Assisted oocyte activation re-envisioned: a more physiological approach.

Area of Science:

• Reproductive biology and assisted reproductive technologies.
• Spermatozoa and oocyte function in fertilization.
• Genetics and molecular mechanisms of fertilization failure.

Background:

• Severe or total fertilization failure after intracytoplasmic sperm injection (ICSI) presents a significant challenge in assisted reproduction.
• Sperm phospholipase C-zeta (PLCζ) is a key mediator of oocyte activation, and its deficiency is linked to fertilization failure.
• Current assisted oocyte activation (AOA) strategies are often empirical, lacking gamete-specific targeting.

Purpose of the Study:

• To identify the gamete-specific causes of severe fertilization failure post-ICSI.
• To evaluate the effectiveness of individualized AOA strategies guided by sperm PLCζ content.
• To compare outcomes of AOA with historical non-AOA ICSI cycles.

Main Methods:

• Pilot study analyzing sperm PLCζ content in ejaculated, epididymal, and testicular spermatozoa.
• Prospective case series of 135 couples with prior fertilization failure undergoing ICSI.
• PLCζ assay determined gamete-specific deficiency, guiding AOA treatment (ionophore-only, rhPLCζ-only, or combined).

Main Results:

• Spermatozoa maturity and origin influenced PLCζ content.
• AOA treatments (ionophore and rhPLCζ) successfully rescued fertilization and improved pregnancy rates compared to historical cycles.
• Dual AOA (ionophore + rhPLCζ) demonstrated superior efficacy, significantly increasing fertilization (73.2%), implantation (31.7%), and ongoing pregnancy rates (63.3%), even with testicular spermatozoa.

Conclusions:

• Recombinant PLCζ enables targeted correction of gamete-specific fertilization failures.
• Dual AOA is highly effective for compounded etiologies and immature spermatozoa.
• These findings support a transition from empirical to individualized AOA approaches.