The controversy in conventional stimulation in DOR
It is a challenge for DOR patients to achieve pregnancy, no matter which protocol applied to IVF. A continuing interest has been vested in DOR research worldwide and many attempts have been made to improve IVF outcomes. Athanasios Papathanasiou et al[12]reports that in a comprehensive review undertaken of RCTs on ‘poor responders/DOR’ published in the last 15 years, The most popular stimulation protocols investigated in such patients are the antagonist protocol, the micro dose flare protocol and the long down-regulation protocol. However, RCTs on popular protocols for poor responders or DOR have reported conflicting results with regard to oocyte yields and reproductive outcomes.
There has been controversy on whether increasing gonadotrophins stimulation doses would improve IVF outcomes. Many studies showed that large gonadotrophins doses do not increase total number of eggs harvested and the number of mature eggs, and there were also no differences clinical pregnancy rates and live birth rates in women with DOR[13]. Several large RCT found incremental doses of FSH to have a direct correlation with the number of oocytes recovered, but with no increment in the number of good-quality blastocysts[14]. Furthermore, the blastocyst/oocyte ratio and fertilization rate demonstrated an inverse relationship with the dose of stimulation[15-16]. Federica Di Guardo concluded that in DOR context, natural cycle/modified natural cycle–in vitro fertilization, as a ‘milder’ approach, could be a reasonable alternative to high-dose/conventional ovarian stimulation in poor ovarian responders, with the aim to retrieve a single oocyte with transferred to a more receptive endometrium[17]. However, even today, many clinicians still believe that higher stimulation doses improve outcomes in poor responders, despite much recent data challenging this view.
Studies show that the concentration of oxidative stress parameters significantly rose after ovarian stimulation. Superoxide generated in the ovary induces apoptosis of granulosa cells to break down follicular walls leading a worsened oocyte quality[18]. Some researches on oxidative stress also indicated that controlled ovarian hyper-stimulation can lead to disruption of oxidative-antioxidative balance in follicle cells and oocytes, which is similar as the aging related changes.