A study finds no significant link between reduced fertility and the biomarkers that indicate having fewer eggs
Age, possibly genetics, and other factors can play a role in fertility, experts say
Dr. Aimee Eyvazzadeh, a San Francisco-based reproductive endocrinologist, sees it almost everyday in her practice.
Women come into the fertility specialist’s office fearful and tearful that they may never have children, she said. The results of their follicle stimulating hormone (FSH) and anti-Müllerian hormone (AMH) blood tests – used to gauge fertility and how many eggs a woman has – are not promising. Some women lose hope.
Yet “a hormone level can never tell you that you can or cannot get pregnant,” Eyvazzadeh said, adding that there is more to fertility than a patient’s FSH and AMH levels. Higher FSH, as well as lower AMH levels, are associated with reduced fertility.
However, a new study published in the medical journal JAMA on Tuesday suggests that having high FSH and low AMH levels – which typically indicate a low ovarian reserve or egg count – might not be significantly tied to reduced fertility after all.
The ability of those biomarkers to predict a woman’s reproductive potential appear to be uncertain, according to the study, of which Eyvazzadeh was not involved.
“Our findings challenge the clinical assumption that diminished ovarian reserve is a cause of infertility, but these findings are important for women,” said the study’s lead author Dr. Anne Steiner, a professor at the University of North Carolina School of Medicine and physician at UNC Fertility.
“Women are partnering and getting married later in life. They are aware of age-related decline in fertility. Women are seeking tests, outside of their age, that inform them about their fertility. Some women may also use such tests to guide their decision-making about freezing eggs,” she said, adding, “Age still remains the best predictor of a woman’s reproductive potential.”
Infertility is typically defined as not being able to get pregnant after one year or longer of unprotected sex, according to the US Centers for Disease Control and Prevention.
About 6% of married women, 15 to 44, are unable to get pregnant after one year of trying in the United States, according to the CDC. Among all women, 15 to 44, about 12% have difficulty getting pregnant or carrying a pregnancy to term.
It’s estimated that about one in every four couples in developing countries could be affected by infertility, according to the World Health Organization.
WHO has called infertility a “global public health issue” and has calculated that more than 10% of women worldwide are impacted.
Could fertility be more about quality of eggs than quantity?
The study involved 750 women, between the ages of 30 and 44, from the area around Raleigh and Durham, North Carolina, who were trying to conceive for up to three months between April 2008 and March 2016. The women didn’t have a history of infertility.
Each woman was given a pregnancy test and was instructed to notify the researchers if they tested positive for pregnancy.
During the course of the study, blood and urine samples from the women were tested and analyzed. The women also completed diaries and questionnaires about their pregnancy attempts, medications, results of pregnancy tests and other data.
The researchers found that, among the women, the probability of conceiving was not any lower for those with low AMH or high FSH levels – even after adjusting the study results for age, body mass index, race, recent contraceptive use, and other factors that might influence fertility.
Women with low AMH levels did not have a significantly different cumulative probability of conceiving by six cycles of trying compared with women with normal levels, according to the study.
Women with high FSH levels did not have a significantly different cumulative probability of conceiving after six cycles compared with women with normal levels, according to the study.
“I was surprised by our results,” Steiner said.
However, Steiner said that she thinks AMH and FSH blood tests could still predict the number of eggs that could be retrieved for in vitro fertilization or IVF.
“Whether or not they predict pregnancy following IVF independent of age is less certain,” she said. “Some studies have shown that they do predict live birth following IVF, others haven’t.”
So if AMH and FSH biomarker levels are not associated with fertility, then what exactly explains reduced fertility among women 40 and older? Most likely, the quality of their eggs, Steiner said.
“As a woman ages, the quality of her eggs also decline,” she said. “When the egg is fertilized, the resulting embryo is more likely to be aneuploid, or not have the normal number of chromosomes. This is why women are less likely to get pregnant … more likely to miscarry, and more likely to have a baby with Down syndrome, as a woman gets older.”
Yet the new study had some limitations, Steiner added.
’You are not a number’
Most of the women involved in the study were white and highly educated. More research is needed to determine whether similar study results would emerge in a more diverse group of women.
The study also did not include assessments of ovulation, the semen of the women’s male partners, and actual live births.
“The main limitation is that conception, not live birth, was the primary outcome. It is possible that diminished ovarian reserve may reduce fertility by increasing the risk of miscarriage,” Steiner said. “The next step is to determine whether or not these biomarkers predict the probability of miscarriage.”
All in all, Eyvazzadeh, the fertility specialist in San Francisco, said that the new study didn’t provide any novel data to the community of fertility doctors.
“We all know that age is the most important factor for women over age 40. Even if your AMH is 2.0 you would never have the ‘ovaries of a 25-year-old,’ ” said Eyvazzadeh, who was not involved in the study.
Rather, “I’ve had patients with pregnancies who when I met them had AMH levels that were undetectable and I’ve helped them have three children over years, but there is something very unique about these women and it’s a genetic profile,” she said. “They all have a fertility genetic profile and we are learning more and more about what this means for women and how their fertility hormone levels fit into this picture.”
Eyvazzadeh added that biomarker levels could point to lower fertility in the context of a woman’s age, genetic profile, and other factors.
“You are not a number … is really what I love that this study will tell women,” she said.
In 2012, a separate team of scientists identified genetic markers in white and black women of reproductive age that were associated with FSH levels. This was the first genome-wide study to evaluate genetic associations with hormone markers of women’s ovarian reserve. The study was published in the journal Human Reproduction.
The discovery of genetic markers could help women and their doctors track and predict fertility decline as they age, according to that study.
As for the new study, its findings help to answer questions about the future fertility potential of a woman without a history of infertility, said Dr. Jennifer Kawwass, assistant professor at Emory University School of Medicine and medical director of IVF and third-party reproduction at the Emory Reproductive Center in Atlanta, who was not involved in the study.
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As the new study suggests, “biomarker tests showing diminished ovarian reserve do not necessarily predict fertility among women without infertility – that being said, fertility decreases with age in all women independent of ovarian reserve testing,” Kawwass said.
“Women are born with a finite number of oocytes, or eggs, that continue to undergo atresia, to die, over their lifetime. As time passes, the chance of pregnancy decreases, and the risk of miscarriage increases,” Kawwass said.
“I often tell patients, ‘age trumps all when it comes to fertility treatment.’ Ovarian reserve parameters are helpful in predicting dose of medication and ovarian response to fertility treatment,” she said. “Ovarian reserve in and of itself does not predict chance of conception particularly in a woman without a known history of infertility.”