Anti-Müllerian hormone (AMH), also known as Müllerian-inhibiting hormone (MIH), is a

glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glyco ...

hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...

structurally related to inhibin and activin from the

transforming growth factor beta Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other ...

superfamily, whose key roles are in growth differentiation and

folliculogenesis :''Although the process is similar in many animals, this article will deal exclusively with human folliculogenesis.'' In biology, folliculogenesis is the maturation of the ovarian follicle, a densely packed shell of somatic cells that contains a ...

. In humans, it is encoded by the

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

, on

chromosome 19 Chromosome 19 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 19 spans more than 58.6 million base pairs, the building material of DNA. It is considered the most gene-rich chromos ...

p13.3, while its

receptor Receptor may refer to: *Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...

is encoded by the gene on chromosome 12. AMH is activated by

SOX9 Transcription factor SOX-9 is a protein that in humans is encoded by the ''SOX9'' gene. Function SOX-9 recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding proteins. It is expressed by proliferating but n ...

in the Sertoli cells of the male fetus. Its expression inhibits the development of the female reproductive tract, or Müllerian ducts ( paramesonephric ducts), in the male

embryo An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...

, thereby arresting the development of fallopian tubes, uterus, and upper vagina. ''AMH'' expression is critical to sex differentiation at a specific time during fetal development, and appears to be tightly regulated by

nuclear receptor In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroid hormone, steroids, thyroid hormone, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to ...

SF-1, transcription GATA factors, sex-reversal gene DAX1, and

follicle-stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, ...

(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 masculinized. AMH is also a product of granulosa cells of the preantral and small antral follicles in women. As such, AMH is only present in the ovary until

menopause Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...

. Production of AMH regulates folliculogenesis by inhibiting recruitment of follicles from the resting pool in order to select for the dominant follicle, after which the production of AMH diminishes. As a product of the granulosa cells, which envelop each egg and provide them energy, AMH can also serve as a molecular biomarker for relative size of the ovarian reserve. In humans, this is helpful because 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 can also be used as a marker for ovarian dysfunction, such as in women with

polycystic ovary syndrome Polycystic ovary syndrome, or PCOS, is the most common endocrine disorder in women of reproductive age. The syndrome is named after the characteristic cysts which may form on the ovaries, though it is important to note that this is a sign and no ...

(PCOS).

Structure

AMH is a dimeric

with a molar mass of 140 kDa. The molecule consists of two identical subunits linked by sulfide bridges, and characterized by the N-terminal dimer (pro-region) and C-terminal dimer. AMH binds to its Type 2 receptor AMHR2, which phosphorylates a type I receptor under the TGF beta signaling pathway.

Function

Embryogenesis

In male mammals, AMH prevents the development of the Müllerian ducts into the

uterus The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The ...

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 eight 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 Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...

) of the target tissue (the fetal Müllerian ducts).

Ovarian

AMH is expressed by

granulosa cells A granulosa cell or follicular cell is a somatic cell of the sex cord that is closely associated with the developing female gamete (called an oocyte or egg) in the ovary of mammals. Structure and function In the primordial ovarian follicle, and ...

of the

ovary The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. ...

during the reproductive years, and limits the formation of primary follicles by inhibiting excessive follicular recruitment by FSH. 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. Some authorities suggest it is a measure of certain aspects of ovarian function, useful in assessing conditions such as

and

premature ovarian failure Primary ovarian insufficiency (POI) (also called premature ovarian insufficiency, premature menopause, and premature ovarian failure) is the partial or total loss of reproductive and hormonal function of the ovaries before age 40 because of fol ...

Other

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 hormone Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effect ...

s, 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 sexually dimorphic brain development and consequent development of gender-specific behaviours. In a clade of '' Sebastes'' rockfishes in the Northwest Pacific Ocean, a duplicated copy of the ''AMH'' gene (called ''AMHY'') is the master sex-determining gene. ''In vitro'' experiments demonstrate that the overexpression of ''AMHY'' causes female-to-male sex reversal in at least one species, '' S. schlegelii''.

Pathology

In men, inadequate embryonal AMH activity can lead to the ''

persistent Müllerian duct syndrome Persistent Müllerian duct syndrome (PMDS) is the presence of Müllerian duct derivatives (fallopian tubes, uterus, and/or the upper part of the vagina) in what would be considered a genetically and otherwise physically normal male animal by typi ...

'' (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 Intersex people are individuals born with any of several sex characteristics including chromosome patterns, gonads, or genitals that, according to the Office of the United Nations High Commissioner for Human Rights, "do not fit typical b ...

conditions,

ambiguous genitalia Intersex people are individuals born with any of several sex characteristics including chromosome patterns, gonads, or genitals that, according to the Office of the United Nations High Commissioner for Human Rights, "do not fit typical ...

, and

cryptorchidism Cryptorchidism, also known as undescended testis, is the failure of one or both testes to descend into the scrotum. The word is from Greek () 'hidden' and () 'testicle'. It is the most common birth defect of the male genital tract. About 3% of ...

. A study published in Nature Medicine found a link between hormonal imbalance in the womb and

(PCOS), specifically prenatal exposure to anti-Müllerian hormone. For the study, the researchers injected pregnant mice with AMH so that they had a higher than normal concentration of the hormone. Indeed, they gave birth to daughters who later developed PCOS-like tendencies. These included problems with fertility, delayed puberty, and erratic ovulation. To reverse it, the researchers dosed the polycystic mice with an IVF drug called cetrorelix, which made the symptoms to go away. These experiments should be confirmed in humans, but it could be the first step in understanding the relationship between the polycystic ovary and the anti-Müllerian hormone.

Blood levels

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 Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a ...

. 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 The follicular phase, also known as the preovulatory phase or proliferative phase, is the phase of the estrous cycle (or, in primates for example, the menstrual cycle) during which follicles in the ovary mature from primary follicle to a fully ...

because of variation over the

menstrual cycle The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that make pregnancy possible. The ovarian cycle controls the production and release of eggs ...

. Also, AMH levels decrease under current use of oral contraceptives and current

tobacco smoking Tobacco smoking is the practice of burning tobacco and ingesting the resulting smoke. The smoke may be inhaled, as is done with cigarettes, or simply released from the mouth, as is generally done with pipes and cigars. The practice is beli ...

Reference ranges

Reference ranges for anti-Müllerian hormone, as estimated from reference groups in the

United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country Continental United States, primarily located in North America. It consists of 50 U.S. state, states, a Washington, D.C., ...

, are as follows: Females: Males: AMH measurements may be less accurate if the person being measured is vitamin D deficient. 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.

Clinical usage

General fertility assessment

Comparison of an individual's AMH level with respect to average levels is 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 30 years).

In vitro fertilization

AMH is a predictor for ovarian response in ''in vitro'' fertilization (IVF). Measurement of AMH supports clinical decisions, but alone it is not a suitable predictor of IVF success. Additionally, AMH levels are used to estimate a woman's remaining egg supply. According to

NICE guidelines The National Institute for Health and Care Excellence (NICE) is an executive non-departmental public body of the Department of Health and Social Care in England that publishes guidelines in four areas: * the use of health technologies withi ...

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 gonadotrophin stimulation in IVF, while a level greater than or equal to 25.0 pmol/L (3.6 ng/mL) predicts a high response.Fertility: assessment and treatment for people with fertility problems
NICE clinical guideline CG156 - Issued: February 2013 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 ''Sensitivity'' and ''specificity'' mathematically describe the accuracy of a test which reports the presence or absence of a condition. Individuals for which the condition is satisfied are considered "positive" and those for which it is not are ...

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.

Natural remedies

Studies into treatments to improve low ovarian reserve and low AMH levels have met with some success. Current best available evidence suggests that

DHEA Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone precursor. It is one of the most abundant circulating steroids in humans. DHEA is produced in the adrenal glands, the gonads, and the brain. It functi ...

improves ovarian function, increases pregnancy chances and, by reducing aneuploidy, lowers miscarriage rates. 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 DHEA has no apparent effect on oocytes or ovarian environments under this range. Studies on CoQ10 supplementation in an aged animal model delayed depletion of ovarian reserve, restored oocyte mitochondrial gene expression, and improved mitochondrial activity. 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.

Vitamin D Vitamin D is a group of Lipophilicity, fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group ar ...

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.

Women with cancer

In women with cancer,

radiation therapy Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally provided as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Rad ...

and

chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemother ...

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 Human oocyte cryopreservation (egg freezing) is a procedure to preserve a woman's eggs (oocytes). This technique has been used to enable women to postpone pregnancy to a later date – whether for medical reasons (such as cancer treatment), or fo ...

. 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.

Biomarker of polycystic ovary syndrome

Polycystic ovary syndrome Polycystic ovary syndrome, or PCOS, is the most common endocrine disorder in women of reproductive age. The syndrome is named after the characteristic cysts which may form on the ovaries, though it is important to note that this is a sign and no ...

(PCOS) is an endocrine disorder most commonly found in women of reproductive age that is characterized by oligo- or anovulation, hyperandrogenism, and polycystic ovaries (PCO). 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. 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. The high levels of androgens, characteristic of PCOS, also stimulate and provide feedback for increased production of AMH, as well. In this way, AMH has been increasingly considered to be a tool or biomarker that can be used to diagnose or indicate PCOS.

Biomarker of Turner syndrome

Turner syndrome Turner syndrome (TS), also known as 45,X, or 45,X0, is a genetic condition in which a female is partially or completely missing an X chromosome. Signs and symptoms vary among those affected. Often, a short and webbed neck, low-set ears, low h ...

is the most common sex chromosome-related inherited diseases in female around the world, with the incidence of 1 in 2000 live female births. 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 amongst 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.

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 Endometriosis is a disease of the female reproductive system in which cells similar to those in the endometrium, the layer of tissue that normally covers the inside of the uterus, grow outside the uterus. Most often this is on the ovaries, fa ...

adenomyosis Adenomyosis is a medical condition characterized by the growth of cells that proliferate on the inside of the uterus ( endometrium) atypically located among the cells of the uterine wall ( myometrium), as a result, thickening of the uterus occurs. ...

, and uterine

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

. Research is underway in several laboratories. If there were more standardized AMH assays, it could potentially be used as a

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...

. 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.

Names

The adjective "Müllerian" is written either "Müllerian" or "müllerian", depending on the governing

style guide A style guide or manual of style is a set of standards for the writing, formatting, and design of documents. It is often called a style sheet, although that term also has multiple other meanings. The standards can be applied either for gene ...

; the derived term with the

prefix A prefix is an affix which is placed before the stem of a word. Adding it to the beginning of one word changes it into another word. For example, when the prefix ''un-'' is added to the word ''happy'', it creates the word ''unhappy''. Particul ...

of "

anti- Anti- is an American record label founded in 1999 as a sister label to Epitaph Records. While Epitaph's focus has mostly been on punk rock, Anti-'s roster includes gospel (Mavis Staples), country (Merle Haggard), hip hop ( Sage Francis, The C ...

" is then "anti-Müllerian", "anti-müllerian", or "antimüllerian". The Müllerian ducts are named after

Johannes Peter Müller Johannes Peter Müller (14 July 1801 – 28 April 1858) was a German physiologist, comparative anatomist, ichthyologist, and herpetologist, known not only for his discoveries but also for his ability to synthesize knowledge. The paramesonephri ...

. 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).

References

{{DEFAULTSORT:Anti-Mullerian Hormone Animal developmental biology Fish hormones Hormones of the embryo Biomarkers