Evaluation of safety, feasibility and efficacy of intra-ovarian transplantation of autologous adipose derived mesenchymal stromal cells in idiopathic premature ovarian failure patients: non-randomized clinical trial, phase I, first in human.

BACKGROUND: Premature ovarian failure (POF) is characterized by the loss of ovarian activity before the age of 40 years. Stem cell therapy has the capability to create a regenerative microenvironment and is a proposed treatment for POF-related infertility due to the presence of renewal folliculogenesis and germ cells in the adult ovaries. In this study, we assessed the safety, feasibility, efficacy and dose adjustment of autologous adipose-derived stromal cells (ADSCs) and their ability to improve ovarian function in POF patients. METHODS: This study was a non-randomized clinical trial, phase I. Nine women with a definitive diagnosis of POF were divided into three groups (n = 3 per group) that received either 5 × 106, 10 × 106, or 15 × 106 autologous ADSCs suspension transplanted in the one ovary. Participants were followed-up at 24 h after the transplantation, and at 1 and 2 weeks, and 1, 2, 3, 6, and 12 months after the transplantation. The primary objective was to evaluate the safety of ADSCs transplantation. Secondary objectives included the effects of ADSCs transplantation on the resumption of menstruation, hormones level (Follicle-stimulating hormone (FSH) and anti-Müllerian hormone), ovarian function (Antral follicle count and ovary volume by ultrasonography evaluation) as well as dose escalation. RESULTS: Participants had not shown any early-onset possible side effects and secondary complications during follow-up. The menstruation resumption was observed in four patients which established for several months. In the 15 × 106 group, two POF patients had a return of menstruation second months after the intervention. Two other POF patients in 5 × 106 and 10 × 106 cell groups reported menstruation resumption at 1 month after the intervention. We observed decreased serum FSH levels of less than 25 IU/l in four patients. In two patients in 5 × 106 and 10 × 106 cell groups, serum FSH showed an inconsistent decline during a 1 year follow up after ADSCs transplantation. The ovarian volume, AMH, and AFC were variable during the follow-up and no significant differences between cell groups (p > 0.05). CONCLUSIONS: We showed the intra-ovarian embedding of ADSCs is safe and feasible and is associated with an inconsistent decline in serum FSH. This should be further investigated with a large RCT. TRIAL REGISTRATION: NCT02603744 , Registered 13 November 2015 - Retrospectively registered, http://www.Clinicaltrials.gov.

Endometriosis fertility index for predicting non-assisted reproductive technology pregnancy after endometriosis surgery: a systematic review and meta-analysis.

BACKGROUND: Results of studies that have assessed the accuracy of the endometriosis Fertility Index (EFI) for predicting non-assisted reproductive technology (ART) pregnancy are inconsistent. OBJECTIVE: We intended to evaluate the accuracy of EFI for the prediction of non-ART pregnancy. SEARCH STRATEGY: Embase, Medline, Scopus and Web of Science were searched up to 5 October 2019. SELECTION CRITERIA: We included studies that used EFI to predict non-ART pregnancy in women with surgically documented endometriosis. DATA COLLECTION AND ANALYSIS: A total of 5547 studies were identified, from which we included 17 studies on 4598 women in the meta-analysis. Eight studies were classified as good quality, and the rest were considered to be of fair quality. Only five (29.41%) studies used appropriate approaches to account for potential confounders. Pooled effect sizes with corresponding 95% CI were calculated using random-effects model. MAIN RESULTS: The cumulative non-ART pregnancy rate at 36 months was 10% (95% CI: 3, 16%; P < 0.001) for women with an EFI of 0-2, which significantly increased to 69% (95% CI: 58, 79%; P < 0.001) for women with an EFI of 9-10. Compared with women with an EFI of 3-4 (18%, 95% CI: 12, 24%; P < 0.001), the combined cumulative non-ART pregnancy rates were 44% (95% CI: 26, 63%; P < 0.001) for women with an EFT of 5-6 and 55% (95% CI: 47, 64%; P < 0.001) for women with an EFI of 7-8. Paired comparison by the chi-square test showed a significant difference between all categories (P < 0.001). The odds ratio (OR) for EFI was 1.33 (95% CI: 1.17, 1.49, P < 0.001) and the summary area under the curve (AUC) was 72% (95% CI: 65, 80%, P < 0.001). CONCLUSION: The current findings highlighted the good performance of the EFI score in predicting the non-ART pregnancy rate. However, these findings should be considered with caution because of the substantial heterogeneity between studies. TWEETABLE ABSTRACT: Review findings show the merits of Endometriosis Fertility Index as having a prognostic ability for non-assisted reproductive technology pregnancy.

CONTROLLED OVARIAN STIMULATION IN ENDOMETRIOSIS PATIENTS CAN BE INDIVIDUALIZED BY ANTI-MÜLLERIAN HORMONE LEVELS.

CONTEXT: Anti-Mullerian hormone (AMH) assay is becoming the best indicator of successful IVF treatment response to fertility drugs and could be a useful marker of embryo implantation potential. Various protocols are being used for controlled ovarian stimulation (COS), but there is an uncertainty regarding the implementation of the best protocol for endometriosis patients and also little evidence is available concerning the clinical value of AMH levels in endometriosis. OBJECTIVE: This study aimed to evaluate the prognostic value of serum AMH levels for pregnancy in COS using GnRH-agonist(GnRH-a) and GnRH-antagonist(GnRH-ant) protocols in endometriosis patients. DESIGN: This is a cross-sectional study between March 2012 and November 2015. SUBJECTS AND METHODS: Data were collected from 249 COS cycles of endometriosis patients, including 129 cycles with GnRH-a and 120 cycles with GnRH-ant. Patients in each group were classified into three subgroups based on their serum AMH levels. The outcomes of ICSI program were evaluated. RESULTS: The ROC curve analysis showed that embryo and oocyte counts and AMH were equally predictive for pregnancy, as demonstrated by a similar area under the curve (AUC) of 0.69, 0.66 and 0.64, respectively. The sensitivity and specificity for prediction of positive pregnancy were 70.91% and 67.01% for embryo counts, 70.91% and 67.53% for oocyte counts at the cutoff values of 5 and 7, respectively, and 83.64% and 52.58% for AMH levels at the cutoff values of 1.3ng/mL. CONCLUSIONS: This study demonstrates that AMH as a single test has substantial accuracy in the prediction of pregnancy using the GnRH antagonist protocol for patients with endometriosis. In other words, AMH assay prior to ovarian stimulation initiation guides the clinicians to choose the antagonist stimulation protocol for the patients with two extreme AMH levels. AMH levels can be used to individualize control ovarian stimulation in endometriosis patients.