Gynaecology Pg No 91 -100

Pathophysiology of PCOS

• Polycystic Ovarian Syndrome (PCOS) is a group of symptoms with varying presentations and complex pathophysiology.

• It used to be called Stein-Leventhal syndrome.

Etiological Factors

• Environmental Factors: Not fully understood.
• Genetic Factors:
  • Complex genetic trait.
  • Chromosome no. 2.
  • Chromosome no. 9.
• Lifestyle Factors: Can contribute to the condition.

Excessive androgen production:

• Ovaries are the main source of androgens.
• Adrenal glands contribute a minor amount (increased DHEA-S).

Pathophysiology:

• Normal androgen levels in females: Not specified in the text.

• Androgen levels in females with PCOS: Increased testosterone levels.

• Defect in Folliculogenesis: Ovarian follicles fail to mature properly leading to anovulation.

• Defect in Insulin action: Insulin resistance is common in PCOS.

• Defect in gonadotropin secretion & action: Disruption in the secretion and action of gonadotropins (LH, FSH) contributes to anovulation.

• Obesity: Present in 40-80% of patients with PCOS but not a defining feature.

Rotterdam Criteria:

• Increased androgen levels:

  • Biochemically: Elevated serum testosterone levels (Hyperandrogenemia).
  • Clinically: Evidence of hyperandrogenism such as hirsutism.

• Ovulatory dysfunction: Secondary amenorrhea or oligomenorrhea (irregular menstrual cycles).

• Polycystic appearance of ovaries:

  • On ultrasound (USG): 12 or more follicles, 2-9 mm in size, in one or both ovaries.
  • Ovarian volume ≥ 10 cc.

• Any two of the above criteria: Provisional diagnosis of PCOS.

Consequences of PCOS:

• Short-Term Complications:

  • Menstrual irregularities.
  • Infertility.
  • Hirsutism.
  • Alopecia.
  • Insulin resistance.

• Long-Term Consequences:

  • Metabolic: Dyslipidemia, diabetes, heart disease.
  • Endocrine: Endometrial cancer (due to increased estrogen in obese females).
  • Other: Sleep apnea, ovarian cancer, non-alcoholic steatohepatitis (NASH) (due to obesity).

Obstetric Complications:

• Infertility, which is often reversible with treatment.

• Increased risk of miscarriage due to low progesterone levels.

• Gestational diabetes due to insulin resistance.

• Pregnancy-induced hypertension (PIH).

• Stillbirth.

• Psychological: Anxiety and depression.

• Metabolic: Metabolic syndrome.

HAIRAN Syndrome:

• Hyper Androgenism
• Insulin Resistance
• Acanthosis Nigricans

Hormonal Profile in PCOS:

• Unchanged: Follicle-stimulating hormone (FSH), estradiol, prolactin and Thyroid-stimulating hormone (TSH).

• Increased: Serum testosterone, DHEA-S, low-density lipoprotein (LDL), anti-müllerian hormone (AMH) and luteinizing hormone (LH) – especially in obese females.

• Affected by androgens and insulin: High-density lipoprotein (HDL), serum progesterone, sex hormone-binding globulin (SHBG).

Anovulation in PCOS:

• Folliculotoxicity of androgens: Androgens damage developing follicles.

• Absence of LH surge: Prevents ovulation.

Management of PCOS:

• First Line: Lifestyle modification, including weight loss, can improve symptoms and lead to spontaneous ovulation in 5-10% of cases.

• Hyperprolactinemia: Should be ruled out in all patients with PCOS as it can cause menstrual irregularities.

Management of Menstrual Irregularities and Hirsutism:

• Menstrual Irregularities:

  • Pubertal/Young Females:

    • Irregular cycles due to anovulation – common until 3 years after menarche.
    • Cycle length: 21-45 days.
    • ≥ 90 days cycle length or onset of menstruation 3 years after menarche needs evaluation.

  • First Line Management:

    • Oral contraceptive pills (OCPs) (very low-dose) – ethinyl estradiol ≤ 20 mcg.
    • Progesterone (3rd/4th generation) – MALA-D/MALA-N may be used.

• Hirsutism:

  • First Line Management:

    • Oral contraceptive pills (OCPs) – low dose and 3rd/4th generation progesterone.
    • Duration: 6 months.
    • Mechanism of Action:
      • Estrogen and progesterone suppress LH and FSH production = decreased androgen production.
      • Estrogen increases sex hormone binding globulin (SHBG) = decreased free testosterone.

  • If OCPs fail: Add spironolactone.

Noteworthy points:

• Spironolactone: Anti-androgenic medication. Use is contraindicated in pregnancy (potential for ambiguous genitalia in male fetus).

• Other drugs used to manage hirsutism:

  • Cyproterone acetate.
  • Flutamide.
  • Finasteride.
  • Metformin (may be slightly effective).
  • Eflornithine (topical medication).
  • Last resort: Continuous GnRH and androgen.

• Ketoconazole: Can cause hirsutism as a side effect.

• Laser Hair Removal: Additional modality for managing hirsutism.

Hirsutism vs. Virilization:

• Hirsutism: Excessive growth of thick, coarse terminal hair in a male pattern. Common sites: lips, chin, periareolar area, chest.
• Virilization: Female acquires male sexual characteristics.

Defect in Gonadotropin Secretion:

• PCOS: Increased pulse frequency of GnRH, leading to increased LH secretion by the pituitary gland. Increased LH levels throughout the cycle.

• Theca cell hyperplasia: Contributes to increased LH levels.

• FSH: LH Ratio:

  • PCOS: 1:2 or 1:3.
  • Normal: Around 1:1.

• Absence of LH surge: Leads to anovulation.

Note:

• Most common cause of hirsutism in young females: PCOS.

• Most common cause of rapid onset hirsutism in young females: Ovarian tumor.

• Distinguishing PCOS from late-onset CAH:

  • 17-OH Progesterone levels (screening test for CAH):
    • ≥ 800 ng: Confirms CAH.
  • ACTH Stimulation test (diagnostic).

• American and European Societies criteria for PCOS: ≥ 20 follicles, 2-9 mm in size, on ultrasound.

• Ovaries can appear normal in PCOS.

Additional Notes:

• It is crucial to evaluate LH and FSH levels on day 2/3 of the menstrual cycle to accurately assess hormonal profiles.

• Menometrorrhagia (irregular bleeding): Can occur in obese PCOS patients due to elevated estrogen levels.

• Endometrial biopsy is indicated in reproductive-age females with PCOS and an endometrial thickness ≥ 12 mm.

Explore the complex pathophysiology of Polycystic Ovarian Syndrome (PCOS) in this quiz. Learn about the etiological factors, including genetic, environmental, and lifestyle influences. Understand the hormonal imbalances and defects in folliculogenesis associated with PCOS.