Ovarian rejuvenation. Is PRP a way to stop the fertility clock?

Anna Voskuilen, MD
Specialist in Obstetrics, Gynecology and Reproductive Medicine

Advanced Maternal Age, Low Ovarian Reserve, PRP: Ovarian & Endometrial Rejuvenation

PRP - is it a way to stop biological clock?
From this video you will find out:
  • Ovarian rejuvenation – is it possible to increase the OR parameter?
  • What are platelets?
  • What are the indications for PRP treatment?
  • What is the procedure?
  • What are the results of the pilot study and controlled trial in the studies on PRP?
  • Which patients can most benefit from PRP?





Is ovarian rejuvenation for me?

In this webinar, Dr Anna Voskuilen Gonzalez, Specialist in Reproductive Medicine at Fertty International, Barcelona, Spain, has been discussing the PRP method, which might be a way to stop the fertility ticking clock.

Dr Gonzalez started her presentation on ovarian rejuvenation by explaining a bit about fertility and age. Women are born with a certain ovarian reserve, and that decreases with age, the decrease becomes more rapid after 35-37, and 40 years and is accompanied by a decrease in terms of oocyte quality. The number of follicles decreases until menopause, when up to 1000 follicles could still be in the ovaries. We can test the ovarian reserve but not the oocyte quality, which is related to age. After 40 years old, there’s difficulty in getting pregnant, there’s a higher rate of miscarriage, and there are more chromosomally abnormal embryos. To check the ovarian reserve, we test that with blood tests like FSH and estradiol, which are done at the beginning of the cycle, and we test, the AMH level (Anti-Müllerian hormone), which is produced by pre-antral and small antral follicles. It does not vary during a cycle, so any woman can do such a blood test whenever she wants to check her AMH level.

The last check is the ultrasound, in which we can do an antral follicle count, it’s possible to see the antral follicles in the ovaries, and those follicles have a bit of liquid inside, and that’s the reason we can see them. Those can be stimulated, and they grow and then become mature oocytes.

Follicle development

In a natural cycle, there is a certain number of antral follicles in each ovary, and all of them could grow, but we don’t have enough hormones for all of them to grow, and generally, 1 follicle grows, and we get 1 egg, and we ovulate just 1 oocyte, and that’s the reason people normally have babies 1 by 1. With IVF treatment, it’s possible to use the available antral follicles and make them grow in response to treatment with hormones and try to get mature eggs.

Until now, nothing has proved to help us increase the number of antral follicles so the basal ovarian reserve parameters. Since it is related to the total amount of ovarian reserve and because the growth of the follicle has an initial preantral phase that is independent of the hormones that we can give. The development of the follicles before the antral follicle stage is still not clearly understood. Some hypotheses have been studied, but more research is still needed to understand them clearly.

Ovarian rejuvenation techniques

Is it possible to increase ovarian reserve parameters?

Ovarian ageing:

  • in an older follicle, the problem is that there’s a decrease in DNA repair, and there are problems dividing the distribution of the genetic material
  • there is also ovarian hypoperfusion, a lower blood supply, which makes it more difficult for the oocyte to repair or mitigate the microstructural damage

the ovarian rejuvenation technique should not only increase ovarian reserve parameters, but also the quality of the oocyte. The main goal is achieving a full-term pregnancy with a healthy baby.

Some different techniques are still being studied, and one of them is PRP treatment (Platelet-Rich Plasma (PRP), but there are others, such as stem cells infusion, and ovarian rejuvenation surgery, which is achieving molecular activation by the fragmentation of the tissue).

Platelet-Rich Plasma (PRP)

What are platelets?

  • they are derived from megakaryocytes which are big cells that in response to different stimulating factors release a little portion of cytoplasm
  • platelets are unnucleated cells created from megakaryocytes that have different functions. One of them, the most known, is the first response in hemostasis, but they have also roles in tissue repair, neovascularization and immunomodulation
  • all these functions are achieved due to the granules that are in the cytoplasm, which contain different growth factors, and that will be released in response to some tissue damage and others

PRP treatment injection has already been used in other fields, such as traumatology (tendinitis, arthritis), dermatology (hair growth, healing of wounds), and odontology. It is also studied in other fields of fertility, like the treatment of refractory endometrium.

PRP procedure can be indicated in patients with poor ovarian response or premature ovarian insufficiency, perimenopause or menopause.

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- Questions and Answers

What is the appropriate age for the PRP treatment?

As I already said, there’s no clear evidence which is saying that PRP is going to help but based on other rejuvenation techniques, it should be under the age of 40 years old. We think that the oocyte quality is not going to improve, and so the outcomes that we want to achieve, the live birth is not going to increase in patients that are more than 40-42 years old because the egg quality is not going to be better, so that would be more or less the idea but I know that some papers have reported live birth in women who are more than 40 years old, or even more than 43.

Can PRP allow a 55-year-old menopausal woman to produce a good egg that is not aneuploid so she can have her own genetic baby?

The answer would be more or less the same, so since we know that the rate of aneuploidy increases with age and above 43-45 years old, it’s very difficult to have a good quality egg that would give us a euploid embryo. Knowing that, of course again, I think that at 55 years old, it would not be a possibility. Based on all of the papers that I have seen, of course, we need more information, and we need to do more studies on it and to see how it goes and to make big trials with a bigger sample and to see if it could increase or not the egg quality, but at the moment it’s something that it’s not clear. After the age of 43-44, it would be very difficult.

What is the success rate after the PRP treatment?

All the papers, all the doctors that are researching on that want to know if it is something that can be effective with patients and with which patients it could be effective and what would be the success rate. That’s the main question that everybody is asking, so to answer that, you need a controlled trial because you need two groups. You need to see what happens in the control group and then to see what happens in the patients that are being treated, and then you can compare the effectiveness. Then we’ll be able to see if it is going to increase the success rate and how is this success rate but again, since we have no more information, what we need is to do more studies on it and more big trials controlled, randomized trials look if there’s something that we can see.

Can PRP be used to relieve symptoms of early menopause before 40?

I’ve read some papers about that, but actually, it is something that it’s still experimental, and that doesn’t seem to have evidence on this kind of use. I think it’s better, in that case, to think about hormonal therapy replacement because it can also be very safe and it can be very controlled. Also, because if PRP injection could affect these symptoms if it had, it would be something temporary. We would not know if it lasts for one month, two months, three months. I’m saying this without knowing if it helps to relieve symptoms, but if it helps, in that cases, maybe it would be something that lasts for one month or two months, so it’s something that I think is not worth doing all the time.

Are there any side effects of PRP?

Till now, they have not seen important side effects, but I have to add that of course, since it’s something that is starting to be done recently, we don’t know if they’re long term side effects, but the side effects that have been reported like bloating, some pain in the ovaries, of course, could also be side effects related to the injection, the same as with an oocyte retrieval like bleeding a little bit of infection, but till now no other side effects have been seen.

Where in the ovary do you inject the PRP- in the follicles or stroma?

In some papers, they said that it was in the oocytes of the ovary, some others said that it was more in the cortex of the ovary where more follicles are there, and then the thing is to activate those follicles that could be senescent in those places. They’ve explained that they introduce the PRP in the oocytes of the ovaries, so they inject it from one side to the other side of the ovary retracting, carefully the needle, and while injecting the PRP, so that small as how it is done.

Do biosimilar FSH drugs have the same effect as human hormones? What is the difference in the result?

When you use other drugs, what you want is to improve what your body does normally a little bit, so actually, you want to achieve a higher number of follicles and the FSH that is used. We are looking to have the most similar FSH to the one that we have, there is some FSH taken from urine, purified urine, and some FSH that are done genetically, so we have different kinds, but all of them are being used, and we know that all of them can help in IVF process, or this stimulating process. It’s also something to take into account. There are different kinds of stimulation protocols, so you have protocols with FSH. Protocols with FSH, and LH, so of course, we always use different drugs and different protocols and what we need is to increase as much as we can these results in our patients.

On what day of the cycle is PRP injection in the ovary recommended?

When they did it in patients without menstruation, menopausal patients, they did the injection any day, of course, because there was no cycle. In patients with cycles, they did it at the beginning of the cycle in the first 10 days of the cycle, they did this injection of the PRP.

I have read PRP has been used to help thickening endometrial lining. Is it more common use now?

It’s something that is being studied as well. It’s still something that needs a little bit more studies, and now it’s maybe starting to be used, but again, we don’t have strong evidence on that. It’s not something that is commonly used. I’m not sure about that because I don’t know how it’s being used within the endometrial lining that they do the injection, and then some days after they repeat the ultrasound to see how it goes.

Does PRP improve egg quality?

At the moment, it doesn’t seem to improve the egg quality, but it’s something that we cannot prove at the moment. There’s no strong evidence on it, so what we need is again what I said is to see if it’s going to increase the egg quality of the embryos that we can have with PRP or if it’s going to increase the main outcome, the live birth because if you increase the live birth rate, and you decrease the miscarriage rate, then you can see also that there’s an improvement in egg quality. We still need a little bit more studies to see if it is going to improve the egg quality.

In which other ways can I improve egg quality?

There are some different kinds of protocols that can be used to try to improve egg quality like some protocols during the stimulation also there can be some supplements, some vitamins that you could take like melatonin or CoQ10, but it’s something that’s also being debated. In some protocols, testosterone can be added before or DHEA, but we still need more studies to see in which way we can offer the best option to the best kind of improvement in egg quality. A lot of the options available are being debated, and we still have to do a lot on this topic.

I used melatonin as a natural substitute for PRP. It did bring my menses back. Do you know anything about the use of melatonin to reverse menopause? Do you know if melatonin affects the thyroid function?

I know that melatonin is being used as an antioxidant, which is a very strong antioxidant. We try to use it, or we’re starting to use it trying to improve the egg quality. In terms of bringing the menses back, I don’t know if it’s something that is going to help. The thing is that comparing it to PRP, I don’t know if PRP would be a good option also for having the menses back. It depends on each patient because if you have a 45-years-old patient that has problems with the menses, who is starting the perimenopause that’s one thing. The other thing is very different when you have a younger patient and you also have to look at a lot of things, so you have to make sure that there are not other factors that are affecting your menstruations, so we have to check the thyroid function, the prolactin and other things, of course, make sure that everything is correct and to check that there are no other causes. In the case of reversing menopause, I don’t know if it’s useful, it’s something that I’ve not checked, but I think it would not be something that is going to help.

Can the results of PRP be replicated in other ways? Like through diet – keto diet?

Actually, not because what they do in PRP treatment is they are trying to use all these cytokines that the platelets are inside and if these growth factors that are there that can regenerate in some way the tissues, so that’s what they think it’s going to help. I don’t think that it may help with a kind of diet. The diets are very important to try to improve general health and some kind of diet could help in improving outcomes. I’m not sure because one thing is the use of the platelets that uses all the cytokines and growth factors, and the other thing is this diet, so I don’t think it’s going to bring the same action.

Are you familiar with any therapies which can help a 50+ woman conceive using her eggs- 3 parent IVF, OvaScience type procedures (physically removing stem cells from the ovarian cortex), etc.?

In this case, in a woman who is more than 50 years, as I said, I think it’s very difficult to know if we can improve the egg quality with ovarian rejuvenation techniques. We still need some studies to see if it something that we could do or not. Till this moment, in the case of PRP injection, we don’t see an improvement, or it doesn’t seem to improve the quality and what we know is that in women over 44-45-year-old almost all the embryos that are created are aneuploid. It’s very difficult to have a euploid embryo. I’ve heard about other options that were done before like mitochondrial transfer but it’s something that has stopped because someone had problems with malformations with babies, and in terms of mitochondrial transplantation, I think there was no good evidence that it was something that was working. It’s still something that is being researched.

I am no 33 and already in menopause. One month ago, I did PRP. My menses are back and I can also notice some more changes in my body. Do you know for how long the effects of the treatment last?

What I have read is that they don’t know exactly, how long these changes can last in the body, so it could be something that lasts for a few months, but it’s something that is not clear yet for how long it can last. That’s why some patients ask about doing PRP injection for the menopause symptoms, and since we don’t know for how long it can last and we think that it lasts for some months, it’s something that it’s not going to help in the menopausal woman to improve these symptoms. I cannot answer your question precisely since I don’t know how long it will work.
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Anna Voskuilen, MD

Anna Voskuilen, MD

Dr Anna Voskuilen González is a Specialist in Obstetrics, Gynaecology and Reproductive Medicine at Reproclinic (formerly known as Fertty International), Barcelona, Spain. She graduated in Medicine in Universitat de Barcelona, and later she got specialized in gynaecology and obstetrics at the Hospital de la Vall d'Hebrón, Barcelona. She studied a master's degree in Assisted Reproduction in IVI/Universidad Juan Carlos I. She also completed an observership at The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine of Weill Cornell Medical College, New York. Interested in research and the physiology of fertility. She speaks Italian, Dutch and English, as well as Spanish and Catalan.
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