New Frontier: Transgender Men Yield Eggs, Babies, Even After Testosterone

Transgender men, who were assigned female sex at birth, show a similar response to ovarian stimulation as cisgender women, even after using testosterone, shows the first formal study of its kind in this patient group.

The transgender patients each had an average of 20 eggs retrieved, and all who transferred embryos eventually achieved a successful pregnancy and delivery, "representing the largest cohort of transgender male patients to be described in the literature thus far," write Nina Resetkova, MD, and colleagues in their article published in Fertility and Sterility.

The research has been hailed as groundbreaking.

Resetkova, a reproductive endocrinologist at Boston IVF, Beth Israel Deaconess Medical Center, Massachusetts, told Medscape Medical News: "These new data show it is reasonable for transmen [female to male transition], even those who have used testosterone for some time, to undergo assisted reproductive technology [ART]."

"We've found that there isn't a decrease in oocyte retrieval and may actually be a slight increase. We found this to be remarkable," she said, emphasizing that these findings should be very reassuring for transgender male patients concerned about fertility.

"Transmales worry that they've thrown in the towel, and by committing to testosterone have started on a pathway with no return, but these data suggest they still have options," Resetkova explained.

"Our study shows that these patients can have ovarian stimulation outcomes that are similar to those of cisgender counterparts, and this seems to be true even in cases of patients who have already initiated hormonal transition with the use of testosterone," she said.

The researcher hopes the results will encourage more referrals for transgender men wishing to explore their fertility options. "Previously, many doctors were reluctant to refer to a fertility practice if their transmale patient had already started testosterone therapy or they had been on it for several years," she said.

Approached for comment, Joshua Safer, MD, a spokesperson on transgender issues for the Endocrine Society, said: "Fertility compromise may represent the single largest risk of medical treatment for some transgender persons. At meetings and in personal communications, several clinical groups have reported successful egg harvest from transgender men."

"However, this is the first careful study of a defined cohort published formally. As such, it serves as an important reference in advancing transgender medical care," noted Safer, Executive Director, Mount Sinai Center for Transgender Medicine and Surgery, New York City.

Need for Guidance on Transgender Male Fertility Care

Previously, there has been an assumption that transgender individuals were not interested in maintaining their reproductive potential, but this has proven untrue. "Several recent studies have demonstrated that transgender people do desire parenthood, or at the least wish to preserve that possibility," note Resetkova and colleagues.

Both the American Society for Reproductive Medicine and the European Society of Human Reproduction and Embryology have issued opinions that transgender patients should have the same access to fertility options as cisgender patients and that fertility preservation options should be discussed before gender transition, they note.

The first and key intervention needed is the ability to preserve fertility through the cryopreservation of gametes before medical or surgical transition. In transgender men, this can be done via oocyte, embryo, or ovarian tissue cryopreservation.

Resetkova and the team at Boston IVF realized there was no published evidence, bar a couple of case reports, to guide clinicians caring for transgender men who wanted to preserve their fertility.

To help fill the research gap, they drew data from a retrospective cohort using electronic medical records from a single large in vitro fertilization (IVF) clinic. The search was conducted from January 2010 to July 2018, because the first transgender man was treated at the clinic in 2010.

To be included in the study, the patient had to identify as a transgender man and have completed an ovarian stimulation cycle for oocyte cryopreservation, embryo cryopreservation, or intended uterine transfer.

"This is the first study to describe transgender cycle parameters and outcomes in such detail and scope," the authors note in their article.

The study aimed to investigate ART outcomes in a female-to-male transgender cohort (n = 26) who wished to preserve fertility through egg freezing and/or undergo IVF with the intention of pregnancy.

Each transgender man was matched with five cisgender women for age, body mass index, and antimullerian hormone level, and egg yield was compared. The 130 cisgender women were in straight relationships where there was difficulty conceiving, mostly because of male-factor, or tubal-factor, infertility; cisgender women with ovulatory dysfunction were excluded.

Can Transgender Men Undergo Egg Harvest Without Stopping T?

The transgender patients were aged 14-39 years, with an average age at cycle start of 28 years. Some patients had not yet undergone any form of medical transition but planned to do so after ART.

The majority (61%) had received testosterone hormonal therapy, and a small number had undergone surgery, for example mastectomy and reconstruction, but none had had a hysterectomy or ovary removal (so-called "bottom" or gender reassignment surgery).

Prior to ART, all patients taking testosterone came off the hormone on average 4 months prior to starting treatment. The mean time on testosterone before seeking ART treatment was 3.7 years and ranged from 3 months to 17 years.

"All patients had intact uterus and ovaries, and all patients had gone through puberty and had not received puberty blocking. This was required for ovarian stimulation and egg freezing," Resetkova explained to Medscape Medical News.

Researchers tracked patient records for outcomes, including oocyte yield, number of mature oocytes, total gonadotropin dose, and peak estradiol levels.

A mean of 19.9 +/- 8.7 oocytes were retrieved per cycle in the transgender cohort, compared with 15.9 +/- 9.6 in the cisgender female group; peak estradiol levels were similar between the two groups. However, the total dose of gonadotropins used was higher in the transgender group compared with the cisgender group (3892 IU vs 2599 IU).

Of the 26 transgender men, 16 had egg preservation (oocyte banking) only. Seven couples had fresh or frozen embryo transfers, with all achieving live births.

Among the patients who planned for IVF with embryo transfer, two intended to carry the pregnancy themselves and the remaining five transferred embryos to their cisgender female partner.

The authors note that many of the transgender patients who ultimately did not choose to proceed with treatment did so because of the need to stop testosterone therapy before initiating a cycle or the burden of cost.

"For many transgender patients, stopping androgen therapy can be both physically and psychologically distressing, especially because many experience the resumption of menses," they observe.

"A logical follow-up question is whether ovarian stimulation can be done with any measure of success without the cessation of testosterone," they note.

"Although our findings are certainly reassuring for patients who have already initiated androgens, they were still all required to stop therapy to proceed with stimulation. This is a barrier to access that should be investigated, and if overcome may increase utilization of ART by transgender male patients," they write.

Safer told Medscape Medical News that, to his knowledge, "A couple of fertility groups...have been clear that the egg harvest could take place while the transgender men were using testosterone."

Testosterone Had No Effect on Egg Retrieval, Led to Higher Yield

The results with regard to the use of testosterone prior to ART were particularly enlightening, said Resetkova, who noted that testosterone therapy did not seem to affect ovarian stimulation.

"Before this study, we did not know if long-term testosterone use had a negative impact on egg reserve but, remarkably, testosterone does not appear to have an effect on the ovarian reserve as measured by egg count," she noted, although she acknowledged that the "study is small."

"In fact, in some ways, it looks like testosterone might even have a beneficial effect on egg count with a trend towards a higher number of eggs in the transmales who used it," she added.

But this is "speculative," she acknowledged, given the low numbers.

Reflecting on why long-term testosterone use may have shown a trend towards greater egg retrieval, Resetkova explained that the environment might be more similar to an individual with underlying elevated testosterone as seen in polycystic ovarian syndrome, and she noted these patients typically have a higher egg yield during IVF therapy.

Commenting on the higher doses of gonadotropins used in transgender patients, Resetkova suggested there could be various reasons for this, given that dosing was at the physician's discretion, including the possibility that they knew the patient only had one chance and therefore higher doses of gonadotrophins may have been administered.

Furthermore, each round of treatment is expensive. The researcher stressed, however, there was no conclusion in this respect based on their data.

Puberty Blocking Might Mean Restrictions on Fertility

When asked by Medscape Medical News whether a transgender man who had undergone puberty blocking before transitioning (ie, someone who had not gone through natural puberty) would be able to follow a similar course to pregnancy as the study participants, Resetkova acknowledged that is a more challenging area.

"We have little data so it's hard to be conclusive, but it's unlikely these patients would have mature hormonal responses and the ovaries might be in a naive state," she hypothesized. "I don't know that they would retain so many options as someone who had gone through natural puberty," she added.

"However, there are research protocols in place at some academic institutions for transgender patients planning to undergo puberty blocking," she observed.

Finally, referring to individuals who transition from male to female using estrogen therapy, Resetkova said that the quality of sperm production might be impaired with long-term estrogen exposure. She added that other centers are looking at this.

"As transgender individuals increasingly seek access to reproductive services, we seek to shed light on the optimal way to provide effective care to these patients," Resetkova and colleagues conclude.

Resetkova has reported no relevant financial relationships.

Fertil Steril. 2019;112:858-865. Abstract

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