What is the best course of action for a 30-year-old female with a 2-year history of amenorrhea on Alysena (ethinyl estradiol and levonorgestrel), presenting with fatigue, depression, and polycystic ovary distribution on ultrasound?

Functional Hypothalamic Amenorrhea (FHA) with Polycystic Ovarian Morphology

This patient most likely has functional hypothalamic amenorrhea (FHA) with polycystic ovarian morphology (FHA-PCOM), not PCOS, and requires immediate discontinuation of combined oral contraceptives, lifestyle modification to address underlying stressors, and consideration of estrogen replacement therapy to prevent bone loss. 1

Critical Diagnostic Distinction

The combination of amenorrhea on combined oral contraceptives (Alysena contains ethinyl estradiol and levonorgestrel) with polycystic ovarian distribution creates diagnostic confusion, but several features point strongly toward FHA rather than PCOS:

• Fatigue and depression are hallmark symptoms of FHA, reflecting the underlying hypothalamic suppression and estrogen deficiency 1
• The 2-year amenorrhea while on oral contraceptives is highly atypical for PCOS, as combined oral contraceptives typically regulate cycles in PCOS patients 2, 3
• FHA-PCOM affects 41.9-46.7% of women with FHA, making polycystic ovarian morphology a common finding that does not indicate PCOS 1

Immediate Management Steps

1. Stop Combined Oral Contraceptives Immediately

Discontinue Alysena now because:

• Combined oral contraceptives suppress the hypothalamic-pituitary-ovarian axis, masking the true hormonal picture and preventing accurate diagnosis 4
• Continued suppression worsens estrogen deficiency and its complications 1
• Hormone testing is unreliable while on hormonal contraception 4

2. Identify and Address Underlying FHA Triggers

Conduct a focused assessment for the three primary causes of FHA 1:

• Energy deficit: Document dietary intake, calculate energy availability (should be >30 kcal/kg lean body mass/day) 1
• Excessive exercise: Quantify exercise frequency, intensity, and duration (working out twice daily, 6 days/week suggests hypothalamic suppression) 4
• Psychological stress: Evaluate for recent stressful life events, anxiety, depression, and stress sensitivity 1
• Weight status: Calculate BMI (FHA patients typically have low or normal BMI, whereas PCOS patients are often overweight) 1

3. Confirm Estrogen Deficiency

After 4-6 weeks off oral contraceptives, assess 1:

• Endometrial thickness on ultrasound (thin endometrium <5mm indicates estrogen deficiency) 1
• Progestin challenge test (negative withdrawal bleed in most FHA cases, though up to 60% may bleed) 1
• Serum estradiol using ultra-sensitive assay if available 1

4. Obtain Diagnostic Hormone Panel

After contraceptive washout period 1, 4:

• LH and FSH levels: Low or normal in FHA (LH:FSH ratio <1 in 82% of FHA patients), versus elevated LH:FSH ratio >2 in PCOS 1
• Total testosterone via LC-MS/MS: Should be normal or low-normal in FHA, elevated in PCOS 4
• SHBG: Higher in FHA than PCOS (lower SHBG suggests PCOS) 1
• AMH: Elevated in both FHA-PCOM and PCOS, but higher levels favor underlying PCOS 1
• TSH and prolactin: To exclude thyroid disease and hyperprolactinemia 4

Therapeutic Approach for FHA-PCOM

Address Root Causes (First-Line Treatment)

Lifestyle modification targeting the underlying trigger is the definitive treatment 1:

• If energy deficit: Increase caloric intake to achieve energy availability >30 kcal/kg lean body mass/day 1
• If excessive exercise: Reduce exercise volume by 25-50%, eliminate high-intensity training temporarily 1
• If psychological stress: Initiate cognitive behavioral therapy, stress management techniques, and consider psychiatric consultation for depression 1
• Target weight restoration: If BMI <18.5 kg/m², weight gain to BMI ≥18.5 kg/m² before considering fertility treatment 1

Estrogen Replacement Therapy

Initiate transdermal estradiol with cyclic progestin to prevent bone loss 1:

• FHA causes estrogen deficiency with risk of reduced bone mineral density 1
• Transdermal estradiol 100 mcg patch twice weekly plus cyclic micronized progesterone 200 mg days 1-12 of each month 1
• Do not use combined oral contraceptives, as they further suppress the hypothalamic-pituitary axis and mask recovery 1

Monitor for Recovery

• Spontaneous menstruation indicates recovery and should prompt reassessment 1
• Recovery typically occurs within 3-6 months if underlying triggers are adequately addressed 1
• Bone density assessment (DEXA scan) if amenorrhea persists >6 months 1

Critical Pitfalls to Avoid

• Do not diagnose PCOS based solely on amenorrhea plus polycystic ovarian morphology—up to 30% of normal women have polycystic ovarian morphology, and 41.9-46.7% of FHA patients have PCOM 1
• Do not continue combined oral contraceptives in suspected FHA—this worsens hypothalamic suppression and delays diagnosis 1, 4
• Do not use clomiphene citrate for ovulation induction in FHA—it is ineffective because the problem is hypothalamic, not ovarian 1
• Do not delay addressing underlying stressors—lifestyle modification is the definitive treatment, not hormonal manipulation 1
• Do not ignore bone health—estrogen deficiency in FHA causes accelerated bone loss requiring intervention 1

If Fertility Desired in Future

Once BMI ≥18.5 kg/m² and underlying triggers addressed 1:

• Pulsatile GnRH therapy is first-line for ovulation induction in FHA-PCOM, equally effective as in FHA without PCOM 1
• Exogenous gonadotropins are second-line but less efficient than pulsatile GnRH 1
• Allow 3-6 months for spontaneous cycle recovery before assisted reproduction 1