In this webinar, Dr Harry Karpouzis, Scientific Director and Founder of Pelargos IVF discussed fertility treatment options for women over 40 whether you’re just starting your journey or seeking additional information.
When talking about women over 40 years old, we have two different things to discuss: the quantity of eggs and the quality of eggs. Both of these factors are very important because they both decrease as a woman ages beyond 40.
A woman is born with about 450,000 eggs on average. A woman ovulates about 400 times in her life. At puberty, a woman has an average of 300,000 eggs, and by her 40s, this drops to about 10,000—a very significant drop, which is about 3% of her eggs from puberty. Keep in mind that by around age 44, there only be about a thousand or even hundreds of eggs. The average age of menopause for a woman is 51, but many women enter this stage earlier. The drop in the number of eggs can start as early as age 27, worsen after 35, and become very steep after 40. This shows that diminished ovarian reserve can occur at younger ages but is more common in women over 40.
Quality of eggs is the most important of the two factors because a woman might still have a lot of eggs, especially in cases like polycystic ovaries, even when she is over 40. However, the quality of eggs is a very significant factor. When we talk about egg quality, we mean it largely involves the chromosomal status of an egg. It is well-established and evidence-based that chromosomal abnormalities increase with advanced age. For example, 30% of eggs are chromosomally abnormal in a woman’s 30s. In her 40s, this percentage increases to 60%, and by age 44, it might be more than 90%.
Why does this happen? There is an increase in the rate of mutations as a woman ages, and there is a breakdown in DNA repair mechanisms. This leads to reduced fertilization, an increased rate of miscarriages, and reduced implantation as a woman gets older, particularly after her 40s.
What are the chances if a woman tries to get pregnant spontaneously? For women under 35, in each cycle, even if she tries every 3 days, the percentage is more than 25%. However, for women in their 40s, the chances of spontaneous conception drop to about 5%, a significant reduction. For women at 45, the chances are about 1%. It’s important to note that the duration of subfertility is equally important. When a couple has been trying for more than six months and the woman is over 40, the chances of subsequent pregnancy drop to about 1% per cycle. This is why women need to be proactive, and IVF is the treatment of choice for women over 40. Any other treatment has much lower success rates, and IVF significantly increases the chances compared to spontaneous conception. However, as a woman gets older, even with IVF, the chances decrease.
How many eggs do we need to retrieve in an IVF cycle per age group to have a good chance? There are many different reports on this, and there isn’t a clear number, but many studies have shown an average number needed in each age group for good chances. For example, when a woman is under 35 years old, retrieving about 5 to 14 eggs gives a good chance of success. If a woman is 38, this number increases to 10 to 25. When a woman is 40 or 41, studies suggest that even if we retrieve 30 eggs, the chances of success might be around 50%.
The more eggs are retrieved, especially in women over 40, the more the chances of some of these eggs being chromosomally normal statistically increase resulting in pregnancy. In women over 40, retrieving more eggs increases the chances.
In previous years, when we tried to retrieve a lot of eggs, the hormone levels would get quite high, which could affect the implantation window during fresh transfers. Nowadays, thanks to a new method of freezing called vitrification, a slow-freezing technique that doesn’t affect the quality of the embryos we know that when hormone levels are high, we always have the option to freeze embryos using vitrification without affecting their quality and transfer them later in a frozen cycle.
The freezing method allows us to use all the tools, including different protocols like clomiphene, low-dose or high-dose stimulation, growth hormones, and trigger shots like Ovitrelle. All these help us create personalized protocols. While many of these treatments can affect hormone levels and the implantation window or endometrium, we don’t have to worry about these issues anymore because we can freeze embryos and transfer them in a frozen cycle without affecting their quality.
What protocol to use? The answer is that we need to follow some general principles.
At Pelargos IVF, we have 5 basic principles: each case is different, follicles guide us, not the other way around, we prefer to keep it initially simple, we personalize every single case, and if the simple and personalized approach is not working, then we innovate.
The gold standard protocol is the antagonist protocol, or short protocol because there is clear evidence that using a long protocol, which involves suppressing the ovaries with agonists like GNRH injections, etc., suppresses ovarian stimulation. This makes it more difficult to stimulate and retrieve more eggs.
Another very common question is whether to use high doses or low doses. It depends on many factors: the number of follicles, the size of follicles, the AMH level, and other factors. This is where personalization becomes very important. Even checking blood tests during stimulation in a short protocol is very, very important. For example, LH is a very important hormone that needs to be checked during every single ultrasound because it provides very important information.
It is also very crucial to decide whether to use the combined contraceptive pill beforehand or not. This also depends on each case. As a general rule, in women with AMH of less than 1 nanogram per mL, it’s better not to use the pill because it can suppress the ovaries. Sometimes it’s inevitable because we need to schedule treatments, and when we do that, we prefer to leave a gap between the last pill and the start of stimulation. This is very important.
With the antagonist protocol, we know that fewer hormones are needed. We also know that we have the option of vitrification (freezing), so implantation is not affected by high hormone levels. If hormone levels go high, we freeze. This minimizes the risk of hyperstimulation. It’s also possible to use the double trigger, and there is clear evidence that in some cases, particularly in women over 40, the double trigger—which means using Ovitrelle and an agonist trigger together—improves the quality of the eggs and can help. This is something we can do with the antagonist protocol.
The number and size of the follicles are very important. We need to measure all the follicles, even if they are less than 5 millimetres or more than 5 millimetres at the beginning of the cycle. This plays a role in determining whether a high dose or a low dose should be chosen.
The cutoff is 4 follicles. If there are more than 4 follicles and the AMH is not very low, it’s better to offer high doses. If there are fewer than 4 follicles, low doses seem to be better because even if we use higher doses, we will not be able to retrieve more eggs, so there is no point in paying for more medication. The AMH level is also very important. When the AMH is less than 0.5, it is better to use low doses because high doses may shut down the ovaries.
Deciding on the trigger is another crucial point. Will it be Ovitrelle? Will it be a combination (dual trigger)? Will it be an Agonist trigger? How many Agonist triggers—one, two, or three? All these decisions depend on estrogen levels and LH levels. How many hours after the trigger should we do the egg collection—35, 36, or 37? In poor responders and women over 40, all these factors play a role. It’s different when LH is low versus when LH is high at the time of the trigger. Every single detail is very important, especially in women over 40, because it’s challenging, and the protocols need to be perfected.
These protocols are used when the AMH is very low, and when there are not more than 4 follicles. In cases like that, even if the doses are increased, it will not help because it’s impossible to stimulate follicles that do not exist.
It’s also an option to combine low-dose protocols with other medications like Clomiphene or Letrozole without using the antagonist because sometimes when we use Orgalutran or Cetrotide, this might slow down the growth of the follicles. It is very important to know when to use it or not. What do we achieve with these combinations? We achieve stimulation in more than one way, increasing the follicles as much as possible, synchronizing them, and getting as many eggs as we can. We also try using medications like Letrozole in some of our innovative protocols to increase androgens, which are very important in follicular recruitment and getting more follicles.
Every single thing in a protocol has a very important reason, and we need to know why we use it. A very important breakthrough in protocols, especially for women over 40 undergoing IVF, is the luteal phase protocol. Sometimes, we see that follicular recruitment is better in the second half of the cycle rather than the first half, so we start not during the period but in the second half of the cycle. This allows us to have 2 egg collections in 1 cycle.
Double stimulation protocols are not for everyone, but they are good for those who can stay longer, especially when travelling abroad, as they want to have 2 egg collections or more eggs in 1 cycle. Is it always possible? No, it is not always possible, and it is not always right because we need to have remaining follicles after the first egg collection to start stimulating again. If we don’t have them, we don’t use these protocols; it’s better to try again.
Some other innovative protocols can be difficult to understand, they are used in very challenging cases. There is the Andro protocol, which uses medications like letrozole, testosterone, Ovitrelle, and DHEA pre-treatments. All these increase the androgens during the cycle, which can lead to better follicular recruitment and more eggs, giving us more chances. Another protocol is the stop-agonist/letrozole/antagonist protocol, which involves lots of medication together and has sometimes given good results when the short protocol is not working.
There are many other medications, such as melatonin, CoQ10, DHEA, vitamin D, folic acid, growth hormone, antioxidants, etc. that many people ask about, and there is some evidence behind them. They are not miraculous; they will not cause pregnancy on their own, but in combination with a good protocol, they can help improve both the quality and number of eggs that we retrieve.
At Pelargos IVF, as Dr Karpouzis mentioned, PRP (Platelet-Rich Plasma) as well as PL PRP, which is much stronger, is performed. Another form of treatment that is sometimes used is stem cell treatment, which involves taking fat tissue from the abdomen and injecting it inside the ovaries. There is some evidence supporting this approach. With these treatments not having fully randomized evidence proving they increase the chances of pregnancy, good data suggests they may help in obtaining a few more eggs. It doesn’t work for all women—it works better in younger women and the age group of 40 to 42.
Many people ask me this very difficult question. My answer, and it’s definite, is that if you are over 40 and you can afford it, PGT-A is recommended. Why? Because the benefits outweigh the risks.
There is clear documentation of results in many units. You need to be sure how the results will be documented because this is very important. If we have euploid embryos with a small mosaicism rate, the results, at least at Pelargos IVF, for a positive pregnancy, regardless of age, can reach 70%. Regarding mosaicism and embryos that are not completely healthy but not completely unhealthy, what are we doing with them? In many units where you don’t have clear documentation, it’s a problem. In units where you do have clear documentation, the answer is you discuss it with a geneticist. If you don’t have euploid embryos, you can transfer them with sometimes good chances, even the embryos that are mosaic.
Keep in mind that when you take a biopsy of an embryo, you check the outside of the embryo, which later becomes the placenta. The inside is not checked, so many times you might check the outside, but the inside might not correlate with the outside. Therefore, sometimes it’s not 100% accurate. Depending on the type of aneuploidy, if it is a segmental aneuploidy if it is one chromosome, which chromosome, low mosaicism, or high mosaicism—you get genetic advice from the geneticist, and you might find out if this embryo gives you some chances. Many transferred mosaic embryos might not implant or miscarry, but if they do implant, most of them conclude in a normal pregnancy.
The reality is that when age is very advanced and AMH is very low, the chances are very low. Are the chances 0? No, they are not 0 unless you are in menopause, but the chances are very low. The doctor you talk to must explain to you in full honesty what the chances are. The decision is yours, the body is yours, but you need to know that if you are 45 or 46, the chances will be less than 1%. Then you decide if you want to try it or not.
Finally, be proactive. When you are over 40, time matters a lot. Do it sooner rather than later. There is no such thing as one protocol that fits all cases—every case is different. Ensure that the laboratories are good because even the best doctor in the world if the laboratory is not good, will not give you the best results.
Trust the doctor that you choose. Even if you have made a bad choice, it’s worse not to trust the doctor that you have chosen. Appreciate honesty, and you need to have luck—very important—because whatever we do, you need to be a bit lucky because we are always talking about statistics. Be optimistic, but be also realistic.
Related reading:
At 43, and with only 1 egg retrieved in the last 2 collections with no fertilization, the situation is not very optimistic. You may not be in menopause and there are still some chances, however you need to realize that the egg quality is often significantly reduced at this age. Given that you’ve had 2 unsuccessful fertilizations, it likely indicates an issue with the quality of the eggs. Unfortunately, genetic material is one aspect we cannot change. Even if we managed to retrieve 1 or 2 more eggs, it might not make a difference.
As I mentioned in my presentation, at 43, you might need to retrieve about 30 eggs to find even 2 chromosomally normal embryo. If you’re only getting 0 or 1 egg per collection, the statistics are not in your favour. Egg donation would be the treatment with the best chances for you, giving you a 70% chance of getting pregnant. However, if you want to try again with your eggs, you can, but the chances are very low based on the information you’ve provided.
DHEA is not a miraculous treatment and there is no conclusive evidence to support its effectiveness. There were some initial positive reports, however, most subsequent studies did not show a significant improvement in pregnancy rates. Some reports suggest that DHEA might help with better follicular recruitment, potentially resulting in more eggs.
If you want to try again with your own eggs, you might consider changing other aspects of your treatment in addition to DHEA. Since DHEA won’t cause harm, and given your age and follicular recruitment, it might be worth trying, but keep in mind that the chances are still low.
At 45, it’s a very difficult age for successful IVF outcomes. While there have been some live births, the statistics are not in your favour, as egg quality significantly declines by this age. There’s no precise number of eggs that would guarantee success, but generally, you would need a lot, and it may be impossible to retrieve enough eggs even after multiple collections. Success at this age is also a matter of luck and DNA quality.
There are some pregnancies and live births that occur at 45, however, the best option at this age is egg donation. If you’re psychologically prepared for this, it might be best to go for it.
Regarding chromosomal quality, we cannot determine the chromosomes of the eggs, we can analyze the embryos for chromosomal normality using PGT-A (Preimplantation Genetic Testing for Aneuploidy). This involves biopsy of the embryos to check if they have normal chromosomes before transferring them. However, finding a chromosomally normal embryo at this age is very challenging.
As I mentioned in my presentation, the best thing to do is to follow the advice of the clinic and doctor you’ve chosen. It’s important to trust their guidance. In cases like yours, I’m a big fan of PGT-A (Preimplantation Genetic Testing for Aneuploidy) to check the chromosomes before transfer, especially if you manage to have more than one blastocyst. If you do PGT-A, you cannot have a fresh transfer as the embryos will need to be frozen. Even if you don’t freeze, you need to ensure all your blood tests, including progesterone levels before the trigger injection, are fine, and that your endometrium is in good condition. If you only have one embryo and choose not to do PGT-A, a fresh transfer could be okay unless there are other factors like endometriosis. In such cases, we prefer to freeze and downregulate the ovaries before transferring the embryo. This is a difficult question, and the answer depends on each case. In most cases, we prefer to freeze, but it depends.
It depends. Stopping smoking is always beneficial, especially when it comes to fertility. However, it also depends on your age. I wouldn’t advise waiting too long if you are 40, 41, 42, or 43 because every month is important at these ages. I would start the process without much delay.
Prolonged smoking, especially heavy smoking, can affect both the quality and quantity of follicles. Stopping smoking might lead to some improvement, but it won’t be a huge improvement within one or two months. The most important factor, even more important than smoking, is age. The decline in egg quality after 40 is steep, so every month counts. I wouldn’t delay IVF much; one or two months after quitting smoking should be enough time to go ahead with IVF.
If you had a euploid embryo, meaning it had normal chromosomes and didn’t implant, you should investigate other factors. Since the embryo was healthy, the focus should be on other potential issues like the implantation window, the condition of the uterine lining, and possible immunological factors. It’s also important to ensure that progesterone levels are optimal before the embryo transfer. A properly biopsied healthy embryo should give you up to a 70% chance of success. Before transferring another healthy embryo, check everything that could impact implantation.
Since you’ve tried both with your own eggs and with embryo donation, and both have failed, the only common factor is your body, specifically the uterine lining. You need to ensure that everything in your uterus is in optimal condition. This includes checking for any issues in the lining and other factors that might affect implantation. Sometimes it’s just bad luck, but it’s important to investigate thoroughly before trying again. You might also consider a different egg or sperm donor after checking everything.
It depends. We use a lot of PGT-A in our practice. If you do a cycle and achieve a chromosomally normal embryo, your chances of success can be as high as 70%. However, if you don’t find a normal embryo, you may need to repeat the cycle. The number of cycles also depends on how many follicles you have. If you only have three follicles, we won’t be able to retrieve more than three eggs in one cycle. The more eggs you can retrieve, the better your chances. Some women may need multiple cycles to collect enough eggs, while others may be more successful in a single cycle depending on their situation.
Double stimulation is an option, but it depends on a few factors. It depends on how many follicles you have and whether there are remaining follicles at the time of egg collection. For instance, if you have a few good-sized follicles, you may retrieve 2 or 3 eggs. The question is whether it’s worth doing double stimulation in the same cycle. If you have only 1 or 2 follicles left, it may not be worth it. However, if there are more remaining follicles, like 3, 4, 5, or 6, then double stimulation could be beneficial because it saves time by allowing for 2 egg collections in 1 cycle.
If time isn’t a concern, sometimes it’s better to wait for your next period and have another stimulation, as the follicular count might be better in the luteal phase. Double stimulation is typically used when an antagonist personalized protocol hasn’t worked, to increase the number of eggs retrieved in 1 cycle. Your follicles guide us; we cannot guide them, so we need to follow their signs.
I’m not a fan of day 3 transfers. Day 3 transfers are often chosen by doctors who want to ensure they can do an embryo transfer, fearing that embryos may not survive to day 5. In a good laboratory, an embryo with the genetic potential to reach day 5 will make it to day 5. It’s important to check other factors, sometimes it’s not just about the eggs, but also the sperm. If the sperm has DNA fragmentation or oxidation, it can result in poor conversion rates to day 5 blastocysts.
While egg quality is difficult to change, I would still recommend persisting and trying again with a day 5 transfer. If you continue to have the same issues despite changing protocols or laboratories, and your embryologist suggests it’s likely an egg quality issue, then you may need to consider options like egg donation or other treatments like PRP (Platelet-Rich Plasma).
You have a good chance with egg donation. Make sure to thoroughly check the sperm, especially if it’s your husband’s sperm, to ensure there are no hidden issues. Sometimes, sperm selection techniques can be helpful. Prepare yourself by making lifestyle modifications, reducing stress, and incorporating some exercise. Techniques like acupuncture have good supporting data and can be beneficial. Additionally, consider body-mind techniques, make sure you’re taking supplements like coenzyme Q10, folic acid, and vitamin D, and check your thyroid levels. These preparations are important to improve your chances of success with egg donation.
Regarding your husband, most likely, you’ll need to use ICSI (Intracytoplasmic Sperm Injection). It’s important to conduct a thorough sperm analysis, which might include checking for oxidation or DNA fragmentation. These tests aren’t standard but are recommended, especially if you’ve had unexplained failures with egg donation or PGT-A embryos. In our practice, we often include an oxidation test and use sperm selection techniques like Zymot instead of ICSI. A detailed analysis of the sperm is crucial, especially when other factors like egg quality can’t be easily modified.
Not necessarily. We vitrify sperm, so the quality isn’t significantly affected. If you’re undergoing treatment abroad, it can be difficult to use fresh sperm. In an ideal scenario, you could freeze sperm as a backup, take antioxidants or multivitamins, and compare fresh and frozen samples to use the best one. However, there are only mild differences between fresh and frozen sperm. If the sperm is thoroughly checked and shows good qualities, you still have very good chances with frozen sperm. For specific issues like oxidation or DNA fragmentation, we sometimes prefer fresh sperm to apply techniques like Zymot or MACS (Magnetic Activated Cell Sorting).
Polycystic ovaries are generally not a good thing, but as you get older, they can be beneficial because, as I told you, the more eggs we get, the better. The number of follicles you have is very good because it means you might be able to get a lot of eggs. However, careful management of the protocol is essential because polycystic ovaries can react in unpredictable ways. It’s important to aim for as many follicles as possible to reach the same size and stage so that you don’t end up with a lot of immature eggs.
Women with polycystic ovaries and this number of follicles at age 42 can have very good chances. You will need a frozen cycle for sure. Whether to do PGT-A or not depends on you. If you have a lot of blastocysts, think positively—it might work.
As I mentioned in the presentation, supplements are not miraculous treatments; they are adjunct treatments used in combination with IVF. The supplements with the most evidence behind them are coenzyme Q10, folic acid, and vitamin D. Melatonin also has some good evidence behind it. You can take these separately or find them in multivitamins. The dosage is very important because I’ve noticed that many people take doses that aren’t enough. These are the most important supplements, but remember, they won’t get you pregnant on their own. As an adjunct treatment, however, they might help.
This is not an easy case. An FSH of more than 20 is very challenging. In cases like yours, the best treatment might be egg donation. However, if you want to pursue your own eggs, I suggest checking every month to see if you can achieve a cycle with an FSH of less than 20, and ideally less than 12. Start your cycle when FSH is lower than 20. Given the situation, I wouldn’t recommend a high-dose protocol because if you only have three or 4 follicles and low AMH, low-dose protocols work better. Even with a higher dose, if you don’t have more follicles, you won’t get more eggs. I would go with a low-dose protocol based on your description, but I would need to review everything thoroughly to give you more specific advice.
I usually prefer to wait 1 cycle for the hormones to go down before starting again.
This is a difficult case. Adhesions after a myomectomy indicate Asherman’s syndrome, which involves scar tissue inside the lining of the womb, leading to a thin endometrium. A thin endometrium is challenging to treat. First, you need to do a hysteroscopy to separate the adhesions and perform adhesiolysis to see if it’s possible to improve the lining.
However, many times, even after adhesiolysis, the tissue at a cellular level doesn’t improve. This condition is often associated with a chronic infection, so you may need antibiotic treatment. If it persists, there are other options like endometrium PRP (Platelet-Rich Plasma) or GCSF (Granulocyte Colony-Stimulating Factor) infusions, which sometimes help. In very persistent cases, stem cell treatments, where fat tissue from your tummy is injected into the endometrium, have shown good results. This is a difficult situation, and in some cases, the only solution is surrogacy, but if done correctly, adhesiolysis might help improve the thickness.
Continue taking your medication as prescribed and avoid making any mistakes with your medications. Maintain a healthy lifestyle, take it easy for the first 3 to 4 days, avoid extreme activities, and think positively.
At age 42, this is not an easy situation. There is an issue with egg quality as well. In cases like this, with repeated failure and no healthy embryos after three attempts, if the sperm has been thoroughly checked and everything else has been tried, the best treatment for you might be egg donation. However, if you’re not ready to go that route and want to try again, PRP (Platelet-Rich Plasma) might be an option. In some women aged 40-42, PRP has worked nicely and might help improve egg quality and increase the number of eggs. If you’re not ready for egg donation, you can try PRP, but be aware that there is no conclusive, randomized evidence behind it.
Yes, it might help, but other treatments could be more effective, such as Clomid and even Ovitrelle in some cases. It’s best to consult a urologist to understand the underlying reason for the low sperm count or motility and discuss the appropriate treatment. Progonal is not a commonly used treatment; we typically reserve it for very difficult cases with significantly reduced sperm count or motility. However, we often prefer other treatments in such situations. Always follow the advice of your doctor.
Yes, I have used it before a cycle, and then after ovulation, I start patients on pills. In Greece, it’s difficult to find, so women often bring it from abroad. We use it as part of a specific protocol when other treatments have failed, to increase intra-follicular androgens. It’s not a miraculous treatment and lacks conclusive evidence, but in combination with other approaches and with a clear rationale, it might help. We include it in one of our protocols.
Generally, when dealing with only 1 egg, we don’t want to risk losing it due to hidden issues with the sperm, so we prefer to use ICSI. ICSI improves fertilization rates because it bypasses potential sperm issues. If you only have 1 egg, it’s better to use ICSI to avoid losing it due to an unseen problem in the sperm. This is a complex topic.
Yes, you can consider egg donation. In Greece, we treat women up to age 54. We have seen reduced success rates in women aged 50-54 compared to younger women, even with egg donation, but generally, the success rates are still good because the problem at this age is usually with the eggs. As long as you have a good endometrium, good thickness, and are healthy, with no major medical issues, you can proceed with the treatment. However, pregnancy at 53 is high-risk, with a greater chance of complications like preeclampsia, diabetes, and hypertension, so you will need careful obstetric management.
It could be a sperm problem, or it could be an egg problem, especially if you are around 42 or 43 years old. If the sperm is good, statistically, it might be an egg problem. Reaching the blastocyst stage is a good sign, but if you haven’t done PGT-A on the embryos, you don’t know if they are chromosomally normal. Sometimes, even high-grade blastocysts can be chromosomally abnormal, which might explain the implantation failures.
Omnitrope is a growth hormone. We use it for women who can obtain it from abroad since it’s difficult to find in Greece. In some cases, it might help, especially in persistent cases that haven’t responded well to previous treatments. I wouldn’t recommend using growth hormone right away for everyone over 40, but in cases where previous attempts have not been successful, it has shown good results. Be cautious with its use as it might cause some weight gain.
No, supplements typically require a more prolonged use to have an effect; two weeks is not enough time to see significant benefits. It’s better to take these medications for a longer period to allow them to have an impact. We usually recommend taking multivitamins and adjunct treatments for more than two weeks for them to play a role. However, the timing also depends on your age and other factors, so it’s important to balance the waiting period with the urgency of your treatment.
