Platelet-rich plasma and the restoration of fertility in POI – ESHRE

Following an increasing number of studies, two new reviews have described treatment with platelet-rich plasma in POI patients as encouraging, but raise questions over the methodology of these studies and how platelet activation might work in the ovary.

Focus on Reproductions first mention of platelet-rich plasma for ovarian rejuvenation came in September 2016 following presentation of a poster at that years annual meeting in Helsinki. A group from Athens had described ovarian rejuvenation and folliculogenesis reactivation in eight menopausal women who were all without menstrual cycles for around five years. Following infusion of the plasma, described as a concentrated source of growth factors and cytokines, menstrual cycles seemed restored after some three months and oocyte retrieval successful in all cases.

Since then, and alongside occasional interest in the popular press, there have been further study reports, several clinics advertising treatment, and now two reviews in scientific journals.(1,2) But even before this interest in reproduction and the restoration of fertility in POI, platelet-rich plasma had been claimed to encourage tissue healing and repair (including hair regrowth), with its most common applications in sports injuries (particularly knees) and arthritis. Golfer Tiger Woods reportedly used PRP to help repair his damaged Achilles tendon in 2010.

Most recently, however, a study from Taiwan in 12 women diagnosed with POI and whose ovaries were injected with a combination of autologous PRP and FSH, has reported fertilisation of the retrieved oocytes and ongoing pregnancies.(3) Weekly ultrasound scanning of the 12 women - all aged 40-50 years with amenorrhea for more than a year - eventually revealed that 11 resumed their menstrual cycle over a mean period of five weeks, most of which were irregular.

In their conclusion the authors reported that PRP with gonadotrophins could increase the probability of pregnancy using autologous oocytes in women with early menopause. The report indicates that 13 mature eggs were retrieved in total, which were then fertilised by ICSI. Two subjects had cleavage stage embryos transferred, one of whom achieved a clinical pregnancy (with one live birth reported elsewhere).(4)

This is just one of several uncontrolled studies on PRP in ovarian rejuvenation, all of which (up to 2020) are listed in fine detail (findings, procedure, controls) by Atkinson et al in their mini review for Human Reproduction. Notable among them is an update from the Athens group reporting data from a total of 120 patients in four pilot studies on poor response in IVF, POI, perimenopause and menopause.(5) With results varying somewhat in each of the pilot studies, the authors reported a significant improvement on the hormonal profile and the ovarian reserve status . . . along with improved intracytoplasmic sperm injection (ICSI) cycle performance concerning POR [poor ovarian response] participants. Such studies are increasing in number, and are described in the HR review as encouraging, although with the caveat that a properly controlled randomised clinical trial will be necessary to confirm the efficacy of ovarian PRP therapy.

Do the results have biological plausibility? Should we take them seriously? Rosario and Anderson describe PRP as a preparation of autologous human plasma with an increased platelet concentration produced by centrifuging a large volume of a patients own blood, which concentrates the multitude of growth factors and cytokines produced by platelets. Evidence is apparently strong that platelets do release a range of cytokines in response to activation, and, say the HR reviewers, cytokine signalling is increasingly apparent in the interrelationships between the oocyte and granulosa and thecal cells. Any dysfunction in this system, they add, results in deficiencies in follicle maturation, ovulation and luteinisation. So one working hypothesis is that PRP may well provide a readily accessible, individualised, cost-effective blend of proangiogenic, proliferative and proinflammatory factors which may stimulate de-novo oogenesis and/or follicle maturation.

In their review of novel approaches to fertility restoration Rosario and Anderson list PRP therapy alongside other means of activating residual primordial follicles in women with POI - for example, when treated with mesenchymal stem cells extracted from bone marrow, placenta and menstrual blood. However, they too note that much of the clinical data so far are derived from studies of PRP infusion.

It's worth noting that the HR review ends with a note of caution. Singled out from the studies reported so far are their lack of control and details of the mechanism of how PRP via platelet activation might work on the ovary. Despite the autologous source of PRP, the latter question is emphasised as a major reason for caution and a need for fundamental research at the cellular level. Dysregulation of early processes in oocyte maturation and subsequent embryo development can lead to drastic changes in the growing foetus, the authors warn, possibly leading to increased risk of disease in early years and onwards.

Back in 2016 and with our first mention of ovarian rejuvenation, the popular press headlines would then signal the end of the menopause, bringing to mind the same speculation raised by Jonathan Tilly and his discovery of egg precursor cells.(6) A few years later a non-peer reviewed paper described improved IVF results in poor prognosis patients following the transfer of mitochondria derived from these same autologous egg precursor cells. That first discovery of Tilly was also publicly presented as the demise of the menopause, but that concept appeared to fail for want of controlled studies and reproducible results. PRP, it seems from the caveats now reported in these two recent reviews, will also need the evidence of robust studies for its further progress.

* One of the two keynote lectures set to open this years ESHRE annual meeting will be from Antonio Pellicer, co-editor of Fertility and Sterility, on Expanding the ovarys reproductive lifespan: Preservation and Rejuvenation.

1. Atkinson A, Martin F, Sturmey RG. Intraovarian injection of platelet-rich plasma in assisted reproduction: too much too soon? Hum Reprod 2021; doi:10.1093/humrep/deab1062. Rosario R, Anderson RA. Novel approaches to fertility restoration in women with premature ovarian insuffiency. Climacteric 2021; doi:10.1080/13697137.2020.18568063. Chao Chin H, Hsu I, Hsu L, et al. Resumed ovarian function and pregnancy in early menopausal women by whole dimension subcortical ovarian administration of platelet-rich plasma and gonadotropins. Menopause 2021; doi:10.1097/GME.0000000000001746.4. Hsu CC, Hsu L, Hsu I, et al. Live birth in woman with premature ovarian insufficiency receiving ovarian administration of platelet-rich plasma (PRP) in combination with gonadotropin: a case report. Front Endocrinol 2020; 11: 50. doi:10.3389/fendo.2020.000505. Sfakianoudis K, Simopoulou M, Grigoriadis S, et al. Reactivating ovarian function through autologous platelet-rich plasma intraovarian infusion: pilot data on premature ovarian insufficiency, perimenopausal, menopausal, and poor responder women. J Clin Med 2020; 9: 1809. doi:10.3390/jcm9061809.6. Johnson J, Canning J, Kaneko T, et al. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature 2004; 428: 145-150.

follicular activationpremature ovarian failureovarian rejuvenationplatelet rich plasma

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Platelet-rich plasma and the restoration of fertility in POI - ESHRE