Current possibilities of nonhormonal ovarian function activation with low ovarian reserve

DOI

https://dx.doi.org/10.18565/aig.2022.2.37-44

Dubinskaya E.D., Gasparov A.S., Krylova N.M., Dmitrieva N.V., Alyoshkina E.V., Ryazanova I.A.
RUDN University, Moscow, Russia

Patients with low ovarian reserve occupy a significant place in the pattern of an infertile marriage. Ovarian reserve is a clinical phenomenon caused by age, genetics, autoimmune mechanisms, and environmental factors. This term is used to describe the reproductive potential and to predict a response to controlled ovulation stimulation in assisted reproductive technology programs. According to a variety of data, the prevalence of low ovarian reserve varies from 5.6 to 35.1%. To date, little is known about the causes of diminished ovarian reserve and its risk factors except the iatrogenic factors associated with surgical intervention. From the clinical point of view, the low ovarian reserve group includes female patients with a poor ovarian response, those with premature ovarian failure, and late reproductive-aged women. Current strategies for controlled ovarian stimulation focus on growing follicles; in this case, dormant primordial follicles cannot be activated by the currently known stimulation protocols. The most successful outcome in patients with a poor response or ovarian insufficiency is pregnancy achieved using donor oocytes, but a large majority of the women think badly of these programs and are looking for alternative solutions. The literature review presents an update on the possibilities, features, and side effects of technologies for nonhormonal ovarian function activation with low ovarian reserve: autologous intraovarian platelet rich plasma (PRP) therapy, stem cell injections, and surgical ovarian activation.
Conclusion: Heterogeneity in study designs and data analysis does not yet allow the effectiveness of the technologies under consideration to be evaluated. For none of them, the exact mechanisms of action are still unknown. However, in our opinion, intraovarian PRP injection is the safest and most effective therapy. At the same time, the features of the technology and its effectiveness in various patient cohorts require further careful study.

infertility

low ovarian reserve

premature ovarian failure

poor response

late reproductive age

nonhormonal ovarian function stimulation

PRP therapy

Full text (in Russian)

Aghajanova L., Hoffman J., Mok-Lin E., Herndon C.N. Obstetrics and Gynecology Residency and Fertility Needs. Reprod. Sci. 2017; 24(3): 428-34. https://dx.doi.org/10.1177/1933719116657193.
Гаспаров А.С., Дубинская Е.Д., Титов Д.С., Лаптева Н.В. Клиническое значение овариального резерва в реализации репродуктивной функции. Акушерство и гинекология. 2014; 4: 11-6. [Gasparov A.S., Dubinskaya E.D., Titov D.S., Lapteva N.V. Clinical value of the ovarian reserve in reproductive function. Obstetrics and Gynecology. 2014; 4: 11-6. (in Russian)].
Подзолкова Н.М., Шамугия Н.Л., Борисова М.С., Аншина М.Б. Сравнение эффективности различных протоколов овариальной стимуляции у пациенток со сниженным овариальным резервом. Проблемы репродукции. 2019; 25(3): 91-8. [Podzolkova N.M., Shamugia N.L., Borisova M.S., Anshina M.B. Comparison of the effectiveness of various stimulation protocols in patients with reduced ovarian reserve. Russian Journal of Human Reproduction. 2019; 25(3): 91-8. (in Russian)]. https://dx,doi.org/10.17116/repro20192503191.
Tal R., Seifer D.B. Ovarian reserve testing: a user's guide. Am. J. Obstet. Gynecol. 2017; 217(2): 129-40. https://dx.doi.org/10.1016/j.ajog.2017.02.027.
Fan Y., Chang Y., Wei L., Chen J., Li J., Goldsmith S. et al. Apoptosis of mural granulosa cells is increased in women with diminished ovarian reserve. J. Assist. Reprod. Genet. 2019; 36(6): 1225-35. https://dx.doi.org/10.1007/s10815-019-01446-5.
Дубинская Е.Д., Гаспаров А.С., Колесникова С.Н., Холбан И.В., Бабичева И.А. Эпигенетика в клинической гинекологии. Вопросы гинекологии, акушерства и перинатологии. 2021; 20(2): 110-6. [Dubinskaya E.D., Gasparov A.S., Kolesnikova S.N., Kholban I.V., Babicheva I.A. Epigenetics in Clinical Gynecology. Vopr. ginekol. akus. perinatol. (Gynecology, Obstetrics and Perinatology). 2021; 20(2): 110-6. (in Russian)]. https://dx.doi.org/10.20953/1726-1678-2021-2-110-116.
Wang J., Liu W., Yu D., Yang Z., Li S., Sun X. Research progress on the treatment of premature ovarian failure using mesenchymal stem cells: a literature review. Front. Cell. Dev. Biol. 2021; 9: 749822. https://dx.doi.org/10.3389/fcell.2021.749822.
Cozzolino M., Marin D., Sisti G. New frontiers in IVF: mtDNA and autologous germline mitochondrial energy transfer. Reprod. Biol. Endocrinol. 2019; 17(1): 55. https://dx.doi.org/10.1186/s12958-019-0501-z.
Blumenfeld Z. What is the best regimen for ovarian stimulation of poor responders in ART/IVF? Front. Endocrinol. (Lausanne). 2020; 11: 192. https://dx.doi.org/10.3389/fendo.2020.00192.
Fàbregues F., Ferreri J., Méndez M., Calafell J.M., Otero J., Farré R. In Vitro follicular activation and stem cell therapy as a novel treatment strategies in diminished ovarian reserve and primary ovarian insufficiency. Front. Endocrinol. (Lausanne). 2021; 11: 617704. https://dx.doi.org/10.3389/fendo.2020.617704.
Herraiz S., Buigues A., Díaz-García C., Romeu M., Martínez S., Gómez-Seguí I., Simón C. et al. Fertility rescue and ovarian follicle growth promotion by bone marrow stem cell infusion. Ferti.l Steril. 2018; 109(5): 908-18.e2. https://dx.doi.org/10.1016/j.fertnstert.2018.01.004.
Jaseem M., Alungal S., Dhiyaneswaran, Shamsudeen J. Effectiveness of autologous PRP therapy in chronic nonhealing ulcer: A 2-year retrospective descriptive study. J. Family Med. Prim. Care. 2020; 9(6): 2818-22. https://dx.doi.org/10.4103/jfmpc.jfmpc_177_20.
Sánchez M., Beitia M., Pompei O., Jorquera C., Sánchez P., Knörr J. et al. Isolation, activation, and mechanism of action of platelet-rich plasma and its applications for joint repair. Submitted: September 9th 2019. Reviewed: November 18th 2019. Published: December 17th 2019. https://dx.doi.org/10.5772/intechopen.90543.
Machlus K.R., Italiano J.E. Jr. The incredible journey: From megakaryocyte development to platelet formation. J. Cell Biol. 2013; 201(6): 785-96. https://dx.doi.org/10.1083/jcb.201304054.
Gremmel T., Frelinger A.L., Michelson A.D. Platelet physiology. Semin. Thromb. Hemost. 2016; 42(3): 191-204. https://dx.doi.org/10.1055/s-0035-1564835.
Kim D.H., Je Y.J., Kim C.D., Lee Y.H., Seo Y.J., Lee J.H., Lee Y. Can platelet-rich plasma be used for skin rejuvenation? Evaluation of effects of platelet-rich plasma on human dermal fibroblast. Ann. Dermatol. 2011; 23(4): 424-31. https://dx.doi.org/10.5021/ad.2011.23.4.424.
Padilla S., Sánchez M., Orive G., Anitua E. Human-based biological and biomimetic autologous therapies for musculoskeletal tissue regeneration. Trends Biotechnol. 2017; 35(3): 192-202. https://dx.doi.org/10.1016/j.tibtech.2016.09.008.
Collins T., Alexander D., Barkatali B. Platelet-rich plasma: a narrative review. EFORT Open Rev. 2021; 6(4): 225-35. https://dx.doi.org/10.1302/2058-5241.6.200017.
Kikuchi N., Yoshioka T., Taniguchi Y., Sugaya H., Arai N., Kanamori A., Yamazaki M. Optimization of leukocyte-poor platelet-rich plasma preparation: a validation study of leukocyte-poor platelet-rich plasma obtained using different preparer, storage, and activation methods. J. Exp. Orthop. 2019; 6(1): 24. https://dx.doi.org/10.1186/s40634-019-0190-8.
Anitua E., Nurden P., Prado R., Nurden A.T., Padilla S. Autologous fibrin scaffolds: When platelet- and plasma-derived biomolecules meet fibrin. Biomaterials. 2019; 192: 440-60. https://dx.doi.org/10.1016/j.biomaterials.2018.11.029.
Bakacak M., Bostanci M.S., İnanc F., Yaylali A., Serin S., Attar R. et al. Protective effect of platelet rich plasma on experimental ischemia/reperfusion injury in rat ovary. Gynecol. Obstet. Invest. 2016; 81(3): 225-31. https://dx.doi.org/10.1159/000440617.
Quintana R., Kopcow L., Sueldo C., Marconi G., Rueda N.G., Barañao R.I. Direct injection of vascular endothelial growth factor into the ovary of mice promotes follicular development. Fertil. Steril. 2004; 82(Suppl. 3): 1101-5. https://dx.doi.org/10.1016/j.fertnstert.2004.03.036.
Panda S.R., Sachan S., Hota S. A systematic review evaluating the efficacy of intra-ovarian infusion of autologous platelet-rich plasma in patients with poor ovarian reserve or ovarian insufficiency. Cureus. 2020; 12(12): e12037. https://dx.doi.org/10.7759/cureus.12037.
Дубинская Е.Д., Гаспаров А.С., Дмитриева Н.В., Крылова Н.М. Интраовариальная аутоплазмотерапия у пациенток с низким овариальным резервом. Вопросы гинекологии, акушерства и перинатологии. 2021; 20(6): 72-80. [Dubinskaya E.D., Gasparov A.S., Dmitrieva N.V., Krylova N.M. Intraovarian autoplasmotherapy in patients with low ovarian reserve. Issues of gynecology, obstetrics and perinatology. 2021; 20(6): 72-80. (in Russian)]. https://dx.doi.org/10.20953/1726-1678-2021-6-72-80.
Sfakianoudis K., Rapani A., Grigoriadis S., Retsina D., Maziotis E., Tsioulou P. et al. Novel approaches in addressing ovarian insufficiency in 2019: Are We There Yet? Cell Transplant. 2020; 29: 963689720926154. https://dx.doi.org/10.1177/0963689720926154.
Cervelló I., Gil-Sanchis C., Santamaría X., Cabanillas S., Díaz A., Faus A. et al. Human CD133(+) bone marrow-derived stem cells promote endometrial proliferation in a murine model of Asherman syndrome. Fertil. Steril. 2015; 104(6): 1552-60.e1-3. https://dx.doi.org/10.1016/j.fertnstert.2015.08.032.
Herraiz S., Romeu M., Buigues A., Martínez S., Díaz-García C., Gómez-Seguí I. et al. Autologous stem cell ovarian transplantation to increase reproductive potential in patients who are poor responders. Fertil. Steril. 2018; 110(3):496-505.e1. https://dx.doi.org/10.1016/j.fertnstert.2018.04.025.
Mirzaei H., Sahebkar A., Sichani L.S., Moridikia A., Nazari S., Sadri Nahand J. et al. Therapeutic application of multipotent stem cells. J. Cell. Physiol. 2018; 233(4): 2815-23. https://dx.doi.org/10.1002/jcp.25990.
Murphy M.B., Moncivais K., Caplan A.I. Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine. Exp. Mol. Med. 2013; 45(11): e54. https://dx.doi.org/10.1038/emm.2013.94.
Liu J., Zhang H., Zhang Y., Li N., Wen Y., Cao F. et al. Homing and restorative effects of bone marrow-derived mesenchymal stem cells on cisplatin injured ovaries in rats. Mol. Cells. 2014; 37(12): 865-72. https://dx.doi.org/10.14348/molcells.2014.0145.
Sanders J.E., Hawley J., Levy W., Gooley T., Buckner C.D., Deeg H.J. et al. Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Blood. 1996; 87(7): 3045-52.
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. https://dx.doi.org/10.1186/s13287-018-1008-9.
Sfakianoudis K., Simopoulou M., Nitsos N., Rapani A., Pappas A., Pantou A. et al. Autologous platelet-rich plasma treatment enables pregnancy for a woman in premature menopause. J. Clin. Med. 2018; 8(1): 1. https://dx.doi.org/10.3390/jcm8010001.
Yoon S.Y. Mesenchymal stem cells for restoration of ovarian function. Clin. Exp. Reprod. Med. 2019; 46(1): 1-7. https://dx.doi.org/10.5653/cerm.2019.46.1.1.
Lee H.N., Chang E.M. Primordial follicle activation as new treatment for primary ovarian insufficiency. Clin. Exp. Reprod. Med. 2019; 46(2): 43-9. https://dx.doi.org/10.5653/cerm.2019.46.2.43.
Hsueh A.J., Kawamura K., Cheng Y., Fauser B.C. Intraovarian control of early folliculogenesis. Endocr. Rev. 2015; 36(1):1-24. https://dx.doi.org/10.1210/er.2014-1020.
Dolmans M.M., Cordier F., Amorim C.A., Donnez J., Vander Linden C. In vitro activation prior to transplantation of human ovarian tissue: Is it truly effective? Front. Endocrinol. (Lausanne). 2019; 10: 520. https://dx.doi.org/10.3389/fendo.2019.00520.
Hsueh A.J.W., Kawamura K. Hippo signaling disruption and ovarian follicle activation in infertile patients. Fertil. Steril. 2020; 114(3): 458-64. https://dx.doi.org/10.1016/j.fertnstert.2020.07.031.
Ingber D.E. Tensegrity: the architectural basis of cellular mechanotransduction. Annu. Rev. Physiol. 1997; 59: 575-99. https://dx.doi.org/10.1146/annurev.physiol.59.1.575.
Hergovich A. Mammalian Hippo signalling: a kinase network regulated by protein-protein interactions. Biochem. Soc. Trans. 2012; 40(1): 124-8. https://dx.doi.org/10.1042/BST20110619.
Lunding S.A., Pors S.E., Kristensen S.G., Landersoe S.K., Jeppesen J.V., Flachs E.M. et al. Biopsying, fragmentation and autotransplantation of fresh ovarian cortical tissue in infertile women with diminished ovarian reserve. Hum. Reprod. 2019; 34(10): 1924-36. https://dx.doi.org/10.1093/humrep/dez152.
Kawamura K., Kawamura N., Hsueh A.J. Activation of dormant follicles: a new treatment for premature ovarian failure? Curr. Opin. Obstet. Gynecol. 2016; 28(3): 217-22. https://dx.doi.org/10.1097/GCO.0000000000000268.
Griesinger G., Fauser B.C.J.M. Drug-free in-vitro activation of ovarian cortex; can it really activate the 'ovarian gold reserve'? Reprod. Biomed. Online. 2020; 40(2):187-9. https://dx.doi.org/10.1016/j.rbmo.2020.01.012.
Адамян Л.В., Дементьева В.О., Асатурова А.В. Новое в репродуктивной хирургии: одноэтапный хирургический метод активации функции яичников. Акушерство и гинекология. 2019; 3: 147-51. [Adamyan L.V., Dementyeva V.O., Asaturova A.V. New technique in reproductive surgery: one-step surgical procedure for ovarian function activation (first clinical observation). Obstetrics and Gynecology. 2019; 3: 147-51. (in Russian)]. https://dx.doi.org/10.18565/aig.2019.3.147-151.
Kawamura K., Ishizuka B., Hsueh A.J.W. Drug-free in-vitro activation of follicles for infertility treatment in poor ovarian response patients with decreased ovarian reserve. Reprod. Biomed. Online. 2020; 40(2): 245-53. https://dx.doi.org/10.1016/j.rbmo.2019.09.007.
Ferreri J., Fàbregues F., Calafell J.M., Solernou R., Borrás A., Saco A. et al. Drug-free in-vitro activation of follicles and fresh tissue autotransplantation as a therapeutic option in patients with primary ovarian insufficiency. Reprod. Biomed. Online. 2020; 40(2): 254-60. https://dx.doi.org/10.1016/j.rbmo.2019.11.009.
Luongo F., Colonna F., Calapà F., Vitale S., Fiori M.E., De Maria R. PTEN tumor-suppressor: the dam of stemness in cancer. Cancers (Basel). 2019; 11(8): 1076. https://dx.doi.org/10.3390/cancers11081076.
Dvorská D., Braný D., Nagy B., Grendár M., Poka R., Soltész B. et al. Aberrant methylation status of tumour suppressor genes in ovarian cancer tissue and paired plasma samples. Int. J. Mol. Sci. 2019; 20(17): 4119. https://dx.doi.org/10.3390/ijms20174119.

Received 21.01.2022

Accepted 25.01.2022

Ekaterina D. Dubinskaya, Dr. Med. Sci., Professor of the Department of Obstetrics and Gynecology with a Course of Perinatology, RUDN University, +7(903)117-55-58,
eka-dubinskaya@yandex.ru, https://orcid.org/0000-0002-8311-0381, 117198, Russia, Moscow, Miklukho-Maklaya str., 8.
Alexander S. Gasparov, Dr. Med. Sci., Professor of the Department of Obstetrics, Gynecology and Reproductive Medicine, Faculty of Continuous Medical Education,
RUDN University, +7(499)450-35-87, 5454444@mail.ru, https://orcid.org/0000-0001-6301-1880, 117198, Russia, Moscow, Miklukho-Maklaya str., 8.
Nadezhda M. Krylova, Assistant at the Department of Obstetrics, Gynecology and Reproductive Medicine, Faculty of Continuing Medical Education, RUDN University, +7(915)421-29-40, Leonad2009@yandex.ru, 117198, Russia, Moscow, Miklukho-Maklaya str., 8.
Natalya V. Dmitrieva, Ph.D., reproductologist at the Clinic "I am healthy", Researcher at the clinical base of the Department of Obstetrics, Gynecology and Reproductive Medicine, RUDN University, +7(903)748-96-26, dmitrieva-doc@yandex.ru, 117198, Russia, Moscow, Miklukho-Maklaya str., 8.
Elizaveta V. Alyoshkina, Assistant of the Department of Obstetrics, Gynecology and Reproductive Medicine, Faculty of Continuing Medical Education, RUDN University, +7(926)768-44-27, alyoshkina.ev@yandex.ru, 117198, Russia, Moscow, Miklukho-Maklaya str., 8.
Irina A. Ryazanova, Assistant of the Department of Obstetrics, Gynecology and Reproductive Medicine, Faculty of Continuing Medical Education, RUDN University, +7(926)417-05-22, irina.ryazanova.doc@yandex.ru, 117198, Russia, Moscow, Miklukho-Maklaya str., 8.

Authors’ contributions: Dubinskaya E.D., Gasparov A.S. – development of the concept and design of the investigation, analysis of the findings, editing; Krylova N.M., Dmitrieva N.V., Alyoshkina E.V., Ryazanova I.A. – data collection, writing the text of the article.
Conflicts of interest: The authors declare that there are no conflicts of interest.
Funding: The investigation has not been sponsored.
For citation: Dubinskaya E.D., Gasparov A.S., Krylova N.M.,
Dmitrieva N.V., Alyoshkina E.V., Ryazanova I.A.
Current possibilities of nonhormonal ovarian function activation with low ovarian reserve.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2022; 2: 37-44 (in Russian)
https://dx.doi.org/10.18565/aig.2022.2.37-44

Current possibilities of nonhormonal ovarian function activation with low ovarian reserve

Dubinskaya E.D., Gasparov A.S., Krylova N.M., Dmitrieva N.V., Alyoshkina E.V., Ryazanova I.A.

Keywords

References

About the Authors

Similar Articles