Anti-Müllerian hormone (AMH), also known by various other names, is a protein that in humans is encoded by the AMH gene. It is a hormone that inhibits the development of the Müllerian ducts (paramesonephric ducts) in the male embryo.
- Species distribution
- Blood levels
- Reference ranges
- In vitro fertilization
- General fertility assessment
- Women with cancer
- Neutering status in animals
- Potential future usage
Although the AMH receptor is expressed in both male and female fetuses, AMH expression has been isolated to male sertoli cells. Expression of AMH is activated by SOX9 in the male Sertoli cells and causes the irreversible regression of the Müllerian ducts. Because AMH expression is critical to sex differentiation at a specific time during fetal development, it appears to be tightly regulated by SF1, GATA factors, DAX1 and FSH. Mutations in both the AMH gene and the type II AMH receptor have been shown to cause the persistence of Müllerian derivatives in males that are otherwise normally virilized.
AMH expression also occurs in ovarian granulosa cells of females postpartum, and serves as a molecular biomarker for relative size of the ovarian reserve. In humans, the number of cells in the follicular reserve can be used to predict timing of menopause. In bovine, AMH can be used for selection of females in multi-ovulatory embryo transfer programs by predicting the number of antral follicles developed to ovulation.
AMH is present in fish, reptiles, birds, marsupials, and placental mammals.
AMH is a protein hormone structurally related to inhibin and activin, and a member of the transforming growth factor-β (TGF-β) family. It is a dimeric glycoprotein. It has a molar mass of 140 kDa.
In humans, the gene for AMH is AMH, on chromosome 19p13.3, while the gene AMHR2 codes for its receptor on chromosome 12.
In mammals, AMH prevents the development of the Müllerian ducts into the uterus and other Müllerian structures. The effect is ipsilateral, that is each testis suppresses Müllerian development only on its own side. In humans, this action takes place during the first 8 weeks of gestation. If no hormone is produced from the gonads, the Müllerian ducts automatically develop, while the Wolffian ducts, which are responsible for male reproductive parts, automatically die. Amounts of AMH that are measurable in the blood vary by age and sex. AMH works by interacting with specific receptors on the surfaces of the cells of target tissues (anti-Müllerian hormone receptors). The best-known and most specific effect, mediated through the AMH type II receptors, includes programmed cell death (apoptosis) of the target tissue (the fetal Müllerian ducts).
AMH is expressed by granulosa cells of the ovary during the reproductive years, and limits the formation of primary follicles by inhibiting excessive follicular recruitment by FSH. Some authorities suggest it is a measure of certain aspects of ovarian function, useful in assessing conditions such as polycystic ovary syndrome and premature ovarian failure. It is useful to predict a poor ovarian response in in vitro fertilization (IVF), but it does not appear to add any predictive information about success rates of an already established pregnancy after IVF. Additionally, AMH levels are used to determine a women's remaining egg supply.
AMH production by the Sertoli cells of the testes remains high throughout childhood in males but declines to low levels during puberty and adult life. AMH has been shown to regulate production of sex hormones, and changing AMH levels (rising in females, falling in males) may be involved in the onset of puberty in both sexes. Functional AMH receptors have also been found to be expressed on neurons in the brains of embryonic mice, and are thought to play a role in sexually dimorphic brain development and consequent development of gender-specific behaviours.
In men, inadequate embryonal AMH activity can lead to the Persistent Müllerian duct syndrome (PMDS), in which a rudimentary uterus is present and testes are usually undescended. The AMH gene (AMH) or the gene for its receptor (AMH-RII) are usually abnormal. AMH measurements have also become widely used in the evaluation of testicular presence and function in infants with intersex conditions, ambiguous genitalia, and cryptorchidism.
In healthy females AMH is either just detectable or undetectable in cord blood at birth and demonstrates a marked rise by three months of age; while still detectable it falls until four years of age before rising linearly until eight years of age remaining fairly constant from mid-childhood to early adulthood – it does not change significantly during puberty. The rise during childhood and adolescence is likely reflective of different stages of follicle development. From 25 years of age AMH declines to undetectable levels at menopause.
The standard measurement of AMH follows the Generation II assay. This should give the same values as the previously used IBC assay, but AMH values from the previously used DSL assay should be multiplied with 1.39 to conform to current standards because it used different antibodies.
Weak evidence suggests that AMH should be measured only in the early follicular phase because of variation over the menstrual cycle. Also, AMH levels decrease under current use of oral contraceptives and current tobacco smoking.
Reference ranges for Anti-Müllerian hormone, as estimated from reference groups in the United states, are as follows:
AMH measurements may be less accurate if the person being measured is vitamin D deficient.
In vitro fertilization
According to NICE guidelines of in vitro fertilization, an anti-Müllerian hormone level of less than or equal to 5.4 pmol/l (0.8 ng/mL) predicts a low response to ovarian hyperstimulation, while a level greater than or equal to 25.0 pmol/l (3.6 ng/mL) predicts a high response. Other cut-off values found in the literature vary between 0.7 and 20 pmol/l (0.1 and 2.97 ng/ml) for low response to ovarian hyperstimulation. Subsequently, higher AMH levels are associated with greater chance of live birth after IVF, even after adjusting for age. AMH can thereby be used to rationalise the programme of ovulation induction and decisions about the number of embryos to transfer in assisted reproduction techniques to maximise pregnancy success rates whilst minimising the risk of ovarian hyperstimulation syndrome (OHSS). AMH can predict an excessive response in ovarian hyperstimulation with a sensitivity and specificity of 82% and 76%, respectively.
Measuring AMH alone may be misleading as high levels occur in conditions like polycystic ovarian syndrome and therefore AMH levels should be considered in conjunction with a transvaginal scan of the ovaries to assess antral follicle count and ovarian volume.
General fertility assessment
Comparison of an individual's AMH level with respect to average levels is also useful in fertility assessment, as it provides a guide to ovarian reserve and identifies women that may need to consider either egg freezing or trying for a pregnancy sooner rather than later if their long-term future fertility is poor. A higher level of anti-Müllerian hormone when tested in women in the general population has been found to have a positive correlation with natural fertility in women aged 30–44 aiming to conceive spontaneously, even after adjusting for age. However, this correlation was not found in a comparable study of younger women (aged 20 to 35 years).
Women with cancer
In women with cancer, radiation therapy and chemotherapy can damage the ovarian reserve. In such cases, a pre-treatment AMH is useful in predicting the long-term post-chemotherapy loss of ovarian function, which may indicate fertility preservation strategies such as oocyte cryopreservation. A post-treatment AMH is associated with decreased fertility.
Granulosa cell tumors of the ovary secrete AMH, and AMH testing has a sensitivity ranging between 76 and 93% in diagnosing such tumors. AMH is also useful in diagnosing recurrence of granulosa cell tumors.
Neutering status in animals
In veterinary medicine, AMH measurements are used to determine neutering status in male and female dogs and cats. AMH levels can also be used to diagnose cases of ovarian remnant syndrome.
Potential future usage
AMH has been synthesized. Its ability to inhibit growth of tissue derived from the Müllerian ducts has raised hopes of usefulness in the treatment of a variety of medical conditions including endometriosis, adenomyosis, and uterine cancer. Research is underway in several laboratories. If there were more standardized AMH assays, it could potentially be used as a biomarker of polycystic ovary syndrome.
The adjective "Müllerian" is written either "Müllerian" or "müllerian", depending on the governing style guide; the derived term with the prefix of "anti-" is then "anti-Müllerian", "anti-müllerian", or "antimüllerian". The Müllerian ducts are named after Johannes Peter Müller.
A list of the names that have been used for the antimüllerian hormone is as follows. For the sake of simplicity, this list ignores some orthographic variations; for example, it gives only one row for "Müllerian-inhibiting hormone", although there are 4 acceptable stylings thereof (cap M or lowercase m, hyphen or space).