M Mashayekhi1, E Mirzadeh2, Z Chekini1, F Ahmadi3, P Eftekhari-Yazdi4, S Vesali5, T Madani6, N Aghdami7. 1. Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, P. O Box: 16635-148, Royan Allay, Eastern Hafez St, Banihashem Sq., Resalat Highway, Tehran, Iran. 2. Department of Regenerative Medicine, Cell Sciences Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, P. O Box: 16635-148, Shaghayegh Alley, Banihashem Sq., Resalat Highway, Tehran, Iran. 3. Department of Reproductive Imaging, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran. 4. Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran. 5. Department of Diabetes, Obesity and Metabolism, Reproductive Epidemiology Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran. 6. Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, P. O Box: 16635-148, Royan Allay, Eastern Hafez St, Banihashem Sq., Resalat Highway, Tehran, Iran. tmadani@royaninstitute.org. 7. Department of Regenerative Medicine, Cell Sciences Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, P. O Box: 16635-148, Shaghayegh Alley, Banihashem Sq., Resalat Highway, Tehran, Iran. nasser.aghdami@royaninstitute.org.
Abstract
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.
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 POFpatients. 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 POFpatients had a return of menstruation second months after the intervention. Two other POFpatients 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.
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