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Editorial |
School of Biological and Molecular Sciences Oxford Brookes University Headington, Oxford OX3 OBP, United Kingdom
Address all correspondence and requests for reprints to: Nigel P. Groome, Oxford Brookes University, School of Biological and Molecular Sciences, Gypsy Lane Campus, Headington, Oxford OX3 0BP, United Kingdom. E-mail: npgroome{at}brookes.ac.uk.
Anti-Müllerian hormone (AMH) is a homodimeric glycoprotein member of the TGF superfamily whose existence was discovered in the 1940s by Alfred Jost. It has a variety of actions, all within the reproductive system (1, 2, 3, 4). Whereas there have been five international workshops on inhibins, activins, and follistatin, there has only been one on AMH, organized by Natalie Josso in France in 2002. Undoubtedly the clinical potential of inhibin measurements was more quickly recognized. However, since that time, those active in the field of reproductive endocrinology cannot fail to have noticed the increasing number of publications recognizing the new potential clinical value of measurements of serum AMH concentrations. Two different immunoassays for AMH are commercially available, one from Immunotech, and another from Diagnostic Systems Laboratories (DSL). Both companies are now owned by Beckman Coulter. Serious consideration is now being addressed to the introduction of AMH assays into routine clinical practice on a wider front. In this light, the paper in this issue of The Journal of Clinical Endocrinology and Metabolism by Hehenkamp et al. (5) is of great interest. It establishes that, whereas concentrations of other ovarian hormones vary considerably through the menstrual cycle, by contrast, AMH is sufficiently constant to allow samples for evaluation to be taken at any time. This finding extends earlier work by Fanchin et al. (6) in suggesting the high reproducibility of repeated serum AMH measurements. There is no data at the moment on possible diurnal variation of AMH levels as has been observed, for example, with inhibin B. It is, perhaps, important to address this issue because it may account for some of the apparent day-to-day variations that are found in serial samples from the same woman (5).
Another contribution of the paper by Hehenkamp et al. (5) is that they report the first comparison of values obtained with each of the two commercial AMH assays. So what can be said objectively about these two AMH immunoassays in use? Both are convenient microplate-based two-site ELISAs using peroxidase labels. A high correlation between values obtained with the two assays is observed, although absolute values in the DSL assay are approximately half of those for the same samples with the Immunotech assay. There is probably no great significance in this difference, which arises because the two assays were established with different preparations of recombinant human AMH. There currently is no international reference standard for AMH, and this is something that would be very useful given the rising clinical usage. Both assays seem to have the sensitivity, reproducibility, and specificity needed for clinical work. The pair of antibodies selected for the current DSL AMH assay were chosen to allow essentially the same assay to work for human, rat, and mouse sera. Also the immunoreactivity measured by the DSL assay has proved sufficiently stable to allow the use of liquid rather than lyophilized AMH standards. Both assays have been successfully applied to serum and follicular fluid samples and have been validated using repeated dilution and recovery experiments.
What exactly does AMH do? In the male, as a Sertoli cell product, a major function is the induction of regression of the Müllerian ducts in male fetuses. This clear role has led to the continued use of the term Müllerian inhibiting substance as an alternative name for the hormone. AMH also plays a role in Leydig cell steroidogenesis (7). In females, AMH is a product of granulosa cells and has an inhibitory effect on primordial follicle recruitment as well as on the responsiveness of growing follicles to FSH (2). Concentrations of AMH are much higher in small antral follicles than preovulatory follicles, and this accounts for the observed fall in circulating AMH after gonadotropin stimulation (4). AMH concentrations in individual follicles appear to be higher in healthy follicles, leading to the suggestion that circulating AMH levels reflect both the quantity and quality of remaining follicles (4).
So what practical clinical applications exist for the measurement of serum AMH? In the male, AMH has long been recognized as an excellent marker for prepubertal testicular development, and has been used to investigate intersex conditions (7). By contrast, serum AMH is not reported to be useful in the prediction of the efficiency of sperm retrieval in men with nonobstructive azoospermia (8). In the female, both human and animal studies (9) suggest that serum AMH concentrations reflect the size of the primordial follicle pool. Serum AMH levels show an excellent correlation with the number of antral follicle seen with vaginal ultrasound (1, 2). This has led to the interest in AMH as a marker for ovarian reserve. In the female, it seems clear from numerous studies that basal AMH is the best single marker for predicting the subsequent ovarian response to gonadotropin stimulation (10). This is true in terms of both the number of oocytes retrieved and the percentage of cycles cancelled (10, 11). There is also evidence to suggest that the quality of oocytes resulting from in vitro fertilization (IVF) pregnancies correlated with maternal serum AMH (12, 13). Although some studies indicate that AMH is useful in predicting successful pregnancies, others do not claim this (14). Many factors influence the probability of pregnancy besides those related to ovarian/follicular functioning, so it is not surprising that AMH measurements are unable to predict outcome in terms of pregnancies. In individual women, serial serum AMH levels appear to offer the potential of charting the decline of ovarian reserve with age and of detecting the onset of menopause (15). Serum AMH concentrations appear to change ahead of other hormonal markers of the menopause (2). It has been claimed recently that measurement of basal AMH can identify women at risk of ovarian hyperstimulation (16). Baseline serum AMH levels in patients with ovarian hyperstimulation syndrome were 6-fold higher than those in normal controls (16).
Serum AMH concentrations are markedly elevated in patients with polycystic ovarian syndrome (PCOS) (17) and decrease significantly when women are treated with metformin (18), suggesting an application of AMH in the initial diagnosis of PCOS and monitoring of therapy. An exciting recent finding is that serum AMH concentrations are elevated in the prepubertal daughters of women with PCOS (19). The authors suggest that AMH may be used as a prepubertal developmental marker for ovarian follicular development (19).
In the treatment of female cancer patients, AMH has several potential applications. It has long been known to be a specific and sensitive tumor marker for granulosa cell tumors of the ovary (20), particularly in postmenopausal women. More recently, AMH has been shown to be a useful marker for the decline in ovarian reserve in women undergoing chemotherapy for other cancers, e.g. breast cancer. This might be a suitable tool to allow selection of less gonadotoxic regimes (21).
So how far has AMH immunoassay gotten toward clinical applications in a typical large teaching hospital? Our collaborators in Rotterdam advise us that, in the infertility clinic at Erasmus MC, serum AMH is now measured routinely in all women undergoing investigation for infertility problems, especially possible PCOS. AMH is used to help to decide whether IVF treatment is advised. They also measure other hormones such as the classical FSH, inhibin B, and estradiol. In future work predicting the number of oocytes retrieved in IVF, it seems that adding d-3 basal inhibin B and FSH measurements will not add significantly to the value of AMH alone (15).
What future clinical research studies are needed in relation to AMH? First, one can anticipate studies correlating the AMH concentrations in individual aspirated follicles with oocyte quality and subsequent successful fertilization and embryo quality. Other groups will surely seek to confirm the use of serum AMH assays to predict those at risk of ovarian hyperstimulation syndrome and introduce this application into clinical practice (16). Whereas basal AMH appears the most predictive of the static hormone tests for ovarian response in IVF, it remains to be determined whether this is superior to dynamic assays of inhibin B (22, 23, 24) or estradiol, which are also claimed to be reproducible from cycle to cycle (25). In relation to granulosa cell tumors, there needs to be a definitive comparison of AMH, total inhibin, and inhibin B to determine which are the most useful markers of disease progression in both premenopausal and postmenopausal women, and whether one or several markers should be used.
With the current pace of AMH research, the boundary between interesting research and clinical practice is difficult to define. The time is coming when clinical groups will hope to read a review article giving firm consensus advice from a panel of experts on how to use AMH assays in their clinical practice. Overall, these are particularly exciting times for those working on clinical aspects of AMH, and this is clearly a hormone for which a time of recognition has come.
Footnotes
Abbreviations: AMH, Anti-Müllerian hormone; IVF, in vitro fertilization; PCOS, polycystic ovarian syndrome.
Received July 7, 2006.
Accepted July 19, 2006.
References
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