{"id":15674,"date":"2021-10-06T09:46:15","date_gmt":"2021-10-06T09:46:15","guid":{"rendered":"https:\/\/clinlabint.com\/?p=15674"},"modified":"2021-10-06T09:53:59","modified_gmt":"2021-10-06T09:53:59","slug":"anti-mullerian-hormone-as-a-biochemical-marker-of-gonadal-development-and-fertility-status","status":"publish","type":"post","link":"https:\/\/clinlabint.com\/anti-mullerian-hormone-as-a-biochemical-marker-of-gonadal-development-and-fertility-status\/","title":{"rendered":"Anti-M\u00fcllerian hormone as a biochemical marker of gonadal development and fertility status"},"content":{"rendered":"
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Anti-M\u00fcllerian hormone as a biochemical marker of gonadal development and fertility status<\/h1>\/ in Featured Articles<\/a> <\/span><\/span><\/header>\n<\/div><\/section>
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Anti-M\u00fcllerian hormone (AMH) plays a critical role in sex differentiation in fetal development and goes on to be important in the regulation of folliculogenesis in women. This article discusses the role of AMH in reproductive physiology and the many different situations where assessment of AMH levels is useful, as well as touching on methods of AMH analysis and reference ranges.<\/h3>\n

<\/p>\n

Synthesis\/processing of anti-M\u00fcllerian hormone<\/strong><\/p>\n

Anti-M\u00fcllerian hormone (AMH), also known as \u2018M\u00fcllerianinhibiting hormone\u2019 and \u2018M\u00fcllerian-inhibiting factor\u2019 is a glycoprotein that belongs to the transforming growth factor-beta (TGF-\u03b2) superfamily. It is synthesized as a large precursor with a short signal sequence followed by the pro-prohormone that forms homodimers. Prior to its secretion, the mature hormone undergoes glycosylation and dimerization to produce a 144-kDa dimer composed of identical disulphide-linked 72-kDa monomer subunits [1]. Each monomer contains a large N-terminal \u2018pro\u2019 region and a much smaller C-terminal \u2018mature\u2019 region, in contrast to other TGF-\u03b2 family members. The hormone requires the N-terminal domain to potentiate the activity of the C-terminal domain for full bioactivity [1,2]. During cytoplasmic transit, part of AMH is cleaved at specific region to produce the biologically active 110-kDa N-terminal and 25-kDa C-terminal homodimers, which remain together in a non-covalent complex [1]. This hormone typically binds to a specific AMH type II receptor (AMH II) on the cell membrane of its target organs (including mesenchymal cells of the M\u00fcllerian ducts, granulosa cells of the ovary, and Sertoli and Leydig cells of the testes) [1,2]. The human gene coding for AMH is located on the short arm of chromosome 19p13.3; this has been sequenced and isolated [3].<\/p>\n

Physiology of AMH<\/strong><\/p>\n

AMH is produced by Sertoli cells of the testes in males and by ovarian granulosa cells in females. Expression during male fetal development prevents the M\u00fcllerian ducts from developing into the uterus, resulting in male sexual differentiation and gonadal development. Hence, AMH is essential for the involution of the M\u00fcllerian ducts (the anlagen of the internal female genitalia in the male fetus) which would otherwise develop into the uterus and fallopian tubes [4]. Sex differentiation in the male fetus is completely dependent on the normal development of testes that will produce two hormones: testosterone by Leydig cells and AMH by Sertoli cells [5]. The AMH-induced regression of the M\u00fcllerian duct allows Wolffian ducts to develop into the male reproductive tract under the influence of testosterone; this process occurs as early as 8 weeks of gestation [6]. AMH is continuously produced by the testicles until puberty, and then levels decrease slowly to post-puberty residual values for the rest of life [7]. In the absence of AMH, the embryo develops into a female, allowing the M\u00fcllerian duct to differentiate into the upper vagina, uterus and oviduct. AMH is not present in ovarian tissues until the 36th week of gestation and is mainly produced by granulosa cells of prenatal and early antral follicles. The circulating levels reflect the number of remaining primordial follicles (termed \u2018ovarian reserve\u2019).<\/p>\n

AMH has an essential role as an autocrine and paracrine regulator of ovarian folliculogenesis and maturation in females [8]. Follicle development in the ovaries consists of two stages: initial recruitment during which the primordial follicles start to mature under the control of follicle-stimulating hormone (FSH), which leads to the growth of a group of small antral follicles among which the dominant follicle, which is destined to ovulate, is subsequently selected. The expression of AMH in granulosa cells starts in primary follicles and typically reaches its maximum in granulosa cells of preantral and small antral follicles up to approximately 6 mm in diameter. At this stage, the follicle growth becomes FSH dependent. The hormone expression then diminishes and becomes undetectable. AMH involvement in its inhibitory role occurs in two distinct stages. First, AMH inhibits the transition of follicles from the primordial maturation stages; thus, it contributes in regulating the number of follicles remaining in the primordial pool. Second, AMH inhibits the follicular sensitivity to FSH and therefore has a role in the process of follicular selection [9].<\/p>\n

Clinical utility of AMH in health and disease<\/strong><\/p>\n

The role of AMH in reproductive physiology has attracted the scientific interest in the use of AMH in many fields in medicine, as discussed below.<\/p>\n

1. Marker of ovarian reserve in female reproduction<\/p>\n

AMH appears to be a reliable hormonal marker with respect to ovarian reserve and fertility assessment in females. A normal AMH level (adjusted for age) usually has a positive reflection with fertility. Also, there are different disorders that may affect women which are associated with ovarian insufficiency or diminished ovarian reserve, i.e. women who were born small for gestational age; type 1 diabetics; autoimmune diseases; and women having undergone ovarian or uterine surgery. All may be at risk of various degrees of reduced ovarian reserve, and ovarian reserve testing by AMH level is significantly important in these groups to assess their overall ovarian reserve [8,9].<\/p>\n

2. Measurement of ovarian response and reserve in assisted reproduction in the management of women with infertility, including in vitro fertilization (IVF) and prediction of pregnancy<\/p>\n

Measurement of serum AMH is important in assessing the ovarian reserve, particularly in assisted reproductive medicine. It is a good prognostic marker of the ovarian response to controlled ovarian stimulation during IVF cycles, and reflects both the number of oocytes retrieved during follicular aspiration and the number of arrested cycles. It may predict poor ovarian response to ovarian hyperstimulation in IVF cycles and women who are prone to ovarian hyperstimulation syndrome (OHSS) [10]. Women who have high AMH levels prior to induction with human gonadotrophins exhibit high rates of live births. This may be attributed to the high level of AMH that corresponds to a greater number of oocytes retrieved from women when using AMH level as a predictor for pregnancy outcome [11]. However, in a cohort of fecund women with a history of one or two prior losses, higher or lower AMH values were not associated withthe fecund ability in unassisted conception [12].<\/p>\n

3. Menopause prediction and diagnosis<\/p>\n

Menopause, which is defined as the final menstrual period, marks the end of the female reproductive life span. This is marked by the decline in the number of ovarian follicles (ovarian reserve) with increasing age. When follicle numbers fall below a critical threshold of a few thousand, the menstrual cycle pattern becomes irregular. At menopause, less than 1000 follicles remain. For human fertility, optimal conditions are present until an average age of 31 years, followed by a gradual decline until natural sterility. It has been postulated that these events follow a time sequence with a more or less fixed interval, with the end of natural fertility occurring some 10 years before menopause. AMH is a stronger predictor of late menopausal transition compared with age, AFC or ovarian volume. AMH might be a better surrogate measure of reproductive age than chronological age alone [13].<\/p>\n

Additionally, menopause is associated with some general health issues, such as osteoporosis, breast cancer, cardiovascular disease, Alzheimer\u2019s disease, and stroke. The ability to predict menopause in premenopausal women by assessing AMH at a relatively young age may help in establishing screening and prevention programmes according to the risk factors for each individual woman [14]. An inverse relationship between AMH and subsequent atherosclerosis risk has been reported that can be applied to humans [15].<\/p>\n

4. Diagnosis and management of women with polycystic ovarian syndrome<\/p>\n

Ovarian dysfunction in women with polycystic ovarian syndrome (PCOS) is characterized by the arrest of follicle maturation and disturbed dominant follicle selection with involvement of AMH in its pathogenesis. As a result, increased serum AMH concentrations (2\u20133-fold) occur in PCOS, reflecting the increased number of early antral follicles. Evidence suggests that assessment of AMH levels may replace polycystic ovarian morphology (PCOM) assessment and features of hyperandrogenism or anovulation as diagnostic criteria for PCOS [16]. Additionally, AMH level in PCOS is associated with the extent of disease, and improved reproductive performance in relation to weight loss, improved ovulatory function with age and ovarian response to infertility treatment by laparoscopic ovarian diathermy can be predicted by initial AMH levels. The observation of elevated AMH levels in prepubertal and adolescent girls with PCOS and daughters of mothers with PCOS allows the use of AMH measurements in early detection of subclinical disease in siblings of PCOS women [16].<\/p>\n

5. AMH and cancer in women<\/p>\n

AMH could play a role in many aspects of cancer management in women. Its measurement may help identify which chemotherapeutic agents are toxic to the ovaries [17]. In addition; AMH can identify reduced ovarian reserve when ovulatory cycles are restored following cessation of cancer treatment. AMH levels are typically reduced during chemotherapy with some recovery 3\u20136 months thereafter [18]; AMH is also a good marker of ovarian function both before and after radiotherapy treatment. In women with breast cancer, the pre-treatment AMH levels are a useful predictor of the long-term post-chemotherapy loss of ovarian function. Pre-treatment AMH measurements may aid in determining treatment options and the need for applying fertility-preservation procedures [19]. A mosaic chart has been instructed for classification of ongoing menses or chemotherapy-related amenorrhea in women with early breast cancer using pre-chemotherapy serum AMH and chronological age [20]. Also, in patients with hormone-sensitive breast cancer, it is important to know when the ovarian reserve is depleted given that this information helps in making decision regarding optimal adjuvant hormonal treatment [21]. There is no significant association between age-specific AMH levels and risk of breast cancer [22,23]; however, a modulatory genetic effect has been investigated [24]. In addition, serum AMH is a tumour marker for the diagnosis and follow-up of ovarian granulosa cell tumours. Postoperatively, serum AMH levels may be used as a marker for the efficacy of surgery and for disease recurrence [13].<\/p>\n

6. Assessment of intersexuality, cryptorchidism, anorchia and puberty disorders<\/p>\n

The concentrations of AMH are sexually dimorphic in children: the measurement of AMH can assist in evaluating those with gonadal disorders. In boys with cryptorchidism, serum AMH is proportional to the testicular tissue. An undetectable value is highly suggestive of anorchia, whereas a measurable is associated with undescended testes. AMH can also help in the differential diagnosis of children with intersex states, with a value above the normal range for females being predictive of the presence of testicular tissue, whereas an undetectable result is suggestive of the absence of testicular tissue. Additionally, AMH can help in the diagnosis of delayed puberty and its differentiation from hypogonadotrophic hypogonadism [5].<\/p>\n

Methods for measuring AMH<\/strong><\/p>\n

AMH assays have evolved in the last two decades, starting as enzymelinked immunosorbent assays (ELISA). In 1999, the first kit was introduced by Immunotech (IOT, France), then in 2003 a second AMH kit was manufactured by Diagnostic Systems Laboratories (DSL, USA). In 2010 Beckman Coulter developed a second generation single two-step; sandwich-type (Gen II) kit, based on analytical collaboration from the aforementioned two firms [25]. This new kit gained increased analytical sensitivity and specificity compared with the other previous assays.<\/p>\n

Since then, more automated assays were added to the market, including kits Ultrasensitive AMH and picoAMH assay (Ansh Labs), UniCel DxI 800, Cobas E601, iFlash 3000 [26\u201328]. Currently, Cobas E601, UniCel DxI 800 and iFlash3000 are the most widely used immunoassay platforms to measure AMH levels. Comparison studies were conducted with numerous observations and conclusions were made in relation to the analytical performance in the clinical setting [25\u201329]. The analytical progress and advancement has expanded the utilization of the different assays in clinical practice. Also, studies have revealed that some interchangeability between AMH assays (Roche Elecsys or Beckman Coulter Access) is associated with modest differences in AMH values and seems to have little effect for personalizing FSH dose in IVF [30].<\/p>\n

Reference range of serum AMH in healthy males and females<\/strong><\/p>\n

At birth, cord blood samples from newborn males typically exhibit high AMH levels, whereas AMH levels are typically undetectable or very low in cord sera from female newborns. At approximately 3 months of age, the levels are typically increased dramatically to its highest levels in both sexes. However, the concentrations in females are greatly reduced compared with male infants. AMH levels typically start to decline at 12 months of age and remain relatively stable during childhood (1\u20139 years of age) in both sexes. During this time frame, boys typically exhibit levels that are increased approximately 35-fold compared with girls. In males, after adolescence and during puberty, AMH levels are significantly reduced with the onset of testosterone synthesis, reaching low levels thereafter [31]. Serum levels of AMH also show a variability between individuals depending on the number of antral follicles among women with different ages, as well as ethnicity: African-American and Hispanic women tend to have lower serum AMH levels compared with Caucasians [32]. The AMH level is also affected by body mass index (where a negative relationship with AMH has been noted), and possibly smoking (which may reduce AMH level) [33,34]. Also, conditions associated with gonadotrophin suppression, particularly hormonal oral contraception use and pregnancy (particularly in the second and third trimesters), usually lower serum AMH levels. The levels usually return to normal after stopping the contraception and following delivery. Serum AMH levels usually do not change significantly and is relatively stable throughout the menstrual cycle making it an attractive determinant of ovarian activity [35]. However, the derivation of age-specific reference values of AMH is worth considering for improved interpretation of the results of AMH tests in practice.<\/p>\n

The authors<\/strong>
\nElham Said AlRisi1* MD, OMSB, FRCPath and
\nProf. Jamal Sharef Mula- Abed2 MBChB, PhD
\n1 Dept. Pathology and Blood Bank, Sohar Hospital, Sohar, Sultanate of Oman
\n2 Faculty of Pharmacy, Philadelphia University, Amman, Jordan
\n*Corresponding author
\nE-mail: elhamalrisi@yahoo.com<\/p>\n<\/div><\/section>
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References<\/strong>
\n1. Wilson CA, di Clemente N, Ehrenfels C, Pepinsky R, Josso N, Vigier B. M\u00fcllerian inhibiting substance requires its N-terminal domain for
\nmaintenance of biological activity, a novel finding within the transforming growth factor-beta superfamily. Mol Endocrinol 1993; 7(2): 247\u2013257.
\n2. Di Clemente N, Jamin SP, Lugovskoy A, Carmilo P, Ehrenfels C, et al. Processing of antimullerian hormone regulates receptor activation by
\na mechanism distinct from TGF-beta. Mol Endocrinol 2010; 24(11): 2193\u20132206.
\n3. Cate RL, Mattaliano RJ, Hession C, Tizard R, Farber NM, et al. Isolation of the bovine and human genes for M\u00fcllerian inhibiting substance
\nand expression of the human gene in animal cells. Cell 1986; 45(5): 685\u2013698.
\n4. Josso N, Racine C, di Clemente N, Rey R, Xavier F. The role of anti-M\u00fcllerian hormone in gonadal development. Mol Cell Endocrinol 1998;
\n145(1\u20132): 3\u20137.
\n5. Lindhardt Johansen M, Hagen CP, Johansen TH, Main KM, Picard JY, et al. Anti-M\u00fcllerian hormone and its clinical use in paediatrics with
\nspecial emphasis on disorders of sex development. Int J Endocrinol 2013; 2013: ID198698.
\n6. Lee MM, Donahoe PK, Silverman BL, Hasegawa T, Hasegawa Y, et al. Measurement of serum M\u00fcllerian inhibiting substance in the evaluation
\nof children with non-palpable gonads. N Engl J Med 1997; 336(21): 1480\u20131486.
\n7. Gripson RP, Rey RA. Anti-m\u00fcllerian hormone and Sertoli cell function in paediatric male hypogonadism. Horm Res Paediatr 2010; 73(2): 81\u201392.
\n8. Broekmans FJ, Visser JA, Laven JS, Broer SL, Themmen AP, Fauser BC. Anti-M\u00fcllerian hormone and ovarian dysfunction. Trends Endocrinol
\nMetab 2008; 19(9): 340\u2013347.
\n9. Visser JA, de Jong FH, Laven JS, Themmen AP. Anti-M\u00fcllerian hormone: a new marker for ovarian function. Reproduction 2006; 131(1): 1\u20139.
\n10. Nakhuda GS, Chu MC, Wang JG, Sauer MV, Lobo RA. Elevated serum M\u00fcllerian-inhibiting substance may be a marker for ovarian hyper
\nstimulation syndrome in normal women undergoing in vitro fertilization. Fertil Steril 2006; 85(5): 1541\u20131543.
\n11. Broekmans FJ, KweeJ, Hendriks DJ, Mol BW, Lambalk CB. A systematic review of tests predicting ovarian reserve and IVF outcome.
\nHum Reprod Update 2006; 12(6): 685\u2013718.
\n12. Zarek SM, Mitchell EM, Sjaarda LA, Mumford SL, Silver RM, et al. Is Anti-M\u00fcllerian hormone associated with fecundability? Findings from the
\nEAGeR Trial. J Clin Endocrinol Metab 2015; 100(11): 4215\u20134221.
\n13. Van Disseldrop J, Faddy MJ, Themmen AP, de Jong FH, Peeters PH, et al. Relationship of serum anti-M\u00fcllerian hormone concentration to age
\nat menopause. J Clin Endocrinal Metab 2008; 93(6): 2129\u20132134.
\n14. Lane AH, Lee MM, Fuller AF, Kehas DJ, Donahoe PK, MacLaughlin DT. Diagnostic utility of M\u00fcllerian inhibiting substances determination in
\npatients with primary and recurrent granulosa cell tumours. Gynecol Oncol 1999; 73(1): 51\u201355.
\n15. Appt SE, Chen H, Clarkson TB, Kaplan JR. Premenopausal anti-M\u00fcllerian hormone concentration is associated with subsequent atherosclerosis.
\nMenopause 2012; 19(12): 1353\u20131359.
\n16. Casadei L, Madrigale A, Puca F, Manicuti C, Emidi E, et al. The role of anti M\u00fcllerian hormone (AMH) in the hormonal diagnosis of polycystic
\novary syndrome. Gynecol Endocrinol 2013; 29(6): 545\u2013550.
\n17. VanBeek RD, Van den Heuvel-Eibrink MM, Laven JS, de Jong FH, Themmen AP, et al. Anti-M\u00fcllerian hormone is a sensitive marker for gonadal
\nfunction in women treated for Hodgkin\u2019s lymphoma during childhood. Clin Enocrinol Metab 2007; 92(10): 3869\u20133874.
\n18. Anderson RA, Cameron DA. Pretreatment serum anti-m\u00fcllerian hormone predicts long-term ovarian function and bone mass after chemotherapy
\nfor early breast cancer. J Clin Endocrinol Metab 2011; 96(5): 1336\u20131343.
\n19. Anderson RA, Wallace WH. Anti-M\u00fcllerian hormone, the assessment of the ovarian reserve, and the reproduction outcome of the young patient
\nwith cancer. Fertil Steril 2013; 99(6): 1469\u20131475.
\n20. Anderson RA, Rosendahl M, Kelsey TW, Cameron DA. Pretreatment anti-M\u00fcllerian hormone predicts for loss of ovarian function after
\nchemotherapy for early breast cancer. Eur J Cancer 2013; 49(16): 3404\u20133411.
\n21. De Vos FY, van Laarhoven HW, Lavan JS, Themmen AP, Beex LV, et al. Menopausal status and adjuvant hormonal therapy for breast cancer:
\na practical guideline. Crit Rev Oncol Hematol 2012; 84(2): 252\u2013260.
\n22. Verdiesen RMG, van Gils CH, Stellato RK, Verschuren WMM, Broekmans FJM, et al. Anti-M\u00fcllerian hormone levels and risk of cancer in women.
\nMaturitas 2021; 143: 216\u2013222.
\n23. Nichols HB, Graff M, Bensen JT, Lunetta KL, O’Brien KM, et al. Genetic variants in anti-M\u00fcllerian hormone-related genes and breast cancer risk:
\nresults from the AMBER consortium. Breast Cancer Res Treat 2021; 185(2): 469\u2013478.
\n24. Peregrin-Alvarez I, Fletcher NM, Saed GM, Roman RA, Detti L. Anti-M\u00fcllerian hormone (AMH) regulates BRCA1 and BRCA2 gene expression
\nafter ovarian cortex transplantation. Gynecol Endocrinol 2021; 37(4): 349\u2013352.
\n25. Kumar A, Kalra B, Patel A, McDavid L, Roudebush WE. Development of a second generation anti-M\u00fcllerian hormone (AMH) ELISA.
\nJ Immunol Methods 2010; 362(1\u20132): 51\u201359.
\n26. Gassner D, Jung R. First fully automated immunoassay for anti-M\u00fcllerian hormone. Clin Chem Lab Med 2014; 52(8): 1143\u20131152.
\n27. Su HI, Sammel MD, Homer MV, Bui K, Haunschild C, Stanczyk FZ. Comparability of antim\u00fcllerian hormone levels among commercially available
\nimmunoassays. Fertil Steril 2014; 101(6): 1766\u201372.e1.
\n28. Feng Y, Chen Y, Liu C, Fu J, Xu J. Comparison of three immunoassay systems for determining serum anti-Mullerian hormone.
\nClin Lab 2021; 67(4): doi:10.7754\/Clin.Lab.2020.200814.
\n29. Bell RJ, Skiba MA, Sikaris K, Liu A, Islam RM, et al. Differing performance of two assays for the measurement of anti-Mullerian hormone in
\npremenopausal women: A cross-sectional study. Clin Endocrinol (Oxf) 2021; 95(1): 169\u2013175.
\n30. La Marca A, Tolani AD, Capuzzo M. The interchangeability of two assays for the measurement of anti-M\u00fcllerian hormone when personalizing the
\ndose of FSH in in-vitro fertilization cycles. Gynecol Endocrinol 2021; 37(4): 372\u2013376.
\n31. Aksglaede L, Sorensen K, Boas M, Mouritsen A, Hagen CP, et al. Changes in anti-M\u00fcllerian hormone (AMH) throughout the life span:
\na population-based study of 1027 healthy males from birth (cord blood) to the age of 69 years. J Clin Endocrinol Metab 2010; 95(12): 5357\u20135364.
\n32. Seifer DB, Golub ET, Lambert-Messerlian G, Benning L, Anastos K, et al. Variation in serum M\u00fcllerian inhibiting substance between white, black,
\nand Hispanic women. Fertil Steril 2009; 92(9); 1674\u20131678.
\n33. La Marca A, Spada E, Grisendi V, Argento C, Papaleo E, et al. Normal serum anti-M\u00fcllerian hormone levels in the general female population and
\nthe relationship with reproductive history. Eur J Obstet Gynecol Reprod Biol 2012; 163(2): 180\u2013184.
\n34. Freeman EW, Gracia CR, Sammel MD, Lin H, Lim LC, Strauss JF 3rd. Association of anti-M\u00fcllerian levels with obesity in late reproductive-age
\nwomen. Fertil Steril 2007; 87; 101\u2013106.
\n35. La Marca A, Stabile G, Carducci Artenisio A, Volpe A. Serum anti-Mullerian hormone throughout the human menstrual cycle. Hum Reprod 2006
\nDec; 21(12): 3103\u20133107.<\/p>\n<\/div><\/section>
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