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expert reaction to paper on biomarkers of ovarian reserves and infertility in older women of reproductive age

Researchers, publishing in JAMA, report among women aged 30-44 years without a history of infertility who had been trying to conceive for 3 months or less, biomarkers indicating diminished ovarian cancer reserve compared with normal ovarian reserve were not associated with reduced fertility.

 

Dr Ali Abbara, Senior Clinical Lecturer in Endocrinology at Imperial College London, & Society for Endocrinology member, said:

“This is a very well conducted study which confirms the results of some previous smaller studies that a single measure of a blood test for ovarian reserve doesn’t predict the chance of getting pregnant over the next 6-12 months. The predominant test that was investigated is called AMH or ‘anti-mullerian hormone’. AMH is a hormone produced by the ovaries. Higher levels of AMH in the blood are associated with more eggs still being present in the ovary, which is referred to as ‘ovarian reserve’. The AMH level peaks in early adulthood and becomes undetectable at menopause. Therefore, theoretically it is attractive to believe that the higher a woman’s AMH is, the more likely it is that she has a good ovarian reserve and have an increased chance of getting pregnant.

“Of course, getting pregnant is not as simple as that and many other factors beyond whether ovulation is occurring regularly, such as the man’s sperm can also influence this chance. It could also be that just having sufficient levels of AMH to indicate that a woman ovulates regularly is enough for her chance of conceiving naturally, and having a higher level does not provide a further advantage in terms of time to pregnancy. An added complexity is that women with very high levels of AMH, are more likely to have a condition called ‘polycystic ovarian syndrome’ (PCOS) which can actually reduce a woman’s chance of ovulating (releasing an egg each month) and therefore reduce her chance of getting pregnant naturally.

“This study was conducted in healthy women without a ‘known’ diagnosis of PCOS or fertility problems. If a woman does have fertility problems (i.e. has been trying to conceive unsuccessfully for a year or more) then these measures of ovarian reserve can still be useful. For example, they can predict how well a woman may respond to IVF treatment and what doses of treatment could be effective in her particular case.

“This study evaluated a single measurement of AMH; a further consideration is that AMH levels tend to converge by the time of menopause. So even if a single AMH level is high, as a woman’s age tends towards menopausal age (~50yrs), there may be a more rapid fall in the AMH level such that most women will have menopause at a similar age (usually 45-55yrs). Therefore a single measurement can similarly be misleading in terms of time to menopause and how many potential years of fertility remain, as there could still be differences in rate of fall of AMH over the years. This means that a woman’s age can have just as much predictive capability of estimating when the menopause will occur in her.

“A small proportion of women (~1%) may have premature menopause starting before the age of 40 years (termed premature ovarian insufficiency) and these women could have near undetectable AMH levels. The study had limited numbers of women with these very low levels and so could not address their particular situation in any detail. Even these women may have some fluctuation in their levels and rarely even some improvement.

“Certainly for the time being, the evidence suggests that a healthy woman without a fertility problem is unlikely to benefit from routine measurement of a marker of ovarian reserve such as AMH (a fertility health check) with regards to predicting her chance of getting pregnant within the next 6-12months. Such tests are still useful for women with fertility problems to help in their diagnosis and decide which fertility treatments are most likely to work for them.”

 

Mr Stuart Lavery, Consultant Gynaecologist, Department of Reproductive Medicine, Hammersmith Hospital, said:

“This is an excellent and timely piece of research confirming that FSH and AMH tests are not predictive of natural pregnancy.  We live in a world where patients place great faith in technology, and often request lots of tests from their doctor. Whilst AMH and FSH have an important place in predicting response to ovarian stimulation in IVF, Steiner and colleagues have done women a great service in helping them avoid unnecessary cost and incorrect judgements around their natural fertility.”

 

Dr Meenakshi Choudhary, Consultant in Reproductive Medicine and Gynaecology, Newcastle upon Tyne Hospitals NHS Trust, said:

“This study further  affirms the belief that ‘one size fits all’ fertility MOT is not a universal formula for those with subfertility and those without. One must administer caution before performing and  interpreting ovarian reserve marker tests (designed as a tool for subfertility & assisted conception management) for those who do not have any concerns with fertility. However, it is evident that fertility declines with age and hence the focus should now be on research determining what causes ovarian ageing and possible markers responsible for it to target futuristic solutions for the age-old egg problem.”

 

Dr Channa Jayasena, Clinical Senior Lecturer at Imperial College London, Consultant in Reproductive Endocrinology at Hammersmith Hospital, & member of the Society for Endocrinology, said:

“This is an excellent and rigorously designed study. Women in their 30s and 40s are often anxious about their future chances of having a baby. Levels of hormones such as AMH and FSH are related to the ovaries, so there has been an increasing trend to use them to predict a woman’s future fertility. This paper supports smaller previous studies, by unequivocally telling us that this is not the case. Hormone levels change with time, so taking a snapshot today tells us very little about what women’s fertility will be like tomorrow.

“Health MOTs performed by NHS work well when they focus on things that have undoubted benefits if treated, like high cholesterol, high blood pressure, or obesity. This study tells us that measuring these hormones to predict fertility in potentially worried and vulnerable women is wrong, and should be stopped.”

 

Prof. Adam Balen, President of the British Fertility Society, said:

“The key thing about this research is that it’s on women who don’t have fertility problems and have only just started trying to conceive. Fertility does decline as both men and particularly women get older and so if you start trying for a baby and think there may be problems, or if you’ve been trying for a year without success, don’t delay before seeking advice from a fertility specialist, who will then guide you to the appropriate tests that are right for your personal situation.”

 

Prof. Richard Anderson, Head of Section of Obstetrics and Gynaecology, MRC Centre for Reproductive Health, University of Edinburgh, said:

“Many more women are concerned about having their first child when older than was the case for previous generations, leading to pressure to seek ‘fertility tests’. This paper, confirming smaller earlier studies, shows that we do not have such a thing.  The most important test is whether a woman is ovulating, i.e. whether she is releasing an egg every month, rather than how many eggs she might have in reserve.  It’s important to note however that this study has only short-term outcomes, the chance of conceiving in the next 6-12 months, and doesn’t examine what these tests might tell us about fertility in say 5 years’ time.”

 

* ‘Association Between Biomarkers of Ovarian Reserve and Infertility Among Older Women of Reproductive Ageby Steiner et al. published in JAMA at on Tuesday 10 October.

 

Declared interests

Dr Ali Abbara: No conflicts of interest

Mr Stuart Lavery: No conflicts of interest.

Dr Meenakshi Choudhary: No relevant conflicts of interest.

Dr Channa Jayasena: No conflicts of interest.

Prof. Adam Balen: No conflicts of interest.

Prof. Richard Anderson: “I have undertaken commercial work with companies producing some of these hormone assays (though not in this context).”

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