Influence of Autologous In Vitro Activation of Ovaries by Stem Cells and Growth Factors on Endocrine and Reproductive Function of Patients with Ovarian Insufficiency-A Clinical Trial Study

Suada Tinjić, Džihan Abazović, Dušica Ljubić, Danilo Vojvodić, Tatjana Božanović, Mirza Ibrišimović, Sergije Marković, Aleksandar Ljubić, Suada Tinjić, Džihan Abazović, Dušica Ljubić, Danilo Vojvodić, Tatjana Božanović, Mirza Ibrišimović, Sergije Marković, Aleksandar Ljubić

Abstract

Background: Premature ovarian failure (POF) can be found in 1% of women at the age of 35-40, mostly due to unknown causes. PI3K-Akt signaling is associated with both ovarian function and growth of primordial follicles. In this study, we examined the effects of autologous in vitro ovarian activation with stem cells and autologous growth factors on reproductive and endocrine function in patients with ovarian impairment.

Materials and methods: The longitudinal prospective observational study included 50 patients (between 30 and 50 years) with a diagnosis of POF and infertility. This multicenter study was performed at Jevremova Special Hospital in Belgrade, Saint James Hospital (Malta), and Remedica Skoplje Hospital, between 2015 and 2018. All patients went through numerous laboratory testings, including hormonal status. The autologous bone marrow mesenchymal stem cells (BMSCs) and growth factors were used in combination for activation of ovarian tissue before its re-transplantation. The software package SPSS 20.0 was used for statistical analysis of the results.

Results: Differences in follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and progesterone (PG) hormone concentrations before and after 3, 6, and 12 months post-transplantation were tested in correlation with the volume of transplanted ovarian tissue. A significant correlation (P=0.029) was found between the change in E2 level after 3 months and the volume of re-transplanted tissues. Also after re-transplantation, 64% of the patients had follicles resulting in aspiration of oocytes in 25% of positive women with follicles.

Conclusion: The SEGOVA method could potentially solve many human reproductive problems in the future due to the large number of patients diagnosed with POF, as well asthe possibility of delaying menopause, thus improving the quality of life and general health (Registration number: NCT04009473).

Keywords: Growth Factors; Ovarian; Premature Ovarian Failure; Stem Cells.

Conflict of interest statement

The authors declare no conflicts of interest.

Copyright© by Royan Institute. All rights reserved.

Figures

Fig.1
Fig.1
Medians, interquartile range and range of follicle stimulating hormone (FSH) before the procedure and 3, 6, and 12 months after procedure (line inside the box is median; the box is interquartile range; the lines outside the box are minimum and maximum values).
Fig.2
Fig.2
Medians, interquartile range and range of luteinizing hormone (LH) before the procedure and after 3, 6, and 12 months (line inside the box is median; the box is interquartile range; the lines outside the box are minimum and maximum values).
Fig.3
Fig.3
Medians, interquartile range and range of estradiol (E2) before the procedure and 3, 6 and 12 months after the procedure (line inside the box is median; the box is interquartile range; the lines outside the box are minimum and maximum values).
Fig.4
Fig.4
Medians, interquartile range and range of progesterone (PG) before the procedure and after 3, 6, and 12 months (line inside the box is median; the box is interquartile range; the lines outside the box are minimum and maximum values).

References

    1. Broekmans FJ, Knauff EAH, te Velde ER, Macklon NS, Fauser BC. Female reproductive ageing: current knowledge and future trends. Trends Endocrinol Metab. 2007;18(2):58–65.
    1. Silva JRV, van den Hurk R, van Tol HTA, Roelen BAJ, Figueiredo JR. Expression of growth differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15), and BMP receptors in the ovaries of goats. Mol Reprod Dev. 2005;70(1):11–19.
    1. Dewailly D, Robin G, Peigne M, Decanter C, Pigny P, CatteauJonard S. Interactions between androgens, FSH, anti-Müllerian hormone and estradiol during folliculogenesis in the human normal and polycystic ovary. Hum Reprod Update. 2016;22(6):709–724.
    1. Carrell DT, Peterson CM. Reproductive endocrinology and infertility. New York: Springer; 2010. pp. 345–345.
    1. Qin Y, Zhao H, Xu J, Shi Y, Li Z, Qiao J, et al. Association of 8q22.3 locus in Chinese Han with idiopathic premature ovarian failure (POF) Hum Mol Genet. 2011;21(2):430–436.
    1. Tinjić S, Abazović Dž, Ljubić D, Vujović S, Vojvodić D, Božanović T, et al. Ovarian rejuvenation. Donald School J Ultrasound Obste Gynecol. 2019;13(2):64–68.
    1. Ljubić A, Abazović D, Vučetić D, Ljubić D, Pejović T, Božanović T. Case report autologous ovarian in vitro activation with ultrasound-guided orthotopic re-transplantation. Am J Clin Exp Obstet Gynecol. 2017;4(5):51–57.
    1. He Y, Chen D, Yang L, Hou Q, Ma H, Xu X. The therapeutic potential of bone marrow mesenchymal stem cells in premature ovarian failure. Stem Cell Res Ther. 2018;9(1):263–263.
    1. Evers JLH. Female subfertility. Lancet. 2002;360(9327):151–159.
    1. Kaspers GJ, Veerman AJ, Popp-Snijders C, Lomecky M, Van Zantwijk CH, Swinkels LM, et al. Comparison of the antileukemic activity in vitro of dexamethasone and prednisolone in childhood acute lymphoblastic leukemia. Med Pediatr Oncol. 1996;27(2):114–121.
    1. Labarta E, de Los Santos MJ, Escriba MJ, Pellicer A, Herraiz S. Mitohondria as a oocyte rejuvenation. Fertil Steril. 2019;111(2):219–226.
    1. Hayashi K, Hikabe O, Obata Y, Hirao Y. Reconstitution of mouse oogenesis in a dish from pluripotent stem cells. Nat Protocol. 2017;12(9):1733–1744.
    1. Hikabe O, Hamazaki N, Nagamatsu G, Obata Y, Hirao Y, Hamada N, et al. Reconstitution in vitro of the entire cycle of the mouse female germ line. Nature. 2016;539(7628):299–303.
    1. Morohaku K, Tanimoto R, Sasaki K, Kawahara-Miki R, Kono T, Hayashi K, et al. Complete in vitro generation of fertile oocytes from mouse primordial germ cells. Proc Natl Acad Sci USA. 2016;113(32):9021–9026.
    1. Friedenstein AJ, Chailakhyan RK, Gerasimov UV. Bone marrow osteogenic stem cells: in vitro cultivation and transplantation in diffusion chambers. Cell Tissue Kinet. 1987;20(3):263–272.
    1. Liu T, Huang Y, Guo L, Cheng W, Zou G. CD44+/CD105+ human amniotic fluid mesenchymal stem cells survive and proliferate in the ovary long-term in a mouse model of chemotherapy-induced premature ovarian failure. Int J Med Sci. 2012;9(7):592–602.
    1. Xiao GY, Liu IH, Cheng CC, Chang CC, Lee YH, Cheng WTK, Wu SC. Amniotic fluid stem cells prevent follicle atresia and rescue fertility of mice with premature ovarian failure induced by chemotherapy. PLoS One. 2014;9(9):e106538–e106538.
    1. Su J, Ding L, Cheng J, Yang J, Li X, Yan G, et al. Transplantation of adipose-derived stem cells combined with collagen scaffolds restores ovarian function in a rat model of premature ovarian insufficiency. Hum Reprod. 2016;31:1075–1086.
    1. Wang Z, Wang Y, Yang T, Li J, Yang X. Study of the reparative effects of menstrual-derived stem cells on premature ovarian failure in mice. Stem Cell Res Ther. 2017;8(1):11–11.
    1. Lai D, Wang F, Yao X, Zhang Q, Wu X, Xiang C. Human endometrial mesenchymal stem cells restore ovarian function through improving the renewal of germline stem cells in a mouse model of premature ovarian failure. J Transl Med. 2015;13(1):155–155.
    1. Zhu SF, Hu HB, Xu HY, Fu XF, Peng DX, Su WY, et al. Human umbilical cord mesenchymal stem cell transplantation restores damaged ovaries. J Cell Mol Med. 2015;19:2108–2117.
    1. Elfayomy AK, Almasry SM, El-Tarhouny SA, Eldomiaty MA. Human umbilical cord blood-mesenchymal stem cells transplantation renovates the ovarian surface epithelium in a rat model of premature ovarian failure: possible direct and indirect effects. Tissue Cell. 2016;48(4):370–382.
    1. Adler DS, Lazarus H, Nair R, Goldberg JL, Greco NJ, Lassar T, et al. Safety and efficacy of bone marrow-derived autologous CD133+ stem cell therapy. Front Biosci (Elite Ed) 2011;3:506–514.
    1. Bongiovanni D, Bassetti B, Gambini E, Gaipa G, Frati G, Achilli F, et al. The CD133+ cell as advanced medicinal product for myocardial and limb ischemia. Stem Cells Dev. 2014;23(20):2403–2421.
    1. Ahmadi H, Baharvand H, Ashtiani SK, Soleimani M, Sadeghian H, Ardekani JM, et al. Safety analysis and improved cardiac function following local autologous transplantation of CD133(+) enriched bone marrow cells after myocardial infarction. Curr Neurovasc Res. 2007;4(3):153–160.
    1. Alvero R. Editorial: Challenging topics in reproductive endocrinology. Curr Opin Obstet Gynecol. 2020;32(5):359–360.
    1. Elkhenany HA, Szojka ARA, Mulet-Sierra A, Liang Y, Kunze M, Lan X, et al. Bone marrow mesenchymal stem cells-derived tissues are mechanically superior to meniscus cells. Tissue Eng Part A. 2020 ahead of print.
    1. Kasapoğlu I, Seli E. Mitochondrial dysfunction and ovarian aging. Endocrinology. 2020;161(2):bqaa001–bqaa001.
    1. Petryk N, Petryk M. Ovarian rejuvenation through platelet-rich autologous plasma (PRP)—a chance to have a baby without donor eggs, improving the life quality of women suffering from early menopause without synthetic hormonal treatment. Reprod Sci. 2020;27(11):1975–1982.
    1. Kawamura K, Kawamura N, Hsueh AJW. Activation of dormant follicles: a new treatment for premature ovarian failure? Curr Opin Obstet Gynecol. 2016;28(3):217–222.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe