National Women’s Health Week
A Potential Role for Anti-Müllerian Hormone in Reproductive Health: A Review
By: Megan Harman
Director’s Note: As we continue National Women’s Health Week, we are highlighting research published in Human Reproduction Update by Dewailly et al that explores the role of Anti-Müllerian hormone (AMH) in female reproductive health. While on the FACTS elective, Megan Harman summarized this 2014 study [1] that discusses why AMH may represent a useful marker of fertility for women across the reproductive lifespan. Read more to learn why this hormone could one day be standardized as a predictor of ovarian reserve, particularly for women diagnosed with anovulatory polycystic ovary syndrome (PCOS).
Introduction
In males, it is well known that anti-Müllerian hormone (AMH) plays a role in sexual differentiation during embryogenesis. Produced by the Sertoli cells in the testes, AMH causes regression of the Müllerian duct, thereby inhibiting development of the female reproductive tract. In females, AMH is produced by the ovaries and is believed to regulate recruitment and growth of primordial follicles. Many studies to date have demonstrated a positive relationship between serum AMH and antral follicle reserve, suggesting potential clinical utility of AMH as a biomarker of fertility.
Though a relationship seems evident, several obstacles hinder the ability to confidently standardize AMH as a useful predictor of ovarian reserve and a woman’s “biological clock.” Nevertheless, the authors believe that once the role of AMH is more clearly defined, there is significant potential to apply this knowledge to understand female fertility throughout the lifespan. This topic review by Dewailly et al explores the current understanding of how AMH works and future avenues by which it might serve as a clinically useful biomarker of fecundity in women.[1]
Understanding the Physiology
In females, AMH is produced by the granulosa cells of small, growing ovarian follicles, primarily those 1-2 mm in diameter. Studies have shown that as a follicle approaches a diameter of 8 millimeters, serum AMH levels decline steadily and appear to drop off sharply in correlation with the selection of larger dominant follicles. While this is partly explained by the higher production of AMH by small antral follicles, additional evidence supports a role of AMH in regulating the threshold of follicular sensitivity to follicle-stimulating hormone (FSH), which stimulates follicle growth.
“AMH is produced by the granulosa cells of small, growing ovarian follicles, primarily those 1-2 mm in diameter.”
In this way, AMH acts as a “gatekeeper” in the process of follicle recruitment. According to the authors, this theory is supported by studies of knockout mice, which demonstrated faster recruitment of primordial follicles in the absence of AMH with a concomitant normal rate of ovulation. This leads to exhaustion of the ovarian reserve of follicles at a much younger age with fewer total ovulatory cycles, and emphasizes the important role of AMH to regulate the pace of primordial follicle utilization.
One difficulty with utilizing AMH as a biomarker is its propensity for high inter-individual variability. Though there seem to be some trends in serum AMH levels by ethnicity and body mass index (BMI), even when controlling for these factors, 89% of the variability in serum AMH can be explained by variation between subjects, with only 11% due to individual fluctuations. In general, younger women tend to have higher AMH values with more variability while older women have a pattern of low serum AMH with low variability. The significant variation in serum AMH between individuals makes determining “normal” values complex and multifactorial.
Role in Assessing Fertility
Although multiple factors influence the age at which a woman approaches menopause, including genetics, environmental and lifestyle factors such as smoking and BMI, studies show AMH may have clinical utility to predict natural fertility. The authors cite two small studies demonstrating that women with low serum AMH adjusted for age will undergo menopause earlier, and those with high serum AMH for their age would undergo menopause at a later age. While these findings suggest a potential role for AMH in predicting the reproductive lifespan of a woman, the data displayed wide confidence intervals and should thus be interpreted and applied clinically with caution.
Though the utility of AMH in estimating the natural end of fertility is still being explored, it has been well established as a tool to predict response to fertility treatments and as a marker of ovarian damage following chemotherapy, radiation, and surgery. A 2003 study was the first to show that women who had cancer during childhood had lower serum AMH levels in adulthood compared to age-matched controls. Similarly, a study in 2010 noted decreased AMH among women treated with chemotherapy for childhood Hodgkin lymphoma. Additionally, even at low doses, radiation therapy to the pelvis is strongly correlated with low or undetectable AMH levels.
“Though the utility of AMH in estimating the natural end of fertility is still being explored, it has been well established as a tool to predict response to fertility treatments and as a marker of ovarian damage following chemotherapy, radiation, and surgery.”
It is important to note that in most of these studies, results were analyzed retrospectively and did not include AMH levels pre-treatment. However, in recent years, new data gleaned from prospective studies suggest that young women with higher AMH levels prior to receiving chemotherapy or radiation are more likely to see a recovery in AMH levels after the initial post-treatment hit. This information indicates AMH may be useful to determine which women may need fertility preservation prior to treatment, or treatment with assisted reproductive technology (ART) down the line.
AMH may be a particularly useful biomarker in children and adolescents undergoing gonadotoxic treatments. FSH and inhibin-B are the current standard indicators used to measure ovarian damage in adults, but they are not useful markers in pre-pubertal females. AMH is detectable in serum at all ages, and could thereby enable clinicians to evaluate and manage ovarian reserve much earlier in this unique population.
For women undergoing fertility treatments, AMH plays an important role in predicting the individual response to treatment and success of assisted conception. A 2011 study showed that women with higher pre-treatment AMH levels were at higher risk of ovarian hyperstimulation syndrome. On the other end of the spectrum, women with lower AMH levels pre-treatment had a poorer response to fertility treatment, though conception was still possible. Although other factors such as age and FSH play a role, once serum levels are further researched and standardized, AMH is likely to be a valuable contributor to determine optimal fertility treatment regimens tailored to the individual.
Polycystic Ovary Syndrome
Polycystic ovary syndrome (PCOS) is an endocrine disorder estimated to affect 5-10% of females and known to impact fertility. Studies show that women with PCOS have 2-4-fold higher serum AMH levels than healthy controls. These elevations in AMH production are postulated to occur via two mechanisms: an increase in the number of follicles, and increased production per follicle due to a poorly-understood intrinsic property of granulosa cells in polycystic ovaries. This is particularly amplified in anovulatory PCOS.
“Studies show that women with PCOS have 2-4-fold higher serum AMH levels than healthy controls.”
Because of the association between AMH and follicle count, some researchers have proposed AMH as a new diagnostic criterion for PCOS. Most studies to date measured serum AMH with older, less sensitive assays, and no scientific consensus exists on the diagnostic criteria for polycystic ovaries on ultrasound. Thus, it is currently difficult to determine a universal threshold for which AMH is predictive of PCOS. More research needs to be done utilizing newly developed assays to determine with accuracy and reliability the serum AMH levels indicative of PCOS.
Conclusion
AMH is a promising clinical tool for various aspects of women’s reproductive health. Yet, much work remains to be done. Due to the variable sensitivities of assays used to measure AMH in the past few decades, many studies cannot be accurately compared and compounded to establish reliable normal serum levels and thresholds for diagnostic criteria. Recently, more sensitive assays have been developed, so the current need is more data.
In the coming years, it is likely new research will help guide clinicians in developing standard values for AMH. A more thorough understanding of “normal” patterns of AMH throughout the reproductive lifespan will enable clinicians to utilize these norms to establish diagnostic criteria for related conditions such as PCOS and subfertility. Perhaps in a few more decades, AMH might even be able to tell us with decent reliability at what age a woman will undergo the menopausal transition. Only time will tell.
Sources
[1] Dewailly D, Andersen CY, Balen A, et al. The physiology and clinical utility of anti-Müllerian hormone in women. Human Reproduction Update. 2014;20(3):370-385. doi:10.1093/humupd/dmt062.
ABOUT THE AUTHOR
Megan Harman
Megan Harman is a fourth-year medical student at Eastern Virginia Medical School in Norfolk, Virginia. She grew up on the Eastern Shore of Maryland and then traveled to Upstate New York to complete her undergraduate education at Cornell University. She will begin training as a family medicine resident at the University of Michigan in June. She has a passion for women’s health and reproductive justice and looks forward to using the knowledge she gained from the FACTS elective to help empower her patients to make informed healthcare decisions best suited to their individual goals.
