A three-parent technique could help trans men have babies

Fertility treatments can be undesirable for transgender men, as they involve pausing gender-affirming hormone therapy and undergoing potentially distressing procedures such as female hormone treatments and vaginal exams.

New evidence suggests combining two existing techniques for the first time could help sidestep those issues. The process involves removing pieces of a transgender man's ovary, extracting eggs from the ovary in the lab, and swapping in parts of an egg from another person before fertilizing them with sperm to create embryos.

Extracting eggs in the lab has helped some people have babies after surviving cancer. And the so-called three-parent technique-using parts of an egg from a third person- has been used in attempts to help people avoid passing genetic disease to their babies and to boost fertility.

The new research suggests that these technologies, used in concert, could also boost a trans man's chances of using his eggs to create a healthy embryo-and potentially have a baby-without having to undergo typical fertility treatments.

The technique could offer more options for trans men who want to have babies using their own eggs, says Antonia Christodoulaki of Ghent University in Belgium, who presented her findings at the European Society of Human Reproduction and Embryology annual meeting in Milan, Italy, last month. Every person should have the right to reproduce," she says.

It's an additional option to enable people to have their own biological children," says Suzannah Williams at the University of Oxford, who was not involved in the research. You do end up with a three-parent family ... [but] it's a great possibility."

Eggs on ice

Ovaries usually contain more than a million eggs at birth. These eggs are all immature, held in suspended animation. It's not until puberty that some eggs start to mature and begin to be released on a monthly basis. Many eggs die, and the total number dwindles with age.

When people want their eggs to be available for IVF, they first undergo hormone treatments. These stimulate their ovaries to release a bumper crop of eggs, which are then removed and may be either frozen or fertilized with sperm.

Transgender men who are considering gender-affirming treatments, and who want biological children, are usually advised to have some of their eggs collected and frozen in the same way. That's because gender-affirming treatments can affect fertility. Testosterone therapy is thought to affect the production of eggs, for example. And some people might choose to have their ovaries removed altogether.

But fertility preservation techniques can cause side effects like breast tenderness and cramping, which might be especially unpleasant for a person who does not identify as female. Vaginal exams at women's health clinics can be distressing, too. Egg collection is considered very uncomfortable and unpleasant, physically and mentally, if you're a trans man," says Williams.

That could be avoided if, instead of using hormones to stimulate the person's ovaries to release mature eggs, doctors could remove pieces of the ovaries themselves, and somehow obtain mature eggs in the lab. This would involve taking immature eggs and coaxing them along in their development, to the stage at which they can be fertilized by sperm.

This has already been achieved in some people who have survived cancer. Some cancer treatments are toxic, especially to eggs and sperm. Adults are often advised to store healthy eggs or sperm before they begin these treatments. But that's not an option for children who haven't yet been through puberty.

If children have parts of their ovaries removed, however, some clinics have been able to use this tissue to later generate mature eggs and fertilize them with sperm, implanting the resulting embryo back into those same people when they are adults. The technique appears to work, and healthy babies have been born. Last year, three US-based reproductive medicine societies issued a statement concluding that the technique should no longer be considered experimental.

The technique has not yet been used to help transgender people have babies, but Christodoulaki and her colleagues believe it might. To find out, they tried the approach in ovaries donated by trans men.

The team started with ovaries donated by 14 transgender men aged between 18 and 24, who had had the organs removed as part of their gender-affirming treatment. All the participants had been undergoing testosterone therapy for an average of 26 months, and some were also taking a drug to stop them from menstruating.

First, the team removed eggs that were days away from being released by the ovary. The team repeated the process with similarly immature eggs donated by cisgender women. After 48 hours in a lab dish, the eggs appeared to be ready to be fertilized with sperm.

In both cases, around half the immature eggs were successfully matured in the lab. But something appeared to go wrong when the team tried to fertilize the eggs with sperm. While 84% of the eggs from cisgender women could be fertilized, the figure was only around 45% for trans men.

By the time the embryos were five days old-the point at which they would normally be transferred into a person's uterus-only 2% of those generated from trans men's eggs were still alive, compared with 25% of the embryos from cis women's eggs.

The team tried to figure out what might be going wrong. Genetic analyses suggested that there were no problems with the DNA of the embryos. That could mean the problem lay in the eggs' cytoplasm-the contents of the cell outside of the nucleus, which contains the DNA.

Cell swaps

If that were the case, then swapping the cytoplasm might solve the problem. To test the theory, the team first removed the DNA-containing nuclei of eggs donated by cisgender women. They then swapped in the nuclei from trans men's eggs. These eggs were then fertilized with donated sperm.

Of the resulting 29 embryos, six survived to the five-day stage-a 20% success rate. Though not terribly high, this is close to the 25% success rate seen in embryos generated with eggs from cis women, says Christodoulaki.

The results are promising, says Jesus Cadenas, a postdoctoral researcher in reproductive biology at Rigshospitalet in Copenhagen, who didn't participate in the research. He cautions that the study was small, but he acknowledges that this is partly because it is difficult to get hold of human eggs and ovaries for research. Either way, it is too soon to offer this as a fertility treatment for trans men, he says.

Christodoulaki agrees. We still don't know the long-term effects on the babies [that would be] born," she says. It's a very promising technology ... but I would not say that we are ready for clinical [use]."

But given that some clinics are already using the technology as part of IVF for infertile women, Williams feels that offering it to trans men is not much of a reach. If a clinic has got an established [three-parent technology offering], this should be easy to roll out," she says.