Matching FSH type to FSHR variant improves IVF outcomes

A new study found that selecting FSH type based on a woman’s FSH receptor (FSHR) genotype may improve IVF pregnancy and live birth rates, particularly when using rFSH for NN genotypes and uFSH for NS or SS genotypes.

When preparing for IVF, patients undergo ovarian stimulation using FSH. There are two main types: recombinant FSH (rFSH, like Gonal-F) and urinary-derived FSH (uFSH), which is found in products like Menopur. Both are effective, but studies suggest that patient responses may vary depending on the genetics of their FSH receptor gene (FSHR).

Receptors are proteins on the surface of cells that receive and respond to signals. In this case, the signal is FSH. The FSHR sits on ovarian cells and responds to FSH by stimulating follicle growth. A common genetic variant in this receptor, called N680S, can affect how strongly the receptor responds to different types of FSH.

People can have different versions of the FSH receptor (FSHR), which is made up of about 695 amino acids. Position 680 is especially important for how the receptor responds to FSH.

At this position, some people have the amino acid asparagine (N), others have serine (S). This small difference can affect how strongly the receptor responds to different types of FSH.

We each have two copies of the FSHR gene, so your genotype could be:

• FSHR NN genotype – these women have two copies of FSHR with asparagine (N) at position 680
• FSHR SS genotype – two copies of serine (S) FSHR
• FSHR NS genotype – one of each (N and S)

Previous studies have shown that people with the NN genotype generally respond better to rFSH, while those with NS or SS genotypes may benefit more from uFSH, but these results were small or inconsistent. A new study by Hjelmér et al. (2025) tested this out in a larger and better designed study.

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Study details

• This was a prospective study conducted between 2016 and 2021 at a medical center in Sweden, where women were randomized to receive either rFSH or uFSH, and genotyping was performed afterward.
• Women were <40 years old with normal ovarian reserve, and infertility due to male factor, tubal factor, or unexplained infertility.
• The primary outcomes was the cumulative pregnancy rate and cumulative live birth rate. This was defined as all pregnancies/live births from the patient’s first ovarian stimulation cycle (including both fresh and frozen cycles).

In terms of sample size, there were 475 women genotyped and randomized to receive rFSH or uFSH:

• 236 received rFSH
• 239 received uFSH
• There were 991 controls that weren’t genotyped.

From the 475 genotype women who randomly received rFSH or uFSH, 221 were “optimally treated” with the right FSH (NN genotype responds optimally to rFSH, NS or SS genotype responds optimally with uFSH).

Genotype-guided FSH choice improved pregnancy and live birth rates

Women were randomized to receive either rFSH or uFSH then genotyped for FSHR genotype:

• Among NS or SS genotypes, the cumulative pregnancy rate was 53% with uFSH versus 43% with rFSH (p= 0.048), showing that uFSH is more effective for this group. There was no significant difference in live birth rates.
• For NN women, there were no significant differences between rFSH and uFSH in pregnancy or live birth rates.

These initial results weren’t very striking, likely because the analysis was spread across six smaller subgroups based on genotype and treatment (e.g. NN + uFSH, NN + rFSH, etc.), which diluted the statistical power. To better demonstrate the benefit of matching FSH type to genotype, the researchers performed an additional analysis after data collection. They focused only on women who, by chance, received the FSH type best suited to their genotype:

• rFSH for NN
• uFSH for NS or SS

This “optimally treated” group was then compared to a larger, non-genotyped control group. These results appeared much stronger.

The cumulative pregnancy rate was 51% in the genotyped group who received the FSH type matched to their FSHR variant, compared to 40% in the non-genotyped control group (odds ratio [95% CI]: 1.40 [1.12–1.75], p= 0.003). Similarly, the cumulative live birth rate was 40% in the genotyped group and 29% in the control group (odds ratio [95% CI]: 1.55 [1.23–1.96], p< 0.001).

The “optimally treated” group was not randomized, unlike the first set of data. This introduces the risk of selection bias because these patients might have had other favorable characteristics that helped their outcomes. A larger randomized study might have made the original genotype-by-treatment results more conclusive.

More eggs when rFSH was given to NN carriers

Women with the NN genotype retrieved an average of 12 eggs when treated with rFSH, compared to 9 eggs with uFSH (p = 0.004). This means NN women had 33% more oocytes when given rFSH! There were no differences in eggs numbers in women with NS or SS genotypes.

S-variant FSHR responds more to uFSH vs rFSH in cells

The researchers tested the function of different FSHR variants in a COS-1 cell line:

• S-variant receptors had significantly higher cAMP production when stimulated with uFSH vs. rFSH, indicating stronger activation. This shows that the FSHR with a serine amino acid (ie. NS or SS genotype) responds more strongly to uFSH than to rFSH.
• NN receptors showed no significant difference between hormone types.

Conclusions

This study found that selecting either rFSH or uFSH based on a person’s FSHR genotype can improve cumulative pregnancy and live birth rates.

They also found that women with the NN genotype retrieved on average 3 more eggs with rFSH compared to uFSH.

In vitro data using cell lines showed S-variant receptors respond better to uFSH than rFSH.

This shows that the FSHR N680S variant likely alters receptor sensitivity and signaling. rFSH may better activate the “N” form of the receptor, while uFSH may better activate the “S” form that’s less sensitive. uFSH generally has a broader mix of isoforms (different versions of FSH) and possibly longer half-life, which might make it better suited for receptors that require a stronger or more sustained signal, like the S variant.

Testing for the FSHR N680S variant could help clinicians choose the best FSH type for each patient, potentially improving IVF success and reducing the number of cycles needed. According to Lund University, the researchers have filed a patent for a swab-based genotyping test and established a company, Dx4Life AB, to bring the product to market.

Study limitations include the focus on first-cycle IVF patients without PCOS or endometriosis, limited power to assess miscarriage or OHSS, use of only one type of rFSH and uFSH, and uncertain relevance across different ethnic groups.

Additionally, the “optimally treated” group was not randomized, raising the risk of selection bias, especially since the original randomized results showed only modest effects. However, the authors note that baseline characteristics were similar between groups, treatment was randomized using sealed envelopes, and genotyping was done after treatment to minimize bias.

Reference

Hjelmér I, Nilsson M, Henic E, Jędrzejczak P, Nenonen H, Ozegowska K, Giwercman A, Kitlinski ML, Giwercman YL. FSH receptor N680S genotype-guided gonadotropin choice increases cumulative pregnancy and live birth rates after in vitro fertilization. Front Endocrinol (Lausanne). 2025 May 13;16:1576090. doi: 10.3389/fendo.2025.1576090. PMID: 40433406; PMCID: PMC12106330.

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About Embryoman

Embryoman (Sean Lauber) is a former embryologist and the founder of Remembryo, an IVF research and fertility education website. After working in an IVF lab in the US, he returned to Canada and now focuses on making fertility research more accessible. He holds a Master’s in Immunology and launched Remembryo in 2018 to help patients and professionals make sense of IVF research. Sean shares weekly study updates on Facebook, Instagram, and Reddit regularly. He also answers questions on Reddit or in his private Facebook group.

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