Platelet-rich plasma (PRP) and ovarian rejuvenation therapy in Assisted Reproductive Techniques (ART)

It depends on the patient.  I have to say that I’m very guarded about the results because, as I mentioned, I think that we don’t know yet the subgroup of patients who are going to be seriously helped or seriously assisted with this technique. We don’t know that, and we have no means of identifying the subgroup of patients.

My personal opinion, based on my experience over the last 35 years with couples dealing with fertility, is that I don’t think it’s suitable for all patients over a certain age. Perhaps, you know, one of the cut-off levels is 43, in my opinion. And why is that? My feeling is that after this particular age group, the quality seriously diminishes—both the quality of the oocyte and the ability of the oocyte to create healthy embryos free of chromosomal anomalies.

I would be very sceptical. I would double counsel and double consult, and treble consult our patients over that age limit. Personally, the evidence is not strong; however, I would not like to do unnecessary treatments on patients where the hope is in single figures for creating a good quality embryo overall.

I would like to ring a bell of caution here because we don’t want to flag PRP as the miracle treatment. We don’t want the health authorities and the governments to ban it, as more or less happened with PGT-A, which is a brilliant technique. However, it was widely used by everyone, adding immense costs and trouble to a lot of patients. Some governments, including the health authorities of Greece, essentially banned it, so it’s not free to perform PGT-A unless you have very clear indications.

I would like to ring a bell of caution here to the patients, but also to our colleagues. Let’s not repeat the same mistakes we did with PGT-A. Let’s be very selective and careful in whom we suggest PRP, especially for fertility. It’s a different indication if you have a 47-year-old who would like to prolong her periods for a while but is not seeking fertility. It’s a different ballgame if we want to inject PRP in the ovary to produce a competent oocyte, competent enough to produce healthy embryos.

In my opinion, 43—42 and a half, 43—is the absolute maximum. Then we need to assess the individual patient. I believe the best candidate would be someone in their mid to late 30s who produces maybe 1 or 2 oocytes and 1 or no embryos following effective stimulation and in whom we have excluded additional comorbidities, such as genetic diseases or infections.

Today we had a very interesting meeting. I mentioned an amazing patient in her 43s who is now pregnant. She is on the 12th week, the 13th week of pregnancy, everything is healthy. She just followed up with a very good result on the 11-week scan and all that. I repeat it, and of course, we have a lot of patients. She achieved pregnancy with one egg. You know, we kept trying and trying with one egg with natural cycles, with very little medication, tablets, and FSH cycles and so forth, and she made it.

The same applies to younger patients. Why am I saying this? I can see someone 32 who has collected 2 eggs and made 1 embryo. Don’t give up. We have a wonderful young patient, 32 years old, from a neighbouring country with multiple ovarian surgeries, and she only produced 1 egg. I told them at the meeting, 6 months down the line, what happened with that patient. I said to them, keep it in mind, guys; she’s going to get pregnant. You know, keep trying, keep going with natural cycles, mild stimulation cycles, 1 egg, 2 eggs. She will get pregnant if we manage to keep her in the game, keep her trying, keep motivating her, keep encouraging her, and keep assisting her in lots of ways—even financially. If we bring her prices down, if we give her a very good opportunity financially to keep going, she will get pregnant.

This is again another take-home message. If a 32-year-old is producing 1 or 2 eggs, she will get pregnant, in my opinion, perhaps without the need for PRP.  I’d rather do 2 or 3 more natural cycles than use PRP, to be honest, on a 32-year-old who’s producing eggs, who’s producing reasonable quality eggs that make at least one embryo.

 Let me give you some encouragement here. I mean, firstly, I challenge you: next year you’re going to be pregnant if you keep trying, and please, please, please find us and send us updates when it’s been done because I’m sure it will happen. That’s my first piece of encouragement.

The second piece of encouragement is that with an AMH of 6.7 picomoles, I would probably expect a little bit more eggs. Please discuss with your doctors perhaps changing a protocol or using a different protocol. Sometimes flogging you with massive doses may not be the trick. It’s like treating your children. Sometimes, if you’re too strict, they do exactly the opposite. Sometimes we have to be mild, the ovaries come to us—the eggs come to us—without much effort. So, my second piece of advice would be to try a different protocol. Perhaps try something milder to identify the right protocol.

Number 3: try for blastocyst. It would be important to see if your embryos go as far as blastocyst because, in my opinion, it makes no huge difference between top-quality day 3 and the blastocyst in a young patient for the first, second, or third time of IVF. When it gets a little bit harder, I think it’s important to see the potency of that embryo by culturing it a little bit more.

So in every cycle, try to do something a little bit different but something with logic. Sometimes we stimulate too much and we burn the follicles. Sometimes maybe we initiate the antagonist too soon or too late. I have an amazing friend in England, Dave G., who happens to be among the most experienced embryologists around. As doctors, as fertility doctors, we always think that 99% of the success is the embryologist, but it seems that some of our embryologists think that 99% is the stimulation. I think it’s somewhere in the middle.

Ovarian stimulation is not as easy as it sounds or as it is made out to be. It requires a little bit of attention. There are some amazing people around who have amazing results, who scan ladies and do blood tests twice a day when the standard is maybe 2 or 3 scans maximum during the cycle. Pay a little bit more attention to the stimulation, I would say. Make sure you exclude factors like DNA fragmentation type issues on both of you. Investigate sperm a little bit more because sperm is important as well, and sperm assessment is not just a reflection of a normal semen analysis—there are other factors as well.

Discuss with the lab again: do they do ICSI, or do they do standard IVF? What sort of incubators do they use? There are a lot of kitchen secrets, and laboratory secrets that any lab should be ready to openly discuss with you, the patient.  I think there’s a lot of exploration to do. If you’re a 32-year-old, my feeling is that you can probably produce more than 2 eggs with effective stimulation. If you grow them to blastocysts and identify good-quality blastocysts, and if you keep going, you will be pregnant within the next 12 months.

I would invest since you have the embryo. The equation is very simple: embryo and you. We have the embryo, so we focus on you. You have 2 components: 1 is the uterus and the neighbourhood of the uterus, and the other component is the climate around your uterus, which is your blood flow, your immune status, your inflammation status, and all that.

I would invest very heavily in ensuring that the endometrium is normal by doing a hysteroscopy, and perhaps an endometrial biopsy. I would check the tubes. Furthermore, I mean, most people don’t pay a lot of attention to the tubes. Why? Because they believe that, it doesn’t matter. It does matter in my opinion. Maybe it doesn’t matter for the majority of patients, but you’re not the bog-standard patient after 8 failed attempts.

Ideally, I would do a laparoscopy and hysteroscopy on you, to be honest, just to ensure there’s no pelvic infection. Even mild endometriosis may affect implantation through inflammation and other mechanisms as well. Laparoscopy and hysteroscopy to exclude any pathology. If there are signs of infection, remove that infection. If you have endometriosis, remove the endometriosis. The chance of having endometriosis, in my opinion, could be as high as 50%, even if nothing shows on the scan, nothing shows on symptoms, and all that after failed implantation.

Make sure you have the right environment for implantation. The gold standard is laparoscopy and hysteroscopy. If that’s the case, then look a bit into the immune factors. A lot of people, many people, and most gynaecologists perhaps don’t believe so much in the immune factors. I’m one of them, but that’s for the standard case. You are not a standard case. Even if the chance of having an immune factor is perhaps no higher than five or 10%, or even less, I think it’s important to explore it.

Look at the thermophilic effect, and of course, then look at various add-ons that you may be given in the preparation protocol. You know, the way the evidence is created, which is fantastic. There are some amazing people all over the world creating evidence, but the evidence is fine overall. You know, it’s like the National Health Systems—they’re fine overall; perhaps that’s not as fine for the fertility patients, if you see what I mean. So you are a special case. I can’t believe you’re unexplained. I think there is a factor there that hasn’t been explored.

Before you implant that precious embryo, make sure you look into areas that perhaps are unlikely to be there, but even excluding them may be very positive for the way forward. Look into fortifying your implantation, the embryo preparation, and the uterine preparation protocol before the embryo transfer. Also, consider endometrial PRP. You know, consider that as well, whether there is some evidence on the endometrium or not.

You’re blessed with an AFC of 12, and presumably, as long as you produce good-quality blastocysts, I don’t think that PRP would add much more. PGT-A would probably help you avoid unnecessary embryo transfers with abnormal embryos. It would probably save you from unnecessary miscarriages of abnormal embryos, and it would more certainly give you the confidence that at least you have normal euploid embryos.

There’s a wonderful recent study—a fascinating study this year—that showed that up until the age of 42 or 43, the implantation chance of a healthy PGT-A-tested euploid healthy DNA embryo is the same regardless of age. Identify 1 or 2 good-quality embryos, and you will get pregnant, in my opinion, through PGT-A. The same applies to you, in my opinion. Look into some other factors that may improve implantation.

Do not forget your anatomy, ladies. You know, I keep repeating that. I mean, IVF specialists these days are amazing, bright lads and lasses. They’re very well-trained and prepared, and they study amazing stuff. However, unfortunately, they haven’t been exposed to the surgical component of fertility. Every fertility unit should have the expertise of anatomical assessment and anatomical literacy on the part of our patients. I mean, IVF is not just IVF medicine; it’s also IVF surgery. I mean, in those old times—in the 90s, in the 80s, in the early 2000s—we were called specialists in fertility medicine and surgery.

Do not forget surgery. Fertility is not just IVF. It’s not just lab; it’s not just stimulation, collection, embryo transfer. It’s also the investigation of the anatomy and perfection of the anatomy to receive a good-quality embryo. Don’t forget the anatomy; don’t forget healthy endometrium, well-prepared endometrium, and a healthy pelvis which is free of endometriosis and free of infection.

To be honest, I don’t know. I don’t have an answer. I think it depends on the setup. Furthermore, I mean, in our setup, we use fresh. If there’s no such privilege, I mean, many labs don’t work every day. They don’t work Sundays, they don’t work weekends, bank holidays, and all that. Or they even have bad patients. I mean, some labs work only 10 days a month or 2 weeks every 6 weeks and so forth.

So it depends on the setting. In my opinion, I don’t have huge experience in PRP, but in my limited practical experience, if it’s possible, I would use fresh. If it’s not possible, then freeze.

In my opinion, the question is not whether it’s available, but whether it’s set up. It took my team and me 10 years to study theoretically for PRP. When we decided to press the button in producing PRP, before we decided whether we were going to use it or not, it took us another 6 months to set up the service.

Then, once we set up the service, and we were happy with the production of good-quality PRP, good concentration, and free of infections, following quality control and all that, it took us another 6 months to decide where to start, how to standardize the patients, the consent forms, the counselling. Setting up a PRP service is fairly more complex than it sounds.

In my opinion, the question is: are there any proper PRP centres?  PRP is not just popping into a doctor’s office, getting a little bit of stuff out of the blood, and then injecting it into the ovary. It’s much more than that. There are some risks involved in all that. At the moment, in my opinion, there are very few centres in Europe that do it.

There’s a huge difference. There’s a difference in the substance we’re injecting. Stem Cell is another ball game altogether, even more controversial, maybe a bit risky and all that. I have no experience in that.

I think that we’re a bit far from using stem cells in clinical practice. Anyone can use it; and can do it as research as long as they follow the research guidelines of safety, quality control, data keeping, presentation, licensing, and so forth.  I think that possibly we have enough evidence to perform PRP in clinical practice, again with caution, but for stem cell therapy I think we’re a little bit far off doing that.