What is the treatment approach for a female patient of reproductive age with amenorrhea and low Follicle-Stimulating Hormone (FSH) levels?

Treatment Approach for Amenorrhea with Low FSH

In a patient with amenorrhea and low FSH, the primary treatment goal is to address the underlying hypothalamic or pituitary dysfunction by correcting energy deficits, reducing excessive exercise, and managing stress—with estrogen replacement therapy indicated if amenorrhea persists beyond 6 months to prevent bone loss and cardiovascular complications. 1, 2

Diagnostic Confirmation and Etiology Assessment

Low FSH with amenorrhea indicates hypogonadotropic hypogonadism, which can result from either hypothalamic dysfunction (functional hypothalamic amenorrhea, FHA) or pituitary failure 1, 3. The distinction is critical for treatment:

• Check LH/FSH ratio: A ratio <1 is seen in approximately 82% of FHA cases, while pituitary failure typically shows both hormones suppressed 1, 3
• Measure estradiol levels: Low estradiol (<30 pg/mL) confirms hypoestrogenism and helps differentiate FHA from other causes 1, 3
• Assess endometrial thickness via ultrasound: Thin endometrium (<5 mm) indicates estrogen deficiency and supports FHA diagnosis 1, 3
• Evaluate for causative factors: Document weight changes, BMI (target ≥18.5 kg/m²), eating patterns, exercise volume (>10 hours/week of intense training is concerning), and psychological stressors 1, 2

Primary Treatment Strategy: Address Underlying Causes

For FHA, lifestyle modification is first-line therapy and should be attempted before hormonal intervention 2:

• Increase energy availability: Target >30 kcal/kg fat-free mass/day through nutritional counseling with a sports dietitian 2
• Reduce excessive exercise: Decrease training volume and intensity if the patient exercises >10 hours/week 2
• Address psychological stressors: Provide counseling for stress management and screen for eating disorders using direct questioning about specific behaviors 2
• Weight restoration: Ensure BMI reaches ≥18.5 kg/m² before considering ovulation induction if fertility is desired 1

Recovery timeline: Menstrual function may take >6 months to resume despite addressing energy deficits, so patience and continued monitoring are essential 2

Hormonal Replacement Therapy

If amenorrhea persists >6 months despite lifestyle modifications, initiate estrogen replacement to prevent long-term complications 1, 2:

• Preferred regimen: Transdermal estradiol 100 μg patch twice weekly with cyclic micronized progesterone 200 mg for 12 days/month 2
• Rationale: This physiologic estrogen replacement protects bone mineral density more effectively than oral contraceptives and addresses the underlying hypoestrogenism 2
• Avoid oral contraceptives as first-line: Combined oral contraceptives mask the problem without correcting the underlying energy deficit and provide false reassurance; they do not protect bone health as effectively as physiologic estrogen 2

Critical indication for bone health monitoring: Obtain DXA scan for bone mineral density if amenorrhea extends beyond 6 months, regardless of age, as prolonged hypoestrogenism significantly increases osteoporosis risk 1, 2

Fertility Treatment (If Pregnancy Desired)

For patients with hypogonadotropic hypogonadism desiring pregnancy, pulsatile GnRH therapy is the most effective treatment 2, 4:

• Pulsatile GnRH: Achieves ovulation rates of 80.8% and ongoing pregnancy rates of 70% per patient in FHA 2
• Alternative: Exogenous gonadotropins can be used if pulsatile GnRH is unavailable, though slightly less effective (77.7% ovulation rate, 63% pregnancy rate) 2
• Prerequisite: Ensure BMI ≥18.5 kg/m² and spontaneous menstrual cycles have resumed before offering ovulation induction 1
• Avoid clomiphene citrate: Not recommended as first-line for FHA due to uncertain efficacy and lack of evidence for improved pregnancy rates 1

Pituitary Failure Considerations

If pituitary failure is suspected (both FSH and LH very low, no response to lifestyle modifications):

• Check prolactin and TSH: Exclude hyperprolactinemia and thyroid dysfunction as reversible causes 3, 5
• Consider MRI of pituitary: Rule out pituitary adenoma or structural abnormalities if clinical features suggest pituitary pathology (headaches, visual changes, galactorrhea) 2, 6
• Treatment: Requires exogenous gonadotropins for ovulation induction rather than pulsatile GnRH, as the pituitary cannot respond 4

Long-Term Monitoring and Complication Prevention

Patients with FHA face significant health risks that require ongoing surveillance 2:

• Bone health: FHA is associated with 2-fold increased risk of fractures; repeat DXA scanning every 1-2 years if amenorrhea persists 2
• Cardiovascular risk: About one-third of FHA patients show endothelial dysfunction, indicating increased cardiovascular disease risk 2
• Psychological support: Screen for eating disorders at every visit, as adolescents frequently minimize symptoms 2

Common Pitfalls to Avoid

• Do not assume amenorrhea in athletes or stressed patients is benign: Other pathology (pituitary adenoma, ovarian tumor) must be excluded even when clinical picture suggests FHA 2
• Do not prescribe oral contraceptives as first-line therapy: This masks the underlying problem and does not address energy deficits or protect bone health adequately 2
• Do not delay bone density assessment: DXA scanning is indicated if amenorrhea extends beyond 6 months, regardless of patient age 2
• Do not overlook eating disorders: Direct questioning about restrictive eating, purging behaviors, and body image concerns is necessary 2

Referral Indications

Refer to endocrinology or gynecology if 1, 2:

• Primary care provider lacks experience managing FHA 2
• Persistently abnormal hormone levels despite treatment 1
• Signs of pituitary pathology (headaches, visual changes, galactorrhea) 2
• Eating disorder requiring multidisciplinary team management 2
• Patient desires fertility and requires ovulation induction 2