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Patients with poor ovarian response (POR) and premature ovarian insufficiency (POI) are challenging to treat, with oocyte donation remaining as the only feasible option to achieve pregnancy in some cases. The Autologous stem cell ovarian transplantation (ASCOT) technique allows follicle development, enabling pregnancies and births of healthy babies in these patients. Previous results suggest that growth factors and cytokines secreted by stem cells are partially responsible for their regenerative properties. Indeed, ASCOT beneficial effects associate with the presence of different bone marrow derived stem cell- secreted factors in plasma. Therefore, the aim of this study was to assess whether ASCOT induce any modifications in the plasma proteomic profile of patients with impaired ovarian reserves. Discriminant analysis highlighted clear distinctions between the plasma proteome before (PRE), during stem cell mobilization and collection (APHERESIS) and three months after ASCOT (POST) in patients with POR and POI. Both the stem cell mobilization and ASCOT technique induced statistically significant modifications in the plasma composition, reversing some age-related protein expression changes. In the POR group, functional analysis revealed an enrichment in processes related to the complement cascade, immune system, and platelet degranulation, while in the POI group, enriched processes were also associated with responses to oxygen-containing compounds and growth hormones, and blood vessel maturation. In conclusion, our findings highlight the potential proteins and biological processes that may promote the follicle activation and growth observed after ASCOT. Identifying plasma proteins that regenerate aged or damaged ovaries could lead to more effective, targeted and/or preventive therapies for patients.

The ovary has a comparatively short functional lifespan compared with other organs, and genetic and pathological injuries can further shorten its functional life. Thus, preserving ovarian function should be considered in the context of women with threats to ovarian reserve, such as ageing, premature ovarian insufficiency (POI) and diminished ovarian reserve (DOR). Indeed, one-third of women with POI retain resting follicles that can be reactivated to produce competent oocytes, as proved by the in-vitro activation of dormant follicles. This paper discusses mechanisms and clinical data relating to new therapeutic strategies using ovarian fragmentation, stem cells or platelet-rich plasma to regain ovarian function in women of older age (>38 years) or with POI or DOR. Follicle reactivation techniques show promising experimental outcomes and have been successful in some cases, when POI is established or DOR diagnosed; however, there is scarce clinical evidence to warrant their widespread clinical use. Beyond these contexts, also discussed is how new insights into the biological mechanisms governing follicular dynamics and oocyte competence may play a role in reversing ovarian damage, as no technique modifies oocyte quality. Additional studies should focus on increasing follicle number and quality. Finally, there is a small but important subgroup of women lacking residual follicles and requiring oocyte generation from stem cells., (Copyright © 2022 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Purpose of Review: We review the techniques recently tested in both animal models and humans to provide a state-of-the-art on adult stem cell ovarian transplant to achieve ovarian rejuvenation in patients with diminished ovarian reserves., Recent Findings: As the firsts reports of spontaneous pregnancies achieved after bone marrow transplantation in oncologic women with primary ovarian insufficiency, increasing evidence supports the regenerative effects of stem cell-based therapies in the ovarian niche. Adult stem cells from several origins promote follicular development, increase ovarian local vascularization, increase follicle and stromal cell proliferation and reduce cell apoptosis and follicular atresia, although they do not modify embryo quality. Therefore, residual quiescent follicles of aged or damaged ovaries might produce competent oocytes in an adequate ovarian environment. Nevertheless, further research is needed to properly evaluate underlying mechanisms, identify best cell sources and design less invasive infusion techniques., Summary: Stem cells may be a relevant therapeutic alternative for ovary regeneration and follicular development in patients with impaired ovaries, such as poor ovarian responders or women diagnosed with primary ovarian insufficiency.

Objective: To evaluate effects of autologous stem cell ovarian transplant (ASCOT) on ovarian reserve and IVF outcomes of women who are poor responders with very poor prognosis., Design: Prospective observational pilot study., Setting: University hospital., Patient(s): Seventeen women who are poor responders., Intervention(s): Ovarian infusion of bone marrow-derived stem cells., Main Outcome Measure(s): Serum antimüllerian hormone levels and antral follicular count (AFC), punctured follicles, and oocytes retrieved after stimulation (controlled ovarian stimulation) were measred. Apheresis was analyzed for growth factor concentrations., Result(s): The ASCOT resulted in a significant improvement in AFC 2 weeks after treatment. With an increase in AFC of three or more follicles and/or two consecutive increases in antimüllerian hormone levels as success criteria, ovarian function improved in 81.3% of women. These positive effects were associated with the presence of fibroblast growth factor-2 and thrombospondin. During controlled ovarian stimulation, ASCOT increased the number of stimulable antral follicles and oocytes, but the embryo euploidy rate was low (16.1%). Five pregnancies were achieved: two after ET, three by natural conception., Conclusion(s): Our results suggest that ASCOT optimized the mobilization and growth of existing follicles, possibly related to fibroblast growth factor-2 and thrombospondin-1 within apheresis. The ASCOT improved follicle and oocyte quantity enabling pregnancy in women who are poor responders previously limited to oocyte donation., Clinical Trial Registration Number: NCT02240342., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)