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Disease and treatment

Doctors in Denmark refreeze transplanted ovary after woman gives birth

Women with ovarian cancer can now have an ovary removed and then have it transplanted when they decide to have children. However, because of the increased risk of cancer recurring in the transplanted ovary, doctors from Denmark have become the first to remove a transplanted ovary after a woman gave birth to twins. The research shows that the refrozen ovary still contains viable eggs.

Most people take being able to have biological children as a given. However, this was not possible for young women with ovarian cancer until very recently. Previously they had to give up their dream of having a biological child since doctors have been concerned that the cancer would recur if they had an ovary transplant. Susanne Hansen, a Danish woman, is the first woman to have a frozen ovary transplanted and then removed after she gave birth to twins.

“This is the first time that a transplanted ovary has been successfully removed and refrozen. Previously, women without ovarian cancer have had their frozen ovary transplanted and given birth to healthy children, but now women with early-stage ovarian cancer can have the opportunity to have children several times without running a great risk of ovarian cancer recurring,” explains Stine Gry Kristensen, a postdoctoral fellow at the Laboratory of Reproductive Biology, Juliane Marie Centre for Women, Children and Reproduction, Rigshospitalet Copenhagen and a driving force behind the new research.

Mice in the mix

The fear that ovarian cancer might recur has previously prevented doctors from transplanting frozen ovaries. Susanne Hansen appeared to only have cancer in her right ovary, so healthy tissue from her left ovary could be frozen and later transplanted. Nevertheless, oncologists conducted many intense discussions and examinations before the ovarian tissue that Susanne Hansen had frozen in 2003 when she had ovarian cancer was retransplanted into her in 2012.

“To ensure that the frozen ovary was not malignant, a piece of the tissue was transplanted into mice that have no immune system. If any cancer cells had survived, they would multiply and we could observe that the mice were sick. We investigated this and demonstrated that there were no cancer cells.”

The mice acted as a bioincubator. Even if only a few cancer cells remained, they would have propagated and could be detected. The ovarian tissue did not make the mice sick and the doctors therefore decided that transplanting the tissue was safe.

Ovaries on overtime

Doubts about whether the cancer could recur, however, prompted the doctors to remove the ovarian tissue after Susanne Hansen gave birth to twins. The researchers were therefore excited to see whether the transplanted ovarian tissue could survive yet another freezing. The good news therefore was that the researchers found that the eggs in the ovarian tissue were still active after being refrozen.

In 2003, Susanne Hansen was 23 years old and was diagnosed with ovarian cancer. Since only the right ovary had cancer, doctors froze part of the healthy tissue from the left ovary.
In 2012, samples of Susanne Hansen’s tissue were surgically transplanted into mice to determine whether the cells in the tissue would develop cancer. Since they did not, doctors transplanted some of the tissue into Susanne. After fertility treatment, Susanne became pregnant but miscarried after 12 weeks. After five more attempts, the Fertility Department of Aarhus University Hospital gave up.
Nevertheless, Peter Humaidan from the Skive Regional Hospital applied a special hormone treatment and ensured that Susanne could become pregnant again, and she gave birth to healthy twin boys in 2015. Despite the risk and the complex procedures,
Susanne Hansen does not regret for a minute that she chose transplantation. “I have always wanted to have children, and being able to have my own – and two! – is fantastic. Thinking that I could theoretically have more children is also wonderful. The process has, however, been very hard physically and mentally, with many treatments and great uncertainty – both about the cancer and whether I would become pregnant. The fact that everything was successful is a bit of a miracle,” explains Susanne Hansen.

The activity in the refrozen ovary means that Susanne Hansen could theoretically have her ovary retransplanted and get pregnant again. However, in this case doctors discourage this. In addition to the complicated process of getting the body reaccustomed to producing the many hormones needed in connection with the menstrual cycle and pregnancy, there are also more important reasons.

In 2012, samples of Susanne Hansen’s tissue were surgically transplanted into mice to determine whether the cells in the tissue would develop cancer. Since they did not, doctors transplanted some of the tissue into Susanne. After fertility treatment, Susanne became pregnant but miscarried after 12 weeks. After five more attempts, the Fertility Department of Aarhus University Hospital gave up. 

“There is an inherent risk of ovarian cancer recurring. Once cancer has developed in one ovary, there is a greater risk of cancer developing in the other ovary. So as soon as Susanne had given birth to her twins, we needed to remove the tissue again to minimize the risk. And even though we had done everything to ensure that there was no active cancer in her tissue, we had some concerns about transplanting it.”

Not everything was removed

Stine Gry Kristensen and Claus Yding Andersen were in for a surprise when they wrote about their research. They asked doctors to measure Susanne Hansen’s hormone levels and discovered that she was still excreting menstrual hormones.

“The conclusion was that some of the transplanted tissue had been left behind. Doctors therefore had to operate again. Since this was the first time we had removed transplanted ovarian tissue, establishing whether all the transplanted tissue had been removed was difficult,” explains Claus Yding Andersen.

The doctors found that two of the nine transplanted strands of the ovary had not been removed in the first operation. The researchers had another surprising result that contributed to significant new knowledge about women and fertility.

“When we examined the tissue that was removed the second time, we found very few eggs – in fact, so few that we would not believe that there were enough to keep the hormone level up and the menstrual cycle functioning. This therefore indicates that relatively few eggs remain when a women reaches menopause.”

Waiting for the right person

Despite the challenges of this new method, the researchers are convinced that many women will prefer refreezing an ovary to having their eggs frozen and implanted. The opportunity to have an ovary frozen and transplanted instead of implanting eggs is a great advance for several reasons.

“When we freeze ovarian tissue, we also freeze thousands of small follicles that each contain one egg. When ovarian tissue is transplanted, a woman’s ovarian function is re-established, including the possibility of getting naturally pregnant and the beneficial effects of sex hormones. Second, retrieving mature eggs requires hormonal stimulation for at least 2 weeks. During this period, the woman cannot be treated for cancer, and this may allow the cancer to develop. Ovarian tissue can be frozen from one day to the next without delaying cancer treatment.”

Researchers from many countries are now visiting the Laboratory of Reproductive Biology to learn about this new method so they can implement it in their countries. The method is also suitable for other genetic diseases, such as those caused by the BRCA1 and BRCA2 genes, in which leaving ovarian tissue in the body greatly increases the risk of cancer.

“These women would also like to have children. In these cases, it is worth considering whether they should have their ovarian tissue frozen when they are young. So when they meet the right person and are ready to have children, we can transplant the tissue. Once a child has been born, we can remove the tissue again. This minimizes the time when the tissue is in place and thereby minimize the risk of cancer developing.”

Fertility preservation and refreezing of transplanted ovarian tissue – a potential new way of managing patients with low risk of malignant cell recurrence” has been published in Fertility & Sterility. The Novo Nordisk Foundation awarded a grant to a main author, Claus Yding Andersen, for the project Expression of Mature and Immature Forms of Anti-Müllerian Hormone in Human Foetal Testes and in Follicles from Adult Ovaries.

Claus Yding Andersen
Professor
Claus Yding Andersen is a professor of human reproductive physiology at The Laboratory of Reproductive Biology, the Department of Fertility at The Juliane Marie Centre, Rigshospitalet, Copenhagen University Hospital and the University of Copenhagen, Denmark. His main research areas are: Ovarian endocrinology Steroido genesis Fertility preservation and cryopreservation of gonadal tissue and human embryonic stem cells He was a member of the team which introduced IVF to Denmark in the mid 1980´s and has worked at The Laboratory of Reproductive Biology since then. He serves on the editorial board of a number of scientific journals, research committees and international societies.
Stine Gry Kristensen
Post doc
Stine Gry Kristensen is a biologist with a PhD in reproductive biology from the University Hospital of Copenhagen. She has been cryopreserving ovarian tissue for fertility preservation since 2009 at the Laboratory of Reproductive Biology in Copenhagen. Her research has been focused on the very early stages of human folliculogenesis.