Intraovarian insertion of autologous platelet growth factors as cell-free concentrate: Fertility recovery and first unassisted conception with term delivery at age over 40

Abstract

Background: The use of autologous platelet-rich plasma as an ovarian treatment has not been standardized and remains controversial.


Case Presentation: A 41½-year old woman with diminished ovarian reserve (serum anti- Müllerian hormone = 0.163 mg/mL) and a history of 10 unsuccessful in vitro fertilization cycles presented for reproductive endocrinology consult. She and her partner declined donor oocyte in vitro fertilization. They were both in good general health and laboratory tests were unremarkable, except for mild thrombocytosis (platelets = 386K; normal range 150-379K) discovered in the female. The patient underwent intraovarian injection of fresh platelet-derived growth factor concentrate administered as an enriched cell-free substrate. Serum anti- Müllerian hormone increased by 115% within 6 wks of treatment. Spontaneous ovulation occurred the month after injection and subsequently the serum human chorionic gonadotropin was noted at 804 mIU/mL. Following an uneventful obstetrical course, a male infant was delivered at term without complication.


Conclusion: This is the first description of intraovarian injection of enriched platelet-derived growth factors followed by unassisted pregnancy and live birth. As a refinement of conventional ovarian platelet-rich plasma therapy, this procedure may be particularly valuable for refractory cases where prognosis for pregnancy appears especially bleak. A putative role for thrombocytosis is also viewed in parallel with mechanisms of action as advanced earlier. With continued experience in ovarian application of autologous platelet growth factors, additional research will evaluate laboratory protocol/sample preparation, injection technique, and patient selection.


Key words: Ovarian rejuvenation, Platelet-rich plasma, Cytokines, Infertility, IVF.

References
[1] Lefebvre J, Antaki R, Kadoch IJ, Dean NL, Sylvestre C, Bissonnette F, et al. 450 IU versus 600 IU gonadotropin for controlled ovarian stimulation in poor responders: A randomized controlled trial. Fertil Steril 2015; 104: 1419– 1425.

[2] Ghahremani-Nasab M, Ghanbari E, Jahanbani Y, Mehdizadeh A, Yousefi M. Premature ovarian failure and tissue engineering. J Cell Physiol 2020; 235: 4217–4226.

[3] Sills ES, Brady AC, Omar AB, Walsh DJ, Salma U, Walsh APH. IVF for premature ovarian failure: first reported births using oocytes donated from a twin sister. Reprod Biol Endocrinol 2010; 8: 31–33.

[4] Pantos K, Nitsos N, Kokkali G, Vaxevanoglou T, Markomichali C, Pantou A, et al. Ovarian rejuvenation and folliculogenesis reactivation in peri-menopausal women after autologous platelet-rich plasma treatment. Hum Reprod 2016 (Suppl.): P–401.

[5] Sills ES, Rickers NS, Li X, Palermo GD. First data on in vitro fertilization and blastocyst formation after intraovarian injection of calcium gluconate-activated autologous platelet rich plasma. Gynecol Endocrinol 2018; 34: 756–760.

[6] Sfakianoudis K, Simopoulou M, Nitsos N, Rapani A, Pantou A, Vaxevanoglou T, et al. A case series on plateletrich plasma revolutionary management of poor responder patients. Gynecol Obstet Invest 2019; 84: 99–106.

[7] Sills ES, Rickers NS, Svid Ch, Rickers JM, Wood SH. Normalized ploidy following 20 consecutive blastocysts with chromosomal error: Healthy 46,XY pregnancy with IVF after intraovarian injection of autologous enriched platelet-derived growth factors. Int J Mol Cell Med 2019; 8: 84–90.

[8] Sills ES, Rickers NS, Petersen JL, Li X, Wood SH. Regenerative effect of intraovarian injection of autologous platelet rich plasma: Serum anti-Mullerian hormone levels measured among poor-prognosis in vitro fertilization patients. Int J Regen Med 2020; 3: 1–5.

[9] Steller D, Herbst N, Pries R, Juhl D, Hakim SG. Impact of incubation method on the release of growth factors in non- Ca2+-activated PRP, Ca2+-activated PRP, PRF and A-PRF. J Craniomaxillofac Surg 2019; 47: 365–372.

[10] Théry C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol 2006; 30: 302201–3022029.

[11] Guo ShCh, Tao ShC, Yin WJ, Qi X, Yuan T, Zhang ChQ. Exosomes derived from platelet-rich plasma promote the re-epithelization of chronic cutaneous wounds via activation of YAP in a diabetic rat model. Theranostics 2017; 7: 81–96.

[12] Marron KD, Sills ES, Cummins PL, Harrity C, Walsh DJ, Walsh AP. Impact of pre-mixing AMH serum samples with standard assay buffer: Ovarian reserve estimations and implications for clinical IVF providers. J Reprod Endocrinol Infertil 2016; 2: 10.

[13] Rosenwaks Z, Navot D, Veeck L, Liu HC, Steingold K, Kreiner D, et al. Oocyte donation. The Norfolk program. Ann N Y Acad Sci 1988; 541: 728–741.

[14] Sauer MV, Paulson RJ, Lobo RA. Reversing the natural decline in human fertility: An extended clinical trial of oocyte donation to women of advanced reproductive age. JAMA 1992; 268: 1275–1279.

[15] Gu Y, Xu Y. Successful spontaneous pregnancy and live birth in a woman with premature ovarian insufficiency and 10 years of amenorrhea: A case report. Front Med 2020; 7: 18.

[16] Sills ES, Wood SH. Autologous activated platelet-rich plasma injection into adult human ovary tissue: Molecular mechanism, analysis, and discussion of reproductive response. Biosci Rep 2019; 39: pii: BSR20190805. 1–15.

[17] Johnson J, Canning J, Kaneko T, Pru JK, Tilly JL. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature 2004; 428: 145–150.

[18] Zhang S, Li P, Yuan Zh, Tan J. Effects of platelet-rich plasma on activity of human menstrual blood-derived stromal cells in vitro. Stem Cell Res Ther 2018; 48: 1–11.

[19] Zhang S, Li P, Yuan Zh, Tan J. Platelet-rich plasma improves therapeutic effects of menstrual blood-derived stromal cells in rat model of intrauterine adhesion. Stem Cell Res Ther 2019; 61: 1–12.

[20] Wood SH, Sills ES. Intraovarian vascular enhancement by stromal injection of platelet-derived growth factors: Exploring subsequent oocyte chromosomal status and IVF outcomes. Clin Exp Reprod Med 2020; 47: 94–100.

[21] Marschalek J, Ott J, Aitzetmueller M, Mayrhofer D, Weghofer A, Nouri K, et al. The impact of repetitive oocyte retrieval on the ovarian reserve: a retrospective cohort study. Arch Gynecol Obstet 2019; 299: 1495–1500.

[22] Hatırnaz Ş, Tan SL, Hatırnaz E, Çelik Ö, Kanat-Pektaş M, Dahan MH. Vaginal ultrasound-guided ovarian needle puncture compared to laparoscopic ovarian drilling in women with polycystic ovary syndrome. Arch Gynecol Obstet 2019; 299: 1475–1480.