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, with either oligo-anovulation or polycystic ovarian morphology required for diagnosis.
  
  

Distinction Between Polycystic Ovarian Morphology and PCOS

• Polycystic ovarian morphology alone does not define PCOS. While some individuals may have polycystic-appearing ovaries on ultrasound, they do not meet the diagnostic criteria unless hyperandrogenism and/or ovulatory dysfunction are present.
  
  

Endocrine and Metabolic Dysregulation

• PCOS is associated with abnormalities in androgen and estrogen metabolism, leading to elevated testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEA-S) in many cases. However, androgen levels vary, and some individuals with PCOS may have normal concentrations.
• Peripheral insulin resistance and hyperinsulinemia play a significant role, contributing to increased gonadotropin stimulation of ovarian theca cells, thereby amplifying androgen production.
• Insulin resistance in PCOS results from postbinding defects in insulin receptor signaling, leading to reduced hepatic synthesis of sex hormone-binding globulin (SHBG) and increased androgenicity.
• Adiponectin, an adipocyte-derived hormone that regulates lipid metabolism and glucose homeostasis, is lower in both lean and obese women with PCOS, further exacerbating metabolic dysfunction.
  
  

Hypothalamic-Pituitary-Ovarian Axis Dysregulation

• PCOS is characterised by increased luteinising hormone (LH) secretion from the anterior pituitary, leading to excessive stimulation of ovarian theca cells and elevated androgen production.
• A relative follicle-stimulating hormone (FSH) deficiency impairs the aromatisation of androgens to oestrogens, contributing to anovulation and menstrual irregularities.
• Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) may further enhance ovarian androgen production, amplifying hyperandrogenism.
  
  

Genetic and Epigenetic Susceptibility

• PCOS exhibits a high heritability, with twin studies estimating a 70% genetic contribution.
• Genome-wide association studies (GWAS) have identified multiple susceptibility loci, including genes involved in steroidogenesis, insulin signaling, and gonadotropin function:
  • DENND1A, THADA, and LHCGR have been consistently linked to PCOS in both Chinese and European populations.
  • FSHR (follicle-stimulating hormone receptor) and CYP17A1 (a key steroidogenic enzyme) have been implicated in gonadotropin sensitivity and androgen excess.
  • A variant in the FTO gene, known to predispose to common obesity, has been associated with increased PCOS susceptibility, emphasising the interplay between body weight regulation and PCOS development.
• Epigenetic factors, such as DNA methylation and X-chromosome inactivation, may also contribute to PCOS by modulating gene expression related to steroidogenesis and insulin metabolism.
  
  

Environmental and Fetal Programming Hypotheses

• Prenatal androgen exposure has been suggested as a potential contributor to PCOS, as elevated fetal androgen levels may alter hypothalamic-pituitary function and affect ovarian development.
• Endocrine-disrupting chemicals (EDCs), such as bisphenol A (BPA), have been implicated in increasing insulin resistance and hyperandrogenism in women with PCOS.
  
  

Ovarian Morphological Changes

• PCOS is characterised by bilaterally enlarged ovaries with thickened, avascular capsules.
• Histopathology reveals hyperplasia of theca stromal cells, contributing 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 hyperinsulinemia exacerbate androgen excess by enhancing ovarian steroidogenesis and reducing hepatic sex hormone-binding globulin (SHBG) synthesis, increasing the levels of 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, which leads to excess LH relative to follicle-stimulating hormone (FSH).
• The elevated LH-to-FSH ratio results in excessive androgen production but insufficient follicular maturation, contributing to chronic anovulation.
• Despite high LH levels, LH receptor desensitisation may occur over time, contributing to persistent anovulatory cycles.
  
  

Ovarian Dysfunction and Folliculogenesis Impairment

• Follicular development is disrupted, leading to accumulation of small antral follicles and characteristic polycystic ovarian morphology.
• Excess androgens interfere with normal follicular selection, causing premature luteinisation of granulosa cells and preventing the formation of a dominant follicle.
• FSH resistance further impairs estrogen production, contributing to ovulatory dysfunction.
  
  

Insulin Resistance and Metabolic Dysregulation

• Peripheral insulin resistance is present in most women with PCOS, independent of obesity.
• Hyperinsulinemia acts as a co-gonadotropin, stimulating ovarian androgen production and impairing hepatic clearance of testosterone.
• Insulin exacerbates LH-driven androgen excess, reinforcing ovulatory dysfunction and metabolic disturbances.
• Increased insulin levels contribute to dyslipidemia and a higher risk of cardiovascular disease.
  
  

Genetic and Epigenetic Contributions

• PCOS has a strong genetic component, with heritability estimates of up to 70% in twin studies.
• Genome-wide association studies (GWAS) have identified several genetic loci linked to PCOS, including:
  • DENND1A, which is involved in ovarian steroidogenesis.
  • THADA, which may contribute to metabolic dysfunction.
  • LHCGR, encoding the luteinizing hormone/choriogonadotropin receptor, playing a role in gonadotropin action.
• Epigenetic modifications, such as DNA methylation and histone modifications, may influence ovarian function and insulin signaling.
  
  

Impact of Obesity on PCOS Pathophysiology

• Obesity exacerbates insulin resistance, leading to more severe hyperinsulinemia, androgen excess, and ovulatory dysfunction.
• Aromatisation of androgens to estrogens in adipose tissue further disrupts hormonal balance, perpetuating chronic anovulation.
• Increased weight gain and metabolic dysfunction elevate the risk of endometrial hyperplasia due to chronic unopposed estrogen exposure.
  
  

Neuroendocrine Dysregulation

• Increased GnRH pulse frequency and decreased progesterone feedback suggest a primary defect in hypothalamic regulation.
• Higher anti-Müllerian hormone (AMH) levels from small antral follicles may contribute to persistently high GnRH pulse rates, further driving LH excess.
• Altered neurotransmitter signaling, particularly involving dopamine and serotonin, has been implicated in the neuroendocrine dysregulation seen 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, the prevalence ranges from 4-12%, with up to 10% of cases diagnosed in gynecologic clinics.
• Studies in Europe report prevalence rates between 6.5-8%, while China and Mexico report 10% and 6%, respectively, suggesting a consistent global prevalence.
  
  

Ethnic and Geographic Differences

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

PCOS and Family History

• PCOS has a strong hereditary component, with first-degree relatives of affected individuals having a 20-40% prevalence, significantly higher than the general population.
• Men in families of women with PCOS may exhibit premature male-pattern baldness, excessive body hair, elevated dehydroepiandrosterone sulfate (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 tumors.
    
    

PCOS and High-Risk Groups

• PCOS prevalence is significantly higher among women with specific risk factors:
  • Oligo-ovulatory infertility.
  • Obesity and/or insulin resistance.
  • Type 1 and Type 2 diabetes, gestational diabetes.
  • A history of premature adrenarche.
  • First-degree relatives with PCOS.
  • Certain racial and ethnic groups (e.g., Mexican Americans, Indigenous Australians).
  • Women on antiseizure medications, particularly valproate, show increased PCOS prevalence.
    
    

Incidence and Referral Bias

• There are no prospective studies documenting PCOS incidence rates.
• The prevalence of obesity among women with PCOS varies globally, but the disorder itself appears relatively uniform across populations.
• Referral bias contributes to higher obesity rates in PCOS clinics, as women with obesity and severe symptoms are more likely to seek medical care, leading to an overrepresentation of obesity in clinical PCOS populations.
  
  

Key Diagnostic Factors

• Presence of Risk Factors: Women with a history of premature adrenarche or a 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, delaying recognition of irregular menstruation and hyperandrogenic features.
• Irregular Menstruation: Found in 75% of women with PCOS, reflecting oligo- or anovulation.
  • Menstrual cycle abnormalities are defined as:
    • <21 or >45 days in those 1 to <3 years post-menarche.
    • <21 or >35 days or <8 cycles per year for those ≥3 years post-menarche to perimenopause.
    • >90 days for any single cycle for those 1 year post-menarche.
    • Primary amenorrhea by age 15 or >3 years after breast development.
  • Up to 40% of hirsute women with regular periods have anovulatory cycles on further testing.
• Infertility: A common presenting complaint due to chronic anovulation.
• Hirsutism: Present in 60% of women with PCOS and assessed using the modified Ferriman-Gallwey score.
  • Hirsutism involves terminal hair growth in androgen-dependent areas: upper lip, chin, chest, back, upper arms, shoulders, linea alba, peri-umbilical region, thighs, and buttocks.
  • More common in Mediterranean, South Asian, and Middle Eastern women, while less frequent in East Asians.
  • Women frequently remove excess hair, making clinical detection more challenging.
    
    

Other Diagnostic Factors

• Acne: Present in 15-25% of women with PCOS but is not specific to the condition.
  • Severe, persistent acne beyond adolescence may be more indicative of PCOS.
• Overweight or Obesity: Depending on ethnicity and culture, 30-80% of women with PCOS are overweight or obese, often exhibiting central obesity (waist-to-hip ratio >0.85 or waist circumference >88 cm).
• Hypertension: Frequently seen but non-specific. Blood pressure should be measured in all women suspected of having PCOS.
• Scalp Hair Loss (Androgenic Alopecia): Affects up to 5% of women with PCOS, presenting as thinning at the vertex and crown while preserving the frontal hairline.
• Oily Skin or Excessive Sweating: May result from hyperandrogenism, but its prevalence in PCOS is unclear.
• Acanthosis Nigricans: A marker of hyperinsulinemia, presenting as brown, velvety, hyperpigmented patches on the nape of the neck, axillae, groin, umbilicus, and sub-mammary areas. More common in obese Black and Hispanic women.
  
  

Risk Factors

• Family History of PCOS: First-degree female relatives have a significantly higher prevalence (20-40% vs. 6-13% in the general population).
• Premature Adrenarche: Up to 50% of cases develop PCOS in adulthood.
• Obesity: Genetic studies suggest obesity is a causal factor in PCOS. Childhood/adolescent obesity may have a stronger impact on PCOS risk than adult obesity.
  
  

Weak Risk Factors

• Low Birth Weight: May predispose individuals to premature adrenarche and hyperinsulinemia, increasing PCOS risk.
• Fetal Androgen Exposure: Daughters of women with congenital adrenal virilising disorders may develop hyperandrogenic features, though no conclusive evidence links fetal androgen exposure to PCOS.
• Environmental Endocrine Disruptors: Women with PCOS have higher bisphenol A levels, which have been linked to insulin resistance and hyperandrogenism, though causality is not established.
  
  

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, while ethnic variations exist.
• Virilising signs, such as male-pattern balding, increased muscle mass, deepening voice, or clitoromegaly, warrant evaluation for other causes of hyperandrogenism, such as androgen-secreting tumors.
  
  

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 assessed in all suspected cases, as obesity exacerbates metabolic risks.
  
  

Acanthosis Nigricans

• A velvety thickening and hyperpigmentation of the skin, commonly seen on:
  • Nape of the neck, axillae, beneath the breasts, elbows, knuckles, and groin.
• Strongly associated with insulin resistance, though syndromic and familial forms exist.
• Can be a cutaneous marker of 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 common in PCOS, often associated with metabolic syndrome.
• Blood pressure readings:
  • Systolic ≥130 mmHg.
  • Diastolic ≥85 mmHg.

Ovarian Examination

• Ovaries may be enlarged, but this is not always present in PCOS.
• Pelvic ultrasound is typically required for assessing ovarian volume and follicle count.
  
  

First-Line Investigations

1. 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.
2. Serum Prolactin
   • Used to exclude hyperprolactinemia, 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.
3. Serum Thyroid-Stimulating Hormone (TSH)
   • Assesses thyroid dysfunction, which may mimic PCOS by causing irregular menses and ovulatory dysfunction.
4. Oral Glucose Tolerance Test (OGTT)
   • Fasting glucose measurement, followed by a 2-hour post-75g glucose challenge.
   • Abnormal glucose tolerance (IGT, diabetes) occurs in up to 40% of women with PCOS.
   • Rescreening recommendations:
     • Every 2 years if normal.
     • Annually if impaired glucose tolerance (IGT) is detected.
   • Fasting insulin >69 to 104 pmol/L (10-15 µU/mL) suggests insulin resistance.
   • Peak insulin >2084 pmol/L (300 µU/mL) indicates severe insulin resistance.
5. Fasting Lipid Panel
   • Evaluates dyslipidemia, 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

1. Serum Total and Free Testosterone
   • Hyperandrogenemia 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.
2. 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.
3. Serum Androstenedione
   • May be the only abnormal androgen, increasing hyperandrogenemia detection by 10%.
4. 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.
5. 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.
6. 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.
7. 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 amenorrhea (low levels) and perimenopause (high levels).
8. Hemoglobin 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 virilization (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

• 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.
    
    

Hyperprolactinemia

• Pathophysiology: Elevated prolactin levels inhibit gonadotropin release, leading to anovulation.
• Clinical Features:
  • Menstrual irregularities and mild hyperandrogenic features.
  • Galactorrhea (milky nipple discharge) may be present.
  • Headache or visual field defects suggest a pituitary tumor.
• 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 signaling cause extreme hyperinsulinemia 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 estrogen symptoms: Osteoporosis, vaginal dryness.
• Investigations:
  • Low serum FSH, LH, and estradiol confirm the diagnosis.
    
    

Premature Ovarian Insufficiency (POI)

• Pathophysiology: Early depletion of ovarian follicles causes estrogen deficiency.
• Clinical Features:
  • Menstrual irregularities (oligomenorrhea, amenorrhea).
  • Signs of estrogen deficiency: Hot flashes, vaginal atrophy.
• Investigations:
  • High FSH, low estradiol 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 estrogen 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.
  
  

Short-Term Complications

• PCOS is the leading cause of anovulatory infertility.
• 50% of women with PCOS experience primary infertility, while 25% experience secondary infertility.
• Key contributing factors:
  • Oligo/anovulation, leading to irregular or absent ovulation.
  • Insulin resistance (IR) and obesity, which impair implantation and increase miscarriage risk.
  • Endometrial dysfunction, vascular alterations, and poor follicular quality affecting fertility.
• Despite reproductive challenges, ovarian reserve is often preserved, leading to a prolonged reproductive window.
• Fertility treatments:
  • Ovulation induction (letrozole, clomiphene) is first-line therapy.
  • Assisted reproductive technologies (ART), including IVF, yield comparable live birth rates to women without PCOS.
    
    

• Women with PCOS have an increased risk of pregnancy-related complications, including:
  • Gestational diabetes mellitus (GDM)
    • 3-fold higher risk than the general population.
    • Up to 22% of pregnancies in PCOS are affected.
  • Pregnancy-induced hypertension and preeclampsia
    • 3-fold higher risk, independent of obesity.
  • Preterm birth
    • Twice as likely in hyperandrogenic PCOS.
  • Cesarean section (C-section)
    • Higher rates, but data remain inconsistent.
  • Neonatal complications
    • 2-fold higher NICU admissions.
    • Increased risk of small-for-gestational-age (SGA) infants.
    • Higher perinatal mortality.
• Preconception screening for BMI, blood pressure, and OGTT is recommended to mitigate risks.
  
  

Long-Term Complications

• 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.
  
  

• 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.
  
  

• 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.
  
  

• 
  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 amenorrhea.
• Progestin therapy or combined hormonal contraception is essential for endometrial protection.
  
  

• 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.
  
  

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

• 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

• 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.
  
  

• 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

• 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.
  
  

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

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