mTOR Inhibition via Low-Dose, Pulsed Rapamycin with Intraovarian Condensed Platelet Cytokines: An Individualized Protocol to Recover Diminished Reserve?

Abstract

No major breakthroughs have entered mainstream clinical fertility practice since egg donation and intracytoplasmic sperm injection decades ago, and oocyte deficits secondary to advanced age continue as the main manifestation of diminished ovarian reserve. In the meantime, several unproven IVF 'accessories' have emerged including so-called ovarian rejuvenation which entails placing fresh autologous platelet-rich plasma (PRP) directly into ovarian tissue. Among cellular responses attributed to this intervention are reduced oxidative stress, slowed apoptosis and improved metabolism. Besides having an impact on the existing follicle pool, platelet growth factors might also facilitate de novo oocyte recruitment by specified gene upregulation targeting uncommitted ovarian stem cells. Given that disordered activity at the mechanistic target of rapamycin (mTOR) has been shown to exacerbate or accelerate ovarian aging, PRP-discharged plasma cytokines combined with mTOR suppression by pulsed/cyclic rapamycin represents a novel fusion technique to enhance ovarian function. While beneficial effects have already been observed experimentally in oocytes and embryos with mTOR inhibition alone, this proposal is the first to discuss intraovarian platelet cytokines followed by low-dose, phased rapamycin. For refractory cases, this investigational, tailored approach could amplify or sustain ovarian capacity sufficient to permit retrieval of competent oocytes via distinct but complementary pathways-thus reducing dependency on oocyte donation.

Keywords: IVF; PRP; mTOR; ovarian reserve; platelet cytokines; rapamycin.

Figure 1

Rapamycin (Sirolimus), a macrolide lactone with potent immunosuppressant, antiproliferative and antifungal properties, received U.S. FDA approval in 1999. While widely used in organ transplant surgery, lower-dose applications of this mTOR inhibitor have successfully decelerated cellular aging to extend lifespan. Any emergent oocyte precursors available after intraovarian PLT cytokine injection may benefit from reduced mTOR activity, as described here.

Figure 2

Schematic for combined intraovarian condensed PLT growth factors (CF/GF) and oral cyclic rapamycin (r ×4). Following IRB approval, the study protocol includes enrollment labs (blue arrow) reviewed within 1 mo of ovarian injection (purple). Weekly oral rapamycin phased one-week-per-month begins 7 d after ovarian injection, where a 3 mg loading dose is followed 1 g/d for the next 6 d (inset). Subsequent testing scheduled monthly (a–a″) allows for close monitoring, intended to improve ovarian reserve sufficient for fertility treatment later (tx).