{"paper_id":"13c314d1-e941-476a-8499-328b999ceb0d","body_text":"841\nEvaluating the Efficacy of Autologous Blood Cell \nDerivative Growth Factor Concentrate-(Abcd-\nEndosera) in Enhancing Endometrial Thickness and \nLive Birth Rates in Patients with Refractory Thin \nEndometrium\nThis work is licensed under Creative Commons Attribution 4.0 License  AJBSR.MS.ID.003026.\nAmerican Journal of\nBiomedical Science & Research\nwww.biomedgrid.com\n---------------------------------------------------------------------------------------------------------------------------------\nMala Raj1#, Shrinivas Chari2# and Vasanthi Palanivel2#*\n1FIRM HOSPITALS, No.65, R-Block, 12th Street, Anna Nagar, Chennai-600 040, India\n2Seragen Biotherapeutics Pvt Ltd, WFF4, Bangalore Bio innovation Centre, Helix Biotech Park, Electronics City Phase 1, Bangalore, Karnataka 560100, \nIndia \n#These authors contributed equally to this work.\n*Corresponding author: Vasanthi Palanivel, Seragen Biotherapeutics Private Limited, WFF4, Bangalore Bioinnovation Centre, Helix Biotech Park, \nElectronics City Phase 1, Bangalore, Karnataka 560100, India.\nTo Cite This Article: Mala Raj, Shrinivas Chari and Vasanthi Palanivel*. Evaluating the Efficacy of Autologous Blood Cell Derivative Growth \nFactor Concentrate-(Abcd-Endosera) in Enhancing Endometrial Thickness and Live Birth Rates in Patients with Refractory Thin Endometrium. \nAm J Biomed Sci & Res. 2024  22(6) AJBSR.MS.ID.003026, DOI: 10.34297/AJBSR.2024.22.003026\nReceived: \n   June 08, 2024;  Published: \n   June 14, 2024\nResearch Article                                                                            Copyright© Vasanthi Palanivel\nISSN: 2642-1747\n \nAbstract\nObjective: To evaluate the efficacy of ABCD-Endosera derived from platelets in enhancing endometrial thickness and live birth \nrates among patients with thin endometrium.\nMethods: This self-controlled pilot study included 50 patients with a history of refractory thin endometrium and minimum \nthree cycle cancellations due to this condition. Participants underwent intrauterine infusions of autologous growth factors ABCD-\nEndosera in their current cycle and were compared to their previous cycle without ABCD-Endosera treatment. \nResults: The endometrial thickness before the treatment was 6.6 mm (±1.1) significantly increased to 8.2 mm (±0.9) on the day \nof embryo transfer with a mean increase of 1.6 mm. Secondary outcomes indicated that embryo transfer was carried out in 94% \n(47/50) of the patients, with 4% (2/50) experiencing cycle cancellation, and 2% (1/50) lost to follow up. The clinical pregnancy \nrate stood at 50% (25/50), while 44% (22/50) did not result in pregnancy. One patient (2%, 1/50) had a biochemical pregnancy, \nand three patients (6%, 3/50) experienced a miscarriage. The live birth rate was 42% (21/50). The procedure was well tolerated \nwithout severe adverse events. \nConclusions: Our findings suggest that ABCD-Endosera significantly improves endometrial thickness and shows promising live \nbirth rates in patients with refractory thin endometrium. This pilot study provides a foundation for future larger trials, suggesting \nABCD- Endosera could offer a viable treatment strategy for patients with thin endometrium seeking successful pregnancies and live \nbirths.\n\n\nAmerican Journal of Biomedical Science & Research\nAm J Biomed Sci & Res                                     Copyright© Vasanthi Palanivel\n842\nPlain Language Summary\nThis study evaluated the effectiveness of a new treatment called \nABCD-Endosera in women with thin endometrium. Thin endome -\ntrium is a condition in which the lining of the uterus is too thin, \nwhich can make it difficult to get pregnant. Fifty women with thin \nendometrium were included in the study. They received intrauter -\nine infusions of ABCD-Endosera, which is a mixture of growth fac -\ntors derived from platelets. The researchers compared the women’s \nendometrial thickness and pregnancy outcomes to their previous \ncycles without ABCD-Endosera treatment. The results showed that \nABCD-Endosera significantly increased endometrial thickness. Of \nthe 50 women, 47 were able to have embryo transfers. The clini -\ncal pregnancy rate was 50%, and the live birth rate was 42%. The \nresearchers concluded that ABCD-Endosera is a safe and effective \ntreatment for women with thin endometrium. It significantly im -\nproves endometrial thickness and shows promising live birth rates. \nIntroduction\nThe human endometrium, which undergoes numerous cycles \nof growth, differentiation, and detachment throughout a woman’s \nlife, plays a crucial role in providing the site for embryo implanta -\ntion and sustaining the normal development and survival of the em-\nbryo. Assisted Reproductive Technologies (ART) heavily rely on the \nsuccessful implantation of a genetically normal embryo within a re-\nceptive endometrium, the innermost epithelial layer lining the uter-\nus. Thin endometrium is a significant cause of implantation failure \nand recurrent pregnancy loss in Assisted Reproductive Technology \n(ART) treatments [1,2]. A morphologically normal endometrium is \na critical factor for the success of ART programs. Current data sug -\ngests that 50% to 66% of implantation failures are linked to inad -\nequate endometrial receptivity. An optimal endometrial thickness \nfor embryo transfer is considered to be 7mm or more [3,4]. A thick-\nness less than 7mm, known as thin endometrium, often results in \nreduced implantation, early-stage miscarriages, premature births, \nlow birth weight infants, and failures in ART programs. Over the \nyears, numerous methods, such as hormonal manipulation through \nextended estrogen dosing or enhancement of endometrial perfu -\nsion via low dose aspirin, pentoxifylline, vitamin E, sildenafil, and \nGranulocyte colony-stim-ulating factor (G-CSF), have been em -\nployed to achieve optimal endometrial thickness. Nevertheless, not \nall thin endometrium cases have demonstrated improvements with \nthese methods. Some studies have reported improved Endometrial \nThickness (ET) following intrauterine Platelet-Rich Plasma (PRP) \nadministration [5,6].\nIn recent years, Platelet-Rich Plasma (PRP) has been investi -\ngated as a potential therapy to improve endometrial thickness and \nreproductive outcomes in women with thin endometrium and the \nconcept of using PRP for in vivo treatment of human thin endome -\ntrium was first introduced in 2015 [7]. PRP represents a promising \nand emerging trend in the field of regenerative and reproductive \nmedicine, particularly for thin endometrium treatment, thereby \ngarnering the interest of IVF specialists. The method involves the \nconcentration of platelets in plasma at a level exceeding that found \nin whole blood which release various growth factors and cytokines  \n \nupon activation, promoting tissue repair and regeneration [8]. \nThe efficacy of this method is attributed to the biologically active \ngrowth factors secreted by platelets, including pro-regenerative, \nproliferative, angiogenic, chemotactic, anti-inflammatory, and an -\nti-apoptotic activities. PRP is rich in growth factors such as vascular \nendothelial Growth Factor (VEGF), Epidermal Growth Factor (EGF), \nPlatelet-Derived Growth Factor (PDGF), Insulin-Like Growth Factor \n(IGF), Transforming Growth Factor (TGF), and other cytokines that \nstimulate proliferation and growth [9,10]. The use of growth fac -\ntors has shown promise in various medical fields, such as wound \nhealing, orthopedics, and dentistry, where they have been used to \npromote tissue regeneration and repair [11]. This evidence sup -\nports the potential therapeutic application of growth factors in the \ntreatment of thin endometrium. The focus has shifted toward the \nuse of Growth Factor Concentrate (GFC) derived from platelets, \nwhich has demonstrated promising results in preclinical studies \n[12]. ABCD-Endosera contains a higher concentration of growth \nfactors and cytokines, which may contribute to its enhanced regen-\nerative effects on the endometrium compared to PRP [13]. Addi -\ntionally, ABCD-Endosera has been shown to promote angiogenesis, \ncell proliferation, and migration, which are critical processes for \nendometrial development and receptivity [14,15]. This pilot study \naims to evaluate the efficacy of ABCD-Endosera, a next generation \ngrowth factor that concentrates preparation [16,17] in improving \nendometrial thickness and live birth rate among patients with thin \nendometrium.\nMethods\nStudy Design and Participants\n This was an IEC approved (Protocol No.: SGN/CHE/ETR/0119), \nself-controlled pilot study conducted between July 2019-Sep 2021. \nA total of 50 patients with a history of thin endometrium under -\ngoing IVF (freeze all approach) were enrolled. After obtaining \ninformed consent, infertile women of age less than 39 years who \nhave EMT persistently less than 7mm on baseline endometrial eval-\nuation before IVF despite standard HRT and normal endometrial \ncavity during hysteroscopic evaluation and women with a history \nof cycle cancellation during FET cycles due to persistent thin endo-\nmetrium were included in the study. \na) Inclusion Criteria\n1. Patients in previous frozen embryo transfer cycles had \ntheir uterine lining which was persistently thin (characterized by \nendometrial thickness<7mm), presented with inadequate response \nto treatments to increase blood flow to the endometrium include \nextended estrogen doses, low-dose aspirin, sildenafil, or Vitamin E \nand therapies like PRP and G-CSF.\n2. Experienced one or more unsuccessful IVF cycles, despite \nhaving good quality embryos ready for transfer.\n3. Women with normal transvaginal ultrasounds and no sig-\nnificant issues in their uterus or nearby areas were included.\n4. Patients tested negative for genital tuberculosis using Ac-\nid-Fast Bacillus (AFB) culture. \n\nAm J Biomed Sci & Res\nAmerican Journal of Biomedical Science & Research\nCopyright© Vasanthi Palanivel\n843\nb) Exclusion Criteria\nPatients were excluded if they had a history of intrauterine ad-\nhesions, endometrial cavity infections, pelvic cancer, severe endo -\nmetriosis, submucosal uterine myomas or endometrial polyps and \nadenomyosis. Endometrial thickness was measured with vaginal \nultrasound at its thickest part in the longitudinal axis of the uterus \nand was performed by the same investigator using a computerized \nvaginal ultrasound. This investigator was blind to the conditions \nof patients. Thin endometrium was defined as the endometrium \nthickness <7mm on the day when progesterone was given in HRT \ncycles [18].\nPreparation of Endometrium\nAll the patients underwent standard Hormone Replacement \nTherapy (HRT) protocols for endometrial preparation. The proto -\ncol involved the incremental use of oral estradiol valerate 2mg/day \nduring days 1-7, 4mg/day during days 8-12, 6mg/day during days \n13 to embryo transfer [38]. Transvaginal ultrasound was used to \nmonitor endometrial thickness, and once it reached 7 mm, 10 mg \nof micronized progesterone acetate was started. When endometri -\nal thickness failed to reach over 7mm, patients were consulted to \nmake decision tocancel the cycle, proceed to a new FET cycle or \nundergo embryo transfer regardless of thin endometrium. The de -\ncision to receive ABCD-Endosera treatment or not was based on the \npatients’ preferences.\nEmbryo Transfer and Outcome Measures\nIn this study Single Embryo Transfer (SET) was employed as \nthe chosen method for transferring embryos in all patients. The \ntransferred embryos were blastocysts that had undergone the pro-\ncess of freezing and thawing. These blastocysts were of high quali -\nty, specifically graded as 4 AA/AB based on the guidelines outlined \nin the Istanbul Consensus workshop [18]. This approach not only \nminimizes the risks associated with multiple pregnancies but also \nensures the transfer of the most viable embryos. SET allows for \na precise evaluation of the individual embryos’ potential for suc -\ncessful implantation, thereby optimizing the chances of achieving \nfavorable pregnancy outcomes. Post-embryo transplantation, the \nluteal phase was supported through a combination of daily intra -\nmuscular injection of 50mg progesterone and nightly administra -\ntion of 200mg vaginal progesterone soft capsules. Serum Human \nChorionic Gonadotropin (HCG) levels were measured 14 days after \nembryo transfer. Vaginal ultrasonography was conducted 35 days \nafter transfer in cases of biochemical pregnancy, while the presence \nof an intrauterine fetal heartbeat was used to define a clinical preg-\nnancy. The primary outcome and endpoint of the study focused on \nendometrial thickness. The secondary endpoints included the clini-\ncal pregnancy rate, defined as the presence of a gestational sac and \nfetal heartbeat on transvaginal ultrasound five weeks after embryo \ntransfer. Additional secondary outcome measures encompassed \nthe miscarriage rate and ongoing pregnancy rate.\nIntervention\nABCD-Endosera was prepared from autologous blood, as pre -\nviously reported. [16,17] After obtaining informed consent, AB -\nCD-Endosera was prepared from concentrated platelets, prepared \nfrom fresh peripheral blood collected from the peripheral vein \nwhich was then subjected to proprietary centrifugation-based se -\nlective enrichment protocol. As presented in Figure 1, three doses \nof ABCD- Endosera (0.8 mL per dose) were prepared from 30mL \nof peripheral blood. For patients receiving ABCD-Endosera treat -\nment, the infusion protocol involved administering the first dose of \n0.8 ml of ABCD-Endosera intrauterine infusion between days 5-7 of \nthe menstrual cycle. The second dose was administered five days \nafter the first dose, and the third dose was given 48 hours before \nembryo transfer. The ABCD Endosera infusion into the uterine cav-\nity was performed using a Tomcat catheter for each administration \n[16,17]. Endometrial and sub endometrial blood flow, crucial for \nsuccessful implantation, was monitored using color Doppler in 2D \nmode on a transvaginal scan. Prior to ABCD- Endosera instillation, \nthese patients had no visible endometrial/sub endometrial blood \nflow, whereas a noticeable improvement in blood flow was evident \npost-treatment as per the different zones of vascularity with refer-\nence to the Applebaum criteria. [19] Biochemical pregnancy was \nconfirmed by positive serum beta-human chorionic gonadotropin \n(β-hCG) two weeks post-embryo transfer, and Transvaginal ultra -\nsound (TVS) was performed after another two weeks to confirm \nclinical pregnancy. \nOutcome Measures\nThe primary outcome of this study was to evaluate the effect \nof intrauterine infusions of ABCD-Endosera on EMT in patients \npresenting with refractory thin endometrium. The secondary out -\ncomes encompassed assessing implantation rates, clinical preg -\nnancy rates, live birth rates, and the reporting of adverse effects. \n(Tables 1,2)\nStatistical Analysis\nData were collected using MS Excel and analyzed using SPSS \nstatistical software (SPSS, Chicago, IL, USA) version 28.0. Categor -\nical variables were expressed as numbers and percentages, while \ncontinuous variables were expressed as mean [standard deviation \n(SD)].\nResults\nThe study included 50 patients with a history of refractory thin \nendometrium (Table-1). The average age of the patients was 33.38 \nyears (±3.3), and they had an average weight of 69.3 kg (±6.4). They \nhad an average infertility duration of 5 years (±2.1), with a men -\nstrual cycle duration averaging 30.3 days (±3.3). The patients had \nundergone an average of 3 intrauterine insemination (IUI) proce -\ndures (±1.2) and 3 previous IVF attempts (±1.2). The average num-\nber of oocytes retrieved was 8.8 (±4.1), and the number of Meta -\nphase II was 6.0 (±3.4). The fertilization rate was 67% (±21%).  The \nendometrial thickness before the treatment was 6.6 mm (±1.1). \nThis value significantly increased to 7.09 mm (±0.54) after dose 1, \n7.9 mm (±0.88) after dose 2, and 8.2 mm (±0.9) on the day of em -\nbryo transfer, showing a significant difference (p < 0.0001) with a \nmean increase of 1.6 mm. Secondary outcomes indicated that em -\nbryo transfer was carried out in 94% (47/50) of the patients, with \n\nAmerican Journal of Biomedical Science & Research\nAm J Biomed Sci & Res                                     Copyright© Vasanthi Palanivel\n844\n4% (2/50) experiencing cycle cancellation, and 2% (1/50) lost to \nfollow-up. The clinical pregnancy rate stood at 50% (25/50), while \n44% (22/50) did not result in pregnancy. One patient (2%, 1/50) \nhad a biochemical pregnancy, and three patients (6%, 3/50) experi-\nenced a miscarriage. The live birth rate was 42% (21/50) (Table-2). \nThe procedure was well tolerated without severe adverse events. \nFigure 1: Preparation and administration of autologous blood cell derivative (ABCD)-Endosera. [16,17]\nTable 1: Basic patient and cycle characteristics. \nStudy Period July 2019-Sep 2021 Average Std Dev p value\nNo of patients 50   \nAge (Years) 33.38 3.3  \nweight (Kg) 69.3 6.4  \nDuration of Infertility (Years) 5 2.1  \nMenstrual Cycle Days (Days) 30.3 3.3  \nPrevious IVF cycle cancellations 3 1.2  \nTotal No of oocyte Retrieved 8.8 4.1  \nMetaphase II 6 3.4  \nFertilization Rate (%) 67 21  \nEndometrium Thickness Before treatment 6.6 1.1  \nEmbryo Transfer Details (n=47) Categories Count (N) Percentage (%)\nNo of Embryos Transferred 1 36 76.5\n 2 11 23.4\nEmbryo Grade Transferred A 26 55.3\n B 19 40.4\n AB 2 4.3\n\nAm J Biomed Sci & Res\nAmerican Journal of Biomedical Science & Research\nCopyright© Vasanthi Palanivel\n845\nTable 2: Outcome Measures.\nPrimary Outcome Measures Average Std Dev p value\nEndometrium Thickness After \nDose 1 7.09 0.54\nEndometrium Thickness After \nDose 2 7.9 0.88\nEndometrium Thickness on the day \nof ET 8.2 0.9 P<0.0001.\nβ-hCG-Positive 25 50\nβ-hCG-Negative 22 44\nCycle Cancellation (%) 2 4\nLost to follow up (%) 6.1 1.2 P<0.0001\nSecondary Outcome Measures Count Categories (N) Percentage (%) Count (N) Percentage (%)\nEmbryo transfer done (%) 47/50 94\nβ-hCG -Positive (%) 25/50 50 76.5\nClinical Pregnancy Rate (%) 25/50 50 23.4\nBiochemical Loss Rate (%) Jan-50 2 55.3\nMiscarriage rate (%) Mar-50 6 40.4\nLive birth rate (%) 21/50 42 4.3\nDiscussion and Conclusion\n In this self-controlled retrospective study, ABCD-Endosera de-\nrived from platelets was found to significantly improve endometri-\nal thickness and live birth rate in patients with thin endometrium. \nThese findings support previous research indicating the therapeu -\ntic potential of platelet-derived growth factors in the management \nof thin endometrium [6,7,9,10,16,17]. This approach directly har -\nnesses the growth factors that are responsible for the efficacy of \nPRP , such as VEGF, PDGF, and TGF-β, which play critical roles in \nendometrial regeneration and tissue repair. The use of growth fac-\ntors in other specialties, such as orthopedics and wound healing, \nhas also demonstrated the potential of growth factors to promote \ntissue regeneration and repair [16-22]. Cryopreservation of plate -\nlet concentrates has been shown to retain the biological activity of \ngrowth factors, such as platelet-derived growth factor (PDGF) and \ntransforming growth factor-beta (TGF-β), enabling their use in var-\nious clinical applications [23-28]. Several studies have demonstrat-\ned that the extraction and storage of growth factors from platelets \nare feasible and effective [29-37]. With concentrated growth fac -\ntors preparation, the targeted growth factors can be more effective-\nly delivered to the endometrial tissue, ensuring that the necessary \nfactors are present in optimal levels to promote tissue regeneration \nand repair. In comparison to the results observed in conventional \nPRP based treatment, our study has shown better improvements in \nendometrial thickness and live birth rate among patients with thin \nendometrium [38]. \nStrengths \nABCD-Endosera is a more targeted and efficient alternative to \nPRP for treating thin endometrium. Unlike PRP , ABCD-Endosera \ndoes not contain pro-inflammatory sources, which may lead to \nmore consistent results across patients. This can result in a more \nstandardized, cost-effective and time-efficient treatment option for \npatients, without compromising efficacy. This approach appears to \noffer several advantages over PRP , including the direct delivery of \nessential growth factors, reduced variability between patients, and \npotential improvements in clinical practice efficiency by preparing \nmultiple doses from a single blood aspiration. This feature reduces \nthe number of patient visits to the hospital, thereby decreasing the \noverall burden on both the patient and healthcare system. Further-\nmore, by cryo-storing ABCD-Endosera for extended periods, the \nwaiting time for patients can be significantly reduced, as doses can \nbe prepared in advance and administered when needed. \nLimitations \nDespite promising results, our pilot study was limited by its \nsmall size and retrospective design. Future large-scale randomized \ncontrolled trials comparing ABCD-Endosera to other treatments \nare needed to optimize its protocols and investigate its synergistic \neffects with other therapies. These trials should also evaluate its \nlong-term safety and efficacy, as well as the mechanisms by which \ngrowth factors promote endometrial regeneration and the optimal \nconcentration for each growth factor. \nSummary \nIn summary, this self-controlled retrospective study has shown \npromising results in the use of growth factor concentrate derived \nfrom platelets to improve endometrial thickness and live birth rate \nin patients with thin endometrium. The advantages of ABCD-Endo-\nsera over PRP , such as the direct delivery of essential growth fac -\ntors, reduced variability between patients, and potential improve -\nments in clinical practice efficiency, warrant further investigation in \nlarger, well-designed trials. \nConflict of Interest \nThe authors declare that the research was conducted in the \n\nAmerican Journal of Biomedical Science & Research\nAm J Biomed Sci & Res                                     Copyright© Vasanthi Palanivel\n846\nabsence of any commercial or financial relationships that could be \nconstrued as a potential conflict of interest. \nFunding\nThere was no support from any funding agency. This research \ndid not receive any specific grant from any funding agency in the \npublic, commercial or not-for-profit sector. \nAuthor contribution statement\nStudy design and concept: Mala Raj, Vasanthi Palanivel Manu -\nscript writing, modification and editing: Vasanthi Palanivel, Mala \nRaj, Shrinivas Chari Review the manuscript and approve the re -\nlease: Mala Raj, Shrinivas Chari, Vasanthi Palanivel.\nAcknowledgements\nWe would like to thank all the staff from Firm Hospitals and \nSeragen Biotherapeutics Pvt Ltd, who helped the authors in con -\nducting the study.\nReferences\n1. Gargett CE (2007) Uterine stem cells: what is the evidence? Human Re -\nprod Update 13(1): 87-101.\n2. Tetsuo Maruyama, Hirotaka Masuda, Masanori Ono, Takashi Kajitani, \nYasunori Yoshimura (2010) Human uterine stem/progenitor cells: their \npossible role in uterine physiology and pathology. Reproduction 140(1): \n11-22.\n3. 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