Is autologous platelet activation the key step in ovarian therapy for fertility recovery and menopause reversal?

Abstract

Platelets are a uniquely mammalian physiologic feature. As the only non-marine vertebrates to experience menopause, humans have a substantial post-reproductive lifespan and are believed to have a limited, non-renewable oocyte supply. Ovarian reserve typically declines after about age 35yrs, marking losses which cannot be recovered by available fertility medications. When in vitro fertilization fails due to low or absent ovarian response, gonadotropin adjustments are often ineffectual and if additional oocytes are occasionally harvested, egg quality is usually poor. This problem was confronted by Greek researchers who developed a new surgical method to insert autologous platelet-rich plasma (PRP) into ovaries; the first ovarian PRP success to improve reproductive outcomes was published from Athens in 2016. This innovation influenced later research with condensed platelet-derived growth factors, leading to correction of oocyte ploidy error, normal blastocyst development, and additional term livebirths. Yet women's health was among the last clinical domains to explore PRP, and its role in 'ovarian rejuvenation' remains unsettled. One critical aspect in this procedure is platelet activation, a commonly overlooked step in the cytokine release cascade considered essential for successful transition of undifferentiated ovarian stem cells to an oocyte lineage. Poor activation of platelets thus becomes an unforced error, potentially diminishing or even negating post-treatment ovarian follicular response. To answer this query, relevant theory, current disagreements, and new data on platelet activation are presented, along with clinical challenges for regenerative fertility practice.

Keywords: Activation; Infertility; Menopause; Platelets; Rejuvenation.

Fig. 1

Schema summarizing signaling dynamics for resting (grey oval) and activated platelets (PLT) following 3 response to agonists (i.e., collagen, thrombin), thromboxane A2 (TxA2), adenosine diphosphate (ADP), and/or. 4 extracellular calcium (Ca²⁺). These mediators contribute to increased PLT 1,2-diacylglycerol (DAG) and inositol 5 1,4,5-triphosphate (IP3). Intracellular PLT Ca²⁺ results in calcium efflux (grey arrow), itself augmented by 6 pharmacologic calcium gluconate (bracket) as activator reagent. These mediators coordinate PLT alpha-granule 7 (green) action to discharge ‘cargo proteins’ (blue) including growth factors & cytokines.