Does the advice on metformin and myo-inositol still apply in a case of suspected functional hypothalamic amenorrhea rather than polycystic ovary syndrome (PCOS)?

Management of Functional Hypothalamic Amenorrhea vs. PCOS: Metformin and Myo-inositol

Metformin and myo-inositol are not recommended for functional hypothalamic amenorrhea (FHA), as they target insulin resistance which is not the underlying pathophysiology in FHA. 1

Differentiating FHA from PCOS

Diagnostic Features of FHA

• FHA is characterized by chronic anovulation due to suppression of the hypothalamic-pituitary-ovarian axis, typically caused by energy deficit, excessive exercise, and/or psychological stress 1
• Key diagnostic features include:
  • Low or normal gonadotropins (especially LH) 1
  • Signs of estrogen deficiency (thin endometrium) 1
  • LH:FSH ratio <1 in approximately 82% of FHA patients (versus >2 in PCOS) 1
  • Negative progestin challenge test in most cases 1
  • Presence of identifiable stressors (energy deficit, excessive exercise, psychological stress) 2

FHA with Polycystic Ovarian Morphology (FHA-PCOM)

• 41.9-46.7% of women with FHA have polycystic ovarian morphology on ultrasound 1
• Despite having PCOM, these patients still have FHA if they show:
  • Clear signs of energy deficiency
  • Estrogen deficiency
  • Typical causes of FHA 2

Appropriate Treatment Approach for FHA

Primary Treatment Strategy

• The cornerstone of FHA treatment is addressing the underlying energy deficit 2, 3
• Specific recommendations include:
  • Increasing caloric intake to achieve energy availability of ≥30 kcal/kg fat-free mass/day 3
  • Regular meals throughout the day to maintain stable glucose levels 3
  • Increasing body fat percentage (>22% may be required for menstrual function restoration) 3
  • Reducing exercise intensity or training volume 3
  • Addressing psychological stress 2, 3

Why Metformin and Myo-inositol Are Not Appropriate

• Metformin and myo-inositol are insulin-sensitizing agents that target insulin resistance, which is not the primary issue in FHA 1, 4, 5
• Myo-inositol works by improving insulin receptor activity and is effective for PCOS where insulin resistance is a key pathophysiological factor 4, 5
• Using these medications in FHA could distract from addressing the actual cause (energy deficit) and delay recovery 2

Appropriate Hormonal Management

• For bone health protection in FHA (with or without PCOM), hormone replacement therapy is recommended over combined oral contraceptives 2
• Preferably transdermal estradiol with cyclic oral progestin to protect bone health 2
• Combined oral contraceptives may inhibit IGF-1 production via first-pass hepatic metabolism, potentially decreasing osteoblastic activity 2

Important Considerations

Contraindications in FHA

• Fasting is strongly contraindicated in women with FHA as it would worsen the underlying energy deficit 2
• The Endocrine Society recommends achieving BMI ≥18.5 kg/m² before considering ovulation induction 1, 2

Long-term Health Implications

• FHA is associated with a 2-fold increased risk of fractures compared to healthy women 2
• Baseline bone mineral density measurement is recommended in those with at least 6 months of amenorrhea 2
• After recovery from FHA, many women with PCOM features see decreases in AMH, androgens, and ovarian volume 2

Monitoring Recovery

• Regular assessment of menstrual function, endometrial thickness, and hormonal parameters is essential 1
• Once spontaneous menstrual cycles of normal duration have resumed, couples should be allowed to conceive spontaneously if other fertility factors are normal 1