen receptors. In the proposed study, we will test this hypothesis by determining the mechanisms by which estrogen mediates sex and gender influences in asthma. In Aim 1, we will determine the contributions of sex chromosome complement (XX vs. XY) vs. gonadal hormones in asthma phenotypes, by developing a mouse house dust mite (HDM) asthma model on the four core genotypes (FCG) model. In Aim 2, we will study the contributions of estrogens to HDM-induced asthma outcomes using male and female gonadectomized mice treated with estradiol, as well as bronchial epithelial cells from male and female healthy and asthma patients to exposed to HDM in the presence/absence of estrogen receptor agonists/antagonists. In Aim 3, we will determine the roles of nuclear (ER) and membrane- bound (GPER-1) estrogen receptors in estrogen-mediated mechanisms of inflammation in HDM-induced asthma, using ER and GPER1 knockout mice. Our studies will be the first to characterize estrogen-mediated mechanisms of inflammation in asthma phenotypes in the male and female lung, contributing to the characterization of sex- and gender-specific factors accounting for inter-individual differences, as well as the effects of feminizing hormone therapy in lung pathobiology. We expect that our studies would serve to develop potential sex- and gender-specific treatments and recommendations for dosage of therapeutic agents to treat and prevent asthma in cis and transgender women.
Explanation:
- Asthma, despite being a relatively old disease, continues to be a significant health problem in the US.
- It has been shown that sex and gender affect the prevalence of Asthma in individuals, especially in relation to sex-specific inflammatory mechanisms. Moreover, women are more likely to not “grow out” of their Asthma.
- Despite this relation, no prior work has checked if sex hormones impact the prevalence of Asthma.
Conclusion:
Asthma shows sex-based bias. This research aims to see how sex hormones affect the disease, potentially creating better treatments for women and transgender men.