A genetic variant that affects how women respond to IVF drugs has been identified, raising the prospect of personalised fertility treatment tailored to an individual’s DNA.
Women who carry the newly discovered variant cannot properly process hormonal drugs that stimulate their ovaries to produce eggs, according to new research that could explain why some couples who appear to be good candidates for IVF fail to conceive during treatment.
The findings, by scientists in the United States, could pave the way for new approaches to fertility treatment by which patients take genetic tests, so the results can be used to select the drug regime that has the maximum chance of success. They could also assist the development of new drugs that stimulate the ovaries by a different biological route, for treating women who respond poorly to existing treatments.
Maria Lalioti, of Yale University in Connecticut, who led the research, said there are already preliminary indications that women with the new genetic variant do better when given lower doses of stimulation drugs. “In the future, this could lead to personalised treatments for a sub-group of patients,” she said.
The research could also shed light on the origins of some cases of unexplained infertility, which may be influenced by genetic variations in the way women respond to natural hormones as well as the synthetic versions given as drugs. Scientists do not yet know how common the variation is: it has so far been identified only in two patients who produced very few eggs during IVF, and Dr Lalioti said she expected it to be rare.
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In a study presented to the European Society of Human Reproduction and Embryology conference in Rome, Dr Lalioti’s team investigated five women having IVF who had produced fewer than four eggs after their ovaries were stimulated with follicle-stimulating hormone (FSH) — the biological trigger that matures eggs. Most women who take this key IVF drug produce between 7 and 18 eggs.
Two of the women were found to have a genetic variation that gave them abnormal receptor proteins for FSH, which allow the ovaries to respond to the hormone. Laboratory studies confirmed that these abnormal proteins impair take-up of FSH. “Our finding explains why these women have a lower response to FSH,” Dr Lalioti said.
“We don’t yet know how to use this to personalise treatment but I think it could be possible. At the moment, the main medication is FSH, so it might be possible to adjust doses. When we know better how FSH signals within the cells, perhaps we can design drugs that bypass the receptor.” Dr Lalioti said the genetic variation appeared to be inherited, and not the result of a random mutation, because the same variant had been found in two patients. She suggested that it could have survived, despite the evolutionary disadvantages of DNA that promotes sub-fertility, because women used to have children earlier and the variant may be less damaging at a younger age.
The findings suggest that the new field of pharmacogenomics, by which drugs are prescribed according to patients’ genetic profiles, is poised to influence fertility treatment. Pharmacogenomics is already used extensively in cancer, where two dozen drugs are available only for patients whose tumours have particular mutations, and the activity of one in ten drugs is known to be affected by genetic variations.
Independent doctors welcomed the research. Stuart Lavery, director of IVF at Hammersmith Hospital in West London and a spokesman for the British Fertility Society, said: “I think there is something in this. There is huge variation in FSH responses and there are a lot of studies coming out on FSH-receptor variation. There does seem to be a lot of genetic variation going on.
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“It’s early days with this study, and the variant doesn’t yet have a particular treatment attached. But it highlights that genetically we’re so different and that hormone-receptor variation is part of that, and that holds out hope for tailoring therapeutic interventions.
“There’s increasing evidence that individual tailoring of medications and protocols is going to work.
We already see that anecdotally, with patients who seem to do particularly well on particular drugs.
This kind of work is going to give us a genetic explanation for that, and help us to choose the best therapy. It may even allow us to design novel drugs.”
Tony Rutherford, consultant in reproductive medicine at Leeds General Infirmary and chairman of the British Fertility Society, said the work could also help to explain the causes of their infertility to patients. “It will help understanding,” he said.
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“It is useful to patients to know why their treatment might not be working. The question then is can we overcome this by increasing doses or designing new versions of FSH that can overcome these issues?”
Clare Lewis-Jones, of the patient charity Infertility Network UK, said: “The response of some patients to the FSH drugs can be poor and new research such as this, which may explain why there can be such variations in response to treatment, could make a huge difference to those patients who fail to respond well. Although more work is needed, research like this is important if we are to develop alternatives methods of treating such patients and help them to benefit from fertility treatment.”