Body, metabolic and renal changes following cross-sex estrogen/progestogen therapy in a rodent model simulating its use by transwomen

Gusmão-Silva, J V; Lichtenecker, Débora Conte Kimura; Ferreira, Lucas Gonçalves; Gois, Í; Argeri, Rogério; Gomes, Guiomar Nascimento; Silva, Magnus R. Dias da

doi:10.1007/s40618-022-01817-3

Cited by 10 publications

(4 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In recent years, a plethora of rodent models have been developed to study the impact of gender-affirming therapy on a variety of outcomes. (24)(25)(26)(27)(28) The vast majority of these studies, however, mimicked the clinical approach in transgender adults. As such, those models were restricted to GAH administration and did not involve puberty suppression to avoid or halt appearance incongruent development in transgender youth.…”

Section: Discussionmentioning

confidence: 99%

Testosterone Restores Body Composition, Bone Mass, and Bone Strength Following Early Puberty Suppression in a Mouse Model Mimicking the Clinical Strategy in Trans Boys

Dubois,

Ciancia,

Doms

et al. 2023

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

Transgender youth increasingly present at pediatric gender services. Some of them receive long‐term puberty suppression with gonadotropin‐releasing hormone analogues (GnRHa) before starting gender‐affirming hormones (GAH). The impact of GnRHa use started in early puberty on bone composition and bone mass accrual is unexplored. It is furthermore unclear whether subsequent GAH fully restore GnRHa effects and whether the timing of GAH introduction matters. To answer these questions, we developed a mouse model mimicking the clinical strategy applied in trans boys. Prepubertal 4‐week‐old female mice were treated with GnRHa alone or with GnRHa supplemented with testosterone (T) from 6 weeks (early puberty) or 8 weeks (late puberty) onward. Outcomes were analyzed at 16 weeks and compared with untreated mice of both sexes. GnRHa markedly increased total body fat mass, decreased lean body mass, and had a modest negative impact on grip strength. Both early and late T administration shaped body composition to adult male levels, whereas grip strength was restored to female values. GnRHa‐treated animals showed lower trabecular bone volume and reduced cortical bone mass and strength. These changes were reversed by T to female levels (cortical bone mass and strength) irrespective of the time of administration or even fully up to adult male control values (trabecular parameters) in case of earlier T start. The lower bone mass in GnRHa‐treated mice was associated with increased bone marrow adiposity, also reversed by T. In conclusion, prolonged GnRHa use started in prepubertal female mice modifies body composition toward more fat and less lean mass and impairs bone mass acquisition and strength. Subsequent T administration counteracts GnRHa impact on these parameters, shaping body composition and trabecular parameters to male values while restoring cortical bone architecture and strength up to female but not male control levels. These findings could help guide clinical strategies in transgender care. © 2023 American Society for Bone and Mineral Research (ASBMR).

show abstract

Section: Discussionmentioning

confidence: 99%

Testosterone Restores Body Composition, Bone Mass, and Bone Strength Following Early Puberty Suppression in a Mouse Model Mimicking the Clinical Strategy in Trans Boys

Dubois,

Ciancia,

Doms

et al. 2023

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

show abstract

“…Two experimental studies using feminizing HT in rodents are available up to now: Gomes et al study focused on brain morphology after feminization therapy [13] and Gusmão-Silva J.V. et al study explored the effects of injectable steroid combinationfrequently used by transwomen -on blood pressure and metabolic outcomes [27]. Although they are relevant for the health impact of HTs, none of them is specifically focused on the implementation of the rodent model for further applications.…”

Section: Discussionmentioning

confidence: 99%

Risk Assessment of Transgender People: Development of Rodent Models Mimicking Gender-Affirming Hormone Therapies and Identification of Sex-Dimorphic Liver Genes as Novel Biomarkers of Sex Transition

Tassinari¹,

Tammaro²,

Lori³

et al. 2022

Preprint

View full text Add to dashboard Cite

Transgender (TG) describes individuals whose gender identity differs from the social norms. Some TG people undergo gender-affirming hormone therapy (HT) and may be considered as a sub-group of population susceptible to environmental contaminants for their targets and modes of action. Aim of the work is to set appropriate HT doses and identify specific biomarkers to implement TG animal models. Four adult rats/group/sex are subcutaneously exposed to 3 doses of HT (plus control) selected starting from available data. Demasculinizing-feminizing model (dMF): β-estradiol plus cyproterone acetate: 0.09+0.33, 0.09+0.93 and 0.18+0.33 mg, 5 times/week. Defeminizing-masculinizing model (dFM): testosterone 0.45, 0.95 and 2.05 mg, 2 times/week. Clitoral gain and sperm count, histophatological analysis of reproductive organs and liver, hormone serum levels and gene expression of sex-dimorphic CYP450 are evaluated. In dMF model, the selected doses, leading to T serum levels at the range of the corresponding cisgender, induced strong general toxicity and cannot be used in long-term studies. In dFM model, 0.45 mg of testosterone represents the correct dose. In addition, the endpoints selected are considered suitable and reliable to implement the animal model. The sex-specific CYP expression is a suita-ble biomarker to set proper (de)masculinizing/(de)feminizing HT and to implement TG animal models.

show abstract

“…Unfortunately, toxicological studies suggested that the selected doses of hormones used were too high to implement the model and likely limited the direct translatability of these results to other animal studies or clinical medicine. Another study by Gusmão-Silva et al treated adult male Wistar rats with a combination of estradiol enanthate and dihydroxyprogesterone acetophenide (E2EN/DHPA) injected every 10 days for 5 months [30]. They demonstrated testosterone/estrogen ratios similar to female rats following treatment but otherwise did not investigate other impacts on reproductive hormones or tissues.…”

Section: Animal Models Of Gaht With Estradiol (E-gaht)mentioning

confidence: 99%

A Review of Animal Models Investigating the Reproductive Effects of Gender-Affirming Hormone Therapy

Raja,

Rubin,

Moravek

2024

JCM

View full text Add to dashboard Cite

Gender-affirming hormone therapy (GAHT) is an important component in the process of transitioning for many transgender and gender-diverse (TGD) individuals. Multiple medical organizations recommend fertility preservation counseling prior to initiation of GAHT; however, there remains little high-quality data regarding the impact of GAHT on fertility and reproductive function. A PubMed literature review was performed using Boolean search operators linking keywords or phrases such as “mouse”, “rat”, “primate”, “animal model”, “transgender”, “gender”, “estrogen”, “testosterone”, “fertility”, and “fertility preservation”. Recent research has produced a number of animal models of GAHT that utilize similar hormonal regimens and produce similar phenotypic results to those used and observed in human patients. Specific to testosterone(T)-containing GAHT, animals demonstrate loss of menstrual cyclicity with therapy, resumption of menses on cessation of therapy, suppression of gonadotropin levels, and physical changes such as clitoromegaly. Models mimicking GAHT for transmasculine individuals in the peripubertal period demonstrate that pretreatment with GnRHa therapy does not modify the effects of subsequent T administration, which were similar to those described in adult models. Both models suggest promising potential for future fertility with cessation of T. With estradiol (E)-containing GAHT, animals exhibit decreased size of testicles, epididymis, and seminal vesicles, as well as ongoing production of spermatocytes, and seminiferous tubule vacuolization. Given the ethical challenges of conducting human studies in this area, high-fidelity animal models represent a promising opportunity for investigation and could eventually transform clinical counseling about the necessity of fertility preservation. Future studies should better delineate the interactions (if any exist) between treatment attributes such as dosing and duration with the extent of reversibility of reproductive perturbations. The development of models of peripubertal feminizing GAHT is an additional area for future work.

show abstract

Body, metabolic and renal changes following cross-sex estrogen/progestogen therapy in a rodent model simulating its use by transwomen

Cited by 10 publications

References 82 publications

Testosterone Restores Body Composition, Bone Mass, and Bone Strength Following Early Puberty Suppression in a Mouse Model Mimicking the Clinical Strategy in Trans Boys

Testosterone Restores Body Composition, Bone Mass, and Bone Strength Following Early Puberty Suppression in a Mouse Model Mimicking the Clinical Strategy in Trans Boys

Risk Assessment of Transgender People: Development of Rodent Models Mimicking Gender-Affirming Hormone Therapies and Identification of Sex-Dimorphic Liver Genes as Novel Biomarkers of Sex Transition

A Review of Animal Models Investigating the Reproductive Effects of Gender-Affirming Hormone Therapy

Contact Info

Product

Resources

About