Genetic Factors Shaping Hormonal Response in IVF Treatment
One of the most common questions I encounter in IVF practice is: “Doctor, why do some women respond so well to the medications while others don’t respond at all?” A significant part of the answer lies in genetics — specifically, in polymorphisms within the FSH and LH receptor genes.

In this article, I will explain what FSH-LH polymorphism is, how it affects IVF treatment, and how it guides personalised protocol planning — in scientific yet accessible language.

FSH and LH: The Fundamental Hormones of IVF

FSH (Follicle-Stimulating Hormone) and LH (Luteinising Hormone) are two key hormones secreted by the pituitary gland that directly regulate the ovaries. In IVF treatment, externally administered FSH preparations stimulate the ovaries to develop multiple follicles. LH contributes to follicle maturation and, through the trigger injection, manages the release of eggs (ovulation).

But how do these hormones act on cells? The answer: through receptors. FSH and LH bind to specific receptors on the surface of ovarian cells. These receptors are encoded by the FSHR and LHR genes — and this is precisely where polymorphism comes into play.

2. What Does Polymorphism Mean?

A polymorphism is a hereditary variation in a gene that occurs in at least 1% of the population. In other words, it means carrying a slightly different version of a gene rather than the “standard” version. This difference may consist of a single DNA base change (SNP — single nucleotide polymorphism).

When it comes to FSH-LH polymorphism, these small changes in the FSHR and LHR genes can either increase or decrease the receptor’s sensitivity to the hormone. The result: one woman may develop 15 follicles in response to a standard FSH dose, while another develops only 2–3.

Most Studied FSHR Polymorphisms

In the scientific literature, the most extensively studied FSHR polymorphism is a two-point variation located in exon 10 of the gene:

• Asn307Ser (rs6165) — in the extracellular domain
• Asn680Ser (rs6166) — in the intracellular domain

These two polymorphisms are in strong linkage disequilibrium with each other. In particular, the Ser/Ser homozygous genotype at position 680 is associated with reduced ovarian sensitivity to FSH. Studies have shown that 75% of women with the Asn/Asn–A/A genotype exhibit a poor response to IVF stimulation.

LHR Polymorphisms

Polymorphisms in the LH receptor gene (LHR) also affect follicular development and oocyte quality. In some LHR variants, the binding capacity of LH to its receptor is reduced; this may require modifications in the treatment protocol, especially during the trigger phase and luteal phase support.

3. Clinical Significance: Why Do Some Patients “Not Respond”?

A common scenario in IVF clinics is this: despite a standard protocol, the expected number of follicles fails to develop; stimulation is extended; the drug dose is increased — yet an adequate response is never achieved. FSHR polymorphism underlies a proportion of these “poor ovarian response” cases.

The opposite picture also exists: in some patients, receptors are hypersensitive, and even a standard dose carries a risk of dangerous ovarian swelling (OHSS — ovarian hyperstimulation syndrome). This too is a polymorphism scenario.

Areas Affected by Polymorphism

• Required gonadotropin (FSH) dose
• Duration of stimulation
• Number of follicles and mature eggs retrieved
• OHSS risk
• Need for LH supplementation
• Choice of trigger protocol

4. Genetic Testing: For Whom and When?

Routine FSH-LH polymorphism testing is not required for every IVF patient. However, in the following situations, genetic evaluation can provide crucial information for protocol selection:

• Patients who previously had unexpectedly poor follicular development in IVF cycles
• Cases with insufficient response despite standard doses
• Patients with low AMH despite being young
• Women who have previously experienced OHSS
• Couples with multiple failed IVF attempts

The test is performed using a simple blood sample. The results directly guide protocol planning by providing both genotype information and clinical prediction.

5. Personalized Protocol: Treatment Based on Polymorphism

Once FSH-LH polymorphism information is obtained, the treatment protocol is tailored according to this genetic profile. A single “standard” protocol is no longer sufficient; a personalized IVF approach represents where science currently leads us.

Low-Sensitivity Receptor (Expected Poor Response) Protocol

• The starting dose of gonadotropins is increased.
• A combination of recombinant FSH and HP-FSH may be considered.
• Gonadotropin preparations with LH activity may be preferred.
• The stimulation duration and monitoring frequency are increased.

High-Sensitivity Receptor (OHSS Risk) Protocol

• The starting dose is kept low, and a gradual increase is planned.
• An antagonist protocol is chosen instead of an agonist protocol.
• A GnRH agonist is used for triggering, and a freeze-all strategy may be applied instead of fresh embryo transfer.
• Luteal phase support is carefully planned.

6. Combination with Other Genetic Factors

FSH-LH polymorphism is never assessed in isolation. When evaluated alongside other gene polymorphisms affecting follicular development (BMP15, GDF9, AMH, AMHR2), a far more comprehensive picture of the patient’s ovarian function emerges. In recurrent failure cases in particular, this broad genetic panel can bring overlooked causes to light.

Conclusion: A Failed Cycle Is Not Fate — It Is an Incomplete Evaluation

FSH-LH polymorphism research provides a scientific answer to the question “why didn’t it work?” in IVF. Rather than applying the same protocol to everyone, understanding the patient’s genetic profile and personalising the protocol accordingly both increases success rates and reduces unnecessary medication burden and risk exposure.

In our clinic, we incorporate this genetic assessment as a standard part of our process — particularly for patients with poor response or recurrent failure. Our goal is to offer each patient a truly personalised treatment plan tailored to their own biology.

Did you experience fewer follicles than expected or no response at all in your previous IVF attempts? Let’s evaluate your situation together. The initial consultation is free and can be done online.