Induction of Follicle Development in Poor Responder Patients Based on Modified in Vitro Activation (MIVA) Approach

The success of IVF treatment in poor responder (POR) patients is low due to decreases in the number of retrieved oocytes. A recent study demonstrated that suppression of Hippo signaling in somatic cells of ovarian follicles induced secondary follicle growth, resulting in successful follicle growth in patients with primary ovarian insufficiency though IVA. To improve the outcome of IVF treatment in POR patients, we modified the original IVA for POR patients. Retrospective cohort study to induce follicle development in poor responder patients. Seventeen patients who received written informed consent and met following four criteria were enrolled: advanced maternal age (=>40 years) or any other risk factor for POR, a previous POR (<=3 oocytes with a conventional stimulation protocol), an abnormal ovarian reserve test (i.e. AFC, 5-7 follicles or AMH, 0.5-1.1 ng/ml), and married women. This study was approved by local ethical committee and adhered to JCMJER criteria (Clinical Trial Registry: UMIN000019204). For mIVA, we excised partial ovarian tissues from one side of ovary under laparoscopic surgery. After removal of medulla tissues, the ovarian cortex was dissected into 1-2 mm square of ovarian cubes and then nine to ten of ovarian cubes were put onto cell culture inserts and cultured overnight to suppress Hippo signaling. After culture, these cubes were auto-transplanted beneath the serosa of both Fallopian tubes. Simultaneously, we made 7-9 of linear cuttings in the ovarian cortex of the contralateral side to induce physical stimulation to the ovary. For oocyte retrieval, all patients received ovarian stimulation after confirmation of decreased LH level (<10 mIU/ml) with GnRHa short protocol administrating recFSH 300 IU for 6-10 days followed by a HCG injection. IVF-ET was performed under regular protocols. The following parameters were compared before (pre-op) and after operation (post-op): number of developed follicles (>φ15mm), fertilization rate, cleavage rate (over 4-cell embryos), clinical pregnancy rate, miscarriage rate and cryopreservation rate. Tabled 1Patients (n=16)Number of folliclesFertilization rate (%)Cleavage rate (%)Clinical pregnancy rate (%)Miscarriage rate (%)Cryopreservation rate (%)pre-op (46 cycles)10011.0a (11/100)10.0b (10/100)2.2 (1/46)100 (1/1)10.0 (1/10)post-op (28 cycles)6737.3a’ (25/67)29.9b’ (20/67)7.5 (2/28) single and twin ongoing0 (0/2)30.0 (6/20)(a-a’, b-b’: p<0.05, Chi-squared test) Open table in a new tab (a-a’, b-b’: p<0.05, Chi-squared test) The modified IVA method improved clinical pregnancy rate due to increases in the numbers of cleaved embryos. Although more patients will require to lead the conclusion, the novel apprach has potential to increase clinical pregnancy rate in POR patients.