Biomarkers of Ovarian Reserve Not Linked to Fertility

Troy Brown, RN

October 10, 2017

Biomarkers used to estimate ovarian reserve were not associated with fertility among women aged 30 to 44 years with no history of infertility who had tried to conceive for 3 months or less, a prospective study has found.

"These findings do not support the use of urinary or blood [follicle-stimulating hormone (FSH)] tests or [antimüllerian hormone (AMH)] levels to assess natural fertility for women with these characteristics," the researchers conclude.

Anne Z. Steiner, MD, from the Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, and colleagues report their findings in an article published online October 10 in JAMA.

"Despite lack of evidence of their utility, biomarkers of ovarian reserve are being used as markers of reproductive potential or fertility tests," the authors write. "Home fertility tests based on day 3 urinary FSH levels are commercially available. Additionally, clinicians use these tests when counseling about elective oocyte cryopreservation."

Therefore, the researchers conducted a prospective time-to-pregnancy study between 2008 and 2016. They enrolled 750 women who gave a blood and urine sample. The researchers adjusted for age, body mass index, race, current smoking status, and hormonal contraceptive use during the preceding year. They also conducted subgroup analyses by age and parity.

"The objective of this study was to determine the extent to which biomarkers of ovarian reserve (early-follicular-phase serum AMH, serum FSH, serum inhibin B, and urinary FSH) were associated with reproductive potential, as measured by the probability of conceiving naturally, in a cohort of women of older reproductive age recruited from the community," the researchers explain. "It was hypothesized that women with biomarker values suggesting diminished ovarian reserve would have a lower probability of conceiving in a given cycle (fecundability) by 6 cycles and by 12 cycles of trying to conceive."

However, the researchers found no association between low AMH (<0.7 ng/mL) or high FSH (>10 mIU/mL) and reduced fecundability or a decreased cumulative probability of conceiving by six or 12 cycles of attempting pregnancy, after adjusting for age, body mass index, race, current smoking status, and hormonal contraceptive use during the preceding year.

Among women with low AMH values, the probability of conceiving by 6 cycles of attempt was 65% (95% confidence interval [CI], 50% - 75%) vs 62% among women with normal values (95% CI, 57% - 66%). Similarly, there was no difference between the two groups after 12 attempting cycles (84%; [95% CI, 70% - 91%] vs 75% [95% CI, 70% - 79%], respectively).

Among those with high serum FSH values, the probability of conceiving by six attempting cycles (63%; 95% CI, 50% - 73%) was also not significantly different compared with women with normal FSH values (62%; 95% CI, 57% - 66%), nor was it different after 12 cycles of attempt (82% [95% CI, 70% - 89%] vs 75% [95% CI, 70% - 78%]).

"Early-follicular-phase inhibin B levels were also not associated with fertility outcomes," the researchers write. The hazard ratio of conceiving during a given cycle was 0.999 per 1 pg/mL increase (95% CI, 0.997 - 1.001).

"Although both ovarian reserve and fertility decline with chronological age when looking at cross-sectional data, there may be little association between a given woman's ovarian reserve and factors that affect her fertility, such as egg quality. [AMH] and FSH levels may, however, affect follicular recruitment in those with diminished ovarian reserve," the authors explain. "It is possible that low AMH allows for a greater proportion of the remaining primordial follicle pool to activate and become growing follicles. Additionally, high FSH seen in women with low reserve could lead to 'superovulation' with multifollicular ovulation, increasing the odds of pregnancy."

"Several Caveats"

The study findings "should be considered in the context of several caveats," Nanette Santoro, MD, from the University of Colorado School of Medicine, Aurora, writes in an accompanying editorial.

Importantly, the study excluded those with known fertility problems or with fertility problems affecting their partners. In addition, as the only pregnancy outcome available was a positive pregnancy test, it is possible that more pregnancy loss and lower live birth rates occurred among women with low ovarian reserve. As well, "although subsequent use of fertility medications may have affected outcomes for the group of women with low AMH, data from women who initiated fertility treatments were censored," Dr Santoro explains.

Dr Santoro points out, "[T]he findings differ from the authors' prior pilot study of 100 women, in which low AMH was associated with reduced odds of conception.... [E]ven though the overall sample size was relatively large, the number of women in the 38- to 44-year-old age group with low AMH was small (n = 28), and the loss to follow-up of women in this group to fertility treatment over the 12-month observation period may have influenced the results," she adds.

Finally, "the within-woman rate of decline in AMH over time is likely to be a useful factor to incorporate into prognostic models; however, serial measurements were not obtained in this study. Most work to date has involved cross-sectional studies with single determinations of AMH. It is possible that a subset of women who have a more rapid rate of decline in AMH levels have a more adverse fertility profile," Dr Santoro explains.

Different Approaches Needed for Women With and Without Infertility

"For clinical researchers who study menopause, AMH has appeared to represent the long-sought-after blood test to help a woman prospectively determine when her final menses will occur," Dr Santoro writes. "It seems 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 (most of whom will not ever come to medical attention for infertility) who may have a number of reproductive advantages that mitigate a low AMH when interpreting these biomarkers. Circulating AMH may mean different things in each of these circumstances."

Clinicians should not evaluate women who have never tried to conceive in a similar manner to how they evaluate women with infertility, Dr Santoro concludes. "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."

One coauthor reports receipt of personal fees from Merck, TherapeuticsMD, Agile Therapeutics, AbbVie, Noven, Pantarhei Bioscience, and Mithra. Dr Steiner and the remaining coauthors have disclosed no relevant financial relationships. Dr Santoro reports membership on the board of directors of the North American Menopause Society, stock options in Menogenix Inc, and consultancy for Astellix/Ogeda Pharmaceuticals.

JAMA. Published online October 10, 2017. Article

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