Recent trends in polycystic ovary syndrome treatment based on adult stem cell therapies
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Abstract
Adult stem cell therapy has emerged as a prominent area of interest in regenerative medicine, drawing attention from numerous researchers who are investigating its potential for treating degenerative diseases, especially those affecting the reproductive system. Despite the growing focus, critical elements such as the optimization of treatment parameters (e.g., transplantation [Tx] route, cell dosage) and enhancement of therapeutic efficacy are still areas of uncertainty. This review paper presents a thorough analysis of recent preclinical and clinical studies on adult stem cell therapy for ovarian dysfunction, specifically targeting conditions like polycystic ovary syndrome (PCOS). By examining these studies, the review seeks to clarify the current state of knowledge and pinpoint gaps in understanding, thereby establishing a robust foundation for future advancements in adult stem cell therapies aimed at ovarian dysfunction. Ultimately, this paper aims to offer valuable insights that could lead to improved treatment strategies in the field of reproductive system diseases.
Introduction
Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder among women of reproductive age, affecting 4% to 20% of this population before menopause [1]. Although the etiology of PCOS is varied and not fully understood, it is recognized as a complex condition influenced by multiple genes, as well as significant factors such as epigenetics and environmental elements, including diet and lifestyle [2]. PCOS is diagnosed based on four main categories of indicators: (1) metabolic dysfunction, (2) hyperandrogenism, (3) polycystic ovarian morphology, and (4) menstrual abnormalities [3]. Despite the broad diagnostic criteria that reflect the multifaceted nature of PCOS, the diagnosis is well-standardized. It addresses the consequences of androgen excess, ovarian dysfunction, and associated metabolic disorders. Moreover, integrating appropriate treatment strategies is essential for the effective management of PCOS [4,5].
Insulin-sensitizing agents, particularly metformin, are widely recommended for managing PCOS because they positively affect a range of symptoms, including irregular menstruation, anovulation, insulin resistance, hirsutism, and obesity [6,7]. Metformin is often prescribed as a first-line treatment to induce ovulation, with robust supporting evidence [8]. However, its benefits might be temporary, and there is a need for caution due to possible gastrointestinal side effects [9]. Therefore, a balanced approach that weighs both efficacy and potential drawbacks is crucial in the treatment of PCOS.
Due to the limitations associated with side effects and therapeutic efficacy of commonly used chemical drugs for PCOS, there is increasing emphasis on investigating the paracrine effects of adult stem cells. These effects are crucial in defending against metabolic diseases, including PCOS [10]. Notably, several scientists have conducted preclinical research demonstrating the significant therapeutic potential of adult stem cell therapy in the treatment of PCOS [11]. This promising avenue of research suggests a potential paradigm shift in the management of PCOS, offering a compelling alternative to conventional chemical drugs. As ongoing research delves deeper into the mechanisms and outcomes of stem cell therapy, it holds the promise of not only overcoming current limitations but also ushering in a new era of more effective and well-tolerated interventions for individuals with PCOS.
This review focuses on exploring the complex mechanisms through which adult stem cells can be therapeutically utilized to address the challenges posed by PCOS. By conducting an in-depth analysis of recent preclinical studies and ongoing clinical trials, we aim to offer valuable insights into the therapeutic potential of stem cell therapy for treating ovarian dysfunction, especially within the context of PCOS. Our objective is to establish a foundation for the development of stem cell interventions that enhance ovarian function and improve reproductive healthcare outcomes for those affected by PCOS.
PCOS as a metabolic disease
PCOS is a prevalent reproductive disorder among women, marked by anovulatory infertility and a spectrum of clinical features such as metabolic dysfunction and hyperandrogenism [2]. The diagnosis of PCOS is complex and often relies on criteria like those established by the Rotterdam Consensus, which stipulates the presence of at least two of the following: irregular ovulation, signs of hyperandrogenism, and polycystic ovaries (Table 1) [12]. The biochemical diagnosis may reveal abnormal hormonal levels, including elevated testosterone and a high luteinizing hormone/follicle stimulating hormone (LH/FSH) ratio [13,14].
Characteristics of polycystic ovary syndrome (Rotterdam criteria)
In addition to reproductive challenges, women with PCOS are at an increased risk of developing type 2 diabetes (T2D) and insulin dysfunction [15,16]. The diagnostic criteria for metabolic syndrome in PCOS include factors associated with insulin resistance, such as abdominal obesity, high triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C), elevated blood pressure, and high fasting glucose levels [17]. Understanding the interplay of reproductive and metabolic factors is essential for an effective diagnosis and tailored management. Addressing both aspects is crucial for improving the health outcomes of women with PCOS.
The underlying pathophysiology of metabolic symptoms in PCOS has not yet been fully elucidated. However, insulin resistance, dyslipidemia, and excess androgens in PCOS can be classified as components of metabolic syndrome [18]. Excessive androgens significantly affect peripheral tissues, contributing to metabolic complications such as obesity and insulin resistance [19]. The liver acts as a metabolic hub, and endocrine disorders in women may be exacerbated through the liver-ovary axis, particularly when pathological changes are present in the liver [20,21]. Insulin resistance, which is prevalent in obesity, is associated with hyperinsulinemia. This condition affects the hypothalamus, leading to increased androgen synthesis [22], ovarian follicle arrest, and elevated LH secretion perpetuating insulin resistance [20].
Obesity, which is common in PCOS, influences follicular development by affecting vascular endothelial growth factor (VEGF)-induced angiogenesis via interleukin 10 (IL-10) secretion from adipocytes [23]. Dyslipidemia, found in 70% of PCOS patients, is characterized by increased levels of low-density lipoprotein (LDL) cholesterol, very LDL cholesterol, TG, and free fatty acids, alongside a decrease in HDL-C [24,25]. PCOS is also associated with metabolic dysfunction-associated fatty liver disease, metabolic dysfunction-associated steatohepatitis, and cardiovascular disease, sharing metabolic symptoms with these conditions [26]. Li et al. [27] observed elevated aspartate transaminase levels in letrozole (LTZ)-induced mice that exhibited hepatic steatosis. The metabolic characteristics of PCOS predispose individuals to cardiovascular diseases such as hypertension, atherosclerosis, and coronary artery disease [28]. Excess androgen also contributes to cardiovascular risks.
This highlights the complex interplay among metabolic factors, liver health, and the diverse manifestations of PCOS, providing valuable insights for potential interventions and targeted treatments. Understanding these intricate connections offers a holistic perspective on the metabolic complexities of PCOS, enabling the development of more personalized therapeutic strategies.
Development of medications for PCOS
PCOS drug therapy aims to achieve metabolic and hormonal balance [29]. Approximately 70% of women with PCOS experience insulin resistance and hyperinsulinemia, highlighting a pathologically similar correlation with T2D [30,31]. Medications targeting shared metabolic traits of T2D and PCOS have been explored [32], such as thiazolidinediones (TZDs), which are exemplified by pioglitazone, enhancing insulin sensitization and ovulation [33,34]. Metformin, commonly used in T2D treatment, not only controls blood glucose but also aids in weight loss, thereby restoring menstrual regularity and increasing pregnancy rates in women with PCOS [35]. Used either alone or in combination with clomiphene citrate, metformin has been concurrently applied in over 60 completed cases across clinical trial phases 3 and 4, as recorded in the Clinical Trials Registry (https://clinicaltrials.gov/) (Table 2).
Clinical studies on PCOS in phases 3 and 4
While metformin offers benefits, its effectiveness may diminish over time. Therefore, there is an urgent need for ongoing, personalized treatment that addresses the complex characteristics of PCOS. This is essential given the varied phenotypic criteria of PCOS, which are influenced by both environmental factors and genetic variations (Table 3) [36-43].
Adverse effects of pharmacotherapy for PCOS
Adult stem cell therapy is emerging as a promising new treatment option for PCOS. Leveraging the regenerative capabilities of stem cells, this innovative method offers potential in tackling the varied symptoms of PCOS. Furthermore, adult stem cell therapy allows for personalized treatment plans that are customized to meet the specific needs of each patient. As research progresses, it is anticipated that adult stem cell therapy will become a crucial component in the holistic management of PCOS, offering renewed hope to those affected by this challenging condition.
Stem cell therapy as a new treatment strategy for PCOS
Stem cells are classified into embryonic, fetal, and adult categories, each raising distinct ethical concerns. Among these, adult stem cells, particularly mesenchymal stem cells (MSCs), are preferred because they have fewer ethical implications compared to embryonic stem cells [44]. MSCs, a specific type of adult stem cells, are known for their self-renewal activity, differentiation potential, immunomodulatory capabilities, and rich cytokine content [45,46]. These properties make them highly promising for various therapeutic applications, including the treatment of ovarian dysfunction. The body of research on MSC-based therapies for ovarian health is expanding, underscoring their regenerative capabilities in both clinical and non-clinical environments. Overall, adult stem cells, especially MSCs, are emerging as valuable resources in the field of regenerative medicine.
Recently, researchers have been exploring the use of adult stem cells in animal models of PCOS to evaluate the effectiveness of stem cell therapy. They are examining various mechanisms of action (MoAs), including anti-inflammatory responses, antioxidant effects, anti-fibrosis properties, anti-apoptotic effects, metabolic regulation, and vascular regeneration. These mechanisms not only help regulate hormones but also enhance follicular development and maturation, shedding light on the potential of adult stem cells to address various aspects of PCOS pathophysiology (Table 4) [47-57]. Understanding the mechanistic intricacies underlying the improvement of ovarian function facilitated by the paracrine effect of MSCs is crucial for refining pharmaceutical interventions that target PCOS treatment modalities [58,59]. In this section, we introduce and summarize several MoAs of stem cell therapy for PCOS that have been the focus of recent studies.
Preclinical studies of stem cell therapy for PCOS
1. Anti-inflammatory responses
Inflammation is known to adversely affect oocyte quality and disrupt ovulation. In PCOS, inflammation is initiated by elevated androgen levels [60]. Studies have shown that inflammatory markers are higher in women with PCOS, which is considered a low-grade chronic inflammatory disease [61,62]. Chronic suppression of androgens does not reduce inflammation in PCOS [63]. Furthermore, proinflammatory stimuli can increase androgen production in theca cells and boost the expression of enzymes involved in androgen synthesis in vitro [64]. Recent studies have demonstrated that anti-inflammatory therapy can decrease ovarian androgen secretion and stimulate ovulation in lean, insulin-sensitive women with PCOS [65]. These findings clearly implicate inflammation as an underlying mechanism of ovarian dysfunction in PCOS, even in the absence of insulin resistance.
Bone marrow MSCs (BM-MSCs) exhibit significant anti-inflammatory effects [66]. These cells not only regulate hormone levels, including FSH and LH, but also reduce the levels of proinflammatory cytokines such as IL-6 and tumor necrosis factor-α (TNF-α). Additionally, BM-MSCs are essential in promoting follicle maturation by modulating the vascular dynamics within the theca cell layer [47]. Furthermore, BM-MSCs inhibit androgen production by downregulating the expression of the cytochrome P450 family 11 subfamily A member 1 (CYP11A1) gene, thereby helping to alleviate symptoms of PCOS. BM-MSCs also improve metabolic dysfunction and restore fertility by counteracting the inflammatory response induced by PCOS through the secretion of anti-inflammatory factors such as IL-10 [48]. Notably, the efficacy of BM-MSCs can be enhanced by treatment with bone morphogenetic protein 2 (BMP2), further highlighting their therapeutic potential in managing PCOS [67].
Adipose-derived MSCs (AD-MSCs) combined with 2-α-naphthylmethyltrimethylammonium iodide (α-NETA) have shown potential in mitigating metabolic and endocrine dysfunction in PCOS rats. This treatment reduced circulating chemokine levels and the expression of chemokine-like receptor-1 (CMKLR1) in white adipose tissue, and also normalized irregular estrous cycles [68]. Additionally, AD-MSC therapy decreased the expression of genes linked to lipid accumulation and angiogenesis in PCOS, while increasing cytosine and guanine (CpG) methylation levels. Overall, AD-MSCs demonstrate promise in treating PCOS by limiting the expansion of subcutaneous adipose tissue [69].
Umbilical cord MSCs (UC-MSCs) have shown a notable ability to improve ovarian dysfunction by inhibiting B-cell proliferation in a dehydroepiandrosterone (DHEA)-induced PCOS mouse model. Additionally, UC-MSC treatment may alleviate ovarian failure by reducing ovarian inflammatory responses in PCOS mice. Following the Tx of UC-MSCs, there was a significant downregulation in the gene expression of proinflammatory factors, specifically TNF-α, IL-1β, and interferon-γ, in the ovaries of these mice. Moreover, the results indicated that administering these cells significantly decreased the percentage of peripheral neutrophils, M1 macrophages, and B cells, while increasing M2 macrophages and regulatory T cells in UC-MSC-treated mice [49].
The diverse effects exhibited by MSCs underscore their potential in addressing various aspects of PCOS. This underscores their complex and promising therapeutic relevance, providing innovative treatment approaches for managing this multifaceted condition.
2. Antioxidant effects
Oxidative stress (OS) is implicated in ovarian dysfunction and ovulation disorders observed in patients with PCOS [70]. It involves an imbalance between oxidants like reactive oxygen species (ROS) and antioxidants, leading to cellular damage and apoptosis [71]. Downregulation of proteins in PCOS affects the Kelch like ECH associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, reducing antioxidant superoxide dismutase (SOD) levels and promoting OS [72]. Low NRF2 expression in the AMP-activated protein kinase (AMPK)/AKT/NRF2 pathway increase ROS production and apoptosis in granulosa cells (GCs), exacerbating OS [73]. Additionally, OS affects mitochondrial function and signaling pathways, further contributing to dysfunction in PCOS [74].
Placenta-derived MSCs (PD-MSCs) have shown significant efficacy in mitigating the effects of OS. PD-MSCs create a favorable microenvironment for tissue repair and regeneration in areas damaged by OS through various mechanisms. PD-MSCs support mitochondrial donation, which diminishes oxidative damage by enhancing free radical scavenging, bolstering host antioxidant defenses, regulating inflammatory responses, improving cellular respiration and mitochondrial function, and protecting damaged cells [75]. Specifically, PD-MSCs have been shown to boost antioxidant factors and facilitate the restoration of organ function, as seen in the liver and ovaries of a thioacetamide (TAA)-injured rat model [50]. Furthermore, the use of PD-MSCs has had a positive effect on follicular development by reducing OS and apoptosis in the ovaries [51]. This dual role in enhancing antioxidants and modulating factors involved in the restoration of organ function underscores the therapeutic potential of PD-MSCs in addressing ovarian dysfunction associated with OS, providing valuable insights for potential interventions in PCOS.
3. Anti-fibrosis effect
Ovarian fibrosis has been reported in cases of PCOS [76]. Ovaries affected by PCOS that exhibit fibrosis are at an increased risk of developing ovarian cancer. Given the known link between progressive fibrosis and PCOS, one therapeutic strategy involves implementing anti-fibrotic measures [77]. MSCs are emerging as a potent cell-based therapy for a wide spectrum of fibrotic conditions due to their immunomodulatory, anti-inflammatory, and anti-fibrotic properties [78]. Specifically, UC-MSCs have shown effectiveness in modulating key aspects of fibrosis related to PCOS. In a testosterone propionate-induced PCOS rat model, UC-MSCs have been observed to increase the number and thickness of GCs and to regulate sex hormones, including estradiol (E2), gonadotropins (LH/FSH), progesterone, and testosterone. Furthermore, when used in conjunction with fibrin gel, UC-MSCs demonstrate an enhanced ability to reduce ovarian fibrosis by downregulating the expression of transforming growth factor-β in the ovary, surpassing the effects seen with naïve UC-MSCs [52]. This comprehensive approach underscores the potential of UC-MSCs not only to address hormonal imbalances but also to mitigate the fibrotic components associated with PCOS, offering a broad therapeutic option for the condition.
4. Anti-apoptotic effect
Hyperandrogenism is recognized as a key factor contributing to the anovulation seen in patients with PCOS, primarily through its disruptive effects on folliculogenesis, including the induction of follicular apoptosis [79]. Apoptosis plays a crucial role in follicular atresia and the cyclic growth and regression of follicles in the human ovary [80], and is closely linked to the pathophysiology of PCOS. Dysregulation of apoptosis-inducing factors in the ovaries has been observed in PCOS patients, leading to an increased number of atretic follicles [81]. The apoptotic loss of GCs is a critical factor that affects oocyte quality and hinders normal follicular development [82]. Preclinical studies have consistently shown that MSCs can reduce GC apoptosis. MSCs accomplish this by activating the Akt pathway through the secretion of growth factors, which leads to the phosphorylation of proapoptotic proteins such as B-cell lymphoma 2 (Bcl-2)-related cell survival promoters, thus providing an anti-apoptotic effect [83]. This mechanistic insight highlights the therapeutic potential of MSCs in addressing the abnormal follicular apoptosis characteristic of PCOS. Recent preclinical studies have further demonstrated the anti-apoptotic efficacy of MSCs in PCOS models. For example, BM-MSCs have significantly reduced the percentage of apoptotic follicles in a testosterone enanthate-induced PCOS mouse model [47]. These findings highlight the potential of anti-apoptotic MSC therapy as a novel approach to manage follicular apoptosis and restore follicular homeostasis in PCOS. Continued research in this field could lead to the development of targeted MSC-based therapies to improve ovarian function and fertility outcomes in individuals with PCOS.
5. Metabolic regulation
Insulin functions as a gonadotropic hormone, primarily enhancing androgen synthesis in the ovaries by activating P450c17 expression in theca cells. Insulin resistance and hyperinsulinemia are typical metabolic characteristics of women with PCOS [19]. Additionally, excessive lipid accumulation in the ovaries impairs steroidogenesis [84]. A key treatment approach for PCOS, marked by endocrine disorders, involves normalizing the metabolic system. In this context, MSCs have proven effective in restoring metabolic balance. MSCs enhance abnormal lipid metabolism by alleviating lysosomal stress and boosting mitochondrial oxidative phosphorylation and adenosine triphosphate levels [85]. BM-MSCs show a significant ability to reverse metabolic phenotypes and restore follicular development by secreting IL-10 in a LTZ-induced PCOS mouse model [48]. PD-MSCs are instrumental in activating the AMPK signaling pathway, which regulates glucose homeostasis. This improvement in glucose metabolism aids in better follicular development and the regulation of sex hormones in ovarian tissues, especially in a TAA-injured rat model [53]. Moreover, PD-MSCs regulate lipid metabolism. Studies show that PD-MSCs enhance lipid metabolism in the liver of TAA and bile duct ligation rat models [51,86,87]. Importantly, PD-MSCs also affect lipid metabolism in the ovaries of TAA rat models, as illustrated in Figure 1. In the serum of the TAA rat model, the Tx of PD-MSCs significantly alters lipid profile indicators. HDL levels, which are notably lower in the non-transplantation (NTx) group compared to the normal group, increase significantly in the PD-MSC Tx group (Figure 1A). Conversely, LDL levels, which are higher in the NTx group compared to the normal group, decreased significantly in the Tx group (Figure 1B). The homeostatic model assessment of insulin resistance (HOMA-IR), a clinical indicator of insulin resistance, showed a significant increase in the NTx group compared to the normal group, while the Tx group demonstrated a significant decrease in HOMA-IR (Figure 1C). Additionally, to confirm lipid droplet accumulation in the ovaries, ovarian tissues stained with BODIPY 493/503 show significant lipid droplet accumulation in the NTx group, which is normalized to levels similar to the normal group with the Tx of PD-MSCs (Figure 1D, 1E). This comprehensive assessment highlights the extensive impact of PD-MSCs in mitigating metabolic and lipid dysregulation associated with PCOS, providing promising insights for therapeutic interventions.
Effect of placenta-derived mesenchymal stem cells on lipid metabolism in the ovary in a thioacetamide-injured rat model. (A) High-density lipoprotein (HDL) cholesterol and (B) low-density lipoprotein (LDL) cholesterol were analyzed in serum of thioacetamide (TAA)-injured rat model. (C) The homeostatic model assessment of insulin resistance (HOMA-IR) was calculated according to the following: glucose (mg/dL) × insulin (mU/mL)/405. (D) The BODIPY 493/503 was stained in ovary of TAA-injured rat model for lipid accumulation analysis. (E) The count of lipid droplet was analyzed by Image J program. NTx, non-transplantation; Tx, transplantation; GC, granulosa cell; TC, theca cell.
a)p<0.05. p-value was determined by a non-parametric Kruskal-Wallis test followed by Conover-Iman’s multiple comparisons with BH correction.
6. Vascular regeneration
The ovarian vasculature is a critical structure within the ovary, responsible for delivering oxygen, nutrients, and cytokines to the follicles [88]. Abnormal ovarian blood flow and impaired vascularization have been observed in women with PCOS [89]. Tahergorabi et al. [90] have proposed investigating the imbalance of ovarian angiogenesis as a novel approach for diagnosing and managing PCOS, noting that body mass index affects VEGF-dependent outcomes. MSCs have demonstrated efficacy in vascular regeneration in various organs by secreting angiogenic growth factors (e.g., VEGF, platelet derived growth factor [PDGF], and hepatocyte growth factor [HGF]). These cytokines play a crucial role in the proliferation of endothelial cells, regulate vascular permeability, and contribute significantly to vascular stabilization [91]. Research on ovarian angiogenesis has already been reported; for instance, studies have found that PD-MSCs improve follicular development through vascular regeneration by activating VEGF and HGF signaling in the ovaries of ovariectomized rat models [92,93]. BM-MSCs have been found to regulate follicular maturation by increasing the expression of CD31 in the theca cell layer of ovarian follicles, leading to a higher number of antral follicles compared to the PCOS group in the testosterone enanthate-induced rat model [47].
7. Paracrine effect in in vitro experiments of adult stem cells
Preclinical studies addressing PCOS have involved both in vitro and in vivo experiments to comprehensively explore the therapeutic potential of MSCs. In addition to traditional in vivo investigations, researchers have conducted in vitro experiments to analyze the secretome of MSCs. This process involves treating PCOS-related cells with conditioned media that is rich in proteins and growth factors secreted by MSCs. The conditioned medium from BM-MSCs has been shown to induce anti-proliferative and anti-apoptotic effects in H295R cells and primary theca cells from PCOS patients [48]. Additionally, the activation of BMP2 by the conditioned medium of BM-MSCs has been demonstrated to regulate enzymes involved in androgen and steroid production [67]. These findings elucidate the intricate molecular interactions between the MSC secretome and PCOS-related cells, indicating potential mechanisms for therapeutic efficacy. Furthermore, in vitro maturation (IVM) medium enriched with conditioned medium from BM-MSCs has significantly improved oocyte maturation in PCOS mice compared to standard IVM medium, improving in vitro fertilization outcomes in the context of PCOS [54]. This integrated approach of in vitro experimentation provides valuable insights into the molecular and cellular interactions driving the therapeutic effects of MSCs in the context of PCOS, with potential implications for optimizing assisted reproductive technologies.
Clinical trials for PCOS using stem cells
Several ongoing clinical trials for PCOS are currently registered on the National Institutes of Health (NIH) Clinical Trials Database (www.clinicaltrials.gov) across various countries. While there is a significant emphasis on trials exploring chemical medications for PCOS, the number of trials investigating adult stem cell therapy is relatively small, with only two such trials listed in Table 5. This disparity highlights the current focus on chemical treatments within the PCOS clinical trial landscape and underscores the need for broader research into adult stem cell therapy. The ongoing trial in this area is a pioneering effort, and further research and initiatives could lead to a more varied and comprehensive approach to managing PCOS. Continued clinical research into both chemical and stem cell therapies is crucial for advancing our understanding and improving treatment options for those affected by PCOS.
Clinical studies of stem cell therapy for PCOS
As indicated in Table 4, the initial clinical trial is designed to assess the effects of UC-MSC on insulin resistance in patients with PCOS. To ensure the study's robustness and to clearly validate the efficacy of the stem cells, it is crucial to recruit suitable participants meticulously. Prospective participants should be women aged between 20 and 40 years who meet the following four inclusion criteria: (1) insulin resistance as defined by the Rotterdam Consensus criteria; (2) clinical evidence of hyperandrogenemia (Ferriman Gallwey score >8); (3) a free androgen index (FAI) >4, along with evidence of polycystic ovaries via transvaginal ultrasound; and (4) a HOMA-IR score ≥1.7. Additionally, individuals meeting any of the following exclusion criteria were not eligible for recruitment: (1) known allergy to any component of Wharton’s jelly-derived MSCs or their secretome; (2) positive diagnosis for hepatitis A, B, C, or human immunodeficiency virus; (3) current treatment with hormones or other forms of insulin resistance therapy; and (4) unwillingness or inability to participate in any part or the entirety of the research process.
During the research period, patients receiving UC-MSCs followed a structured treatment protocol. Each patient was given a placebo tablet daily for 30 days and received a single intravenous injection of 300,000 cells per kilogram of body weight of UC-MSCs. Additionally, participants were administered a daily nasal drop of growth medium (0.5 mL) for the same duration. After completing this Tx process, the treatment's effectiveness was evaluated using various measurements. Serum sampling occurred between days 10 and 12 of the follicular phase to analyze FAI, insulin, plasma glucose, and insulin resistance. FAI, a ratio used to assess abnormal androgen status, was calculated using the formula: total testosterone×100/sex hormone binding globulin (SHBG). Insulin resistance was assessed using HOMA-IR and the homeostatic model assessment of β-cell function (HOMA-β). HOMA-IR was calculated as (insulin×glucose)/22.5, and HOMA-β, which evaluates β-cell secretion function, was calculated as (20×insulin)/(glucose–3.5). Subsequently, comprehensive profiling of cytokines, adipokines, and hormones was performed. Levels of SHBG and anti-Müllerian hormone were measured during the follicular phase on days 10–12 and at 1-, 3-, and 6-month intervals post-stem cell administration. Leptin and adiponectin profiles were assessed at the same post-administration intervals. Additionally, levels of TNF-α, IL-1β, IL-6, and IL-10 were measured at these times. It is crucial to verify the results of these measurements to determine whether UC-MSCs contribute to improving the treatment mechanisms of PCOS. However, the results are not yet available as the clinical trial is still in the recruiting phase. This ongoing study highlights the need for further research and trials to explore the potential of stem cells in treating PCOS.
According to the NIH Clinical Trials Database (www.clinicaltrials.gov), a new clinical trial has recently begun, focusing on the safety and efficacy of intravenously administered cultured allogeneic adult UM-MSCs for treating PCOS. This trial administers a single intravenous dose of UC-MSCs, specifically 2×106 cells per kg of body weight, to eligible young women. Follow-up assessments, which include hormone levels and ultrasounds, are scheduled for 3, 6, and 12 months after treatment. Participants must be women aged 18 years and older with a confirmed diagnosis of PCOS via ultrasound. The exclusion criteria are designed to omit individuals with active infections, active cancer, chronic multisystem organ failure, pregnancy, clinically significant abnormalities in pre-treatment laboratory evaluations, any medical condition that could compromise the patient's safety, ongoing drug abuse, previous organ transplants, hypersensitivity to sulfur, or an inability to provide proper informed consent. The primary objective of the study is to monitor for potential adverse events or complications. The secondary objective is to assess the global improvement score on a scale from 0% to 100% over a 4-year follow-up period. This research aims to provide valuable insights into the safety and potential efficacy of UC-MSCs in managing PCOS, offering a comprehensive understanding of the treatment's impact throughout the follow-up period.
Conclusion
The potential of stem cell therapy in treating PCOS is becoming increasingly evident. Stem cells have shown positive effects in enhancing various aspects of metabolic regulation and ovarian function. These improvements include hormonal balance, follicle development, anti-apoptosis, and antioxidant responses in GCs, vascular remodeling, and genetic stability, as highlighted in our previous study (Figure 2). These promising findings suggest the potential for PCOS patients to benefit from targeted therapies, offering alternatives to conventional treatments for related conditions such as diabetes. However, it is crucial to underscore the need for further research, particularly in the form of clinical trials involving stem cells for PCOS patients. As stem cells are validated as a novel treatment strategy for addressing ovarian dysfunction, several critical steps require attention. These steps include a thorough evaluation of the therapeutic mechanisms of stem cells, the establishment of quality management standards for their clinical applications, and the implementation of legal regulations to ensure safety. These measures collectively contribute to advancing the field and fostering the responsible and effective use of stem cell therapy in managing PCOS.
Summary of the therapeutic effect of placenta-derived (PD)-mesenchymal stem cells (MSCs) on polycystic ovary syndrome (PCOS). The dysfunctions associated with PCOS are ameliorated to normal follicular development through the regulation of various modes of action by the paracrine effects of PD-MSCs. ROS, reactive oxygen species; IGFBP2, insulin-like growth factor-binding protein 2; SIRT1, sirtuin 1; FOXO1, forkhead box protein O1; PI3K, phosphoinositide 3-kinase; IRS1, insulin receptor substrate 1; GLUT4, glucose transporter 4; SOD, superoxide dismutase.
Notes
Conflict of interest
Gi Jin Kim is the owner of PLABiologics Co. Ltd. (hereafter referred to as PLABiologics) and holds stock in the company. Ji Woong Han is an employee of PLABiologics and received a salary for this study. The remaining author, Hyeri Park, has no conflicts of interest to declare.
Author contributions
Conceptualization: HP, GJK. Data curation: HP. Project administration: GJK. Visualization: HP. Writing-original draft: HP. Writing-review & editing: GJK. Approval of final manuscript: HP, JWH, GJK.