In this session, Dr Uliana Dorofeyeva, Director of International Cooperations at IVMED, Ukraine, and a Medical Director at OVOGENE Egg Donor Bank discussed what ovarian ageing means and how oocyte quality decreases with age.
Dr Uliana Dorofeyeva started by explaining that our goal is to achieve a pregnancy as soon as possible. Patients are indeed referring to us at different times and ages. Very often, Ukraine, as a country legally providing oocyte donation and surrogacy, is not a country where patients are contacting us with initial infertility. These patients have often had negative attempts in the past and experienced a lot of IVF treatment already. They are looking for a second opinion, the best option, or alternative options for the treatment. We will talk a lot about those. Another goal we have created for our entire team is to maximize the success rate for the first and initial cycle together with us for each patient. Again, you will refer to the fact that you have already had so many negative attempts, and we will explain what we will do differently to maximize the success and get the treatment done successfully within the first attempt.
However, in Ukraine, being a country with many unique treatment options legally available and also many experimental options available, after learning in detail all your medical history and records, we offer those screening regimens which quite often were not recommended before. For example, immune treatment, individual window of implantation, and key receptors, among many others. We also offer treatments, including extremely successful oocyte donation alternatives, such as pronuclear transfer with donor cytoplasm, surrogacy, and any kind of treatment. By combining all these and after completing full screening, we achieved a very successful IVF treatment.
Another goal is to reduce multiple pregnancies and guarantee safety in IVF. This is crucial, of course, and to help as many patients as possible. Being in Ukraine may reduce the costs, understanding the low limits. We may offer those treatments which are available in Ukraine, and we may use the most effective techniques we are practising right now.
If we are talking about our biological clock, even now we are spending our follicles. We are producing our oocytes depending on which level of FSH we have right now. We are involving one or several follicles to grow and to recruit the oocyte inside the ovary.
Some of our cells are getting into the process of apoptosis. For any woman who decides to have a goal of getting fertility treatment done, timing should be crucial, independent of which age you are, but specifically, if you are over 35 and higher.
To understand the time and why it is so crucial, and also what we are losing by wasting our time or postponing our IVF treatment, we need to understand this graph.
The number of under follicles which we are going to spend during all our entire life is dedicated, is settled for the fetus, for the female fetus, during her antenatal development. So, since we are seven months inside the uterus of our mothers’ wombs, we already have our total number of resources of our antral follicles which we are going to use during all our entire life. After the first meiotic arrest, once we are born, we are born with a certain number of antral follicles, which is around two million. Until the period of puberty, until the first menstruation, when we started it, we have a second meiotic arrest, and we are left with about four hundred thousand to five hundred thousand antral follicles in both of our ovaries.
Since we are starting every menstrual cycle, depending on which age we are, the younger we are, the higher the number of antral follicles which are recruited in our every next menstrual cycle. So, if we are in our young age, the total number of follicles is about 20 in every ovary. If we are getting older, the total number of follicles is getting lower. However, every cycle a new cohort of oocytes is being recruited and has the potential to grow.
During our entire life of ovulation and having menstruations, we have between 400 and 500 ovulation cycles. If the hypothalamus is producing a certain dose of FSH, this certain small dose of FSH is recruiting only one follicle, which is growing up to being a dominant follicle and is able to ovulate and produce the oocyte inside of this. So, all others on the stages, they are just getting into the process of atresia, and atresia is their death. So, we will not be able to use any of those follicles at any time in our future.
This means we started our cycle; we recruited a certain number of follicles depending on which age we are, and depending on how much follicle-stimulating hormones we received, many follicles were growing in order to respond to the FSH and produce oocytes. If they produced oocytes, we are able to collect these oocytes, and we can freeze these oocytes, we can fertilize these oocytes, we can use these for future use. If we haven’t given additional FSH dosage, so they were not recruited. However, still they just disappeared.
That’s why this is so important to understand this process for women who are in their older maternal age because they still produce some of their cohort of the follicles every cycle. They are given a small amount, but still, they can recruit a certain amount of the follicles. So, this is so important to use those, this small amount, in order either to keep it frozen or to use for the IVF treatment.
99.9%, even I would say more, of our follicles are going through the process of atresia. So, they are lost, and we have no chances to use them during our entire life.
There are many anti-ageing therapies now that we are all successfully using. We all like to look younger, and very often, we keep a healthy lifestyle, which is also important, and we will talk about this. However, there is no chance to improve the quality and the safety of the ovary. We can only manage the timing.
Anti-ageing therapies for the ovaries exist, and we may talk about ovarian rejuvenation, which is still an experimental method but is being used very successfully. There is a certain cohort of patients for whom we would recommend this method, but it should be done before the treatment. As soon as you decide to have your treatment done, we can improve the number and the quality of the received oocytes by performing the ovarian rejuvenation technique. However, this is not a long-lasting procedure, and it will not last forever.
It’s true that the average age for the first delivery in the world is increasing. Every decade, the age of women delivering their first baby increases by two years. If we keep this tendency, as responsible fertility doctors understanding this trend, we need to offer effective treatment for those women who are coming to us in their older and older maternal age. They are still expecting successful treatment and believe they will achieve it. We have periods which we divide into optimal fertility, declining fertility, end of fertility, premenopausal, and menopausal age. This is the timing when we are producing fewer and fewer oocytes.
The full IVF cycle is absolutely different for different ages of our patients. However, once we start our simulation, we have ovarian stimulation and oocyte retrieval. There are certain demands for the IVF stimulation cycle. The most important is to guarantee safety but also to receive an optimal number and quality of oocytes, which, after fertilization and embryo cultivation, we will select the best quality embryos in order to transfer into the uterus, with the expectation to end up with a clinical pregnancy.
If possible, we aim to freeze additional embryos for future use. If we are talking about patients of advanced maternal age, our aim would be to select such a stimulation protocol to produce at least one euploid embryo to have the possibility to be implanted.
If we are talking about the ideal stimulation protocol and gold standards in stimulation, the rules would be different for different ages of the patients.
For the young population of normal gonadotropic women, the best stimulation medication will be recombinant FSH, which will lead to sufficient follicular development and an optimal number of oocytes retrieved.If we are talking about the patient population over 35 years old, in addition to recombinant FSH, we need to add LH. This should be added from the first day of the stimulation cycle as we need to work with both types of receptors, LH and FSH, in order to recruit more follicles and achieve a higher quality of retrieved oocytes.
At any age of the patient, we need to fully control the cycle to achieve an individualized number of oocytes with the optimal amount of medications used and no complications for the patient. Based on the profile of the patient, this can be absolutely different. You need to discuss this specifically with your treating physician, depending on your hormonal profile, the antral follicle count, previous outcomes, and the stimulation protocols which were offered by the doctors.
There are some general rules; for example, the maximum effective dose recommended is 300 international units for any age of the patient. However, for lower responders, even a lower dosage of medication is considered to be more effective because, regardless of the dose, there is a certain yield of follicles to be recruited. Increasing the dosage does not necessarily increase the number of recruited follicles.
Oocyte number and quality are strongly correlated. Receiving more oocytes increases the probability of obtaining more blastocysts, regardless of the patient’s age. It also increases the probability of obtaining euploid embryos, thus enhancing the cumulative or multiple pregnancy rate per cycle. For older patients, the aim would be to receive at least one euploid embryo.
Poor responders are defined as those patients for whom less than three oocytes were retrieved in their previous stimulated cycle, or those with an AMH (Anti-Müllerian Hormone) level less than 0.5 ng/mL. The best protocol should be offered to receive at least one euploid embryo. This best protocol could include the Shanghai protocol, double stimulation, letrozole in the stimulated cycle, or other pre-treatment options. Many options are available, but they all need to be individualized.
If we are talking about the possibility and probability for you at any age to produce healthy oocytes, you probably know that the quality and quantity of the oocytes we might produce decreases with age. We may do a lot and try different methods and techniques to produce as many as possible and of the highest quality possible.
However, there will probably be a day when some physician in some location will offer you oocyte donation as an alternative to achieve your successful treatment. Right now, this is the best alternative, widely available, and gives a success rate between 50% to 60%. Even in good places like our clinic, we have never had less than a 60% clinical pregnancy rate for oocyte donation treatment, even with very poor sperm quality. So, regardless of your age, this is a very successful and appropriate treatment.
We need to understand these mechanisms and how we can overcome them. We must ensure that we address the issues related to the oocytes you are producing, even if we have less quality and quantity. Oxidative stress, changes in mitochondrial activity, mitochondrial dysfunction, and endoplasmic reticulum dysfunction, along with issues with calcium channels and the level of calcium inside the cell, all contribute to poorer embryo development and poorer quality of the embryo, which is correlated with oocyte quality.
There are treatment strategies, such as calcium ionophore, which we are using for advanced maternal age oocytes to activate the cells to be healthier and achieve better embryo development.
We can overcome oxidative stress by giving a supplement. Here, you can see the graphs explaining how long it takes for the primordial follicle to grow into the small antral follicle, which will be already sensitive to FSH and capable of producing the oocyte inside the follicle. Usually, this entire process takes over 200 days. These 200 days from today will result in your new dominant follicle, which will produce the oocyte inside, and this is an ongoing process.
For men, they renew their sperm every third day, but this is not the same for women. Women produce a new cohort, and this is a constant process, happening only once every 200 days but continuously, so a new pool of follicles is generated every day. This process started more than three months ago, which is very important for patients in their older maternal age.
It is crucial to have the right level of androgens. We have already talked about the importance of LH for older maternal age, but androgens are also essential. Androgens help FSH connect with the receptors and aid in the previous luteal phase for our follicles to prepare for the new cycle. That’s why some supplements like dehydroepiandrosterone sulfate (DHEA) are very commonly used by our patients. However, we need to discuss all supplements, including DHEA, because the data about their effectiveness is not fully confirmed.
Many patients and clinicians recommend supplements and antioxidants for the treatment or before the treatment for many patients. However, there is limited evidence suggesting the efficacy of these antioxidants or supplements in improving fertility, and the trials exploring this area have yielded varied results.
I am not against patients taking supplements. However, I always ask patients to inform their physician about what they are taking, including the dosage in milligrams, the number of pills per day, and the duration of use. The side effects of overdosing on these medications can be significant. Therefore, it is very important that your physician is aware of and can correct the average dosage or ensure the safety of these treatments. This applies not only to crucial medications like FSH and direct stimulation medications but also to others that play a role in your treatment cycle and affect your general somatic status.
What is the best evidence? What we consider as being the best evidence in medicine and why we are recommending something, and we would like not to communicate or not to comment for something else. There is missing trend advice or being read in the forum etc but this will be the very down line. But what we consider as being true based on high evidence, this is at least clinical research or trials or coherence systematic review or meta-analysis.
So, all this information does not confirm that the supplements which we are recommending for improving fertility or rejuvenate the process of producing the oocyte as being as maximum effective. As I said folic acid, this is something what is confirmed. All the others we as a clinician we are not fully against, but we need to understand that there is not much evidence for this.
IVF treatment has been widely used worldwide for less than 50 years. Before 50 years ago, we had no experience with any kind of IVF, and if a patient faced infertility, there was no treatment available. Right now, we are all using IVF treatment and are very successful in this. Those topics are still experimental, but our scientific team and clinical team believe that this is the future and a great alternative for those patients who have already tried the general approach, different stimulation regimens, and produced their own oocytes but are not ready for the alternative of full oocyte donation.
What controls oocyte quality? We mentioned this before, but these are small organelles named mitochondria, which provide energy for the cells. If we get less energy for the cells, we encounter problems in embryo development and fertilization. If there is no battery, there is no work and no further growth.
The number of mitochondria decreases in aged oocytes. Additionally, these mitochondria undergo morphological changes. Most importantly, the mitochondrial DNA, which contains a small part of our genetic material, develops lesions. Due to these factors, the cell’s overall function is altered, which can block fertilization and the further development of the embryo. Consequently, mitochondrial dysfunction leads to lower IVF success rates, reduced fertilization, and higher aneuploidy rates for the embryos.
What’s the main solution? The solution, as we mentioned before, is conventional oocyte donation. In this process, a healthy, mature oocyte from a donor is fertilized with the husband’s sperm and then transferred into the uterus of the intended mother.
What causes poor egg quality? The causes of poor oocyte quality, apart from maternal age, include genetic factors, endometriosis, and other factors such as:
The alternatives we are going to talk about include the fact that if we can solve the issue of mitochondrial dysfunction, we can offer patients the option of using their nuclear DNA. By using the nucleus of the embryo, which contains more than 99% of the genetic material, patients can have a genetically related baby.
Oocyte donation may seem like an easy alternative from the physician’s perspective because we know that the probability of getting pregnant is very high for this patient. However, patients still have the right to carry their genetic material and their genes during pregnancy. There are psychological and ethical considerations for patients before they accept full oocyte donation treatment, and these need to be considered as well.
Alternatives for oocyte donation include:
The spindle is the small organelle inside the cell responsible for the division of the genetic material of the oocyte. This organelle is crucial for mitosis. If the spindle is intact and of good quality, mitosis will proceed properly, resulting in a zygote. If we get a zygote, it has the potential to develop into a four-cell embryo, then an eight-cell embryo, a morula, and eventually a blastocyst.
Only specialized software can detect the spindle within the oocyte. We check the spindle particularly in patients of advanced maternal age because some oocytes, even if they are mature and have nice cytoplasm, might lack organelles within the cell. These oocytes might have polar bodies and appear morphologically correct; however, upon checking the spindle, we might find the oocyte to be empty, meaning there is no potential for fertilization. These oocytes often remain unfertilized, even after ICSI (intracytoplasmic sperm injection).
Spindle transfer is a technique where we replace the entire cytoplasm of a poor-quality oocyte. If the spindle is not observed in the patient’s oocyte, we obtain cytoplasm with the spindle and healthy mitochondria, and we transfer it into the maternal egg, giving the nucleus within the oocyte the potential to develop correctly, be fertilized properly, and form a blastocyst that can implant.
As shown in the scheme, the spindle is removed from the donor oocyte and placed into the maternal oocyte. The reconstructed zygote is then fertilized, and we can observe the pronuclear stage of the zygote, which will develop further into a blastocyst.
The advantage of spindle transfer is that it provides families affected by mitochondrial diseases, and patients of advanced maternal age, the opportunity to create healthy embryos that have the potential to develop into pregnancies. Mitochondrial donation is commonly needed in some countries with a high prevalence of mitochondrial diseases. In these cases, there is relatively less mechanical damage and more political considerations for these embryos. However, this procedure needs to be done in the right laboratory by highly skilled embryologists.
Pronuclear transfer is very similar to the process we just described. However, for pronuclear transfer, we fertilize both the oocyte from the donor and the oocyte from the patient using the husband’s sperm. Once we receive the zygotes, we exchange the pronuclei inside the zygotes. We remove the pronucleus from the maternal oocyte and place it into a healthy oocyte with young mitochondria from the donor. With further development, there is no risk for fertilization issues because the transfer occurs between zygotes. This technique results in better blastocyst outcomes.
This method provides the potential for patients with mitochondrial diseases to have a healthy child. The technique requires experienced handling and special cultivation methods during micromanipulation.
Another issue related to genetic abnormalities in patients is worth discussing. Many of our patients, during the initial consultation when we discuss their probability of getting pregnant, need clear and thorough information. We strive to educate our patients comprehensively, and many of them are already well-informed. We greatly appreciate that they understand what we are discussing, what procedures we are going to perform, and how, together as a team, we aim to achieve the goal of pregnancy.
However, there are challenges we cannot overcome. For instance, even 30% of all oocytes from donors are already aneuploid. This fact is well-known: even if we are young and healthy and trying to conceive, we often do not conceive from the first sexual intercourse. It sometimes takes several months or even up to a year to achieve pregnancy, largely due to oocyte quality. This is important to remember.
When considering patients’ oocytes and embryos, it’s crucial to note that if a patient is over 35 years old, 50% of the embryos we receive may be aneuploid. This makes it challenging to obtain blastocysts. If we manage to get one or two blastocysts, we are very happy for that patient. However, if we perform pre-implantation genetic testing and check the rate of healthy embryos, we often find that this rate is lower than expected, and sometimes we have zero euploid embryos. This can lead to a cancelled embryo transfer, which is difficult to explain to patients, especially when we are hoping for a different result.
Therefore, it is essential to consider these factors when planning treatment for any patient of reproductive age.
We have an opportunity to check, and we are not giving the patient false expectations of transferring non-healthy embryos into the uterus and giving them a risk of implanting those non-healthy embryos. Then, you know, overcoming these issues with a pregnancy, which is not right. So, the options we are offering include oocyte testing. We can check if this oocyte is healthy and if the oocyte is going to produce a healthy embryo.
We also offer PGD-A (Pre-implantation Genetic Diagnosis for Aneuploidy) or NGS (Next-Generation Sequencing) testing of the embryos, which is specifically recommended for patients in their advanced maternal age.
Another factor, which is not connected to embryo quality but is related to implantation potential, includes aspects like thyroid function, the immune status of the patient, individual windows of implantation, and embryo-endometrial crosstalks. These are many points that need to be confirmed and checked for all our patients to maximize their chances of getting pregnant.
Just a few words regarding Ukraine. Right now, we have over 60 private IVF centres in Ukraine, many of which offer treatments for international patients. However, you need to be very careful when selecting the clinic. I would highly recommend talking to the team to get as much information as possible and also seeking advice from your friends and colleagues. Additionally, egg donation forums can be very helpful. With so many clinics available, you might come across a nice picture online, but it’s important not to be surprised afterwards. Most clinics, however, are reliable and offer high efficiency and quality communication.
It’s important to mention that we have legal oocyte donation and surrogacy, as well as the export of biological materials. We will have another webinar later this week to discuss legislation in Ukraine in more detail, so there’s not much to say about it in this webinar. However, I would like to note that even if you are located outside of Ukraine and cannot travel right now, you have options. If oocyte donation is legal in your country, you can ask your clinic, or you can ask us, as we send a lot of biological materials all over the globe. You can see on the map in green the locations where we are sending our vitrified donor oocytes. This means you may avoid travelling to Ukraine but can still get your egg donation treatment done in your country if it is legal and if you have this option.
This is only for conventional oocyte donation, not for mitochondrial transfer, surrogacy, or any procedures like ovarian rejuvenation. For single women, we also offer the option of sperm donors and their samples, and even embryo donation if recommended by your clinician. Additionally, surrogacy is an option available for couples.
You have a right to transport your biological materials between the clinics, between the countries. You can store your materials in any destination you feel is right to do so. This transportation is always done under the conditions of international rules and safety. You can also ask us if you need help with that.
Very important to say, and I like this scientific paper coming from Israel. Israel, probably you know, is the only country which covers all IVF treatment completely free until a family has three children. They published a paper on live birth rates after unlimited free IVF and checked the couples over four years. So, 95.9% of the couples conceived if they had unlimited chances. This means they waited zero time. As soon as they had the opportunity to start their cycle, they started, and they used as many of their biological materials as they could produce. Israel is also the country where the average number of stimulations per patient is 18, which is extremely high. However, we can see the results that if you keep using your option for IVF treatment and keep trying, there is still a high probability of getting pregnant and having a successful delivery. They included not only information about clinical pregnancy but also live birth rates.
Another data set comes from the UK. You may see that within nine IVF cycles, even with their own oocytes (which are shown in blue on the graph) for women between the ages of 40 to 42, we get a maximum cumulative clinical pregnancy rate of 25% up to 30%. It does not go higher. But with their own oocytes before the age of 40, and specifically with donor oocytes, there is an increase. With donor oocytes, it comes closer to 100% if we repeat and repeat our IVF cycle.
So, just a few more minutes regarding genetically certified oocyte technology and why we decided to offer this. You may see the image of the donor oocyte under how we do the morphological evaluation. This is high-performance microscopy, and we are checking in detail all the morphological features of the oocyte, including the spindle. After conducting a clinical trial, we did a polar body biopsy on around 1,978 oocytes. The number of aneuploid oocytes from the donors was 25%. After that, we decided to offer NGS (Next-Generation Sequencing) testing or polar body testing for a selected group of our donors from the Origin Egg Bank. So far, this is a unique option available only from our bank. We understand that when a patient decides on oocyte donation, they expect a blastocyst to come from almost every donor oocyte. They expect donor oocytes to be as high in quality as possible.
By offering NGS testing and checking the euploidy of the donor oocyte, we avoid the fact that 25% or up to 30% of those oocytes may be aneuploid. We understand that when patients decide to use donor oocytes, they probably expect to get a blastocyst from every oocyte. We cannot expect this without additional checks for the donor oocytes because donors are human beings, and they produce 20% to 30% of their oocytes being aneuploid. This specific testing allows us to offer patients the highest quality and the highest probability for blastocyst creation and implantation potential for those embryos. Most programs in oocyte donation are not doing this so far, but we believe that this is the best option for patients.
The last thing is that in our team, we don’t believe in the diagnosis called “unexplained infertility.” For us, this means that the clinicians were not able to find the true cause of infertility, and we should keep looking for the reason why this couple has not gotten pregnant until now. If we keep looking, we will find out what the reason is because there are many causes. For many patients, there will be multiple reasons, and we need to find as many reasons as possible and overcome them to be successful in our IVF treatment.
To conclude, there are many different treatment options in IVF to achieve the goal of parenthood. These options include using one’s own oocytes, experimental treatments, and treatments involving third-party reproduction. A second opinion is recommended due to specific limits in the countries. Very often, something you have heard about or read may not be practiced in the country where you are or where you plan to be treated. In such cases, you should keep looking for those options elsewhere.
The most effective treatment for patients of advanced maternal age right now is oocyte donation. However, there are experimental treatments available in IVF that are effective and may be widely accepted in the future. Genetically certified oocytes are an advanced technology currently offered only by Origin Egg Bank to increase the chances of euploid blastocyst outcomes and pregnancy chances for patients. Polar body biopsy does not affect oocyte quality, morphology, or survival rate during vitrification or thawing. We also offer this technique for patients of advanced maternal age, specifically for those who would like to freeze their oocytes.
According to international regulations, it is not recommended to freeze oocytes for future use if the patient is over 38 years old. However, if she is even 40 but still has the potential to produce oocytes, we can offer her several cycles of stimulation. This is because it is more probable that we would need to combine several treatment procedures to gather all the oocytes from these treatments. We would also recommend checking the genetic status of her oocytes to understand what she can rely on in the future. Genetically tested oocytes have a significantly better euploidy blastocyst rate and implantation outcome. The risk of chromosomal abnormalities dramatically decreases after polar body and embryo NGS testing.
If you are here with us and listening to this webinar but haven’t tried all the mentioned options, you should keep trying. Remember the publication from Israel: the more cycles you do, and if you just do not stop, but continue your treatment, there is still a high chance for you to get pregnant.
We have a group of patients, and we did this for the treatment of the patients. But it was also important for us to understand what the inclusion criteria should be and how it works for different patient populations, different age groups, and different AMH (Anti-Müllerian Hormone) levels.
Initially, we accept any patient for the ovarian rejuvenation technique who has the desire to try her last chance of producing her own oocytes, provided she is still cycling. Even if she is not regularly cycling, she is still cycling and has at least an AMH level over 0.15 or at least 0.1. This is based on data from the number of patients we treated in our centre. The most successful patients were those who had their AMH level over 0.15 or at least 0.1.
If a patient has less than 0.1 AMH, we may include her in the initial protocol for oocyte rejuvenation. We may try to do an initial cycle of oocyte rejuvenation, and then we check how she responds in terms of her FSH (Follicle-Stimulating Hormone) level and AMH level and if any antral follicles are seen in the ovary. If there is a good reaction and prospective prognosis, we will continue with the second and third cycles. We do a maximum of three ovarian rejuvenation procedures for each patient and do not recommend more than three. We would suggest some alternative options.
However, some patients, especially those who have an AMH level over 0.1, respond even after the first oocyte rejuvenation technique, and it works quite effectively. The process involves taking about 20 millilitres of blood from the patient. We prepare this blood in our facility, which takes about one and a half hours. The blood is centrifuged to obtain platelet-rich plasma (PRP) of about one to two millilitres, which is then injected under ultrasound supervision into the ovaries. The injection is divided into equal amounts for each ovary. Usually, this is done under general anaesthesia, so the procedure is very similar to how we do oocyte pickup.
After the procedure, we ask patients to check their FSH, and AMH levels, and undergo ultrasound evaluation for antral follicle growth every week, for a maximum of two months. We supervise the patient during this period. As soon as we see that a follicle is growing, we start the stimulation cycle.
In terms of the mechanism of how this works, it involves the fact that 200 days prior, pre-antral follicles become sensitive to FSH. By introducing the PRP into the cortex of the ovary, we help these pre-antral follicles mature faster and become ready to respond to FSH. This increases the cohort of follicles that have the potential to grow and recruit an oocyte inside. However, we need to understand the time frame. We do PRP, monitor it, and decide when to start stimulation based on the injection and the hormonal checks.
So, it’s immediately before the cycle because we never know how you will react to the PRP (Platelet-Rich Plasma) procedure. For some patients, if they are good prognostic patients, I would say that, depending on if you are cycling, we would do PRP at the very beginning of your cycle, in the early follicular stage. Then, if we see that follicles are already growing, we will start the injection of FSH (Follicle-Stimulating Hormone) immediately after we have seen a few follicles growing.
For good responders, we may start stimulation within the same cycle when we did the PRP. However, for some patients, it’s different because they are not producing grown follicles that we can check under the ultrasound scan so early. For these patients, we perform the procedure one or two months before the cycle, depending on the follicle growth.
I’ve read about this, and they’ve been contacted by some patients who are getting this supplement. However, there is no evidence; there are very few publications that we would consider fully scientific and which we may rely on. However, I have no proof of this.
I would say that it depends on the facility you are working with for your outside donation or vitrified outside donation. As we are running the outside bank and the number of all sides being vitrified and formed by our team is just extremely high, our technique is absolutely great, and we don’t see any difference, as well as with some of our clinics to where we are supplying our biological materials.
However, this is true, meaning if the process is well established and strictly followed by the protocol, there is no difference because the survival rate of the oocytes is between 95 and 100 %. But if you are talking about some centres that have very limited experience, because this is all experience in the hands of the embryologist, they need to follow strictly the timing for the oocyte vitrification and warming. So, if this process is not well established, there is a slight difference.
We have a cutoff of 80% for the survival rate for the vitrified oocytes, and we consider those who have been having over 80% survival rate. In those centres where you probably should use better fresh oocytes which have less than 80% survival rates, you better work with fresh materials. However, in our hands, vitrified are much better because they are immediately available, there is a wide variety, and there is no clinical difference.
I would say that in order to certify the patient for the pronuclear or spindle transfer, this should be a patient who produces her own oocytes. We have a cutoff that, if we have at least three maternal oocytes, we will go for the procedure. We can get those three oocytes in different stimulation cycles or one stimulation cycle. However, if we have less than three, we do not recommend continuing.
For now, the oldest patient we had for spindle transfer was 47 years old. However, we need to check patient variation as it is different. We need to get more information about your image, if you are cycling, what is the antral follicle count, and maybe if you have some oocytes frozen elsewhere. There are many questions we need to ask to confirm this.
The success rate again would be divided into the group of patients who started preparation for mitochondrial or spindle transfer and who ended up with the treatment. Many questions arise once they start the preparation. For example, we were not able to retrieve their own oocytes or the number and quality of the oocytes were not appropriate. For instance, we received oocytes, but they were not M2, and we needed M2 to keep working with them.
There is a high number of patients willing to get maternal or spindle transfer who did not end up with the transfer. However, for those who did micromanipulations with their cells, grew embryos, and finally had embryo transfer, the success rate for this very complicated population was 56%. So far, this includes 16 pregnancies. This is a small number, and every pregnancy would increase or decrease our percentage. Therefore, it is better to talk about absolute numbers rather than percentages.
The cost is higher, of course, than the regular oocyte donation. I am not able to provide you the full cost; you need to contact our coordinators for this.
I may provide the total number of live births so far, which is 19 from our programs. The total number of clinical pregnancies is 16. However, the total number of patients who started treatment needs to be divided into those with a good prognosis and those with less favourable prognosis. The total number was over 40, but not all of them went through the whole process and reached the embryo transfer stage.
Those who did not end up with the embryo transfer in their spindle or pronuclear transfer were recommended for alternative treatments and still got pregnant. We are talking here about the cumulative pregnancy rate, starting from the initial inquiry of wanting to have a baby and ending with actually having a baby, but using different techniques.
I was showing these graphs with the evidence, so probably for the pronuclear and maternal spindle transfer, we are still in the early stages because this is still experimental. However, there is no alternative; this is the only option. We have a lot of data, and I can show you many figures for different groups of patients. For example, regular oocyte donation is very successful, but this success also comes from the large figures and many years of experience, continuously improving, as we did with the MGS (Mitochondrial Genome Sequencing) testing of the oocytes right now.
Not directly on the oocyte quality. However, you know that hormones have cross-communication between them. The most important thing is to have enough of everything. If you’re talking about advanced maternal age, there should be enough estrogen. Estrogen is a very important hormone for everything: your heart, your bones, your somatic status, your skin, hair, and even your mind.
Getting too much androgens will affect your body. There is no direct harmful effect that I have read about, but there will be disorganization between the hormones and receptors. I would not recommend getting more than 75 milligrams per day, as this is the maximum recommended amount, which is widely accepted.
