Anti-Müllerian hormone (AMH) and its significance in women’s fertility

By: Sherry Faye   
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The first immunoassays for anti-Müllerian hormone (AMH) were developed in 1990.1,2 Since then, AMH has emerged as a key marker of ovarian reserve3 due to its ability to reflect the number of small antral and pre-antral follicles present in the ovaries. This has led to it playing an increasingly important clinical role in the management of women’s reproductive health.4

A woman is born with her maximum number of ovarian follicles, which decline with time until the eggs are depleted at menopause. Ovarian reserve refers to her current supply of eggs, which is closely associated with reproductive potential. Not all women have the same number of follicles, and their number declines at varying levels as a woman ages. 

Generally, a woman with a low AMH level for her age could expect to go through an earlier menopause, while someone with a high level at the same age might expect this to occur later. There are also times when the ovary does not age as predicted—for example, following cancer treatments which are toxic to the ovaries. This is why screening for ovarian reserve is a fundamental part of fertility assessment.

 

AMH’s role in IVF

The development of effective, readily available contraception has given women more control over their reproductive lives, making it possible for them to delay having children until their thirties and, increasingly, into their forties. However, because fertility drops off markedly 10 to 15 years before menopause, by delaying pregnancy a woman can run the risk of age-related infertility as ovarian reserve declines. As a result of these social changes, an increasing number of women over 30 are seeking assisted reproductive technologies to help them conceive.5

Women with normal AMH values will tend to have a good response to ovarian stimulation and have more eggs retrieved. In general, having a higher number of eggs improves the success rate because clinicians are more likely to have at least one high quality embryo available for transfer back to the uterus.Women with a high AMH level run the risk of ovarian hyper-stimulation syndrome (OHSS), a potentially life-threatening condition. At the other extreme, women with a low AMH are not likely to respond well to in vitro fertilization and can therefore be offered appropriate counselling or alternative treatment options.

Controlled ovarian response

AMH is becoming the biomarker of choice for predicting response to controlled ovarian stimulation. Assessing AMH levels helps clinicians make judgements about the likely success of IVF and identifies extremes of response. Therapeutic strategies can therefore be tailored to a woman’s likely response, making it safer and more effective
(Figure 1)6.

Figure 1. Strategic modeling of controlled ovarian stimulation on the basis of AMH. The introduction of individualized AMH-tailored controlled ovarian stimulation utilizing agonist and antagonist protocols and different FSH dosage has been reported to reduce the incidence of OHSS and increase pregnancy rates, thus making IVF safer and more effective as associated with improved IVF cycle. (Modified with permission from Nelson et al., [2009]15 and Yates et al., [2011]14). (AMH was measured with the DSL assay). AMH; anti-Mullerian Hormone. Chart reprinted from La Marca A and Sunkara SK. Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice. Hum Reprod Update.2014;20(1):124-140. With permission of Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

 

Conventional measures to assess a woman’s potential to produce eggs, such as measurement of follicle stimulating hormone (FSH), oestradiol, inhibin B, and chronological age can be unreliable.7 FSH, oestradiol, and inhibin B levels change markedly through the menstrual cycle, while intra-individual and intra-cycle serum AMH levels are relatively stable, allowing more flexibility in the timing of testing.7,8 Dynamic tests of ovarian reserve can also be used, including the Clomiphene Citrate Challenge Test (CCCT) or Gonadotrophin Releasing Hormone Agonist Stimulation Test (GAST). However, these are costly and require an injection and repeated blood tests, so they are not widely used in clinical practice. 

Traditionally the antral follicle count (AFC) measured by ultrasound was used to predict ovarian reserve. AFC and AMH are well correlated and both are effective in predicting pregnancy rates and the number of oocytes collected following controlled ovarian stimulation (COS). The main advantages of AMH are its very low cycle variability and that it is a simple blood test without the need for subjective interpretation.9

Cancer treatment and fertility

The relationship between AMH and the number of small growing follicles also makes the biomarker useful for assessing the gonadal toxicity of cancer therapy and loss of ovarian reserve. Levels fall rapidly with the onset of cancer treatment, with subsequent recovery dependent on the degree of ovarian damage. AMH appears to identify which treatments may spare the ovaries, and may give clinicians additional information to direct therapeutic choices in children and women of childbearing age with cancer.

By using AMH values to assess ovarian reserve and individualize risk, more invasive methods of fertility preservation may be appropriate for women with a low AMH, while those with high values for their age may decide to start cancer treatment without delay.

Most evidence comes from breast cancer studies and is based on the assumption that a woman with a higher pre-treatment AMH before chemotherapy will be more likely to retain ovarian function. A prospective study in women with newly diagnosed breast cancer linked high levels of AMH  detected before treatment with retaining long-term ovarian function five years after surgery.10 Pretreatment serum AMH was seen to be markedly higher in women who continued to have menses. The predictive value of AMH for post-chemotherapy ovarian function has subsequently been confirmed,11 allowing the development of prediction tools which combine age and AMH.

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Figure 2. Classification mosaic chart for ongoing menses (M) or chemotherapy-related amenorrhea (A) using prechemotherapy serum AMH and chronological age as predictor variables, in women with early breast cancer. The primary cut-off values are both for AMH, with below 0.53 ng/ml predicting amenorrhea and above 2.84 ng/ml predicting ongoing menses. Between these AMH levels there is an age threshold at 38.6 years, above which amenorrhea is predicted and below which ongoing menses are predicted. The classification schema has sensitivity 98.2% and specificity 80.0%. Reprinted with permission from Anderson et al; European Journal of Cancer (2013).

 

Key marker of ovarian reserve

Women who delay pregnancy run the risk of developing age-related infertility as their ovarian reserve declines. AMH levels can guide women regarding the status of their biological clock and may reduce the need for fertility treatments on these patients.3,9 Assessing AMH levels can help clinicians make judgements about the likely success of treatment and identify a woman’s risk of excessive ovarian stimulation.12,13 By directing treatment towards those women identified by AMH as most likely to benefit, it can reduce the emotional and financial burden of failure.14

Research continues to demonstrate the unique role for AMH in assessing ovarian potential—either in determining ovarian reserve or predicting response to COS. AMH will therefore continue to see greater acceptance and wider adoption into routine clinical practice.

Sherry Faye serves as director of Global Scientific Affairs for Beckman Coulter Diagnostics. She trained as a clinical biochemist in the UK’s National Health Service and has held senior roles in the global diagnostics industry for the past 20 years, spanning R&D, marketing and scientific affairs.

References

  1. Hudson PL, Dougas I, Donahoe PK, et al. An immunoassay to detect human Müllerian inhibiting substance in males and females during normal development. J Clin Endocrinol Metab. 1990;(70):16-22. 
  2. Josso N,  Legeai L, Forest M, Chaussain J, Brauner R. An enzyme linked immunoassay for anti-müllerian hormone: a new tool for the evaluation of testicular function in infants and children. J Clin Endocrinol Metab. 1990;(70):23-27.
  3. La Marca A, Sighinolfi G, Radi D, et al. Anti-Müllerian hormone (AMH) as a predictive marker in assisted reproductive technology (ART). Hum Reprod Update. 2010;(16):113-130.
  4. Hagen CP, Aksglaede L, Sørensen K, et al. Serum levels of anti-müllerian hormone as a marker of ovarian function in 926 healthy females from birth to adulthood and in 172 turner syndrome patients. J Clin Endocrinol Metab. 2010;95(11):5003-5010.
  5. Balasch J. Investigation of the infertile couple: investigation of the infertile couple in the era of assisted reproduction technology: a time for a reappraisal. Hum Reprod. 2000;(15):2251-2257.
  6. La Marca A, Sunkara SK. Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice. Hum Reprod Update. 2014;20(1):124-140. 
  7. Van Disseldorp J, Lambalk CB, Kwee J, et al. Comparison of inter- and intra-cycle variability of anti-Müllerian hormone and antral follicle counts. Human Reprod. 2010;(25):221-227.
  8. Rustamov O, Pemberton PW, Roberts SA, et al. The reproducibility of serum anti Müllerian hormone in sub-fertile women: within and between patient variability. Fertil Steril. 2011;(95):1185-1187.
  9. Kovacs G. How to improve your ART Success: An evidence based review of adjuncts to IVF. Cambridge, England: Cambridge University Press; 2011.
  10. Anderson RA, Cameron DA. Pre-treatment serum anti-müllerian hormone predicts long-term ovarian function and bone mass after chemotherapy for early breast cancer. J Clin Endocrinol Metab. 2011;96:1336-1343.
  11. Anderson RA, Rosendahl M, Kelsey TW, Cameron DA. Pre-treatment anti-Müllerian hormone predicts for loss of ovarian function after chemotherapy for early breast cancer. Eur J Cancer. 2013;49:3404-3411.
  12. Nelson SM, Yates R, Fleming R. Serum Anti-Müllerian hormone and FSH: prediction of live birth and extremes of response in stimulated cycles- implications for individualization of therapy. Human Reprod. 2007;22(9):2414-21.
  13. Riggs RM, Duran EH, Baker MW, et al. Assessment of ovarian reserve with anti-Müllerian hormone: a comparison of the predictive value of anti-Müllerian hormone, follicle-stimulating hormone, inhibin B, and age. Amer J Obstet and Gynecol. 2008;199;8(2):202.e1-8.
  14. Yates AP, Rustamov O, Roberts SA et al. Anti-Müllerian hormone tailored stimulation protocols improve outcomes whilst reducing adverse effects and costs of IVF. Hum Reprod.2011;26(9):2353-2362.24(4):867-875. 
  15. Nelson SM, Yates RW, Lyall H, et al. Anti-Müllerian hormone-based approach to controlled ovarian stimulation for assisted conception. Hum. Reprod. 2009;24(4):867-875.
Anti-Müllerian hormone (AMH) and its significance in women’s fertility
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Sherry Faye
serves as director of Global Scientific Affairs for Beckman Coulter Diagnostics.

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