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Table of Contents
Year : 2021  |  Volume : 4  |  Issue : 1  |  Page : 1-3

Application of regenerative medicine in cancer-related endometrial damage

Department of Reproductive Medicine, Mother and Child Hospital, New Delhi, India

Date of Submission31-Oct-2021
Date of Acceptance31-Oct-2021
Date of Web Publication17-Dec-2021

Correspondence Address:
Dr. Nalini Kaul
Department of Reproductive Medicine, Mother and Child Hospital, D-64, Defence Colony, New Delhi 110024.
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2589-9597.332641

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How to cite this article:
Kaul N. Application of regenerative medicine in cancer-related endometrial damage. Onco Fertil J 2021;4:1-3

How to cite this URL:
Kaul N. Application of regenerative medicine in cancer-related endometrial damage. Onco Fertil J [serial online] 2021 [cited 2023 Mar 29];4:1-3. Available from: https://www.tofjonline.org/text.asp?2021/4/1/1/332641

In recent years, the emergence of regenerative medicine has added a new dimension to fertility treatments. Regenerative therapies aim at repairing and rejuvenating tissue/organs affected by disease or the aging process. Though the full clinical potential is still to be realized, regenerative medicine offers hope to women with refractory endometrium and premature ovarian insufficiency.

Endometrial receptivity is pivotal for embryo implantation, and endometrial thickness is used as a prognostic marker of endometrial receptivity in in-vitro fertilization (IVF) cycles. Thin endometrium, defined as an endometrium less than 7 mm in thickness on the day of LH surge, is associated with implantation failure and reproductive loss. Endometrial damage caused by chronic infections such as genital tuberculosis and surgical procedures, such as repeated and extensive curettage, destroy the basal endometrial layer leading to varying degrees of intrauterine adhesions (Asherman’s syndrome, AS) and consequently a thin endometrial lining. Cancer treatment is also an important cause of thin endometrium. Radiotherapy to the pelvis leads to vascular damage and fibrosis of the uterus, and in endometrial cancer, repeated curettage and prolonged progestational therapy damage the basal endometrium. The management of a thin endometrium has remained a challenge despite the many therapeutic choices offered. Two promising regenerative therapies leveraging the body’s innate healing response[1] have emerged in recent years for endometrial regeneration. These are an intrauterine infusion of platelet-rich plasma (PRP) and the use of stem cells.

The bilayered human endometrium exhibits an immense capacity to regenerate. The functional layer of the endometrium is shed at menstruation, and subsequent growth and differentiation occur from the basal endometrial layer under the influence of estrogen and progesterone.[2] Endometrial stem cells are involved in the regeneration and repair of the endometrium through direct differentiation or paracrine effects. Endometrial stem/progenitor cells have been identified in the basal and functional layers of the endometrium.[3] Damage to the basal endometrial layer during surgery or infections may lead to damage of these cells. Though stem cells can survive without estrogen, stem-cell niches that provide the microenvironment and direction for stem-cell growth and differentiation require estrogen to activate them.[4] The stem-cell niche in the endometrium is proposed to be around the spiral arteries.[5]

Adult stem cells derived from menstrual blood,[6] bone marrow (BM),[7] umbilical cord,[8] and adipose tissue[9] have exhibited a potential to regenerate endometrium and have been used in patients with AS or refractory endometrium. It is possible that stem cell-mediated paracrine factors participate in endometrial proliferation by activating stem-cell niches, promoting angiogenesis and immunomodulation. The delivery of the prepared stem-cell concentrate is carried out via the selective catheterization of the uterine artery and then the spiral arteriole under radiological control, using the femoral route. Direct insertion into the uterine cavity has also been advocated; however, the former route is deemed to be more effective.[10] The efficacy and viability of stem cells have been enhanced by the use of tissue engineering using scaffolds.[8]

In the field of oncofertility, however, the use of stem cells for endometrial regeneration has not received adequate attention.[11] The use of high-dose estrogen therapy to treat thin endometrium[12] may be risky in survivors of endometrial cancer as it can increase the risk of recurrence. The important question to address here is whether it is safe to consider the use of stem cells in cancer survivors. There is a controversy regarding the role of stem cells in tumor progression. Some authors have reported that mesenchymal stem cells (MSCs) can inhibit tumor growth and angiogenesis by regulating the immune environment via paracrine factors, whereas others have shown that a multipotent population of stem cells can promote tumor growth and induce therapy resistance.[11] Cao et al. (2018)[8] reported on clinical trials using MSCs from different tissues for endometrial regeneration in AS and endometrial atrophy. There was no tumorigenicity reported in any of these studies. It has been suggested that endometrial regeneration may depend partly on the recruitment of BM-derived cells (BMDCs), which are then differentiated into nonhematopoietic endometrial cells. Freshly isolated MSCs and endothelial progenitor cells along with BMDC hypoblast-like stem cells induced the maximum degree of endometrial regeneration in mice given nonlethal irradiation.[13] This suggests that the contribution of BMDCs for endometrial regeneration may be important and could be used potentially to regenerate the endometrium after radiotherapy damage. There is an urgent need to develop safe and effective techniques to treat damaged endometrium, especially in cancer survivors. If the safety and effectiveness of stem-cell therapy can be established, it would go a long way in improving the menstrual function and reproductive capability of these patients.

Another regenerative therapy that is generating interest is the intrauterine infusion of autologous PRP. PRP has been used in several branches of medicine, starting with dermatology and orthopedics, because of its ability to promote tissue healing and regeneration. Platelets when activated excrete several growth factors and cytokines that are associated with healing and regeneration and also have an antimicrobial activity. These include transforming growth factor-beta, fibroblast growth factor, insulin-like growth factors 1 and 2, vascular endothelial growth factor, and epidermal growth factor.[14],[15] Autologous PRP is obtained by centrifuging blood obtained from the individual and separating the pellet of platelets.[16] This platelet concentrate is then delivered directly into the uterine cavity via a catheter. Tissue reparative efficacy with PRP can be expected with a platelet concentrate that has five to 10 times the normal concentration of platelets.[17] Platelet concentration <1,000 × 106/mL is not reliable for enhancing wound healing (Marx RE 2001). The ideal concentration and exact mechanism of action remain to be defined. Intrauterine PRP administration has added a new dimension to the treatment of refractory endometrium. It is being used extensively in IVF clinics because of the ease of preparation and administration. Encouraging results have been shown in various studies, not only on endometrial thickness but also on implantation. Safety will always remain a concern in oncofertility patients as one is introducing a concentrate of growth factors, which might result in the reactivation of the disease.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Kami D, Gojo S. Tuning cell fate: From insights to vertebrate regeneration. Organogenesis 2014;10:231-40.  Back to cited text no. 1
Spencer TE, Hayashi K, Hu J, Carpenter KD. Comparative developmental biology of the mammalian uterus. Curr Top Dev Biol 2005;68:85-122.  Back to cited text no. 2
Gargett CE, Schwab KE, Deane JA. Endometrial stem/progenitor cells: The first 10 years. Hum Reprod Update 2016;22:137-63.  Back to cited text no. 3
Gargett CE, Nguyen HP, Ye L. Endometrial regeneration and endometrial stem/progenitor cells. Rev Endocr Metab Disord 2012;13:235-51.  Back to cited text no. 4
Cervelló I, Gil-Sanchis C, Santamaría X, Faus A, Vallvé-Juanico J, Díaz-Gimeno P, et al. Leucine-rich repeat-containing G-protein-coupled receptor 5-positive cells in the endometrial stem cell niche. Fertil Steril 2017;107:510-9.e3.  Back to cited text no. 5
Ma H, Liu M, Li Y, Wang W, Yang K, Lu L, et al. Intrauterine transplantation of autologous menstrual blood stem cells increases endometrial thickness and pregnancy potential in patients with refractory intrauterine adhesion. J Obstet Gynaecol Res 2020;46:2347-55.  Back to cited text no. 6
Santamaria X, Cabanillas S, Cervelló I, Arbona C, Raga F, Ferro J, et al. Autologous cell therapy with CD133+ bone marrow-derived stem cells for refractory Asherman’s syndrome and endometrial atrophy: A pilot cohort study. Hum Reprod 2016;31:1087-96.  Back to cited text no. 7
Cao Y, Sun H, Zhu H, Zhu X, Tang X, Yan G, et al. Allogeneic cell therapy using umbilical cord MSCs on collagen scaffolds for patients with recurrent uterine adhesion: A phase I clinical trial. Stem Cell Res Ther 2018;9:192.  Back to cited text no. 8
Lee SY, Shin JE, Kwon H, Choi DH, Kim JH. Effect of autologous adipose-derived stromal vascular fraction transplantation on endometrial regeneration in patients of Asherman’s syndrome: A pilot study. Reprod Sci 2020;27:561-8.  Back to cited text no. 9
Liu Y, Tal R, Pluchino N, Mamillapalli R, Taylor HS. Systemic administration of bone marrow-derived cells leads to better uterine engraftment than use of uterine-derived cells or local injection. J Cell Mol Med 2018;22:67-76.  Back to cited text no. 10
Lv Q, Wang L, Luo X, Chen X. Adult stem cells in endometrial regeneration: Molecular insights and clinical applications. Mol Reprod Dev 2021;88:379-94.  Back to cited text no. 11
Evans J, Salamonsen LA, Winship A, Menkhorst E, Nie G, Gargett CE, et al. Fertile ground: Human endometrial programming and lessons in health and disease. Nat Rev Endocrinol 2016;12:654-67.  Back to cited text no. 12
Gil-Sanchis C, Cervello I, Khurana S, Faus A, Verfaillie C, Simon C. Contribution of different bone marrow-derived cell types in endometrial regeneration using an irradiated murine model. Fertil Steril 2015;103:1596-605.  Back to cited text no. 13
Aghajanova L, Houshdaran S, Balayan S, Manvelyan E, Irwin JC, Huddleston HG, et al. In vitro evidence that platelet-rich plasma stimulates cellular processes involved in endometrial regeneration. J Assist Reprod Genet 2018;35:757-70.  Back to cited text no. 14
Ferrari AR, Cortrezzi S, Borges E Jr, Braga D, Souza MDCB, Antunes RA. Evaluation of the effects of platelet-rich plasma on follicular and endometrial growth: A literature review. JBRA Assist Reprod 2021;25:601-7.  Back to cited text no. 15
Dawood AS, Salem HA. Current clinical applications of platelet-rich plasma in various gynecological disorders: An appraisal of theory and practice. Clin Exp Reprod Med 2018;45:67-74.  Back to cited text no. 16
Sharara FI, Lelea LL, Rahman S, Klebanoff JS, Moawad GN. A narrative review of platelet-rich plasma (PRP) in reproductive medicine. J Assist Reprod Genet 2021;38:1003-12.  Back to cited text no. 17


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