Anti-Müllerian hormone (AMH), also known asMüllerian-inhibiting factor (MIF), is aprotein that in humans is encoded by theAMHgene.
AMH is aglycoproteinhormone that belongs to thetransforming growth factor beta superfamily, which also includesinhibin and activin. These hormones play important roles in cell growth, development, and theformation of ovarian follicles.[5] In humans, the AMH gene is located onchromosome 19p13.3,[6] while itsreceptor is produced by theAMHR2 gene onchromosome 12.[7]
In male embryos, AMH is switched on by theSOX9 gene inSertoli cells of the developing testes.[8] AMH acts to block the development of theMüllerian ducts (also calledparamesonephric ducts), which would otherwise form the uterus, fallopian tubes, and upper part of the vagina. This ensures that male reproductive organs can develop properly.[9][10][8] The production of AMH during this specific window of fetal development is tightly regulated by other factors, including thenuclear receptorSF-1,GATA transcription factors, the sex-determining geneDAX1, andfollicle-stimulating hormone (FSH).[11][12][13] Mutations in theAMH gene or its receptor (type II AMH receptor) can result in the persistence of Müllerian duct structures in otherwise normally developed males.[14]
In females, AMH is produced bygranulosa cells in developing ovarian follicles, especially in the early (preantral and small antral) stages. AMH is present in the ovaries untilmenopause.[15] One of its main functions is to regulate how many follicles are recruited from the resting pool, helping to control which one becomes dominant and is selected for ovulation. After this selection, AMH levels in that follicle drop.[15][16] Because AMH is secreted by granulosa cells, which support and nourish the developing egg, its levels in the blood can be used as a marker to estimate a woman'sovarian reserve, or the number of remaining eggs.[17][18] In cattle, AMH can be used to predict how many follicles a cow will develop for embryo transfer, helping select the best animals for breeding programs.[19] AMH is also studied as a diagnostic marker for ovarian disorders, such aspolycystic ovary syndrome (PCOS).
AMH is adimericglycoprotein with amolar mass of 140 kDa.[20] The molecule consists of two identical subunits linked by sulfide bridges, and characterized by the N-terminal dimer (pro-region) and C-terminal dimer.[5] AMH binds to its Type 2 receptorAMHR2, which phosphorylates a type I receptor under theTGF beta signaling pathway.[5]
In male mammals, AMH prevents the development of theMüllerian ducts into theuterus and other Müllerian structures.[9] The effect is ipsilateral, that is each testis suppresses Müllerian development only on its own side.[21] If no hormone is produced from the gonads, the Müllerian will develop thanks to the presence of Wnt4 , while theWolffian ducts, which are responsible for male reproductive parts, will die due to the presence of COUP-TFII.[22] Amounts of AMH that are measurable in the blood vary by age and sex. AMH works by interacting with specificreceptors 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).[citation needed]
Phylogenetically, theamh gene first appears amongcartilaginous fishes in line with the appearance of paired Müllerian ducts. Inteleost fishes, there is no Müllerian duct, as male and female both develop gonoducts as a posterior extension of the gonads. Despite this,amh is expressed. During embryo development, the undifferentiated gonads expressamh expression at low and equal levels for both sexes. Later, in males,amh expression increases and remains high during and after puberty in adults.[23][24] In the female chicken embryo, the right duct and the right gonad regresses, both mediated by AMH, but the left duct remains, likely protected byestrogen.[23]
AMH is produced by granulosa cells from pre-antral and antral follicles, restricting expression to growing follicles, until they have reached the size and differentiation state at which they are selected for dominance by the action of pituitary FSH. Ovarian AMH expression has been observed as early as 36 weeks' gestation in the humans' fetus.[25] AMH expression is greatest in the recruitment stage of folliculogenesis, in the preantral and small antral follicles. This expression diminishes as follicles develop and enter selection stage, upon which FSH expression increases.[26] Some authorities suggest it is a measure of certain aspects of ovarian function,[27] useful in assessing conditions such aspolycystic ovary syndrome andpremature ovarian failure.[28]
AMH production by theSertoli 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 ofsex hormones,[29] 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 in neurons in the brains of embryonic mice, and are thought to play a role in sexuallydimorphic brain development and consequent development of gender-specific behaviours.[30] In a clade ofSebastes rockfishes in the Northwest Pacific Ocean, a duplicated copy of theAMH gene (calledAMHY) is the master sex-determining gene.[31]In vitro experiments demonstrate that the overexpression ofAMHY causes female-to-male sex reversal in at least one species,S. schlegelii.[31]
In males, inadequate embryonal AMH activity can lead topersistent Müllerian duct syndrome (PMDS), in which a rudimentary uterus is present and testes are usuallyundescended. 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 withintersex conditions,ambiguous genitalia, andcryptorchidism.[32]
Female offspring of pregnant mice injected with AMH developpolycystic ovary syndrome (PCOS)-like symptoms, including infertility, delayed puberty, and erratic ovulation. Injection ofGnRH antagonistcetrorelix prevents the appearance of reproductive defects in this context. This implies excess of AMH may cause PCOS through GnRH signaling.[33]
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 duringpuberty.[34] The rise during childhood and adolescence is likely reflective of different stages of follicle development.[35] From 25 years of age AMH declines to undetectable levels at menopause.[34]
The standard measurement of AMH follows theGeneration 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.[36]
Weak evidence suggests that AMH should be measured only in the earlyfollicular phase because of variation over themenstrual cycle. Also, AMH levels decrease under current use of oral contraceptives and currenttobacco smoking.[37]
Reference ranges for anti-Müllerian hormone, as estimated fromreference groups in theUnited States, are as follows:[38]
Females:
| Age | Unit | Value |
|---|---|---|
| Younger than 24 months | ng/mL | Less than 5 |
| pmol/L | Less than 35 | |
| 24 months to 12 years | ng/mL | Less than 10 |
| pmol/L | Less than 70 | |
| 13–45 years | ng/mL | 1 to 10 |
| pmol/L | 7 to 70 | |
| More than 45 years | ng/mL | Less than 1 |
| pmol/L | Less than 7 |
Males:
| Age | Unit | Value |
|---|---|---|
| Younger than 24 months | ng/mL | 15 to 500 |
| pmol/L | 100 to 3500 | |
| 24 months to 12 years | ng/mL | 7 to 240 |
| pmol/L | 50 to 1700 | |
| More than 12 years | ng/mL | 0.7 to 20 |
| pmol/L | 5 to 140 |
AMH measurements may be less accurate if the person being measured is vitamin D deficient.[39] Note that males are born with higher AMH levels than females in order to initiate sexual differentiation, and in women, AMH levels decrease over time as fertility decreases as well.[39]
Comparison of an individual's AMH level with respect to average levels[34] is useful in fertility assessment, as it provides a guide toovarian reserve. Because one's AMH level cannot be altered by any external factors, it helps identify whether a woman needs to consider either egg freezing or trying for a pregnancy sooner rather than later if their long-term future fertility is poor.[40][failed verification] 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.[37] However, this correlation was not found in a comparable study of younger women (aged 20 to 30 years).[37]
AMH is a predictor for ovarian response inin vitro fertilization (IVF). Measurement of AMH supports clinical decisions, but alone it is not a strong predictor of IVF success. Women with lower levels of AMH are still able to get pregnant[41] Additionally, AMH levels are used to estimate a woman's remaining egg supply.[42]
According toNICE guidelines ofin 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 gonadotrophin stimulation in IVF, while a level greater than or equal to 25.0 pmol/L (3.6 ng/mL) predicts a high response.[43] 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.[36] Subsequently, higher AMH levels are associated with greater chance of live birth after IVF, even after adjusting for age.[37][44] 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 ofovarian hyperstimulation syndrome (OHSS).[45][46] AMH can predict an excessive response in ovarian hyperstimulation with asensitivity and specificity of 82% and 76%, respectively.[47]
Measuring AMH alone may be misleading as high levels occur in conditions likepolycystic ovarian syndrome and therefore AMH levels should be considered in conjunction with atransvaginal scan of the ovaries to assessantral follicle count[48] and ovarian volume.[49]
Studies into treatments to improve low ovarian reserve and low AMH levels have met with some success. Current best available evidence suggests thatDHEA improves ovarian function, increases pregnancy chances and, by reducing aneuploidy, lowers miscarriage rates.[50] The studies into DHEA for low AMH show that a dose of 75 mg for a period of 16 weeks should be taken. Improvement of oocyte/embryo quality with DHEA supplementation potentially suggests a new concept of ovarian aging, where ovarian environments, but not oocytes themselves, age. DHEA has positive outcomes for women with AMH levels over 0.8 ng/mL or 5.7 pmol/L[51] DHEA has no apparent effect on oocytes or ovarian environments under this range.[citation needed]
Studies have demonstrated a decline in CoQ levels with age. Studies onCoQ10 supplementation in an aged animal model delayed depletion of ovarian reserve, restored oocyte mitochondrial gene expression, and improved mitochondrial activity.[52] Therefore, CoQ10 is used as a stimulator of the mitochondrial ATP formation in the electron transport chain when it's naturally deficient in ovarian aged patients. Authors note that to replicate the 12–16 weeks of using CoQ10 supplements on mice to achieve these results would be the equivalent to a decade in humans.[52]
Vitamin D is believed to play a role in AMH regulation. The AMH gene promoter contains a vitamin D response element that may cause vitamin D status to influence serum AMH levels. Women with levels of vitamin D of 267.8 ± 66.4 nmol/L show a 4 times better success rate with IVF procedure than those with low levels of 104.3 ± 21 nmol/L. Vitamin D deficiency should be considered when serum AMH levels are obtained for diagnosis.[39]
In women with cancer,radiation therapy andchemotherapy 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 indicatefertility preservation strategies such asoocyte cryopreservation.[37] A post-treatment AMH is associated with decreased fertility.[35][37]
Granulosa cell tumors of the ovary secrete AMH, and AMH testing has asensitivity ranging between 76 and 93% in diagnosing such tumors.[37] AMH is also useful in diagnosing recurrence of granulosa cell tumors.[37]
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.[53]
Polycystic ovary syndrome (PCOS) is an endocrine disorder most commonly found in women of reproductive age that is characterized by oligo- oranovulation,hyperandrogenism, andpolycystic ovaries (PCO).[54] This endocrine disorder increases AMH levels at nearly two to three times higher in women with PCOS than in normal type women. This is often attributed to the increased follicle count number characteristic of PCOS, indicating an increase in granulosa cells since they surround each individual egg.[55] However, increased AMH levels have also been attributed not just to the increased number of follicles, but also to an increased amount of AMH produced per follicle.[56] The high levels of androgens, characteristic of PCOS, also stimulate and provide feedback for increased production of AMH, as well.[26] In this way, AMH has been increasingly considered to be a tool or biomarker that can be used to diagnose or indicate PCOS.[citation needed]
Turner syndrome is the most common sex chromosome-related inherited diseases in females around the world, with the incidence of 1 in 2000 live female births.[57] One of the significant pathological features is the premature ovarian failure, leading to amenorrhea or even infertility. Follicle stimulating hormone and inhibin B were recommended to be monitored routinely by specialists to speculate the condition of ovary. Recently, anti-Müllerian hormone is advised as a more accurate biomarker for follicular development by several researchers. The biological function of anti-Müllerian hormone in ovary is to counteract the recruitment of primordial follicles triggered by FSH, reserving the follicle pool for further recruitment and ovulation. When menopause takes place, the serum concentration of anti-Müllerian hormone will be nearly undetectable among normal women. Thus, variations in AMH levels during childhood may theoretically predict the duration of any given girl's reproductive life span, assuming that the speed of the continuous follicle loss is comparable between individuals.[58]
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 includingendometriosis,adenomyosis, and uterinecancer. Research is underway in several laboratories.If there were more standardized AMH assays, it could potentially be used as abiomarker ofpolycystic ovary syndrome.[59]
In mice, an increase in AMH has been shown to reduce the number of growing follicles and thus the overall size of the ovaries. This increase in AMH production reduces primary, secondary and antral follicles without reducing the number of primordial follicles suggesting a blockade of primordial follicle activation. This may provide a viable method of contraception which protects the ovarian reserve of oocytes during chemotherapy without extracting them from the body allowing the potential for natural reproduction later in life.[60]
The adjectiveMüllerian is writteneitherMüllerian ormüllerian, depending on the governingstyle guide; the derived term with theprefixanti- is thenanti-Müllerian,anti-müllerian, orantimüllerian. The Müllerian ducts are named afterJohannes Peter Müller.[61]
A list of the names that have been used for the antimüllerian hormone is as follows. For the sake of simplicity, this list ignores someorthographic variations; for example, it gives only one row for "Müllerian-inhibiting hormone", although there are four acceptable stylings thereof (capital M or lowercase m, hyphen or space).
| Protein name styling | Protein symbol |
|---|---|
| Anti-Müllerian hormone | AMH |
| Müllerian-inhibiting factor | MIF |
| Müllerian-inhibiting hormone | MIH |
| Müllerian-inhibiting substance | MIS |
| Müllerian duct inhibitory factor | MDIF |
| Müllerian regression factor | MRF |
| Anti-paramesonephric hormone | APH |
