Use of autologous adipose-derived mesenchymal stem cells for ovarian rejuvenation in poor responder IVF patients: a phase 1 randomized placebo-controlled double-blind crossover study

Background: Despite the application of various methods to augment ovarian responsiveness, the management of poor ovarian responders remains challenging and pregnancy rates following in vitro fertilization are poor. Advances in adult stem cell research and their clinical application has prompted interest in their use in assisted reproduction. We report the first double-blind, randomized, placebo-controlled clinical study using autologous human stromal vascular fraction (SVF) containing adipose-derived stem cells (ADSCs) for ovarian rejuvenation. Materials and methods: Thirty patients were recruited. Twenty-one had lower-than-expected reserves for their age and 9 had premature ovarian insufficiency. Patients were randomized into a placebo group (10) and an intervention group (20). SVF was obtained from adipose tissue following abdominal liposuction; the ADSC component was characterized using flow cytometry. Three equal insertions, adjusted based on ovarian volume, were performed at monthly intervals via an ultrasound-guided transvaginal needle puncture. The SVF was not cultured before transplantation. Those in the placebo group were then crossed over to the intervention group and received a single SVF (maximally concentrated) insertion (crossover group). Results: The median viable SVF cell number inserted per patient over 3 months, and the percentage of mesenchymal stem cells (MSC) thereof, was 1.6×106 and 13.2%, respectively. Resulting anti-Mullerian hormone (AMH) changes were variable over the treatment course with a notable placebo effect. Patients with premature ovarian insufficiency showed no change in AMH, both to intervention and placebo. Despite this, a temporary return of menses was noted in a third of patients while on treatment. Patients with low reserves for age showed an increase in AMH, although not statistically significant when compared to placebo. In the crossover group, insertions were limited to one intervention comprising all cells; here a significantly higher median of 3.4×106 SVF cells were injected containing an average of 16.9% MSCs. No significant change in AMH was noted. To date 12 patients have undergone ovarian stimulation and in vitro fertilization after stem cell therapy; of these 9 have had embryo transfers with a resulting pregnancy rate of 33%. There were also 2 spontaneous pregnancies. Conclusion: Although the application of SVF-derived ADSCs for ovarian rejuvenation remains experimental, the current study provides further support for the safety of this approach and presents encouraging results as to its efficacy in assisted reproduction.