Fertility owes Preservation to a Sheep

The journal Human Reproduction reported a 27-year old woman in Belgium has delivered a healthy baby boy. That would not be newsworthy if she had not been rendered sterile at 13 years old by a life-saving bone marrow transplant for sickle cell anemia.

This was neither conception with a donor egg, nor from a mature egg retrieved and frozen from her ovaries before chemotherapy. But it did involve one of her eggs, so she could become the birth mother and genetic mother. So how did it happen?

Shortly before curative treatment for sickle cell, her gynecologist harvested strips of tissue from her right ovary for frozen storage. In excellent health a decade later, her tissue was thawed and transplanted to the now sterile left ovary, as well as elsewhere. After 5 months, she had her first period, which confirmed that eggs had survived inside their follicles, and she continued having regular periods until conceiving naturally within two years. Yes, it gave her periods and fertility without any further medical help—naturally!

It’s a newsworthy case because she is first to deliver after transplanting an ovary stored from childhood. Girls undergoing sterilizing treatment are rarely offered fertility preservation, and this can be their only option. The first case of its kind was 20 years ago for a two-year-old Yorkshire infant called Harriet. We would never have suggested it except she had to undergo an operation to remove a kidney tumor, which gave us the chance to safeguard some of her ovaries “just in case.” I don’t know if she has requested the hospital to have her tissue back, but it is wise to wait until ready to start a family because we can’t predict how long a transplant will function before it fails and then plunges her back to a menopausal condition.

There have been about 40 births to women worldwide after a frozen ovary transplant, all of them healthy to my knowledge. And there is a further series of 11 women who received a fresh transplant donated by a sister at the Infertility Center of St. Louis led by my colleague, Sherman Silber, M.D. He recently reported in Reproductive BioMedicine Online that menstrual cycles have returned in every case. Two women are still cycling after 8 years, with 11 births in all. It has turned into a rather robust procedure.

While ovary transplants have been in the news for over a decade, there is no full account in public space of how they originated. The story depended on a sheep, but the idea was really a brainstorm in a blind alley. Science doesn’t always proceed linearly, and sometimes backs out of a cul-de-sac to find the main highway.

Around 25 years ago at Edinburgh University, I naively mentioned on a BBC TV science documentary that I was testing if fetal ovarian tissue can restore fertility in adult animals. This was before the era of egg donation and at a time when egg freezing was considered unsafe. Since there are more eggs in fetal ovaries than after birth, the prospects of a long functioning graft seemed high—provided the eggs were healthy for making babies. When the experiments were successful, women with premature menopause or Turner’s syndrome urged me forward, but it was an idea stillborn.

I was the target of huge opposition and not a little opprobrium from bioethicists, churches, politicians, and just about everyone else. A senior American scientist even warned me not to travel to the USA because people were saying the procedure would encourage abortion for donating tissue. Nothing was further from my mind than that horrific idea, because my research agenda was entirely pro-fertility! I had simply believed it is better to do some good with discarded tissue than no good at all, although I acknowledged there were issues about safety and consent.

The bumpy ride did, however, take me back to a new and much less controversial agenda. It was a time when cancer survival rates were starting to climb, especially for children, but sooner or later the highly toxic and aggressive treatment could make them sterile. Men had the option of semen freezing, but there was no equivalent chance of preserving fertility for children. I started to wonder if ovary banking for girls and testis banking for boys was the answer.

Roslin Institute
Frosty conceived after ovary freezing and transplantation in Scotland

We had modest hopes because freezing whole tissue is harder than single cells, but if it worked with sheep ovaries we were hopeful of the same for patients. I remember working with my colleague David Baird in a cold operating room at the experimental farm outside Edinburgh where Dolly the cloned sheep was born a few years later. We returned frozen ovarian tissue to the same ewes a month after a harvesting operation. Four to five months later the animals showed signs of graft activity, the same delay we have observed in patients. Not long afterwards, there was a pregnancy, and a little “Frosty” was born.

The Daily Telegraph September 23, 1999
The Daily Telegraph September 23, 1999

A research fellow who returned to the USA from my lab was first to transplant frozen tissue to a patient. It happened to be on my birthday in 1999 and the eve of emigration to a job at McGill University that the patient came to the UK and visited my lab. There was a huge splash in the media, perhaps because there was no other news that day!

Unfortunately for her, the graft was not successful. It had been frozen as minute fragments at an unknown center, but the attention she received encouraged others, and there was happier news for them. By 2004, the first birth was reported, and this too in Belgium.

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Room for a Womb – a transplant story

It seems particularly fitting to congratulate a Swedish colleague who announced the world’s first successful uterine transplant the same week that the Nobel Prize for Physiology and Medicine is announced from Stockholm. Not that the transplant will earn him the Prize one day, which is awarded for a scientific breakthrough rather than a technical tour de force. Surgeons have long known how to hook up blood vessels, but have balked at challenges about transplant safety, longevity, and ethics.

Sherman Silber, M.D.
Roger Gosden discussing an experiment with Sherman Silber after a lecture

Mats Brannström has been working on the project for about fifteen years, or as long as I have known him. We used to chat at fertility preservation conferences when I was working on ovarian transplants. My goal was frozen-preservation of ovaries for young cancer patients who were likely to be sterilized by chemotherapy or radiation: when they were clear of disease we would transplant the thawed organs back to restore natural menstrual cycles and fertility. Around the globe, over thirty patients have conceived healthy children after an ovarian transplant. I also worked with the brilliant surgeon, Sherman Silber of St. Louis, who restored years of menstrual cyclicity and fertility to women who had an ovary donated by their genetically-identical twin sister. There is no greater satisfaction for a researcher than to witness their work leaping from the laboratory to the clinic.

uteru,s ovarian and fallopian tubes
Human female reproductive organs

But transplanting reproductive tissue can be troubling, if not actually controversial. For us, it was the question of whether an ovary that was removed for storage before the disease was cured might seed cancer cells in the patient as a transplant? For womb transplanters, the major question they face is, “Why do it, when it is so risky?”

Mats explained that the idea didn’t come out of the blue: one of his patients asked if it could be done. She was having a hysterectomy and desperately wanted the experience of gestating a baby. Her inquiring mind set him on a journey to help women like herself. For women who still have ovaries, they can have in vitro fertilization (IVF) before surgery to store embryos in the freezer until they are ready for transfer to the transplant. But, unlike our identical twins, they need constant treatment with drugs to suppress the immune system that naturally tries to reject the foreign organ.

Objectors point out the alternatives for women who lack a uterus. First, there is child adoption, although not such an easy option as in the past. Second, there is surrogacy in which a “tummy mummy” is commissioned to carry the baby. This can be arranged either by conception in her own body, using sperm from the patient’s husband or a donor, or by IVF in which embryos from the commissioning couple are transferred to the third party, so the child is genetically related to them. But surrogacy is outlawed in some countries, including Sweden, as it is in some U.S. states and for Muslims.

Medical practitioners are less paternalistic than they used to be. In the past, they were more comfortable proscribing (as well as prescribing) treatment if it made them uneasy or in their clinical wisdom it did not seem to be in the best interests of their patient. Nowadays, as we come to our doctors after consulting other specialists and surfing the Internet for the latest medical research, we are increasingly telling them what we think they should do! In the parlance of bioethics, the Autonomy/ Beneficence pendulum is swinging from right to left, from B to A, which can take a doctor on a hike into swampy ethical territory. I sympathize with them for wondering why a hazardous uterine transplant should be attempted if it is not life-saving but, on the other hand, I think we ‘fertiles’ can too easily underestimate the grief of childlessness and the lengths that people will go to achieve one of the greatest joys in life—parenthood.

Queen Amalia, Mullerian agenesis
Beautiful Queen Amalia of Greece (1818-1875) by Stieler

Most women who seek a transplant have had a hysterectomy to treat cancer or another medical condition. Some were born without a uterus because of a genetic abnormality with a name that can throw a student at exam time—Mayer-Rokitansky-Küster-Hauser syndrome. This was the condition that Queen Amalia of Oldenburg (1818-1875) had, and her inability to give King Otto an heir caused their expulsion from Greece. Perhaps a transplant would have saved the monarchy.

I don’t know who should take credit for the original idea of uterine transplantation. I don’t think I deserve that honor (if it is such), but exactly thirty years ago I mentioned it at a conference in another Nordic state, Finland. My suggestion didn’t cause any rumbles, as I expected, perhaps because the audience was too polite to pronounce me ‘off the wall.’ When I returned home to the Edinburgh Medical School, I took the opportunity one day to ask senior colleagues in the common room what they thought of the idea. The gray silence that followed spoke more than anything they might have uttered.

I never thought any more about it until I moved to McGill University and collaborated with a skillful Chinese microsurgeon. We transplanted ovaries, fallopian tubes, and segments of uterus en bloc from donor rats to sterile recipients. Treated with immunosuppressive drugs, the transplants survived and gestated healthy pups. But those were rats. Nobody talked about transplanting a human womb.

The first clinical case was reported in 2000 from Saudi Arabia. It ended in disaster. A blood clotting problem necessitated emergency removal of the womb, amid international criticism. The bad news did not deter a Turkish surgeon, who had famously performed the first full face transplant in his country. In 2013, all was going well when the 22 year-old patient conceived after embryo transfer, but when her fetus was scanned at 8 weeks it was found to have no beating heart and, sadly, had to be terminated.

Meanwhile, Professor Brannström was cautiously honing techniques, testing them in monkeys, and assembling a multidisciplinary team. Patients were carefully selected for the best chance of success, and most had recruited a relative or friend as a donor. Mats deserves credit for not rushing to be first, which is a great accolade in medicine and science.

Seven of the first nine transplants survived. It did not matter that some donors were postmenopausal, because the uterus ages far more slowly than the ovaries. The successful patient did, however, develop pre-eclampsia which forced an early delivery by Caesarean section. But mother and baby boy are doing well and I salute them and my old chum.

Next Post: Rehabbing Peter Rabbit

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