Ovarian Rejuvenation: using platelet-rich plasma injections into ovaries

The topic of today's post is fertility related. Some human fertility practitioners are performing injections of platelet-rich plasma (PRP) into ovaries and having an increase in IVF success for their patients, while others say it does nothing to help. Ok folks, this topic has been controversial. Medical Doctors (MD) and Veterinary Medical Doctors (VMD/DVM) learn to practice evidence-based medicine. This means that there needs to be objective, non-biased scientific evidence in order for a doctor to prescribe or make recommendations for treatment or management of a condition. First, however, is to do no harm. Is our recommendation going to cause harm to our patient? Are the benefits of the treatment outweighing the risks? The scientific research is still new, but when you are a woman of late reproductive age, and you have been struggling for years to conceive your own biological child, you are then faced with the decision of obtaining eggs from a donor so that you can build your family. Personally, I would go either way, but my husband would like to try for our own joint biological child first. I think I mentioned before, I am on all sorts of online forums and groups with women sharing their stories and looking for insight. Some of these women go through 3 or 5, or sometimes 10 IVF cycles without a successful pregnancy and birth of a child at the end. This hurts women in more ways than we can count - money, time lost, the envy and emotional anguish of watching your friend's children grow up, while you have nothing to show for the struggles you have been through, many women suffer in silence. Some women feel really depressed, honestly, we cannot even come up with the words, but they feel defeated when they are faced with the question, do I try another round with my own eggs, or try for a child with donor eggs? No one can answer that question for you. So, if there was a way for you to recruit additional follicles, in an attempt to get more embryos for IVF, you would probably do it, money aside. What if there was a way to improve your oocyte quality? What if there was a way to take you from minimal antral follicular count, to having multiple follicles to be aspirated for IVF? I certainly would be willing to try! There has been a number of research reports, prospective clinical trials and case reports, on the use of autologous platelet-rich plasma injected into the ovaries in women who have diminished ovarian reserve. They call it Ovarian Rejuvenation. Where it started: It seems to have all started in Athens, Greece with a pilot study published in 2016 [1]. The full research was published in May 2020 [2], which gives you an idea of how long it takes for scientific research to be published (I know from personal experience). Women in the study had an average age of 45 years, all older than 40 years, without a menstrual cycle for 4-5 months. This is considered perimenopausal (or nearing menopause). All eight women in the pilot study had eggs retrieved. 1-2 eggs were mature, and 1-2 embryos developed to be able to freeze for each woman. Yes, 1-2 eggs is not a lot, nor is 1-2 embryos a lot. But think about it this way: if you have zero follicles available, because you are no longer cycling, and you receive a treatment that allows you to get 1-2 embryos - that's 100-200% increase from what you had previously! The risks: The risks are similar to egg retrieval using ultrasound-guided follicular aspiration. Instead of the needle going into the ovary to collect fluid, the fluid is injected into the ovary. The fluid that is being injected is from your own blood, so taking it from the blood in your arm, filtering it and removing the red blood cells, and taking the proteins that are left and injecting it into your ovaries. Women going through IVF are already aware of the risks of sedation and oocyte collection, and we go through it because the benefit (potential baby) outweighs the risks. The benefits: Ovarian Rejuvenation is kind of a funny term. But however you want to call it, the benefits thus far have been the recruitment of more antral follicles from that dormant collection of primordial follicles. Remember primordial follicles are the early stage follicles, well, there is no fluid in those follicles at that stage, just a layer of cells and a dormant oocyte. Perhaps they do not know all the proteins or growth factors involved in improving the oocyte quality and recruitment or activation of growth of more primordial follicles, but if you are successful, the benefit is your own biological child. To me, the benefits far exceed the risks. Yes, there is a possibility that it wouldn't work. So, definitely do your research to see which practitioners are experienced with this and what the laboratory success is like. Research in Autologous Platelet-Rich Plasma As a veterinarian, we use a patient’s own (autologous) serum to help with healing corneal ulcers. We take the blood from the patient, spin the blood so that the heavier red blood cells drop to the bottom of the test tube, and then remove the clear serum from this test tube, placing it alone into a dropper for eye drops on a patient’s injured eye. For serum, you wait for a clot to form in the blood sample, and you spin it removing the clot and platelets. For plasma, you are not allowing it to clot, but filter the cells out and take the proteins with the fluid. In Ovarian Rejuvenation, researchers take a patient’s blood, spin out the red blood cells, and take the remaining plasma (fluid left over with proteins including platelets) and inject it into the recipients ovaries. Studies show that the higher the platelet count, the higher the success of the treatment. In simple terms, platelets release many growth factors (see below). Once in the ovary, these growth factors regulate folliculogenesis (follicle growth). Growth and differentiation factor 9 appears to be one of the important ones in preventing follicle atresia and granulosa cell death (important cells in the follicles that assist with ovulation) [3]. This factor also assist with energy production prior to the LH surge and ovulation, which requires a significant amount of cell energy. There are several other factors in PRP, and their importance in follicle activation and growth is more complicated than this list makes it seem. Due to the complexity of cell signaling pathways, there is unlikely one single growth factor that is the key to increasing ovarian activity. Gene activation is not a simple A to B to C, there are co-factors involved for enzyme function, molecules that can bind to several different receptors, and cells with many receptors that can bind different molecules, amongst so many other activities! Yes, the technique and protocols are new. Five to six years in research is still considered new, but by the standards of the technological world, five to six months is old. Let's take a look at some of the published research on PRP for ovarian rejuvenation. When you are scouring the internet, primary literature is going to be the go to for the evidence of whether something works or does not. A personal blog, or even a company website, isn't where you want to find your evidence. Remember, the plural of anecdote is not data! You want to be looking for peer-reviewed scientific research. Not all journals are treated the same, some being highly regarded and others have yet to prove themselves. A note on journal ranking: Journals are ranked based on how much their research impacts the overall scientific community. How often is a single article used as the nidus of another researcher's work? Journal rankings can be found online. Certainly that plays a role on whether you think your research is pivotal, and should be published in a highly reputable journal, or if your research is a small addition to the scientific community. When I was in school and completing my Master of Science I had access to a lot of primary literature through our online library. Sadly, I do not have access to this now that I have graduated, however, Google Scholar is a great free resource, with links to abstracts and sometimes there are free full text articles online. Yay, science! The most recent article I found was published in January 2021 in the journal Endocrines (it's a newer, open access journal, no impact factor listed). This article reviews the studies that are completed to date, as well as theories of how PRP works to increase oocyte quality and the number of follicles recruited for egg retrieval. The full text is available online and you can download a pdf copy if you so desire. Success Rates: People want to know what the success rate is. Do 100% of women who receive the treatment have an increase in follicles? Not always. While the pilot study [1] mentioned 8 out of 8 women succeeded to the embryo stage, it is not always the case. In a larger study [4], the women selected for PRP treatment were women with low ovarian reserve that had attempted at least two previous IVF cycles unsuccessfully. Of the 38 women who were treated, 4 conceived naturally (10.5%). Seventy-five percent (15/20) of women who went through IVF demonstrated successful retrieval of one to three eggs. Eight of these were fresh embryo transfers with 5 pregnancies from these (62.5%). The other seven had frozen embryos. Five were transferred, with 2 pregnancies (28.6%). Overall, 28% (11/38) of women had a successful pregnancy following PRP treatment. Not bad for these women who suffered for years of trying to conceive. The chart below may make it easier than words. Women have seen improvement in ovarian parameters including an increase in their AMH [4,5] and a decrease in their FSH [4]. Those that had significant responses were patients who had more platelets in their blood sample to be injected [3,4,5]. Case reports, while only demonstrating a single patient, provide a little glimmer of hope. This one [6], showing a women at 41 year of age, having 10 unsuccessful IVF cycles, undergoing PRP injections, and then subsequently fell pregnant natural, with the successful birth of a healthy baby. Or this case report [7] of a women with improvement in the chromosomes of her embryos. Need I say more? Further Research As I mentioned, this protocol is new. Which means that it has to go through government health bodies prior to it being officially available mainstream. In September 2020 [8], a group published a commentary in the journal Reproductive Sciences stating that there were 13 clinical trials registered or in progress. It is always promising to see that funding and time is going towards new ways to improve our fertility. Where can you get the procedure? I cannot find anywhere in Canada (currently) offering the service. If you know of any, please point me in that direction! So what are your options? Obviously traveling abroad or even out of country across the border is not really feasible during a global pandemic! As things improve in our world, then perhaps these will be safely available. U.S. Clinics California: Center For Reproductive Health & Gynecology - https://www.reproductive.org/ - Two locations in California (Beverly Hills and Sherman Oaks) - Dr. Najmabadi also founded the CRHG Mexico Fertility Center in Punta Mita, Mexico Gen 5 Fertility Center - https://gen5fertility.website/what-we-do/ - San Diego (Research published ?) Hanabusa IVF - https://www.hanabusaivf.com/unique-approach/ovarian-rejuvenation/ New York: CNY Fertility - https://www.cnyfertility.com/prp-for-ivf/ New Hope Fertility - https://www.newhopefertility.com/ovarian-rejuvenation/ Rejuvenating Fertility Center - https://www.rejuvenatingfertility.com/prp-ovarian-rejuvenation/ Clinical Trials in the U.S. In case you are interested in participating in a clinical trial (Last updated Feb 28, 2021). Search here for updated trials. New Jersey - https://clinicaltrials.gov/ct2/show/NCT04163640 New York - https://clinicaltrials.gov/ct2/show/NCT04278313 Tennessee - Tennessee Reproductive Medicine - https://trmbaby.com/library/treatments/ovarian-rejuvenation-clinical-trial/ Abroad Greece: Genesis Athens Clinic - https://www.genesisathens.gr/en/video/international Mexico: Punta Mita Fertility Center - https://puntamitafertilitycenter.com/ovarian-rejuvenation-prp/ Clinical trials abroad: Abu Dhabi - https://clinicaltrials.gov/ct2/show/record/NCT04381299 Egypt - https://clinicaltrials.gov/ct2/show/record/NCT04149028 Greece - https://clinicaltrials.gov/ct2/show/NCT03951194 Obviously you should discuss this with your doctor prior to making any decisions! Check the clinics success rate with the procedure as that may help your decision. And of course, stay safe during these COVID times. Looking for more information? Check out the links. The Facebook Support Group: Ovarian Rejuvenation/PRP Citations: [1] Pantos, K., Nitsos, N., Kokkali, G., Vaxevanoglou, T., Markomichali, C., Pantou, A., ... & Sfakianoudis, K. (2016, July). Ovarian rejuvenation and folliculogenesis reactivation in peri-menopausal women after autologous platelet-rich plasma treatment. In Abstracts, ESHRE 32nd Annual Meeting (pp. 3-6). [2] Sfakianoudis, K., Simopoulou, M., Grigoriadis, S., Pantou, A., Tsioulou, P., Maziotis, E., ... & Pantos, K. (2020). Reactivating ovarian function through autologous platelet-rich plasma intraovarian infusion: pilot data on premature ovarian insufficiency, perimenopausal, menopausal, and poor responder women. Journal of Clinical Medicine, 9(6), 1809. [3] Vo, T. K. C., Tanaka, Y., & Kawamura, K. (2021). Ovarian Rejuvenation Using Autologous Platelet-Rich Plasma. Endocrines, 2(1), 15-27. [4] Petryk, N., & Petryk, M. (2020). Ovarian Rejuvenation Through Platelet-Rich Autologous Plasma (PRP)—a Chance to Have a Baby Without Donor Eggs, Improving the Life Quality of Women Suffering from Early Menopause Without Synthetic Hormonal Treatment. Reproductive Sciences, 27(11), 1975-1982. [5] Sills, E. S., Rickers, N. S., Petersen, J. L., Li, X., & Wood, S. H. (2020). Regenerative Effect of Intraovarian Injection of Activated Autologous Platelet Rich Plasma: Serum Anti-Mullerian Hormone Levels Measured Among Poor-Prognosis In Vitro Fertilization Patients. International Journal of Regenerative Medicine, 1(2), 2-5. [6] Sills, E. S., Rickers, N. S., & Wood, S. H. (2020). Intraovarian insertion of autologous platelet growth factors as cell-free concentrate: Fertility recovery and first unassisted conception with term delivery at age over 40. International Journal of Reproductive BioMedicine, 18(12), 1081. [7] Sills, E. S., Rickers, N. S., Svid, C. S., Rickers, J. M., & Wood, S. H. (2019). Normalized ploidy following 20 consecutive blastocysts with chromosomal error: healthy 46, XY pregnancy with IVF after intraovarian injection of autologous enriched platelet-derived growth factors. International journal of molecular and cellular medicine, 8(1), 84. [8] Park, H. S., Ulin, M., & Cetin, E. (2020). Ovarian Rejuvenation Using Platelet-Rich Plasma: a Promising Option for Women in Early Menopause to Have a Baby. Reproductive Sciences, 27(11), 1983-1984.

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