Many trans or nonbinary individuals grapple with gender dysphoria, an enduring distress caused by a conflict between the sex assigned at birth and the gender they identify with.

Among a myriad of gender-affirming care options, which range from adopting a chosen name and pronouns to medical interventions, many turn to hormone therapies, such as testosterone or estradiol, which have been shown to improve mental well-being and quality of life by promoting the development of secondary sex characteristics that match an affirmed gender, such as facial hair growth or breast development.

“Gender-affirming hormone therapy is often a life-saving intervention and not merely an option or luxury for individuals with gender dysphoria,” explained Molly Moravek, a clinician and associate professor in the Department of Obstetrics and Gynecology at the University of Michigan. “The science behind these treatments is well established and clearly proven to be efficient.” 

Long-term uncertainty

At the University of Michigan, Moravek, along with her colleagues Ariella Shikanov, an associate professor of biomedical engineering, and Vasantha Padmanabhan, professor of pediatrics, have indicated that that while these therapies can have a transformative impact on individuals’ lives, there are knowledge gaps and uncertainty around the long-term consequences of their use, especially when it comes to reproductive health.

“Despite the prevalence of [trans and/or gender diverse] people on gender-affirming hormone therapies, the impact of long-term gender-affirming hormone therapies on reproductive health is largely unknown,” said Moravek. “In fact, the [trans] community has identified the effect of gender-affirming hormone therapies on future reproductive capacity and offspring health as a priority for research.”

At present, many face the daunting challenge of making critical reproductive health decisions with insufficient information at their disposal. “National and international medical organizations recommend fertility preservation counseling prior to starting gender-affirming hormone therapies, but these recommendations are based on an assumption of loss of fertility, not data,” added Padmanabhan.

There is therefore an urgent need for strong, evidence-based research that not only respects and acknowledges the unique experiences of trans individuals but also highlights the importance of investigating how gender-affirming hormone therapies impact important aspects of their health, such as reproduction.

Addressing knowledge gaps

Moravek, Shikanov, and Padmanabhan said their collaboration was inspired by the lack of data by which clinicians could counsel transgender and gender-diverse individuals about the effects of gender-affirming hormone therapy on their future fertility.

“To address this, we developed the first animal model to study the effects of gender-affirming hormone therapies on fertility and general health of the offspring,” said Shikanov. Some of their findings were recently published in a paper in Advanced Biology.

The study focused on assessing the impacts of estradiol-containing hormone therapy in individuals assigned male at birth who are undergoing gender-affirming treatment. In these cases, gender-affirming hormone therapy typically involves lifelong administration of estradiol, the primary form of estrogen, along with a class of drugs called anti-androgens, which prevent androgens like testosterone from exerting their biological effects in the body.

The researchers noted in their paper that existing human data concerning the testicular effects of estradiol-containing hormone therapies are primarily derived from observational studies conducted around the time of surgery. These studies often involved short-term exposure, variable estradiol formulations, and differing rates of anti-androgen usage, resulting in inconsistent findings.

“For patients interested in fertility or fertility preservation after long-term estradiol-containing gender-affirming hormone therapy exposure, there are limited, conflicting data on the effects on testicular function and sperm parameters, and there are no standards instructing clinicians how long [estradiol] needs to be stopped, if at all, prior to pursuing attempts at conception or sperm cryopreservation,” said Moravek.

“Further, it is unknown if the effects of [estradiol hormone therapies] on reproductive function can be partially or completely reversed by cessation of estradiol or if fertility preservation is the best means for safeguarding future fertility potential,” she continued. “The goal of this study was therefore to provide preliminary animal data on the reproductive effects of estradiol-containing gender-affirming hormone therapy.”

Estradiol and sperm motility

In the paper, male mice were treated with estradiol hormone therapy at low, intermediate, and high doses. The researchers found testosterone and follicle stimulating hormone levels in the blood were suppressed while estradiol levels were elevated to levels observed in female mice — mimicking what happens in human patients on a similar regimen.

All doses appeared to have at least some effect on the testes and bladder, but the most significant finding was that six weeks of estradiol therapy resulted in altered sperm motility, though it did not alter the presence of mature sperm.

“Sperm with altered motility is less likely to fertilize an egg and may result in inability to conceive,” said Shikanov. “However, altered motility is only one aspect of impaired spermatogenesis (sperm maturation). We anticipate that longer [estradoil therapy] may eliminate mature sperm altogether.”

While some caution needs to be taken not to assume that the findings in mice will be identical to those in humans, the team think that this study in animal models will spur further clinical research, with the long-term goal of providing the data needed to help clinicians appropriately counsel patients on the reproductive effects of estradiol hormone therapy.

“Additional studies, such the effect of estradiol hormone therapy on testes and genetic changes induced in the testes and in the sperm are currently being pursued,” said Shikanov. “More importantly, whether these effects are reversible after estradiol cessation and whether these effects become less reversible with time will be critical for the clinicians and the trans community to know.”

The team are also eager to use their animals models to understand the effects of estradiol hormone therapy on reproduction following treatment with puberty blockers in adolescents, as well as investigate the effects on the health of offspring born from gametes exposed to estradiol.

“Our current findings and future investigation in animal models or through clinical observation will shed further light on the effects on offspring’s general health and fertility,” said Shikanov.

Reference: Molly B. Moravek, Ariella Shikanov, et al., A Mouse Model to Investigate the Impact of Gender Affirming Hormone Therapy with Estradiol on Reproduction, Advanced Biology (2023). DOI: 10.1002/adbi.202300126

Feature image: A lab mouse. Published under Creative Commons Attribution-Share Alike 2.0