, Mingming Wang 2,*1 Institute of Applied Biotechnology, College of Agronomy and Life Science, Shanxi Datong University, 037009 Datong, Shanxi, China
2 Department of Physiology, School of Basic Medical Sciences, Xuzhou Medical University, 221009 Xuzhou, Jiangsu, China
Abstract
Objective: The review aims to provide an overview of the pathogenesis, clinical manifestations, and treatment methods of polycystic ovary syndrome (PCOS). Mechanism: The etiology of PCOS is multifaceted, intricately intertwined with genetic determinants, dysregulation of the hypothalamic-pituitary-ovarian axis, adrenal androgen excess, ethnic predilections, insulin resistance, persistent inflammatory cascades, lifestyle variables, non-coding RNA (ncRNA), and oxidative stress manifestations. Findings in Brief: Advances in PCOS research have led to updated diagnostic criteria that focus on irregular menstruation, along with the introduction of new treatments such as glucagon-like peptide-1 (GLP-1) agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors. Additionally, innovative reproductive technologies like in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI) are showing promise in improving fertility outcomes for PCOS patients. Genetic and epigenetic studies are uncovering potential for personalized therapeutic interventions. Individuals with PCOS face increased risks of complications during pregnancy, such as pregnancy-induced hypertension and multiple gestation complications. Such advancements underscore the significance of precise diagnosis, personalized treatment approaches, and interdisciplinary collaboration in managing PCOS effectively. Conclusions: This review undertakes a comprehensive scrutiny of contemporary PCOS studies, illuminating its clinical manifestations, underlying pathophysiological mechanisms, and evolving treatment modalities. Advocating for a patient-centric, evidence-driven approach is imperative in mitigating the adversities associated with PCOS and fostering holistic well-being.
Keywords
- polycystic ovary syndrome (PCOS)
- symptoms
- causes
- treatment
Polycystic ovary syndrome (PCOS), a prevalent endocrine disorder affecting women of reproductive age, is characterized by hormonal imbalances, ovarian cysts, and irregular menstrual cycles [1]. Epidemiologically, PCOS impacts approximately 5–10% of women globally, rendering it one of the most common endocrine disorders in women [2]. It is a primary cause of infertility and is associated with an increased risk of type 2 diabetes, cardiovascular disease, and endometrial cancer [3]. While the exact etiology of PCOS remains elusive, it is thought to be linked with genetic and epigenetic factors, insulin resistance (IR), and imbalances in sex hormones [4].
The diagnosis of PCOS involves the assessment of clinical symptoms, such as
irregular menstrual cycles and signs of androgen excess, in addition to measuting
hormonal levels and detectingovarian cysts using ultrasound. The widely accepted
Rotterdam criteria for diagnosing PCOS, defined by the European Society of Human Reproduction and Embryology (ESHRE) and the American
Society for Reproductive Medicine (ASRM) in 2003, require the fullfillment of at
least two of the following criteria: (1) clinical or biochemical evidence of
hyperandrogenism; (2) oligo-ovulation or anovulation; and (3) visualization of
polycystic ovaries through ultrasound, characterized by an ovarian volume
Currently, the management of PCOS prioritizes controlling symptoms and reducingthe long-term health risks associated with the condition. This encompasses lifestyle interventions such as dietary modifications and exercise to enhance insulin sensitivity, as well as medications to regulate menstrual cycles, lower androgen levels, and facilitate ovulation in women seeking conception [8]. Ongoing research into the fundamental mechanisms of PCOS and its associated health risks has the potential to yield more precise and effective treatments. Moreover, increased awareness and improved early detection of PCOS could alleviate the impact of this disorder on women’s health.
Clinical features of PCOS include menstrual irregularities, infertility, high androgen levels, and hirsutism [9]. Menstrual irregularities manifest as infrequent or heavy periods, amenorrhea, and dysfunctional uterine bleeding, while infertility and subfertility are commonly observed [10]. Additional symptoms may include acne, excessive hair growth, and hair loss [11]. Light brown, velvety hair on the neck, armpits, and groin, as well as the presence of a “string of pearls” small cysts in the ovary, may also be observed [12].
PCOS is characterized by a diverse array of ovarian cysts, setting it apart from
other ovarian cystic disorders. These cysts result from the imbalance between
follicle growth and ovulation. They may present as single or multiple cysts,
contributing to the distinctive appearance of the ovaries during ultrasound
examination [13]. The cysts are typically small (
PCOS can lead to complications beyond reproductive health, encompassing metabolic syndrome, obesity, diabetes, cardiovascular diseases, impaired insulin sensitivity, abnormal blood lipids, sleep apnea, and mood disorders [16, 17, 18, 19]. Acknowledging and addressing these complications in the comprehensive management of PCOS is crucial to minimize the long-term impact on the affected individual’s overall health and well-being.
PCOS has been associated with 11 gene loci according to PCOS genome-wide association studies (GWAS) [20]. The variant rs11031006 has been associated with luteinizing hormone (LH) levels in quantitative trait GWAS analysis [21]. Amin et al. [22] identified significant associations between two intronic prolactin receptor gene (PRLR) variants (rs13436213 and rs1604428) and the risk of PCOS within a cohort of 212 Italian families characterized by type 2 diabetes and PCOS phenotypes. Moreover, the analysis of vitamin D receptor (VDR) single nucleotide polymorphisms (SNPs) (rs4516035, rs2107301, rs1544410, rs731236, rs2228570, rs3782905, rs7975232, rs739837, and rs11568820) revealed significant associations with different PCOS phenotypes [23]. In the hyperandrogenism subtypes of PCOS, polymorphisms associated with reproductive symptoms and metabolic syndrome, characterized by excessive androgen production predominantly originating from the ovaries and adrenal glands, have been identified [24]. Adrenal hyperandrogenism reportedly affects 20%–30% of PCOS patients, and specific polymorphisms such as rs1360780, rs3800373, rs9470080, rs1043805, and rs7705037 are correlated with androgen levels in PCOS patients, especially within the hyperandrogenism subtype [25].
The majority of women and adolescents with hyperandrogenic PCOS exhibit an increased LH levels, which imply increased gonadotropin-releasing hormone (GnRH) pulse frequency, increased LH pulse amplitude, and exaggerated LH responses to exogenous GnRH [26]. In contrast, these patients exhibit a relative deficiency of follicle-stimulating hormone (FSH), as anticipate under persistently high-frequency GnRH stimulation [27]. Persistently elevated LH pulse frequency and an elevated LH:FSH ratio are indicative of hyperactive GnRH pulse secretion [28].
Excessive release of GnRH leads to elevated levels of LH, which subsequently increases androgen levels. Elevated LH levels inhibit the function of FSH, which disrupts follicular development and ultimately leads to polycystic ovarian changes. In healthy women, the LH:FSH ratio typically ranges between 1 and 2, while in PCOS patients, this ratio is often reversed and may reach as high as 2 or 3 [29]. In the PCOS group, several parameters, including body weight, LH, FSH, LH:FSH ratio, insulin, glycated hemoglobin A1c (HbA1c), estradiol, testosterone, thyroid-stimulating hormone (TSH), progesterone, and sex hormone-binding globulin (SHBG) levels, were significantly altered compared to controls. Furthermore, within different PCOS subgroups, elevations in LH levels and LH:FSH ratios were associated with elevations in insulin, testosterone, and AMH levels, and decreases in SHBG levels [30].
Excessive adrenal androgens, especially the increased secretion observed during puberty, may have a significant impact on the development of PCOS. The presence of elevated adrenal androgens during puberty is closely associated with the onset of PCOS in patients [31]. Observations include typical and atypical adrenal hyperplasia with 21-hydroxylase deficiency, the presence of polycystic ovaries on ultrasound, elevated elevated LH levels, excess ovarian androgen production, and early manifestation of adrenal dysfunction in high-risk patients progressing to PCOS [32]. A study indicates an increasing trend in the likelihood of cytochrome P450 enzymes (CYP) 21 heterozygous mutations among adolescent females with excessive androgens [33]. Children and adolescents with excessive androgens exhibit elevated levels of 17-hydroxyprogesterone following adrenocorticotropic hormone (ACTH) stimulation, along with a higher prevalence of missense mutations compared to asymptomatic individuals with congenital adrenal hyperplasia [34].
Several studies have shown that there are phenotypic differences in women with
PCOS among different racial and ethnic groups [35, 36, 37]. For instance, women of
Middle Eastern, Mediterranean, Indian, and South Asian descent exhibit higher
rates and/or severity of hirsutism in PCOS compared to East Asian or Caucasian
women [35, 36]. These findings may be related to differences in genetic
inheritance or enzyme expression patterns within different groups, particularly
concerning the enzyme 5-alpha reductase. This enzyme plays a pivotal role in
converting testosterone to the more potent androgen dihydrotestosterone, which is
implicated in the pathogenesis of PCOS [38]. East Asian women have a low
5-
Hispanic women are more predisposed than non-Hispanic white women to exhibit elevated fasting insulin levels and higher Homeostatic Model Assessment of IR (HOMA-IR) scores, with a moderate degree of heterogeneity not solely explained by age, body mass index (BMI), or PCOS criteria [39, 40]. Hispanic and white women are comparable in terms of glucose, lipid, and blood pressure parameters [40]. These results suggest impaired glucose metabolism responses in Hispanic women with PCOS, potentially predisposing them to a higher risk of developing metabolic sequelae such as type 2 diabetes. A recent retrospective review of medical records of overweight and obese adolescent female PCOS patients aged 11–21 revealed that Hispanic adolescents with PCOS exhibited higher levels of HbA1c and alanine aminotransferase (ALT) at diagnosis compared to those with only one elevated marker or neither marker elevated. Overlal, this suggests an increased susceptibility to developing type 2 diabetes among this population [41]. Current international PCOS guidelines do not recommend routine ALT screening in PCOS. Therefore, further research is needed to determine whether targeted screening for HbA1c and ALT would benefit Hispanic adolescents with PCOS [42].
Hispanic women, in particular, represent a population warranting further investigation, given previous research indicating that they exhibit the most severe phenotype for both hyperandrogenism and metabolic effects amon women with PCOS [43, 44]. As a consequence, Hispanic women not only experience a higher prevalence of hirsutism and acne but also exhibit a higher tendency to have increased IR [40, 43, 44], a higher proportion of abnormal fasting insulin and glucose levels, and a higher prevalence of metabolic syndrome compared to non-Hispanic Whites and non-Hispanic Blacks with PCOS
IR is a metabolic condition characterized by decreased cellular glucose utilization despite normal insulin levels, leading to compensatory hyperinsulinemia. Hyperinsulinemia directly impacts ovarian cells, disrupting normal follicular development and impairing ovulation [45]. The excessive insulin circulating in the bloodstream alters the hormonal milieu within the ovaries, leading to increased production and secretion of androgens [46]. Moreover, IR contributes to increased androgen secretion, causing characteristic PCOS symptoms such as hirsutism, acne, and male pattern baldness. Excess androgens can disrupt egg maturation and release, resulting in irregular or absent menstrual cycles and difficulties with conception. Additionally, excess androgens can hinder embryo implantation, thereby affecting fertility outcomes for PCOS patients [47, 48]. IR also carries broader implications beyond the reproductive system, contributing to a cascade of metabolic disturbances that increase the risk of developing other health conditions such as type 2 diabetes, cardiovascular disease, and metabolic syndrome.
Studies have shown that inflammation processes play a role in ovulation and the
dynamics of ovarian follicles [49, 50]. Visceral adipose tissue (fat around
internal organs) can augment inflammation by producing inflammatory cytokines and
attracting immune cells such as monocyte chemoattractant proteins [51]. This can
lead to the maintenance of the inflammatory state in adipocytes [52, 53]. Adipose
tissue dysfunction is essential in the pathophysiology of PCOS, even in patients
with lower levels of adiposity [54]. Inflammatory markers, including C-reactive
protein (CRP), interleukin-18 (IL-18), interleukin-6 (IL-6), tumor necrosis
factor-
Various lifestyle factors, including diet, stress, sleep disturbance, circadian disruption, and exposure to environmental chemicals have been investigated for their potential role in the pathogenesis of PCOS [56]. Understanding the role of these factors is crucial for developing comprehensive management strategies and optimizing the outcomes for women affected by PCOS.
Diet plays a fundamental role in modulating metabolic health, and emerging evidence suggests that dietary patterns may influence the development and progression of PCOS. Studies have explored associations between specific dietary components, such as carbohydrates, fats, and proteins, and their impact on IR, hormone levels, and overall metabolic profile in women with PCOS [57, 58]. Furthermore, dietary factors like calorie intake, glycemic index, and dietary fiber have also been investigated for their potential effects on PCOS [59]. Stress and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis have been proposed as potential contributors to the pathogenesis of PCOS. Chronic stress can disturb hormonal balance and exacerbate metabolic disturbances, leading to a worsening of PCOS symptoms. Furthermore, a study showed associations between stress levels and abnormal menstrual cycles, androgen excess, and IR in women with PCOS [60]. Sleep disturbance and circadian disruption have also garnered attention in PCOS research. Disrupted sleep patterns, such as sleep apnea, irregular sleep schedules, and poor sleep quality, have been associated with increased IR, higher androgen levels, and metabolic disturbances in women with PCOS [61]. Environmental chemicals, such as endocrine disruptors, have received increasing attention as potential contributors to the development and progression of PCOS. Certain environmental chemicals, like bisphenol A (BPA) and phthalates, can interfere with hormonal regulation and have been implicated in the dysregulation of sex hormone levels, IR, and adverse reproductive outcomes [62].
Recent research in PCOS has revealed the involvement of ncRNAs in the pathogenesis and progression of the disease. ncRNAs, including microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), have been found to play crucial roles in regulating gene expression, follicular development, insulin sensitivity, and steroidogenesis in the context of PCOS [63].
Several recent studies have demonstrated dysregulated expression of specific miRNAs such as miR-126, miR-146a, miR-196a2, and miR-499 in PCOS and their association with IR, abnormal folliculogenesis, and hyperandrogenism [64, 65]. In our previous study, we reported that miR-96-5p could be an androgen-regulated miRNA that directly targets FOXO1 and functions in PCOS development [66]. Additionally, miR-27a-3p was found to promote apoptosis in PCOS granulosa cells by targeting SMAD5 [67]. Treatment of human granulosa-like tumor cell line (KGN) with insulin attenuated the downregulation of miR-27a-3p, and this effect seemed to be mediated by signal transducer and activator of transcription STAT1 and STAT3 [67]. Furthermore, the dysregulation of lncRNAs, such as HOTAIR and MALAT1, has been implicated in the regulation of steroidogenesis and follicular growth in PCOS [68, 69]. Additionally, emerging evidence suggests that circRNAs, such as circRHBG and circFoxo3, may mediate androgen excess and follicular development in PCOS [70, 71]. These findings highlight the significance of ncRNAs in the pathophysiology of PCOS and provide potential therapeutic targets for the management of this complex endocrine disorder. Further elucidation of the intricate regulatory networks involving ncRNAs in PCOS will undoubtedly deepen our understanding of the disease and may lead to the development of novel diagnostic and therapeutic strategies.
Oxidative stress occurs as a result of an imbalance between oxidants and antioxidants. Reactive oxygen species (ROS), well-known potent oxidants, are naturally produced in the body and play essential roles in normal cell function and physiological processes. However, excessive ROS and other oxidants can overwhelm the body’s antioxidant defense system, leading to disruptions of normal physiological functions in women. Recent research underscores the significant role of oxidative stress in the pathogenesis of PCOS, as it is closely associated with elevated androgen levels, IR, disrupted ovulation, and mitochondrial damage in PCOS patients [53].
In laboratory experiments, oxidative stress downregulates the expression and secretion of SHBG, leading to heightened serum androgen levels in PCOS patients [72]. In a PCOS rat model, NOX4 deficiency in rats can potentially improve the symptoms of PCOS by reducing oxidative stress and cell apoptosis via activating the nuclear transcription factor NRF-2/hemeoxygenase 1 (Nrf-2/HO-1) signal pathway [73]. Oxidative stress promotes IR in the skeletal muscles of PCOS mice. N-acetylcysteine (NAC), an antioxidant, has shown the potential to decrease ROS production, improve mitochondrial function, and reverse IR in skeletal muscles of PCOS mice. Elevated androgen levels and IR also contribute to reduced mitochondrial DNA copy number and decreased ROS levels in uterine mitochondria during pregnancy. Consequently, this leads to impaired uterine mitochondrial function and an imbalanced redox state, resulting in lower pregnancy rates and increased miscarriage rates in PCOS patients [74].
Other factors determining the prevalence or phenotype of PCOS may include environmental toxins and socioeconomic status, with limited understanding of the role that geography, such as proximity to large bodies of water, altitude, latitude/longitude, climate, or terrain, play in determining the prevalence or presentation of PCOS [75, 76].
Therapeutic strategies for PCOS encompass non-pharmacological and pharmacological approaches. Non-pharmacological treatments for PCOS include lifestyle modifications, psychological counseling, surgical interventions, and Traditional Chinese Medicine (TCM) [77]. These therapies play an integral role in the multi-disciplinary and personalized management of PCOS. Pharmacological interventions, such as oral contraceptives (OCs), metformin, anti-androgens, thiazolidinediones (TZDs), glucagon-like peptide-1 (GLP-1) receptor agonists, insulin-sensitizing agents, aromatase inhibitors (AIs), and antioxidants, are beneficial for patients with PCOS-related ovulation disorders and infertility [78, 79, 80].
Lifestyle modifications form the cornerstone of PCOS management, as recommended by leading clinical guidelines such as those from the American College of Obstetricians and Gynecologists (ACOG) and the Endocrine Society [6, 7]. These modifications, aimed at improving metabolic parameters and symptom alleviation, encompass weight loss, increased physical activity, and informed dietary choices. The impact of weight management in PCOS, strongly linked to obesity, which is significant. A systematic review and meta-analysis highlights the benefits of modest weight reduction—typically ranging from 5–10%—in improving insulin sensitivity, promoting menstrual regularity, and mitigating hyperandrogenism [81]. A balanced diet, mindful eating, and regular exercise are essential components. Aiming for a minimum of 150 minutes of moderate-intensity exercise per week aligns with the Physical Activity Guidelines for Americans, contributing to cardiometabolic health and symptom management in PCOS [82]. Practical options include activities such as walking, swimming, or cycling [83]. Regarding dietary considerations, emphasizis is placed on the importance of a balanced diet rich in fruits, vegetables, whole grains, lean proteins, and healthy fats, while also reducing intake of refined carbohydrates to enhance insulin response and glucose regulation [84].
PCOS often leads to significant emotional and psychological challenges, particularly concerning infertility, body image, and metabolism-driven complications. Supportive psychological counseling, including cognitive-behavioral therapy (CBT) and dialectical behavior therapy (DBT), effectively addresses these concerns, promoting coping and resilience [85]. Integrative care, which may involve couples counseling, provides valuable support for issues such as infertility and sexual health [86]. PCOS-specific support groups establishes empathetic communities that offer emotional solidarity and can enhance mental well-being.
For severe cases of PCOS unresponsive to conservative measures, surgical interventions guided by organizations such as the ACOG may be considered appropriate. For instance, laparoscopic ovarian drilling (LOD) has demonstrated efficacy in reducing androgen levels and improving fertility in drug-resistant cases [87]. Bariatric surgery, primarily indicated for individuals with morbid obesity, provides significant metabolic improvements and symptom relief, warranting consideration following comprehensive assessment [87].
Acupuncture and herbal therapy from TCM offer emerging complements to conventional PCOS management [76]. Acupuncture may contribute to normalizing menstrual cycles, reducing hyperandrogenism, and enhancing insulin sensitivity in women with PCOS [88]. These effects may be mediated through the regulation of certain hormones and neurotransmitters, as well as the modulation of sympathetic and parasympathetic nervous system activity. Herbal therapy has shown potential in regulating menstrual cycles, improving insulin sensitivity, reducing androgen levels, and addressing associated symptoms such as hirsutism and acne [89]. However, further rigorous research, employing well-designed studies and larger sample sizes, is necessary to establish the efficacy, mechanisms of action, and safety profile of acupuncture and herbal therapy for PCOS.
OCs are widely prescribed for regulating menstrual cycles and alleviating hyperandrogenic symptoms in women with PCOS. These formulations, containing estrogen and progestin, play a crucial role in hormone level regulation and reduction of androgen production. The choice of OCs formulation is tailored to meet the specific needs and preferences of each individual patient. Metformin, a medication primarily used for diabetes, enhances insulin sensitivity and diminishes hyperandrogenism, making it particularly beneficial for overweight and obese individuals with IR. However, its overall effictiveness and safety in the broader PCOS population are subject to debate, requiring further investigation [78]. Anti-androgenic medications such as spironolactone and cyproterone acetate are indicated for severe hyperandrogenism, effectively lowering androgen levels and alleviating symptoms such as hirsutism and acne. Nonetheless, the long-term use of these drugs requires careful consideration due to potential side effects, including breast tenderness, breast enlargement, and liver toxicity [90]. TZDs, as insulin-sensitizing agents, enhance insulin sensitivity and reduce hyperandrogenism; they are recommended for patients with severe IR and metabolic complications. However, their use is restricted by side effects such as weight gain, increased risk of hypoglycemia, and potential cardiovascular risks [91]. GLP-1 receptor agonists present a novel therapeutic approach for PCOS management, facilitating weight loss, improving insulin sensitivity, and regulating glucose metabolism. Emerging evidence indicates their potential effectiveness for obese patients with PCOS, underscoring the need for further research to confirm their safety and efficacy [92]. Other insulin-sensitizing agents, including dipeptidyl peptidase-4 (DPP-4) inhibitors and sulfonylureas, may be considered in PCOS management, albeit with concerns about weight gain and hypoglycemia restrict their role in clinical practice [93].
AIs, employed to suppress estrogen synthesis by inhibiting the enzyme aromatase, are widely used in the management of breast cancer and hormone-dependent tumors [94]. Nonetheless, their use in PCOS management is generally not recommended for several reasons. Firstly, there is limited evidence regarding their efficacy, with some studies suggesting potential benefits but overall weak support. Secondly, potential side effects of AIs, such as hot flashes, vaginal dryness, and decreased bone mineral density, can significantly impact patient quality of life [94]. Lastly, long-term use of AIs has been linked to an increased risk of uterine hyperplasia and cancer, emphasizing the importance of close monitoring and consideration of alternative treatments [95]. Given these factors, caution is advised when considering the use of AIs in PCOS management.
Letrozole, a specific AI, is typically administered from day 3 to day 7 of the menstrual cycle at doses ranging from 2.5 to 7.5 mg per day, with incremental increases of 2.5 mg [96]. Common side effects of letrozole include gastrointestinal disturbances, fatigue, hot flashes, headaches, and abdominal pain [97]. Additionally, due to a lack of high-quality evidence, using AIs as the primary pharmacological therapy for infertility in women with PCOS is not recommended, necessitating further research [98]. However, a recent systematic review and meta-analysis have suggested letrozole should be considered as a first-line agent for ovulation induction due to its therapeutic benefits and lack of harm to the fetus, providing an alternative when other options are not feasible [99]. For anovulatory patients with PCOS, the combined use of metformin and clomiphene citrate (CC) has demonstrated improved clinical live birth rates, surpassing the efficacy of metformin or CC alone [100].
The use of antioxidants, such as alpha lipoic acid, vitamin C, vitamin E, coenzyme Q (CoQ10), NAC, resveratrol (RSV), melatonin, carnitine, selenium, magnesium, and zinc supplementation, among others, in PCOS treatment has shown promising results in countering oxidative stress [101]. Experiments conducted on PCOS patients have demonstrated that antioxidants not only improve the ovarian environment, promoting follicular maturation and increasing the number of oocytes, but also regulate lipid and glucose metabolism, as well as vascular endothelial cell function. This helps alleviate obesity and reduce the occurrence of chronic complications, ensuring long-term patient benefits [102]. Studies have also indicated that statin treatment reduces blood lipid levels and possesses antioxidant stress-reducing effects, leading to decreased androgen levels [103, 104].
The field of PCOS research is evolving rapidly, with emerging findings that impact the understanding and treatment of the syndrome. Key developments include:
Recent advances in PCOS research have led to significant developments in diagnosis and treatment. Updated guidelines from the ESHRE and the ASRM have improved the consistency of PCOS diagnosis and treatment. These guidelines incorporate serum AMH testing as an alternative to pelvic ultrasonography for diagnosing adult PCOS [6, 7]. The core diagnostic criteria remain unchanged, emphasizing irregular menstruation, hyperandrogenism, and polycystic ovarian morphology as the primary indicators for PCOS diagnosis. The updated guidelines also highlight the importance of irregular menstruation as a primary clinical manifestation of PCOS and advocate for increased evaluation of comorbidities such as cardiovascular disease, glucose intolerance, and endometrial cancer. For adolescents, distinct diagnostic protocols have been delineated based on criteria outlined in BioMed Central (BMC) Medicine in 2020 [105]. In conclusion, the guidelines prioritize diligent monitoring and evidence-based management of the ‘risk status’ in PCOS, enhancing the precision and personalization of care to bolster patient outcomes.
Emerging treatments for managing PCOS-related IR and metabolic dysfunction are also under investigation, including GLP-1 receptor agonists, sodium-glucose co-transporter 2 (SGLT2) inhibitors, and medications targeting obesity. GLP-1 receptor agonists are a class of medications that mimic the action of glucagon-like peptide 1, a gut hormone that stimulates insulin secretion and slows gastric emptying [91]. SGLT2 inhibitors are a relatively new class of anti-diabetic medications that inhibiting glucose reabsorption in the kidney, increasing glucose excretion in the urine, thereby lowering blood glucose levels [106]. Obesity significantly contributes to IR and metabolic dysfunction in PCOS. Consequently, obesity-targeting medications have emerged as a potential treatment option for managing PCOS-related IR and metabolic dysfunction. These medications have shown promising results in managing IR and metabolic dysfunction in patients with type 2 diabetes, and they are now being investigated for their potential role in PCOS [107]. A study showed that using semaglutide in obese PCOS patients could have positive outcomes in weight loss and improvements in metabolic markers like HOMA-IR and fasting blood glucose [108]. Most patients experienced significant in weight loss, with some even achieving normalization of their menstrual cycles. Semaglutide appears to be a valuable option for those who may not have responded well to lifestyle modifications alone [108].
These treatments have shown promise in experimental and clinical trials, but challenges remain in their clinical adoption [109]. Safety and long-term efficacy in PCOS patients, potential impact on fertility, fetal development, and cardiovascular health, individual variations in treatment response, optimal dosing regimens, and drug interactions with conventional anti-diabetic medications and OCs all require in-depth investigation. Thus, further research is warranted to understand the full potential and limitations of these novel therapeutic strategies.
Innovative approaches in reproductive technology have not only improved fertility outcomes but also enhanced the overall quality of life for PCOS patients. Here, we summarize the advancements in reproductive management strategies, focusing on the role of in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI), as well as novel non-invasive techniques such as uterine artery embolization (UAE) for the treatment of uterine fibroids and endometrial abnormalities in PCOS patients.
IVF, a laboratory procedure wherein eggs are fertilized by sperm, has revolutionized fertility treatment for many women with PCOS who struggle with infertility [110]. The introduction of ICSI, a technique wherein a single sperm is directly injected into an egg, has further improved the success rates of IVF procedures [111]. These technologies have enabled PCOS patients to achieve pregnancies that were previously deemed unattainable. Nevertheless, the process can be physically and emotionally challenging, with a relatively higher risk of multiple pregnancies associated with these techniques (IVF and ICSI). Therefore, it is imperative for healthcare providers to carefully evaluate each patient’s unique circumstances and determine the most suitable reproductive management strategy [112, 113].
PCOS patients often experience complications related to uterine fibroids and endometrial abnormalities, may manifest in symptoms such as heavy menstrual bleeding, pelvic pain, and infertility [114]. Conventional treatments for these conditions involve invasive surgical interventions, which carry significant risks and complications. To addresse these concerns, novel non-invasive techniques such as UAE have been explored as alternative treatment options. UAE involves the injection of embolic agents into the uterine arteries to block the blood supply to the fibroids, resulting in their shrinkage and alleviation of associated symptoms. This minimally invasive procedure offers several advantages over traditional surgical approaches, including a reduced risk of complications, shorter recovery time, and better preservation of uterine function [115].
In addition to reproductive management and non-invasive therapies, researchers are exploring other innovative approaches to address the complexities of PCOS. These include personalized medicine, and complementary and alternative medicine such as acupuncture, yoga, herbal remedies, and psychological support [116]. Innovative management strategies for PCOS offer patients hope and relief as diverse and integrated approaches continue to emerge. These strategies encompass reproductive technology, non-invasive therapies, personalized medicine, lifestyle adjustments, medication, and psychological support. However, implementing these innovative therapies requires clinicians to close monitor of individual differences and treatment responses, ensuring optimal efficacy while minimizing potential risks. Interdisciplinary research and collaboration are also crucial in PCOS management, drawing upon experts from various fields such as endocrinology, gynecology, reproductive medicine, and psychiatry, thereby advancing PCOS diagnosis and treatment standards.
Pregnancy-induced hypertension (PIH) is one of the leading causes of maternal mortality during the perinatal period, posing a significant threat to maternal and infant health [117]. Current research indicates that women with PCOS have a 3–4 times increased risk of developing PIH and a threefold increased risk of developing gestational diabetes mellitus (GDM) [118]. IR, obesity, and hyperandrogenism are the primary factors that elevate the risk of developing hypertension in pregnancy among women with PCOS [119].
Due to the characteristic of oligo/anovulation in women with PCOS, they often require ovulation induction drugs (such as clomiphene, letrozole, others) and assisted reproductive technologies like IVF, which can impact their rate of multiple gestation. Multiple gestation is associated with various obstetric and neonatal complications. The incidence of multiple gestation in PCOS patients is higher, leading to an increased risk of complications including premature rupture of membranes, preterm birth, postpartum hemorrhage, and fetal developmental abnormalities [120]. Preterm birth stands as the most prevalent complication of multiple gestation, with twin pregnancies having a six-fold increased risk of preterm birth compared to singleton pregnancies and a ten-fold increased risk of delivering low birth weight infants [121, 122].
Recent advancements in genomics have uncovered potential genetic susceptibility loci and epigenetic markers linked to PCOS, shedding light on its etiology and pathophysiology and offering the potential for personalized therapeutic interventions.
Genetic susceptibility loci denote specific genome regions associated with an increased risk of developing PCOS, as revealed by several GWAS that have underscored the significant influence of genetic factors in the etiology of PCOS [123]. These large-scale studies have identified common genetic variations significantly associated with PCOS diagnosis, including loci involved in insulin signaling, lipid metabolism, androgen synthesis, and GnRH regulation. Epigenetics, however, explores heritable changes in gene function that occur without altering the underlying DNA sequence, potentially influencing disease development like PCOS. Research on PCOS has investigated epigenetic markers such as DNA methylation [124] and histone modification [125], revealing abnormal epigenetic patterns in PCOS patients, thereby suggesting a role for epigenetics in the syndrome’s pathophysiology.
Despite progress, genetic and epigenetic investigations in PCOS remain in their early stages, requiring further research to validate and expand the current understanding of these factors. Developing personalized therapeutic interventions based on genetic and epigenetic findings necessitates the development of cost-effective diagnostic tests and treatment protocols. Ethical considerations, including patient privacy, genetic discrimination, and potential unintended consequences of genetic testing, must also be addressed through guidelines and regulations to protect patient rights and ensure responsible clinical use of genetic and epigenetic data.
As our understanding of the genetic and epigenetic foundations of PCOS continues to advance, personalized therapeutic interventions based on these findings hold promise for improving clinical outcomes in individuals with PCOS, enabling them to lead healthier and more fulfilling lives.
This review comprehensively analyzes current PCOS research, elucidating its clinical manifestations, underlying mechanisms, and evolving therapeutic approaches. Despite significant progress, challenges persist due to the incomplete understanding of the complex etiology of PCOS and the lack of tailored treatment options. Moving forward, the research community must focus on unraveling underlying causes of the disease, refining diagnostic protocols, and developing precise treatments to improve patient care. Establishing a comprehensive, ongoing management strategy is essential for enhancing preventive measures, diagnostic accuracy, treatment outcomes, and the quality of life for individuals with PCOS. Emphasizing a patient-centered, evidence-based approach will be crucial for alleviating the burden of PCOS and promoting overall well-being.
The research study was designed by all authors, with HB responsible for manuscript writing, and MW and HD contributing to editorial revisions. All authors have reviewed and approved the final manuscript.
Not applicable.
The authors would like to express their sincere gratitude to their respective institutions, Xuzhou Medical University and Shanxi Datong University, for their support in literature research and collection. We would like to thank Dr. Richard Mprah for English language editing.
This review was supported financially by the Outstanding Talent Research Funding of Xuzhou Medical University (Grant No. RC20552029).
The authors declare no conflict of interest.
References
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