Bibliography in Assisted Reproductive Technology (ART)

In an ever-evolving field marked by rapid scientific progress and increasing clinical complexity, it is essential to remain updated on key innovations, best practices, and the most relevant publications.

Compiled and reviewed by the clinical team at the xxxxxx—one of Paris’ most established and active ART centers—this summary offers a concise yet rigorous overview of recent advances in the field. Drawing from high-impact international journals, the work highlights emerging techniques, evolving protocols, and critical findings in ART.

With this bibliographical review, we aim to offer an original tool to aid in scientific monitoring, positioned between the conventional abstract and the often lengthy and time-consuming full reading of the original article. This hybrid format ensures substantial time savings by enabling the rapid and targeted identification of publications that, based on their content, warrant an in-depth reading.

Regular updates will follow to keep pace with the dynamic landscape of ART.

Polycystic Ovary Syndrome (PCOS)

Dr Cécile François

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Dr François durand

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Overview

Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder affecting reproductive-aged women globally, with significant health implications beyond reproductive function. It is a complex syndrome characterized by a wide range of clinical presentations and its pathogenesis is multifactorial and not fully understood. While diagnostic criteria have evolved over time, the Rotterdam criteria are currently the most widely used, defining PCOS based on the presence of at least two of three features: oligo-anovulation/anovulation, hyperandrogenism, and polycystic ovarian morphology (PCOM). Hyperandrogenism and insulin resistance are central to the pathophysiology of PCOS, contributing to both reproductive and metabolic dysfunction. Genetic and environmental factors, as well as potential epigenetic and immune system involvement, are increasingly recognized as contributors to PCOS development. Metformin is a commonly used treatment, particularly for addressing insulin resistance and improving metabolic parameters, with benefits also observed in menstrual cyclicity and ovulation. The heterogeneity of PCOS phenotypes necessitates a stratified approach to diagnosis and treatment.

  • PCOS is the most common endocrine disorder in reproductive-aged women.
  • Prevalence estimates vary, but studies suggest it affects between 5% and 26% of reproductive-aged females worldwide. In India, recent findings indicate a prevalence of 8.2% to 22.5%.
  • The prevalence depends on factors such as region (rural or urban) and lifestyle (physical work and eating habits).
  • PCOS was first described in 1935 by Stein and Leventhal as an endocrine disorder responsible for oligo-ovulatory infertility.
  • There is ongoing debate about the most relevant diagnostic criteria for PCOS.
  • Rotterdam 2003 criteria are the most extensively used classification globally, although not universally accepted. These criteria require the presence of two out of the following three features:Oligo-ovulation/anovulation
  • Hyperandrogenism (clinical or biochemical)
  • Polycystic ovarian morphology (PCOM)
  • The NIH/NICHD 1990 criteria included:
  • Hyperandrogenism/hyperandrogenemia
  • Anovulation or oligo-ovulation
  • Exclusion of other associated disorders (thyroid, hyperprolactinemia, congenital adrenal hyperplasia)
  • The Androgen Excess Society (AES) 2006 guidelines emphasized hyperandrogenism as central to the diagnosis, requiring hirsutism and/or biochemical hyperandrogenism, along with either oligo-anovulation and/or PCOM. This excluded the phenotype of oligo-anovulatory women with PCOM but without hyperandrogenemia.
  • PCOM is defined using transvaginal ultrasound with a transducer frequency ≥ 8 MHz, typically as ≥20 follicles per ovary and/or an ovarian volume of ≥10 cm3 in either ovary. The threshold for follicle count has evolved from earlier criteria.
  • Current guidelines still recommend the Rotterdam criteria as the basis for clinical diagnosis.
  • The variability between PCOS phenotypes defined by the Rotterdam criteria has raised concerns about classification for research and treatment recommendations.
  • Irregular menstrual cycles/ovulatory dysfunction: This is a hallmark feature, typically presenting as oligo-amenorrhea (cycles > 35 days apart or <8 menses a year). Ovulation can be confirmed with serum progesterone or luteinizing hormone assessment in cases of uncertain menstrual history. Irregular menses in adolescents require age-specific definitions.
  • Hyperandrogenism: This is a key feature, resulting from excessive ovarian and adrenal androgen secretion. Clinical symptoms include hirsutism (excessive hair growth, quantified by the modified Ferriman–Gallwey score), acne, alopecia (hair loss), central obesity, and acanthosis nigricans (skin pigmentation). Biochemical hyperandrogenism is assessed by measuring circulating androgens, primarily testosterone, androstenedione, DHEA, and DHEAS. Elevated free or unbound testosterone is particularly indicative. Androgen hypersecretion leads to premature development of ovarian follicles, multiple small antral follicles, and anovulation.
  • Polycystic Ovarian Morphology (PCOM): Characterized by the presence of multiple small antral follicles in the ovaries on ultrasound.
  • Metabolic dysfunction: Frequently associated with PCOS, including insulin resistance, hyperinsulinemia, obesity (particularly abdominal obesity), and an increased risk of type II diabetes and cardiovascular diseases.
  • Infertility: Anovulatory infertility and poor oocyte or embryo quality are common in women with PCOS due to abnormal follicular development.
  • Increased risk of other conditions: Endometrial cancer, gestational diabetes, and pregnancy-induced hypertension.
  • PCOS is a complex, multifactorial syndrome with unknown precise etiology.
  • Hereditary and environmental factors are interwoven with the occurrence of PCOS.
  • Genetic factors: Family history of PCOS among first-degree relatives, early sexual maturation, premature development of the fetus. Around 30 genes are associated with PCOS development.
  • Environmental factors: Physical inactivity, unhealthy diet (junk food high in fat, salt, sugar, AGEs), and obesity.
  • Hyperandrogenism and Insulin Resistance (IR) are central to the pathophysiology.Hyperandrogenism: Can be caused by excessive ovarian and adrenal androgen secretion. Abdominal adiposity also triggers hyperandrogenism, cytokine secretion, and oxidative stress, impacting oocyte quality.
  • Insulin Resistance: A condition where insulin has a reduced biological effect even at high concentrations, disrupting glucose transfer and utilization. It is strongly correlated with hyperinsulinemia, testosterone, and androstenedione levels in PCOS women. While insulin receptor gene mutations are rare, IR is common in both overweight and lean women with PCOS. Hyperinsulinemia can indirectly stimulate androgen production by the ovaries and adrenal glands, and suppress SHBG secretion by the liver.
  • Genetics of IR and Hyperandrogenism: Specific genes involved in steroidogenesis (CYP11a, CYP17, CYP19, CYP21), androgen receptors (AR), sex hormone-binding globulin (SHBG), luteinizing hormone (LH) and its receptor, follicle-stimulating hormone receptor (FSHR), Anti-Mullerian Hormone (AMH), follistatin, insulin, insulin receptor (INSR), insulin receptor substrates (IRSs), calpain-10 (CAPN10), fat mass and obesity gene (FTO), and PPAR-γ are linked to PCOS and its associated features.
  • Epigenetic phenomena: Excessive exposure to testosterone in utero for female fetuses is proposed as a potential etiology, affecting the expression of genes related to ovarian steroidogenesis, insulin action, and GnRH pulsatility. This developmental programming can impact adult life, including a higher prevalence of PCOS.
  • Immune regulation: The role of the immune system in the pathogenesis of PCOS is being investigated. Increased inflammatory markers are observed in women with PCOS. Kisspeptin, a protein involved in puberty and GnRH release, is also linked to elevated LH levels in women with PCOS.
  • PCOS is associated with a significantly increased risk of numerous comorbidities, including:
  • Hirsutism and Hypertrichosis
  • Female infertility (associated with anovulation and other origins)
  • Amenorrhea and Oligomenorrhea
  • Non-inflammatory disorders of the female genital tract
  • Type 2 diabetes (with varying definitions)
  • Obesity (due to excess calories and other forms)
  • Other nutritional deficiencies
  • Endometriosis (diagnosis and infertility)
  • Excessive, frequent, and irregular menstruation
  • Pain (limb, back, neck, head, and abdominal)
  • Abdominal and pelvic pain
  • Migraine (with and without aura)
  • Disorders of the thyroid gland (including hypothyroidism)
  • Disorders of the skin appendages
  • Personality disorders, bipolar affective disorders, postpartum depression, eating disorders, and phobic anxiety disorders
  • Abnormal products of conception
  • Maternal disorders related to pregnancy
  • AMH is produced by ovarian follicles and plays a crucial role in female fertility and follicular development.
  • Variations in the AMH gene are associated with PCOS.
  • Elevated serum AMH levels are observed in PCOS patients.
  • Research is exploring the use of AMH levels as a diagnostic biomarker for PCOS and PCOM, but current guidelines do not recommend using AMH as a single test for diagnosis or as an alternative marker for PCOM. However, meta-analyses are investigating its efficacy in adult and adolescent women for diagnosing PCOS and PCOM. Age-specific reference ranges for AMH are being developed to improve diagnostic performance.
  • Metformin is a commonly used medication for PCOS, particularly addressing insulin resistance and its associated metabolic effects.
  • Mechanism of action: Metformin targets mitochondrial complex I, increasing AMP levels and activating AMPK. This leads to:
  • Enhanced glycolysis and suppressed gluconeogenesis in the liver.
  • Improved insulin sensitivity and increased systemic glucose uptake (by promoting GLUT4 translocation in skeletal muscle).
  • Reduced lipolysis and lipogenesis in adipose tissue.
  • Influences gut microbiota and hormones (GLP-1, PYY), affecting glucose homeostasis.
  • In the ovary, it may modulate FSHR activity and lower androgen levels by inhibiting steroidogenic enzymes (HSD3B2 and CYP17-lyase) through mitochondrial-mediated pathways.
  • Benefits in PCOS:Significantly reduces serum androgen levels.
  • Improves insulin sensitivity and reduces hyperinsulinemia.
  • Restores menstrual cyclicity and can trigger ovulation, improving fertility outcomes.
  • May improve metabolic parameters and reduce the risk of type 2 diabetes.
  • While metformin can contribute to weight loss in some individuals, studies have shown similar weight loss in both metformin-treated and placebo groups with lifestyle modification.
  • Metformin is often used in combination with lifestyle modifications (diet and exercise) for optimal results.
  • It can be used alone or in combination with other treatments like oral contraceptives or spironolactone.
  • The heterogeneity of PCOS necessitates a systematic classification and stratified approach to diagnosis and treatment.
  • Different phenotypes exist based on the Rotterdam criteria combination.
  • Subgroups have been identified based on hormonal and metabolic markers, such as a “reproductive subtype” (lower BMI, insulin; higher LH, SHBG; severe infertility) and a “metabolic subtype” (higher BMI, glucose, insulin; lower SHBG, LH; increased androgen excess symptoms). These subtypes may have distinct genetic associations.
  • Insulin resistance in PCOS can be tissue-specific, affecting skeletal muscle and adipose tissue more than the ovary, adrenal glands, and liver.

Criteria for diagnosing PCOS

The understanding and diagnosis of Polycystic Ovary Syndrome (PCOS) have evolved significantly since its initial description in 1935. The criteria for diagnosing PCOS have changed over time, leading to different classification systems and highlighting the syndrome’s heterogeneous nature.

Historically, Stein and Leventhal first described PCOS in 1935, noting features like hirsutism, obesity, amenorrhea, and bilateral enlarged polycystic ovaries.

The first attempt at a clinical definition was made in 1990 by the National Institutes of Health/National Institute of Child Health and Human Development (NIH/NICHD). The NIH 1990 criteria required the presence of hyperandrogenism (clinical and/or biochemical) and oligo- or chronic anovulation, while excluding other related disorders like thyroid conditions, hyperprolactinemia, and congenital adrenal hyperplasia. Ultrasonographic evidence of polycystic ovaries was considered suggestive but not diagnostic. Using the NIH definition, PCOS affects about 6% of women of reproductive age.

In 2003, a consensus workshop in Rotterdam, sponsored by the European Society of Human Reproduction and Embryology (ESHRE) and American Society for Reproductive Medicine (ASRM), broadened the diagnostic criteria. The Rotterdam criteria define PCOS by the presence of any two of the following three features: oligo-ovulation or anovulation, hyperandrogenism (clinical or biochemical), and polycystic ovarian morphology (PCOM) on ultrasound, after excluding other relevant disorders. This led to the identification of four phenotypes:

  • Type A (Classic): Polycystic ovaries (PCO), chronic anovulation (CA), and Hyperandrogenism (H).
  • Type B (Classic): Chronic anovulation (CA) and hyperandrogenism (H).
  • Type C (Ovulatory): Polycystic ovaries (PCO) and hyperandrogenism (H).
  • Type D (Non-androgenic): Polycystic ovaries (PCO) and chronic anovulation (CA).

The Rotterdam criteria increased the prevalence of PCOS to approximately 6% to 20%, and in some studies, up to three times compared to the 1990 NIH criteria. Importantly, these criteria allowed for a diagnosis of PCOS without hyperandrogenism, which was a shift from the NIH criteria that viewed hyperandrogenism as the primary defect. However, there has been debate regarding whether women exhibiting PCOM and ovulatory dysfunction but lacking biochemical or clinical hyperandrogenism should be diagnosed with PCOS, and all three classifications (NIH, Rotterdam, AE-PCOS) remain in use.

The Androgen Excess and PCOS Society (AE-PCOS) in 2006 proposed criteria that centered on hyperandrogenism, requiring hirsutism or hyperandrogenemia, along with either oligo-anovulation or polycystic ovaries. The AE-PCOS criteria would diagnose PCOS even if PCOM or hyperandrogenemia were not prevalent. The AE-PCOS society specifically excluded the presumed normoandrogenic PCOS phenotype D from the diagnosis.

The variability and overlap between these classification systems have caused clinical confusion and were seen as hindering scientific understanding. Despite this, the Rotterdam criteria remain the most widely used and accepted. The 2018 International Evidence-Based Guideline for the Assessment and Management of PCOS supported the use of modified Rotterdam criteria, diagnosing PCOS if any two of clinical or biochemical hyperandrogenism, evidence of oligo-anovulation, or PCOM on ultrasound are present, after excluding other relevant disorders. The latest 2023 international evidence-based guideline for PCOS also recommends using these criteria for adults, while noting that for adolescents, both hyperandrogenism and ovulatory dysfunction must be present for diagnosis, as ultrasound and AMH testing have low specificity in this population.

  • Polycystic Ovarian Morphology (PCOM): The definition and assessment of PCOM using ultrasound have been challenging. Criteria have evolved from needing 10 or more follicles (2-8mm) on transabdominal ultrasound to thresholds of 12 or more follicles (2-9mm) or ovarian volume > 10 cm³ for either ovary using transvaginal ultrasound in the 2003 Rotterdam criteria. More recently, the recommended threshold using newer transvaginal ultrasound technology (≥8 MHz transducer frequency) has increased to ≥20 follicles per ovary and/or ovarian volume ≥10 cm³. The accuracy and reproducibility of follicle number counts depend on the operator’s skills and the equipment used. Transabdominal ultrasound may also be used, which can affect accuracy, and transvaginal ultrasound may not be acceptable to all women. Ultrasound is not recommended for diagnosing PCOS in women with a gynecological age less than 8 years due to the presence of multiple follicles in this age group, which could lead to overdiagnosis.
  • Hyperandrogenism: While considered a critical diagnostic factor, there is a need for standardization in testosterone assays.
  • Age-Related Changes: Follicle number and AMH levels decline with age in both women with and without PCOS. This suggests a need for age-specific thresholds for diagnosis. Some studies have shown that age-stratified thresholds for AMH can improve its predictive performance for PCOS diagnosis compared to a single non-age-adjusted threshold. Recognition of these changes over time is important, especially when evaluating older patients.
  • Heterogeneity: The significant heterogeneity in the phenotypic expressions of PCOS makes identifying and managing it challenging. Patients exhibit diverse features across reproductive, endocrine, metabolic, dermatological, and psychosocial domains, which can be exacerbated by obesity, ethnicity, and changes over time.
  • Anti-Müllerian Hormone (AMH): Elevated serum AMH levels are significantly higher in women with PCOS compared to those without it. AMH is secreted by granulosa cells of preantral and small antral follicles, and levels correlate strongly with follicle number on ultrasound. AMH has been proposed as a potential surrogate marker for ovarian morphology. While promising, there is significant heterogeneity in studies regarding diagnostic accuracy and proposed thresholds, and standardization of AMH measurement is needed. Due to these limitations, most recent guidelines do not recommend using AMH levels as an alternative for PCOM detection or as a single test for PCOS diagnosis. However, the 2023 international guideline mentions elevated AMH levels as an alternative finding for polycystic ovaries on ultrasound in adults. A recent meta-analysis conducted as part of the 2023 guideline investigated the inclusion of AMH in diagnostic criteria, finding pooled sensitivity of 0.79 and specificity of 0.87 for AMH in diagnosing PCOS in adults.

The diverse phenotypes arising from the different diagnostic criteria have highlighted the need for better stratification of PCOS. The Rotterdam criteria’s four phenotypes (A, B, C, D) represent different combinations of the three diagnostic features. Phenotype A is the most common, especially in younger women. Phenotype D is characterized by PCOM and chronic anovulation without hyperandrogenism.

The existence of multiple classification systems and the heterogeneity of symptoms have led to calls for a more systematic classification based on underlying etiologies and individual needs. Some research suggests that the current four phenotypes might not fully capture the diversity of PCOS and that stratifying the condition could lead to evidence-based precision diagnosis and treatment.

One proposed reclassification suggests two primary entities instead of four phenotypes. This concept, based on observations, proposes:

  • Hyperandrogenic (H-PCOS): Includes current phenotypes A, B, and C, characterized by persistent hyperandrogenism across age and often associated with metabolic abnormalities like metabolic syndrome.
  • Hyper-/Hypoandrogenic (HH-PCOS): Primarily represents the current phenotype D. This phenotype is hyperandrogenic in younger women (< age 25), may have normal androgens between 25-35, and becomes hypoandrogenic after age 35 due to insufficient adrenal androgen production. HH-PCOS is mostly characterized by a hyperactive immune system (inflammation and autoimmunity) and is generally not associated with increased metabolic syndrome risk. This phenotype is often underdiagnosed, especially in older women.

This proposed stratification suggests that H-PCOS may be a primarily metabolic condition, while HH-PCOS might be more immunologically driven. Differentiation between these two entities is seen as crucial for future research and clinical progress. A recent genetic clustering study supports the idea of distinct PCOS subtypes based on genomic differences, identifying reproductive and metabolic subtypes. The reproductive subtype was linked to lower BMI, lower insulin, higher LH and SHBG, and more severe infertility and irregular menstruation, with variants in genes related to ovarian function. The metabolic subtype was associated with higher BMI, higher glucose and insulin, lower SHBG and LH, and increased risk of androgen excess symptoms, with variants in genes related to glucose metabolism.

In summary, the evolving diagnostic criteria for PCOS, moving from strict definitions to broader ones and incorporating features like PCOM and potentially AMH, have increased the recognized prevalence and highlighted the syndrome’s heterogeneity. The challenges in consistently applying criteria, especially regarding PCOM assessment and age-related changes, contribute to diagnostic difficulties. This heterogeneity underscores the limitations of current phenotypic classifications and drives the need for better stratification based on underlying etiologies (metabolic vs. immune) and genetic factors. Precision diagnostics using novel biomarkers and machine learning methods, validated in diverse populations, are needed to improve diagnosis and tailor treatment strategies.

FAQ

The diagnosis of PCOS typically relies on specific diagnostic criteria. The most widely used criteria are the Rotterdam criteria (2003), which require the presence of any two out of the following three features: 1) oligo-ovulation or anovulation (irregular or absent menstrual cycles), 2) hyperandrogenism (either clinical signs like excessive hair growth [hirsutism], acne, or alopecia, or biochemical evidence of elevated androgen levels), and 3) polycystic ovarian morphology (detected via ultrasound, typically defined by a specific number of follicles and/or ovarian volume). It is crucial to exclude other disorders that can mimic PCOS symptoms, such as thyroid disorders, hyperprolactinemia, or congenital adrenal hyperplasia, before making a diagnosis. Other criteria, such as the National Institutes of Health (NIH) 1990 criteria and the Androgen Excess Society (AES) criteria, also exist and emphasize different aspects of the syndrome, which can lead to variations in prevalence estimates depending on the criteria used.

PCOS presents with a range of symptoms that can vary in severity among individuals. Common symptoms include menstrual irregularities (oligomenorrhea or amenorrhea), signs of hyperandrogenism such as hirsutism, acne, and alopecia, and difficulty conceiving due to anovulation. Beyond reproductive issues, PCOS is frequently associated with metabolic dysfunction, including insulin resistance and compensatory hyperinsulinemia. This metabolic profile significantly increases the risk of developing type 2 diabetes, gestational diabetes, and cardiovascular diseases. Obesity, particularly abdominal obesity, is also common in women with PCOS and can exacerbate both hyperandrogenism and insulin resistance. Other associated health issues can include an increased risk of endometrial cancer due to prolonged exposure to high estrogen levels without regular progesterone shedding, sleep apnea, depression, and anxiety.

The exact cause of PCOS is complex and not fully understood, but it is believed to be multifactorial, involving a combination of genetic and environmental factors. Genetic predisposition plays a significant role, with a higher prevalence of PCOS among first-degree relatives. Specific genes involved in steroidogenesis (like CYP11a, CYP17, CYP19, and CYP21), androgen receptor function (AR), sex hormone-binding globulin (SHBG) synthesis, and insulin signaling (like the insulin gene, insulin receptor gene (INSR), and insulin receptor substrate genes (IRSs)) have been implicated in the development of PCOS. Environmental factors such as physical inactivity, unhealthy eating habits high in fat and sugar, and obesity are also linked to its occurrence. Furthermore, there is a hypothesis suggesting that excessive exposure to androgens during fetal development might epigenetically program certain genes, influencing ovarian function, insulin action, and GnRH pulsatility, potentially contributing to PCOS later in life.

Hyperandrogenism is a key feature of PCOS, characterized by excessive production of androgens by the ovaries and adrenal glands. These elevated androgen levels contribute to the clinical symptoms of hirsutism, acne, and alopecia. Biochemically, this can manifest as elevated levels of testosterone, androstenedione, DHEA, and DHEAS. In PCOS, the enzymes involved in androgen synthesis can have enhanced activity, leading to increased androgen production. Hyperinsulinemia, often present in PCOS, can further stimulate androgen production in the ovaries. Excessive androgens also interfere with normal follicular development in the ovaries, leading to the formation of multiple small antral follicles and contributing to anovulation and infertility. The pulsatile release of GnRH from the hypothalamus, which stimulates the pituitary gland to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH), is also altered in PCOS, often resulting in a higher LH:FSH ratio, which further promotes ovarian androgen production.

Insulin resistance (IR) is a physiological condition where the body’s cells do not respond effectively to insulin, leading to higher-than-normal insulin levels (hyperinsulinemia). While not a universal feature, IR is highly prevalent in women with PCOS, affecting both lean and overweight individuals. Insulin resistance is considered a significant pathophysiological factor in PCOS, contributing to many of its metabolic and reproductive abnormalities. Hyperinsulinemia stimulates androgen production in the ovaries, exacerbating hyperandrogenism. It also suppresses the production of sex hormone-binding globulin (SHBG) by the liver. Since SHBG binds to testosterone, lower SHBG levels result in higher levels of free, biologically active testosterone, further contributing to hyperandrogenism. Insulin resistance in skeletal muscle and adipose tissue can lead to decreased glucose uptake and increased lipolysis, contributing to dyslipidemia and increased risk of type 2 diabetes.

Anti-Müllerian Hormone (AMH) is a protein produced by the granulosa cells in the ovaries. It plays a crucial role in follicular development and inhibits the growth of primary follicles. Women with PCOS typically have significantly elevated serum AMH levels compared to women without the condition. This is thought to be due to the increased number of small antral follicles characteristic of polycystic ovarian morphology, which are the primary source of AMH production. Elevated AMH levels contribute to the disruption of follicular development and anovulation seen in PCOS. While AMH is associated with PCOS and has been investigated as a potential diagnostic marker, current guidelines do not recommend using it as a single test for diagnosis or as a direct alternative marker for polycystic ovarian morphology. However, research continues to explore the utility of AMH in diagnosing and characterizing PCOS, particularly in specific age groups and phenotypes.

The management of PCOS is multifaceted and depends on the individual’s symptoms, health goals, and the specific phenotype of PCOS. Lifestyle modifications, including weight loss through diet and exercise, are often the first line of treatment, as even modest weight loss can improve menstrual regularity, reduce hyperandrogenism, and enhance insulin sensitivity. For managing hyperandrogenism and menstrual irregularities, combined oral contraceptive pills are frequently prescribed. For women with insulin resistance, medications like metformin are often used to improve insulin sensitivity, which can indirectly help regulate menstrual cycles and reduce androgen levels. For infertility, various treatments are available, including lifestyle changes, ovulation induction medications like clomiphene citrate or letrozole, and assisted reproductive technologies like IVF. Emerging treatments and ongoing research are exploring the roles of other medications and interventions targeting specific aspects of PCOS pathophysiology.

The classic description of PCOM included an increased number of follicles 2-9 mm in size, often arranged peripherally in a “string of pearls” pattern, around a bright echodense stroma. However, markers such as stromal area, stromal echogenicity, and follicular distribution have not been found to have significant predictive power when used alone or combined with follicle number and/or ovarian volume. These features were excluded from the definition of PCOM in 2003 and by subsequent major criteria. Using the thresholds proposed by the 2003 Rotterdam criteria, a significant percentage (30–50%) of normo-androgenic, ovulatory women could meet criteria for PCOM. This led to the conclusion that the thresholds needed revision. Much of the variation in reported follicle counts is attributed to changes in ultrasound technology; increased transducer frequency (≥8 MHz) improves the detection of antral follicles, necessitating higher threshold levels. Studies using newer transvaginal ultrasound technology with a transducer frequency of 8 MHz or more recommend increasing the threshold. A task force report from the Androgen Excess and PCOS (AEPCOS) society in 2014 recommended increasing the threshold to ≥25 follicles per ovary and/or an ovarian volume threshold of ≥10 cm³. More recently, the 2018 International Evidence Based Guidelines suggested a slightly reduced follicle number threshold of ≥20 follicles per ovary and/or an ovarian volume of ≥10 cm³.

Yes, genetic factors are implicated in the etiology of PCOS. The CYP11a gene is involved in increased androgen levels. Specifically, single nucleotide polymorphism (SNP) in the CYP11a gene has been found to be responsible for increased androgen levels via the luteinizing hormone signaling pathway. A case study in the South Indian population found about 15 allelic variations in the CYP11a gene, with the 8 repeat allele being the most prevalent and associated with a 3 times increased risk of developing PCOS. The CAPN10 gene encodes a calcium-dependent cysteine protease known as calpain 10, which facilitates insulin secretion and action. Existing data suggest that PCOS is directly related to insulin resistance and type 2 diabetes. Some studies have found four SNPs related to the CAPN10 gene (SNP-19, SNP-43, SNP-44, and SNP-63) were linked with PCOS, and specifically SNP-44 was associated with PCOS in the Spanish population. However, other studies found no relationship between three CAPN10 SNPs (SNP-43, SNP-44, and SNP-45) and PCOS, suggesting that absolute conclusions about the CAPN10 gene and PCOS cannot yet be drawn and require further study.

Historically, different criteria have been used to diagnose PCOS, which has impacted reported prevalence.

  • The National Institute of Child Health and Human Development (NIH) criteria defined PCOS by the presence of both clinical and/or biochemical signs of hyperandrogenism and oligo- or chronic anovulation. Under these criteria, ultrasonographic evidence of polycystic ovaries was considered suggestive, but not strictly diagnostic.
  • The Rotterdam Criteria, established in 2003, broadened the definition to include any two out of three key characteristics: oligo-amenorrhea, hyperandrogenism (clinical or biochemical), and polycystic-appearing ovarian morphology (PCOM) on ultrasonography. This allowed for PCOS diagnosis without hyperandrogenism, which was a primary requirement in the 1990 NIH criteria. The Rotterdam criteria defined four phenotypes (A, B, C, and D) based on combinations of these features.
  • The Androgen Excess and PCOS Society (AE-PCOS) criteria, proposed in 2006, focused on PCOS as a predominantly hyperandrogenic syndrome. Their diagnostic measures included: (1) hyperandrogenism (either hirsutism or hyperandrogenemia); (2) ovarian dysfunction (oligo-ovulation/anovulation or polycystic ovaries); and (3) exclusion of related disorders causing excess androgen production. The AE-PCOS classification considered PCOS even if PCOM or hyperandrogenemia were not prevalent.

Regardless of the criteria used, PCOS is a diagnosis of exclusion, meaning disorders that mimic its clinical features must be ruled out. Delays in diagnosis can lead to the progression of comorbidities.

PCOS is characterized by a combination of features. The widely accepted diagnostic criteria rely on the presence of at least two of the following three key characteristics:

  • Chronic anovulation or oligo-ovulation: This refers to infrequent or absent ovulation, often manifesting as irregular or absent menstrual periods (oligo-amenorrhea), defined as cycles >35 days apart or <8 menses a year.
  • Hyperandrogenism: This involves elevated levels or effects of androgens (male hormones). It can be clinical (visible signs) and/or biochemical (measured hormone levels).
  • Polycystic ovarian morphology (PCOM): This refers to the appearance of the ovaries on ultrasound, typically showing an increased number of small follicles.

Clinical manifestations of hyperandrogenism can include hirsutism (excessive hair growth in a male pattern), acne, and female pattern hair loss. Biochemical hyperandrogenism can be indicated by elevated total or free testosterone, or calculated indices of free testosterone.

Hyperandrogenism, meaning excess androgen production or action, is a central feature in the diagnosis of PCOS, particularly emphasized by the Androgen Excess Society criteria. Elevated androgen levels are found in PCOS patients. Increased androgen production in theca cells contributes to excessive androgen production in PCOS. Hyperandrogenism can be assessed through:

  • Clinical signs: The most common clinical manifestation is hirsutism, which is excessive terminal hair growth in a male pattern distribution, affecting 60–70% of PCOS patients. The Modified Ferriman–Gallwey (MFG) scoring system is typically used to quantify hirsutism by scoring hair growth at nine different anatomical sites. Different MFG score thresholds have been proposed (ranging from ≥3 to ≥8), and threshold levels should consider patient ethnicity. Other clinical signs include acne and female pattern hair loss.
  • Biochemical analysis: This involves measuring androgen levels in the blood. Elevated total or free testosterone, or calculated indices of free testosterone (like FAI, BioT), are markers. High-quality assays should be used for accurate evaluation of these analytes. DHEAS and ANSD can also be considered. Evidence suggests a genetic basis for hyperandrogenemia in PCOS.

Anti-Müllerian hormone (AMH) levels are being investigated for their potential role in diagnosing PCOS and detecting PCOM. AMH is a marker of ovarian function produced by granulosa cells, and its production is increased in polycystic ovaries. Elevated serum levels of AMH are found in patients with PCOS.

  • A 2023 international evidence-based guideline meta-analysis investigated the inclusion of AMH levels in diagnostic criteria.
  • The meta-analysis found that in adult women, pooled sensitivity and specificity for using AMH levels to diagnose PCOS were 0.79 and 0.87, respectively, across 68 studies.
  • For adolescents, the pooled sensitivity and specificity were lower (0.66 and 0.78, respectively) across 11 studies. AMH levels alone are considered insufficient for PCOS diagnosis and non-specific for PCOM in adolescents.
  • For detecting PCOM in adults, pooled sensitivity and specificity were 0.79 and 0.87, respectively, across 7 studies.
  • The 2023 international guideline now recommends AMH levels for defining PCOM in adults in accordance with the diagnostic algorithm.
  • However, AMH levels alone are still considered insufficient for PCOS diagnosis.
  • There is significant heterogeneity in AMH levels across studies, influenced by multiple factors. Because of this, no international cut-off value could be recommended for diagnosing PCOS or detecting PCOM, emphasizing the need for research on more individualized cut-off values.

Insulin resistance (IR) and accompanying compensatory hyperinsulinemia are strongly associated with PCOS. The diagram illustrates that hyperinsulinemia is linked to insulin resistance, which triggers ovarian theca cells to increase LH and androgen production, leading to hyperandrogenism, a key feature of PCOS. Hyperinsulinemia can contribute to hyperandrogenism. Insulin-related ovarian regulatory systems play a role in both health and disease. Alterations or polymorphism associated with the CAPN10 gene, which encodes a protein involved in insulin action and secretion, are linked to PCOS, further supporting the connection between PCOS, insulin resistance, and type 2 diabetes.

Yes, the sources suggest a genetic basis for PCOS. PCOS is considered to have a genetic predisposition. Specific genes and genetic variations have been studied in relation to PCOS development:

  • Variations (allelic variations) in the CYP11a gene are associated with increased androgen levels in PCOS patients. Studies suggest that polymorphism in the CYP11a gene is a cause of developing PCOS.
  • The CYP17 gene encodes an enzyme involved in the formation of dehydroepiandrosterone and androstenedione. Its activity can be enhanced.
  • The CAPN10 gene encodes a calcium-dependent cysteine protease involved in insulin secretion and action. Polymorphism associated with this gene results in PCOS because PCOS is related to insulin resistance and type 2 diabetes. Four SNPs (SNP-19, SNP-43, SNP-44, and SNP-63) related to the CAPN10 gene were found to be linked with PCOS in one study, although other studies found no such relationship with certain SNPs, suggesting the need for further research.
  • Functional genetic variation in the Anti-Müllerian Hormone pathway has also been linked to PCOS.

Metformin is a medication that has been used in the treatment of PCOS, including for related infertility. It is an insulin-sensitizing drug. Metformin is the most commonly used insulin sensitizer in women with PCOS.

  • Its mechanism of action involves reducing serum androgen levels, improving insulin sensitivity, and restoring menstrual cyclicity. It can also be successful in triggering ovulation.
  • Many studies suggest that metformin, when used to treat PCOS, significantly improves insulin sensitivity and reduces serum androgen levels.
  • As a result of these effects, metformin may be useful in treating PCOS-related infertility. Meta-analyses have examined fertility and ovulation outcomes in PCOS patients treated with metformin compared to placebo.
  • Metformin appears to be less effective in patients with significant obesity (BMI > 35 kg/m²).
  • There is no consensus on the appropriate dosage or whether it should be adjusted for body weight. Common dosages range from 500 to 3000 mg/day.
  • Metformin is considered safe in pregnancy, although customary advice is often to avoid it once pregnancy occurs. There is conflicting evidence regarding its efficacy for preventing early pregnancy loss, gestational diabetes, preterm birth, and pre-eclampsia, though some studies suggest benefits. There are also ongoing concerns regarding its long-term safety for offspring metabolic health.

Metformin is an insulin-sensitizing drug that has been used to treat PCOS. Studies have shown that metformin, when used for PCOS, can significantly reduce serum androgen levels, improve insulin sensitivity, restore menstrual cyclicity, and successfully trigger ovulation. As a result, metformin may be useful in treating PCOS-related infertility. While potential benefits include preventing early pregnancy loss and limiting excess gestational weight gain (GWG) in PCOS pregnancies, there are conflicting reports regarding its efficacy for other outcomes like gestational diabetes mellitus (GDM), preterm birth, and pre-eclampsia. Metformin appears less effective in significantly obese patients with a BMI greater than 35 kg/m². Although customary advice is to avoid it once pregnancy occurs, metformin seems to be safe in pregnancy.

list of sources

Siddiqui, S., Mateen, S., Ahmad, R., & Moin, S. (2022). A brief insight into the etiology, genetics, and immunology of polycystic ovarian syndrome (PCOS). Journal of Assisted Reproduction and Genetics, :(0123456789), 2439–2473. https://doi.org/10.1007/s10815-022-02625-7. (Received: 6 June 2022; Accepted: 19 September 2022)

van der Ham, K., Laven, J. S. E., Tay, C. T., Mousa, A., Teede, H., & Louwers, Y. V. (2024). Anti-m€ullerian hormone as a diagnostic biomarker for polycystic ovary syndrome and polycystic ovarian morphology. Fertility and Sterility, 122(4), 727–739. https://doi.org/10.1016/j.fertnstert.2024.05.163. (Received: March 6, 2024; Revised: May 23, 2024; Accepted: May 28, 2024; Published online: June 27, 2024)

Xu, Y., & Qiao, J. (2022). Association of Insulin Resistance and Elevated Androgen Levels with Polycystic Ovarian Syndrome (PCOS): A Review of Literature. Journal of Healthcare Engineering. (Received: 25 December 2021; Revised: 8 February 2022; Accepted: 12 February 2022; Published: 21 March 2022).

Christ, J. P., & Cedars, M. I. (2023). Current Guidelines for Diagnosing PCOS. Diagnostics, 13(6), 1113. https://doi.org/10.3390/diagnostics13061113. (Received: 2 February 2023; Revised: 25 February 2023; Accepted: 3 March 2023; Published: 15 March 2023)

Luan, Y. Y., Zhang, L., Peng, Y. Q., Li, Y. Y., Liu, R. X., & Yin, C. H. (2022). Immune regulation in polycystic ovary syndrome. Clinica Chimica Acta, 531, 265–272. https://doi.org/10.1016/j.cca.2022.04.234. (Received: 24 January 2022; Received in revised form: 11 April 2022; Accepted: 15 April 2022; Available online: 18 April 2022)

Saadati, S., Mason, T., Godini, R., Vanky, E., Teede, H., & Mousa, A. (2025). Metformin use in women with polycystic ovary syndrome (PCOS): Opportunities, benefits, and clinical challenges. Diabetes, Obesity and Metabolism, 27(Suppl. 3), 31–47. https://doi.org/10.1111/dom.16422. (Published: 2025)

Joshi, A. (2024). PCOS stratification for precision diagnostics and treatment. Frontiers in Cell and Developmental Biology, 12, 1358755. https://doi.org/10.3389/fcell.2024.1358755. (Received: 20 December 2023; Accepted: 23 January 2024; Published: 08 February 2024)

Shukla, A., Rasquin, L. I., & Anastasopoulou, C. (2025). Polycystic Ovarian Syndrome. In StatPearls [Internet]. StatPearls Publishing. (Last Update: May 4, 2025).

Gleicher, N., Darmon, S., Patrizio, P., & Barad, D. H. (2022). Reconsidering the Polycystic Ovary Syndrome (PCOS). Biomedicines, 10(7), 1505. https://doi.org/10.3390/biomedicines10071505. (Received: 6 April 2022; Accepted: 15 June 2022; Published: 25 June 2022)

Attia, G. M., Almouteri, M. M., & Alnakhli, F. T. (2023). Role of Metformin in Polycystic Ovary Syndrome (PCOS)-Related Infertility. Cureus, 15(8), e44493. https://doi.org/10.7759/cureus.44493. (Review began: 08/23/2023; Review ended: 08/29/2023; Published: 08/31/2023)

Bibliography

Polycystic ovarian syndrome (PCOS) is recognized as a prevalent endocrine and metabolic disorder affecting females of reproductive age. It is characterized by a combination of signs and symptoms, leading it to be considered a heterogeneous disorder. The prevalence of PCOS varies depending on the diagnostic criteria used, with estimates ranging from approximately 6–20% in reproductive-aged women, 5–10%, 4–12%, 6–10%, up to 1 in 10, and 5%-26%. Symptoms often begin early during puberty.

Diagnosis of PCOS

Diagnosing PCOS can be complex due to its diverse presentation and the existence of multiple diagnostic criteria. Historically, Stein and Leventhal first described PCOS as an endocrine disorder linked to oligo-ovulatory infertility in 1935. Over time, different criteria have been developed by major scientific societies and health authorities.

The Rotterdam criteria (2003) are the most extensively used and widely accepted. According to these criteria, a woman can be diagnosed with PCOS if she presents with any two of the following three features, after excluding other related disorders:

  • Hyperandrogenism (clinical signs like hirsutism or biochemical evidence).
  • Oligo- or an-ovulation (irregular or absent menstrual cycles).
  • Polycystic ovarian morphology (PCOM) on ultrasound.

Prior to Rotterdam, the National Institutes of Health/National Institute of Child Health and Human Development (NIH/NICHD) criteria (1990) defined PCOS by the presence of both clinical/biochemical hyperandrogenism and anovulation or oligo-ovulation, requiring the exclusion of associated disorders like thyroid dysfunction, hyperprolactinemia, and congenital adrenal hyperplasia. The NIH criteria considered polycystic ovaries on ultrasound suggestive but not necessarily diagnostic.

The Androgen Excess and PCOS Society (AE-PCOS) criteria (2006) emphasized hyperandrogenism as a primary feature. This classification requires hyperandrogenism (either hirsutism or hyperandrogenemia) and ovarian dysfunction (oligo-ovulation/anovulation or polycystic ovaries), with the exclusion of other disorders causing excess androgen production. The AE-PCOS criteria allowed for a PCOS diagnosis even if PCOM or hyperandrogenemia were not both present.

All three major diagnostic classifications necessitate the exclusion of other conditions that can mimic PCOS symptoms. Despite these established criteria, debate continues regarding the most relevant approach for diagnosis. The latest international evidence-based guideline recommendations were updated in 2023. Anti-Müllerian hormone (AMH) levels have also been investigated for their effectiveness in diagnosing PCOS and polycystic ovarian morphology in adults and adolescents.

Etiology and Pathophysiology

The exact cause (etiology) of PCOS remains unclear. However, it is understood to be a complex disorder influenced by environmental and genetic factors.

Genetic factors play a crucial role. Family history studies indicate that PCOS is more prevalent in certain families, particularly among first-degree relatives. Studies suggest a significant percentage of sisters of women with PCOS are also affected. PCOS is considered a multigenic disorder with strong epigenetic factors. Genome-wide association studies (GWAS) have identified multiple genetic loci associated with PCOS, many involved in insulin resistance, ovarian steroidogenesis, steroid hormone biosynthesis, the PI3K-Akt signaling pathway, adrenal cortisone reductase deficiency, and gonadotrophic dysregulation. These studies suggest a common genetic architecture across different diagnostic criteria.

Environmental factors also contribute significantly. These include environmental toxins, such as bisphenol-A and endocrine disruptors, diet, nutrition, physical inactivity, and unhealthy eating habits. Alterations during prenatal development, such as exposure to excess AMH or androgens, may also be an etiologic mechanism.

The pathophysiology of PCOS involves multiple interlinked factors. A key component is the persistent hormonal imbalance, leading to the formation of multiple small antral follicles and irregular menstrual cycles, which ultimately causes infertility. Hyperandrogenism and ovulatory dysfunction are central problems.

A major factor in PCOS pathogenesis is insulin resistance (IR), often accompanied by compensatory hyperinsulinemia. There is a high prevalence of visceral adiposity linked to IR, regardless of overall obesity. Hyperandrogenism is directly linked to insulin resistance and hyperglycemia. This relationship forms a vicious cycle.

The interconnected pathophysiologies include:

  • Hyperandrogenism.
  • Insulin resistance/Hyperinsulinemia.
  • Inflammation.
  • Oxidative stress.
  • Advanced Glycation End Products (AGEs) elevation, which exacerbates symptoms and is linked to ovarian dysfunction.

Hyperandrogenism causes insulin resistance and hyperglycemia, promoting ROS (reactive oxygen species) formation, oxidative stress, and abdominal adiposity. In turn, inflammation, ROS production, insulin resistance, and hyperandrogenemia increase. This creates a self-perpetuating cycle. Errors in hormonal cross-talk between the hypothalamus, pituitary gland, and ovaries also play a role.

Genetics and Molecular Insights

Reviewing the genetics of PCOS involves examining genes phenotypically linked to the condition. Genome-wide association studies have connected specific genes at 11 loci with PCOS-associated symptoms like infertility, insulin resistance, and type 2 diabetes. Microarray or RNA sequencing studies of granulosa cells, oocytes, and cumulus cells (CCs) in women with PCOS have aided the understanding of its etiology.

Transcriptome analysis revealed that the transposable element (TE) expression profiles and global gene expression patterns in PCOS patients were distinctly different from healthy individuals. Functionally significant pathways in PCOS oocytes show anomalies. Specifically, genes vital for microtubule processing, such as TUBB8 and TUBA1C, are abundantly expressed in PCOS oocytes. Oxidative phosphorylation and metabolic pathways are dysregulated in both CCs and oocytes of women with PCOS.

Certain endogenous retrovirus 1 (ERV1) elements on chromosomes 2, 3, 4, and 5 are significantly induced and linked to the expression levels of protein-coding genes like the tubulin-related TUBA1C, TUBB8P8, and TUBA8 genes. The unusual high expression of TUBB8, TUBA1C, and ERV1 offers potential biomarkers for PCOS and may contribute to impaired oocyte development.

While the intricate molecular processes underlying PCOS and low oocyte quality remain unclear, these genetic and TE findings provide unique molecular characteristics of the condition.

Immunology and Inflammation

PCOS is linked to chronic low-grade inflammation. This involves an imbalance in pro-inflammatory factor secretion, endothelial cell dysfunction, and leukocytosis. Hormonal and immune dysregulation are characteristic of PCOS. Low progesterone levels, due to oligo/anovulation in PCOS patients, may overstimulate the immune system, leading to increased estrogen production and potentially autoantibodies.

Immune cells and regulatory molecules are crucial in maintaining metabolic homeostasis and regulating immune responses in PCOS. Inflammatory cell infiltration in fat and ovarian tissue, along with increased inflammatory medium secretion, can worsen chronic inflammation, impair tissue cell function, and result in ovarian dysfunction and metabolic disorders. The breakdown of immune homeostasis is associated with the pathology of PCOS. Immune molecules like antibodies, complements, and lymphokines produced by antigen-stimulated immune cells (T lymphocytes and macrophages) play a direct role in the immune response and have functions linked to pathological changes in PCOS. Detecting immune molecule expression in PCOS patients is considered important for assessing their inflammatory state and potential long-term complications. Alterations within the follicular microenvironment are also intricately involved in the development of infertility in women with PCOS.

Associated Conditions and Manifestations

PCOS is associated with numerous comorbidities and manifestations that impact health across the lifespan. These include:

  • Infertility.
  • Insulin resistance and metabolic syndrome.
  • Type 2 diabetes.
  • Cardiovascular diseases and risks.
  • Abdominal obesity or visceral adiposity.
  • Psychological disorders, such as depression.
  • Cancer, particularly endometrial cancer.
  • Obstructive sleep apnea.
  • Metabolic dysfunction-associated steatotic liver disease (MASLD).
  • Hirsutism, acne, and seborrheic dermatitis.
  • Irregular menstrual cycles or anovulation.
  • Poor oocyte quality.

These conditions are often interrelated with the core pathophysiologies of PCOS.

Other Relevant Concepts and Treatments

The document also briefly mentions other factors and potential treatments:

  • Metformin is noted as having a beneficial effect in maintaining endocrine abnormalities and ovarian function. It is used for PCOS-related infertility and has shown effectiveness in reducing serum androgen levels, improving insulin sensitivity, restoring menstrual cyclicity, and triggering ovulation.
  • Kisspeptin is a protein that aids in the onset of puberty and increases GnRH pulsatile release during ovulation. The role of KNDy neurons in the GnRH pulsatile signal needed for reproduction is also elaborated upon.
  • The role of BMP (bone morphogenetic proteins) in folliculogenesis and their expression in oocytes and granulosa cells is explained.
  • Expression of GDF8 and SERPINE1 in PCOS is detailed.
  • Initiation of antiandrogen treatment at an early age (≤ 25 years) might be helpful for spontaneous conception in women with PCOS.
  • The development of PCOS following the use of antiepileptic and psychiatric medications is also discussed.

In conclusion, PCOS is a widespread and complex disorder involving multi-organ systems. While its precise etiology remains elusive, genetic and environmental factors are key contributors. The pathophysiology is characterized by a vicious cycle involving hormonal imbalance, hyperandrogenism, insulin resistance, inflammation, oxidative stress, and AGEs. Genetic research is uncovering specific genes and molecular pathways involved, while immunology studies highlight the role of chronic inflammation. Effective management involves addressing the diverse clinical manifestations and associated metabolic and reproductive complications.

Polycystic Ovarian Syndrome (PCOS) is a widely recognized endocrine and metabolic disorder that affects females of reproductive age. It is considered a heterogeneous disorder due to its varied presentation of signs and symptoms. The prevalence of PCOS varies, with estimates ranging from approximately 6–20% in reproductive-aged women, up to 1 in 10, and 5%-26%, depending on the diagnostic criteria used. Symptoms often manifest early during puberty.

Diagnosing PCOS can be challenging due to its heterogeneity and the existence of multiple diagnostic criteria developed over time. The Rotterdam criteria (2003) are the most widely used. These criteria require the presence of any two of the following three features, after excluding other related disorders: hyperandrogenism, oligo- or an-ovulation, and polycystic ovarian morphology (PCOM). Other criteria include those from the National Institutes of Health (NIH/NICHD) and the Androgen Excess and PCOS Society (AE-PCOS), which emphasize hyperandrogenism as a key feature. All diagnostic classifications necessitate the exclusion of other conditions mimicking PCOS.

Polycystic ovarian morphology (PCOM), the presence of multiple small follicles visualized on ultrasound, is one of the potential diagnostic features. However, the use of ultrasound in practice has remained controversial due to various challenges. This has led to the proposal of alternative markers for determining PCOM.

Anti-Müllerian Hormone (AMH) has emerged as a candidate for such a marker and as a potential diagnostic tool for PCOS itself. AMH is a protein produced by granulosa cells of the ovarian follicles. Its levels are strongly correlated with the number of antral follicles. Women with PCOS are known to have higher levels of AMH compared to ovulatory women without PCOS. This elevated AMH may be related to the increased number of small antral follicles characteristic of PCOM. Furthermore, AMH might be linked to hyperandrogenism through aromatase inhibition, which is often observed in women with PCOS.

Despite the observed association between high AMH and PCOS, significant heterogeneity exists between studies investigating the role of AMH levels as a diagnostic marker. This heterogeneity has left the precise diagnostic role of AMH unclear.

The document “Anti-müllerian hormone as a diagnostic biomarker for polycystic ovary syndrome and polycystic ovarian morphology: a systematic review and meta-analysis” addresses this uncertainty through a comprehensive systematic review and meta-analysis. This study, an update of a prior review, was conducted to inform the recommendations in the updated 2023 international evidence-based guideline for the assessment and management of PCOS. The main objective was to assess the diagnostic accuracy of AMH for PCOS and PCOM. Specifically, it aimed to answer three key questions:

  1. Is AMH effective in diagnosing PCOS in adult women?
  2. Is AMH effective in diagnosing PCOS in adolescents?
  3. Is AMH effective in detecting PCOM in adults?

The study conducted searches in six databases until July 31, 2023, including eligible studies published in English reporting sensitivity, specificity, and/or area under the curve values for AMH. Data extracted included study population, age, BMI, AMH assay type, cut-off values, sensitivity, specificity, and AUC values. The quality of studies was assessed using the quality assessment of diagnostic accuracy studies tool.

The meta-analysis yielded the following key findings:

  • For the diagnosis of PCOS in adults, based on 68 studies, the pooled sensitivity was found to be approximately 0.79 to 0.80, and the pooled specificity was approximately 0.87. However, there was high heterogeneity observed across these studies (I² = 86% for sensitivity and I² = 91% or 87% for specificity).
  • For the diagnosis of PCOS in adolescents, based on 11 studies, the pooled sensitivity was approximately 0.66, and the pooled specificity was approximately 0.78.
  • For detecting PCOM in adults, based on 7 studies, the pooled sensitivity was approximately 0.79, and the pooled specificity was approximately 0.87.
  • For detecting PCOM in adolescents, AMH levels were found to be nonspecific.

Based on these results, the meta-analysis concluded that AMH levels alone are insufficient for the diagnosis of PCOS. This is because PCOS is a heterogeneous and multicomponent diagnosis. However, the study demonstrated that AMH level is a reasonably sensitive and specific marker for detecting PCOM in adults.

The high heterogeneity observed in the studies was mainly attributed to variations in AMH threshold levels, assay types, and differences in age, BMI, and control group characteristics. Consequently, the study could not recommend a single international cut-off value for AMH, emphasizing the need for further research to determine more individualized cut-off values.

As a result of this work, the 2023 international evidence-based PCOS guideline now recommends the use of AMH levels for defining PCOM in adults. This is considered a significant change in the diagnostic criteria. Specifically, AMH is incorporated into the guideline diagnostic algorithm as an endocrine substitute for the ultrasound assessment of PCOM in adults with either (but not both) irregular cycles or hyperandrogenism. This change is expected to potentially reduce the inconvenience and cost of diagnosis.

While the meta-analysis focused on the diagnostic utility of AMH, it’s important to remember that PCOS is a complex disorder with various contributing factors, including genetic and environmental influences, persistent hormonal imbalances, and underlying pathophysiologies such as insulin resistance, hyperinsulinemia, chronic low-grade inflammation, oxidative stress, and elevated AGEs. Insulin resistance is considered a major cause of PCOS and its manifestations. Treatments like metformin are utilized to address insulin resistance and can positively impact endocrine abnormalities and ovarian function.

In summary, the systematic review and meta-analysis on AMH as a diagnostic biomarker provided crucial evidence for the 2023 international guidelines. It confirmed that while AMH is a useful and reasonably accurate marker for detecting PCOM in adults, offering a potential alternative to ultrasound, it is not sufficient as a sole diagnostic test for PCOS due to the syndrome’s complex and heterogeneous nature. The integration of AMH for PCOM definition in adults represents a significant update in PCOS diagnosis.

The document “Association of Insulin Resistance and Elevated Androgen Levels with Polycystic Ovarian Syndrome (PCOS)- A Review of Literature” focuses on two key pathophysiological factors considered major drivers of Polycystic Ovarian Syndrome (PCOS): insulin resistance (IR) and elevated androgen levels. This review positions these two factors as central to understanding the disease and its associated manifestations.

PCOS is described in the sources as the most prevalent endocrine and metabolic disorder among women of reproductive age. Its prevalence is estimated to be around 6–10% in women at the reproductive stage, with some reports suggesting it may be double that rate. Other sources provide prevalence estimates ranging from approximately 6–20%, up to 1 in 10, and potentially 5%-26% depending on the diagnostic criteria used.

PCOS is considered a heterogeneous disorder due to its varied presentation of signs and symptoms. The classic features often associated with PCOS include elevated levels of androgens (hyperandrogenism), ovulatory dysfunction (such as oligo- or an-ovulation and irregular menstrual cycles), and morphological abnormalities of the ovaries, specifically polycystic ovarian morphology (PCOM). While various diagnostic criteria exist, the Rotterdam criteria (2003) are widely used, requiring the presence of any two of these three features after excluding other conditions. The Androgen Excess and PCOS Society (AE-PCOS) criteria, however, emphasize hyperandrogenism as a core requirement.

The primary document highlights that there is a noteworthy elevation of androgen in PCOS which causes substantial misery and infertility problems. The overexposure of androgen is directly linked with insulin resistance and hyperinsulinaemia. Although many factors are involved in PCOS, resistance to insulin and enhanced levels of androgen are considered the major causes of the syndrome. This review specifically aims to provide a concise and comprehensive outlook for the understanding of insulin resistance and androgen overexposure in PCOS.

Expanding on this central theme from other sources, insulin resistance in PCOS is sometimes described as being tissue-specific. While organs like the ovary, adrenal glands, and liver might remain insulin-sensitive, peripheral tissues such as skeletal muscle and adipose tissue can develop insulin resistance. This leads to decreased glucose absorption by these tissues and increased fat breakdown (lipolysis). Hyperinsulinemia, an elevated level of insulin in the blood, is a common finding in women with PCOS and is considered a compensatory reaction to the insulin resistance.

This compensatory hyperinsulinemia plays a significant role in the pathophysiology of hyperandrogenism. Excess insulin indirectly stimulates the ovaries and adrenal glands, leading to an increase in androgen production. More precisely, hyperinsulinemia is thought to increase the production of androgens in the ovarian theca cells, especially when stimulated by Luteinizing Hormone (LH). This excess androgen contributes to follicular arrest and subsequent anovulation, which in turn leads to irregular menstrual cycles and infertility. Additionally, hyperinsulinemia suppresses the production of Sex Hormone-Binding Globulin (SHBG) by the liver. SHBG binds to testosterone and other sex hormones in the bloodstream, so when SHBG levels are low, the levels of free, biologically active testosterone increase, contributing to the hyperandrogenic state. Measuring SHBG levels can even serve as a proxy measure for the severity of hyperinsulinemia in women with PCOS.

Beyond the direct impact of IR and hyperandrogenism on reproductive function, the review emphasizes that PCOS is related to various health issues. PCOS is linked to cardiac metabolic miseries and potently increases the risk of heart diseases. Endometrial cancer is also a serious concern which is reported with exceedingly high incidence in women with PCOS. Other sources reinforce and expand upon these comorbidities, linking PCOS to metabolic syndrome, obesity, type 2 diabetes, cardiovascular risks, depression, obstructive sleep apnea, and metabolic dysfunction-associated steatotic liver disease (MASLD). The review highlights the interconnectedness of these abnormalities, forming a potential vicious cycle involving insulin resistance, inflammation, oxidative stress, and hyperandrogenemia.

The document also mentions treatment interventions related to insulin resistance and hypersecretion of insulin. Metformin is discussed as a treatment modality. Other sources further elaborate on its role, indicating that metformin, used to treat PCOS, has been shown to significantly reduce serum androgen levels, improve insulin sensitivity, restore menstrual cyclicity, and successfully trigger ovulation. It is utilized to address insulin resistance and is considered helpful in maintaining endocrine abnormalities and ovarian function.

Regarding diagnosis, while the primary document focuses on the underlying pathophysiology, it’s important to contextualize this within the diagnostic landscape discussed in other sources and our conversation. Diagnosing PCOS can be complex. The Rotterdam criteria are widely used. PCOM, typically assessed by ultrasound, is one of the diagnostic features. However, ultrasound use has faced controversies [Conversation history synthesis]. Anti-Müllerian Hormone (AMH) has emerged as an alternative marker [Conversation history synthesis]. Elevated AMH levels are often observed in women with PCOS, correlating with the increased number of small antral follicles [Conversation history synthesis]. The systematic review and meta-analysis discussed previously found that while AMH levels alone are insufficient for the diagnosis of PCOS due to its heterogeneity, AMH level is a reasonably sensitive and specific marker for detecting PCOM in adults. Consequently, the 2023 international evidence-based PCOS guideline now recommends AMH levels for defining PCOM in adults, serving as an endocrine substitute for the ultrasound assessment in specific cases. This reflects an evolving understanding and the use of new biomarkers in diagnosing components of this complex syndrome.

In conclusion, the document “Association of Insulin Resistance and Elevated Androgen Levels with Polycystic Ovarian Syndrome (PCOS)- A Review of Literature” effectively highlights insulin resistance and elevated androgen levels as primary drivers and major causes of PCOS. It underscores their direct link and their contribution to both reproductive issues like infertility and significant metabolic comorbidities. By focusing on these key pathophysiological factors, the review provides valuable insights into the underlying mechanisms of PCOS, which, when combined with the broader understanding of the syndrome’s heterogeneity and the role of other factors and diagnostic approaches like AMH (as discussed in other sources), paints a more complete picture of this challenging condition.

It highlights that much of the confusion surrounding PCOS diagnosis stems from the broad heterogeneity of symptoms experienced by affected women, leading to a number of different diagnostic criteria over the years. Accurate diagnosis is emphasized for both clinical care and research.

The document outlines the historical progression of PCOS diagnostic criteria:

  • In 1990, the National Institute of Child Health and Human Development (NIH) made the first attempt to produce a clinical definition of PCOS. Under these criteria, PCOS was defined by the presence of both clinical and/or biochemical signs of hyperandrogenism and oligo- or chronic anovulation. At this time, ultrasonographic evidence of polycystic ovaries was considered suggestive but not necessarily diagnostic. This NIH definition viewed hyperandrogenism as the primary defect. This approach conflicted with the leading practice in the United Kingdom and much of Europe, where polycystic ovaries on ultrasound were considered the “defining feature of PCOS”.
  • The debate continued until 2003, when 27 PCOS experts met in Rotterdam, the Netherlands, sponsored by the European Society of Human Reproduction (ESHRE) and American Society for Reproductive Medicine (ASRM). This meeting resulted in a joint consensus statement commonly known as the “Rotterdam Criteria”. These criteria significantly broadened the phenotypic expression of PCOS. The Rotterdam criteria defined PCOS by the presence of any two out of the following three key characteristics: oligo-amenorrhea (referring to oligo- or anovulation), hyperandrogenism (clinical or biochemical), and polycystic-appearing ovarian morphology (PCOM) on ultrasonography. The introduction of the Rotterdam criteria led to an increase in the reported prevalence of PCOS, in some studies increasing as much as three times compared to diagnosis using the 1990 NIH criteria. A key shift was that the Rotterdam criteria allowed for the diagnosis of PCOS without hyperandrogenism.

The source also mentions the Androgen Excess and PCOS Society (AE-PCOS). Although not detailing their specific criteria within this text, it implicitly positions their perspective within the ongoing discussion about defining PCOS, noting that they have expressed opinions related to the diagnosis.

The source states that the presence of multiple classification systems (like NIH and Rotterdam) caused clinical confusion and was seen as delaying scientific progress in understanding PCOS. Consequently, in 2012, the NIH held an evidence-based methodology workshop that again recommended using the broader 2003 Rotterdam criteria. This workshop specifically identified four sub-phenotypes within the Rotterdam criteria based on combinations of the three features: (1) androgen excess and ovulatory dysfunction, (2) androgen excess and PCOM, (3) ovulatory dysfunction and PCOM, and (4) androgen excess, ovulatory dysfunction, and PCOM.

The Rotterdam criteria are described as remaining the most widely used and accepted criteria for PCOS. They were once again unanimously supported in the 2018 International Evidence-Based Guideline for the Assessment and Management of PCOS. The source therefore focuses on defining the sub-components of the 2003 Rotterdam criteria: hyperandrogenism, oligo-anovulation, and PCOM.

Regarding the impact and implications of PCOS diagnosis, the source emphasizes that receiving a diagnosis of PCOS should not be given lightly. It is associated with significant psychological distress, reduced well-being, depression, and fears about future health and fertility. The source also notes that women often report receiving either no information or inadequate information about their diagnosis. Furthermore, diagnosis can be delayed for approximately a quarter of women with PCOS, sometimes by two or more years. While it is not completely clear if the burden is due to the diagnosis process or the syndrome itself, the source argues that given the importance of the syndrome, women are owed a timely and appropriate diagnosis.

The source concludes by reflecting on the continued debate over criteria and the often inadequate clinical care provided within the current diagnostic framework, posing the question of whether it is time to revisit the diagnosis of PCOS after almost 20 years (since the 2003 Rotterdam criteria).

It positions PCOS as the most common endocrine disorder affecting females. PCOS is described as a heterogeneous disease with various etiologies and outcomes.

Patients with PCOS frequently report symptoms such as infertility, irregular menstruation, acne, seborrheic dermatitis, hirsutism, and obesity. The source suggests that PCOS can stem from hypothalamic-pituitary-ovarian axis dysfunction, heredity, or metabolic abnormalities. Other sources also highlight that the most accepted diagnostic criteria for PCOS is the Rotterdam criteria, which involves the presence of at least two out of three features: hyperandrogenism, oligo- or anovulation, and polycystic ovaries. The persistent hormonal imbalance in PCOS is noted to lead to the formation of multiple small antral follicles and irregular menstrual cycles, ultimately causing infertility among females.

A key focus of the “Immune regulation in polycystic ovary syndrome.pdf” source is that PCOS is characterized by chronic low-level inflammation. This chronic inflammation involves an imbalance in pro-inflammatory factor secretion, endothelial cell dysfunction, and leukocytosis. Other sources also support the concept of chronic inflammation in PCOS. It is also stated that PCOS is distinguished by hormonal and immune dysregulation. Immune cells and immune regulatory molecules are considered to play critical roles in maintaining metabolic homeostasis and regulating immune responses during PCOS.

The source specifically discusses the role of macrophages in the immune regulation of PCOS, noting their importance as anti-infective cells in the body’s natural immune response and as essential antigen-presenting cells in specific immunity. It highlights that in lean PCOS patients, there were more macrophages and pro-inflammatory factors in adipose tissue, contributing to insulin resistance (IR). An abnormally elevated insulin level is said to promote androgen production in ovarian theca cells, decrease insulin receptor autophosphorylation in ovarian granulosa cells, aggravate the ovarian chronic inflammatory response and IR, and worsen the pathological process of PCOS.

Insulin resistance is considered one of the most important etiological factors in PCOS, affecting approximately 85% of patients. The source “Immune regulation in polycystic ovary syndrome.pdf” illustrates how hyperandrogenism causes insulin resistance and hyperglycemia, leading to oxidative stress and abdominal adiposity. In consequence, inflammation, reactive oxygen species (ROS) production, insulin resistance, and hyperandrogenemia also increase. This creates a cycle where these pathophysiologies are interrelated. Other sources corroborate the strong association between insulin resistance and PCOS.

Furthermore, macrophages can release cytokines and chemokines into the bloodstream, such as IL-6, IL-10, IL-18, MIF, and TNF-α, which result in systemic, chronic low-grade inflammation. Chronic inflammation is considered the root cause of ovarian dysfunction. The DHEA-induced PCOS mouse model demonstrated an increase in peripheral M1 macrophages and a decrease in M2 macrophages, suggesting that PCOS is characterized by a shift in macrophage polarization from an anti-inflammatory M2 state to a proinflammatory M1 state.

The source also mentions that because of oligo/anovulation, patients with PCOS tend to have low progesterone levels. These low progesterone levels are hypothesized to overstimulate the immune system, leading to increased estrogen production and the development of various autoantibodies. The breakdown of immune homeostasis is linked to the pathology of PCOS. Immune molecules produced by antigen-stimulated immune cells (T lymphocytes and macrophages) play a direct role in the immune response and have biological functions linked to many pathological changes associated with PCOS. Detecting the expression of immune molecules in PCOS patients is considered critical for determining their inflammatory state and assessing long-term complications.

Overall, “Immune regulation in polycystic ovary syndrome.pdf” concludes that the abnormal androgenic turbulence secretion in PCOS causes chronic inflammation, IR, oxidative stress, and cystic follicles. Simultaneously, inflammatory cell infiltration in fat and ovarian tissue, along with increased inflammatory medium secretion, can worsen chronic inflammation, affect tissue cell function, and lead to ovarian dysfunction and metabolic disorders. While the clinical importance and underlying mechanisms of immune cells or immune regulatory molecules in PCOS require further understanding, a better grasp of immune regulatory molecules and autoantibodies is seen as critical for developing therapeutic strategies to minimize injury, improve PCOS outcomes, and provide better treatment options in the future.

Other sources support the concept of immune system involvement and autoimmunity in PCOS. One source mentions that PCOS may be an autoimmune disorder and discusses autoantibody studies in women with reproductive failure. The concept of a hyperactive immune system, mostly due to autoimmunity and inflammation, is also proposed as a characteristic of a specific PCOS phenotype (HH-PCOS).

PCOS is described as the most common endocrine condition among women of reproductive age. Its prevalence is estimated to be between approximately 6–20%. It is characterized by a combination of signs and symptoms, making it a heterogeneous disorder.

The sources highlight that the most accepted diagnostic criteria for PCOS is the Rotterdam criteria, which defines the syndrome by the presence of at least two out of three key features: clinical or biochemical hyperandrogenism, oligo- or anovulation (often manifesting as irregular or absent periods), and polycystic-appearing ovarian morphology (PCOM) on ultrasound. PCOS is also associated with various comorbidities and manifestations, including infertility, acne, hirsutism (excess hair growth), psychological distress, obesity, and an increased risk of metabolic disorders like insulin resistance (IR), type 2 diabetes, cardiovascular diseases, and pregnancy complications. Insulin resistance is considered one of the most important etiological factors and is strongly associated with PCOS, affecting approximately 85% of patients. The sources indicate that hyperandrogenism, IR, inflammation, and oxidative stress are interrelated pathophysiologies in PCOS.

Metformin, a synthetic biguanide, is a medication widely used to manage type 2 diabetes. However, it is also commonly prescribed for women with PCOS, primarily to address insulin resistance and its associated metabolic and reproductive disturbances. Women with PCOS seem predisposed to insulin resistance, which may be a root cause of their health problems.

Metformin acts as an insulin-sensitizing agent. By reducing overall basal and post-prandial plasma glucose, metformin helps improve blood sugar tolerance in type 2 diabetes patients. It enhances sensitivity to insulin by boosting peripheral glucose assimilation, decreasing hepatic glucose synthesis, and decreasing intestinal glucose absorption. In women with PCOS, besides increasing insulin sensitivity, metformin has been shown to lower insulin levels. Critically, this reduction in insulin levels can subsequently reduce levels of androgen in the blood, thereby diminishing hyperandrogenism. Studies have shown that metformin dramatically reduced the ability of theca cells to produce testosterone and androsten-edione in vitro. Additional studies suggest metformin lowers androgen production by the adrenal glands and ovaries, reduces luteinizing hormone from the pituitary, and increases the liver’s capacity to produce SHBG. The source notes that metformin exerts actions on adipose tissue, skeletal muscles, ovary, and endothelium, tissues impacted by insulin resistance. Metformin may also have immunomodulatory effects, and protective effects against endothelial dysfunction.

The sources detail findings from various studies and meta-analyses regarding the efficacy of metformin in non-pregnant women with PCOS:

  • Metformin has been used in PCOS treatment since 1994.
  • Numerous randomized controlled trials (RCTs) and systematic reviews have assessed its efficacy, demonstrating variable but frequently beneficial effects across metabolic, hormonal, and reproductive outcomes compared to placebo or other treatments.
  • Specifically, metformin has been shown to lead to greater reductions in BMI and improvements in menstrual cycle duration and frequency compared to placebo, sometimes alone or combined with lifestyle intervention. Prolonged use can augment ovulation rate and regulate menstrual cycles.
  • Research studies have shown metformin can successfully promote ovulation in PCOS patients, making its usage an appropriate first-line medication, though it should be utilized in combination with a lifestyle change.
  • A study involving 156 PCOS women found that 46% ovulated after receiving metformin, compared to 24% in a placebo/no medication group.
  • The combination of clomiphene and metformin is considered more beneficial than single therapy for ovulation and pregnancy in PCOS women. Metformin was also useful in reducing the risk of ovarian hyperstimulation in women with PCOS undergoing in vitro fertilization.
  • Metformin enhances insulin-mediated glucose elimination in PCOS women.
  • Metformin may help alleviate endocrine abnormalities, control ovarian function, and potentially help obese PCOS patients lose weight.

Metformin’s role is also discussed in the context of other treatments:

  • Some studies have compared metformin with myo-inositol, with one meta-analysis suggesting myo-inositol improved fertility outcomes by modulating hyperandrogenism more effectively, although ovarian function and BMI were not significantly different.
  • Other insulin-sensitizing agents like pioglitazone and rosiglitazone are considered effective for IR, abnormal glucose tolerance, hyperandrogenemia, ovulation rate, and menstrual regularity in PCOS patients. A combination of metformin and pioglitazone has been reported to have synergistic clinical profiles, but should be avoided if pregnancy is desired due to teratogenic effects. Inositol is also noted as a novel insulin-sensitizing agent with high efficiency in PCOS women.

The review also examines the use of metformin during pregnancy in women with PCOS. PCOS pregnancies often have higher rates of complications, including miscarriage, preterm birth, and gestational diabetes (GDM).

  • Metformin is suggested to help improve how the body responds to insulin during pregnancy, which may help reduce complications.
  • Metformin may lessen the risk of gestational diabetes (GDM) in women with PCOS.
  • Some studies showed lower miscarriage rates in women with PCOS treated with metformin.
  • Metformin’s metabolic regulating effects, and protective effects against endothelial dysfunction, suggest a role in preventing adverse outcomes including excess gestational weight gain (GWG), GDM, macrosomia, and preeclampsia, which are often exacerbated in PCOS pregnancies.

Despite the potential benefits, the use of metformin in PCOS presents clinical challenges. The document emphasizes that metformin is not a “one-size-fits-all solution”. Its effects vary by treatment duration, metabolic profile, and individual characteristics. More high-quality research is needed to better understand which women benefit most from metformin use across the diverse PCOS spectrum. Furthermore, the long-term usage of metformin to alleviate PCOS-related problems remains uncertain, requiring substantial research. Assessing any long-term effects on children exposed to metformin during pregnancy is also highlighted as an area needing more research. While meta-analyses of early pregnancy exposure to metformin suggest no increased risk of major malformations , the long-term impact on offspring is still being studied.

In conclusion, the document underscores that metformin is a widely prescribed medication for women with PCOS, primarily leveraging its insulin-sensitizing properties to improve metabolic, hormonal, and reproductive outcomes and potentially reduce pregnancy complications. However, the effectiveness varies among individuals, necessitating further research to identify optimal candidates and fully understand long-term implications for both the mother and potential offspring.

PCOS is described as the most common endocrine disorder of reproductive-aged women, affecting approximately 6–20% of this population globally, although prevalence estimates vary depending on the diagnostic criteria applied. It is characterized as a heterogeneous illness or disorderliness due to its diverse features and symptomology. These symptoms can include infertility, irregular menstrual cycles or oligo- or anovulation, acne, and hirsutism (excess hair growth).

The historical context of PCOS diagnosis is discussed, noting that it was first described by Stein and Leventhal in 1935. Over the years, various diagnostic criteria have been proposed.

  • The National Institutes of Health (NIH) criteria (1990) defined PCOS by the presence of both clinical and/or biochemical signs of hyperandrogenism and oligo- or chronic anovulation, with ultrasonographic evidence of polycystic ovaries being suggestive but not strictly diagnostic. Using the NIH criteria, PCOS was identified in about 6% of women of reproductive age.
  • The Rotterdam criteria (2003), established by the European Society of Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM), became the most widely used and accepted criteria. These criteria broadened the definition to include any two out of three key features: oligo-ovulation or anovulation, hyperandrogenism (clinical and/or biochemical), and polycystic ovarian morphology (PCOM) on ultrasonography, after excluding related disorders. The use of Rotterdam criteria significantly increased the reported prevalence of PCOS, sometimes up to three times higher compared to the NIH criteria, and importantly, allowed for a diagnosis of PCOS without the presence of hyperandrogenism. Some interpretations even suggested diagnosis with only one polycystic ovary present.
  • The Androgen Excess and PCOS Society (AE-PCOS) criteria proposed measures including hyperandrogenism (hirsutism or hyperandrogenemia) and ovarian dysfunction (oligo-ovulation/anovulation or polycystic ovaries), plus exclusion of related disorders. The AE-PCOS classification considered PCOS even if PCOM or hyperandrogenemia were not prevalent, and this society considers PCOS primarily a disorder of androgen excess.

The existence of multiple classification systems has resulted in clinical confusion and is viewed as delaying scientific progress. While the Rotterdam criteria remained the last word for some time, a 2012 NIH workshop recommended their continued use but also identified sub-phenotypes within these criteria. The 2018 International Evidence-Based Guideline for the assessment and management of PCOS also supported the Rotterdam criteria.

More recently, the 2023 international evidence-based guideline update for PCOS diagnosis in adults still requires the presence of 2 out of the 3 criteria (clinical or biochemical hyperandrogenism, ovulatory dysfunction, and findings of polycystic ovaries on ultrasound), but now also includes elevated AMH (Anti-Müllerian hormone) levels as an alternative to ultrasound for defining PCOM in adults. This is considered a significant change expected to reduce inconvenience and diagnosis cost.

However, despite these advancements, the diagnosis remains challenging. The clinical diagnosis is primarily an exclusion diagnosis, meaning other disorders mimicking the features must be ruled out. Key features like hyperandrogenism (diagnosed via clinical signs or biochemical tests like free/bioavailable testosterone and androstenedione), oligo- or anovulation (often irregular cycles, though anovulation can occur with regular cycles, requiring progesterone tests for confirmation), and PCOM (assessed by ultrasound) present difficulties. Ultrasound accuracy depends on the operator and equipment, and its utility is limited in adolescents or women with less than 8 years post-menarche due to the natural presence of multi-follicular ovaries in this age group. AMH levels are strongly correlated with ovarian antral follicle number and are a potential biomarker, but AMH alone is insufficient for a PCOS diagnosis and is not recommended for adolescents due to low specificity. Diagnostic cut-offs, whether for ultrasound or some lab tests, are based on fluctuating ranges and sometimes arbitrary percentiles, limiting precision.

Beyond the core diagnostic features, PCOS is associated with numerous comorbidities. Insulin resistance (IR) is considered one of the most important etiological factors and a major cause of PCOS and its manifestations. Elevated androgen levels are directly linked with insulin resistance and hyperinsulinaemia. Other associated conditions include obesity, type 2 diabetes, cardiovascular diseases, psychological distress, and an increase in inflammation and oxidative stress. Obesity and PCOS often coexist and may have a bidirectional causal relationship.

The etiology of PCOS is still largely unknown and complex, likely representing a group of disorders with overlapping metabolic and reproductive problems. Environmental and genetic factors are primarily involved. Alterations during prenatal development are also considered a potential etiologic mechanism.

The document “PCOS stratification for precision diagnostics and treatment.pdf” highlights that the clinical diagnosis is primarily an exclusion diagnosis. The phenotypic heterogeneity throughout the reproductive lifespan further complicates diagnosis, as PCOS symptoms can overlap with normal changes during menarche and the menopausal transition. Current diagnostic methods are described as expensive, time-consuming, and imprecise. Furthermore, both physicians and patients express dissatisfaction with available diagnosis and treatment options due to challenges in diagnosis, delayed experiences, and less-than-optimal treatment plans. Delays in diagnosis, which occur for approximately a quarter of women for two or more years, contribute to the progression of comorbidities. Receiving a PCOS diagnosis is also associated with significant psychological distress.

This leads to the central argument for PCOS stratification. The document proposes that a systematic stratification of the condition is an approach to create evidence-based, shared, and standardized guidelines for diagnosis and treatment. Recognizing that PCOS is a multi-system disorder with neuroendocrine, gonadal, and metabolic components, likely emerging through multiple etiologies, underscores the need for stratification. The document mentions that PCOS subtyping has identified two subtypes: obesity and reproductive, though many women do not fit either. Another perspective discussed in the sources proposes reclassifying PCOS into two entities: a hyperandrogenic phenotype (H-PCOS), encompassing Rotterdam phenotypes A, B, and C, primarily characterized by metabolic abnormalities, and a hyper-/hypoandrogenic phenotype (HH-PCOS), representing Rotterdam phenotype D, which in about 85% of cases is characterized by a hyperactive immune system, mostly due to autoimmunity and inflammation. This proposed reclassification suggests these may represent distinct genomic entities. Studies that do not stratify patients by phenotype are often considered uninterpretable.

The document emphasizes the urgent need for precision diagnostics using a combination of novel biomarkers and machine learning methods. High AMH levels are noted as a potential biomarker closely correlated with the number of ovarian antral follicles. The need for rigorous validation in larger, multi-ethnic, and well-characterized adolescent cohorts is stressed.

Ultimately, the goal of systematic sub-classification and stratification is to understand distinct PCOS etiologies, which would guide evidence-based precision diagnosis and treatment strategies. Subtype-specific strategies for early screening, accurate diagnosis, and management throughout life are seen as ways to optimize healthcare resources and reduce unnecessary testing, paving the way for personalized care.

Metformin, mentioned in the etiology review source and the focus of the previous synthesis, is a key medication used in PCOS, primarily addressing insulin resistance. However, the effectiveness of treatments like metformin can vary, and the target document’s emphasis on stratification suggests that understanding the specific subtype or etiology might eventually lead to more precise and effective therapeutic choices, moving away from a “one-size-fits-all” approach. The need for more research to identify which women benefit most from specific treatments, like metformin, is highlighted elsewhere, supporting the rationale for stratification presented in the target document.

Definition and Prevalence: PCOS is identified as the most common endocrine disorder among females of reproductive age worldwide. Its prevalence is reported to range between 5% and 26%, with this variability depending on the specific diagnostic criteria applied. Historically, the condition was initially described by Stein and Leventhal in 1935.

Pathophysiology: The pathophysiology of PCOS primarily involves insulin resistance and a high prevalence of visceral adiposity, notably occurring irrespective of whether obesity is present. This complex interplay is understood to cause errors in the hormonal communication system between the hypothalamus, the pituitary gland, and the ovaries.

Associated Comorbidities: PCOS is associated with a significant number of related health conditions, known as comorbidities. The document lists several important comorbidities including:

  • Infertility.
  • Metabolic syndrome.
  • Obesity.
  • Type 2 diabetes.
  • Increased cardiovascular risks.
  • Depression.
  • Obstructive sleep apnea.
  • Endometrial cancer.
  • Metabolic dysfunction-associated steatotic liver disease (MASLD).

Diagnosis: The document emphasizes that the diagnosis of PCOS is widely accepted among specialty society guidelines. The core diagnostic approach requires the presence of at least 2 out of 3 specific criteria. These criteria are:

  1. Chronic anovulation.
  2. Hyperandrogenism, which can be either clinical (observable signs) or biological (detected through biochemical analysis).
  3. Polycystic ovaries.

Crucially, PCOS is characterized as a diagnosis of exclusion. This means that before a diagnosis of PCOS can be definitively made using the established criteria, other medical conditions that exhibit clinical features similar to PCOS must be carefully ruled out.

Importance of Timely Diagnosis and Management: The document underscores the critical need for the timely diagnosis of polycystic ovarian syndrome. A key reason for this urgency is that delays in diagnosis can unfortunately lead to the progression of associated comorbidities. When diagnosis is delayed, it also becomes more challenging to successfully implement lifestyle intervention, which is highlighted as a crucial component for improving both the specific features of PCOS and the overall quality of life for affected individuals.

Effective management involves not only making an accurate and timely diagnosis but also actively screening patients with polycystic ovary syndrome for comorbid conditions. The document calls for the implementation of appropriate management strategies for these patients and stresses the importance of applying interprofessional team strategies to enhance care coordination and improve patient outcomes.

In summary, the “Polycystic Ovarian Syndrome – StatPearls – NCBI Bookshelf.pdf” source presents PCOS as a very common endocrine disorder with a complex pathophysiology centered on insulin resistance and visceral adiposity. It outlines the widely accepted diagnostic criteria involving chronic anovulation, hyperandrogenism, and polycystic ovaries as the basis for diagnosis, while also stressing the necessity of excluding other conditions. The document explicitly highlights the significant burden of associated comorbidities and strongly advocates for the importance of timely diagnosis and comprehensive, team-based management, including lifestyle interventions and screening for comorbidities, to mitigate the progression of the condition and its related health issues.

Drawing on previously published research and new supportive evidence, the authors propose a fundamental shift in how PCOS is defined and categorized.

PCOS: A Complex and Poorly Understood Syndrome

Polycystic Ovarian Syndrome is widely recognized as the most common endocrine disorder among females of reproductive age globally. Its prevalence is reported to range significantly, between 5% and 26%, depending heavily on the specific diagnostic criteria used. Despite being arguably the most common clinical diagnosis in reproductive medicine, PCOS is still described as only poorly understood.

The document “Reconsidering the Polycystic Ovary Syndrome (PCOS)” highlights that PCOS is more accurately described as a “syndrome”, meaning a collection of clinical conditions or features, rather than a single, unified disorder. This acknowledgment of heterogeneity is crucial, as the diverse features experienced by women with PCOS have historically led to confusion surrounding its diagnosis.

Critique of Current Diagnostic Approaches (Notably the Rotterdam Criteria)

Historically, the first attempt to create a clinical definition was by the National Institute of Child Health and Human Development (NIH) in 1990, which defined PCOS by the presence of both clinical and/or biochemical hyperandrogenism and oligo- or chronic anovulation. Polycystic ovaries on ultrasound were considered suggestive but not strictly diagnostic. This contrasted with practices in some regions where polycystic ovaries were seen as the defining feature.

The widely accepted Rotterdam criteria, established in a 2003 consensus workshop, broadened the definition of PCOS. These criteria require the presence of at least 2 out of 3 key features: chronic anovulation (or oligo-amenorrhea), hyperandrogenism (clinical or biological/biochemical), and polycystic ovaries on ultrasound (polycystic ovarian morphology – PCOM). While adopted by many specialty societies, the Rotterdam criteria are seen by some experts, including the authors of “Reconsidering the Polycystic Ovary Syndrome (PCOS)”, as potentially premature and even self-defeating.

The core criticism raised in “Reconsidering the Polycystic Ovary Syndrome (PCOS)” is that the Rotterdam criteria, by aggregating different clinical features under one umbrella, may have overemphasized clinical symptomatology while losing sight of crucial differences in underlying etiologies, pathophysiology, and likely genomics. The broadening of criteria allowed for PCOS diagnosis without hyperandrogenism, which was seen by the 1990 NIH criteria and later by the Androgen Excess and PCOS Society (AE-PCOS) as the primary defect. The AE-PCOS criteria specifically emphasized hyperandrogenism and ovarian dysfunction, excluding conditions mimicking excess androgen production. The continued debate over diagnostic criteria and the recognition of significant heterogeneity highlight a need for greater clarity.

Furthermore, PCOS is recognized as a diagnosis of exclusion. This means other disorders presenting with similar clinical features must be ruled out before a definitive PCOS diagnosis is made based on the established criteria.

Receiving a diagnosis of PCOS is associated with significant psychological distress, reduced well-being, depression, and fears about future health and fertility. There is also evidence that diagnosis can be delayed.

Proposed Reclassification into Two Entities: H-PCOS and HH-PCOS

The authors of “Reconsidering the Polycystic Ovary Syndrome (PCOS)” propose replacing the current four clinical phenotypes recognized under criteria like the Rotterdam criteria with just two entities:

  1. Hyperandrogenic phenotype (H-PCOS).
  2. Hyper-/hypoandrogenic phenotype (HH-PCOS).

This proposed reclassification stems from the understanding that PCOS is a multi-system disorder involving neuroendocrine, gonadal, and metabolic components, and thus likely arises from multiple etiologies.

Distinguishing Characteristics of H-PCOS and HH-PCOS

Under this new proposed model:

  • H-PCOS would encompass the current Rotterdam phenotypes A, B, and C. This entity is proposed to be primarily characterized by metabolic abnormalities, including features associated with metabolic syndrome.
  • HH-PCOS would represent the current Rotterdam phenotype D. This phenotype is suggested to be primarily characterized by a hyperactive immune system, often driven by autoimmunity and inflammation.

This distinction aligns with discussions in other sources about chronic low-grade inflammation being related to PCOS and the interrelation between insulin resistance, inflammation, oxidative stress, and hyperandrogenism. Insulin resistance and elevated androgen levels are considered major causes of PCOS and its related manifestations. Insulin resistance is highly prevalent in PCOS, and hyperandrogenism can cause insulin resistance and hyperglycemia.

The Significant Role of Age in HH-PCOS

“Reconsidering the Polycystic Ovary Syndrome (PCOS)” particularly emphasizes the importance of age in understanding PCOS, especially in the context of the proposed HH-PCOS phenotype. The authors observed that PCOS patients at their center above the age of 35 were almost exclusively of the current Rotterdam phenotype D (which would become HH-PCOS). Crucially, these women presented with hypoandrogenism.

The document posits that in HH-PCOS (phenotype D), hypoandrogenism typically develops after age 35. This suggests that the hyperandrogenic phase may transition to a hypoandrogenic phase over time in this specific group. The authors propose that HH-PCOS is an underdiagnosed medical entity, particularly in women over 35.

Implications for Treatment and Management

The proposed reclassification into distinct H-PCOS and HH-PCOS entities is argued to likely establish two distinct genomic entities. This genomic difference, they suggest, could potentially be identified using polygenic risk scores. One clustering analysis in the literature is noted as supportive of this concept.

A systematic sub-classification of PCOS based on understanding distinct etiologies is advocated to guide evidence-based precision diagnosis and treatment. The document “Reconsidering the Polycystic Ovary Syndrome (PCOS)” offers supportive evidence from a case-controlled study suggesting that androgen supplementation can overcome the relative treatment resistance often seen in in vitro fertilization (IVF) for HH-PCOS patients above age 35 who exhibit hypoandrogenism.

Other sources discuss various management approaches for PCOS. Metformin, for instance, is mentioned as having beneficial effects on endocrine abnormalities and ovarian function. It is considered useful in treating PCOS-related infertility by potentially reducing serum androgen levels, improving insulin sensitivity, and restoring menstrual cyclicity and ovulation. Metformin’s role in managing metabolic aspects and insulin resistance in PCOS is well-documented. Lifestyle intervention is also highlighted elsewhere as critical for improving PCOS features and quality of life.

Challenges and Future Directions

The authors acknowledge that studies on PCOS rarely stratify patients by existing phenotypes, making it difficult to fully understand the natural history and treatment responses within specific subgroups. Referral biases can also influence study populations.

The shift towards recognizing distinct underlying etiologies and phenotypes, as proposed in “Reconsidering the Polycystic Ovary Syndrome (PCOS)”, requires further research to validate the proposed two-entity model (H-PCOS and HH-PCOS) and its genetic and pathological underpinnings. This refined understanding could lead to more targeted diagnostic approaches and potentially more effective, phenotype-specific treatments for this complex and heterogeneous condition. While current guidelines are evolving, incorporating markers like AMH for defining PCOM in adults, a more fundamental reclassification based on etiology, as suggested by Gleicher et al., represents a significant potential shift in the field.

In conclusion, “Reconsidering the Polycystic Ovary Syndrome (PCOS)” challenges the prevailing diagnostic paradigm, arguing that grouping diverse presentations under a single syndrome obscures critical etiological and pathological differences. By proposing a reclassification into a metabolically driven H-PCOS and an immune-mediated, age-influenced HH-PCOS, the authors advocate for a more precise, etiology-based approach to diagnosis and treatment, particularly highlighting the potential significance of age-related hypoandrogenism and androgen supplementation in the HH-PCOS subset. This perspective underscores the ongoing need for research to unravel the complex nature of PCOS and develop more targeted interventions.

Polycystic Ovary Syndrome (PCOS) stands as the most common endocrine disorder affecting females of reproductive age. Its reported prevalence varies, ranging approximately from 4% to 26% depending on the diagnostic criteria used. Despite its widespread occurrence, PCOS is characterized by significant heterogeneity in its presentation, encompassing a combination of signs and symptoms that have historically led to challenges in its definition and understanding. The diagnosis of PCOS is typically based on criteria such as the revised 2003 Rotterdam consensus, which requires the presence of at least two out of three features: chronic anovulation or oligo-amenorrhea, clinical and/or biochemical hyperandrogenism, and polycystic ovaries on ultrasound (PCOM). Other criteria, like those from the Androgen Excess and PCOS Society (AE-PCOS), have also emphasized hyperandrogenism. Regardless of the specific criteria, PCOS is considered a diagnosis of exclusion, meaning other conditions with similar symptoms must be ruled out.

One of the most significant clinical consequences of PCOS is infertility, being the main cause of anovulatory infertility in women. Infertility is reported to affect a large percentage of women with PCOS, around 74% based on some aggregated data. This underscores the critical need for effective treatments targeting fertility in this population.

Pathophysiology Linking PCOS to Infertility: Insulin Resistance and Hyperandrogenism

The sources consistently highlight the intricate relationship between insulin resistance (IR) and elevated androgen levels as central to the pathophysiology of PCOS and its associated manifestations, including infertility. While the exact etiology of PCOS remains unclear, environmental and genetic factors are considered primarily involved. However, resistance to insulin and enhanced levels of androgen are considered the major causes of PCOS.

Insulin resistance is highly prevalent in women with PCOS and is thought to contribute to the hyperandrogenism observed in many patients. Hyperandrogenism itself can cause insulin resistance and hyperglycemia. This vicious cycle involves hyperinsulinemia (compensatory increase in insulin due to resistance) triggering ovarian theca cells to increase the production of luteinizing hormone (LH) and androgens. This rise in intraovarian androgens is thought to play an important role in the anovulatory cycle characteristic of PCOS-related infertility. The interconnectedness of hyperandrogenism, insulin resistance, inflammation, and oxidative stress is also recognized.

Metformin: A Therapeutic Option Targeting Insulin Resistance and Hyperandrogenism

Given the significant role of insulin resistance and hyperandrogenism in PCOS pathophysiology and infertility, therapeutic strategies often target these pathways. Metformin, a synthetic biguanide, is an insulin-sensitizing agent that has been used in the treatment of PCOS since 1994. It is widely used for managing type 2 diabetes but is commonly prescribed in PCOS to address insulin resistance and related metabolic and reproductive disturbances.

Mechanism of Action Relevant to PCOS and Infertility

Metformin’s benefits in PCOS are primarily attributed to its effects on insulin sensitivity and subsequent impact on androgen levels and ovarian function.

  • Insulin Sensitivity: Metformin enhances sensitivity to insulin by boosting peripheral glucose assimilation, decreasing hepatic glucose synthesis, and decreasing intestinal glucose absorption. It lowers overall basal as well as postprandial plasma glucose. In women with PCOS, it enhances insulin-mediated glucose elimination and lowers insulin levels.
  • Androgen Reduction: By lowering insulin levels, which directly stimulate ovarian androgen production, metformin can reduce levels of androgen in the blood. Research indicates that metformin can dramatically reduce the ability of theca cells (within the ovary) to produce testosterone and androsten-edione. Additional studies suggest it reduces androgen production from both the adrenal glands and ovaries by lowering pituitary LH levels and increasing the liver’s production of SHBG (sex hormone-binding globulin), which binds to androgens, reducing their free, active levels.
  • Restoration of Ovarian Function: The reduction in insulin and androgen levels appears to have a positive impact on ovarian function. Metformin is shown to help control ovarian function and restore menstrual cyclicity. Crucially, studies have shown that metformin can successfully promote or trigger ovulation in patients with PCOS.

Metformin’s Role in Treating PCOS-Related Infertility

Based on its mechanism of action, metformin is considered useful in treating PCOS-related infertility. It is even considered an appropriate first-line medication for ovulation induction in patients with PCOS, particularly in non-obese women and those resistant to clomiphene alone.

Evidence supporting Metformin’s use in infertility includes:

  • Studies showing that 46% of PCOS women receiving metformin ovulated, compared to 24% receiving placebo or no medication.
  • Meta-analyses and studies demonstrating its effectiveness in promoting ovulation.
  • Research suggesting that combinatorial regimens of clomiphene and metformin are considered more beneficial than single therapy of clomiphene or metformin for ovulation and pregnancy in PCOS women.
  • Metformin has been shown to be a useful treatment in reducing the risk of ovarian hyperstimulation in women with PCOS undergoing in vitro fertilization (IVF).

Beyond ovulation induction, metformin has been associated with improved pregnancy outcomes, including lower miscarriage rates and a reduced risk of gestational diabetes (GDM), a common complication in PCOS pregnancies. It may also protect against other adverse pregnancy outcomes often exacerbated in PCOS, such as excessive gestational weight gain, macrosomia, and preeclampsia.

Broader Benefits and Considerations

In addition to its reproductive benefits, metformin can help alleviate endocrine abnormalities in PCOS patients and has shown beneficial effects on various metabolic parameters, including reducing chronic low-grade inflammation (indicated by decreased C-reactive protein) and improving lipid profiles. While some studies suggested it might help obese PCOS patients lose weight, other findings were less conclusive, emphasizing that weight loss effects might depend on whether it’s used alone or in combination with lifestyle changes.

However, the sources also point to challenges and limitations regarding Metformin use:

  • It is not a “one-size-fits-all solution” for all women with PCOS.
  • While effective in improving some metabolic markers, Metformin alone may not significantly impact fasting glucose, serum lipids, or anthropometric characteristics in all PCOS women.
  • The long-term utilization of metformin remains uncertain when considering the prevention of distant PCOS complications, and a large quantity of research is required to draw conclusions on its long-term benefits.
  • More high-quality research is needed to understand which women benefit most from Metformin and to assess any long-term effects on children exposed to Metformin during pregnancy.

It’s important to note that metformin is often recommended to be utilized in combination with lifestyle changes, which are also critical for improving PCOS features and quality of life. Other insulin-sensitizing agents like pioglitazone and rosiglitazone, and novel agents like inositol, are also mentioned as effective in treating aspects of PCOS, sometimes with synergistic effects when combined with Metformin.

Integrating the Understanding of PCOS Heterogeneity

The “Reconsidering Polycystic Ovary Syndrome (PCOS)” document and other sources highlight the profound heterogeneity of PCOS. The proposed reclassification into distinct H-PCOS (primarily metabolic) and HH-PCOS (potentially more immune/autoimmune mediated) phenotypes suggests that different underlying etiologies exist. While Metformin effectively targets the metabolic component (insulin resistance), the response to Metformin might potentially differ between these proposed subgroups, though the provided sources specifically on Metformin use in infertility do not explicitly stratify patients by these proposed new phenotypes. The previous discussion mentioned age playing a significant role in HH-PCOS, with hypoandrogenism developing after age 35 in this group. This age-related shift could theoretically influence treatment responses, suggesting that a metabolic intervention like Metformin might have varying efficacy depending on the patient’s specific age and underlying phenotype, although this specific hypothesis regarding Metformin and age-related HH-PCOS is not detailed in the Metformin-focused sources.

Conclusion

In summary, the provided sources, particularly “Role of Metformin in Polycystic Ovary Syndrome (PCOS)-Related Infertility.pdf” and others, provide substantial evidence for the role of Metformin as a valuable therapeutic agent in managing PCOS-related infertility. Its efficacy stems from its ability to target key pathophysiological drivers: insulin resistance and subsequent hyperandrogenism. By improving insulin sensitivity, reducing androgen levels, and restoring menstrual cyclicity, Metformin effectively promotes ovulation and improves fertility outcomes, particularly when used alone or in combination with clomiphene. It also offers benefits during pregnancy, reducing risks like miscarriage and gestational diabetes. However, given the complex and heterogeneous nature of PCOS, as highlighted by documents like “Reconsidering Polycystic Ovary Syndrome (PCOS)”, Metformin is not a universal solution, and further research is needed to define its long-term benefits and optimize its use for specific PCOS phenotypes and patient profiles, potentially paving the way for more precision medicine approaches.

Course outline :
Polycystic Ovary Syndrome in Assisted Reproduction: Diagnostic Evolution, Phenotypic Stratification, and Optimized Therapeutic Strategies for Infertility Management

  • Definition and Prevalence: Polycystic Ovary Syndrome (PCOS) is the most common endocrine and metabolic disorder affecting approximately 6–20% of females in reproductive age globally. It is considered a heterogeneous syndrome rather than a single disease.
  • Key Clinical Features: PCOS is primarily characterized by hyperandrogenism, oligo- or anovulation, and polycystic ovarian morphology (PCOM). Most symptoms often arise early during puberty.
  • Associated Comorbidities: PCOS is interconnected with significant health issues such as insulin resistance (IR), cardiovascular diseases, abdominal obesity, psychological disorders, and infertility. It also carries an increased risk for endometrial cancer. These pathophysiologies are largely interrelated.

Historical Diagnostic Criteria:

    • Stein and Leventhal (1935): First described PCOS, noting hirsutism, obesity, amenorrhea, and enlarged polycystic ovaries.
    • NIH 1990 Criteria: Defined PCOS by the presence of hyperandrogenism (clinical and/or biochemical) and oligo- or chronic anovulation, with exclusion of other disorders.
    • Rotterdam 2003 Criteria (ESHRE/ASRM): Broadened the definition, requiring any two of the three key features: oligo-ovulation/anovulation, hyperandrogenism, and/or polycystic ovarian morphology (PCOM), after excluding related disorders. This significantly increased PCOS prevalence compared to NIH criteria.
    • AE-PCOS Society 2006 Criteria: Emphasized hyperandrogenism as central, requiring it plus ovarian dysfunction (oligo-ovulation/anovulation or PCOM) and exclusion of other disorders.
    • Current International Guidelines (2018 & 2023): Continue to support the Rotterdam criteria, with updated PCOM definitions.

Challenges in PCOM Assessment by Ultrasound:

    • The definition of PCOM using ultrasound (ovarian volume and/or follicle number per ovary – FNPO) is complex, relying on operator skills, equipment sensitivity, and the type of ultrasound (transvaginal vs. transabdominal).
    • Current recommendations for adults include ≥20 follicles per ovary or ovarian volume ≥10 cm³ using transvaginal ultrasound (≥8 MHz).
    • Ultrasound is not recommended for PCOS diagnosis in adolescents (gynecological age <8 years) due to the physiological presence of multifollicular ovaries during reproductive maturation, which could lead to overdiagnosis.

Role of Anti-Müllerian Hormone (AMH):

    • AMH levels are 2-3 times higher in PCOS patients and positively correlate with the severity of reproductive dysfunction and follicle excess.
    • The 2023 international guideline now recommends AMH levels for defining PCOM in adults, especially when an accurate ultrasound is unavailable.
    • However, AMH levels alone are insufficient for overall PCOS diagnosis due to its heterogeneity. AMH is also non-specific for PCOM in adolescents and is influenced by factors like age, BMI, and assay type.

Rotterdam-Based Phenotypes: PCOS is a heterogeneous syndrome with varied clinical presentations. The Rotterdam criteria identify four distinct phenotypes:

    • Type A (Classic): Hyperandrogenism + chronic anovulation + PCOM.
    • Type B: Hyperandrogenism + chronic anovulation (no PCOM).
    • Type C: Hyperandrogenism + PCOM (ovulatory).
    • Type D (Non-Androgenic/Lean): PCOM + chronic anovulation (no hyperandrogenism). This phenotype is often undiagnosed, particularly in older ages.

Proposed H-PCOS and HH-PCOS Classification: A newer classification suggests two distinct diagnostic entities: Hyperandrogenic (H-PCOS) and Hyper-/Hypoandrogenic (HH-PCOS).

    • H-PCOS (including current phenotypes A, B, and C) is primarily characterized by metabolic abnormalities and consistently high androgen levels.
    • HH-PCOS (reflecting phenotype D) exhibits age-dependent androgen levels: hyperandrogenic when young (<25 years), normal (25-35 years), and hypoandrogenic (>35 years). This phenotype is often linked to a hyperactive immune system (inflammation and autoimmunity) and an increased miscarriage risk, but typically without significantly increased metabolic syndrome risk.
    • This reclassification suggests that phenotype D (HH-PCOS) may be more treatment-resistant to IVF at older ages, a resistance that can be reversed by androgen supplementation.

Precision Diagnostics: The heterogeneity of PCOS highlights the need for subtype-specific strategies for accurate diagnosis and personalized management, potentially using novel biomarkers and machine learning.

  • Insulin Resistance and Hyperandrogenism: These are central to PCOS pathophysiology and infertility. Hyperinsulinemia, a compensatory response to IR, stimulates ovarian theca cells to produce androgens, leading to follicular arrest and anovulation.
  • Follicular Development and Oocyte Quality: PCOS is associated with abnormal follicular development, anovulatory infertility, and poor oocyte or embryo quality. Elevated oxidative stress markers in follicular fluid contribute to compromised oocyte quality.
  • Chronic Low-Grade Inflammation: PCOS is characterized by chronic low-grade inflammation. Inflammatory cytokines and oxidative stress directly impair oocyte quality and endothelial function, contributing to infertility.
  • Endometrial Receptivity: PCOS, especially with insulin resistance, hyperandrogenemia, and obesity, can lead to reduced endometrial receptivity, resulting in lower embryo implantation rates and adverse pregnancy outcomes.
  • Miscarriage Risk: Women with PCOS have a high incidence of spontaneous abortions (25-73%) in the first trimester. Metformin treatment may reduce this risk.

First-Line Management:

    • Lifestyle Modification: Dietary therapy and physical activity are essential first-line interventions for PCOS. Even a modest weight loss (~5%) can restore fertility, improve metabolic health, regulate androgens, and normalize menstrual cycles.

Pharmacological Interventions:

    • Metformin: An insulin-sensitizing agent used in PCOS since 1994, even without diabetes. It improves insulin sensitivity, reduces insulin and testosterone levels, regulates menstrual cycles, and enhances ovulation and pregnancy rates. Metformin is an effective first-line drug for ovulation promotion and may reduce the risk of ovarian hyperstimulation syndrome (OHSS) in IVF cycles.
    • Ovulation Induction Agents:
      • Letrozole is considered the first-line therapy for infertility in PCOS patients.
      • Clomiphene Citrate (CC), often combined with metformin, can improve ovulation and clinical pregnancy rates in anovulatory women with PCOS.
    • Antiandrogen Treatment: Early initiation of antiandrogen treatment (≤25 years) may aid spontaneous conception in PCOS women with severe hyperandrogenism.

Assisted Reproductive Technology (ART):

    • In Vitro Fertilization (IVF) and In Vitro Maturation (IVM) are utilized for fertilization and embryo implantation in PCOS patients.
    • Laparoscopic Ovarian Drilling (LOD): This technique, established in 1984, can replace ovarian wedge resection. It improves insulin resistance and androgen production, leads to high pregnancy rates (~84%), and is associated with a lower incidence of miscarriages. It’s also considered a first-line treatment if CC fails.

Emerging Therapeutic Approaches:

    • Androgen Supplementation: For HH-PCOS patients, especially those over 35 years with hypoandrogenism, pre-supplementation with dehydroepiandrosterone (DHEA) has been shown to overcome IVF treatment resistance, normalizing pregnancy outcomes.
    • Stem Cell Therapy: Bone marrow mesenchymal stem cells (BM-hMSCs) and their secreted factors, including bone morphogenetic proteins (BMPs), show promise in regulating steroidogenesis and androgen production, representing a potential future therapy for PCOS.
  • Summary: PCOS is a complex, heterogeneous disorder affecting multiple organ systems, requiring accurate diagnosis and effective management due to its significant impact on reproductive health and long-term metabolic risks.
  • Ongoing Challenges: The precise etiology and full progression of PCOS remain unclear. Diagnostic challenges persist due to phenotypic heterogeneity across the lifespan and limitations of current diagnostic tools.
  • Future Perspectives: Future research should prioritize precision diagnostics to identify clinically relevant PCOS subtypes, utilizing genomic and comprehensive clinical data from diverse populations. This will facilitate the development of subtype-specific, age- and ethnicity-specific treatment options for improved patient outcomes and more efficient healthcare resource utilization. Further studies are needed on the long-term impact of metformin and the role of anti-inflammatory mediators in improving fertility outcomes for PCOS patients.