Biology:Anti-Müllerian hormone

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Short description: Mammalian protein found in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Anti-Müllerian hormone (AMH), also known as Müllerian-inhibiting hormone (MIH), is a glycoprotein hormone structurally related to inhibin and activin from the transforming growth factor beta superfamily, whose key roles are in growth differentiation and folliculogenesis.[1] In humans, it is encoded by the AMH gene, on chromosome 19p13.3,[2] while its receptor is encoded by the AMHR2 gene on chromosome 12.[3]

AMH is activated by SOX9 in the Sertoli cells of the male fetus.[4] Its expression inhibits the development of the female reproductive tract, or Müllerian ducts (paramesonephric ducts), in the male embryo, thereby arresting the development of fallopian tubes, uterus, and upper vagina.[5][6][4] AMH expression is critical to sex differentiation at a specific time during fetal development, and appears to be tightly regulated by nuclear receptor SF-1, transcription GATA factors, sex-reversal gene DAX1, and follicle-stimulating hormone (FSH).[7][8][9] 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.[10]

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.[11] So AMH makes it possible to predict the age at which menopause will occur.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.[11][12] 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.[13] In humans, this is helpful because the number of cells in the follicular reserve can be used to predict timing of menopause.[14] 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.[15] AMH can also be used as a marker for ovarian dysfunction, such as in women with polycystic ovary syndrome (PCOS).

Structure

AMH bound to its type II receptor, AMHR2 (PDB: 7L0J)

AMH is a dimeric glycoprotein with a molar mass of 140 kDa.[16] The molecule consists of two identical subunits linked by sulfide bridges, and characterized by the N-terminal dimer (pro-region) and C-terminal dimer.[1] AMH binds to its Type 2 receptor AMHR2, which phosphorylates a type I receptor under the TGF beta signaling pathway.[1]

Function

Embryogenesis

In male mammals, AMH prevents the development of the Müllerian ducts into the uterus and other Müllerian structures.[5] The effect is ipsilateral, that is each testis suppresses Müllerian development only on its own side.[17] In humans, this action takes place during the first eight weeks of gestation. If no hormone is produced from the gonads, the Müllerian will develop thanks to the presence of Wnt4 , while the Wolffian ducts, which are responsible for male reproductive parts, will die due to the presence of COUP-TFII.[18] 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).

Ovarian

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.[19] 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.[20] Some authorities suggest it is a measure of certain aspects of ovarian function,[21] useful in assessing conditions such as polycystic ovary syndrome and premature ovarian failure.[22]

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,[23] 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.[24] 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.[25] In vitro experiments demonstrate that the overexpression of AMHY causes female-to-male sex reversal in at least one species, S. schlegelii.[25]

Pathology

In males, inadequate embryonal AMH activity can lead to 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.[26]

A study published in Nature Medicine found a link between hormonal imbalance in the womb and polycystic ovary syndrome (PCOS), specifically prenatal exposure to anti-Müllerian hormone.[27] 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.[28] The rise during childhood and adolescence is likely reflective of different stages of follicle development.[29] From 25 years of age AMH declines to undetectable levels at menopause.[28]

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.[30]

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.[31]

Reference ranges

Reference ranges for anti-Müllerian hormone, as estimated from reference groups in the United States , are as follows:[32]

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.[33] 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.[33]

Clinical usage

General fertility assessment

Comparison of an individual's AMH level with respect to average levels[28] is useful in fertility assessment, as it provides a guide to ovarian 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.[34] 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.[31] However, this correlation was not found in a comparable study of younger women (aged 20 to 30 years).[31]

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 strong predictor of IVF success. Women with lower levels of AMH are still able to get pregnant[35] Additionally, AMH levels are used to estimate a woman's remaining egg supply.[36]

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 gonadotrophin stimulation in IVF, while a level greater than or equal to 25.0 pmol/L (3.6 ng/mL) predicts a high response.[37] 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.[30] Subsequently, higher AMH levels are associated with greater chance of live birth after IVF, even after adjusting for age.[31][38] 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).[39][40] AMH can predict an excessive response in ovarian hyperstimulation with a sensitivity and specificity of 82% and 76%, respectively.[41]

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[42] and ovarian volume.[43]

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 improves ovarian function, increases pregnancy chances and, by reducing aneuploidy, lowers miscarriage rates.[44] 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[45] 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.[46] 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.[46]

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.[33]

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.[31] A post-treatment AMH is associated with decreased fertility.[29][31]

Granulosa cell tumors of the ovary secrete AMH, and AMH testing has a sensitivity ranging between 76 and 93% in diagnosing such tumors.[31] AMH is also useful in diagnosing recurrence of granulosa cell tumors.[31]

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.[47]

Biomarker of polycystic ovary syndrome

Polycystic ovary syndrome (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).[48] 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.[49] 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.[50] The high levels of androgens, characteristic of PCOS, also stimulate and provide feedback for increased production of AMH, as well.[20] 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 is the most common sex chromosome-related inherited diseases in female around the world, with the incidence of 1 in 2000 live female births.[51] 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.[52]

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.[53]

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.[54]

Names

The adjective Müllerian is written either Müllerian or müllerian, depending on the governing style guide; the derived term with the prefix anti- is then anti-Müllerian, anti-müllerian, or antimüllerian. The Müllerian ducts are named after Johannes Peter Müller.[55]

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 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

See also

References

  1. ↑ 1.0 1.1 1.2 "Anti-Müllerian hormone: structure, properties and appliance". Ginekologia Polska 87 (9): 669–674. 2016. doi:10.5603/gp.2016.0064. PMID 27723076. 
  2. ↑ "Isolation of the bovine and human genes for Müllerian inhibiting substance and expression of the human gene in animal cells". Cell 45 (5): 685–698. June 1986. doi:10.1016/0092-8674(86)90783-X. PMID 3754790. 
  3. ↑ "Insensitivity to anti-müllerian hormone due to a mutation in the human anti-müllerian hormone receptor". Nature Genetics 11 (4): 382–388. December 1995. doi:10.1038/ng1295-382. PMID 7493017. 
  4. ↑ 4.0 4.1 "Timing and irreversibility of Müllerian duct inhibition in the embryonic reproductive tract of the human male". Developmental Biology 106 (2): 394–398. December 1984. doi:10.1016/0012-1606(84)90238-0. PMID 6548718. 
  5. ↑ 5.0 5.1 The in vivo roles of müllerian-inhibiting substance. Current Topics in Developmental Biology. 29. 1994. pp. 171–87. doi:10.1016/S0070-2153(08)60550-5. ISBN 9780121531294. 
  6. ↑ "AMH/MIS: what we know already about the gene, the protein and its regulation". Molecular and Cellular Endocrinology 211 (1–2): 21–31. December 2003. doi:10.1016/j.mce.2003.09.007. PMID 14656472. 
  7. ↑ "Nuclear receptor steroidogenic factor 1 regulates the müllerian inhibiting substance gene: a link to the sex determination cascade". Cell 77 (5): 651–661. June 1994. doi:10.1016/0092-8674(94)90050-7. PMID 8205615. 
  8. ↑ "Wilms' tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression". Cell 93 (3): 445–454. May 1998. doi:10.1016/s0092-8674(00)81172-1. PMID 9590178. 
  9. ↑ "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. July 1998. doi:10.1242/dev.125.14.2665. PMID 9636081. 
  10. ↑ "Persistence of Müllerian derivatives in males". American Journal of Medical Genetics 89 (4): 218–223. December 1999. doi:10.1002/(sici)1096-8628(19991229)89:4<218::aid-ajmg6>3.0.co;2-e. PMID 10727997. 
  11. ↑ 11.0 11.1 "Anti-Müllerian hormone and polycystic ovary syndrome: a mountain too high?". Reproduction 139 (5): 825–833. May 2010. doi:10.1530/REP-09-0415. PMID 20207725. 
  12. ↑ "Anti-Müllerian hormone and progesterone levels produced by granulosa cells are higher when derived from natural cycle IVF than from conventional gonadotropin-stimulated IVF". Reproductive Biology and Endocrinology 13: 21. March 2015. doi:10.1186/s12958-015-0017-0. PMID 25889012. 
  13. ↑ "Anti-Müllerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment". Molecular Human Reproduction 10 (2): 77–83. February 2004. doi:10.1093/molehr/gah015. PMID 14742691. 
  14. ↑ "Relationship of serum antimüllerian hormone concentration to age at menopause". The Journal of Clinical Endocrinology and Metabolism 93 (6): 2129–2134. June 2008. doi:10.1210/jc.2007-2093. PMID 18334591. 
  15. ↑ "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. March 2011. doi:10.1095/biolreprod.110.088187. PMID 21076084. 
  16. ↑ [1] "Antimüllerian hormone (AMH) not only a marker for prediction of ovarian reserve". Physiological Research 60 (2): 217–223. 2011. doi:10.33549/physiolres.932076. PMID 21114374. 
  17. ↑ Medical Physiology: A Cellular and Molecular Approaoch. Elsevier/Saunders. 2003. p. 1114. ISBN 978-1-4160-2328-9. 
  18. ↑ An Introduction to Behavioral Endocrinology, Randy J Nelson, 3rd edition, Sinauer
  19. ↑ "Anti-Mullerian hormone (AMH) as a predictive marker in assisted reproductive technology (ART)". Human Reproduction Update 16 (2): 113–130. 2009-09-30. doi:10.1093/humupd/dmp036. PMID 19793843. 
  20. ↑ 20.0 20.1 "Role of Anti-Müllerian Hormone in pathophysiology, diagnosis and treatment of Polycystic Ovary Syndrome: a review". Reproductive Biology and Endocrinology 13: 137. December 2015. doi:10.1186/s12958-015-0134-9. PMID 26691645. 
  21. ↑ "Anti-mullerian hormone predicts menopause: a long-term follow-up study in normoovulatory women". The Journal of Clinical Endocrinology and Metabolism 96 (8): 2532–2539. August 2011. doi:10.1210/jc.2010-2776. PMID 21613357. 
  22. ↑ "Anti-Müllerian hormone: a new marker for ovarian function". Reproduction 131 (1): 1–9. January 2006. doi:10.1530/rep.1.00529. PMID 16388003. 
  23. ↑ "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. October 2004. doi:10.1016/j.jsbmb.2004.07.002. PMID 15555913. 
  24. ↑ "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): 7203–7208. April 2009. doi:10.1073/pnas.0902253106. PMID 19359476. Bibcode: 2009PNAS..106.7203W. 
  25. ↑ 25.0 25.1 "A duplicated amh is the master sex-determining gene for Sebastes rockfish in the Northwest Pacific". Open Biology 11 (7): 210063. July 2021. doi:10.1098/rsob.210063. PMID 34255977. 
  26. ↑ "Surgical and genetic aspects of persistent müllerian duct syndrome". Journal of Pediatric Surgery 29 (1): 61–65. January 1994. doi:10.1016/0022-3468(94)90525-8. PMID 7907140. 
  27. ↑ "Elevated prenatal anti-Müllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood". Nature Medicine 24 (6): 834–846. June 2018. doi:10.1038/s41591-018-0035-5. PMID 29760445. 
  28. ↑ 28.0 28.1 28.2 "A validated model of serum anti-müllerian hormone from conception to menopause". PLOS ONE 6 (7): e22024. 2011. doi:10.1371/journal.pone.0022024. PMID 21789206. Bibcode: 2011PLoSO...622024K. 
  29. ↑ 29.0 29.1 "The physiology and clinical utility of anti-Mullerian hormone in women". Human Reproduction Update 20 (3): 370–385. 2014. doi:10.1093/humupd/dmt062. PMID 24430863. 
  30. ↑ 30.0 30.1 "Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice". Human Reproduction Update 20 (1): 124–140. 2013. doi:10.1093/humupd/dmt037. PMID 24077980. 
  31. ↑ 31.0 31.1 31.2 31.3 31.4 31.5 31.6 31.7 "Anti-Müllerian hormone: ovarian reserve testing and its potential clinical implications". Human Reproduction Update 20 (5): 688–701. 2014. doi:10.1093/humupd/dmu020. PMID 24821925. 
  32. ↑ For mass values: For molar values: Derived from mass values using 140,000 g/mol, as given in:
  33. ↑ 33.0 33.1 33.2 "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): 2450–2455. July 2012. doi:10.1210/jc.2012-1213. PMID 22508713. 
  34. ↑ "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): 604–608. December 2007. PMID 18024272. 
  35. ↑ "Relevance of anti-Mullerian hormone measurement in a routine IVF program". Human Reproduction 23 (6): 1359–1365. June 2008. doi:10.1093/humrep/den108. PMID 18387961. 
  36. ↑ "Does a Low AMH Level (Anti-Mullerian Hormone) Indicate Infertility?". http://www.fertileheart.com/does-a-low-amh-level-indicate-infertility/. 
  37. ↑ Fertility: assessment and treatment for people with fertility problems. NICE clinical guideline CG156 - Issued: February 2013
  38. ↑ "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. 2014. doi:10.1093/humupd/dmu003. PMID 24532220. 
  39. ↑ "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. September 2007. doi:10.1093/humrep/dem204. PMID 17636277. 
  40. ↑ "Anti-Müllerian hormone-based approach to controlled ovarian stimulation for assisted conception". Human Reproduction 24 (4): 867–875. April 2009. doi:10.1093/humrep/den480. PMID 19136673. 
  41. ↑ "AMH and AFC as predictors of excessive response in controlled ovarian hyperstimulation: a meta-analysis". Human Reproduction Update 17 (1): 46–54. 2011. doi:10.1093/humupd/dmq034. PMID 20667894. 
  42. ↑ "Mullerian Inhibiting Substance is an ovarian growth factor of emerging clinical significance". Fertility and Sterility 88 (3): 539–546. September 2007. doi:10.1016/j.fertnstert.2007.02.014. PMID 17559842. 
  43. ↑ "Ovarian reserve and reproductive age may be determined from measurement of ovarian volume by transvaginal sonography". Human Reproduction 19 (7): 1612–1617. July 2004. doi:10.1093/humrep/deh285. PMID 15205396. 
  44. ↑ "Dehydroepiandrosterone (DHEA) supplementation in diminished ovarian reserve (DOR)". Reproductive Biology and Endocrinology 9: 67. May 2011. doi:10.1186/1477-7827-9-67. PMID 21586137. 
  45. ↑ "Improvement in diminished ovarian reserve after dehydroepiandrosterone supplementation". Reproductive Biomedicine Online 21 (3): 360–365. September 2010. doi:10.1016/j.rbmo.2010.04.006. PMID 20638339. 
  46. ↑ 46.0 46.1 "Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging". Aging Cell 14 (5): 887–895. October 2015. doi:10.1111/acel.12368. PMID 26111777. 
  47. ↑ "Measurement of serum anti-Müllerian hormone concentration in female dogs and cats before and after ovariohysterectomy". Journal of Veterinary Diagnostic Investigation 23 (3): 524–527. May 2011. doi:10.1177/1040638711403428. PMID 21908283. 
  48. ↑ "Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: the Rotterdam criteria are premature". The Journal of Clinical Endocrinology and Metabolism 91 (3): 781–785. March 2006. doi:10.1210/jc.2005-2153. PMID 16418211. 
  49. ↑ "Diagnostic criteria for PCOS: Is there a need for a rethink?". Best Practice & Research. Clinical Obstetrics & Gynaecology 37: 5–11. November 2016. doi:10.1016/j.bpobgyn.2016.03.009. PMID 27151631. 
  50. ↑ "Anti-Mullerian Hormone: A Marker of Ovarian Reserve and its Association with Polycystic Ovarian Syndrome". Journal of Clinical and Diagnostic Research 10 (12): QC10–QC12. December 2016. doi:10.7860/JCDR/2016/20370.8988. PMID 28208941. 
  51. ↑ "Clinical manifestations and diagnosis of Turner syndrome". Wolters Kluwer. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-turner-syndrome?search=turner%20syndrome&topicRef=7386&source=see_link. 
  52. ↑ "Serum levels of anti-Müllerian hormone as a marker of ovarian function in 926 healthy females from birth to adulthood and in 172 Turner syndrome patients". The Journal of Clinical Endocrinology and Metabolism (The Journal of Clinical Endocrinology&Metabolism) 95 (11): 5003–5010. November 2010. doi:10.1210/jc.2010-0930. PMID 20719830. 
  53. ↑ "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. 2013. doi:10.1093/humupd/dmt061. PMID 24345633. 
  54. ↑ "AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy". Proceedings of the National Academy of Sciences of the United States of America 114 (9): E1688–E1697. February 2017. doi:10.1073/pnas.1620729114. PMID 28137855. Bibcode: 2017PNAS..114E1688K. 
  55. ↑ Biology Today: An Issues Approach (Third ed.). New York: Garland Science. 2004. p. 296. ISBN 978-1-136-83875-0. 



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