What treatment approach is recommended for women with FSH (Follicle-Stimulating Hormone) receptor polymorphism who are poor responders to fertility treatments?

FSH Receptor Polymorphism in Poor Responders

For women with FSH receptor polymorphisms who are poor responders to fertility treatment, the primary strategy is to maximize oocyte retrieval through alternative ovarian stimulation protocols (natural cycle, minimal stimulation, or luteal phase stimulation) rather than standard protocols, while recognizing that these patients require higher FSH doses and have inherently reduced receptor sensitivity that cannot be overcome by genetic testing alone. 1

Understanding the Genetic Basis

The FSH receptor gene polymorphisms, particularly at positions 680 (Asn680Ser) and 307 (Thr307Ala), create discrete receptor variants that affect ovarian response to exogenous FSH stimulation. 2, 3

• The Ser680/Ser680 genotype is associated with poor ovarian response, with 36% of poor responders carrying this homozygous variant and a 21% cycle cancellation rate compared to other genotypes. 4
• The AA genotype at position 307 combined with Asn/Asn at position 680 (A/A-Asn/Asn) carries the highest risk, with 75% of women with this combination being poor responders (odds ratio 7.92). 3
• These polymorphisms are nearly completely linked in Chinese populations (D'=0.95, r²=0.84), meaning testing one position effectively predicts the other. 2
• Women with AA and SS genotypes have significantly higher basal FSH levels (7.38±2.07 vs 6.34±1.75 IU/L for other genotypes), indicating baseline ovarian dysfunction. 2

Critical Limitation of Genetic Testing

FSHR gene polymorphisms are NOT decisive factors in poor response—low ovarian reserve measured by AMH is far more crucial. 5

• Low serum AMH values were observed in 75% of poor responders, regardless of FSHR genotype. 5
• FSHR variants including Asn680Ser, Ala189Val, Thr449Ile, and Ile160Thr did not prove to be decisive factors in treatment outcomes. 5
• Functional FSHR splicing variants (exon deletions and intron insertions) affecting the extracellular ligand-binding domain show markedly decreased cAMP activation and may represent more significant genetic causes of poor response than common polymorphisms. 6

Ovarian Stimulation Protocol Selection

For poor responders with confirmed or suspected FSHR polymorphisms, alternative protocols should be tried when standard stimulation fails to retrieve oocytes. 1

Standard Approach First

• Routine ovarian stimulation is recommended initially for patients with acceptable ovarian reserve, recognizing individual differences in response exist. 1
• The goal is to increase the number of oocytes retrieved and obtain more embryos for selection. 1

Alternative Protocols When Standard Fails

• Natural cycle retrieval can be attempted when oocyte collection fails after routine stimulation. 1
• Minimal ovarian stimulation represents a middle ground approach. 1
• Luteal phase stimulation offers an unconventional timing option. 1

Critical Patient Counseling

Patients must be informed of the risk of low oocyte numbers, having no transferable embryos, or complete treatment failure when using alternative protocols. 1

FSH Dosing Considerations

Women with Ser680/Ser680 or AA genotypes require longer stimulation periods and higher FSH doses, though the clinical benefit of dose escalation remains uncertain given the underlying receptor dysfunction. 2, 4

• Days for ovulation induction are slightly longer in AA and SS genotype carriers. 2
• The weight of FSHR polymorphisms as a factor in treatment outcome is probably low, acting in concert with other environmental and genetic factors. 4

Laboratory Technique Optimization

ICSI is generally recommended for poor responders to minimize interference from maternal granulosa cells and paternal spermatozoa in genetic testing accuracy. 1

• Blastocyst trophoblast cell biopsy (5-8 cells) is the preferred method as it has minimal effect on embryo development potential. 1
• A 'freeze-all' embryo strategy should be applied in fresh cycles. 1

When Polymorphism Testing May Be Useful

FSHR genotyping could potentially guide personalized FSH therapy according to genetic background, though this remains investigational rather than standard practice. 2

• The A/A-Asn/Asn genotype shows significantly lower FSHR mRNA expression in granulosa cells compared to G/G-Asn/Ser genotype (P=0.029). 3
• This genotype could serve as a potential predictive marker for poor response, allowing earlier consideration of alternative protocols. 3

Common Pitfalls to Avoid

• Do not rely solely on FSHR genotyping to predict treatment outcomes—AMH and ovarian reserve markers are more predictive. 5
• Do not assume higher FSH doses will overcome receptor polymorphism effects—the issue is receptor sensitivity, not hormone availability. 2, 4
• Do not delay consideration of alternative protocols in confirmed poor responders with unfavorable genotypes, as standard stimulation is unlikely to succeed. 1
• Do not overlook functional FSHR splicing variants when common polymorphisms are absent but poor response persists. 6