Assisted yes, but where do we draw the line?

Abstract

In a recent report in Reproductive Biomedicine Online by Ebner et al., a comprehensive multi-centre study was presented on the use of a calcium ionophore, A23187, to artificially activate oocytes from patients who had poor fertilization rates in previous cycles. Under physiological conditions, the calcium increase in oocytes at activation is caused by influx and release from specific stores and ion channels, and has precise temporal, quantitative and spatial patterns. Calcium ionophores may release Ca(2+) in an uncontrolled fashion from intracellular stores that would not normally be involved in the activation process. Ionophores, including A23187, have a multitude of effects on cell homeostasis, not yet defined in oocytes, that may have long-term effects, for example on gene expression. We suspect that the successful births reported by Ebner et al. are a result of the overriding influence of the injected spermatozoa, rather than the effect of the ionophore; nevertheless, such an invasive non-physiological approach to assisted reproduction techniques is worrying, especially as epigenetic effects may result in future generations.

A preliminary report of successful cleavage after calcium ionophore activation at ICSI in cases with previous arrest at the pronuclear stage

“…A23187 has previously been reported as an effective treatment in cases of partial or complete fertilization failure after ICSI (Montag and Ebner, 2011), resulting in improved fertilization (Tesarik and Sousa, 1995), pregnancy (Chi et al, 2004;Rybouchkin et al, 1997), and healthy live birth (Eldar-Geva et al, 2003;Kamiyama et al, 2012;Ebner et al, 2015). Use of calcium ionophore in the clinic is still regarded as an experimental treatment (Santella and Dale, 2015;Thompson, 2015) and should only be used in highly selected cases and under strict consent and monitoring conditions, such as applied in this study (Van Blerkom et al, 2015).…”

“…Chemical oocyte activation is the most widely used method for activation after ICSI (Ebner et al, 2012), and can be achieved with a variety of chemical agents such as 7% ethanol (Presicce and Yang, 1994), strontium chloride (Cuthbertson et al, 1981), phorbol ester (Cuthbertson and Cobbold, 1985), thimerosal (Fissore and Robl, 1993), and Ca 2+ ionophores (Hosseini et al, 2008;Meo et al, 2007;Santella and Dale, 2015;Van Blerkom et al, 2015).…”

Cellular and molecular aspects of oocyte maturation and fertilization: a perspective from the actin cytoskeleton

“…However, there are presently no data reporting that its application induces the Ca 2+ oscillations that are critical for successful oocyte activation and the high quality blastocyst formation [155,156]. The Ca 2+ -ionophore, which elicits a single Ca 2+ increase, thus not mimicking the Ca 2+ oscillation at natural fertilization [157], may still lead to proteolysis of cyclin B and to a reduction in the CDK1 activity. However, the amount of Ca 2+ released may not ensure that these events occur and persist.…”

Single Ca2+ transients vs oscillatory Ca2+ signaling for assisted oocyte activation: limitations and benefits

“…Besides the substantial cellular stress that Ca 2+ ionophores might exert by altering membrane permeability, safety concerns remain regarding the induction of a single Ca 2+ transient which differs remarkably from the physiological oscillatory Ca 2+ response (Santella & Dale 2015, van Blerkom et al 2015. Accumulating evidence supports the biosafety of ionomycin as an activating agent.…”