In this webinar, Dr Uliana Dorofeyeva, Director of International Cooperations at IVMED, Ukraine, and a Medical Director at OVOGENE Egg Donor Bank discussed various aspects of egg donation, embryo donation, and double donation and addressed genetic inheritance.
It’s known that everyone is different, as well as children are or will be. Before starting with a thorough explanation of the creation of the embryo, Dr Dorofeyeva talks about the cells, which are the strategic cells for the embryo creation and the future child presence.
For this, it’s important to talk about the human oocyte, which will come from:
The most important part, which consists of genetic material, is the nucleus. It’s essential to remember about the cytoplasm as well, and according to Dr Uliana, they’re learning more and more about organelles and the structure of the cells. Moreover, the mitochondria also play a crucial role in the genetic inheritance and creation of the embryo.
The mitochondria are located in the cytoplasm, and the zona pellucida, the first polar body, corona radiata (follicular cells) are very important in terms of the organelles and guarantee the safety of the creation of the cell and the development. However, they don’t have genetic material, so it’s important to remember that genetic material people have in the nucleus and the cytoplasm, meaning in mitochondria, are located in the cytoplasm.
Talking about the human sperm, there’s a head with the nucleus inside, which is the part used for ICSI. There’s the mitochondria, also located in the midpiece of the spermatozoa, but this part of the cell isn’t used for fertilization. It can be used for conventional IVF; however, through science, it can be confirmed that it doesn’t take part in fertilization.
Dr Dorofeyeva explains that inside the cell, in the nucleus, there are chromosomes created from the DNA that consists of the genes.
In addition, 99.9% of the human DNA is identical, and even though everyone’s different, 99.9% of the DNA is the same. The 0.1% difference is in personal and physical characteristics, such as appearance, height, constitution as well as the development of the disease.
DNA is the chemical inside the nucleus of the cell that carries the genetic instructions for making living organisms. It’s also the material inside the nucleus of the cell that carries genetic information, and the scientific name is deoxyribonucleic acid.
On the other hand, chromosomes are the packages of genes and other DNA in the nucleus of a cell. A chromosome contains hundreds and thousands of genes. Moreover, humans have 23 pairs of chromosomes, 46 in total, where 44 are autosomes that have different genes and also diseases, mutations, and the presence of the individual. In addition, two of them are sex chromosomes, which are responsible for male or female status.
Also, each parent contributes one chromosome to each pair, so children get half of their chromosomes from their mother and half from their father. Chromosomes are long stretches of DNA, within which lie genes. A single chromosome may contain hundreds of genes and for some genes, the doctor already knows their location as well as their coding.
You will probably know that some scientists are working on full genome sequencing; however, even though there is a lot of development, the full genome isn’t treated yet and every day, week, or month, doctors are learning more and more about this.
The gene is the functional and physical unit of the heredity passed from the parent to the offspring. It’s also a section of DNA that carries the information for a particular trait or characteristic. If you’re talking about how the baby will look, it may be the phenotypical characteristics, such as eye colour, hair colour, and production of particular enzymes as well as specific characteristics and diseases. Moreover, a trait is any gene-determined characteristic and is often determined by more than one gene. On the contrary, alleles are different forms of the same gene, for example, talking about eye colour, the alleles are responsible for blue, brown, and green colour.
Furthermore, full genome sequencing is based on a DNA molecule and, as previously mentioned by Dr. Dorofeyeva, they are developing this a lot.
Proteins are very important to take into account when talking about oocyte donation and genetics.
Proteins are also the most important class of material in the body. They aren’t just building blocks for muscles, connective tissues, skin, and other structures, they are also needed to make enzymes, which are complex proteins that control and carry out nearly all chemical processes and reactions within the body. At the same time, the body produces thousands of different enzymes and the entire structure and function of the body is governed by the types and amounts of proteins the body synthesizes.
Protein synthesis is controlled by genes which are contained on the chromosomes, meaning that the DNA is also based on the production of protein.
When talking about DNA, there’s another class of genetic material which isn’t DNA itself, but RNA, the ribonucleic acid. It’s different from DNA by the lack of one oxygen atom, and it’s involved in different cell processes, such as protein synthesis. This is like a pre-DNA.
In relation to oocyte donation, if the DNA is coming from the nucleus, RNA will be present in the mother’s body and will be synthesized by the body of the mother who’s carrying the genetic material from the donor and the father. According to Dr Dorofeyeva, they still don’t have a lot of information, but many scientists are sure about the impact of RNA on the DNA function, production, and coding as well. There will probably be more information about it in the future.
Mitochondria are tiny structures inside the cells that synthesize molecules used for energy; thus, it’s responsible for energy production for the cell and give power for development.
The development is the most important thing for embryo production, talking about IVF. Unlike other structures, inside cells each mitochondrion contains its own circular chromosome.
There’s a chromosome, which contains DNA and is called mitochondrial DNA. This codes for some, not all, of the proteins that make up the mitochondrion. Moreover, it usually comes only from the person’s mother because, generally, when an egg is fertilized, only mitochondria from an egg become part of the developing embryo. In addition, mitochondria from the sperm usually do not become part of the developing embryo.
It can also be seen that in the mitochondria there are chromosomes and also parts of genes which are detected and connected to some diseases, such as Parkinson’s, dystonia, and more. Dr Dorofeyeva mentions they have a treatment, already called mitochondrial treatment, and are working more on mitochondrial donation which gives a possibility for the intended parents to use the structure of DNA from the central DNA (from the nucleus), and also DNA for mitochondria.
With regards the phenotypical signs of the baby, such as the colour of the future child’s eyes, even if the parents will be carriers of the genes, which phenotypically produces people to have brown or dark eyes, doesn’t mean that the child will also have dark eyes 100%.
As can be seen in the image shown by Dr Dorofeyeva, in the upper line both parents have dark eyes; however, the probability for the child carrying dark eyes will be just 75% while there’s also the possibility of having green and blue eyes as well. Everyone also has strong and big genes; so, modern science can predict the physical characteristics of a baby, which will be inherited from the mother and father. All this information is encoded into the genes.
For this reason, there’s a division between strong genes and weak genes.
Strong genes:
These are just related to the phenotypical signs.
Weak genes:
Following the difference between strong and weak genes, in the following image you can see how genes work:
For instance, strong genes like brunette and curly hair come from the mother; however brown eyes come from the father and are inherited in their child.
Another example is red hair is not inherited by the boy, but instead the brown hair of the father as well as the big nose.
Moreover, Dr Dorofeyeva mentions it’s important to remember that the person’s physical characteristics are the results of the displacement of several genes of their parents, so it cannot always be predicted exactly how they will be divided and, certainly, how the baby will look like because genes can even skip several generations and reappear. This means that a person can inherit certain genes from their grandparents or great-grandparents. That’s why is important to select phenotypical characteristics when talking about oocyte donation.
In all oocyte donation programs, all the characteristics are available. In addition, egg donation is the most effective way of getting pregnant for those patients who have problems with their oocyte production, older patients and advanced maternal age, patients after having therapy or patients who have a reduced ovarian reserve. Therefore, at any age, oocyte donation is the best treatment.
Talking about egg donor selection criteria, based on the knowledge received from genetics, there are two important characteristics which usually the doctor recommends to take care of. It also depends on if you’re going to tell your baby that he or she was born due to the usage of oocyte donor or not.
If you decide not to tell the baby about the oocyte donation, you need to think about the following:
For instance, if you and your parent have blood type O, you need to select the donor with only the blood type O because the probability of getting another blood type is 0. Therefore, the baby whose mother and father have that type O will get only that blood type. However, if you have blood type A and your husband is blood type B, the child can get any blood type. For this reason, you can also select donors with any blood type.
It’s usually easy to understand this structure, but if you need to consult about this, you can ask your physician once you’re using oocyte donation. Nevertheless, it depends if you’re going to say this to your baby or not.
This is important to take into account. You also need to remember that 50% of the genome of a baby will come from your husband and also from strong or big genes, so you will get the probability of those genes being present in the baby, meaning the phenotypical characteristics.
It’s still uncertain, but mitochondria and RNA play quite an important role; thus, very often, you can ask your friends, colleagues, or patients; once a baby is born using oocyte donation, all parents say that he or she is very much looking like them even though the oocyte comes from the mother or from a donor.
This is what will be given to the baby once he or she develops in the family. There may be some examples of identical twins growing up in different families, and they’ve got different habits.
This is also important and it’s considered nowadays as a good clinical practice. Doctors can already perform a lot of tests for different gene mutations which can be done for your oocyte donor and male partner.
If you will get this genetic match, you can avoid for a baby, the fact that he or she will be carrier of the patients. It’s not obligatory; however, it’s a good clinic practice which can be offered by the clinics or by the oocyte banks.
Based on these characteristics, you may select your donor. You can also consider embryo donation while considering the points mentioned by Dr Dorofeyeva. Usually, banks or clinics offer a database of wide characteristics and important things. If oocyte donation is possible in your country, your clinic can import biological materials or your treatment. There are many successful cases like this and, if oocyte donation isn’t possible in your country, you can travel to Ukraine to get it fully done there.
Dr Dorofeyeva talks about the poor quality of eggs and the crucial role of mitochondria in older maternal age because it’s the battery of the cell and, if the mitochondria is older again, the level of the activity goes down.
If the activity goes down, this is very important for the embryo creation and embryo development. Therefore, the doctor can get fertilization arrest and low-quality embryos. For this reason, they use treatments with pronuclear transfer or mitochondrial transfer which is one of the successful treatments for advanced maternal age.
This treatment gives you a probability of keeping your genome, approximately 98% of the genome comes from the nucleus, while 2% comes from the mitochondria.
According to the doctor, each couple has a social and genetic right to carry their own genes during pregnancy, so this is a great alternative for those who still may produce a few of their own oocytes. However, the results of the treatment are inappropriate and there’ll be a probability of using a pronuclear transfer for the creation of your embryos.
What is a pronuclear transfer?
The pronuclear transfer happens when fertilizing both your oocyte and the donor’s oocyte with your husband’s sperm. Once the doctors have two pronucleus, they’re taking pronuclei with the donor’s fertilized out, and then put them into the cytoplasm, including your mitochondria which helps to develop embryos better. Therefore, by doing this, you’re mixing the genetic material and you have probability to carry your genes.
Some of the advantages of this transfer are:
However, there are already very successful cases.
This is the rate of medical abnormalities which increases with age. However, even in oocyte donors, there’s a probability of getting oocytes which will be euploid. This probability is up to 30%.
The best clinical practice in oocyte donation, recommended by the doctor, is to perform oocyte NGS testing or NGS testing of the embryos before transferring them. This is to increase and maximize the chances for successful IVF treatment using oocyte donation.
Also, by testing the polar body of the oocyte, the doctor can be sure that it’s euploid and has the best chance to create a high quality blastocyst because if they have a high quality blastocyst and a great endometrium, well prepared and responsive, this will be the most successful case.
One of the advantages is the fact that the oocyte donation program mostly brings financial responsibilities for patients and it’s not the first IVF treatment which has happened already for the family mostly.
We would like to optimize and maximize the chances. – says the doctor.
To conclude her presentation, she mentions some important points to take into account:
We’ve been working with oocyte donation for many years already and my experience started in 2006, and during all these years in our clinical facilities, we had a separate department which we called the ‘oocyte donation department’ where people worked, especially for donor recruitment, stimulation, screening, and they keep all the records for oocyte donors and all the approaches are controlled by them.
So, they’re within the clinical structure, starting from advertisement, as I said, their motivation, they keep contact with all our donors, they have great communication and relationship with them, and it’s valuable for us everything our egg donors are doing. We take care of their health status, as I said, motivation screening, and safety. Everything like this. So, they like to come to our facilities to be an egg donor. Also, we may provide more information, and you can check our database; however, this is a really wide database of widescreen and very responsible and effective oocyte donors.
Yes, of course, there’s a chance as well, and you just need to follow the recommendation as we mentioned for the selection of the donor, of your oocytes and your sperm based on the phenotypical characteristic and based on your characteristics, including the blood group and the all critical phenotypical signs. Once during the pregnancy, potentially RNA will play the role of enzyme production and, still, this process isn’t well explained; however, there’s a chance that this baby will look more like you because of this process because you will carry this embryo. However, it’s probably a joke, but I think it’ll be very related to this topic that once people are living longer together, they become very similar to each other and also the habits and phenotypical characteristics and everything from your baby will be very similar.
It’s not like the decision of not using oocyte donation or embryo donation, if there’s no other chance medically to get a baby, considering the fact of how your baby will look, it’s not appropriate. So, there is less risk that your baby will not look like you have not decided to use oocyte donation or embryo donation. I’m not sure if I explained this correctly; however, I would recommend using oocyte donation or embryo donation and working with your physician for the recommendation of how to select the most appropriate donor and don’t think that this is a risk, that the baby will not look like you. It’ll be your baby, and you will get a relationship with this baby and with your partner. This will be the greatest achievement you can get.
No. If there’s an issue in improper implantation for the genetically tested embryos, you should look for the reason for the non-developing embryo after being euploid and genetically healthy. There could be something in your endometrium your uterus or your immune system that’s not giving a chance for this embryo to implant properly or to develop properly. Usually what you need to consider would be the implantation window. This is a screening done in several ways, mostly this is an electronic microscopy of the pinopodes that have been growing during the implantation window of the endometrium or gene sequencing for also successful implantation.
You can ask your doctor for this test as well as the immune status and your immune response for the embryo because if your immune system is very active, your embryo could be considered an enemy of your body and the cells can play a crucial role not to give a right development for this. So, some treatments, such as IVIG or Intralipids, may help you as well. The point of implantation or antibody treatment like thyroid, antibodies, is where you need to look for the reasons.
Yes. Pronuclear transfer or mitochondrial transfer is the treatment which we recommend to those patients who still produce their own eggs because we need to have a source of the genetic material coming from the nucleus, mostly for these patients. If you’re producing your eggs, independently, we may use those materials to create your embryos and, specifically for your case, I think it would be a great decision to use mitochondrial transfer or pronuclear transfer, and you will successfully keep your nuclear DNA for the creation of your embryos.
It’s not about DNA because we just explained that DNA comes from the nucleus, from the donor and the mitochondrial DNA; this is all we currently know about DNA. This information can be connected to RNA activities and enzyme production because the enzymes can change the reading of the DNA. This is what we were talking about—we can address this in the first questions about epigenetics. However, this information regarding 40% is not confirmed yet; it’s still an assumption or a hypothesis based on what we may predict or think. For example, if we’re checking genome sequences, gene mutations, and allele carriers in babies born using oocyte donation, they retain the genome of the donor and the father. So, the genetic material still originates from those sources.
However, in the process of creating new life, there are newly formed mutations and nuclear components. So, there is a lot of discussion about the fact that, once during the pregnancy, even with the genetic material from the donor and father, the maternal environment influences gene expression and plays a role in shaping the epigenetic profile of the baby. However, this is not yet fully confirmed.
Donors are also individuals, and the only clinical base providing oocyte donation—whether through direct selection or an oocyte bank—can do their best to select so-called proven donors. For example, after we perform the selection of the donor based on criteria such as age and phenotypical characteristics, and after initial screening by psychologists and geneticists, we select three out of ten candidates. However, after we complete the first stimulation cycle and assess the outcome of the donor’s treatment, we may determine that certain donors are not suitable for future cycles.
We conduct a thorough selection process not just for the donor as an individual but also for the quality of her oocytes. We categorize oocytes into three quality levels: Q1, Q2, and Q3. If a donor primarily produces Q2 or Q3 oocytes, we discontinue using her for future stimulation cycles. As we gather more data from using donor oocytes across different samples, we accumulate information on blastulation rates and clinical pregnancy outcomes.
Some donors, referred to as “VIP” or proven donors, demonstrate excellent blastulation rates and high clinical success rates. Others may have relatively lower outcomes, and based on these clinical results, we exclude those donors from the database.
You might ask how we can predict this from the very beginning. Compared to some clinics, we perform additional tests by analysing oocyte morphology and offering genetic screening, as I previously mentioned. We can offer only euploid (genetically normal) oocytes, but this depends on the patient’s treatment plan. Additionally, we maintain a database of donor cycle outcomes, allowing us to recommend proven donors if needed.
Furthermore, tissue compatibility plays a role. We are developing a new protocol for screening and selection based on tissue matching, which involves HLA receptors or KIR receptors. This means that in the future, we may be able to match a donor not only based on genetics but also on immunological compatibility—similar to how donor organs are selected for recipients. This is an emerging field that is not yet commonly used, but even without it, oocyte donation remains highly successful in our centre. Nevertheless, this approach represents the next step in optimizing donor selection.
There is a lot of information which we would need to clarify. First, what was the quality of those embryos? Whether they were blastocysts or not, I assume they were blastocysts, but then we would need to ask for the quality of those blastocysts just based on the morphological reading, like what was the grade of the blastocyst and the quality? However, the fact that if they were not tested for their genetic status, unfortunately, some embryos that even come from a donor can be aneuploid and aneuploid would not be successfully implanted. I would recommend using or doing the NGS testing of the embryos. However, great endometrium is not much to say. We need to know the thickness of this endometrium, we need to check the probability of your implantation window. This is what I mentioned 11% of the mood window of implantation, meaning in natural cycles you can get pregnant because the embryo is counting and talking with the endometrium, when is the best time for implantation, and the window of implantation can be moved, either to the beginning of the cycle.
This means that, usually, we transfer embryos on day 6, like 6 days of progesterone, and we transfer blastocysts, which have 5 days of their development. This is the routine practice everywhere; however, 11% of the patients, will not have their endometrium ready for implantation at that time, and embryo is inside our uterus for up to 48 hours, and if the implantation window is moved either for the beginning or later, within the period during 2 days, we can just transfer the embryos. However, if the endometrium is not ready, they will have no chance to implant, and once the window of implantation is open, the embryo will not be alive.
That’s why we need to check the implantation window potential, specifically for patients like you with 10 IVF attempts previously. If you had the same transfer on the same day, on day 6 of your progesterone, so maybe something will be there. Your hypogonadism probably was covered by the hormones, so your estrogen level should be fine. If you had a medicated cycle, prepare for your embryo transfer; however, the thickness of the endometrium should be over 7 millimetres. This is something optimal for the success of implantation. This less thickness of the endometrium, the probability of success of implantation is going down. So, I would recommend testing embryos to make sure they are genetically passing and to consider testing your window for implantation, having so many failed cycles before.
In Ukraine, there’s a recommendation to donate not more than 8 times, and this is what we keep also as a rule for our donors. However, from practical experience, we don’t see any changes between the quality of the oocytes being produced in the first in comparison to for example, the sixth cycle of a donor, if this is a good donor if she’s a good responder because we’re explaining this process also to our donors and patients that every month we’re getting a certain number of follicles which are ready to grow. All the follicles we can see during the ultrasound, all small ones over 2 millimetres, and depending on which age we are, a certain number is available. For oocyte donors, this is usually between 10 and 20 in each ovary, and only because the hypothesis is producing a small amount of FSH, which is enough to grow one follicle.
We’re producing one dominant follicle in that cycle; however, all others will disappear, so they will never be used again. So, in one month, we receive 10 to 20 follicles in our ovaries, one develops to become dominant and ovulates, but all others come into the process of apoptosis, and they just disappear. What we’re doing once we’re performing the IVF cycle, is just helping with an additional dosage of FSH to grow all those follicles which are ready to grow and are sensitive to exogenous and endogenous FSH. We’re not decreasing the potential of a new cycle to recruit new follicles because a new cycle is a new page for us as women. New oocytes will be produced again, ready for FSH stimulation. That’s why there are no differences and no harm for the oocyte donors as well as for the patients during their ovarian stimulation.
