AMH – modern evaluation of ovarian reserve

Part two of the expert cycle “AMH – Anti-Müllerian Hormone”, or modern evaluation of ovarian reserve, discusses the female fertility assessment based on the anti-Müllerian hormone test results. The most recent scientific reports prove that the AMH is one of the best indicators allowing to predict the efficacy of assisted reproductive technologies. In the next part, the Readers will have the opportunity to learn about the fundamentals of female fertility diagnosis.

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AMH (Anti-Müllerian Hormone) – modern evaluation of ovarian reserve

It is commonly known that as a woman ages, her reserve of eggs diminishes, and so does her ability to have children. Decrease in fertility is observed from the 30th year of age and the risk of failure in achieving pregnancy within a year of efforts grows from 5% (20-25 years of age) to 30% (35-38 years of age). A woman’s age and her ovarian reserve can also impact the quality of egg cells. An appropriate marker as a predictive factor prognosing the possibility of conceiving becomes indispensable in the assessment of the individual chance of a couple with the history of infertility starting the treatment using assisted reproductive techniques.

The parameters which have been described best and which play the most important role in the evaluation of the efficacy of assisted reproductive technologies (ART) in women are: age, ovarian reserve, egg quality, and in men: semen quality (vitality, sperm DNA fragmentation level). Now, with parameters including a woman’s age, antral follicle count (AFC), level of anti-Müllerian hormone (AMH), inhibin B, FSH level on cycle day 3, we can assess a woman’s body response to ovarian stimulation. This information, however, is still insufficient; patients with infertility problem want to obtain from a clinician the possibly most precise answer regarding their chances for pregnancy.

The most recent scientific reports prove that the best parameter for the precise assessment of the chance of infertile patients for bearing a child is the AMH hormone [1]. The anti-Müllerian hormone, or Müllerian-Inhibiting Substance (MIH), is a glycoprotein dimer which belongs to the transforming growth factor-β family [2, 3]. It occurs in women and in men but plays a different role in both of these sexes. In women, the significant presence of AMH is found only after the puberty period in the granulosa cells of primary ovarian follicles with the diameter of 4 to 6 mm where it is produced [4, 5]. The fact of the exclusively ovarian origin of AMH was confirmed by La Marca et al. in their study where the AMH level was undetectable in women in the period of 3-5 days following the bilateral resection of ovaries [6]. The serum AMH level reflects the pool of small ovarian follicles which is indicated by the fact that decrease in the number of growing follicles is preceded by decrease in the level of AMH in peripheral blood [7]. Its highest expression is observed in pre-antral and antral follicles. By its paracrine activity, AMH inhibits the FSH-stimulated growth and development of other primary follicles, at the same time ensuring the selection of the dominant follicle [8]. Due to the constant level of AMH during a woman’s menstrual cycle, it is a unique endocrine parameter which assesses the function of female gonads [6, 8], ideal as:

• fertility assessment indicator,
• parameter of the number of growing ovarian follicles – ovarian reserve marker,
• prognostic factor of premature ovarian failure.

AMH as the fertility parameter provides information on both the pool and the quality of ovarian follicles a woman in a given period of sexual maturity possesses. With a woman’s age, the reserve of ovarian follicles decreases, which is reflected by circulating AMH levels. At birth, a female newborn has 1 to 2 million oocytes; in the period of puberty – only 300 to 500 thousands are left; from this, 498 thousand undergo atresia and only 400 to 500 oocytes mature and ovulate. As a woman ages, AMH level decreases [9, 10] to undetectable level in the period of menopause [7, 8]. Anti-Müllerian hormone measurement allows to assess the actual fertility of a woman and estimate the time period in which she will be able to get pregnant. AMH does not show correlation with body mass index, and despite the fact that as a woman ages, AMH level decreases and BMI increases, no dependence between these parameters is observed, which suggests that a reverse correlation is rather secondary and dictated by a woman’s age [10]. Changes in AMH levels are not observed also in situations of decreasing level of endogenous gonadotropins decreases, such as pregnancy [6], supply of GnRH agonists [11] and when a woman takes contraceptive pills [10-14]. This indicates that the activity of ovaries is non-cyclical, FSH-independent and lasts even in cases of pituitary FSH suppression, thus proving that the level of AMH reflects the constant, FSH-independent growth of ovarian follicles [5].

Close relationship between AMH level and the pool of primary ovarian follicles provides also other important information in the diagnosis of ovarian dysfunctions. In women with hypogonadotropic hypogonadism, AMH levels are normal, which indicates that the process of ovarian follicle recruitment is not abolished [6], which was confirmed by Van Elburg et al. in case of young non-menstruating women with anorexia nervosa [15]. At the same time, in the case of hypergonadotropic hypogonadism characterized by secondary amenorrhea related to premature ovarian failure (POF), serum AMH levels are very low – or even undetectable – and correlate closely with the number of small ovarian follicles [16]. Determination of the AMH level plays also a significant role in the diagnosis of the initial stage of premature ovarian failure in still normally menstruating women with a moderate increase in pituitary gonadotropin levels. The beginning ovarian failure in its first stage can manifest itself as irregular menstrual cycles (temporary ovarian failure), and within 3 to 10 years proceeds to the stage of menopause [5, 17]. Previous studies have shown that the determination of the AMH level allows to differentiate precisely between the initial stage of POF with regular menstrual cycles and the stage of temporary ovarian failure in patients who do not meet all criteria of POF syndrome [5, 18]. The etiology of the early loss of ovarian follicles can have genetic, autoimmune, inflammatory background or be related to radio- or chemotherapy. AMH levels which correlate positively with the number of primary ovarian follicles allow the application of AMH as the precise marker of premature ovarian failure. The information provided by AMH allows women to assess their fertility, plan future children, secure against the loss of egg cells by oocyte or ovarian tissue cryopreservation. Long-term scientific studies have demonstrated that the measurement of AMH level is the reliable and early marker of ovarian damage and its decrease precedes changes of other parameters of female gonad function [20-23]. The evaluation of gonadal toxicity of chemo- or radiotherapy carried out with the use of AMH would allow to establish appropriate algorithms of clinical management which would be individual for every patient, avoiding the need to consider when the fertility preservation approach should be applied [5].

Higher AMH values are observed in women with polycystic ovary syndrome (PCOS), which is the result of enhanced AMH synthesis and secretion by granular cells [7, 24]. In relation to normal ovaries, in polycystic gonads, AMH concentration in granulosa cells seems to be 75 times higher [25], which can be caused by the disturbed process of folliculogenesis, thus leading to excessive accumulation of pre-antral and antral ovarian follicles [26]. Higher levels of AMH observed before puberty in girls with the family history of PCOS and in adolescent women with PCOS who menstruate regularly can indicate that the change in the process of follicular development takes place in infancy and early puberty, before the clinical manifestation of dysfunctional ovarian phenotype [27, 28]. AMH level shows close correlation with the severity of PCOS. The number of primary follicles observed in polycystic ovaries is 6 times higher as compared with healthy ovaries, which can result from the inhibiting effect of high AMH levels on the decrease in the pool of primary follicles, thus delaying the aging process in ovaries [24]. AMH seems to be a highly specific and sensitive diagnostic parameter of PCOS capable of replacing the important diagnostic criterion which is the number of antral follicles and applicable also in situations where ultrasound exam is not available [29]. Measurement of AMH levels can be useful in establishing therapeutic management in women with PCOS as a predictive factor of response to clomiphene citrate, or in the evaluation of the efficacy of treatment with drugs improving the biological effects of insulin [30].

Decline of reproductive functions caused by decreasing reserve of ovarian follicles and quality of oocytes with age, reflected by a significant decrease in AMH level, proves that AMH is an ideal marker of ovarian reserve evaluation and a reliable predictive factor of future reproductive life. Other parameters applied in the analysis of ovarian reserve reduction include increased FSH level, decreased level of inhibin B, antral follicle count (AFC) in ultrasound examination. Current scientific studies indicate that the most precise parameter of ovarian reserve is AMH [5, 9, 31].

Evaluation of ovarian reserve aims to:

• detect young patients with low ovarian reserve – faster treatment
• detect middle-aged patients who still have valuable egg cells – establishment of further clinical management
• exclude patients without chances for achieving pregnancy (costs and burden of treatment)

In 2002, Seifer et al. demonstrated the relationship between AMH concentration and ovarian response to stimulation with gonadotropins [32]. This report initiated the avalanche of scientific studies, with the effect that it had been demonstrated that AMH constitutes the prognostic factor of ovarian response to the process of ovarian stimulation and in consequence allows to predict the effects of treatment with assisted reproductive technologies. The fact that the level of AMH in a woman’s menstrual cycle is constant allows to use it as the independent marker of ovarian response in the process of controlled ovarian stimulation in ART methods [5, 33]. AMH, by reflecting the likely reaction of female gonads to the process of stimulation with gonadotropin analogs, allows to predict both poor and excessive response and to adjust the appropriate pharmacological doses. This ensures the effect of treatment in the case of women with POF and prevents the occurrence of ovarian hyperstimulation syndrome (OHSS) [34-35]. The next step in scientific research was the desire to find effective answer to the question frequently asked to clinicians by infertile patients: “what is our chance of having a child?” Scientific studies were conducted concerning the correlation of AMH levels with embryo morphology and incidence of aneuploidies [37]. In 2009, Nelson et al. conducted a prospective study among 340 patients attempting at IVF in which he demonstrated the significant increase in the rate of births with the increased serum AMH levels. However, such results could be related to the positive correlation between AMH levels and high number of obtained oocytes [33]. Meanwhile, Łukaszuk et al. in their study confirmed the results obtained by Nelson, indicating the statistically significant relationship between AMH values and birth rates in women subjected to IVF [1]. This has been the largest study conducted so far, based on the population of 607 patients. The study demonstrated that the chances for having a child were highest with AMH exceeding 2.4 ng/mL; they were twice lower when AMH was 1 ng/mL, and the lowest with AMH below 0.2 ng/mL. Moreover, AMH above 1.4 ng/mL provided a fourfold increased chance for having a child compared to the situation where AMH was 0.6 ng/ml [1]. Furthermore, when assessing the patients’ age, chances for having a child in women aged over 37 were 50% lower than in women aged under 35 [1]. The difference in pregnancy rate depending on the patients’ age was 30.9% in the group with high AMH levels and 26.6% in cases with low ovarian reserve (AMH 0.6-1.4 ng/mL) [1]. The study results demonstrate that AMH can be a nearly ideal parameter, allowing the precise determination of the patients’ chance for a child and establishing the appropriate strategy of clinical management in assisted reproduction centers.

To sum up, anti-Müllerian hormone plays a significant role in the process of folliculogenesis and steroidogenesis, enabling the increasingly better understanding of the pathophysiology of female gonads. The analysis of dependencies between the levels of AMH and ovarian follicle pool allows to assess precisely a patient’s fertility in various periods of her life, estimate the time for starting a family in the case of women pursuing professional career, plan the appropriate strategy of clinical management in the case of cancer patients or patients with premature ovarian failure. Close correlation with the number of primary ovarian follicles allows to assess the expected ovarian response to stimulation with gonadotropin analogs in assisted reproduction programs, thus ensuring the possibility to establish the effective algorithm of ovarian stimulation with the highest possible number of ovarian follicles obtained without adverse reactions. Recent studies show that using AMH makes it possible to predict a chance of having a child and propose the appropriate personalized therapeutic procedure for every infertile couple who comes to a fertility clinic. However, many issues relating to the physiology and clinical role of AMH still remains unexplained and requires further research. Future scientific studies focus on extra-ovarian importance of AMH. AMH type II receptors have been found in tissues outside ovaries such as endometrium, human cancer cell lines, of cervical, endometrial origin or coming from ovarian epithelium or mammary gland [38-43].

Authors of the article: Kinga Waszak, MD, PhD; K. Łukaszuk, Professor of the Medical University in Gdańsk

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