Ovarian Stimulation in IVF: Lecture Notes

Goals & Evolving Priorities in Ovarian Stimulation

• Safety always comes first → minimise OHSS, luteal phase defects, long‐term risks.
• Efficacy (pregnancy & live-birth rate) must stay high while achieving safety.
• Cost-effectiveness crucial in low- and middle-income settings (e.g., India): identical efficacy at lower total drug cost is preferred.
• Patient-centred convenience:
– Fewer injections (“reduce the number of pricks”).
– Fewer clinic visits via easier monitoring or long-acting formulations.
– Preference for antagonist or long-acting agents to enable a “one-daily” approach.

Basic Physiology Refresher: Why Both FSH & LH Matter

• Two-cell / two-gonadotrophin concept:
– LH → theca cells → cholesterol → progesterone → androgens.
– Androgens diffuse to granulosa; under FSH, aromatase → oestrogen.
• Early follicular phase
– Only 1\,\% of endogenous LH activity (≈ 1.2–2.5\,\text{IU}) is enough for normal follicles in young women.
– Low LH ↓ intra-ovarian androgen → ↓ FSH‐receptor expression → hypo-response.
• Exogenous LH beneficial ONLY when endogenous LH is inadequate:
– Pituitary down-regulated (long agonist protocols).
– Genetic LH/FSH receptor polymorphisms.
– Advanced age (biologically weak LH).
• Excess LH (> 5\,\text{IU} in early follicular phase) can be harmful → ↑ androgen ↑ apoptosis, especially in PCOS.

Markers to Individualise Stimulation

• Age: still the single best predictor of oocyte/embryo competence, not ovarian reserve.
• AMH (anti-Müllerian hormone):
– >3.5\,\text{ng/mL} → hyper-responder.
– 1–2\,\text{ng/mL} → “optimal–to–poor” majority (≈70 % of Indian attendees).
– <0.5\,\text{ng/mL} → very poor reserve. • AFC (antral follicle count): – <5 each ovary → genuine low reserve. – 10–20 both ovaries → normal. – >24 → hyper-response / OHSS risk.
• Combine AMH + AFC for dosing algorithms (ex: CONSORT, La Marca, or clinic-specific nomograms).

How Many Oocytes Are Really Needed? (Counselling Toolkit)

• SART/ESHRE calculators suggest:
– <32 y: \ge 6 mature oocytes yield \approx1 euploid blastocyst (80 % fertilisation ⇒ 4 Day-3 ⇒ 2 blastocysts ⇒ 1 euploid). – 35–37 y: need \approx11 MII to net 3 blastocysts → 1 euploid. – ≥40 y: \ge 20 MII to gather 5 blastocysts → 1 euploid. • Live-birth curves (HFEA 1991-2010): – Fresh-only era: implantation rose until \approx15 oocytes; >20 dropped due to supraphysiologic hormones.
– Freeze-all paradigms: cumulative live-birth plateaus at 25 oocytes (~70 %).
• Key counselling mantra: “More eggs beyond 25 per retrieval rarely raise cumulative LB >70 %.”

Stimulation Does NOT Increase Embryo Aneuploidy

• Multiple RCTs & meta-analyses (Monitored vs natural, different triggers, long vs antagonist) show:
– Chromosomal abnormality rate driven by AGE, not by gonadotrophin dose/protocol.
– P<0.05 equality in >3 000 embryos (e.g., study of 326 stimulated vs 42 unstimulated).

Protocol Choices in Daily Practice

1. Long GnRH-Agonist (Down-Regulation)

• 0.5 mg leuprolide for ≥10 d → 0.25 mg until hCG.
• Pros: tight synchrony, prevents premature LH surge.
• Cons: more injections, hypo-estrogenic SE, ↑ LH depletion → may need LH/HMG add-back.

2. GnRH-Antagonist (Flexible Preferred)

• Start antagonist (0.25 mg) when leading follicle \ge13–14\,\text{mm} or E2 >400\,\text{pg/mL}.
• Long-acting antagonist (e.g., degarelix) under study; benefits = single shot, near-zero premature surge.

3. Progestin-Primed (PPOS)

• Oral medroxy-progesterone acetate (MPA) or dydrogesterone blocks LH surge; lab must freeze-all.
• Attractive for cost (no antagonist) & convenience; evidence good for normal & high responders.

4. Flair / Ultra-short, DuoStim, Shanghai etc.

• Limited evidence; cancellation ~60 % in author’s experience; reserve for fertility preservation.

Starting FSH Doses (Monotherapy)

• Large RCTs: 150 IU vs 225 IU:
– More oocytes with 225 IU, but OHSS ↑, no LBR gain.
• Practical algorithm (normal BMI 20–30 kg/m²):

\begin{array}{ll}
\text{Hyper-responders (AMH>3.6 / AFC>20)} & 150\,\text{IU} \
\text{Normal responders (AMH 1–3, AFC 10–20)} & 150–225\,\text{IU} \
\text{Low responders (AMH<1 / AFC<5)} & 300–375\,\text{IU}
\end{array}

Combination Therapy (FSH + LH/HMG)

• Rationale: provide LH activity where endogenous LH low / polymorphism / age.
• Author’s mix-therapy rules:
– Add 75 IU HMG to ALL cycles in POSEIDON 1 (young expected poor).
– Group-2 (>35 y, normal AMH) → 225 FSH + 75 HMG; if hyper-responder need 300 FSH + 150 FSH? Actually author uses 300 + 150.
– Group-3 (<35 y, AMH<1) → 300–375 FSH + 75 HMG. – Group-4 (>35 y, AMH<1) → 225 FSH + 75 HMG ± step-up.

POSEIDON Concept Recap

• Unexpected vs expected poor & sub-optimal responders differentiated by age (<35/≥35) and ovarian reserve (AFC≥5? AMH≥1?).
• Aim: produce ≥1 euploid blastocyst → define target oocyte number & adjust dose.

Synchronisation / Pretreatment Options

• Estradiol valerate 2 mg bd × 10 d (author’s favourite) for group 3/4 before antagonist start.
• OCP for 14–21 d + pill-free gap 5–7 d equally effective per Cochrane.
• Short agonist “micro-flare” shown inferior (fewer oocytes) → rarely used now.

Trigger & OHSS Prevention

• Agonist trigger (0.2 mg triptorelin) in antagonist cycles eliminates early OHSS.
• Dual trigger (0.2 mg triptorelin + 1 000–1 500 IU hCG) when ≥3 matured follicles still keeps OHSS low but supports luteal phase.

DuoStim vs Random-Start

• Author preference: random-start luteal stimulation (second pick-up in same cycle only if opportunity) > formal “Shanghai” DuoStim.
• Reported cancellation ~60 % with DuoStim in their data; reserve for urgent fertility preservation.

Take-Home Numerical Nuggets

• Endogenous LH physiologic window: 1.2–2.5\,\text{IU} (adequate) vs >5\,\text{IU} (harmful early).
• One baby requires:
– \ge6 mature oocytes if <32 y.
– \ge11 if 35–37 y.
– \ge20 if ≥40 y.
• Cumulative LB plateaus once retrieval fetches \approx25 oocytes (freeze-all era).
• First embryo transfer delivers LB ≈70 %; second adds 20 %; third brings cumulative ≈92–95 %.

Practical Checklist for Modern ART Clinician

  1. Measure AMH + AFC + weight at baseline.

  2. Assign POSEIDON group → set oocyte target.

  3. Choose antagonist protocol for most; agonist long only if historical preference.

  4. Pretreat with estradiol 10 d for low reserve; use OCP or nothing for others.

  5. Start FSH per algorithm; add 75 IU HMG if age >35 or suspected LH polymorphism.

  6. Begin antagonist at 13–14 mm or day 6.

  7. Trigger with GnRH-a when ≥3 follicles ≥17 mm; add low hCG if freeze-all not planned and OHSS risk low.

  8. Elect freeze-all when ≥10–12 oocytes or P >1.5 ng/mL.

  9. Counsel that stimulation does not raise aneuploidy; age does.

  10. Target ≤25 oocytes per retrieval; beyond that, risk ↑ with no LB gain.

Key Messages

• “One-daily, one-stimulation” dream achievable via long-acting antagonists or oral progestins.
• LH is a potent but ‘notorious’ hormone—use only where endogenous LH truly deficient.
• Individualisation = combine physiology (FSH/LH), markers (AMH/AFC), and patient goals (cost, time, safety).
• Synchronisation, not double-stimulation, is cornerstone for poor reserve.
• Ultimately: Safety + Efficacy + Convenience + Cost → optimise protocol choice & dose.