Fertility Chronicles is proud to present a special blog series, “From the Fertility Experts,” where leading fertility experts answer commonly asked questions for patients about their fertility health and treatment options. We hope this series can help patients navigate their personal fertility journeys.—Catherine T. Yang, Editor, Fertility Chronicles
Univfy’s “Fertility Chronicles” guest blogger Dr. Ernesto Bosch shares his insights advice on personalizing infertility treatment:
In the third installment of this series, I will discuss some of the emerging ideas for identifying patient-specific genetic traits that impact your individual controlled ovarian stimulation (iCOS) response.
Your genetic profile may ultimately hold the key to unlocking your iCOS identity and finding your best stimulation protocol. Mutations in genes for the follicle stimulating hormone (FSH) receptor, luteinizing hormone (LH) receptor, and LH molecule can interfere with fertility by affecting the normal ovarian response to stimulation. FSH and LH receptors are proteins made by your ovarian cells to “sense” the FSH and LH hormones. It is this “sensing” that causes the ovaries to respond to FSH and LH hormones, and the strength of this sensing is determined by the shape and effectiveness of the receptor proteins, which are, in turn, determined by your genetics hardwired in your DNA.
At least four FSH receptor gene mutations may explain poor FSH response, and other FSH receptor genetic variations (called variants) have been associated with normal responses. For instance, women with ovarian dysfunction tend to have the Ser/Sergene allele for the FSH receptor. Women with a good response to FSH are more likely to have the Asn/Ser allele. Although research in this area is preliminary, identifying your genetic iCOS fingerprint may someday be able to identify the best stimulation protocols for you.
Likewise, variants in the LH receptor gene have also been associated with variable FSH responses. In at least one study, patients who needed very high doses of FSH were more likely to have a specific LH receptor variant. For these patients, they were found to have better outcomes when LH was added with FSH to their ovarian stimulation protocol. So in the future, understanding a patient’s unique genetic profile can inform the physician not only about the appropriate FSH dose, but also whether LH is likely to be beneficial.
Identifying your iCOS profile based on tests for both biomarkers and gene variants will allow physicians to tailor the ovarian stimulation protocol for each patient. To maximize the benefit of each IVF cycle, identifying your ultimate goal is also important. For instance, the best endpoint for patients is a healthy singleton live birth. Standard protocols may deliver a high number of eggs, but many of these eggs may not be good enough to create a healthy singleton pregnancy. Alternatively, they may deliver many more eggs than needed, resulting in excessive embryo storage. With the increasing interest in both single embryo transfer and minimizing excess embryo storage, the need to use targeted protocols to maximize oocyte quality, but not necessarily oocyte number, is becoming ever more urgent.
What are some of the barriers to finding a patient’s individualized protocol “match”? Science and medicine have generally been geared toward researching and understanding the most common patient types or diseases, following the “blockbuster” model. Diseases affecting relatively few patients are called “orphan” diseases and inspire little interest because they affect too small a market to justify large R&D investments. Similarly, this lack of financial incentives has affected the development of diagnostic tests to identify sub-populations of IVF patients and patient-specific therapies based on these tests.
To carry out more finely-tuned personalized treatment for each individual patient, we need to have personalized prognostics, which can include knowing a patient's AMH levels, androgen levels, response to a prior IVF treatment, or genetic variants for LH and FSH receptors, as well as her personalized chances of success, as certain protocols may help patients who have lower chances of success.
Since roughly half of IVF patients do not become pregnant in their first cycle, there is clearly room for improvement in optimizing IVF for sub-groups of patients. The next revolutionary step towards maximizing benefits and minimizing risks of IVF lies in identifying specific patient “types” that would benefit from adjusting the standard protocols.