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Unleashing the potential of stem cells to help poor responders

      There have been multiple advances in assisted reproductive technology (ART) since the first baby from in vitro fertilization (IVF) baby was born 40 years ago, including intracytoplasmic sperm injection and preimplantation genetic testing. However, one patient group remains the most challenging – the poor responder (PR). After attempting multiple IVF cycles that are often cancelled due to little or no ovarian response, devastated PR patients feel they have little or no hope to conceive with their own eggs. For the contemporary fertility specialist, providers are often frustrated by lack of therapeutic options to offer other than donor egg. The article by Herraiz and colleagues (
      • Herraiz S.
      • Romeu M.
      • Buigues A.
      • Martínez S.
      • Díaz-García C.
      • Gómez-Sequí I.
      • et al.
      Autologous stem cell ovarian transplantation to increase reproductive potential in poor responder patients.
      ) opens a new window of hope for the PR group by unleashing the potential of stem cells for ovarian rejuvenation. In their study, Herraiz et al. (
      • Herraiz S.
      • Romeu M.
      • Buigues A.
      • Martínez S.
      • Díaz-García C.
      • Gómez-Sequí I.
      • et al.
      Autologous stem cell ovarian transplantation to increase reproductive potential in poor responder patients.
      ) introduce the beneficial effects of autologous stem cell ovarian transplant (ASCOT) on ovarian reserve and IVF outcomes for PR patients with a very poor prognosis.
      In this prospective observation pilot study of 17 women defined as PRs using the ESHRE criteria, bone marrow derived stem cells (BMDSC) were delivered directly to one ovary for each patient in an effort to optimize the recruitment of existing dormant follicles to improve IVF outcomes. The study consisted of BMDSC mobilization to peripheral blood by granulocyte colony stimulating factor treatment and subsequent collection by aphaeresis. Cells were delivered into the ovarian artery by intra-arterial catheter. In each patient, the contralateral ovary served as a control. Shortly after, patients then proceeded with controlled ovarian hyperstimulation for IVF with preimplantation genetic screening. Main endpoints included clinical improvement of ovarian reserve as measured by antral follicle count (AFC) and antimüllerian hormone (AMH) levels, monitored up to five months after ASCOT, as well as cycle number (cancelled and completed), number of mature oocytes retrieved, number of euploid embryos, and pregnancy and live birth rate (including spontaneous pregnancies). An additional component of the study looked at growth factors released by BMDSC.
      Results after ASCOT were promising for PRs. ASCOT resulted in a significant improvement in AFC two weeks after treatment. The team defined success as an increase in AFC ≥3 follicles and/or two consecutive increases (two standard deviations) in AMH levels, and with this criteria ovarian function improved in 81.3% of women. These positive effects were associated with the presence of fibroblast growth factor-2 (FGF-2) and thrombospondin (THSP-1) in the aphaeresis sample. Among the 15 patients, five pregnancies were achieved: 2 after embryo transfer and 3 by natural conception. This corresponds to a 33.3% pregnancy rate in a group of poor prognosis women where oocyte donation was the only practical option after several IVF attempts and years of infertility. It should be noted that after preimplantation genetic screening, the embryo euploidy rate was low (16.1%).
      The findings of this study may be applicable to more than just the PR patient. The ESHRE criteria defines a PR as fulfilling strict criteria: collection of 3 or fewer oocytes in two prior ovarian stimulation cycles (one cycle in women over 40) or collection of three or fewer oocytes in a single stimulation cycle and an abnormal ovarian reserve test: AFC < 5–7 follicles or AMH < 0.5–1.1 ng/mL, or abnormal ovarian reserve testing alone in those over 40 years of age (
      • Ferraretti A.P.
      • La Marca A.
      • Fauser B.C.
      • Tarlatzis B.
      • Nargund G.
      • Gianaroli L.
      • et al.
      ESHRE consensus on the definition of ‘poor response’ to ovarian stimulation for in vitro fertilization: the Bologna criteria.
      ). Indeed, ovarian stem cell therapy can also benefit other groups with a clinically significant reduction in the pool of primordial follicles, such as those with diminished ovarian reserve (DOR) as well as those with primary ovarian insufficiency (POI). An important point is that with DOR, and very often with POI, the ovary contains residual dormant primordial follicles that theoretically might be activated with this treatment. In fact, earlier this year Herraiz et al. (
      • Herraiz S.
      • Buigues B.
      • Díaz-García C.
      • Romeu M.
      • Martinez S.
      • Gomez-Seguí I.
      • et al.
      Fertility rescue and ovarian follicle growth promotion by bone marrow stem cells.
      ) reported on the benefits of stem cell treatment in a POI mouse model. Fertility rescue and spontaneous pregnancies were achieved after BMDSC infusion in mice whose ovaries were induced by chemotherapy to simulate PRs and ovarian insufficiency. In the same study, when human BMDSCs were infused into mice xenografted with human ovarian cortex from PR patients, injected cells were engrafted close to vessels and granulosa cells, promoting follicular growth to the secondary stage. They also demonstrated in both murine and human xenografted tissue that BMDSC infusion increased ovarian stroma proliferation and blood vessel formation while decreasing apoptosis (
      • Herraiz S.
      • Buigues B.
      • Díaz-García C.
      • Romeu M.
      • Martinez S.
      • Gomez-Seguí I.
      • et al.
      Fertility rescue and ovarian follicle growth promotion by bone marrow stem cells.
      ).
      Just as ART has made leaps and bounds in terms of progress, so has the potential of stem cell therapies. It has been known for some time that patients with POI due to chemotherapy can achieve spontaneous pregnancy after bone marrow transplant, suggesting that residual follicles could be activated somehow by mesenchymal stem cells. It has been postulated that factors present in bone marrow can help foster a favorable ovarian environment for follicular activation. Currently, select populations of mesenchymal stem cells have been identified as pluripotent. It has been postulated that these cells can migrate into damaged tissue via bloodstream and undergo differentiation into the cells identical with the cells of target tissue (
      • Fazeli Z.
      • Abedindo A.
      • Omrani M.D.
      • Ghaderian S.M.H.
      Mesenchymal stem cells (MSCs) therapy for recovery of fertility: a systematic review.
      ). The exact mechanism of action to explain how mesenchymal stem cells can activate residual follicles in those who are PRs or have severe DOR remains unknown, but mechanical signaling may play a role. The authors have helped build upon the body of regarding the regenerative ability of stem cells by identifying soluble factors known to be secreted by BMDSCs and correlating those with ovarian reserve parameters after ASCOT. Women with a positive response in terms of AFC and AMH had higher FGF-2 and THSP-1 levels in the ASCOT infusion sample than those without a positive response. FGF-2, expressed in early human follicles, is a key player in estrogen production associated with the improved follicular development. THSP-1 has been recognized as a mediator of ovarian angiogenesis and folliculogenesis. The authors suggest that these soluble growth factors likely played a role in improved AFC in patients who received ASCOT (
      • Herraiz S.
      • Romeu M.
      • Buigues A.
      • Martínez S.
      • Díaz-García C.
      • Gómez-Sequí I.
      • et al.
      Autologous stem cell ovarian transplantation to increase reproductive potential in poor responder patients.
      ). The authors also noted that the positive increase in AFC for PR women occurred during the first four weeks after treatment, indicating that secondary follicles most likely to benefit after ASCOT treatment (
      • Herraiz S.
      • Romeu M.
      • Buigues A.
      • Martínez S.
      • Díaz-García C.
      • Gómez-Sequí I.
      • et al.
      Autologous stem cell ovarian transplantation to increase reproductive potential in poor responder patients.
      ).
      In conclusion, if supported by future clinical studies, autologous stem cell ovarian transplant could represent a paradigm shift for fertility treatment for PRs and women with severe DOR. In fact, ASCOT could potentially be used for women with POI, including rejuvenating the ovaries following gonadotoxic cancer treatment. While obvious sources for bias that could explain the results are not apparent, it is possible that confounding factors might explain the impressive pregnancy outcomes observed. It is essential that the mechanisms involved are elucidated and future risks are assessed before the method is adopted, because there is a tendency of a new technique to show initial promise before limitations are understood.
      The ultimate use of these techniques might be to treat age-related ovarian senescence. Although current evidence remains limited, if future experiments continue to substantiate the promise of ASCOT, the technique could prove as revolutionary to ART as IVF or ICSI. The field of ovarian treatment with stem cell technology is rapidly growing. If ASCOT is substantiated with larger studies, the ability to unleash the power of stem cells to rejuvenate the ovary can offer new hope to millions of women with poor ovarian response, DOR and even POI.

      Acknowledgments

      Supported, in part, by the Howard and Georgeanna Seegar Jones Endowment.

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