Clinical practice perspectives on adipose-derived stem cells and platelet-rich plasma for female infertility treatments

Infertility poses a significant global health burden, especially in cases where diminished ovarian reserve and endometrial injury limit the success of standard assisted reproductive technology treatments. Platelet-Rich Plasma (PRP) have gained attention as novel regenerative tool and adipose-derived stem cells (ADSCs) has recently gained lots of interest owing to their easy availability, multipotent characteristics, and paracrine activity. The combination of PRP and ADSCs acts better than each one individually and acts synergistically to promote tissue regeneration. This review addresses studies on the application of PRP and ADSCs in reproductive medicine, specifically targeting ovaries and uterus. In ovaries, ADSCs and PRP demonstrated potential for functional recovery in premature ovarian insufficiency, early menopause, and chemotherapy-induced ovarian damage, showing menstrual restoration, hormonal normalization, and stimulation of follicle growth. ADSC-derived exosomes and conditioned medium promoted oocyte maturation, lowered oxidative stress, improved blastocyst development, and increased embryo survival. Additionally, findings indicate that intrauterine delivery of ADSCs and PRP enhances endometrial thickness, angiogenesis, and receptivity, with reports of improved implantation and pregnancy outcomes in women with thin endometrial lining or Asherman’s syndrome. Collectively, these results underscore the regenerative promise of ADSCs and PRP in overcoming various infertility causes. ARTICLE HIGHLIGHTS ADSCs and PRP offer regenerative potential for ovarian and endometrial repair. Combination therapy demonstrates synergistic paracrine and angiogenic effects. Early clinical studies show improved ovarian and endometrial function but remain limited. Standardized preparation and dosing protocols are urgently needed. Long-term safety and offspring outcomes require further study. ADSC–PRP therapy may serve as a future adjunct to ART in select patients. 1. Introduction As the incidence of infertility is expected to continue increasing through 2040 [Citation1], there is an urgent need for innovative strategies that move beyond symptomatic management to true regenerative repair of reproductive tissues because conventional treatments, such as hormone replacement, surgery and assisted reproductive technologies (ART), offer only partial solutions [Citation2]. The etiologies of infertility are multifactorial with diminished ovarian reserve (DOR) and premature ovarian insufficiency (POI), usually managed with hormone replacement therapy (HRT) or oocyte donation [Citation3], are among the most difficult causes to treat in cases where the patient desire genetically related children [Citation4]. Additionally, endometrial damage leading to thin endometrial lining often resists medical and surgical interventions leading to the use of surrogacy [Citation5] and recurrent implantation failure (RIF) represents another frustrating diagnosis for both the patients and their physicians. Thus, there is a critical need to help patients struggling with these conditions. The combined use of platelet-rich plasma (PRP) and adipose-derived mesenchymal stem cells (ADSCs) as regenerative therapies have been demonstrated in experimental and early clinical models [Citation6,Citation7]. PRP provides concentrated growth factors that enhance healing [Citation7], while ADSCs are multipotent, easily harvested cells with strong paracrine and immunomodulatory properties [Citation8]. Preclinical studies in periodontal, tendon, bone, cartilage, skin, cardiovascular, and neural models consistently demonstrated that co-administration of PRP and ADMSCs significantly improved outcomes, compared to either treatment alone, showing enhanced angiogenesis, reduced inflammation, improved tissue remodeling, and better functional recovery [Citation9–11]. Among the different sources of mesenchymal stem cells [Citation12], ADSCs stand out because they are plentiful, can be obtained through minimally invasive procedures, and possess both multipotent differentiation potential and strong paracrine signaling capacity [Citation13–15]. In addition to their capacity for engraftment and lineage differentiation, ADSCs release a diverse array of bioactive factors—including extracellular vesicles (exosomes)—that influence angiogenesis, fibrosis, immune modulation, and cell survival [Citation13–15]. These characteristics make ADSCs promising candidates for targeting key mechanisms that contribute to reproductive dysfunction, such as depletion of ovarian follicles, poor oocyte quality, poor fertilization, impaired embryonic development, and endometrial injury [Citation16–18]. This review aims to provide a critical analysis of current evidence on the use of ADSCs and PRP in reproductive medicine, with particular emphasis on their effects on the ovary and uterus. By examining both reported benefits and existing limitations, this review seeks to clarify the translational promise of ADSC–PRP therapies as adjuncts to ART and to highlight the preparation of ADSC–PRP combination therapy in clinical practice as well as the major challenges that need to be resolved before these approaches can be integrated into routine clinical practice. 2. Summary of PRP preparation and its use in reproductive medicine PRP, derived from a patient’s own blood, an autologous concentrate enriched with growth factors including as Platelet-Derived Growth Factor (PDGF), Transforming Growth Factor-beta (TGF-β), Vascular Endothelial Growth Factor (VEGF), Insulin-like Growth Factor (IGF), among others [Citation19], has emerged as a regenerative therapy in multiple fields of medicine and has been widely applied in orthopedics [Citation20], dermatology [Citation21], and wound healing [Citation22] for its regenerative, angiogenic, and anti-apoptotic properties [Citation23–26]. In reproductive medicine, PRP has been studied for its potential to restore ovarian function in women with DOR or premature ovarian insufficiency (POI) [Citation26], to enhance endometrial receptivity in cases of thin endometrial lining (EMT) or recurrent implantation failure (RIF) [Citation25], and to improve ovulatory and hormonal profiles in PCOS [Citation27,Citation28]. The existing data have reported encouraging findings—including improvements in ovarian reserve markers (such as anti-Mullerian hormone [AMH]), antral follicle count (AFC), oocyte quality, blastocyst formation, and implantation rates—yet results remain inconsistent, and robust randomized controlled trials (RCTs) are scarce (). PRP is an autologous blood-derived product that contains a platelet concentration significantly higher than that of peripheral blood. It is prepared by centrifuging a small volume of the patient’s blood to separate its components and isolating the fraction rich in platelets and plasma proteins. Typically, approximately 30–40 mL of peripheral blood is collected from the patient via venipuncture into anticoagulant-treated tubes. Samples are first centrifuged at 1500 × g for 5–15 minutes to separate the blood components into red blood cells, a buffy coat, and plasma. The upper fraction containing platelet-poor plasma (PPP) is then carefully removed, leaving the platelet-rich fraction above the buffy coat. This fraction is then transferred to a new sterile tube and subjected to a second centrifugation step (1500–3000 × g for 5–10 minutes) to further concentrate the platelets. The resulting platelet pellet is resuspended in a reduced volume of plasma, yielding approximately 4–6 mL of PRP (, Step 1). A major challenge in the use of PRP lies in the significant variability among available devices and preparation methods, which leads to inconsistent platelet concentrations, leukocyte content, and activation profiles, ultimately producing heterogeneous biologic products and variable patient outcomes [Citation29]. Many commercial PRP extraction devices exist, each capturing platelets and non-platelet cellular components to differing degrees generally yielding different platelet counts. This lack of standardization has led to individualized dosing strategies that account for tissue type, pathology, and clinical goals. PRP can be broadly classified into pure PRP, leukocyte-poor PRP (LP-PRP), leukocyte-rich PRP (LR-PRP), and platelet-rich fibrin (PRF), each with distinct biological properties. Plasma-based PRP and PRF preparations, for example, rely more heavily on fibrin polymerization and gradual fibrinolysis to sustain factor release. Device-dependent factors—including blood volume processed, anticoagulant choice, centrifugation profiles, spin cycles, and acceleration–deceleration forces—further influence platelet yield and leukocyte subpopulation capture. The heterogeneity in these formulations impacts immunomodulation, angiogenesis, and tissue repair, underscoring the need for validated classification systems and reproducible protocols [Citation29]. In both research and clinical practice, there is an urgent need to adopt standardized protocols for PRP administration in reproductive medicine to ensure reproducibility and comparability of outcomes [Citation30]. Standardization should encompass several key aspects: (i) the method of PRP preparation, as centrifugation speed, duration, and leukocyte content directly influence platelet yield and growth factor concentrations; (ii) the number and anatomical location of injections, whether targeted into each ovary for “ovarian rejuvenation” or directly into the endometrial lining for “uterine regeneration”; (iii) the precise volume of PRP administered per site, since both under- and overdosing may alter biological activity; (iv) the needle gauge and technique used for PRP delivery, which determine accuracy, tissue penetration, and patient comfort; and (v) the menstrual cycle phase or treatment cycle context during which PRP is applied, given that hormonal milieu and endometrial receptivity vary significantly across phases. Without consensus on these critical parameters, published studies remain heterogeneous, and results are difficult to interpret collectively. Consequently, while early evidence suggests promising effects of PRP on ovarian function, endometrial receptivity, and implantation outcomes, the lack of standardized methodology continues to fuel debate, leaving the clinical utility of PRP in reproductive medicine uncertain and in need of rigorous validation through well-designed randomized controlled trials. 3. Preparation of autologous ADSC-rich sample Most published studies on ADSCs to date have relied on enzymatic digestion methods (e.g., collagenase-based) followed by culture expansion prior to intraovarian or intrauterine use [Citation10,Citation14,Citation31,Citation32]. However, to align with FDA minimal manipulation requirements, clinical practice increasingly employs mechanical isolation systems that process adipose tissue without enzymatic reagents [Citation33]. These closed, sterile devices enable removal of oil and infranatant components while preserving the stromal vascular fraction (SVF) naturally enriched with ADSCs. Both enzymatic and mechanical methods have unique strengths: enzymatic digestion yields higher cell counts and purity, whereas mechanical systems offer regulatory compliance, shorter preparation times, and autologous safety [Citation34–36]. There are several steps in order to prepare adipose rich in ADSCs in clinical practice (see ). Microfat is composed of adipose tissue and ADSCs. Nanofat, or filtered lipids, are made by the mechanical emulsification of microfat, which contains growth factors, bioactive cytokines, tissue stromal vascular fraction and ADSCs. In clinical practice, the goal is to collect microfat first then emulsify it to nanofat that will be added to the PRP the combination of which to be injected into the ovaries or the uterus. One mL of nanofat usually contain 400,000 ADSCs on average [Citation37]. 3.1. Preparation of microfat by miniliposuction (, Step 2) In clinical use, autologous adipose tissue is aspirated from subabdominal or flank areas through a small incision under local anesthesia and processed mechanically to yield microfat and nanofat fractions enriched with ADSCs. The processed adipose is subsequently emulsified through a series of filtration and transfer steps to achieve a uniform suspension suitable for combination with PRP. Multiple validated commercial systems are available for this purpose, each with minor differences in centrifugation speed, connector size, and filtration technology [Citation34,Citation35]. The description herein reflects general principles drawn from peer-reviewed protocols rather than endorsement of a specific proprietary system. The authors describe the preparation as aspiration of adipose tissue from subabdominal fat pads through a small infraumbilical incision, as detailed in previously published protocols where concentrated adipose tissue microfat is prepared using the FDA-approved Progenikine® Concentrating System (Emcyte Corporation, Fort Myers, FL, USA) [Citation34,Citation35]. The preparation methods summarized here are based on established literature and not original procedural experience. Adipose tissue is aspirated from subabdominal fat pads through a 2 mm infraumbilical incision. Prior to aspiration, a Klein’s tumescent solution—containing lidocaine (1%), epinephrine (1 mg/mL, 1:1,000), sodium bicarbonate (10 mEq/L), and normal saline—was slowly infiltrated using a 2.1 mm × 20 cm tumescent infiltrator. Approximately 20 mL of fat mixed with tumescent solution is then harvested manually with a 2.4 mm × 20 cm cannula harvester with 1 mm side holes, using a 60 mL syringe. The Progenikine® system, designed for harvesting and concentrating autologous adipose tissue, enables purification, emulsification, and condensation of lipoaspirate by efficiently removing oil and infranatant contaminants [Citation34,Citation35]. Following injection of the harvested adipose into the disposable Progenikine® kit, samples are centrifuged at 1500 RPM for 3.5 minutes with a counterbalanced load. This process separated the lipoaspirate into three layers: oil lipids (upper layer), condensed adipose (middle layer), and infranatant fluid (lower layer) (, Step 2). The oil and infranatant were discarded by aspiration through the designated ports, and the purified condensed adipose is collected from the bottom port into a 10 mL syringe, yielding approximately 6 mL of microfat. This microfat is subsequently processed using the Tulip System (Tulip Medical Products, San Diego, CA) to generate nanofat for clinical use (, Step 2). 3.2. Preparation of the nanofat from the microfat The emulsification of microfat is usually performed using the Tulip System [Citation34–36]. After harvesting and cleaning, the microfat was loaded into 10 mL syringes and initially emulsified by transferring the contents 20 times back and forth between two syringes connected with a 2.4-mm Tulip transfer connector. The procedure was then repeated with progressively smaller connectors, first with a 1.4-mm transfer and subsequently with a 1.2-mm transfer, each for 20 passes, until the fat became fully liquefied and displayed a pale-yellow appearance. The resulting product was further refined by passing it once through a nanotransfer block containing a double filter (400 µm and 600 µm single-use cartridge nets). The final yield was approximately 6 mL of nanofat collected into a 10 mL syringe, ready for use. 4. Administration of adipose-PRP into the ovaries and uterus The combined preparation of nanofat and PRP, referred to as Adipose-PRP, is obtained by mixing 6 mL of nanofat (containing approximately 400,000 ADSCs/mL of nanofat) with 4 mL of PRP under sterile conditions, followed by vigorous shaking to ensure homogeneity. From the 10 mL mixture, 6 mL is aspirated into a 10 mL syringe for intraovarian administration (, Step 3). Under intravenous sedation and transvaginal ultrasound guidance, approximately 3 mL of the Adipose-PRP mixture is injected into each ovary. Delivery is performed into the subcortical layers using a 22-gauge needle and guide, with 5–8 punctures per ovary to achieve multifocal diffusion of the preparation [Citation30,Citation38,Citation39]. For intrauterine application, PRP injection is carried out under hysteroscopic guidance [Citation40–42]. A diagnostic hysteroscope (5–7 mm in diameter) is introduced into the uterine cavity, and following careful inspection of the endometrium, an injection needle passed through the operating channel is used to deliver Adipose-PRP directly into the subendometrial tissue (, Step 3). Injections are performed across multiple quadrants of the cavity, including the anterior, posterior, and fundal walls, with approximately 2 mL administered per site, yielding a total of approximately 6 mL [Citation40–42]. Strict care is taken to ensure intramural delivery and to prevent pooling of PRP within the cavity. This combined intraovarian and intrauterine approach allows precise localization of Adipose-PRP, thereby maximizing regenerative potential while minimizing risks and patient discomfort. 5. Why the combination of PRP and ADIPOSE ADSCs? ADSCs are attractive therapeutic candidates; however, their survival and integration at transplantation sites remain limited. Combining PRP with ADSCs offers potential synergy [Citation9–11], yet the molecular mechanisms of PRP action on adipose tissue biology were poorly defined until it has been shown that PRP markedly enhanced ADSC viability, proliferation, and migration while reducing apoptosis [Citation43]. In that study, human PRP was prepared from the blood of healthy donors undergoing surgery. PRP gels were generated by activation with thrombin and calcium. Human ADSCs were isolated from adipose tissue biopsies and cultured. The experiments assessed (i) cell growth and viability via sulforhodamine assay, (ii) cell cycle progression by BrdU/PI staining, (iii) migration through transwell assays, (iv) intracellular signaling by Western blot for Akt/ERK and caspase-3, (v) adipogenic differentiation by Oil Red O staining and RT-PCR for PPARγ and aP2, and (vi) cytokine/growth factor release from adipocytes by multiplex assays. Their results showed that PRP promotes ADSC survival, growth, and migration by increasing ADSC viability up to 4-fold compared to fetal bovine serum. The effect scaled with platelet concentration, with “high platelet” PRP inducing faster proliferation. PRP promoted G1-to-S phase progression, reduced caspase-3 cleavage, and activated Akt/ERK pathways. Migration assays confirmed that PRP enhanced ADMSC motility by up to 2-fold, supporting both proliferative and chemo-attractant effects. As for adipogenesis and adipocyte survival, PRP did not impair adipogenic differentiation, as evidenced by normal lipid accumulation and PPARγ/aP2 expression. Mature adipocyte viability was not reduced, and leptin production increased threefold with PRP exposure. This indicated that PRP sustains adipocyte function while augmenting metabolic signaling. Finally, PRP-treated adipocytes secreted significantly higher levels of IL-6, IL-8, IL-10, IFN-γ, and VEGF, suggesting an enhanced pro-angiogenic and immunomodulatory profile. The findings underscore PRP’s role in shifting adipocyte secretome toward a pro-regenerative phenotype [Citation43]. These findings suggest that PRP enhances stem cell-driven regeneration while modulating adipocyte secretory activity, favoring tissue repair processes. These findings highlight the therapeutic potential of combining PRP with ADSCs in regenerative applications. Equine studies provide important translational insights into the regenerative potential of combining PRP with ADSCs [Citation44]. In vitro experiments demonstrated that PRP significantly enhanced ADSC proliferation in a dose-dependent manner [Citation44]. Overall, these findings further underscore the synergistic effects of ADSCs and PRP by improving the quality of tissue regeneration, thereby reinforcing their potential value as regenerative strategies. 6. Clinical applications of ADSCS 6.1. Ovarian applications of ADSCs ADSCs are being explored across multiple ovarian contexts because they are abundant, easily harvested, and exert potent paracrine, angiogenic, and immunomodulatory effects that may restore a dysfunctional ovarian microenvironment. Preclinical and early clinical investigations indicate that ADSCs can ameliorate chemotherapy-induced damage, partially reverse endocrine disturbances characteristic of premature ovarian insufficiency (POI), and improve gamete and embryo competence via mitochondria, extracellular vesicles, or conditioned products. Collectively, these lines of evidence suggest a broad regenerative role for ADSCs in ovarian repair; however, heterogeneity in models, dosing, delivery routes, and outcome measures still limits comparability and clinical translation. 6.1.1. Intraovarian administration of ADSCs for POI (Preclinical and human studies) POI affects up to 3.5% of reproductive-age women and remains largely irreversible, with current management centered on symptom-directed hormone therapy and donor oocytes [Citation45,Citation46]. Rodent work in cyclophosphamide models showed that intraovarian ADSCs restored follicle and corpus luteum numbers, increased angiogenesis (CD34), improved litter size, and upregulated VEGF, IGF-1, HGF, and StAR mRNA, while fluorescent tracking localized donor cells to the thecal layer rather than oocytes, supporting a paracrine mechanism; single-factor administration reproduced only partial benefits, and no intergenerational adverse effects were detected [Citation47–49]. Overall, intraovarian ADSC therapy appears safe and biologically active but requires larger randomized trials with standardized protocols to establish efficacy, dose, and mechanism. These encouraging preclinical findings have prompted early human trials evaluating the feasibility and safety of autologous ADSC transplantation in women with POI. In a first-in-human, dose-escalation phase I study (n = 9) [Citation50], unilateral intraovarian injection of autologous ADSCs (5–15 × 10^6 cells) was feasible and safe, with no acute or delayed complications, resumption of menses in four participants within two months, and declines of FSH below 25 IU/L in four cases over follow-up to 12 months; AMH, ovarian volume, and antral follicle counts varied without clear dose–response. 6.1.2. ADSC’s exosomes for poor oocyte quality ADSC-derived extracellular vesicles (EVs/exosomes) deliver proteins, RNAs, and metabolites that modulate oxidative stress, apoptosis, and cell-cycle control [Citation51,Citation52]. In porcine parthenogenetic embryo culture, ADSC-EV supplementation improved blastocyst rates and quality, increased intracellular glutathione, reduced ROS and apoptosis, and upregulated pluripotency and mitotic regulators—implicating an SRC–AKT–CDK1 axis—although in vivo validation is lacking [Citation53]. In chemotherapy-induced POI mouse models, human or murine ADSC exosomes restored follicle numbers and ovarian histology, normalized E2/FSH/AMH, reduced oxidative stress and granulosa-cell apoptosis, and acted via suppression of AMPK/mTOR-mediated autophagy or activation of SMAD2/3/5 signaling; pathway knockdown abrogated protection [Citation54,Citation55]. Together, these data position ADSC exosomes as a cell-free therapeutic that recapitulates key benefits of ADSC paracrine signaling, but translation will require dose-finding, cargo characterization, reproductive outcome studies, and long-term safety assessment. 6.1.3. Co-culture systems and In vitro applications (experimental evidence) ADSCs and their derivatives enhance in vitro maturation and embryo development by providing a trophic microenvironment. In porcine models, ADSC co-culture or conditioned medium increased nuclear maturation and cleavage, improved blastocyst cell numbers, and upregulated GDF9/BMP15, growth-factor receptors, and anti-apoptotic transcripts, with lower ROS [Citation56]. In bovine systems, ADSC lysate boosted blastocyst yield and post-thaw survival without the lipid accumulation and apoptosis associated with serum, improving cryotolerance while preserving developmental gene expression [Citation57]. Direct co-culture with bovine ADSCs outperformed granulosa-cell systems, increasing blastocyst rates and cell counts without inducing stress markers [Citation58]. Encapsulation of murine early follicles with ADSCs in alginate enhanced survival, growth, antrum formation, steroidogenesis, and meiotic competence, indicating that ADSCs can sustain folliculogenesis through paracrine support [Citation31]. Although these models are preclinical and species-specific, they collectively suggest that ADSC-based co-culture strategies can improve oocyte competence, embryo quality, and follicle development, warranting rigorous testing in human ART with standardized readouts and clinical endpoints. 6.2. Uterine applications of ADCSS for injured endometrium Intrauterine adhesions (IUAs), or Asherman’s syndrome, along with refractory thin endometrium, remain major challenges in reproductive medicine, often unresponsive to conventional therapies such as hormonal supplementation, vasoactive agents, or intrauterine biologics like PRP or G-CSF [Citation24,Citation59–63]. ADSCs, with their accessibility, multipotency, and paracrine activity, have recently been investigated as a regenerative strategy for restoring endometrial structure and function [Citation64]. 6.2.1. Animal studies Preclinical models demonstrate that ADSCs enhance endometrial regeneration through anti-fibrotic, angiogenic, and trophic mechanisms. In rat IUA models [Citation65], ADSCs delivered via acellular human amniotic membrane scaffolds increased endometrial thickness, glandular density, microvessel formation, and receptivity markers (ERα, PR, integrin αVβ3, LIF), while ADSC transplantation alone improved pregnancy rates to 60% compared with 0% in saline controls [Citation65]. Scaffold-based approaches, such as collagen–ADSC composites, further improved cellular proliferation, vascularization, and reduced fibrosis, achieving up to 50% pregnancy rates and 28% implantation in treated uterine horns [Citation66]. In mice with ethanol-induced thin endometrium, both fresh and cryopreserved ADSCs restored thickness, reduced fibrosis, and significantly improved implantation rates (47–69 vs. 8% in untreated controls), with angiogenesis via VEGF upregulation identified as a primary mechanism [Citation67]. Across studies, transplanted ADSCs localized to the basal layer or stroma, exerting effects primarily via paracrine signaling rather than direct differentiation. Limitations of these models include short follow-up, small sample sizes, xenogeneic settings, and lack of large-animal or mechanistic validation. Building on these preclinical observations, a limited number of human studies have begun exploring the safety and therapeutic potential of ADSCs for endometrial regeneration. 6.2.2. Human studies Early clinical experiences also suggest safety and efficacy of ADSCs for severe endometrial injury. In a retrospective two-arm study of 41 women with Asherman’s syndrome [Citation68], intrauterine ADSC injections significantly increased endometrial thickness (from 4.9 to 8.2 mm), with subsequent implantation, pregnancy, and live birth rates of 66.7, 57.1, and 47.6%, respectively, compared with negligible outcomes pretreatment. A smaller pilot trial [Citation41] in six women with severe refractory thin endometrium demonstrated increased endometrial thickness (from 3.0 mm to 6.9 mm), improved trilaminar morphology, and partial restoration of menstruation. One conception occurred, though it ended in miscarriage. Both studies reported no major complications, aside from minor liposuction-related bruising, confirming safety. However, limitations include very small cohorts, lack of standardized cell characterization or dosing protocols, reliance on historical controls, and limited fertility outcomes. Together, animal and early human studies provide proof-of-concept that ADSCs can restore endometrial structure, enhance vascularization, and improve receptivity, thereby increasing the potential for implantation and pregnancy in cases of thin endometrium or Asherman’s syndrome. Nonetheless, methodological heterogeneity, limited mechanistic insight, and small-scale trials highlight the need for larger, well-designed clinical studies to establish efficacy, optimize delivery approaches (direct injection vs. scaffold-based), and define safety for translation into reproductive practice. 7. Discussion The integration of ADSCs and PRP into reproductive medicine represents an important step toward regenerative solutions for infertility. Collectively, the data from animal studies and preliminary human trials demonstrate that ADSCs and their derivatives—exosomes and conditioned media—exert beneficial effects on ovarian and uterine tissue through mechanisms including angiogenesis, anti-fibrosis, immunomodulation, and paracrine signaling [Citation47–49]. PRP, enriched with growth factors and cytokines, complements these effects by enhancing ADSC survival, proliferation, and functional activity [Citation43]. This synergy has been observed across multiple systems, with ADSC–PRP combinations improving cell viability, migration, vascularization, and tissue repair compared to either modality alone [Citation9–11]. To enhance generalizability, this review refers to mechanical ADSC isolation techniques generically, acknowledging that a variety of commercially available systems can achieve comparable outcomes. While ADSCs exhibit strong regenerative and immunomodulatory effects, potential risks should be recognized. Although tumorigenic transformation of culture-expanded ADSCs has not been demonstrated in human studies, prolonged in vitro expansion may theoretically induce genomic instability. Allogeneic ADSC use, while practical for standardized preparations, carries risks of immune sensitization and graft rejection, underscoring the importance of autologous protocols in current practice. Procedural complications such as infection or liposuction-related morbidity are rare but possible. Compared with bone marrow– or umbilical cord–derived mesenchymal stem cells (MSCs), ADSCs are more abundant, easier to harvest, and yield higher cell numbers per gram of tissue. However, bone marrow MSCs may exhibit greater osteogenic and angiogenic capacity, while umbilical cord MSCs show lower immunogenicity, which may favor their allogeneic use. To date, most reproductive trials have used autologous ADSCs or stromal vascular fraction due to ease of preparation and favorable regulatory status. Ovarian applications have likewise demonstrated meaningful effects: animal models show recovery of folliculogenesis, endocrine function, and fertility after chemotherapy-induced ovarian damage, while early human studies in POI report restoration of menses and partial normalization of gonadotropin levels [Citation50]. ADSC-derived exosomes extend the therapeutic potential, offering innovative, cell-free approaches to improving oocyte quality and embryo development [Citation54,Citation55]. Furthermore, embryo-level interventions with ADSC-conditioned media, lysates, or co-culture systems have improved blastocyst development, cryotolerance, and oocyte competence in preclinical models, suggesting applications for in vitro maturation (IVM) and IVF optimization [Citation56–58]. In the uterus, ADSC-based therapies have shown promise in restoring endometrial thickness, gland density, vascular integrity, and expression of receptivity markers in models of intrauterine adhesions and thin endometrium [Citation65–67]. Encouragingly, limited clinical reports suggest improved implantation and pregnancy outcomes following ADSC or SVF therapy in patients with refractory endometrial dysfunction [Citation41,Citation68]. Despite these advances, substantial challenges remain. First, methodological heterogeneity across studies—including variation in ADSC preparation (enzymatic vs. mechanical processing), culture expansion, dosing, route of administration, and scaffold use—limits comparability and translation. Second, most evidence is derived from small cohorts or preclinical models, with limited follow-up, making it difficult to assess long-term safety, durability of ovarian or endometrial function, and potential risks to offspring. Third, mechanistic clarity is incomplete, particularly regarding the molecular mediators of ADSC–PRP synergy and how these interact with reproductive immune and stromal microenvironments. Fourth, regulatory and ethical considerations—especially concerning exosome-based therapies—require careful evaluation. From a regulatory standpoint, autologous ADSC use in the United States is governed by FDA guidelines on minimal manipulation and homologous use, whereas the European Medicines Agency (EMA) classifies most stem cell–based products as advanced therapy medicinal products (ATMPs) [Citation33]. Off-label or unapproved use outside controlled studies remains ethically sensitive, emphasizing the need for transparent reporting, patient consent, and harmonization of international standards. Addressing these gaps will be critical for moving ADSC–PRP therapies from experimental promise into validated clinical practice. Despite encouraging results, the current human evidence remains limited by small, non-randomized studies with short follow-up durations and absence of sham or placebo controls. Considerable heterogeneity in PRP composition, ADSC preparation, and patient selection further complicates interpretation. Moreover, publication bias favoring positive outcomes cannot be excluded, as null or negative results are seldom reported. Recent single-cell transcriptomic and proteomic studies have revealed that adipose-derived stem cells are not a uniform population but comprise distinct subtypes with variable angiogenic, fibrotic, and immunomodulatory capacities. Integrating these omics-level insights into reproductive models could improve our understanding of ADSC behavior within ovarian and endometrial niches, guiding cell selection and potency assays for clinical applications. Given the increasing number of small-scale and non-randomized reports on intraovarian and intrauterine ADSC–PRP therapy, future meta-analyses and systematic reviews are warranted to quantify pooled effect sizes for key outcomes such as AMH improvement, endometrial thickness, pregnancy rate, and live birth. Harmonized reporting standards—such as CONSORT and PRISMA extensions for cellular interventions—would enhance comparability and enable more robust evidence synthesis. Long-term safety data remain sparse. Although animal studies have not shown teratogenicity or multigenerational abnormalities following ADSC administration, human follow-up is generally limited to 6–12 months. Future studies should evaluate offspring health, tumorigenic potential, and genomic stability to confirm the absence of late adverse effects. Such safety monitoring is critical before widespread adoption of regenerative therapies in reproductive-age women. From a clinical standpoint, patient selection is likely to be crucial for optimizing regenerative outcomes. Candidates who may derive the greatest benefit include women with POI, DOR, or refractory thin EMT unresponsive to conventional therapies. In contrast, patients with advanced age-related infertility or severe uterine pathology may experience limited regenerative response. Integration of ADSC–PRP therapy into ART protocols could involve intraovarian or intrauterine administration prior to IVF cycles, timed preceding ovarian stimulation. Economic considerations also warrant attention: although ADSC–PRP preparation is minimally invasive, it remains resource-intensive, and cost-effectiveness relative to donor oocyte cycles or surrogacy should be formally assessed. Incorporating these therapies into evidence-based, patient-specific ART algorithms may ultimately determine their feasibility in clinical practice. 8. Conclusion ADSCs, particularly when combined with PRP, represent a versatile and promising regenerative platform for reproductive medicine. Preclinical and early clinical studies consistently indicate that ADSC–PRP interventions can restore endometrial receptivity, partially recover ovarian function, and enhance oocyte and embryo competence. These benefits appear to arise from both direct tissue interactions and paracrine mechanisms, including delivery of growth factors, exosomes, and mitochondria. Importantly, ADSCs are abundant, easily harvested, and generally well tolerated, while PRP provides a biocompatible scaffold rich in regenerative mediators. Nevertheless, the field is still in its infancy. Current evidence, while compelling, is constrained by methodological heterogeneity, small patient numbers, and a lack of long-term follow-up. Standardized preparation methods, harmonized dosing protocols, and robust randomized controlled trials are urgently needed to confirm safety, efficacy, and durability. If these challenges are met, ADSC–PRP therapies could shift infertility management away from symptomatic treatments toward true regenerative repair, offering new hope for patients with diminished ovarian reserve, premature ovarian insufficiency, thin endometrium, or recurrent implantation failure. Ultimately, ADSC–PRP integration has the potential to become a transformative adjunct to assisted reproductive technologies, aligning with the broader vision of precision and personalized reproductive care. Although ADSC–PRP therapies represent a promising regenerative strategy, their clinical application remains in an exploratory stage. The reported benefits should be interpreted cautiously until validated by adequately powered, randomized phase II/III trials with standardized preparation methods, safety monitoring, and long-term follow-up. At present, these approaches are best regarded as investigational adjuncts rather than established clinical interventions. Author contributions Z.M. performed conceptualization, literature review, drafting, critical revisions, and final approval of the manuscript. Acknowledgments Generative AI tools (ChatGPT, GPT-5, OpenAI) were used to assist in language editing, formatting, and reference organization under author supervision. All intellectual content and scientific interpretation were developed solely by the authors. Disclosure statement The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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