So hello again, everyone. Thank you for having me here today. So I'm here today to talk about fertility preservation before cancer treatment. So this field is rapidly expanding because of improving survival rates in cancer. So this is the outline of my presentation. First, I'll give an overview of fertility preservation. Then I'll talk about some barriers to fertility preservation and how do we overcome them. So first of all, what is fertility preservation? It is the process of saving or protecting eggs, sperms, embryos, or ovarian reproductive tissue so that a person can use them to have biological children in the future. There are several indications for fertility preservation. And for the purpose of today, I'll focus on the medical indications. And it can be because of malignant disease or benign disease that affects ovarian function. It is well-established that gonadal function is compromised by oncological treatment. And that includes chemotherapy, pelvic radiotherapy, or pelvic surgeries when you remove the ovaries. With the loss of hormonal function of the ovaries, hormone replacement can be given. But the loss of fertility is often permanent. And here comes the role of fertility preservation. Why is fertility preservation important? We know that it is associated with grave psychosocial consequences. Some studies have shown that young women with a pretreatment desire for children retain this desire years after the cancer diagnosis. So even after they are treated of their cancer, failing to fulfill this desire of having children is associated with worse mental health and social consequences. And other studies have shown that if these women, these young women, they become infertile, infertility causes them to have a loss of control over their future goals of setting a family. And in both men and women, it gives a threat to their gender roles and can cause a barrier to existing or new romantic relationships. In recent years, there are guidelines on fertility preservation from international societies of oncology and reproductive medicine. And in these guidelines, they all say that patients and families have the right to know that if the fertility is at risk before gonadotoxic treatment. And that is even if there's no time to do anything about it, even if there's nothing that can be done, if the prognosis is poor, or even if we as healthcare professionals do not think that it is a good idea or necessary to preserve fertility. So patients and their families have the right to know. Fertility preservation for women can be divided into methods of cryopreserving reproductive cells like oocytoembryo freezing or ovarian tissue freezing. And there are also methods that limits the impact of treatment. So for those aimed at cryopreserving the reproductive cells, the most common would be oocytoembryo freezing. And this requires the use of technique used in in vitro fertilization. In which case, in IVF, the eggs are collected from the ovaries and fertilized with the sperms to form embryos and embryos is then put back into the womb. In what happens in a normal IVF situation, usually it started when the woman has her period and will start injections, usually follicular stimulating hormone or HMG. And in this case, gonadotrophins are given to stimulate the ovaries. At the same time, we'll be giving antagonists to suppress premature ovulation. We'll do scanning in between and when the follicles are big enough, we would give an HCG injection that is to trigger the final oocyte maturation. And 36 hours later, egg retrieval will be done. After which will be fertilized with the sperm to form embryos and embryos would then be transferred back into the womb. Two weeks later, pregnancy tests will be done to see if this cycle is successful. In oocyte or embryo cryopreservation, we modify this cycle a little bit, but it still takes about two weeks time. So first of all, instead of waiting for the women to start her period, we can do a random start anytime in her cycle to save time because we know that these women, they need to go for their cancer treatment as soon as possible. And then we can also give a long acting FSH, which is available now. This can reduce the number of injections that they have because one injection is equivalent to the first seven days of injections compared to the previous regimen. We can also use progesterone primed regimens where instead of giving antagonist injections, they can take oral tablets. This can improve their quality of life by reducing the number of injections they have because at that point of time, they may be already overwhelmed with many investigations of their cancer and also the impending cancer treatment. In oocyte cryopreservation, after egg retrieval, the embryologists would then see if the eggs are mature to see if they can freeze them and then they would not fertilize with the sperm and will not have embryo transfer. In embryo cryopreservation, it would be fertilized with the sperm and then subsequently the embryo is frozen. There are further modifications in the cycle that we can do in estrogen sensitive tumors. For example, we can give letrozole co-treatment, letrozole is an aromatase inhibitor, so it can reduce the estradiol level during the ovarian stimulation. And in women, for example, with endometrial cancer or atypical endometrial hyperplasia, it can be done with the Mirena in situ. So after the ovarian follicles are big enough in IVF, we need to collect the eggs. So this is usually done transvaginally with an ultrasound guided approach. So you can see in the diagram here, we have an ultrasound probe put in the vagina and the needle that passes through the vagina into the ovaries. You can see it's a real time ultrasound guided. So this video here is showing the oocyte retrieval process where you can see the needle puncturing into the ovarian follicles to aspirate the follicles. And the follicular fluid would then be handed over to our embryologist to see if there are oocytes in them. But it is an invasive procedure, so it's associated with some possible side effects including ovarian hyperstimulation syndrome that can present with abdominal distension, vomiting and fluid in the abdominal lungs. And also there can be complications arising from the egg collection, like bleeding from the ovaries or pelvic infection. And this is especially the case in some hematological cancer where the woman has thrombocytopenia or neutropenia and in gynecology cancers, if there is a pelvic tumor, there is a possibility where the tumor cells can disseminate. With OHSS, nowadays in the modern day clinic, OHSS is, well, OHSS is a known complication of IVF, but nowadays moderate and severe OHSS is quite rare. When we looked at our data in 2022 with 715 stimulation cycles, because at that time we had some shortage of medication and basically we used a regimen similar as that used for fertility preservation for all of our women, the moderate and severe OHSS rate was quite low. It was only 0.28%. And we can also further modify the IVF regimen using a gonadotropin-releasing hormone agonist to trigger final oocyte maturation. And with these measures, with these measures, basically we can further reduce the OHSS rate. However, bear in mind that with cancer patients, because they need to go to their cancer treatment as soon as possible, even with mild OHSS, a delay in cancer treatment can be significant to them. So we really have to be very careful and try to reduce complications as much as we can. But as you can appreciate from the previous slides, oocyte or ovarian cryopreservation, even with all the modification, it still takes about two weeks time. In some women, they need to require immediate cancer treatment, like for example, those hematological cancers, where even two weeks is too long for them. Or in prepubertal girls, it's not possible to stimulate the ovaries. In these cases, ovarian tissue cryopreservation may be an option. However, because ovarian tissue cryopreservation is actually like preserving the ovarian tissue strips, it's not suitable for women with ovarian cancer or in those with cancers with high propensity for ovarian metastasis, like hematological cancers, or in women with BRCA mutation. Because in these cases, you risk in the future when you transplant this ovarian tissue back to them, you could be transplanting the tumor cells back to them as well. What happens in ovarian tissue cryopreservation, the women needs to require two surgeries. The first surgery is to extract the ovarian tissue. And most of the time nowadays, we can do it laparoscopically. And then we retrieve the healthy ovarian tissue. There would be risks of surgery, including infection, risk of injury or bleeding, as well as that of general anesthesia. The healthy ovarian tissue would then be cut into strips in the lab and frozen. And in the future, when the woman is in remission and ready for pregnancy, we can then thaw the frozen ovarian strips and then transplant them back into her body. So it could be either transplanted in the remaining ovary or it could be transplanted into the peritoneum. Again, it would require a second surgery. So there would be risks of surgery. So this slide shows a newspaper clipping. And back in 2016, this was a woman who had right oophorectomy at nine years old to preserve her fertility. At that time, she was pre-pubertal. She has beta thalassemia and required bone marrow transplant. So before the bone marrow transplant, she had right oophorectomy as a form of preserving the ovarian tissue. So at that time, she was the first case in the world who were pre-pubertal, girl, frozen ovaries, subsequently transplanting the ovaries back into the ovarian tissue back and had a successful live birth. So you can see that this field is actually expanding rapidly because just less than, just only seven, eight years ago, that was the first case in the world where they successfully had a live birth in a pre-pubertal ovarian tissue prior preservation. So I like to keep this slide to remind us how rapidly this is really improving because over this seven years, eight years, nowadays, there are already more than 290 pregnancies reported in the literature for ovarian tissue freezing resulting in live birth. This was the data in 2022, so there are more now, and there is quite a good live birth rate of 28%. So even just a few years ago, this was considered experimental, but in recent guidelines, this technique is established and no longer experimental. So I try to compare the different methods that I've talked about here in this table. So we said that the most common methods of fertility preservation in women would be oocyte or embryo freezing. So these techniques would take about two weeks time, whereas ovarian tissue freezing, it can be done within days if facilities are available. So all of them now have sufficient evidence that these techniques work as fertility preservation. For oocyte freezing, it's flexible because for young women, they may not have a partner at the point where they do fertility preservation, or even if they do have a partner, they can change the partner. Whereas if you freeze the embryos, the embryo is already formed with their existing partner, so they cannot change their partner in the future. The legislation probably differs in different parts of the world, but in Hong Kong, they have to be legally married when they do embryo freezing, and also they cannot change their partner. And if anything happens to their partner, they cannot use the embryos to create a posthumous child. With ovarian tissue freezing, again, it's quite flexible. So oocyte embryo freezing requires a minor procedure, which is invasive, a transvaginal ultrasound guided oocyte retrieval, whereas ovarian tissue freezing requires laparoscopy, and it's not suitable for certain cancers. So I've talked about the methods of cryopreserving reproductive cells. Next, I would like to talk about a few methods that limits the impact of treatment. Gonadotropin-releasing hormone agonists have been used to suppress ovaries to protect from the effects of chemotherapy. So how this is given, it's usually given one to two weeks before the first chemotherapy treatment and continued until the treatment is completed, until the cancer treatment like chemotherapy is completed. Injection is given every one to three months, depending on the preparation. So there are one month preparation, there are three months preparation. Most of the evidence so far on gonadotropin-releasing hormone agonists in protecting the ovaries come from breast cancer. And also, if you look at the literature in detail, the outcome that is seen is mostly in terms of ovarian function, for example, resumption of menstruation instead of fertility. So instead of whether they managed to achieve a live birth. And in guidelines, it says that it is a method of protecting the ovaries, but there is limited evidence in most types of cancers. And also, it should not replace oocyte or embryo freezing or ovarian tissue freezing. There are some side effects of these injections. Mostly they are short term. There will be menopausal symptoms like cough flushes, night sweats, mood changes, difficulty sleeping, et cetera. And another method that may limit the impact of treatment would be ovarian transposition. So that is to surgically reposition the ovaries outside the pelvic radiation treatment field to reduce ovarian exposure to the radiation. Again, this would require a surgical procedure. Nowadays, it can be done using a minimally invasive approach. It's suitable for women who undergo pelvic radiation. So for women who do not have adequate time for egg or embryo freezing or pre-pubertal girls. So in these cases, it can be considered. However, it does not protect against systemic chemotherapy. So basically, it only removes, like moves the ovary away from the radiation field as far as possible. But it really, if the woman or the girl requires systemic chemotherapy, it doesn't protect against the effect. Also, the uterus is still in the radiation field. So in literature, there are lots of evidence saying that the uterus is also affected by the radiation. So even if they manage to get pregnant in the future, there is high risk of adverse effects on future fertility, like increase of miscarriage, intrauterine growth restriction, or infertility because of the lining of the endometrium also being affected. For men, it is usually more straightforward. Usually it's by sperm banking. It can be done quickly in the same day. Whereas in contrast to women where time is needed for ovarian stimulation and pre-pubertal boys, it's more complicated. Pre-pubertal boys, testicular tissue freezing is the only method, but currently it's still experimental. And with testicular tissue freezing so far, there are no live births in human, but we do have live births from animals like rabbits, rats, pigs, and monkeys. So this is Grady, which was born using the testicular tissue freezing and then subsequently transplanting back and subsequently have a live monkey birth. So next I would like to talk a little bit about the barriers to fertility preservation. And to understand that we can first look at it from the doctor's perspective. So there's this data from Hong Kong. It was a cross-sectional questionnaire survey done in 2016, so several years ago. So clinicians in various public hospitals were asked a questionnaire to assess their awareness, attitude, and knowledge about fertility preservation in cancer patients. So in that study, it showed that the awareness and knowledge about fertility preservation among clinical practitioners looking after cancer patients was weak. At that time, less than half of the respondents were familiar with fertility preservation, and more than half have never referred a patient for fertility preservation. So that questionnaire also tried to assess the reasons why they did not refer the patients for fertility preservation. So at that time, there were several reasons cited, including the lack of available time before treatment, the worry of risk of recurrence or the poor prognosis of patients, financial constraints of patients, the need for cancer treatment as a top priority, and also a lack of awareness of such service. However, almost all of them agreed that a dedicated center should be set up for fertility preservation, and more than two-thirds agreed that fertility preservation should be provided as a public service. And then we tried to look at it at the patient's perspective as well. So we did a questionnaire study in Hong Kong. It was looking at the knowledge, attitude, and intention on fertility preservation in breast cancer patients. It was a multi-center study, including the breast units, clinical oncology units, the gynecology units, as well as the Hong Kong Cancer Fund and some private practitioners. So this was recently published a few months ago. So in our questionnaire survey, 44% of women had heard of fertility preservation. So again, less than half of them have heard of fertility preservation, but a significant proportion of women felt that their fertility concerns were affected by their decision for cancer treatment in some way. So it's significant. So then we tried to look at their knowledge and acceptance of different modes of fertility preservation. So for those who have heard of fertility preservation, most of them would have heard of oocyte prior preservation, oocyte donation or adoption, but they may not have heard of methods like freezing ovarian tissue or gonadotropin-releasing hormone analogs. And then we also looked at how likely they will go for these fertility preservation methods, which is shown in the gray bar, and you can see that the acceptance is generally low. So how do we try to overcome the barriers? The number one barrier would be the cost, because for a cancer patient, they already may need to bear the cost of oncological investigations and treatment, and they would have anticipated loss of earnings because they may not be working and have to treat their cancer. Obviously, the practice varies in different countries, but in Hong Kong, previously, fertility preservation was only available as a private service, which can be quite costly. And in our survey, we tried to, again, look at what the patient's perspective on the cost was. So most of them supported that fertility preservation should either be offered free by the government or at least have some subsidies. So a few years ago, we started a pilot public-funded fertility preservation program to women who fit the certain criteria. And I'm happy to say that after the pilot project, now the public-funded fertility preservation program is available. And also, we are lucky to have the support from Hong Kong Cancer Fund, who helps support this. So I think this is very important for our young cancer patients who have fertility concerns. Number two barrier would be the timing, because we know that they need to go for the cancer treatment as soon as possible. So we try to see them within one week. And in the first visit, we basically take the history, do all the investigations, talk about the fertility preservation options. And if they agree, we will sign the consent. And the sperm freezing can be offered on the same day, whereas oocyte embryo freezing, if they want to do it, they can start as soon as the next day. With the random start approach that I've talked about earlier in this presentation, we can save time instead of waiting for the woman's period. But having said that, if they would go for oocyte or embryo freezing, it still requires around two weeks. And to improve access and to improve, to shorten the timing to offering fertility preservation, we really need to continually expand our oncofertility network, because there are many, many specialists looking after the patients. So if we have a good network, then referral can take part promptly. And another area that I would like to talk about is the post-cancer treatment follow up. Because fertility preservation is not only about saving ovarian tissue, saving oocytes or embryos. It really is about looking after the woman's reproductive health. So a woman may go into premature ovarian insufficiency after cancer treatment. So we may need to do investigations on hormonal profile or may need to prescribe hormonal therapy. If they have fertility wish, we have to make sure that they are fit for pregnancy. So we need to liaise with the oncologist to see if they are fit for pregnancy and to help them. And for men, after cancer treatment, they can have a semen analysis and hormonal profile to see if they need to continue to freeze the sperm. And when we looked at our experience a few years ago of women who had fertility preservation with us, we tried to track them and we found that only 15% were followed up at a reproductive endocrinology clinic after their cancer treatment. So and in men, it's even worse because most of the time there's no systematic follow up in terms of their reproductive health. So I think this is an area where we can continue to improve. So to conclude, oncofertility is a rapidly evolving field. I think over the years, there is improving awareness of fertility preservation from doctors as well as from patients. But we need to continually expand our oncofertility network to help continue to improve this awareness even more. We need to provide realistic fertility counseling to patients. So this should take into account the individual's patient's condition. It is a chance to have a biological child, but it's not guaranteed to success. And we really also need to take into account the individual's oncological situation to see if it is prudent to have fertility preservation at that point or whether they should stabilize their oncology condition first. We need to continually enhance post-treatment follow up as well. So this is the end of my presentation. This is my team, and I'm happy to work together with them to help our patients. And I would welcome any questions and comments from you.

fertility preservation

cancer treatment

reproductive cells

cryopreservation

ovarian tissue freezing

sperm banking