What is the best stimulation protocol for in vitro fertilization (IVF) in a young patient with low Anti-Müllerian Hormone (AMH) levels?

Optimal IVF Stimulation Protocol for Young Patients with Low AMH

For young patients with low AMH undergoing IVF, use a GnRH antagonist protocol with individualized FSH dosing based on AMH levels, starting with higher doses (150 IU/day or corifollitropin for AMH <12 pmol/L) rather than standard protocols, as this approach maintains comparable pregnancy rates while optimizing oocyte yield in this challenging population. 1, 2

Understanding the Clinical Context

Low AMH in young patients represents a distinct clinical scenario that requires careful interpretation:

• AMH loses predictive specificity in extreme low ranges, especially in young patients - women under 35 years with extremely low AMH (≤0.4 ng/mL) can still achieve clinical pregnancy rates of 27%, compared to 41% in normal AMH patients 3
• Age trumps AMH in young patients - the ovarian reserve marker should be interpreted cautiously in women under 25 years, as AMH fluctuates significantly throughout the menstrual cycle in this age group 4
• Low AMH indicates incipient ovarian insufficiency but not necessarily treatment futility - there is a wide range of AMH levels in healthy young women, and low values suggest reduced but not absent follicle pool 4

Recommended Stimulation Protocol Algorithm

First-Line Approach: GnRH Antagonist with AMH-Based FSH Dosing

For AMH <12 pmol/L (approximately <1.7 ng/mL):

• Use maximal stimulation with corifollitropin 100-150 mcg (based on body weight <60 kg vs ≥60 kg) as the initial gonadotropin 2
• This reduces the proportion of poor responders from 47% to 24% compared to standard 150 IU/day dosing 2
• Start GnRH antagonist (ganirelix 250 mcg or cetrorelix 250 mcg) on stimulation day 5-6 5, 6

For AMH 12-24 pmol/L (approximately 1.7-3.4 ng/mL):

• Use recombinant FSH 150 IU/day throughout stimulation 2
• Initiate GnRH antagonist on day 5-6 of gonadotropin administration 1

Critical adjustment: Do NOT use 100 IU/day FSH dosing even for higher AMH values within the low range, as this leads to 38% unintended low oocyte retrieval (<5 oocytes) 2

Protocol Execution Details

Stimulation initiation:

• Begin recombinant FSH on cycle day 2-3 at the doses specified above 5, 6
• Random-start protocols can be initiated at any point in the menstrual cycle if time-sensitive treatment is needed, without waiting for specific cycle days 1

GnRH antagonist administration:

• Start ganirelix 250 mcg or cetrorelix 250 mcg subcutaneously on stimulation day 5-6 5, 6
• Continue daily until hCG trigger day 5, 6
• This prevents premature LH surge (occurs in only 0-1.9% of cycles) while maintaining adequate estradiol levels 5, 6

Monitoring and trigger:

• Continue both FSH and GnRH antagonist until at least 3 follicles reach ≥17 mm diameter 5
• Trigger with hCG when adequate follicular development achieved 5, 6
• Median treatment duration is 5 days of GnRH antagonist (range 1-15 days) 6

Alternative Protocol: Mild Stimulation with Clomiphene Citrate

For patients prioritizing cost reduction or medication burden:

• Use clomiphene citrate with low-dose gonadotropins plus GnRH antagonist (CC/Gn/GnRH-ant protocol) 7
• This achieves comparable implantation, clinical pregnancy, and ongoing pregnancy rates to high-dose long protocols in poor responders 7
• Significantly reduces gonadotropin consumption and treatment duration 7
• Results in fewer oocytes retrieved but maintains equivalent final pregnancy outcomes 7

However, this approach has trade-offs:

• Higher cycle cancellation rates due to lack of ovarian response compared to high-dose protocols 7
• Fewer total oocytes and embryos available for cryopreservation 7

Emerging Option: In Vitro Maturation (IVM)

Consider IVM for urgent cases or repeated poor response:

• IVM achieves 59.7% oocyte maturation rates with comparable fertilization and embryo development to standard protocols 4, 1
• Two approaches available: transvaginal retrieval IVM (OPU-IVM) with 73-82% maturation rates, or ovarian tissue oocyte IVM (OTO-IVM) with 57-70% maturation rates 4
• Particularly valuable when time constraints prevent standard ovarian stimulation 1
• Can be performed without extensive hormonal stimulation, reducing medication burden 1

Critical Pitfalls to Avoid

Dosing errors:

• Do not use 100 IU/day FSH in young patients with low AMH, even if AMH is in the "higher" range of low values - this leads to excessive poor response rates 2
• Avoid under-stimulation based solely on AMH without considering age and clinical context 3

Protocol selection mistakes:

• Do not exclude young patients from IVF based on low AMH alone - pregnancy is still achievable, especially in women <35 years 3
• Avoid GnRH agonist long protocols in poor responders, as GnRH antagonist protocols demonstrate better outcomes in this population 8

Monitoring oversights:

• Do not rely on AMH alone for treatment decisions in women under 25 years due to significant menstrual cycle fluctuations 4
• Ensure baseline FSH and estradiol assessment to rule out premature ovarian insufficiency before proceeding 4, 9

Expected Outcomes and Counseling

Realistic expectations:

• Target oocyte retrieval of 5-14 oocytes optimizes pregnancy rates while minimizing OHSS risk 1, 10
• Young patients with extremely low AMH can achieve 17-27% clinical pregnancy rates depending on age 3
• Cumulative live birth rates of 32-35% per started cycle are achievable with appropriate protocols 2

Important counseling points:

• Low AMH does not preclude pregnancy but indicates reduced ovarian reserve requiring optimized stimulation 4
• Multiple cycles may be necessary to achieve pregnancy 3
• Consider fertility preservation counseling given risk of further ovarian reserve decline 4, 9
• Contraception remains necessary even with low AMH, as spontaneous pregnancy can occur 9