What causes a patient to be anovulatory?

Common Causes of Anovulation in Women

Polycystic ovary syndrome (PCOS) is the most common cause of anovulation in women of reproductive age, affecting 4-6% of the general population and up to 25% in women with temporal lobe epilepsy. 1

Anovulation occurs when the ovaries fail to release an egg during the menstrual cycle, leading to infertility and menstrual irregularities. Understanding the underlying causes is essential for proper diagnosis and treatment.

Major Causes of Anovulation

1. Polycystic Ovary Syndrome (PCOS)

• Pathophysiology: Characterized by hyperandrogenic chronic anovulation 1
• Hormonal changes:
  • Accelerated pulsatile GnRH secretion
  • Insulin resistance and hyperinsulinemia
  • Hypersecretion of luteinizing hormone (LH)
  • Elevated testosterone levels
  • LH/FSH ratio often >2 1
• Clinical features:
  • Menstrual irregularities (oligomenorrhea or amenorrhea)
  • Hirsutism
  • Acne
  • Obesity or weight gain
  • Polycystic ovaries on ultrasound (>10 peripheral cysts)

2. Functional Hypothalamic Amenorrhea (FHA)

• Pathophysiology: Functional reduction in pulsatile GnRH secretion 1
• Triggers:
  • Psychological stress
  • Excessive exercise
  • Energy deficit/weight loss
  • Psychological disorders 1
• Hormonal profile:
  • Reduced LH and sometimes FSH levels
  • Low mid-luteal progesterone (<6 nmol/l) 1

3. Hyperprolactinemia

• Mechanism: Elevated prolactin inhibits GnRH pulsatility
• Causes:
  • Pituitary tumors
  • Medications
  • Hypothyroidism
  • Stress
• Clinical features:
  • Galactorrhea
  • Amenorrhea
  • Infertility 1

4. Thyroid Dysfunction

• Both hypothyroidism and hyperthyroidism can disrupt ovulation
• Affects the metabolism of sex hormones and their binding proteins 1

5. Life Stage-Related Causes

• Adolescence: Immature hypothalamic-pituitary-ovarian axis
• Perimenopause: Declining ovarian function
• Lactation: Elevated prolactin suppresses ovulation 1

6. Other Endocrine Disorders

• Primary pituitary disease
• Premature ovarian failure
• Congenital adrenal hyperplasia 1

7. Iatrogenic/Medication-Related

• Medications that can cause anovulation:
  • Antipsychotics
  • Antiepileptics (especially valproate) 1
  • Chemotherapy
  • Hormonal contraceptives

8. Environmental and Lifestyle Factors

• Environmental pollutants: Heavy metals, endocrine disruptors 2
• Lifestyle factors:
  • Obesity or underweight
  • Extreme exercise
  • Poor nutrition
  • Chronic stress 2

Diagnostic Approach

Key Laboratory Tests

• Hormonal assessment:
  • LH and FSH levels (day 3-6 of cycle)
  • Progesterone (mid-luteal phase)
  • Testosterone
  • Prolactin (morning, resting)
  • Thyroid function tests 1
• Metabolic assessment:
  • Fasting glucose and insulin
  • Glucose/insulin ratio 1

Imaging

• Pelvic ultrasound: To identify polycystic ovaries or other structural abnormalities
• Pituitary MRI: If hyperprolactinemia is detected 1

Treatment Considerations

Treatment should target the underlying cause of anovulation:

1. For PCOS:

   • Weight loss for overweight/obese patients
   • Clomiphene citrate as first-line ovulation-inducing agent
   • Metformin for insulin resistance
   • Low-dose FSH therapy if clomiphene fails 3

2. For Functional Hypothalamic Amenorrhea:

   • Address underlying stressors
   • Weight gain if underweight
   • Pulsatile GnRH therapy 1

3. For Hyperprolactinemia:

   • Dopamine agonists (e.g., bromocriptine, cabergoline) 4

4. For Thyroid Dysfunction:

   • Appropriate thyroid hormone replacement or suppression

Clinical Pitfalls and Caveats

1. Diagnostic challenges: FHA with polycystic ovarian morphology (FHA-PCOM) can be mistaken for PCOS phenotype D (PCOM and oligo/anovulation without hyperandrogenism) 1

2. Medication effects: Always review medications, especially antiepileptics like valproate which can contribute to reproductive endocrine disorders 1

3. Weight considerations: Both underweight and obesity can cause anovulation through different mechanisms

4. Incomplete evaluation: Failure to measure mid-luteal progesterone levels may miss anovulation in women with regular bleeding patterns

5. Long-term health risks: Chronic anovulation in PCOS is associated with increased risk of endometrial hyperplasia and cancer due to unopposed estrogen 5

By identifying the specific cause of anovulation, clinicians can implement targeted treatments to restore ovulatory function, improve fertility outcomes, and reduce long-term health risks.