Ovarian Rejuvenation Research Articles

O-060 Ovarian rejuvenation - fact or fiction?

Abstract Ovarian aging is a reality and a physiological process which occurs with age resulting in to premature depletion of eggs . POI occurs in approximately 1% of the women who have not reached 40 years of age. The frequency is roughly 4–8% in women experiencing secondary amenorrhea and 10–28% in cases of primary amenorrhea .The prevalence of POI was higher in countries with medium and low human development indexes . . We analysed 1000 infertile patients of less than 40 years . 110 patients had AFC less then 2 and opted for egg donor program . cycle cancellation was due to nonavailability of eggs on OPU was seen in 4% cases in our analysis . Presence of oogonial stem cells (OSCs) in the ovarian cortex , hinting at a possibility of therapeutic stimulation of post-natal folliculogenesis in subfertile women it is postulated that ovarian aging or insufficiency could be reversed if OSCs are provided a healthy environment. Ovarian rejuvenation therapy is a new and innovative approach to enhancing fertility in this group of patients . It is often carried out using platelet-rich plasma (PRP) or stem cell therapy. Ovarian Rejuvenation with Stem cells is also called Autologous Stem Cell Transplant in the Ovary (ASCOT). PRP is having lots of advantages like therapeutic effect, cost effectiveness, ease of isolation and autologous nature. However some drawbacks are also there like inconclusive efficacy and lack of understanding of mechanism of action, lack of RCT /fundamental research . regenerative processes organized by platelet cytokines in somatic cells are poorly understood . PRP infusion may only be an appropriate treatment for select ovarian disorders. perimenopausal women and women deemed to be POR benefitted the most from the treatment, more so than POI and menopausal patients . platelet cytokines are ligands that attach to cell membrane receptors—not the nucleus . no case of tumorogenic activity observed in any clinical context so far . Further reassurance comes from work in other human tissue treated with PRP, where accelerated growth of healthy cells was noted without triggering malignant transformation . 13 registered clinical trials investigating the effect of PRP on ovarian rejuvenation .few of these trials describe the inclusion of appropriate PRP controls. It is only from well-controlled trials, built on detailed mechanistic understanding that we can clarify the platelet-mediated effects of PRP therapy in ovarian rejuvenation and folliculogenesis. The PRP injections into the ovaries are safe, productive, and a natural treatment that may help women with premature ovarian insufficiency to give birth to their own child . Stem cell therapy is attracting attention in the field of regenerative medicine and is advancing rapidly. Many recent studies have applied stem cell therapy to treat reproductive system diseases; however, data are not yet available as to whether this therapy shows enhanced therapeutic effects. It is evident that stem cell therapies have potential in treating POI. Stem cells and their exosomes, including content such as miRNAs, show positive effects in enhancing and restoring various aspects of ovarian function, such as folliculogenesis, the GC apoptosis rate, vascular formation, and genetic stability. Among the 10 clinical trials in the NIH database, only 4 have been completed; the rest are ongoing, recruiting and/or active. Research subjects have been selected by strict standards. Although there are several active ongoing clinical trials for POI using stem cell-based therapeutics, there are restrictions in each country regarding ethical and clinical concerns from the health-care community .Potential of stem cell therapies in treating POI still needs further research and clinical results.

O-168 The therapeutic potential of stem cells for ovarian rejuvenation

Abstract Stem cells and induced pluripotent stem cells (iPSCs), hold immense promise in regenerative medicine due to their ability to differentiate into various cell types. However, in the context of ovarian rejuvenation, controversies surround the concept of post-natal oogenesis in mammals, challenging the established belief that female mammals are born with a finite pool of oocytes. Recent studies refute the presence of ovarian stem cells, sparking debates in the scientific community. The proposed use of ovarian stem cell-derived mitochondria for oocyte rejuvenation, known as AUGMENT, aimed to enhance fertility but fell short of expectations in clinical trials. Conversely, autologous stem cell ovarian transplantation (ASCOT) seems to offer a promising avenue to increase reproductive potential by replenishing ovarian function. While still under investigation, initial results show encouraging outcomes. Furthermore, recent advancements in in vitro generation of oocytes from stem cells present a groundbreaking approach to overcome infertility associated with ovarian failure. By mimicking the natural process of oogenesis, researchers aim to provide new opportunities for fertility preservation and treatment. These developments underscore the dynamic landscape of stem cell research in reproductive medicine, offering hope for addressing infertility and expanding our understanding of reproductive biology.

Management of Poor Ovarian Response

Poor ovarian response (POR) occurs in approximately 9-24% of patients in ART. It presents a challenge to the reproductive consultant and causes immense emotional distress to the couple. Over the last few decades, ART has seen an improvement on both the clinical and embryological front however, adequate management of POR remains elusive. Etio-pathogenesis of the condition is poorly understood and varying definitions of POR have been used in studies. In recent years the POSEIDON criteria have been proposed to define this group of ‘low-prognosis’ patients and to optimize management. POSEIDON groups are assigned based on age and ovarian reserve. The patient groups are thus the unexpected poor responder’s having a normal ovarian reserve and the expected poor responders who have a poor ovarian reserve, to begin with. Management strategies to improve oocyte numbers and quality include manipulation of pituitary suppression and OS regimes, addition of LH and use of mild stimulation. The Duo- stim protocol has proved successful in increasing egg numbers, using the follicular and luteal phases of the same cycle. Adjuvant therapies which have shown promise in recent years are the use of Testosterone gel, Growth hormone, Co-enzyme Q10. Ovarian rejuvenation using Intra-ovarian platelet-rich plasma, ovarian activation and use of autologous stem cells is exciting and ongoing research in this area may yield evidence in future. The speaker will share her experience with the use of IOPRP for improving ovarian reserve during the lecture.

Ovarian Rejuvenation for Diminished Ovarian Reserve

Addressing fertility challenges, particularly those stemming from advancing maternal age, requires innovative and effective solutions. This presentation navigates the frontier of ovarian rejuvenation for diminished ovarian reserve, examining whether it remains a myth or emerges as a promising reality. The lecture offers a comprehensive review of various ovarian rejuvenation technologies available today. It will investigate the clinical studies, accumulated evidence, and overall clinical utility, creating a foundation for understanding the effectiveness and limitations of each approach. A significant portion will be dedicated to the role and potential of Platelet-Rich Plasma (PRP) treatments in ovarian rejuvenation. This segment will include clinical study data and firsthand experiences, providing a practical perspective on PRP application. Further, an exploration into the basic research that supports PRP usage will be presented. This knowledge illuminates how PRP might influence the ovarian environment and potentially restore ovarian function. In conclusion, the lecture aims to initiate dialogue on ovarian rejuvenation and rehabilitation as alternative treatment strategies for patients contending with diminished ovarian reserve. Through this exploration, the presentation hopes to offer insights into the current landscape of fertility treatments in women with diminished ovarian reserve.

#98 : Autologous Platelet-Rich Plasma Administration’s Efficacy in Patients with Low Ovarian Reserve: A Systematic Review and Meta-Analysis

Background and Aims: Autologous platelet-rich plasma (PRP) as a novel therapeutic approach has been utilized in multiple aspects of medicine because it contains stem cells and growth factors. There is still controversy over the effectiveness of this strategy in managing infertile women with low ovarian reserve due to the lack of evidence-based studies. This study aimed to systematically investigate and meta-analyze the best available evidence from clinical trials evaluating the impact of autologous platelet-rich plasma on low ovarian reserve. Methods: Systematic searches in electronic databases including PubMed, Cochrane, and Google Scholar use relevant search terms. We included infertile women with low ovarian reserve in single-arm clinical trials. Ovarian reserve parameters were measured before and after PRP injection into the ovaries. Data were extracted from each eligible study, then pooled (meta-analysis). The risk of bias (RoB) was evaluated using RoB 2 assessment tools. Results: Three hundred and one articles were collected and excluded, leaving six eligible studies, then classified into two subgroups: poor ovarian response (POR) and primary ovarian insufficiency (POI). Following PRP injection, infertile women showed an improvement in ovarian reserve. There was a significant increase in anti-Mullerian hormone (AMH) level (MD = 0.12, 95% CI [0.005; 0.23], I2=99%, subgroup differences p=0.33), a significant increase in antral follicle count (AFC) (MD = 1.88, 95% CI [0.86; 2.89], I2=93%, subgroup differences p=0.67), with a non-significant reduction in follicle-stimulating hormone (FSH) level (MD = 0.32, 95% CI [0.18; 0.46], I2=94%, subgroup differences p=0.02). According to the RoB’s assessment, the original research studies’ overall quality was a low risk of bias. Conclusions: Autologous platelet-rich plasma may increase AMH and AFC, but not FSH. Although it was discovered beneficial in enhancing ovarian reserve and effective for ovarian rejuvenation, further research with a large number of samples and strong evidence is still required.

Platelet Therapy and Ovarian Rejuvenation in Women with Premature Ovarian Failure

Introduction: Premature Ovarian Failure (POF) is a disease that occurs before the age of 40 due to dysfunction of the ovaries. In these women، the production and secretion of estrogen hormone is not done properly. Such a situation causes irregular or interrupted periods، disturbances in the ovulation process and occurrence of menopausal symptoms. Premature ovarian failure makes it difficult for women to get pregnant، so more research in this field is necessary.
 Conclusion: The results showed that one of the recommended ways to repair and regenerate the failing ovarian tissue was the use of platelet-rich plasma (PRP). The positive effects of PRP were dependent on the high concentration of growth factors in the alpha granules of platelets. The results of this review article showed that the use of platelet-rich plasma in restoring ovarian function could be considered as a treatment method in these patients.

Ovarian rejuvenation by PRP (Platelet –Rich Plasma)

Ovarian rejuvenation by PRP (Platelet –Rich Plasma)

MTOR Inhibition via Low-Dose, Pulsed Rapamycin with Intraovarian Condensed Platelet Cytokines: An Individualized Protocol to Recover Diminished Reserve?

No major breakthroughs have entered mainstream clinical fertility practice since egg donation and intracytoplasmic sperm injection decades ago, and oocyte deficits secondary to advanced age continue as the main manifestation of diminished ovarian reserve. In the meantime, several unproven IVF 'accessories' have emerged including so-called ovarian rejuvenation which entails placing fresh autologous platelet-rich plasma (PRP) directly into ovarian tissue. Among cellular responses attributed to this intervention are reduced oxidative stress, slowed apoptosis and improved metabolism. Besides having an impact on the existing follicle pool, platelet growth factors might also facilitate de novo oocyte recruitment by specified gene upregulation targeting uncommitted ovarian stem cells. Given that disordered activity at the mechanistic target of rapamycin (mTOR) has been shown to exacerbate or accelerate ovarian aging, PRP-discharged plasma cytokines combined with mTOR suppression by pulsed/cyclic rapamycin represents a novel fusion technique to enhance ovarian function. While beneficial effects have already been observed experimentally in oocytes and embryos with mTOR inhibition alone, this proposal is the first to discuss intraovarian platelet cytokines followed by low-dose, phased rapamycin. For refractory cases, this investigational, tailored approach could amplify or sustain ovarian capacity sufficient to permit retrieval of competent oocytes via distinct but complementary pathways-thus reducing dependency on oocyte donation.

Multichannel Recovery Potential with Activated Autologous Intraovarian Platelet-Rich Plasma and Its Derivatives.

Platelet-rich plasma (PRP) is an 'orthobiologic' with recognized roles in plastic surgery, musculoskeletal disorders, dentistry, dermatology, and more recently, 'ovarian rejuvenation'. Intraovarian PRP involves a complex secretome discharged after platelet activation, comprising multiple cytokine mediators delivered surgically to older or inactive ovarian tissue. Loss of oocyte meiotic fidelity and impaired fertilization accompanying advanced maternal age are already managed by IVF, but only with eggs provided by younger donors. However, if the observed effect of rectifying embryo ploidy error can be proven beyond case reports and small series, activated PRP (or its condensed plasma cytokines) would deliver a welcome therapeutic disruption that is difficult to overstate. Because shortcomings in ovarian function are presently addressed mainly by pharmacological approaches (i.e., via recombinant gonadotropins, GnRH analogs, or luteal support), autologous PRP would represent an unusual departure from these interventions. Given the diversity of platelet cargo proteins, the target response of intraovarian PRP is probably not confined to oocytes or follicles. For example, PRP manipulates signal networks driving improved perfusion, HOX regulation, N-glycan post-translational modification, adjustment of voltage-gated ion channels, telomere stabilization, optimization of SIRT3, and ribosome and mitochondria recovery in older oocytes. While multichannel signals operating on various pathways are not unique to reproductive biology, in intraovarian PRP this feature has received little study and may help explain why its standardization has been difficult. Against this background, our report examines the research themes considered most likely to shape clinical practice.

Use of autologous adipose-derived mesenchymal stem cells for ovarian rejuvenation in poor responder IVF patients: a phase 1 randomized placebo-controlled double-blind crossover study

Background: Despite the application of various methods to augment ovarian responsiveness, the management of poor ovarian responders remains challenging and pregnancy rates following in vitro fertilization are poor. Advances in adult stem cell research and their clinical application has prompted interest in their use in assisted reproduction. We report the first double-blind, randomized, placebo-controlled clinical study using autologous human stromal vascular fraction (SVF) containing adipose-derived stem cells (ADSCs) for ovarian rejuvenation. Materials and methods: Thirty patients were recruited. Twenty-one had lower-than-expected reserves for their age and 9 had premature ovarian insufficiency. Patients were randomized into a placebo group (10) and an intervention group (20). SVF was obtained from adipose tissue following abdominal liposuction; the ADSC component was characterized using flow cytometry. Three equal insertions, adjusted based on ovarian volume, were performed at monthly intervals via an ultrasound-guided transvaginal needle puncture. The SVF was not cultured before transplantation. Those in the placebo group were then crossed over to the intervention group and received a single SVF (maximally concentrated) insertion (crossover group). Results: The median viable SVF cell number inserted per patient over 3 months, and the percentage of mesenchymal stem cells (MSC) thereof, was 1.6×106 and 13.2%, respectively. Resulting anti-Mullerian hormone (AMH) changes were variable over the treatment course with a notable placebo effect. Patients with premature ovarian insufficiency showed no change in AMH, both to intervention and placebo. Despite this, a temporary return of menses was noted in a third of patients while on treatment. Patients with low reserves for age showed an increase in AMH, although not statistically significant when compared to placebo. In the crossover group, insertions were limited to one intervention comprising all cells; here a significantly higher median of 3.4×106 SVF cells were injected containing an average of 16.9% MSCs. No significant change in AMH was noted. To date 12 patients have undergone ovarian stimulation and in vitro fertilization after stem cell therapy; of these 9 have had embryo transfers with a resulting pregnancy rate of 33%. There were also 2 spontaneous pregnancies. Conclusion: Although the application of SVF-derived ADSCs for ovarian rejuvenation remains experimental, the current study provides further support for the safety of this approach and presents encouraging results as to its efficacy in assisted reproduction.

P-798 Comprehensive evaluation of autologous Platelet-Rich Plasma infusion in ovarian rejuvenation

Abstract Study question This study aimed to the evaluation of PRP injection in women with ovarian dysfunction (with POR, POI, perimenopause and menopause) to promote the ovarian rejuvenation. Summary answer Intraovarian infusion of autologous PRP exhibited remarkable evidence and promising results to restore ovarian insufficiency. What is known already Ovarian dysfunctions, such as premature ovarian insufficiency (POI) and poor ovarian response (POR) are conditions, characterized by the collapse of ovarian function and are considered currently as a global public health issue. Primary factors that are associated with female infertility include endocrine dysfunction, failure of embryo implantation, endometriosis, and other related pathologies such as polycystic ovary syndrome (PCOS), various environmental factors and inflammatory disease. For this purpose, the rejuvenation of the ovaries using the intraovarian PRP injections may result in increased release of follicles from the available reservoir, and can potentially increase the possibility of a successful pregnancy. Study design, size, duration This study was designed as a randomized prospective observational pilot study. A number of 582 participants were interested to participate. The whole study was performed between May 2018 and December 2021. The patients were subdivided into 5 groups, followeeed by autologous blood collection, PRP preparation and intraovarian injection. The follow-up of the patients lasted for 2 months. Participants/materials, setting, methods The classification of the participants was performed into the following groups: Group A (22-38 years), Group B (39-44 years), Group C (45-57 years), Group D (48-50 years) and Group E (51-56 years). 60 ml of autologous blood was collected from each patient, followed by the preparation of PRP. Intraovarian PRP injection was performed and monitoring of the ovarian function including the quantification of FSH, LH, AMH and E2 for two constitutive menstrual cycles, was performed. Main results and the role of chance For group A, decrease of more than 50% was detected for the FSH and LH whereas, the levels of E2 and AMH were elevated by more than 44% and 31%, respectively in all participants Moreover, statistically significant differences regarding the levels of FSH (p = 0.001), LH (p = 0.046) , E2 (p = 0.035) and AMH (p = 0.012), were observed after the 1st and 2nd month of follow-up. In group B, a statistically significant decrease in FSH (p < 0.001) and LH (p = 0.001) levels were observed in all participants. In parallel, the elevation of E2 and AMH levels was observed. Moreover, 28% of the participants with diagnosed POI, after the PRP infusion, achieved successful pregnancies and live births. In group C, after the PRP infusion, a reduction in FSH and LH levels with a parallel increase of E2 and AMH levels was detected. In group D, the levels of FSH and LH slightly declined after the PRP infusion. Also, the levels of E2 and AMH were increased. In group E, the levels of FSH and LH declin Limitations, reasons for caution No classifications between responders and no responders after the PRP administration were performed. Additionally, no presence of control groups in each category nor the determination of the growth factor content of the produced PRP was performed. The relatively limited time for the follow-up can also be considered a further limitation. Wider implications of the findings The administration of autologous PRP can be considered a safe and tolerable alternative approach to the classical ones for ovarian rejuvenation. This in turn could result to better conceiving rates, thus may beneficially improve the social impact of women with ovarian dysfunction. Trial registration number 10/10/19

P-615 Ovarian rejuvenation with human placenta hydrolyzate

Abstract Study question Is it possible to rejuvenate the ovaries with human placenta hydrolyzate? Summary answer Injecting human placenta hydrolyzate into the ovaries can activate dormant follicles and produce mature oocytes in patients with ovarian insufficiency. What is known already Patients with low ovarian reserve and/or ovarian failure are a difficult category for reproductive specialists. Attempts to rejuvenate the ovaries have been made for several years. The use of adjuvant therapy such as PRP can activate dormant follicles. Human placenta hydrolyzate contains growth factors, hormones, trace elements, vitamins. Administration of human placenta hydrolyzate directly to the ovaries can also activate folliculogenesis and oogenesis. Study design, size, duration A cohort study was conducted, which involved 20 women with low ovarian reserve who underwent IVF / ICSI at the Person ICCR in 2022. AMH, FSH, the number of antral follicles, the number of received oocytes were determined before the injection of the human placenta hydrolyzate (JAPAN BIO PRODUCTS Co, LTD, Japan) into the ovaries and 1-3 months after procedures. Participants/materials, setting, methods All patients had previously undergone IVF/ICSI. 20 women with infertility, mean age was 39±6 years. In September-October 2022, we received a human placenta hydrolyzate intraovarially. The human placenta hydrolyzate was injected into the ovaries as in a transvaginal puncture with a 20 G needle, 1 ml into each ovary. All participants gave their voluntary informed consent to the procedure. Main results and the role of chance On the 2-3rd day of the cycle before the procedure, the average level of AMH was 0.11±0.09 ng/ml, FSH 38.11±10.86 mIU/ml, the number of antral follicles 1.18±0, 38, the number of mature oocytes obtained on TVP, 0.68±0.19. After the introduction of the human placenta hydrolyzate into the ovaries, measurements were repeated 1-3 months later: AMH was 0.46±0.18 ng/ml, p = 0.09; FSH was 13.54±7.86 mIU/ml, p = 0.074; CAF 1.96±0.17, p = 0.068; oocytes M2 1.51±0.38, p = 0.058. Due to small cohort size and short follow-up time, we believe that ovarian activation by placental hydrolyzate takes place, this is especially noticeable in the number of obtained mature oocytes that went for freezing or fertilization: 4 patients received embryos suitable for PGT-A, one the embryo (mosaic) was transferred into the uterine cavity and pregnancy occurred. There was no any side effect after the injection. Limitations, reasons for caution Limitations relate to study design. More patients and longer follow-up are also needed. Wider implications of the findings Ovarian rejuvenation is currently an adjuvant therapy, high-level evidence is not yet available. However, for women with POI and POR, any opportunity to improve the chances of obtaining their own oocytes is valuable. Trial registration number NO APPLICABLE

P-801 Human umbilical cord perivascular cells (HUCPVC) reduce ovarian fibrosis and improve pregnancy rates in a mouse model of natural ovarian aging

Abstract Study question Does repeated intravenous administration of human umbilical cord perivascular cells (HUCPVC) during the period of ovarian aging prevent age-related fertility decline in a mouse model? Summary answer Repeated administration of first trimester and term HUCPVC improved pregnancy rates and reduced ovarian fibrosis in a mouse model of natural ovarian aging. What is known already Mesenchymal stromal cells (MSC), such as first trimester (FTM) and term human umbilical cord perivascular cells (HUCPVC), may be good cell candidates to mitigate side-effects of oncotherapy, including infertility, and are also gaining interest in ovarian rejuvenation strategies. The intraovarian or systemic administration of various sources of mesenchymal stromal cells in animal models of advanced reproductive age have been previously reported to improve ovarian reserve, follicle activation and function, via multiple proposed mechanisms. However, mating studies have not previously been performed to demonstrate fertility preservation. In addition, the optimal dose regimen and timing of treatment has not been established. Study design, size, duration Pre-clinical randomized controlled study in a mouse model of natural ovarian aging from 6 months to 12 months, including a negative control group (vehicle-treated), a cell control group (fibroblast-treated) and 3 experimental groups (HUCPVC, 2 sources and 2 dose regimens; n = 10-15 per group). All parameters were compared with young control female mice (6-8 weeks, 6 months). Cell injections and all assessments were blinded. Participants/materials, setting, methods 6-month-old ICR mice randomized into 4 groups received 6 monthly tail vein injections of 1x106 HUCPVC (FTM or term), fibroblast cells or HBSS (vehicle control). A 5th group received a single injection of FTM HUCPVC at 11M (n = 5). Pregnancy and litter size data were collected after breeding trials. The total number of follicles per ovary and picrosirius red (PSR) staining were quantified. Serum anti-Mullerian hormone (AMH) and C-reactive protein (CRP) were analyzed by ELISA. Main results and the role of chance No differences in mortality rates (P = 0.2) and animal weights were observed. The weight gain in FTM and term HUCPVC treated animals was significantly greater than in the other groups, over the duration of the study (P = 0.04). Animals that received 6 injections of FTM and term HUCPVC showed significantly higher pregnancy rates at 12M (100%, 80%) (P = 0.007; P = 0.048, respectively), when compared to animals that received HBSS (40%) and were similar to pregnancy rates of 6-8weeks (100%) and 6M (77%) groups. Fibroblast-treated and 1x FTM HUCPVC-treated groups showed 60% pregnancy rates. Age-associated declines in litter sizes and ovarian reserve indicators were observed as expected, but not rescued by cell treatments, except for levels of AMH which were increased in the group that received 1x FTM HUCPVC injections when compared to HBSS controls (P = 0.04). Age-associated increases in ovarian stroma fibrosis were observed with aging in the control groups (P < 0.0001), and were significantly reduced in 6x FTM HUPCVC, 6x term HUCPVC and 1x FTM HUCPVC groups, when compared to HBSS and fibroblast controls (P < 0.0001; P = 0.01 and P < 0.0001, respectively). An age-associated increase in CRP (P = 0.01) was significantly decreased in 6x FTM HUCPVC-treated groups, when compared to HBSS (P = 0.04). Limitations, reasons for caution Pregnancy rate (the main outcome measured in this study) may confound some of the secondary outcomes analyzed (CRP levels). Use of ovarian tissue for histological analysis and limited serum samples precluded further molecular analyses to assess potential mechanisms for the effects of HUCPVC. Wider implications of the findings FTM HUCPVC have anti-inflammatory and anti-fibrotic effects, and represent a promising source of MSC to prevent fertility decline in women of advanced reproductive age. Trial registration number Not Applicable

Intraovarian Platelet-Rich Plasma Injections: Safety and Thoughts on Efficacy Based on a Single Centre Experience With 469 Women.

Ovarian rejuvenation is an innovative procedure intended to restore ovarian fertility and development during the climacteric and has been used to enhance fertility in women with premature ovarian insufficiency (POI). This retrospective study was conducted to determine the effects of an intraovarian platelet-rich plasma (PRP) injection on ovarian stimulation outcomes in women referred to an in vitro fertilisation centre. Methods-Population: This was a retrospective observational study, and the inclusion criteria included women of reproductive age with at least one ovary with a history of infertility, hormonal abnormalities, an absence of a menstrual cycle, and premature ovarian failure. During the patient's first consultation, a detailed reproductive history was recorded, a pelvic scan for ovarian size was conducted, and hormonal analysis for follicle-stimulating hormone (FSH), anti-Müllerian hormone (AMH), estradiol (E2), and luteinizing hormone (LH) was conducted. In the study, 469 women with a history of infertility, hormonal abnormalities, an absence of a menstrual cycle, and premature ovarian failure had hormonal levels recorded up to four months after treatment, and these were included in the study. The volume of peripheral blood required to prepare 6-8 mL of PRP for administration was 40-60 mL. The initial concentration of platelets in the peripheral blood sample was about 25000/µL, whereas the prepared PRP had a concentration of 900.000/µL. A volume of approximately 2-4 mL per ovary, depending on the ovarian volume, was used for the intraovarian injection. PRP intervention had significant effectson FSH concentration at the α = 0.05 level. Statistically significant increases in normal values of FSH and E2were observed for months three and four after the PRP intervention for all age groups. The results of our observational study revealed that a PRP intraovarian injection is associated with improved ovarian tissue and function. Future randomised clinical trials are needed to shed light on the use of PRP in ovarian rejuvenation before offering it routinely in clinical practice.

Population Dynamics, Plasma Cytokines and Platelet Centrifugation: Technical and Sociodemographic Aspects of 'Ovarian Rejuvenation'.

While advanced reproductive technologies have attained remarkable increases in sophistication, success, and availability since the 1980s, clinicians always meet a therapeutic impasse when the ovarian reserve reaches exhaustion. Irrespective of fertility aspirations, the decline in and eventual collapse of ovarian estrogen output means that menopause arrives with tremendous physiologic changes and reduced overall productivity. Because more women are gaining in longevity or delaying the age at pregnancy, the number of affected patients has never been larger. As concerns regarding standard hormone replacement therapy and the limitations of IVF are confronted, a workable path to enable primordial germ cell recruitment and de novo oocyte development would be welcome. Proof-of-concept case reports and clinical studies on autologous activated platelet-rich plasma (PRP) or its condensed cytokine derivatives suggest a way to facilitate these goals. However, ovarian PRP faces vexing challenges that place 'ovarian rejuvenation' under caution as it enters this therapeutic space. Here, we review key features of experimental human ovarian stem cell isolation/handling and reaffirm the need to harmonize laboratory protocols. Recognizing the regenerative science borrowed from other disciplines, specimen centrifugation, platelet processing, and condensed plasma cytokine enrichment are highlighted here. As the refinement of this rejuvenation approach would promise to reprogram adult ovarian physiology, the disruption of established treatment paradigms for infertility, menopause, and perhaps overall women's health seems likely. Emerging roles in reproductive biology and clinical practice are thus placed in a broader social and demographic context.

Promising Future of PRP Treatment for Ovarian Rejuvenation: An In-House Experience of an IVF Institute

Objectives: Over the past few years platelet-rich plasma (PRP) has been shown to have beneficial effects on various organs and sites in the human body. Its effect on restoration of tissue engineering has gained tremendous popularity. Its effect in the field of reproductive medicine only got implemented in last decade. Methods: In this retrospective observational study, we observed 84 cases of ovarian rejuvenation at a fertility clinic from the year 2016 to 2019, out of which 45 were done for the indication of primary ovarian insufficiency for females that fall in the category 3 and 4 of Poseidon criterion. We did an autologous PRP ovarian treatment for each participant. The primary outcome was achieving a biological pregnancy after the procedure. Results: Out of 45 patients in the present study, 27 had achieved biological pregnancy, of which Eight were natural pregnancies, and the remaining 19 had received IVF or IUI as a fertility treatment. Out of these 27 biological pregnancies, 20 patients had a live birth, one had an ectopic pregnancy, and six had miscarriages. Conclusions: The process of autologous intraovarian treatment with PRP definitely helped patients with diminished ovarian reserve to conceive their own genetic offsprings, whose otherwise best option would have been to go through a donor egg program. Hence, PRP definitely deserves a place in the field of reproductive medicine to combat the condition of premature ovarian failure.

Ovarian Rejuvenation by the Autologous Platelet-rich Plasma: Current Status and Future Scope

Ovarian Rejuvenation by the Autologous Platelet-rich Plasma: Current Status and Future Scope

Is autologous platelet activation the key step in ovarian therapy for fertility recovery and menopause reversal?

Platelets are a uniquely mammalian physiologic feature. As the only non-marine vertebrates to experience menopause, humans have a substantial post-reproductive lifespan and are believed to have a limited, non-renewable oocyte supply. Ovarian reserve typically declines after about age 35yrs, marking losses which cannot be recovered by available fertility medications. When in vitro fertilization fails due to low or absent ovarian response, gonadotropin adjustments are often ineffectual and if additional oocytes are occasionally harvested, egg quality is usually poor. This problem was confronted by Greek researchers who developed a new surgical method to insert autologous platelet-rich plasma (PRP) into ovaries; the first ovarian PRP success to improve reproductive outcomes was published from Athens in 2016. This innovation influenced later research with condensed platelet-derived growth factors, leading to correction of oocyte ploidy error, normal blastocyst development, and additional term livebirths. Yet women's health was among the last clinical domains to explore PRP, and its role in 'ovarian rejuvenation' remains unsettled. One critical aspect in this procedure is platelet activation, a commonly overlooked step in the cytokine release cascade considered essential for successful transition of undifferentiated ovarian stem cells to an oocyte lineage. Poor activation of platelets thus becomes an unforced error, potentially diminishing or even negating post-treatment ovarian follicular response. To answer this query, relevant theory, current disagreements, and new data on platelet activation are presented, along with clinical challenges for regenerative fertility practice.

One Side Ovarian Rejuvenation: A Quasi-Experimental Study of the Effect of the Autologous Platelet Rich Plasma in Poor Ovarian Responders in IVF.

The poor ovarian response is the most important limiting factor in the success of in vitro fertilization (IVF). The aim of this study was to evaluate the outcome of intraovarian injection of autologous platelet-rich plasma (aPRP) on the oocyte number and IVF outcomes in poor ovarian responders (POR). This quasi-experimental study was performed from August 2021 to December 2021, in Vali-e-Asr Infertility Clinic affiliated with Tehran University of Medical Sciences, Tehran, Iran. There were 12 POR patients selected based on the criteria of Bologna group 4 who underwent two IVF cycles with similar antagonist regimens in a 70-day-interval. Immediately after the Oocytes Pick-Up (OPU), there was a 4cc of autologous PRP multifocal intramedullary injection done into their right ovaries in the first IVF cycle (case group). On the other hand, their left ovaries were considered as the control group. The patients underwent the second IVF cycle after 70 days. Those who had undergone aPRP experienced a significant increase of the mean of antral follicular count (AFC) (from 1.91±0.79 to 2.50±0.90, p=0.043). There was a significant increase in the number of embryos from the right ovary (intervention group) compared to the left ovary (control group) after PRP, but there was no significant difference in the number of embryos in the right ovary before and after the intervention (from 0.25 ±0.45 to 1.08±0.79, p=0.705). There was no significant change in the number of oocytes, AMH, and FSH in the case and control groups before and after the intervention (p>0.05). According to the results of this study, it seems that in females with POR, intraovarian aPRP had no effect on the outcomes (embryos number, number of oocytes, FSH and AMH level), except for an increase in AFC.

Epigenetics, ovarian cell plasticity, and platelet-rich plasma: Mechanistic theories.

Ovarian platelet-rich plasma (PRP) is claimed to restore the fertility potential by improving reserve, an effect perhaps mediated epigenetically by platelet-discharged regulatory elements rather than gonadotropin-activated G-protein coupled receptors, as with stimulated in vitro fertilization (IVF). The finding that fresh activated platelet releasate includes factors able to promote developmental signaling networks necessary to enable cell pluripotency tends to support this theory. The mechanistic uncertainty of intraovarian PRP notwithstanding, at least two other major challenges confront this controversial intervention. The first challenge is to clarify how perimenopausal ovarian function is reset to levels consistent with ovulation. Perhaps a less obvious secondary problem is to confine this renewal such that any induced recalibration of cellular plasticity is kept within acceptable physiologic bounds. Thus, any 'drive' to ovarian rejuvenation must incorporate both accelerator and brake. Ovarian aging may be best viewed as a safeguard against pathologic overgrowth, where senescence operates as an evolved tumor-suppression response. While most ovary cells reach the close of their metabolic life span with low risk for hypertrophy, enhanced lysosomal activity and the proinflammatory 'senescence-associated secretory phenotype' usually offsets this advantage over time. But is recovery of ovarian fitness possible, even if only briefly prior to IVF? Alterations in gap junctions, bio-conductive features, and modulation of gene regulatory networks after PRP use in other tissues are discussed here alongside early data reported from reproductive medicine.