Anti-Müllerian hormone

anti-Müllerian hormone
Identifiers
Symbol AMH
Entrez 268
HUGO 464
OMIM 600957
RefSeq NM_000479
UniProt P03971
Other data
Locus Chr. 19 p13.3
anti-Müllerian hormone receptor, type II
Identifiers
Symbol AMHR2
Entrez 269
HUGO 465
OMIM 600956
RefSeq NM_020547
UniProt Q16671
Other data
Locus Chr. 12 q13

Anti-Müllerian hormone also known as AMH is a protein that, in humans, is encoded by the AMH gene.[1] It inhibits the development of the Müllerian ducts (paramesonephric ducts) in the male embryo.[2] It has also been called Müllerian inhibiting factor (MIF), Müllerian-inhibiting hormone (MIH), Müllerian-inhibiting substance (MIS), and Anti-paramesonephric hormone (APH).[3] It is named after Johannes Peter Müller.

Although the AMH receptor is expressed in both male and female fetuses, AMH expression has been isolated to male sertoli cells.[4] Expression of AMH is activated by SOX9 in the male Sertoli cells and causes the irreversible regression of the Müllerian ducts.[5] 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.[6][7][8] 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.[9]

AMH expression also occurs in ovarian granulosa cells of females postpartum, and serves as a molecular biomarker for relative size of the ovarian reserve.[10] In humans, the number of cells in the follicular reserve can be used to predict timing of menopause.[11] 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.[12]

Species distribution

AMH is present in fish, reptiles, birds, marsupials, and placental mammals.

Sources

AMH is secreted by Sertoli cells of the testes during embryogenesis of the fetal male. In females, it is secreted by the granulosa cells of ovarian follicles.

Structure

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.[13]

Gene

In humans, the gene for AMH is AMH, on chromosome 19p13.3,[1] while the gene AMHR2 codes for its receptor on chromosome 12.[14]

Function

Embryogenesis

In mammals, AMH prevents the development of the Müllerian ducts into the uterus and other Müllerian structures.[2] The effect is ipsilateral, that is each testis suppresses Müllerian development only on its own side.[15] 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.[16] 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. 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).

Ovarian

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.[10][17] Some authorities suggest it is a measure of certain aspects of ovarian function,[18] useful in assessing conditions such as polycystic ovary syndrome and premature ovarian failure.[19] 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.[20] Additionally, AMH levels are used to determine a women's remaining egg supply.[21]

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 hormones,[22] 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.[23]

Pathology

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.

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.[24] The rise during childhood and adolescence is likely reflective of different stages of follicle development.[17] From 25 years of age AMH declines to undetectable levels at menopause.[24]

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.[25]

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.[26]

Reference ranges

Reference ranges for Anti-Müllerian hormone, as estimated from reference groups in the United states, are as follows:[27]

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.[28]

Clinical usage

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.[29] 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.[25] Subsequently, higher AMH levels are associated with greater chance of live birth after IVF, even after adjusting for age.[26][30] 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)[31][32] AMH can predict an excessive response in ovarian hyperstimulation with a sensitivity and specificity of 82% and 76%, respectively.[33]

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[34] and ovarian volume.[35]

General fertility assessment

Comparison of an individual's AMH level with respect to average levels[24] 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.[36] 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.[26] However, this correlation was not found in a comparable study of younger women (aged 20 to 35 years).[26]

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.[26] A post-treatment AMH is associated with decreased fertility.[17][26]

Granulosa cell tumors of the ovary secrete AMH, and AMH testing has a sensitivity ranging between 76 and 93% in diagnosing such tumors.[26] AMH is also useful in diagnosing recurrence of granulosa cell tumors.[26]

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.[37]

See also

References

  1. 1 2 Cate RL, Mattaliano RJ, Hession C, Tizard R, Farber NM, Cheung A, Ninfa EG, Frey AZ, Gash DJ, Chow EP (Jun 1986). "Isolation of the bovine and human genes for Müllerian inhibiting substance and expression of the human gene in animal cells". Cell 45 (5): 685–98. doi:10.1016/0092-8674(86)90783-X. PMID 3754790.
  2. 1 2 Behringer RR (1994). "The in vivo roles of müllerian-inhibiting substance". Current Topics in Developmental Biology. Current Topics in Developmental Biology 29: 171–87. doi:10.1016/S0070-2153(08)60550-5. PMID 7828438.
  3. ↑ Minkoff E, Baker P (2004). Biology Today: An Issues Approach (Third ed.). New York: Garland Science. p. 296. ISBN 1136838759.
  4. ↑ Rey R, Lukas-Croisier C, Lasala C, Bedecarrás P (Dec 2003). "AMH/MIS: what we know already about the gene, the protein and its regulation". Molecular and Cellular Endocrinology 211 (1-2): 21–31. doi:10.1016/j.mce.2003.09.007. PMID 14656472.
  5. ↑ Taguchi O, Cunha GR, Lawrence WD, Robboy SJ (Dec 1984). "Timing and irreversibility of Müllerian duct inhibition in the embryonic reproductive tract of the human male". Developmental Biology 106 (2): 394–8. doi:10.1016/0012-1606(84)90238-0. PMID 6548718.
  6. ↑ Shen WH, Moore CC, Ikeda Y, Parker KL, Ingraham HA (Jun 1994). "Nuclear receptor steroidogenic factor 1 regulates the müllerian inhibiting substance gene: a link to the sex determination cascade". Cell 77 (5): 651–661. doi:10.1016/0092-8674(94)90050-7. PMID 8205615.
  7. ↑ Nachtigal MW, Hirokawa Y, Enyeart-VanHouten DL, Flanagan JN, Hammer GD, Ingraham HA (May 1998). "Wilms' tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression". Cell 93 (3): 445–454. doi:10.1016/s0092-8674(00)81172-1. PMID 9590178.
  8. ↑ Viger RS, Mertineit C, Trasler JM, Nemer M (Jul 1998). "Transcription factor GATA-4 is expressed in a sexually dimorphic pattern during mouse gonadal development and is a potent activator of the Müllerian inhibiting substance promoter". Development 125 (14): 2665–2675. PMID 9636081.
  9. ↑ Belville C, Josso N, Picard JY (Dec 1999). "Persistence of Müllerian derivatives in males". American Journal of Medical Genetics 89 (4): 218–223. doi:10.1002/(sici)1096-8628(19991229)89:4<218::aid-ajmg6>3.0.co;2-e. PMID 10727997.
  10. 1 2 Weenen C, Laven JS, Von Bergh AR, Cranfield M, Groome NP, Visser JA, Kramer P, Fauser BC, Themmen AP (Feb 2004). "Anti-Müllerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment". Molecular Human Reproduction 10 (2): 77–83. doi:10.1093/molehr/gah015. PMID 14742691.
  11. ↑ van Disseldorp J, Faddy MJ, Themmen AP, de Jong FH, Peeters PH, van der Schouw YT, Broekmans FJ (Jun 2008). "Relationship of serum antimüllerian hormone concentration to age at menopause". The Journal of Clinical Endocrinology and Metabolism 93 (6): 2129–34. doi:10.1210/jc.2007-2093. PMID 18334591.
  12. ↑ Rico C, Médigue C, Fabre S, Jarrier P, Bontoux M, Clément F, Monniaux D (Mar 2011). "Regulation of anti-Müllerian hormone production in the cow: a multiscale study at endocrine, ovarian, follicular, and granulosa cell levels". Biology of Reproduction 84 (3): 560–571. doi:10.1095/biolreprod.110.088187. PMID 21076084.
  13. ↑ Hampl R, Šnajderová M, Mardešić T (2011). "Antimüllerian hormone (AMH) not only a marker for prediction of ovarian reserve". Physiological Research / Academia Scientiarum Bohemoslovaca 60 (2): 217–223. PMID 21114374.
  14. ↑ Imbeaud S, Faure E, Lamarre I, Mattéi MG, di Clemente N, Tizard R, Carré-Eusèbe D, Belville C, Tragethon L, Tonkin C, Nelson J, McAuliffe M, Bidart JM, Lababidi A, Josso N, Cate RL, Picard JY (Dec 1995). "Insensitivity to anti-müllerian hormone due to a mutation in the human anti-müllerian hormone receptor". Nature Genetics 11 (4): 382–8. doi:10.1038/ng1295-382. PMID 7493017.
  15. ↑ Page 1114 in: Walter F., PhD. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 1300. ISBN 1-4160-2328-3.
  16. ↑ An Introduction to Behavioral Endocrinology, Randy J Nelson, 3rd edition, Sinauer
  17. 1 2 3 Dewailly D, Andersen CY, Balen A, Broekmans F, Dilaver N, Fanchin R, Griesinger G, Kelsey TW, La Marca A, Lambalk C, Mason H, Nelson SM, Visser JA, Wallace WH, Anderson RA (2014). "The physiology and clinical utility of anti-Mullerian hormone in women". Human Reproduction Update 20 (3): 370–385. doi:10.1093/humupd/dmt062. PMID 24430863.
  18. ↑ Broer SL, Eijkemans MJ, Scheffer GJ, van Rooij IA, de Vet A, Themmen AP, Laven JS, de Jong FH, Te Velde ER, Fauser BC, Broekmans FJ (Aug 2011). "Anti-mullerian hormone predicts menopause: a long-term follow-up study in normoovulatory women". The Journal of Clinical Endocrinology and Metabolism 96 (8): 2532–9. doi:10.1210/jc.2010-2776. PMID 21613357.
  19. ↑ Visser JA, de Jong FH, Laven JS, Themmen AP (Jan 2006). "Anti-Müllerian hormone: a new marker for ovarian function". Reproduction 131 (1): 1–9. doi:10.1530/rep.1.00529. PMID 16388003.
  20. ↑ Broer SL, van Disseldorp J, Broeze KA, Dolleman M, Opmeer BC, Bossuyt P, Eijkemans MJ, Mol BW, Broekmans FJ (2013). "Added value of ovarian reserve testing on patient characteristics in the prediction of ovarian response and ongoing pregnancy: an individual patient data approach". Human Reproduction Update 19 (1): 26–36. doi:10.1093/humupd/dms041. PMID 23188168.
  21. ↑ Indichova J. "Does a Low AMH Level (Anti-Mullerian Hormone) Indicate Infertility?". http://www.fertileheart.com. Retrieved 6 February 2015. External link in |website= (help)
  22. ↑ Trbovich AM, Martinelle N, O'Neill FH, Pearson EJ, Donahoe PK, Sluss PM, Teixeira J (Oct 2004). "Steroidogenic activities in MA-10 Leydig cells are differentially altered by cAMP and Müllerian inhibiting substance". The Journal of Steroid Biochemistry and Molecular Biology 92 (3): 199–208. doi:10.1016/j.jsbmb.2004.07.002. PMID 15555913.
  23. ↑ Wang PY, Protheroe A, Clarkson AN, Imhoff F, Koishi K, McLennan IS (Apr 2009). "Müllerian inhibiting substance contributes to sex-linked biases in the brain and behavior". Proceedings of the National Academy of Sciences of the United States of America 106 (17): 7203–8. doi:10.1073/pnas.0902253106. PMC 2678437. PMID 19359476.
  24. 1 2 3 He H, Yu FX, Sun C, Luo Y (2011). Vitzthum VJ, ed. "CBP/p300 and SIRT1 are involved in transcriptional regulation of S-phase specific histone genes". PLOS ONE 6 (7): e22024. doi:10.1371/journal.pone.0022024. PMC 3137624. PMID 21789216.
  25. 1 2 La Marca A, Sunkara SK (2013). "Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice". Human Reproduction Update 20 (1): 124–40. doi:10.1093/humupd/dmt037. PMID 24077980.
  26. 1 2 3 4 5 6 7 8 Broer SL, Broekmans FJ, Laven JS, Fauser BC (2014). "Anti-Müllerian hormone: ovarian reserve testing and its potential clinical implications". Human Reproduction Update 20 (5): 688–701. doi:10.1093/humupd/dmu020. PMID 24821925.
  27. ↑ For mass values: For molar values: Derived from mass values using 140,000 g/mol, as given in:
    • Hampl R, Šnajderová M, Mardešić T (2011). "Antimüllerian hormone (AMH) not only a marker for prediction of ovarian reserve". Physiological Research / Academia Scientiarum Bohemoslovaca 60 (2): 217–223. PMID 21114374.
  28. ↑ Dennis NA, Houghton LA, Jones GT, van Rij AM, Morgan K, McLennan IS (Jul 2012). "The level of serum anti-Müllerian hormone correlates with vitamin D status in men and women but not in boys". The Journal of Clinical Endocrinology and Metabolism 97 (7): 2450–5. doi:10.1210/jc.2012-1213. PMID 22508713.
  29. ↑ Fertility: assessment and treatment for people with fertility problems. NICE clinical guideline CG156 - Issued: February 2013
  30. ↑ Iliodromiti S, Kelsey TW, Wu O, Anderson RA, Nelson SM (2014). "The predictive accuracy of anti-Müllerian hormone for live birth after assisted conception: a systematic review and meta-analysis of the literature". Human Reproduction Update 20 (4): 560–570. doi:10.1093/humupd/dmu003. PMID 24532220.
  31. ↑ Nelson SM, Yates RW, Fleming R (Sep 2007). "Serum anti-Müllerian hormone and FSH: prediction of live birth and extremes of response in stimulated cycles--implications for individualization of therapy". Human Reproduction 22 (9): 2414–2421. doi:10.1093/humrep/dem204. PMID 17636277.
  32. ↑ Nelson SM, Yates RW, Lyall H, Jamieson M, Traynor I, Gaudoin M, Mitchell P, Ambrose P, Fleming R (Apr 2009). "Anti-Müllerian hormone-based approach to controlled ovarian stimulation for assisted conception". Human Reproduction 24 (4): 867–875. doi:10.1093/humrep/den480. PMID 19136673.
  33. ↑ Broer SL, Dólleman M, Opmeer BC, Fauser BC, Mol BW, Broekmans FJ (2011). "AMH and AFC as predictors of excessive response in controlled ovarian hyperstimulation: a meta-analysis". Human Reproduction Update 17 (1): 46–54. doi:10.1093/humupd/dmq034. PMID 20667894.
  34. ↑ Seifer DB, Maclaughlin DT (Sep 2007). "Mullerian Inhibiting Substance is an ovarian growth factor of emerging clinical significance". Fertility and Sterility 88 (3): 539–46. doi:10.1016/j.fertnstert.2007.02.014. PMID 17559842.
  35. ↑ Wallace WH, Kelsey TW (Jul 2004). "Ovarian reserve and reproductive age may be determined from measurement of ovarian volume by transvaginal sonography". Human Reproduction 19 (7): 1612–7. doi:10.1093/humrep/deh285. PMID 15205396.
  36. ↑ Cupisti S, Dittrich R, Mueller A, Strick R, Stiegler E, Binder H, Beckmann MW, Strissel P (Dec 2007). "Correlations between anti-müllerian hormone, inhibin B, and activin A in follicular fluid in IVF/ICSI patients for assessing the maturation and developmental potential of oocytes". European Journal of Medical Research 12 (12): 604–8. PMID 18024272.
  37. ↑ Dewailly D, Lujan ME, Carmina E, Cedars MI, Laven J, Norman RJ, Escobar-Morreale HF (2013). "Definition and significance of polycystic ovarian morphology: a task force report from the Androgen Excess and Polycystic Ovary Syndrome Society". Human Reproduction Update 20 (3): 334–352. doi:10.1093/humupd/dmt061. PMID 24345633.
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