Pre-Clinical Success for a New Gender-Affirming Surgery

Transplants could allow transgender people to make their own hormones.

Posted December 9, 2025 | Reviewed by Abigail Fagan

Some transgender , non-binary , and gender diverse individuals take hormones as part of their gender-affirming care. Gender-affirming hormone therapy treatments alter blood hormone levels and suppress communication between three "HPG" regions: the hypothalamus, pituitary, and gonads (ovaries and testes). These three typically communicate with each other to maintain healthy levels of gonad-derived hormones, particularly the steroid hormones estrogen , testosterone , and progesterone. Gender-affirming hormone therapy is safe and effective (1), as continual treatments maintain hormones at levels necessary to address the body’s homeostatic needs and produce changes in line with an individual's embodiment goals .

It is the responsibility of biomedical scientists to ensure the experiences of all individuals are reflected in our research, including those of the transgender, non-binary, and gender diverse community. Already, researchers have capitalized on animal models to understand the effects of gender-affirming hormones on health needs, but we should also seek to improve and expand current options. Ovarian and testicular tissue transplants are being used and developed to replace these organs for cisgender individuals who may have lost them due to injury, disease, or cancer therapy. The same technique may allow transgender, non-binary, and gender-diverse individuals to produce their own gender-affirming hormones after receiving different- sex gonad (ovary or testis) transplants.

Ethically, novel techniques must be examined in animal models before being used in clinical research. So, I collaborated with researchers who previously developed mouse models of gender-affirming hormone therapy to determine whether mice could provide a useful model to learn more about this novel technique. Our findings were recently published in Advanced Biology . We removed the gonads from male and female mice and then replaced them with gonads from genetically matched donors. Females received testis transplants, and males received ovarian transplants (different-sex transplants)–control animals received transplants matching their removed gonads ( same-sex transplants).

To track the integration of transplanted gonads, we characterized HPG function before and after surgeries. Changes over time indicated both different- and same-sex gonads were communicating with the brain and pituitary. Hormone levels and tissue analysis at the end of the experiment supported the success of these transplants. For example, males and females with testes had elevated testosterone, and many transplants were starting to produce sperm. Additionally, transplanted ovaries from males and females displayed large antral follicles (see image), structures that both produce and depend on estrogen to develop. Strikingly, ovaries from some male mice had corpora lutea, progesterone-producing structures that typically form after ovulation. This is fascinating because ovulation requires physiology previously thought to only exist in the brains of female mice.

To understand how different-sex gonads could integrate into a new HPG, we compared gene expression in relevant hypothalamic brain regions and the pituitary. Regardless of the animals’ sex, those that received ovaries had significantly higher expression of the estrogen receptor-alpha gene in a brain region associated with the process of ovulation. Neurons with the protein from this gene can be influenced by estrogen. Similarly, in a brain region responsible for the cyclic release of hormones, animals that received testis transplants had higher expression levels for two neurotransmitter genes . This plasticity of brain gene expression in adult mice in response to a new gonad is a novel finding, and these changes to gene expression may be critical to the integration of different-sex gonad transplants. Many questions remain before gonad transplant technology can be translated into a clinical procedure, but our study suggests mice can offer some critical answers.

In future clinical settings, this procedure will likely rely on donor tissue, and the potential for transplanting gametes (sperm and egg) will be an important topic for both donors and transplant recipients. A fascinating alternative would be to take stem cells from patients and use genetic manipulations and growth factors to create hormone-producing tissues (2). Transplanting these designer tissues into the patient would allow them to produce gender-affirming hormones using their own cells. By making additional changes to stem cells, viable sperm or eggs may be created, allowing for the production of genetic offspring using desired gametes. In conjunction with new techniques currently available or in development for cisgender individuals, like artificial ovaries (3), uterus transplants (4) and functional phalloplasty (5), gender-affirming transition options may one day include reproductive systems and function.

See: Pfau, D. R., Rionda, M. A., Cho, E., Clark, J. G., Kruger, R. E., Chan-Sui, R. K., Padmanabhan, V., Moravek, M.B. & Shikanov, A. (2025). Functional Integration of Different-Sex Gonad Transplants into the Adult Mouse Hypothalamic Pituitary Gonadal Axis. Advanced Biology, e00316. https://doi.org/10.1002/adbi.202500316

Hembree, W. C., Cohen-Kettenis, P. T., Gooren, L., Hannema, S. E., Meyer, W. J., Murad, M. H., ... & T’Sjoen, G. G. (2017). Endocrine treatment of gender-dysphoric/gender-incongruent persons: an endocrine society clinical practice guideline. The Journal of Clinical Endocrinology & Metabolism , 102 (11), 3869-3903, https://doi.org/10.1210/jc.2017-01658
Li, Z., Fan, Y., Xie, C., Liu, J., Guan, X., Li, S., ... & Su, Z. (2022). High-fidelity reprogramming into Leydig-like cells by CRISPR activation and paracrine factors. PNAS nexus , 1 (4), pgac179. https://doi.org/10.1093/pnasnexus/pgac179
C. A. Amorim and A. Shikanov, The Artificial Ovary: Current Status and Future Perspectives, Future Oncology 12, no. 20 (2016): 2323–2332. https://doi.org/10.2217/fon-2016-0202
Richards, E. G., Ferrando, C. A., Farrell, R. M., & Flyckt, R. L. (2023). A “first” on the horizon: the expansion of uterus transplantation to transgender women. Fertility and Sterility , 119 (3), 390-391. https://doi.org/10.1016/j.fertnstert.2023.01.017
Gurjala, A. N., Nazerali, R. S., Salim, A., & Lee, G. K. (2016). World's first baby born through natural insemination by father with total phalloplasty reconstruction. Annals of Plastic Surgery , 76 , S179-S183. https://doi.org/10.1097/SAP.0000000000000769

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Daniel Pfau, Ph.D., (they/them/their) is a queer, intersex, and non-binary neuroscientist specializing in sex differences and endocrinology.

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