Unknowns around the long-term effects of gender-affirming hormonal treatment on fertility in transgender individuals, especially adolescents, and what this means for fertility preservation, should be red flags for clinicians, according to one expert addressing the issue at the recent virtual ENDO 2021 meeting.

“One of the main concerns regarding fertility preservation in this population is that the decision to seek gender-affirming therapy is often made early in the reproductive lifespan, and for many patients this is well before the consideration of…child-bearing,” remarked Marie Menke, MD, an ob/gyn from University of Michigan, Ann Arbor, Michigan, presenting in a session dedicated to state-of-the-art approaches to gamete preservation.

“These patients need to consider simultaneously their desire for gender-affirming therapy and their desire for child-bearing,” she added, explaining that gender-affirming therapy typically requires suppression of the hormonal axis that supports reproduction.

“This level of shared decision-making requires time and multidisciplinary involvement in the face of…limited data, and even with the best of counseling it can be quite overwhelming,” Menke stressed.

Specifically, the effects of gender-affirming therapy on both fertility and fertility preservation options in transgender individuals in comparison to the general population are areas that require much more research, she emphasized.

On the topic of adolescents specifically, she said they are “a special population,” as many seeking medical therapy for gender dysphoria have never considered long-term fertility goals or desires. Reports of such discussions during pediatric gender care vary greatly depending on the age of the patient and their geographic location.

And where such conversations have happened, “often there is no recollection by patients of such discussion prior to referral to endocrinology,” she emphasized.

Session co-moderator Irene Su, MD, a reproductive endocrinologist at the University of California San Diego, said shared decisions with patients have to be made every day, even though data are limited.

“Little is known about both the adverse medical impact of gender-affirming hormonal therapy on fertility potential, as well as the psychosocial impact of interrupting/reversing gender-affirming hormonal therapy in the future to attempt fertility,” she told Medscape.

But, “because there are reasons to be concerned about an adverse impact on fertility, transgender individuals need access to fertility risk and preservation counseling,” she stressed.

Su has a special interest in improving reproductive health in young cancer survivors and this involves similar discussions around fertility preservation — a medical subspecialty known as “onco-fertility.”

There is a greater pool of knowledge in this field compared with fertility preservation and family planning in transgender patients, Su noted.

“While we need similar data in transgender individuals, what we’ve learned from the cancer survivor population is that they and their families want to know about known and unknown fertility risks and options, even if they ultimately do not choose to undertake fertility preservation procedures,” she explains.

Desire for Future Kids, but <10% Currently Preserve Fertility

Menke said the estimated prevalence of individuals who identify as transgender is around 0.7% of the US population, and she observed that, “by and large, fertility management involves tissue cryopreservation.”

She presented survey data showing that between 33%-54% of transgender and nonbinary individuals report a desire to have biological children currently, or in the future, and 94.6% are also strongly in support of transgender people having access to fertility preservation procedures.

Likewise, an online cross-sectional survey of over 1100 people in the general population found that 76.2% agree that transgender individuals should be offered fertility preservation, and 60% support fertility preservation in minors.

Multiple professional societies support counseling in regard to options for fertility preservation and recommend that it should be offered to transgender individuals.

The American Society for Reproductive Medicine (ASRM), the American College of Obstetricians and Gynecologists (ACOG), the World Professional Association for Transgender Health (WPATH), and the Endocrine Society all advocate that individuals seeking gender-affirming medical treatment should receive multidisciplinary counseling regarding fertility preservation prior to puberty suppression in adolescents, and prior to cross-sex hormone treatment in both adolescents and adults.

But despite all of these recommendations and the survey findings, fertility preservation rates in transgender patients are low, “at less than 10%,” reported Menke.

Fertility preservation counseling and management ideally needs to begin prior to initiation of hormone therapy, stressed Menke.

Given the limited data on the long-term effects of gender-affirming therapy on fertility and its preservation, such counseling often leads to a myriad of questions, she further explained.

“Patients ask ‘What are the chances of having biological children if I don’t pursue fertility preservation?’, and ‘How likely am I to have a biological child if I do pursue fertility preservation?’, as well as issues around access to care with patients asking, ‘Will I be able to pursue this option [of fertility preservation]?’ “

“The chance of having a biological child if fertility preservation is pursued is similar to those [patients with cancer] who receive ‘onco-fertility’ care, which has a good prognosis,” she explained.

However, issues around access to care, and the cost of it, can be barriers.

What Does a Transgender Male, Born Female, Need to Do?

For transgender males, options for fertility preservation include the recommended option of cryopreservation of the eggs (oocytes), although freezing of embryos and/or ovarian tissue are also possible.

The latter would be required in a prepubertal individual if they wanted to start puberty blockers and then go straight onto cross-sex hormones, Menke noted, although she said it’s not definitively known if prepubertal ovarian tissue is capable of being stimulated in the future to produce viable mature oocytes.

In someone who has gone through puberty, the ideal time to freeze eggs is before beginning gender-affirming hormone therapy, Menke explained. This is because it is not known whether testosterone has any adverse impact on oocyte development.

“We just don’t have definitive data that long-term testosterone isn’t gonadotoxic,” she said in response to a question about this after her talk.

Assessment of the reproductive consequences of gender-affirming therapy in transgender males can also be complicated by coexisting conditions, Menke explained.

For example, up to 58% of transgender males have polycystic ovary syndrome (PCOS) prior to transitioning, she noted. PCOS itself, and/or the gender-affirming therapy, may causes histologic changes of the ovarian tissue, for example hyperplasia of ovarian stroma, and it’s not yet known to what extent this may impact future fertility, if present, she noted.

For oocyte preservation in female to male transgender individuals, stimulation with gonadotropins for 2-3 weeks is needed, and the procedure is invasive, requiring repeated vaginal ultrasounds. During this period, estradiol levels are supraphysiologic, and there is potential for breast development and vaginal bleeding post-retrieval, which individuals will need to be counseled about, Menke noted.

And the cost of this also needs to be factored into the equation. Depending on insurance coverage, costs may be covered — and where there is no precedent, individuals can try referring their insurance companies to the ‘oncofertility consortium access-to-care model’, Menke advised.

But if there is no coverage, the average cost for one egg-freezing cycle ranges from $10,000-$17,000 in the US, and often two to three cycles are needed to generate sufficient oocytes to be sure of a pregnancy. In addition, there are storage costs. Plus, there will be the cost of any future intervention to achieve a pregnancy, she stressed.

How long frozen oocytes remain viable is also still a matter of scientific debate, although “as the technology changes from slow-freeze to vitrification,” this time period should lengthen, Menke said.

In transgender males who have not preserved oocytes or embryos prior to transitioning, it’s necessary to stop testosterone to have the best chance of harvesting viable gametes, Menke said. And individuals undertaking this need to take into account all of the above-mentioned side effects of egg harvesting.

And although there have been reports of successful pregnancies with eggs retrieved from transgender males who have temporarily stopped testosterone, fertilization and embryo development following discontinuation of testosterone still require “additional investigation,” she observed,

Furthermore, “There are case reports of oocyte stimulation and retrieval of mature oocytes while patients continue testosterone therapy, and this may be an option in the future,” she noted, again stressing that it’s not known if excess testosterone is gonadotoxic.

Other options for fertility preservation in the transgender male include embryo cryopreservation, but this still involves hormonal stimulation and invasive procedures, and would require the use of a sperm donor in a person who doesn’t currently have a partner (or who has one, but not necessarily one with whom they want to create a child).

For transgender males there is also the possibility of using a surrogate mother for the pregnancy, she noted.

What About Transgender Women, Assigned Male at Birth?

For those assigned male at birth who wish to take puberty blockers, fertility preservation would require cryopreservation of testicular tissue, although Menke stressed that this is still considered “experimental.”

In the postpubertal period, the simplest option is to cryopreserve semen, with this ideally being performed prior to the individual commencing gender-affirming hormone therapy, Menke said.

If this is not done prior to beginning hormonal treatment, estrogen will need to be discontinued for fertility preservation, she noted.

Return of sperm function following cessation of estrogen may be limited — “expect at least 3 months before return of reproductive function,” Menke said. And even this may not be sufficient to restore normal spermatogenesis, she cautioned. “Absent or reduced spermatogenesis or morphological changes to Sertoli cells [have been reported in transgender women].”

Also, “there are needs for multiple attempts at ejaculation and storage requirements” for this approach. Cost for freezing sperm in the US, if not covered by insurance, is around $400, she noted, with storage costs ranging from $100 to up to $800 a year.

“Case reports using cryopreserved sperm [in transgender individuals] are promising overall…with clinical pregnancy rates following IVF with cryopreserved sperm…equivalent to patients without evidence of male factor fertility,” Menke reported.

However, she emphasized the fact that IVF, or intracytoplasmic sperm injection (ICSI), will still be necessary for conception, with potential additional costs.

And some individuals may need to undergo surgical removal of sperm postpuberty; this is typically performed where there is evidence of male factor infertility, for example.

Embryo cryopreservation requires a partner or use of donor oocytes, and again will have cost implications.

In conclusion, Menke reiterated that use of fertility preservation techniques among transgender people is low, and is more frequently accessed by transgender females. Among the identified barriers to fertility preservation are cost, lack of information, invasiveness of procedures, and desire not to delay medical transition.

Menke has disclosed no relevant financial relationships. Su has received a speaker honorarium from Ferring Pharmaceuticals. 

ENDO 2021: The Endocrine Society Annual Meeting: Oral presentation in session: State-of-the-art approaches for gamete preservation with consideration for emerging and challenging cases. Presented March 20, 2021.

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