Polycystic ovary syndrome (PCOS)

Diagnostic Criteria

Rotterdam Criteria (2003)

• Requires at least two of the following three:
  • Oligo- or anovulation (irregular menstrual cycles or absence of ovulation)
  • Clinical or biochemical hyperandrogenism (hirsutism, acne, androgenic alopecia, or elevated serum androgens)
  • Polycystic ovarian morphology (≥20 follicles per ovary measuring 2–9 mm or an ovarian volume ≥10 cm³ in at least one ovary)

National Institutes of Health (NIH) Criteria (1990)

• Requires the presence of both hyperandrogenism and ovulatory dysfunction.

Androgen Excess and PCOS Society (AE-PCOS) Criteria (2006)

• Emphasises hyperandrogenism as the central feature.
• Either oligo-anovulation or polycystic ovarian morphology is required for diagnosis.

Distinction Between Polycystic Ovarian Morphology and PCOS

• Polycystic ovarian morphology alone does not define PCOS.
• Some individuals may have polycystic-appearing ovaries on ultrasound without meeting diagnostic criteria.
• Diagnosis requires hyperandrogenism and/or ovulatory dysfunction.

Endocrine and Metabolic Dysregulation

• PCOS is associated with abnormalities in androgen and oestrogen metabolism, leading to elevated testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEA-S) in many cases.
• Androgen levels vary, and some individuals with PCOS may have normal concentrations.
• Peripheral insulin resistance and hyperinsulinaemia contribute to increased gonadotropin stimulation of ovarian theca cells, amplifying androgen production.
• Insulin resistance results from postbinding defects in insulin receptor signalling, reducing hepatic synthesis of sex hormone-binding globulin (SHBG) and increasing free androgen levels.
• Adiponectin levels are reduced in both lean and obese women with PCOS, worsening metabolic dysfunction.

Hypothalamic-Pituitary-Ovarian Axis Dysregulation

• PCOS is characterised by increased luteinising hormone (LH) secretion from the anterior pituitary.
• Excessive LH stimulates ovarian theca cells, increasing androgen production.
• Relative deficiency of follicle-stimulating hormone (FSH) impairs aromatisation of androgens to oestrogens, contributing to anovulation and menstrual irregularities.
• Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) may further amplify ovarian androgen production.

Genetic and Epigenetic Susceptibility

• PCOS exhibits high heritability; twin studies suggest a 70% genetic contribution.
• GWAS have identified several susceptibility loci related to steroidogenesis, insulin signalling, and gonadotropin function.
• DENND1A, THADA, and LHCGR are consistently linked to PCOS in Chinese and European populations.
• FSHR and CYP17A1 are implicated in gonadotropin sensitivity and androgen production.
• The FTO gene, linked to obesity, is associated with increased PCOS susceptibility.
• Epigenetic mechanisms such as DNA methylation and X-chromosome inactivation may influence gene expression related to PCOS.

Environmental and Fetal Programming Hypotheses

• Prenatal androgen exposure may disrupt hypothalamic-pituitary function and ovarian development, predisposing to PCOS.
• Exposure to endocrine-disrupting chemicals (EDCs), such as bisphenol A (BPA), may increase insulin resistance and hyperandrogenism in women with PCOS.

Ovarian Morphological Changes

• PCOS is associated with bilaterally enlarged ovaries with thickened, avascular capsules.
• Histopathological findings include hyperplasia of theca stromal cells, leading to persistent follicular arrest and anovulation.

Endocrine Dysregulation and Androgen Excess

• PCOS is a hyperandrogenic state driven by excess ovarian androgen production, primarily testosterone and androstenedione.
• Luteinising hormone (LH) is elevated, leading to increased thecal cell stimulation and excessive androgen synthesis.
• Insulin resistance and hyperinsulinaemia exacerbate androgen excess by enhancing ovarian steroidogenesis and reducing hepatic sex hormone-binding globulin (SHBG) synthesis, increasing circulating free androgens.
• Dysregulation of steroidogenic enzymes, particularly P450c17, contributes to increased androgen biosynthesis.

Gonadotropin Secretion Abnormalities

• PCOS is characterised by increased gonadotropin-releasing hormone (GnRH) pulsatility, leading to excess LH relative to follicle-stimulating hormone (FSH).
• The elevated LH-to-FSH ratio promotes excessive androgen production but insufficient follicular maturation, contributing to chronic anovulation.
• Despite elevated LH levels, receptor desensitisation may occur, perpetuating anovulatory cycles.

Ovarian Dysfunction and Folliculogenesis Impairment

• Follicular development is disrupted, leading to an accumulation of small antral follicles and polycystic ovarian morphology.
• Excess androgens interfere with follicular selection, causing premature luteinisation of granulosa cells and preventing dominant follicle formation.
• FSH resistance impairs oestrogen production, reinforcing ovulatory dysfunction.

Insulin Resistance and Metabolic Dysregulation

• Most women with PCOS have peripheral insulin resistance, independent of obesity.
• Hyperinsulinaemia acts as a co-gonadotropin, stimulating ovarian androgen production and impairing hepatic testosterone clearance.
• Insulin synergises with LH to exacerbate androgen excess, reinforcing metabolic and reproductive abnormalities.
• Elevated insulin contributes to dyslipidaemia and heightened cardiovascular risk.

Genetic and Epigenetic Contributions

• PCOS has a strong genetic basis, with heritability estimates of up to 70% in twin studies.
• GWAS have identified multiple PCOS-related loci:
  • DENND1A (ovarian steroidogenesis)
  • THADA (linked to metabolic dysfunction)
  • LHCGR (affecting gonadotropin receptor function)
• Epigenetic factors such as DNA methylation and histone modifications influence ovarian function and insulin signalling.

Impact of Obesity on PCOS Pathophysiology

• Obesity worsens insulin resistance, amplifying hyperinsulinaemia, androgen excess, and anovulation.
• Increased aromatisation of androgens to oestrogens in adipose tissue disrupts hormonal feedback.
• Weight gain and metabolic dysfunction increase the risk of endometrial hyperplasia due to chronic unopposed oestrogen exposure.

Neuroendocrine Dysregulation

• PCOS is associated with increased GnRH pulse frequency and impaired progesterone-mediated feedback, indicating hypothalamic dysregulation.
• Elevated anti-Müllerian hormone (AMH) from small antral follicles may sustain high GnRH pulse frequency and LH dominance.
• Altered neurotransmitter signalling involving dopamine and serotonin may contribute to neuroendocrine disturbances in PCOS.

Global Prevalence and Variability

• PCOS is a common endocrine disorder, affecting between 4% and 20% of reproductive-age women worldwide, depending on the diagnostic criteria used.
• Prevalence by diagnostic criteria:
  • National Institutes of Health (NIH) Criteria (1990) – 6% (5–8%).
  • Rotterdam Criteria (2003) – 10% (8–13%).
  • Androgen Excess and PCOS Society (2006) – 10–15%.
• In the United States, prevalence ranges from 4–12%, with up to 10% of cases diagnosed in gynaecologic clinics.
• Studies in Europe report prevalence rates between 6.5–8%.
• China and Mexico report prevalence rates of 10% and 6%, respectively, suggesting a consistent global distribution.

Ethnic and Geographic Differences

• Phenotypic expression varies across ethnicities:
  • Hirsutism is less common in East Asian women than in White women with similar androgen levels.
  • Hispanic women in the US show greater impairments in glucose metabolism compared to White women.
  • Indigenous Australian women exhibit higher rates of hirsutism.
  • A study in southern Chinese women found a 10.5% prevalence of hirsutism, with increased acne, menstrual irregularities, polycystic ovaries, and acanthosis nigricans.

PCOS and Family History

• PCOS has a strong hereditary component.
• First-degree relatives of affected women have a 20–40% prevalence, much higher than the general population.
• Male relatives may show premature male-pattern baldness, excessive body hair, elevated DHEAS, and insulin sensitivity abnormalities.

PCOS and Associated Conditions

• PCOS accounts for 80–90% of cases of female hyperandrogenism.
• Among women presenting with androgen excess or ovulatory dysfunction:
  • 80% are diagnosed with PCOS.
  • 3% have hyperandrogenism-insulin resistance-acanthosis nigricans syndrome.
  • 1.5% have 21-hydroxylase-deficient non-classic adrenal hyperplasia.
  • 0.6% have classic 21-hydroxylase-deficient adrenal hyperplasia.
  • 0.2% have androgen-secreting tumours.

PCOS and High-Risk Groups

• PCOS prevalence is significantly higher among:
  • Women with oligo-ovulatory infertility.
  • Women with obesity and/or insulin resistance.
  • Those with type 1 or type 2 diabetes or gestational diabetes.
  • Individuals with a history of premature adrenarche.
  • First-degree relatives of women with PCOS.
  • Certain ethnic groups (e.g., Mexican Americans, Indigenous Australians).
  • Women on antiseizure medications, especially valproate.

Incidence and Referral Bias

• No prospective studies have documented true PCOS incidence.
• The prevalence of obesity in women with PCOS varies globally.
• Referral bias inflates obesity rates in clinic-based studies, as women with obesity and more severe symptoms are more likely to seek care.

Key Diagnostic Factors

Presence of Risk Factors

• Women with a history of premature adrenarche or family history of PCOS are at higher risk.
• First-degree female relatives have a 20–40% prevalence, significantly higher than the general population.

Female of Reproductive Age

• Symptoms often begin at puberty but may be masked by early use of oral contraceptives.
• This can delay recognition of menstrual irregularities and hyperandrogenic features.

Irregular Menstruation

• Found in 75% of women with PCOS, reflecting oligo- or anovulation.
• Definitions of menstrual abnormalities:
  • <21 or >45 days in those 1 to <3 years post-menarche.
  • <21 or >35 days or <8 cycles/year for those ≥3 years post-menarche to perimenopause.
  • 90 days for any single cycle for those 1 year post-menarche.
    Primary amenorrhoea by age 15 or >3 years after thelarche.
• Up to 40% of hirsute women with regular periods have anovulatory cycles upon further testing.

Infertility

• A common presenting feature due to chronic anovulation.

Hirsutism

• Present in 60% of women with PCOS.
• Evaluated using the modified Ferriman-Gallwey score.
• Affects androgen-dependent areas (e.g. upper lip, chin, chest, back, thighs).
• More prevalent in Mediterranean, South Asian, and Middle Eastern women; less common in East Asians.
• Hair removal practices can obscure clinical detection.

Other Diagnostic Factors

Acne

• Affects 15–25% of women with PCOS.
• Severe or persistent acne beyond adolescence may be more indicative of PCOS.

Overweight or Obesity

• Affects 30–80% of women with PCOS depending on ethnicity and setting.
• Central obesity common (waist-to-hip ratio >0.85 or waist circumference >88 cm).

Hypertension

• Frequently observed but non-specific.
• Blood pressure should be routinely checked.

Scalp Hair Loss (Androgenic Alopecia)

• Seen in up to 5% of women with PCOS.
• Thinning at the crown with preservation of the frontal hairline.

Oily Skin or Excessive Sweating

• May occur due to hyperandrogenism, though prevalence data are lacking.

Acanthosis Nigricans

• A sign of insulin resistance.
• Appears as dark, velvety plaques on the neck, axillae, groin, or under the breasts.
• More common in obese Black and Hispanic women.

Risk Factors

Family History of PCOS

• First-degree relatives show 20–40% prevalence compared to 6–13% in the general population.

Premature Adrenarche

• Up to 50% of girls with premature adrenarche develop PCOS later.

Obesity

• Genetic evidence supports a causal link.
• Obesity in childhood or adolescence appears to pose a stronger risk than adult-onset obesity.

Weak Risk Factors

Low Birth Weight

• Associated with higher risk of premature adrenarche and later insulin resistance.

Fetal Androgen Exposure

• Daughters of women with virilising congenital adrenal hyperplasia may show hyperandrogenic features.
• No conclusive evidence yet for a direct causal relationship with PCOS.

Environmental Endocrine Disruptors

• Higher bisphenol A (BPA) levels seen in women with PCOS.
• Associated with insulin resistance and hyperandrogenism, though causality remains unproven.

Hirsutism and Virilising Signs

• Excessive terminal hair growth in a male distribution pattern is a hallmark sign.
• The modified Ferriman-Gallwey (mFG) score is used to assess hirsutism, grading 9 body areas (upper lip, chin, chest, upper/lower abdomen, thighs, back, arms, buttocks) from 0 (no hair) to 4 (frankly virile).
• A total score ≥8 is considered abnormal in adult White women, though thresholds vary by ethnicity.
• Virilising signs—such as male-pattern balding, increased muscle mass, deepening voice, or clitoromegaly—warrant investigation for other causes of hyperandrogenism, including androgen-secreting tumours.

Obesity and Central Adiposity

• Approximately 50% of women with PCOS have abdominal obesity.
• Defined as waist circumference >35 inches (88 cm) or waist-to-hip ratio >0.85.
• Body mass index (BMI) should be measured in all suspected cases, as obesity intensifies metabolic risk.

Acanthosis Nigricans

• A velvety thickening and hyperpigmentation of the skin, most often affecting:
  • Nape of the neck
  • Axillae
  • Beneath the breasts
  • Elbows
  • Knuckles
  • Groin
• Strongly linked to insulin resistance; familial and paraneoplastic variants also exist.
• May serve as a cutaneous marker of internal malignancy.

Staging of acanthosis nigricans

• 0: Absent
• 1: Present but not visible to casual observation
• 2: Limited to the base of the skull
• 3: Extends to lateral neck but not visible anteriorly
• 4: Visible from the front
• 5: Circumferential involvement

Blood Pressure Abnormalities

• Hypertension is commonly seen in PCOS and is frequently part of the metabolic syndrome.
• Diagnostic thresholds:
  • Systolic blood pressure ≥130 mmHg
  • Diastolic blood pressure ≥85 mmHg

Ovarian Examination

• Ovaries may be enlarged on physical exam, but this is not universally present.
• Pelvic ultrasound is usually required to evaluate ovarian volume and follicle count.

First-Line Investigations

 Serum 17-Hydroxyprogesterone

• Used to exclude 21-hydroxylase-deficient non-classic adrenal hyperplasia (NCAH).
• Values between 6–24 nmol/L (200–800 ng/dL) require further adrenocorticotropic hormone (ACTH) stimulation testing.
• Levels >24 nmol/L (>800 ng/dL) suggest adrenal hyperplasia.

Serum Prolactin

• Used to exclude hyperprolactinaemia, which can cause oligo- or anovulation.
• Mild elevations (870–1304 pmol/L, 20–30 ng/mL) are common in PCOS without an associated pituitary adenoma.
• Markedly elevated levels may suggest prolactinoma.

Serum Thyroid-Stimulating Hormone (TSH)

• Assesses thyroid dysfunction, which may mimic PCOS by causing irregular menses and ovulatory dysfunction.

Oral Glucose Tolerance Test (OGTT)

• Fasting glucose measurement, followed by a 2-hour post-75 g glucose challenge.
• Abnormal glucose tolerance (IGT, diabetes) occurs in up to 40% of women with PCOS.
• Rescreening:
  • Every 2 years if normal.
  • Annually if IGT is detected.
• Fasting insulin >69–104 pmol/L (10–15 µU/mL) suggests insulin resistance.
• Peak insulin >2084 pmol/L (300 µU/mL) indicates severe insulin resistance.

Fasting Lipid Panel

• Evaluates dyslipidaemia, commonly found in PCOS.
• Findings:
  • Elevated total cholesterol, LDL-cholesterol, triglycerides.
  • Low HDL-cholesterol.
• Treatment is initiated if cardiovascular risk is high.

Second-Line Investigations

 Serum Total and Free Testosterone

• Hyperandrogenaemia is present in 60–80% of women with PCOS:
  • 70% have elevated free testosterone.
  • 40% have elevated total testosterone.
  • 25% have elevated dehydroepiandrosterone sulfate (DHEAS).
• Obesity lowers sex hormone-binding globulin (SHBG), increasing free testosterone despite normal total testosterone.
• Should be tested in the follicular phase, in the morning, and at least 3 months post-hormonal therapy cessation.

Serum DHEAS

• The only elevated androgen in 10% of women with PCOS.
• Elevations >2 standard deviations above the mean suggest androgen excess but hold limited diagnostic value unless rapid virilisation is present.

Serum Androstenedione

• May be the only abnormal androgen, increasing hyperandrogenaemia detection by 10%.

Pelvic Ultrasound (Transvaginal Preferred)

• Findings:
  • ≥20 follicles per ovary (2–9 mm in diameter) or increased ovarian volume (≥10 mL).
• Present in 75% of PCOS cases, but also found in up to 25% of normal women.
• Should be performed during early follicular phase (day 3–5) after a spontaneous or withdrawal bleed.
• Not recommended in adolescents due to poor specificity.

Serum Anti-Müllerian Hormone (AMH)

• Considered an alternative to ultrasound in adults but not recommended for diagnosis in adolescents due to low specificity.
• Higher levels in PCOS reflect increased follicular count.
• Meta-analysis sensitivity: 0.78, specificity: 0.87.

Luteal Phase Progesterone Measurement

• Conducted on days 20–24 of the menstrual cycle.
• Used to confirm ovulation:
  • Levels >6.4 to 25.4 nmol/L (>2–8 ng/mL) suggest ovulation has occurred.
  • Flat progesterone levels indicate anovulation.

Serum Luteinising Hormone (LH) and Follicle-Stimulating Hormone (FSH)

• Elevated LH-to-FSH ratio (>3:1) is seen in two-thirds of PCOS cases.
• More common in lean women.
• Also helps differentiate hypothalamic amenorrhoea (low levels) and perimenopause (high levels).

Haemoglobin A1c (HbA1c) or Fasting Plasma Glucose

• Screening for insulin resistance and metabolic syndrome.
• Fasting glucose 5.6–6.9 mmol/L (100–125 mg/dL): Impaired fasting glucose (IFG).
• HbA1c 39–47 mmol/mol (5.7–6.4%): Prediabetes.
• Fasting glucose ≥7.0 mmol/L (126 mg/dL) or HbA1c ≥48 mmol/mol (≥6.5%): Diabetes.

Nonclassic Congenital Adrenal Hyperplasia (NCCAH)

• Pathophysiology: Partial 21-hydroxylase deficiency results in excess androgen precursors.
• Clinical Features:
  • Menstrual irregularities, hirsutism, and acne, similar to PCOS.
  • Common in Mediterranean, Hispanic, and Ashkenazi Jewish populations.
• Investigations:
  • Morning follicular-phase 17-hydroxyprogesterone:
    • <6 nmol/L (200 ng/dL): Rules out NCCAH.
    • 24 nmol/L (800 ng/dL): Suggests NCCAH.
    • ACTH stimulation test required for intermediate values. A peak >30 nmol/L (1000 ng/dL) confirms the diagnosis.

Androgen-Secreting Tumors (Ovarian/Adrenal)

• Pathophysiology: Ovarian or adrenal tumors autonomously secrete high levels of androgens.
• Clinical Features:
  • Rapid-onset virilisation (within months) and progressive worsening of hirsutism.
  • Signs: Frontal balding, deepening voice, clitoromegaly, severe muscle mass increase.
• Investigations:
  • Serum total testosterone >6.9 nmol/L (>200 ng/dL): Suggestive of an ovarian tumor.
  • DHEAS >7000 ng/mL: Suggestive of an adrenal tumor.
• Imaging:
  • Pelvic ultrasound: Ovarian tumor detection.
  • CT scan of the adrenals: If DHEAS is markedly elevated.

Cushing’s Syndrome

• Pathophysiology: Excess cortisol production from adrenal tumors or pituitary ACTH overproduction.
• Clinical Features:
  • Central obesity, moon facies, abdominal striae, muscle weakness, and osteoporosis.
  • Menstrual irregularities and hirsutism, overlapping with PCOS.
• Investigations:
  • 24-hour urinary free cortisol:
    • 248 nmol/24 h (90 µg/24 h): Suggestive.
  • Low-dose dexamethasone suppression test:
    • Failure to suppress cortisol <138 nmol/L (<5 µg/dL) confirms diagnosis.
  • Late-night salivary cortisol: Elevated in Cushing’s.

Hyperprolactinaemia

• Pathophysiology: Elevated prolactin levels inhibit gonadotropin release, leading to anovulation.
• Clinical Features:
  • Menstrual irregularities and mild hyperandrogenic features.
  • Galactorrhoea (milky nipple discharge) may be present.
  • Headache or visual field defects suggest a pituitary tumour.
• Investigations:
  • Serum prolactin:
    • Markedly elevated (>100 µg/L or 100 ng/mL): Suggests prolactinoma.
  • MRI of the pituitary: If prolactin levels are significantly elevated.

Thyroid Dysfunction

• Pathophysiology: Hypothyroidism or hyperthyroidism can cause menstrual irregularities.
• Clinical Features:
  • Hypothyroidism: Fatigue, cold intolerance, weight gain, constipation.
  • Hyperthyroidism: Weight loss, nervousness, heat intolerance.
• Investigations:
  • TSH and free T4:
    • High TSH, low free T4: Primary hypothyroidism.
    • Low TSH, high free T4: Hyperthyroidism.

Severe Insulin Resistance Syndromes

• Pathophysiology: Genetic mutations affecting insulin signalling cause extreme hyperinsulinaemia and androgen excess.
• Clinical Features:
  • Severe insulin resistance, hyperandrogenism, and acanthosis nigricans.
  • Lipodystrophy may be present.
• Investigations:
  • Fasting insulin >556 pmol/L (>80 µU/mL).
  • Peak insulin >2084 pmol/L (>300 µU/mL) during OGTT.

Exogenous Androgen Use (Androgenic/Anabolic Drugs)

• Pathophysiology: Exogenous androgens suppress gonadotropins, mimicking PCOS features.
• Clinical Features:
  • Hyperandrogenism with rapid progression.
  • History of drug use: Testosterone, anabolic steroids, danazol, androgenic progestins.
• Investigations:
  • Serum androgen profile: Variable depending on the specific drug.
  • Discontinuation of the drug results in resolution of symptoms.

Hypogonadotropic Hypogonadism

• Pathophysiology: Deficient GnRH secretion leads to low FSH and LH, resulting in anovulation.
• Clinical Features:
  • Anovulation with absent hyperandrogenism.
  • Low oestrogen symptoms: Osteoporosis, vaginal dryness.
• Investigations:
  • Low serum FSH, LH, and oestradiol confirm the diagnosis.

Premature Ovarian Insufficiency (POI)

• Pathophysiology: Early depletion of ovarian follicles causes oestrogen deficiency.
• Clinical Features:
  • Menstrual irregularities (oligomenorrhoea, amenorrhoea).
  • Signs of oestrogen deficiency: Hot flushes, vaginal atrophy.
• Investigations:
  • High FSH, low oestradiol confirms diagnosis.

Apparent Cortisone Reductase Deficiency

• Pathophysiology: Defective 11β-hydroxysteroid dehydrogenase type 1 reduces cortisone-to-cortisol conversion, leading to adrenal androgen excess.
• Clinical Features:
  • Indistinguishable from PCOS.
• Investigations:
  • Urinary free cortisol elevated.
  • Ratio of tetrahydrocortisols to tetrahydrocortisone <0.08 (normal: 0.5–2.0).

Lifestyle Management

• First-line intervention for all women with PCOS, irrespective of BMI.
• Weight loss (as little as 5-7%) can restore ovulation in up to 80% of overweight or obese women, improve insulin sensitivity, and reduce androgen levels.
• Exercise and dietary interventions improve fertility outcomes, metabolic health, and pregnancy outcomes, though no single diet is superior.
  
  

Management in Women Pursuing Fertility

• Letrozole (Aromatase Inhibitor)
  • Reduces estrogen synthesis, increasing FSH to stimulate follicular growth.
  • Superior to clomiphene citrate for ovulation induction, pregnancy rates, and live birth rates.
  • Less risk of multiple pregnancies compared to gonadotropins.
• Clomiphene Citrate (Selective Estrogen Receptor Modulator)
  • Blocks oestrogen receptors at the hypothalamus, increasing FSH secretion.
  • Up to 25% of women are resistant, requiring combination therapy.
  • Multiple pregnancy risk: 5-10%.
• Metformin (Insulin-Sensitizing Agent)
  • Can restore ovulation and improve menstrual regularity in insulin-resistant women.
  • Less effective than letrozole or clomiphene, but used adjunctively.
• Combination Therapy (Clomiphene + Metformin)
  • More effective than either agent alone for ovulation induction.
  • Improves pregnancy and live birth rates.
    
    

• Gonadotropins (FSH, hMG)
  • Directly stimulate follicular development.
  • Higher risk of multiple pregnancies and ovarian hyperstimulation syndrome (OHSS).
  • Requires careful monitoring with ultrasound and oestradiol levels.
• Laparoscopic Ovarian Drilling (LOD)
  • A surgical alternative for clomiphene-resistant women.
  • Similar effectiveness to gonadotropins but lower risk of multiple pregnancies.
  • Risk of adhesion formation and potential ovarian insufficiency.
    
    

• In Vitro Fertilization (IVF)
  • Reserved for failed ovulation induction or severe infertility.
  • Risk of ovarian hyperstimulation, requiring careful stimulation protocols.
  • Metformin adjunctively reduces OHSS risk.
    
    

Management in Women Not Pursuing Fertility

• Oral Contraceptive Pills (OCPs)
  • First-line therapy for menstrual regularity and endometrial protection.
  • Preferred progestins: Desogestrel, Norgestimate, Drospirenone (low androgenicity).
  • Avoid levonorgestrel, as it may worsen metabolic profiles.
• Cyclic Progestin Therapy
  • For those who cannot take OCPs, medroxyprogesterone or micronised progesterone can be used every 1-2 months.
• Metformin
  • May restore menstrual cyclicity, but its endometrial protective effect is unclear.
  • Used as an alternative in those with contraindications to OCPs.
    
    

• OCPs
  • Reduce ovarian androgen production and increase sex hormone-binding globulin (SHBG).
  • Effective for mild hirsutism and acne.
• Anti-Androgens
  • Spironolactone (50-100 mg twice daily)
    • Most commonly used anti-androgen.
    • Should be combined with contraception, as it is teratogenic to male fetuses.
  • Finasteride (5α-reductase inhibitor)
    • Blocks testosterone conversion to dihydrotestosterone (DHT).
    • Used in androgenic alopecia and hirsutism-resistant cases.
  • Cyproterone Acetate
    • Available outside the United States.
    • More potent anti-androgen effect.
• Metformin
  • May decrease androgen levels, though less effective than OCPs and anti-androgens.
• Topical and Mechanical Treatments
  • Eflornithine cream: Slows facial hair growth.
  • Laser and electrolysis: Long-term hair removal after hormonal therapy.
  • Minoxidil: Effective for androgenic alopecia, but must be used continuously.
    
    

• Weight Loss
  • Improves insulin resistance and androgen levels.
  • Even modest weight loss (5-10%) can restore ovulation.
• Metformin
  • First-line for women with insulin resistance or prediabetes.
  • Improves glucose tolerance and reduces diabetes risk.
• Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists
  • Exenatide, Liraglutide, Semaglutide
  • Effective for weight loss and insulin resistance.
  • May improve menstrual frequency and androgen levels.
• Dyslipidemia Management
  • Statins are used if LDL is elevated.
  • Lifestyle modification is first-line.
    
    

• Endometrial Hyperplasia & Cancer
  • OCPs or cyclic progestins are recommended to prevent unopposed oestrogen exposure.
• Cardiovascular Disease Risk
  • Women with PCOS have increased risk of atherosclerosis and hypertension.
  • Statins, antihypertensives, and weight management reduce risks.
• Obstructive Sleep Apnea
  • Common in obese women with PCOS.
  • CPAP therapy improves insulin sensitivity and cardiovascular outcomes.
• Non-Alcoholic Fatty Liver Disease (NAFLD)
  • More prevalent in PCOS due to insulin resistance.
  • Weight loss and metformin improve liver function.
    
    

Metabolic and Cardiovascular Risk

 Insulin Resistance and Type 2 Diabetes Mellitus (T2DM)

• Up to 40% of women with PCOS have insulin resistance, independent of BMI.
• Women with PCOS are at a 2–5 times increased risk of developing T2DM.
• The American Association of Clinical Endocrinologists and American College of Endocrinology recommend diabetes screening by age 30, with earlier testing for those at high risk.

Cardiovascular Disease (CVD)

• Elevated LDL and triglycerides, reduced HDL, and endothelial dysfunction contribute to increased CVD risk.
• Hypertension prevalence is higher in women with PCOS.
• Long-term studies suggest women with PCOS may have increased risks of stroke and myocardial infarction, though more research is needed to confirm causality.
• Lifestyle interventions (weight loss, exercise, and dietary modifications) and metformin use may help reduce the risk of diabetes and atherosclerosis.

Endometrial and Reproductive Risks

 Endometrial Hyperplasia and Cancer

• Chronic anovulation leads to unopposed oestrogen exposure, increasing the risk of endometrial hyperplasia and carcinoma.
• RCOG guidelines recommend inducing withdrawal bleeding with progestogens at least every 3–4 months to prevent endometrial overgrowth.

Fertility

• Anovulation is common, but many women can conceive with ovulation induction therapy.
• Aging does not necessarily restore ovulation, though some improvement in menstrual regularity occurs in some women after their 30s.
• Fertility declines naturally with age, and untreated PCOS may exacerbate age-related fertility reduction.

Hyperandrogenic Symptoms Across the Lifespan

•  Androgen-related symptoms (hirsutism, acne, alopecia)
  • Typically improve after menopause due to ovarian function decline.
  • However, biochemical hyperandrogenism may persist in some women.
  • No confirmed association with breast or ovarian cancer, so no additional screening beyond standard recommendations is required.
    
    

Long-Term Outlook and Treatment Considerations

• PCOS symptoms recur if treatment is stopped, requiring lifelong management.
• Obesity exacerbates metabolic and reproductive risks, reinforcing the importance of sustained lifestyle interventions.
• Long-term monitoring of glucose levels, lipid profiles, and cardiovascular health is crucial.

Long-Term Complications

 Type 2 Diabetes Mellitus (T2DM)

• PCOS is an independent risk factor for T2DM.
• 20–40% of obese women with PCOS develop glucose intolerance or T2DM by their 40s.
• Even non-obese women with PCOS have 1.5–3 times the risk.
• One-third of women with PCOS progress to T2DM within 2–3 years of diagnosis.
• Routine glucose screening is recommended, particularly in high-risk women.

Cardiovascular Disease (CVD)

• PCOS is associated with higher prevalence of CVD risk factors, including:
  • Hypertension: Twice as common in women with PCOS.
  • Dyslipidemia: 70% prevalence with low HDL and high triglycerides.
  • Elevated inflammatory markers: CRP, homocysteine, IL-6.
  • Endothelial dysfunction and subclinical atherosclerosis.
  • Higher prevalence of coronary artery calcification and increased carotid intima-media thickness.
• Despite increased CVD markers, evidence linking PCOS to cardiovascular events remains inconclusive.
• Women with PCOS should undergo routine cardiovascular risk assessment.

 Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

• Previously termed non-alcoholic fatty liver disease (NAFLD).
• 40–55% of women with PCOS have MASLD.
• 10% progress to MASH (formerly NASH), with 20–30% of these developing cirrhosis.
• Androgen excess correlates with increased MASLD risk.
• Metabolic dysfunction in PCOS increases the likelihood of fibrosis and cirrhosis.
• Lifestyle interventions, insulin sensitisers, and lipid-lowering therapy are the main treatments.

 Endometrial Hyperplasia and Cancer

• Chronic anovulation leads to prolonged unopposed estrogen exposure, increasing the risk of:
  • Endometrial hyperplasia.
  • Endometrial cancer (3-fold higher risk than controls).
• Routine screening with ultrasound or biopsy is advised in women with persistent amenorrhoea.
• Progestin therapy or combined hormonal contraception is essential for endometrial protection.

Metabolic Syndrome

• Defined by central obesity, insulin resistance, hypertension, and dyslipidemia.
• Present in 30% of women with PCOS.
• Women with PCOS have 2–3 times increased odds of metabolic syndrome.
• Adolescents with PCOS are 3 times more likely to develop metabolic syndrome than controls.

Hypertension

• Increased risk of hypertension, especially in premenopausal women.
• Associated with vascular stiffness, endothelial dysfunction, and obesity.
• Annual blood pressure monitoring is advised.

Dyslipidemia

• Most common lipid abnormalities in PCOS:
  • Elevated LDL, triglycerides, and ApoB/A1 ratios.
  • Low HDL cholesterol.
  • Small dense LDL particles, which are more atherogenic.
• Regular lipid screening every 3–5 years is recommended.

Psychological and Sleep-Related Complications

Mental Health Disorders

• High prevalence of depression, anxiety, and eating disorders.
• Women with PCOS have 4 times the risk of depression and 5.6 times the risk of anxiety.
• Increased body image concerns and social isolation.
• Higher rates of binge-eating disorder and bulimia.
• Routine screening for mood disorders is recommended.

Obstructive Sleep Apnea (OSA)

• 20–45% of women with PCOS have OSA or sleep-disordered breathing.
• Higher prevalence in obese and insulin-resistant women.
• All women with PCOS should be screened for OSA and referred for evaluation if symptoms are present.

Oncology Risk

Endometrial Cancer

• PCOS is associated with a higher risk of endometrial cancer.
• Chronic unopposed estrogen exposure leads to endometrial hyperplasia.
• Routine endometrial surveillance and progestin withdrawal therapy are recommended.

Ovarian and Breast Cancer

• No conclusive evidence links PCOS to ovarian or breast cancer.
• Routine cancer screening follows general population guidelines.

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