In a premenopausal woman who received a 3.75 mg leuprolide depot on cycle day 21 and presents on day 3 of menses with bilateral simple ovarian cysts measuring approximately 21 cm total, what are the possible causes and how should this be managed?

Management of Bilateral Ovarian Cysts Following Leuprolide Administration

Most Likely Cause

These bilateral simple cysts measuring 21 cm are almost certainly GnRH agonist-induced functional ovarian cysts resulting from the initial "flare effect" of leuprolide administered on cycle day 21. 1, 2

The timing and presentation are classic for this phenomenon:

• Leuprolide causes an initial surge in FSH/LH release before achieving down-regulation, leading to ovarian stimulation and cyst formation in the first 2 weeks after administration 1, 3
• In patients with polycystic ovarian syndrome (PCOS), the incidence of follicular cysts ≥20 mm following GnRH agonist administration is approximately 15.5%, though this can occur in any premenopausal woman 2
• The cysts typically develop within 2 weeks of GnRH agonist therapy and are associated with elevated estradiol levels 1

Immediate Diagnostic Steps

Measure serum estradiol (E2) levels immediately to determine whether these are functional hormone-producing cysts or simple non-functional cysts:

• If E2 > 35 pg/mL: These are functional cysts producing estrogen and require waiting for spontaneous regression 2
• If E2 < 35 pg/mL: These represent down-regulated cysts that can be monitored expectantly 2

Perform transvaginal ultrasound to confirm the cysts are truly simple (anechoic, thin-walled, no solid components) and not complex masses 4

Management Algorithm

For Functional Cysts (E2 > 35 pg/mL):

• Expectant management is the standard approach, as these cysts resolve spontaneously in most cases 1, 2
• Repeat E2 levels every 5-7 days until down-regulation is achieved (E2 < 35 pg/mL), which typically occurs within 5.8 ± 2.9 days 2
• Repeat ultrasound in 2-4 weeks to document resolution 1
• Do NOT aspirate or surgically intervene unless there are signs of torsion, rupture, or hemorrhage 1

For Non-Functional Cysts (E2 < 35 pg/mL):

• These cysts do not contraindicate continuation of treatment if the patient is undergoing fertility therapy 2
• Monitor with serial ultrasounds every 2-4 weeks 2
• Spontaneous resolution is expected 1

Critical Clinical Pitfalls to Avoid

Do NOT administer HCG or any additional gonadotropins while functional cysts are present with elevated E2, as this can worsen ovarian hyperstimulation 1

Do NOT assume malignancy based on size alone - GnRH agonist-induced cysts can be quite large (mean size 42 ± 7.3 mm in functional cysts) but are benign 2

Do NOT perform surgical intervention unless there is:

• Acute abdomen suggesting torsion or rupture 1
• Failure to resolve after 6-8 weeks 5
• Solid components on ultrasound suggesting neoplasm 4

When to Consider Alternative Diagnoses

Consider gonadotroph adenoma if:

• Cysts persist beyond 8 weeks 6
• Patient has chronic oligomenorrhea/amenorrhea with persistently elevated E2 6
• Dramatic worsening of hyperstimulation after leuprolide rather than improvement 6
• In such cases, obtain MRI of the pituitary and measure FSH, LH, and prolactin levels 6

Prevention in Future Cycles

If this patient requires additional GnRH agonist therapy:

• Consider pretreatment with oral contraceptives for 1-2 months before GnRH agonist administration to suppress baseline ovarian activity 1
• Use the "long protocol" with earlier cycle initiation (cycle day 1-3) rather than mid-luteal administration 1
• Monitor E2 levels on day 14-15 after GnRH agonist administration in all subsequent cycles 2

Expected Timeline for Resolution

Most GnRH agonist-induced ovarian cysts resolve spontaneously within 2-6 weeks without intervention 1, 2

Menses typically resume normally after cyst resolution 5