Intraovarian Injection of Platelet-rich Plasma in Assisted Reproduction: Too Much too Soon?

Lloyd Atkinson; Francesca Martin; Roger G. Sturmey

Disclosures

Hum Reprod. 2021;36(7):1737-1750. 

In This Article

How Might PRP Induce Ovarian Rejuvenation?

Given the complexity of platelet signalling and activation, the precise details of how platelets initiate their full range of physiological effects remain unclear. However, it is well established that platelets release a range of cytokines in response to activation (Roh et al., 2016). Cytokine signalling is increasingly being shown to be involved in the interrelationship among the oocyte, granulosa and thecal cells, with dysfunction in this ecosystem resulting in deficiencies in follicle maturation, ovulation and luteinisation (Orisaka et al., 2006; Field et al., 2014). A number of the cytokines that regulate follicle development are released by platelets through secretion of their alpha and dense granule contents during platelet activation (Table II). Therefore, a working hypothesis is that PRP may provide a readily accessible, individualised, cost-effective blend of proangiogenic, proliferative and proinflammatory factors which may stimulate de-novo oogenesis and/or follicle maturation.

One possible explanation of the observed effects of PRP on the ovary might be that it acts in a proangiogenic manner (Kakudo et al., 2014) via action of platelet-released cytokines (Table II), including, for example VEGF. Primordial follicles typically rely on stromal blood vessels, but become progressively encapsulated in a thecal capillary network during maturation, a process which is mirrored by increased VEGF expression that persists through to corpus luteum formation (Gordon et al., 1996; Barboni et al., 2000; Danforth et al., 2003; Pauli et al., 2005). Heterozygous knockdown of the hypoxia-response element within the VEGFA promoter or VEGFR antagonism in mouse ovaries leads to vascular malformation, resulting in a poor ovarian response to stimulation (Feng et al., 2017), indicative of a role for VEGF in follicle development and the overall importance of correctly regulated vascularisation in follicle development. Another major constituent of platelet releasate, platelet-derived growth factor (PDGF), has also been implicated in regulating vessel formation and maturity. This was demonstrated via intraovarian injection with an anti-PDGF antibody in rats by Pascuali et al. (2015), who consequently observed a reduction in follicle maturation paired with an increase in follicle atresia. This direct evidence for the importance of proangiogenic factors in follicle development supports the idea that PRP and/or platelet releasate can increase blood supply to the immature follicle pool and/or OSCs and encourage their maturation.

An additional potential explanation for the positive effects of PRP on the ovary is via sphingosine-1-phosphate (S1P) (Ono et al., 2013; Urtz et al., 2015). S1P has been isolated from follicular fluid at high nanomolar concentrations (Von Otte et al., 2006) and there is evidence to suggest that it can promote follicle maturation, likely through increased expression of CCN2, a connective tissue growth factor shown to drive follicle maturation (Cheng et al., 2015). Platelet alpha granules contain abundant stores of S1P, which is released upon activation and have been measured at over 300 nM per 1 × 10[7] platelets. If a linear relationship between S1P concentrations and platelet count exists, this would estimate that in studies that have infused activated PRP into the ovary, the amount of S1P delivered is approximately 9 μM, close to the range reported to be beneficial by Cheng et al. (2015). However, a recent study involving both murine and human follicles and human-to-murine xenotransplantation reported that although CCN2 expression was elevated in response to supraphysiological S1P doses, there was no increase in the number of follicles. By contrast, ovaries receiving S1P treatment suffered a significant reduction in follicle number compared to control counterparts (Pors et al., 2020). These findings again highlight the uncertainty of the effect of factors released by activated platelets on oocyte and follicle development and clinicians must be careful when considering such approaches.

Although it is theorised that PRP supports the development of follicles from OSCs, alternative explanations must be considered. In a study by Hosseini et al. (2017), PRP was found to improve the growth and viability in vitro of preantral follicles isolated from human ovaries post-mortem, supporting the notion that PRP may aid ovarian rejuvenation through supporting development of existing primordial follicles. However, this application relies on the patient having a supply of oocyte-containing follicles, thus, rendering the approach unsuitable for women who have experienced ovarian exhaustion. Panda et al. (2020) expressed the need for better-controlled studies to confirm the conclusions drawn by Cakiroglu et al. (2020), which found that the number of remaining follicles within the ovaries of women with POI determines their response to PRP infusion, and that women without any antral follicles are unlikely to respond to PRP.

The prospective pilot study by Sfakianoudis et al. (2020b) determined that perimenopausal women and women deemed to be POR benefitted the most from the treatment, more so than POI and menopausal patients. In an article by Sfakianoudis et al. (2020a), they describe how novel techniques (such as PRP, ovarian stem cells transplant and ovarian tissue transplant) may effectively treat ovarian insufficiency by reactivating follicular growth through restoring the microenvironment of the ovary. Therefore, it should be acknowledged that PRP infusion may only be an appropriate treatment for select ovarian disorders.

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