In the JournalsPerspective

Biomarkers of low ovarian reserve fail to predict infertility

Anne Steiner
Anne Z. Steiner

Biomarkers indicating diminished ovarian reserve compared with normal ovarian reserve were not associated with reduced fertility among women of late reproductive age, refuting previous beliefs about using these biomarkers as predictors of fertility, according to findings published in JAMA.

“Patients who have not been diagnosed with infertility may go to their primary practitioners’ offices asking to assess fertility to make decisions about timing conception or freezing eggs,” Anne Z. Steiner, MD, MPH, from the department of obstetrics and gynecology at the University of North Carolina, Chapel Hill, told Healio Family Medicine. “Before this study, it was presumed that these tests would predict a woman’s ability to conceive naturally, but these results challenge the clinical dogma that diminished ovarian reserve leads to infertility.”

Steiner and colleagues examined ovarian reserve biomarkers in women aged 30 to 44 years without a history of infertility to determine the links between these biomarkers and reproductive potential. Researchers followed the participants from 2008 to March 2016 to measure the cumulative probability of conception by 6 and 12 cycles of attempt and relative fecundability. They tested early-follicular-phase serum level of anti-müllerian hormone (AMH), follicle-stimulating hormone (FSH) and inhibin B and urinary level of FSH.

Of 750 women included in this analysis, those with low AMH values (< 0.7 ng/mL), high serum FSH values (> 10mIU/mL) and high urinary FSH values (> 11.5 mIU/mg creatinine) did not have a significantly different predicted probability of conceiving by 6 cycles of attempt compared with women with normal values or by 12 cycles of attempt.

In addition, inhibin B levels were not linked to the probability of conceiving in each cycle. Although AMH levels decreased and urinary FSH increased as women aged, these biomarkers were not linked to reduced fecundability or a lower cumulative conception probability by 6 or 12 cycles of attempt.

“Low ovarian reserve does not indicate that a woman will necessarily have difficulty conceiving naturally. Age remains the best predictor of a woman’s reproductive potential. Therefore, tests indicating normal or high ovarian reserve should not be used as justification to delay attempts to conceive,” Steiner said. “Also, when it comes to attempting pregnancy, understanding menstrual cycle characteristics are also important. Ovulation predictor kits, basal body temperature charting and cervical mucus monitoring can help women know if they are ovulating and time intercourse.”

In an accompanying editorial, Nanette Santoro, MD, from the University of Colorado School of Medicine, Aurora, wrote that these findings challenge clinicians to think more carefully about the biological meaning of AMH. Based on these results, Santoro explained, women who have never attempted to conceive should not be examined like those with infertility.

“Doing so can not only provide potentially misleading and anxiety-producing results but may also lead to costly fertility preservation treatments that have no value,” she wrote.

Santoro added that it appears critical to distinguish the infertile population, “who have already tried unsuccessfully to become pregnant and are therefore encountered in clinical practice, from the noninfertile population, which consists of a group of women who may have a number of reproductive advantages that mitigate a low AMH when interpreting these biomarkers.” – by Savannah Demko

Disclosures: Santoro reports being a member on the North American Menopause Society board of directors, having stock options in Menogenix and serving as a consultant for Astellas/Ogeda Pharmaceuticals. Steiner reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

Anne Steiner
Anne Z. Steiner

Biomarkers indicating diminished ovarian reserve compared with normal ovarian reserve were not associated with reduced fertility among women of late reproductive age, refuting previous beliefs about using these biomarkers as predictors of fertility, according to findings published in JAMA.

“Patients who have not been diagnosed with infertility may go to their primary practitioners’ offices asking to assess fertility to make decisions about timing conception or freezing eggs,” Anne Z. Steiner, MD, MPH, from the department of obstetrics and gynecology at the University of North Carolina, Chapel Hill, told Healio Family Medicine. “Before this study, it was presumed that these tests would predict a woman’s ability to conceive naturally, but these results challenge the clinical dogma that diminished ovarian reserve leads to infertility.”

Steiner and colleagues examined ovarian reserve biomarkers in women aged 30 to 44 years without a history of infertility to determine the links between these biomarkers and reproductive potential. Researchers followed the participants from 2008 to March 2016 to measure the cumulative probability of conception by 6 and 12 cycles of attempt and relative fecundability. They tested early-follicular-phase serum level of anti-müllerian hormone (AMH), follicle-stimulating hormone (FSH) and inhibin B and urinary level of FSH.

Of 750 women included in this analysis, those with low AMH values (< 0.7 ng/mL), high serum FSH values (> 10mIU/mL) and high urinary FSH values (> 11.5 mIU/mg creatinine) did not have a significantly different predicted probability of conceiving by 6 cycles of attempt compared with women with normal values or by 12 cycles of attempt.

In addition, inhibin B levels were not linked to the probability of conceiving in each cycle. Although AMH levels decreased and urinary FSH increased as women aged, these biomarkers were not linked to reduced fecundability or a lower cumulative conception probability by 6 or 12 cycles of attempt.

“Low ovarian reserve does not indicate that a woman will necessarily have difficulty conceiving naturally. Age remains the best predictor of a woman’s reproductive potential. Therefore, tests indicating normal or high ovarian reserve should not be used as justification to delay attempts to conceive,” Steiner said. “Also, when it comes to attempting pregnancy, understanding menstrual cycle characteristics are also important. Ovulation predictor kits, basal body temperature charting and cervical mucus monitoring can help women know if they are ovulating and time intercourse.”

In an accompanying editorial, Nanette Santoro, MD, from the University of Colorado School of Medicine, Aurora, wrote that these findings challenge clinicians to think more carefully about the biological meaning of AMH. Based on these results, Santoro explained, women who have never attempted to conceive should not be examined like those with infertility.

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“Doing so can not only provide potentially misleading and anxiety-producing results but may also lead to costly fertility preservation treatments that have no value,” she wrote.

Santoro added that it appears critical to distinguish the infertile population, “who have already tried unsuccessfully to become pregnant and are therefore encountered in clinical practice, from the noninfertile population, which consists of a group of women who may have a number of reproductive advantages that mitigate a low AMH when interpreting these biomarkers.” – by Savannah Demko

Disclosures: Santoro reports being a member on the North American Menopause Society board of directors, having stock options in Menogenix and serving as a consultant for Astellas/Ogeda Pharmaceuticals. Steiner reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

    Perspective

    Ovarian reserve refers to the pool of fertilizable eggs that remain within the ovary, a pool that naturally declines with age. It has long been recognized that as women approach menopause, low anti-Müllerian hormone (AMH) levels decrease and follicle-stimulating hormone levels increase. However, the significance of these biomarkers in predicting conception in both fertile and infertile women is unknown. Despite this uncertainty, AMH has gained popularity among OB/GYNs and fertility specialists as a “fertility test.” It is not uncommon to see a new patient who is scared and confused about her potential to have a child based on the finding of a low AMH.

    This is the first large, well-designed prospective analysis of the significance of ovarian reserve markers in predicting pregnancy in women aged 30 to 44 years without a prior infertility diagnosis. Women who were enrolled had just begun to try naturally for pregnancy within the last 3 months. Interestingly, the researchers found that low ovarian reserve/low AMH does not predict fecundability — monthly chance of conceiving — even in women aged up to 44 years. This lack of effect was noted for up to 12 months of trying to conceive. Limitations of the study are the relatively small number of women in their 40s and the inability to determine whether the pregnancies that were conceived ended in miscarriage vs. live birth.

    The findings of this study are not completely surprising and are in line with our own in vitro fertilization experience at Cleveland Clinic. Women undergoing IVF with low AMH levels require more medications to stimulate their ovaries and may grow fewer eggs for retrieval than women with a high AMH, but we still find that age — rather than ovarian reserve — remains the biggest predictor of who actually becomes pregnant with embryo transfer. This likely reflects egg and embryo quality rather than quantity as the most important factor in successful pregnancy. 

    This study should give physicians pause before they order a test that can cause unnecessary worry in a low-risk population. These biomarkers are likely not useful as a “fertility test” in patients without a history of infertility. However, a distinction must be made between the population examined in this study — women without prior infertility — and patients older than 37 years who are seeing an infertility specialist, and have diminished ovarian reserve and an established infertility diagnosis. This population may be quite different than the study population, and ovarian reserve biomarkers may still be of value in counseling this group and planning necessary treatments. 

     

    • Rebecca Flyckt, MD
    • OB/GYN
      Director, Fertility Preservation and Cancer Program
      Cleveland Clinic

    Disclosures: Healio Family Medicine was unable to confirm Flyckt's relevant financial disclosures prior to publication.