Polycystic Ovary Syndrome: Pathophysiology, Diagnosis and Management

Polycystic ovary syndrome (PCOS) is a complex and heterogenous disorder affecting 10-13% of women of reproductive age globally ^1,2. The diagnosis of PCOS is most widely based on the Rotterdam consensus, requiring the presence of at least two of the following: oligo- or anovulation, clinical or biochemical hyperandrogenism and polycystic ovarian morphology on ultrasound ^3.

PCOS is associated with reproductive dysfunctions including menstrual irregularity, infertility, as well as metabolic disorders such as insulin resistance, lipidaemia, fatty liver disease and psychological impacts such as anxiety and depression ^4–6. Despite its high prevalence and associated lifelong risks, the pathophysiology of PCOS remains incompletely understood.  It is proposed to involve complex interactions between genetic and environmental factors which contribute to its heterogenous clinical presentations ^7,8.

Stein and Leventhal first described in 1935 that women with a cluster of symptoms including amenorrhoea, infertility, obesity and hirsutism appeared to link with physical change in the ovaries ⁹ . Since this groundbreaking finding, research into PCOS has expanded all over the world. Consequently, the understanding of the PCOS is shifted from merely physical changes in the ovaries to a complex disorder involving neuroendocrine and metabolic signalling abnormalities.

Neuroendocrine mechanisms

Evidence suggests that the primary aetiology of PCOS may involve a neuroendocrine trigger, characterised by chronic hyperactivation of GnRH neurones. Elevated levels of Anti-Müllerian Hormone (AMH) in mothers may overstimulate GnRH neurones in the fetus ¹⁰, while the prenatal androgen exposure altered GABAergic neurones, leading to rapid firing of GnRH neurones in the hypothalamus ¹¹. Together, these mechanisms contribute to increased GnRH pulsatility, resulting in elevated secretion of luteinizing hormone (LH) relative to follicle-stimulating hormone (FSH). Consequently, this elevated LH further enhances ovarian steroidogenesis in ovarian theca cells and impairs follicular development ¹². These mechanisms lead to the classical features of PCOS, including hyperandrogenism, oligo- or anovulation and polycystic ovarian morphology (PCOM).

Metabolic dysfunction and adiposity

In addition to neuroendocrine dysregulation, metabolic dysfunction also plays a crucial role in the pathophysiology of PCOS. The key metabolic feature is insulin resistance which is distinct from Type 2 Diabetes mellitus (T2DM) or simple obesity and is proposed to be due to post-receptor signalling defect ¹³. Consequently, this hyperinsulinaemia results in impaired insulin action in the uptake of glucose into skeletal muscle whilst it directly stimulates ovarian androgen secretion ¹³ and suppresses hepatic production of sex hormone-binding globulin (SHBG) ^6. Furthermore, adipose tissue dysfunction contributes to the metabolic phenotypes of PCOS. The alterations in adipokine secretion such as increased leptin and reduced adiponectin and ghrelin levels in PCOS contribute to impaired energy homeostasis and a state of chronic low-grade inflammation ^14,15. Together, these metabolic disturbances not only further worsen androgen excess and reproductive disturbances but are also associated with higher risk of cardiometabolic complications such as cardiovascular disease, T2DM, fatty liver disease.

Genetics and causal mechanisms of PCOS

PCOS is a complex and highly heritable disorder with marked variation in genetic and biological characteristics. Genome-wide association studies (GWAS) have identified over 14 loci, involving the HPO axis (LHCGR, FSHR), androgen biosynthesis (DENND1A), and metabolic signalling (INSR, THADA) which are independently associated with the risk of developing PCOS ^16.

Centrally, variants in the gene involving GnRH pulse generator, particularly within KNDy (Kisspeptin-neurokinin-dynorphin) network such as KISS1 and TAC3/TACR3 as well as GABAergic receptor subunits can trigger a hyper-active GnRH pulse generator ^17,18. Peripherally, variants in the genes DENND1A can be associated with androgen overproduction in ovarian theca cells ¹⁹ while mutations in INSR (Insulin Receptor) gene can be linked with insulin signalling defect resulting in insulin resistant in PCOS ¹³

In addition, Mendelian randomisation (MR) studies provide strong evidence supporting obesity as a causal risk factor for PCOS. Genetically predicted higher BMI and overall adiposity are associated with a two- to threefold increased risk of PCOS, with both early-life and adult obesity demonstrating independent effects ⁸. Central adiposity has also been shown to exert a causal effect, highlighting the importance of both fat distribution and total adiposity ^20,21. In contrast, reverse MR analyses have not demonstrated a causal effect of PCOS on obesity, supporting a unidirectional relationship from obesity to PCOS ^8,20, despite anecdotal reports from women with PCOS suggesting a tendency towards weight gain.

Overall, these findings support that PCOS arises from a complex interaction between inherited neuroendocrine susceptibility and metabolic drivers such as obesity. This also explains the heterogeneity of PCOS, with some individuals exhibiting predominantly reproductive features and others demonstrating a more metabolically driven phenotype.

Classification of PCOS

PCOS has been classified using clinical diagnostic criteria, most commonly the Rotterdam consensus, which defines the syndrome based on the presence of at least two of the following features: hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology ³. This framework allows the classification of PCOS into four distinct phenotypes (A–D), reflecting different combinations of these features (Table 1).

Table 1. Classical Rotterdam phenotypes of PCOS

Phenotypes A and B are generally considered more severe, with more pronounced endocrine and metabolic disturbances, whereas phenotypes C and D often represent milder or variant forms of the syndrome. While this classification provides a practical diagnostic framework, it does not fully capture the underlying biological mechanisms or the variability in metabolic risk observed among women with PCOS.

In response to these limitations, more recent approaches have applied data-driven methods to refine PCOS classification based on biochemical and metabolic characteristics. Using clustering analyses of reproductive and metabolic parameters, distinct subtypes have been identified, including a reproductive subtype characterised by higher luteinising hormone (LH) and anti-Müllerian hormone (AMH) levels, and a metabolic subtype characterised by higher body mass index (BMI), insulin levels and lower sex hormone-binding globulin (SHBG) ²². These subtypes demonstrate differing clinical outcomes and risk profiles, suggesting that PCOS represents a spectrum of disorders rather than a single entity (Table 2).

Table 2. Data-driven classifications of PCOS based on clustering approaches

Diagnosis of PCOS

The initial evaluation of PCOS involves a comprehensive clinical, biochemical and radiological assessment. Clinically, patients should be evaluated for menstrual irregularities, features of hyperandrogenism such as hirsutism and acne, and markers of metabolic dysfunction including obesity and central adiposity. Biochemical investigations include reproductive hormones such as luteinising hormone (LH), follicle-stimulating hormone (FSH), oestradiol, total and free testosterone, androstenedione, sex hormone-binding globulin (SHBG) and anti-Müllerian hormone (AMH).

In addition, international guidelines have strongly recommended undertaking comprehensive metabolic assessments in patients with PCOS ^23,24. These include detailed history of smoking status, family history, sleep apnoea, measurement of blood pressure as well as assessment of fasting glucose, insulin, HbA1c, lipid profile and liver function tests for monitoring cardiometabolic risk associated with PCOS. Investigations to exclude alternative diagnoses, including thyroid function tests, prolactin and 17-hydroxyprogesterone, should also be performed. Transvaginal ultrasound is the gold standard for assessing polycystic ovarian morphology. Finally, screening for psychological health is important given that depression, anxiety and mood disorders are highly prevalent in patients with PCOS ³.

Fig. 1. A comparative schematic of the divergent neuroendocrine feedback loops between a normal state (left) and Polycystic Ovary Syndrome (right).

(A) Normal HPG Axis:  The Hypothalamus (top centre) and Anterior Pituitary secrete pulsatile GnRH, followed by LH and FSH which stimulate healthy ovarian follicles (left). As follicles mature, they produce oestrogen and sex-steroids that provide direct ‘-ve feedback’ (dashed line) to slow GnRH.

(B) Increased GnRH Pulsatility in PCOS: This hyper-pulsatile GnRH signalling preferentially stimulates the pituitary to secrete high ↑LH. This ↑ LH targets the ovarian theca cell to overproduce androgens. This excess androgen maintains the primary feedback error and prevents follicles from developing, leading to Polycystic Ovarian Morphology (PCOM). High circulating androgens (Testosterone) directly ‘antagonise’ or block the brain’s sensitivity to progesterone’s inhibitory signal. This disables the brain’s internal brake, causing the GnRH pulse generator to fire at a rapid, pathological frequency (depicted as the red sinusoidal wave).

Management of PCOS

The management of polycystic ovary syndrome (PCOS) is complex and requires an individualised approach based on the patient’s predominant clinical features, including reproductive, metabolic and hyperandrogenic manifestations. The current gold standard for treatment is defined by the 2023 International Evidence-based Guideline, which synthesises over 3,000 studies to provide a unified framework ³

I. First-Line Therapy: Lifestyle Intervention

The foundational treatment for all PCOS phenotypes regardless of BMI is lifestyle modification.

1. • The Consensus: Multicomponent lifestyle intervention (diet, exercise and behavioural strategies) is the first-line therapy to improve insulin sensitivity and reproductive outcomes.
   • Exercise specifics: The 2023 guidelines recommend a minimum of 150 min/week of moderate-intensity aerobic activity or 75 min/week of vigorous intensity, plus muscle-strengthening activities on two non-consecutive days ^3.

II.Pharmacological Management of Hyperandrogenism & Cycle Regulation

For women not seeking immediate pregnancy, the goal is to protect the endometrium and manage dermatological symptoms (acne/hirsutism) ²⁵

• Combined Oral Contraceptive Pills (COCPs): Remain the first-line pharmacological treatment for irregular cycles and hirsutism. They work by suppressing LH (decreasing androgen production) and increasing SHBG (decreasing free testosterone).
• Anti-Androgens: Agents like spironolactone are recommended as “add-on” therapy if COCPs and cosmetic measures are insufficient after 6 months.

III. Metabolic Management & Insulin Sensitizers

Addressing insulin resistance in women with PCOS is crucial to improve the syndromic feature of PCOS as well as reduce the long-term cardiovascular risk ^4,13.

• Metformin: Recommended specifically for those with a BMI ≥25 kg/m² or high-risk metabolic profiles. It improves insulin sensitivity and can aid in weight loss and cycle regularity.
• Inositols: The 2023 guidelines officially recognised Inositol (specifically Myo-inositol) as an experimental/complementary therapy that may improve metabolic markers and ovulation, though it is not yet ranked above Metformin.IV. Infertility and Ovulation Induction
  The hierarchy of infertility treatment has been redefined by the superiority of Letrozole over Clomiphene ²⁶.

• • First-Line: Letrozole (an aromatase inhibitor) is now the preferred first-line agent for ovulation induction, as it results in higher live birth rates and lower multiple pregnancy rates compared to Clomiphene Citrate.
  • Second-Line: If letrozole fails, gonadotropins or laparoscopic Ovarian Drilling (LOD) are recommended.

Future directions for PCOS

Future directions in the management of PCOS are increasingly focused on a precision medicine approach that targets the underlying pathophysiological mechanisms rather than individual symptoms. Emerging therapies targeting metabolic dysfunction, such as glucagon-like peptide-1 (GLP-1) receptor agonists and sodium–glucose cotransporter 2 inhibitors (SGLT-2), show promise in improving both metabolic and reproductive outcomes, particularly in women with obesity ²⁷. In parallel, novel neuroendocrine-targeted therapies, including neurokinin 3 receptor antagonists and kisspeptin modulators, aim to directly regulate GnRH pulsatility and restore reproductive function ²⁸. Together, these developments highlight a shift towards mechanism-based and individualised management, which may ultimately improve long-term reproductive and cardiometabolic outcomes in women with PCOS.

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Author Information

Sandhi Wynn Nyunt

MBBS, MPH, MRCP (UK), PhD candidate (Imperial College London).

Clinical Research Fellow at Imperial College London.

Speciality Registrar in Endocrinology and Diabetes, Imperial College Healthcare NHS trust, London, UK