Oral Ovulation Induction Agents
| Feature | Clomiphene Citrate | Letrozole | Clinical Implication |
|---|
| Mechanism | Blocks hypothalamic estrogen receptor → perceived estrogen deficiency → FSH rise | Inhibits aromatase → transient estrogen drop → FSH rise | Same end result (FSH rise) by different routes |
| Estrogen receptor status | Blocked throughout body | Intact — free to respond to follicular estradiol | Letrozole allows normal endometrial/cervical response |
| Endometrium | Thin, poorly proliferating (anti-estrogenic) | Normal proliferation once follicle produces estradiol | Better implantation environment with letrozole |
| Cervical mucus | Viscous, impermeable | Normal permeability | Better sperm penetration with letrozole |
| Multiple gestation | Higher (~8–13%) | Lower (~3–7%) | Intact feedback limits excess recruitment with letrozole |
| Preferred use | Second-line (some non-PCOS cases) | First-line for PCOS ovulation induction | Letrozole standard of care in PCOS per guidelines |
Gonadotropin Preparations
WHO Group I — Hypogonadotropic Hypogonadism
Requires FSH + LH
- Both FSH and LH absent or minimal
- FSH alone fails: no LH → no theca androgen production → no aromatase substrate
- Treatment: human menopausal gonadotropin (FSH + LH activity) OR recombinant FSH + recombinant LH
- Two-cell model principle: LH drives theca androgens; FSH converts them to estradiol
WHO Group II — Normal Gonadotropins (e.g. PCOS)
FSH Alone Sufficient
- Endogenous LH present — theca androgen production intact
- Recombinant FSH (follitropin alfa/beta) or urinary FSH appropriate
- Recombinant preparations: consistent potency, subcutaneous pen device
- Urinary preparations: lower cost, generally equivalent live birth rates
ART Stimulation Protocols
Older / Longer Protocol
Long GnRH Agonist Protocol
- GnRH agonist started mid-luteal phase → full pituitary downregulation (10–14 days)
- Then begin FSH stimulation; continue agonist throughout
- Total duration: ~4–6 weeks
- Cannot use GnRH agonist trigger (pituitary downregulated)
- Higher OHSS risk in high responders
Preferred — Shorter Protocol
GnRH Antagonist Protocol
- Start FSH stimulation at cycle day 1–2
- Add antagonist when leading follicle ~14 mm (day 5–6)
- Immediate blockade — no flare
- Total duration: ~10–14 days
- Enables GnRH agonist trigger → near-zero severe OHSS
- Preferred for PCOS, high AMH, most patients today
OHSS — Pathophysiology & Prevention
Pathophysiology
VEGF → Vascular Permeability → Third-Space Shift
- hCG → sustained LH receptor stimulation on multiple corpora lutea
- Multiple corpora lutea → massive VEGF production
- VEGF → capillary permeability increase → ascites, pleural effusion
- Intravascular hypovolemia + hemoconcentration → VTE risk
- Early OHSS: hCG trigger (days 3–9)
- Late OHSS: embryonic hCG (week 4–6) — more severe, more prolonged
Prevention & Management
Hierarchy of Interventions
- Best prevention: GnRH agonist trigger (antagonist cycle) + freeze-all
- Adjunct: cabergoline (dopamine agonist) modulates VEGF receptor signaling
- Low FSH starting dose in high-AMH/PCOS patients
- Severe OHSS management: IV fluids, paracentesis, anticoagulation (LMWH)
- Thromboembolism: leading preventable cause of OHSS mortality
Core Rule — hCG Drives OHSS
Human chorionic gonadotropin triggers OHSS by providing sustained LH receptor stimulation to multiple corpora lutea → massive VEGF production. GnRH agonist trigger replaces this with a brief endogenous LH surge → near-zero severe OHSS. Freeze-all prevents late OHSS from embryonic hCG. Anticoagulation prevents thromboembolism in severe disease.