Anthropological Review • Vol. 81(3), 325–340 (2018)
Anthropological Review Available online at: https://content.sciendo.com/anre Journal homepage: www.ptantropologiczne.pl
Ovarian activity regulation by anti-Müllerian hormone in early stages of human female life, an overview Małgorzata Jusiakowska-Piputa, Maria Kaczmarek
Department of Human Biological Development, Institute of Anthropology, Faculty of Biology, Adam Mickiewicz University, Poznań, Poland
Abstract: The present study aimed at describing the anti-Müllerian hormone (AMH), with special focus on molecular background for ovarian activity, in particular the role AMH plays in sex determination and gonadogenesis process in early stages of prenatal life and folliculogenesis in postnatal life. It is a review of the literature currently indexed and abstracted in MEDLINE, SCOPUS and Google Scholars. The process of sex determination and gonad differentiation occurring during embryogenesis was discussed along with underlying molecular mechanisms. In the postnatal life the impact of AMH on the process of folliculogenesis was described. Clinical use of recent findings was shown as well. Genetic studies and molecular analyses have demonstrated that AMH is highly conservative, indicating its significance in reproductive process on the background of evolutionary processes.
Key words: AMH, sex determination, gonad differentitation, folliculogenesis, in vitro fertilization, androgens
Introduction chromosome and it consists of 5 exons (Cohen-Haguenauer et al. 1987). The Anti-Müllerian hormone (hereinafter last codes the domain with C-terminus. called AMH) was discovered by German AMH is a dimeric glycoprotein consisting medicine professor Peter Müller (1801– of 560 amino acids, classified in the be- 1858). He worked on embryology at the ta-TGF superfamily. An AMH molecule University in Bonn. He was able to ob- occurs in a precursor form. It contains serve pairs of structures characteristic two domains: a larger one, containing of early fetal development and unknown N-terminus region and a substantially substance acting on these structures. In smaller one, ended with a C-terminus. 1940, Alfred Jost first described a sub- Primary form of the molecule possess- stance of nuclear origin and influencing es both domains bound by a non-cova- regression of Müllerian ducts. In 1986 lent bond (AMHNC). After proteolytic Cate et al. identified and described the enzymes cut the bond, the mature end substance. Genes responsible for AMH with C-terminus and the proregion with expression have been isolated from hu- N-terminus are bound with a disulfide man DNA. bridge. It has not yet been determined, Human gene coding AMH is locat- when proteolysis takes place-during hor- ed on the shortest arm of the 19 p.13.3 mone secretion or in the target tissue.
Review Article Received May 15, 2018 Revised August 14, 2018 Accepted August 17, 2018 DOI: 10.2478/anre-2018-0026 © 2018 Polish Anthropological Society 326 Małgorzata Jusiakowska-Piputa, Maria Kaczmarek
Transformation of the primary, inac- Materials and methods tive form of AMH molecule facilitates attachment to the receptor and release A literature search was performed of of ligand, mature homodimer with C-ter- SCOPUS, PubMed, and Web of Science minus and proregion with N-terminus reviews for the years 2000-2017 un- (di Clemente et al. 2010). Comparative der the following key phrases/words: model for AMH has been created based
Figure 1. Flow diagram of literature review
Sexual determination of a developing oviducts, uterus and upper portion of embryo is strictly associated with the sex vagina is automatically activated in the chromosome profile and depends on the absence of Sry gene. This has turned out presence of Y chromosome containing not to be as obvious for humans, as the the TDF-Testis Determining Factor re- commencement of female developmental gion (Nussey and Whitead 2001). Here, pathway, differentiation and stabilization the SRY protein coding genes are present: of ovaries, seems to require the presence The SRY factor initiates differentiation of of several transcription factors (Tevosian Sertoli cells, already in a bipotential go- 2013; Lin and Capel 2015; Biason-Lauber nad of the embryo. These will constitute and Chaboissier 2015). nearly half the volume of testes. These Primary urogenital system of a fetus cells commence AMH secretion approxi- is of mesodermal origin. During organo- mately 55–60 days after fertilization. This genesis, pairs of protrusions are formed process is activated with approx. one from the epithelium that lines the body week delay relative to Leydig cells that cavity, which form the precursor of the produce testosterone. The time and site developing urogenital system. In the for initiation of secretion of key hormones course of subsequent differentiation, for the development of male embryo is they are transformed into Wolf ducts and significant due to the negative feedback an even meso-kidney. It consists of three of their influence in the implementation segments: pronephros, mesonephros and of male developmental pathway. metanephros. The process of female development Approximately 4 weeks after fertil- appears to be more complex for humans ization, strands of cells appear on both than previously thought. Observations sides of mesonephros, known as genital conducted on rodents suggest that the ridges, which will become populated by process of ovarian differentiation and primary sexual cells-gonocytes of endo- transformation of Müllerian ducts into dermal origin. About 5 weeks after fer- 328 Małgorzata Jusiakowska-Piputa, Maria Kaczmarek tilization, primary sex cords differentiate mentation and regression giving the onset from the epithelium lining the body cavity, of the ovarian medulla, along with vascu- which constitute the scaffolding for gono- larized stroma. At the same time, cortical cytes. This process initiates formation cords are created from the proliferating of morphologically undifferentiated go- gonad epithelium. They will give the be- nads. Expression of Sry gene in a XY fetus ginning of a line of granular cells, which, promotes differentiation of testes with a by forming a single layer around oogonia network of ducts assuming the form of a will form primordial follicle with theca of horseshoe. Leydig cells are formed from follicle. This takes place around 10 weeks the epithelium of sex ridges and are of after fertilization. First primordial follicles mesenchymal origin. Eight weeks post are formed in fetal ovaries approximately fertilization, testosterone secretion be- 15–16, while ready Graafian follicle in 23– comes activated. Sertoli cells are differen- 24 week post fertilization (Reynaud et al. tiated from epithelial mesoderm, which 2004). Due to proliferation of granulosa commence AMH secretion at approx. one cells, granular and thecal layer are formed, week time interval relative to Leidig cells. which constitute important sources for se- In the embryogenesis process, under the cretion of steroid hormones and AMH. influence of maternal estrogens, pairs of The moment of AMH expression germs of Müllerian ducts are formed from during embryogenesis is of key signifi- mesodermal epithelium. cance. The time shift associated with dif- Functional development of a gonad ferentiation of male and female fetus may takes place about 7 weeks after fertiliza- be associated with the fact of AMH in- tion, which is exhibited via secretion of fluence on regression of Müllerian ducts. trace amounts of estradiol by as yet phe- AMH receptors located on cellular mem- notypically undifferentiated gonads. It branes of Müllerian ducts of a female fetus should be emphasized that at the same are subject to regression. In this manner, time, testis commence testosterone pro- even trace amounts of AMH produced by duction. Forty-five days since the begin- granular cells of the forming follicles can- ning of human embryogenesis, ovary is not have a destructive impact on Mülleri- identifiable only because the gonad has an ducts, which are then transformed into not yet transformed into early testes. In oviducts, uterus and the upper portion of the third trimester of gestation, in the case vagina. AMH production is detectable in of absence of SRY protein female develop- 24 week of gestation in granular cells of mental pathway becomes activated and go- preantral follicles (Kuiri-Hanninen et al. nads differentiate into ovaries, regression 2011). In both sexes, initiation of AMH of Wolf ducts is activated and Müllerian transcription is subject to a strict control ducts begin development towards forma- in terms of place and time. It is of key im- tion of oviduct, uterus and upper portion portance for normal development and for- of vagina (Munsterberg and Lovell-Badge mation of the most important biological 1991). Approximately 5–6 weeks after fer- function of organisms-reproduction. tilization the primary sex ridges, and then sex cords with primary sexual cells initiate Mechanism of molecular regulation formation of ovary, which will constitute the source of AMH secretion. The Wolf Determination of the direction and sexu- ducts degenerate. Cords undergo frag- al determination during embryogenesis Ovarian activity regulation by anti-Müllerian hormone in early life 329 take place already in first weeks after fer- cells will be responsible for secretion of tilization. In the initial stage of develop- AMH, an important regulator during im- ment, i.e. approx. 6 weeks, bipolar, phe- plementation of developmental programs notypically undifferentiated gonads are (different for both sexes) and the func- formed. The genetic program of a fetus is tional performance of the reproductive determined by a set of sex chromosomes: system. XY, XX imposes the sex determination Research has confirmed that the pri- direction, provided the developmental mary sex determination associated with process has normal course. This consists chromosome Y, activating programmed of numerous genetic and signaling con- cascade of molecular interactions is more nections with synergistic or antagonistic conservative than previously thought. relationship, regulating the correct deve- lopmental pathway. Gonad differentiation Chromosome Y determines the de- velopmental processes of a male fetus by The process of formation and stabili- recording the Sry gene, coding the TDF zation of initially bipotential gonads in (Testis Determining Factor). Formation humans commences on the 32 day post of programmed testes requires activation fertilization. Numerous transcription fac- of such factors as NR5A1, SF1 incorporat- tors are activated during embryogenesis, ing them in the expression of Sox9 gene which activate the process of develop- which is of key significance for the subse- ment and differentiation. Several genes quent reactions. The activated signaling were distinguished in research conducted cascade acts as positive or negative inter- on mice, such as: Lh9, Gata4, Emx2, Wt1, action of factors or reactions. As a result Chx2, Nr5a and Six1/4, influencing forma- of activation of developmental program tion of bipotential gonads in embryos of for male fetus by Sry gene, the possibil- both sexes (Svingen and Koopman 2013). ity for activation of reactions for female WT1 (+KTS) and LH9 bind and activate developmental pathway is automatically the Sf1 gene promoter. Similarly, Cbx2 terminated (Barrionuevo 2005; Vidal et will activate Sf1 expression. Emx 2 is re- al. 2001; Chaboissier et al. 2004). sponsible for normal proliferation at the Absence of Sry gene results in signal- early stage of gonad development, further ing activation characteristic of initiation contributing to the signal reaction of the of the development of ovaries and re- developmental pathway of supporting pressing effect for activation of nuclear cell line, which will commence secretion signaling network. In Vertebrata, sexual of AMH at a different time and site of determination of gonads is associated gonadogenesis. This is of particular im- with determination of lines of germ cells: portance, as they are differentiated at an spermatozoa or oocytes (de Falco and earlier stage than germ cells. First, Sertoli Cambel, 2009). cells and then granular cells are formed. System of supporting cells, Sertoli and SOX9 and SF1 initiate expression of AMH granular cells, is activated, which, at lat- (MIS) gene. AMH, by binding with AMH- er stages of development, in relationship RII receptor commences signal via acti- with the hypothalamic-pituitary-gonadal vation of AMHRI. AMH is regulated by axis will play the key regulatory and en- SF1 and other transcription factors such docrine role. Both types of supporting as WT1(+KTS) and GATA4. Activation 330 Małgorzata Jusiakowska-Piputa, Maria Kaczmarek of signaling elements takes place on the located on membranes of thecal cells of basis of positive and negative regulation the theca and granular cells of ovarian correlation. AMH results in regression of follicles (Juuula et al. 2012). Müllerian ducts formed during embryo- Cells of the developed follicular ap- genesis and development of XY fetus. paratus exhibit high dynamism, partici- Pdgf and Dhh, genes are also expressed in pating in cyclical transformations under Sertoli cells, which subsequently contrib- the impact of hormones and successfully ute to the process of Leydig cells forma- entering the pathway of apoptosis. This tion, where the steroidogenesis process process commenced in embryonic life will further includes SF1. Testosterone secre- cease only during menopause. In 18 week tion initiates directional organization of of gestation, ovaries contain 7 million fol- testes and development of internal gen- licles (te Velde and Pearson 2002). Go- ital organs (Tanaka and Nishinakamura nads of female fetus contain as many as 2014). Following formation of testes and 1–2 million of them. Before a girl attains involution of Müllerian ducts, AMH will sexual maturity, they will amount to 400 remain at a stable, relatively low level. In thousand, and after menopause approx. female fetus, approx. 10 weeks post fer- 1000 follicles will remain in the ovaries. tilization and regression of AMH recep- Value of AMH concentration is reduced tors in cellular membranes of Müllerian during embryonic life, as well as after the ducts, the neutral gonad differentiates birth (Lasala et al. 2011; Lukas-Croisie into ovary. This process is automatically et al. 2003; Rey et al. 2006). Numerous activated in the case of absence of SRY transcription factors participate in the and signal cascade associated with the process of primary follicle formation, protein, leading to testes differentiation. whose expression and signal reactions Wnt4 and Rspo1 and the negatively cor- have not been fully researched (Fowler related beta-catenin effector substance et al. 2009). FIG-alpha is one of the fac- activate the program for female develop- tors with real impact on the process of mental pathway. Expression of the Fox primary follicle formation that has been gene is activated in the postnatal period discovered (Soyal et al. 2000). The tran- and it becomes a part of maintaining fe- sition from primordial to primary stage of male developmental pathway. Analogous a follicle is regulated by key transcription function is played in male fetus by the factors: NOBOX, SOHLH1 and SOHLH2. Dmrt1 gene. GDF9 (Laitinen et al. 1998; Dong et al.1996) and BMP15 (Di Pasquale et al. Folliculogenesis and anti-Müllerian 2004) factors regulate the development hormone of preantral and antral follicle. At this de- velopmental stage, attained in 24 week of Thirty two weeks post fertilization, the gestation, the follicle commences AMH process of development of female gonad secretion. AMH regulates follicle recruit- is accomplished. From this moment, ova- ment and transition to the subsequent ry in correlation with the hypothalam- developmental stage via inhibition of ic-pituitary axis assumes its key endo- FSH receptors, which may lead to selec- crine function. Pituitary gland of female tion of one, that will attain the stage of fetus produces gonadotropic hormones, Graafian follicle and will become released FSH and LH, which act through receptors during ovulation (Durlinger et al.1999, Ovarian activity regulation by anti-Müllerian hormone in early life 331
Visser et al. 2006). AMH secretion by al. (1994) and di Clemente et al. (1994). preantral and small antral follicles occurs Genomic sequence recording AMHRII is independently of the influence of FSH. located on chromosome 12 (13q12) and Follicles in excess of 8 mm are FSH-de- it consists of 11 exons. 3 first constitute pendent. The increasing level of FSH at the record of extracellular domain, 4 the follicular stage influences increase of exon is a transmembrane domain while estrogen concentration, which, acting via 7 remaining ones-intracellular domain. negative feedback influence the decrease The sequence is 8.7 kb long. AMHRII are of AMH concentration in the follicle. It present in Müllerian ducts and gonads has been demonstrated that the level of of both sexes (Baarends et al., 1994; di AMH correlates with the concentration Clemente et al. 1994). AMH type II re- of estrogens in small antral follicles. This ceptors have also been found in the en- statement is confirmed by observation of dometrium (Renaud et al. 2005) and in polymorphisms occurring in AMH and mammary and prostatic glands (Hoshiya AMHRII receptor. Damaged genes influ- et al. 2003). AMH type I receptor in com- enced the clear decrease of the level of bination with AMHRII participates in E2. Action of AMH is based on its affin- signal transfer. ity to AMHRII receptor, which attaches The fact of a different interaction be- functionally to AMHRI. The formed com- tween sexual cells and AMH secretion plex triggers tyrosine phosphorylation in Sertoli and granular cells during go- reaction, leading to commencing reaction nadogenesis leads to interesting obser- via SMAD protein activation. They are vations. They have been confirmed by involved in transfer and transduction of the study conducted by Behringer et al. signal in cellular nucleus, influencing the (1990) on transgenic mice. It has been transcription of target genes by attaching demonstrated that Sertoli cells can sur- to specified elements of the promoter. vive independently, even if reproductive The initialized signal cascade is accompa- cells have been damaged or destroyed, nied by elements with activator and effec- while granulocytes in the case of female tor functions (Shi and Massague 2003). line have a different behavior. SMAD are associated with transferring High AMH levels appear to be toxic signal to the nucleus and are activated for oocytes undergo premature meiosis. solely by ligands of the large beta-TGF Concentration of the hormone in the fol- family (Massague et al. 1996). AMHRII licle within specified time interval may receptor possesses affinity to one ligand be slightly increased and toxic for germ type, contrary to AMHRI, which attaches cells. It is suspected that this mechanism to several types of ligands. Type I receptor constitutes a certain type of regulation, is common for selected factors belonging optimizing time and site of subsequent to the beta-TGF superfamily, including developmental processes. human bone morphotic factor BMP, apart AMH concentration reflects secretion from AMH ligand it may attach e.g. ALK, of only those follicles that are vascular- corresponding to BMP. AMHRI could ized. Despite the auto-and paracrine se- probably result in a defective or lethal cretion, AMH value in blood serum re- morphogenesis of bones. AMH type II re- flects well the pool of ovarian follicles ceptor was discovered and cloned by two (La Marca, Sunkara 2014).The hormone independent research teams: Baarends et influences aromatase inhibition in gran- 332 Małgorzata Jusiakowska-Piputa, Maria Kaczmarek ular cells, which converts androgens to developmental and control processes. Re- estrogens via blockage of cytochrome ex- search on the seasonal variability of AMH pression (Grossman et al. 2008). concentration was conducted by Dennis Interesting variability is expressed et al. (Dennis et al. 2012), which trans- by AMH depending on the season of the lates into better understanding and di- year, which is associated with exposure recting reproductive processes and thus- to sunlight and expression of D3dihy- the reproductive success. droxyvitamin. 25OH-D influences neg- AMH regulates ovarian follicle re- ative regulation of AMH via AMHRII cruitment for subsequent stages of follic- receptor mechanism and SMAD 1/5/8 ulogenesis via reduction of their sensitiv- protein mediation (La Marca, Sunk- ity to FSH (Durlinger et al. 2002; Visser ara 2014, Su et al. 2014; Gassner et al. et al. 2006). This process requires strong 2014). As an effect of D3 vitamin, ex- molecular basis in the form of a range of pression of the receptor gene is reduced, transcription factors, which will imple- SMAD phosphorylation is reduced and ment the process by means of positive or its location in the nucleus is altered. Re- negative regulation. The fact that AMH is productive potential is increased due to highly conservative in evolutionary terms repression properties of AMH and reduc- allows to assume that the above present- tion the sensitivity of AMHRII receptor ed developmental process with its contri- and SMAD proteins by 25OH-D. This is bution appears to be most advantageous exhibited by a more efficient differentia- in biological terms. tion of granular cells in the follicle and Recent studies on women with polycys- enables their major portion to develop tic ovaries (PCOS) who have higher level properly. This increases the chance for of androgens have shown that early follicu- the selection of the best dominant folli- lar growth may be promoted by androgens cle during ovulation. Reproductive po- (Fig. 2). During the pre-antral (gonado- tential increases significantly, as 25OH-D tropin-independent) follicle growth, FSH concentration correlates negatively with stimulates follicle growth via theca cell-de- the level of AMH, balancing inhibition in rived androgens. Selected androgens may
Figure 2. Working model showing how selective androgens appear capable of improving early stages of folliculogenesis. See text for explanation. Modified after Lebbe and Woodruff (2013). Ovarian activity regulation by anti-Müllerian hormone in early life 333 exert effects via androgen receptors (AR) Experimental studies through transcriptional regulation but also via enhanced FSH receptor expression AMH, as a member of a large family of modulating follicle stimulating hormone molecular growth factors beta-TGF, con- (FSH) activity in granulosa cells. The AMH stitutes an important component in the is produced by preantral and small antral control over the ovarian follicle pool, follicles. AMH through the inhibition of occurrence at trace amounts and for a FSH receptors regulates premature recruit- short period during prenatal develop- ment of ovarian follicles. FSHR expression ment, determs correct course of a range / activation occurs under androgen control. of interactions implementing genetically AMH inhibits the conversion of androgens programmed sex determination pathway, to estrogens by blocking the expression while in the reproductive period it consti- of aromatase induced by FSH (Lebbe and tutes a significant regulator of the ovari- Woodruff 2013). an balance (Yigong S, Massagué J. 2003). The relationship between anti-Mulle- AMH molecular model, due to high- rian Hormone and FSH and their effect ly conservative C-terminus of its mole- on the regulation of steroid hormones cule, constitutes the object of scientific is shown in Fig. 3. Positive or negatively research and investigations. A series of conjugated loops maintain balance during studies utilizing animal models were con- folliculogenesis limiting excessive recruit- ducted, which have proven that the evo- ment of ovarian follicles. The maintenance lutionary process adopted and fixed main of the proper concentration of androgens regulatory mechanisms in the process and estrogens in the individual stages of of developmental pathway realization. ovarian follicle development is responsible In certain species, they have undergone for the regulation of the menstrual cycle some modifications, yet a common trend and ovulation. The effect of androgens on has been observed in the field of function the expression of AMH has not been fully of AMH in the majority of Vertebrata, in- understood yet (Dewailly et al. 2016). cluding humans.
Figure 3. Relationship between anti-Müllerian hormone and FSH and their effect on the regulation of ste- roid hormones during early stages of folliculogenesis. See text for explanation. Modified after Dewailly et al. (2016). 334 Małgorzata Jusiakowska-Piputa, Maria Kaczmarek
The human gene coding AMH has the morphism in prenatal development due length of 2.8 kb (Cate et al. 1989) and to the effect of AMH. Time shift caused it is mapped in the 19p.13.3 position. It by varying AMH coding gene expression has been cloned for numerous mammal is of high significance. In Sertoli cells it as well as fish, salamander, reptile and is activated on 8 week post fertilization, bird species (Halm et al. 2007; Pala et al. whereas in female fetus this process takes 2008). The expression pattern of genes place on 24 week in granular cells of the coding AMH is similar in Vertebrata, yet formed ovarian follicles. AMH actively the expression method and certain mod- participates in the process of folliculo- ifications in the genomic sequence read- genesis, which is the expression of high ing stem from species particularities. evolutionary specialization (Durlingr et It has been determined that the or- al. 2002). tholog group is characterized, similarly The carboxylic portion of the AMH to humans, regression of Müllerian ducts glycoprotein molecule remains strong- during the embryogenesis of the male sex. ly conservative in evolutionary terms, This includes a marsupial-tammar walla- which is confirmed by the comparison by (Pask et al. 2004), American alligator of amino acid sequence between: mouse (Western et al. 1999) or chicken (Car- and human and mouse and cattle in ré-Eusèbe et al. 1996; Neeperet al. 1996). terms of the percentage contribution of This observation has not been confirmed homologues: 95% and 94 % of homol- in representatives of such species as Cau- ogy. The minor differences between the data amphibia, Pleurodeleswaltl, the Iberian species stem from the respective 5 and 6 ribbed newt, representatives of salaman- changes in the group, which comprises ders. Male individuals retain Müllerian approx. 106 amino acids.The presence ducts (Al-Asaad et al. 2013). The discov- of cysteine has also been considered, as ery of AMH orthologs among teleost fish- it is highly valuable as predictor of evo- es came as a surprise, for which AMHRII lutionary conservationism (Cate et al., genes could be cloned and full regression 1986). of Müllerian ducts was observed. The observed pattern of gene expres- In fishes, AMH plays the key role for sion: amh, sox9a, sox9b and cyp19a1a and proliferation of reproductive cells and go- regulatory reaction in the zebrafish com- nad maturation. This allows to conclude ply with that observed for mammals, that in the course of evolution, AMH thus confirming the conservatism of the was responsible for an increasing range expression pattern. However, different of molecular reactions. This is confirmed species may exhibit various regulatory by the fact that in higher vertebrates, the mechanisms and interactions between scope of AMH effect has covered regula- genes, as in the case of e.g. chicken or tion of the follicular system in the ova- alligator embryos, where amh expression ries of adult females (Visser and Them- precedes sox9 expression (Smith et al., men 2005) or control of Leydig cells in 1999, Western et al.,1999, Oreal et al., males (Racine et al. 1998). Its previous 2002). role was limited solely to the function of AMH constitutes a negative regulator differentiation of bipolar gonads. Regu- of the CYP19a1 gene in mammal ovarian lation of human embryogenesis enables follicles. The product of the gene expres- confirmation of the fact of high sexual di- sion is aromatase, an enzyme controlling Ovarian activity regulation by anti-Müllerian hormone in early life 335 conversion of androgens to estrogens. productive age (van Rooij et al. 2002; van This female steroid hormone affects re- Rooij et al. 2005) and for prediction of productive success. Expression of the time to menopause (Tehrani et al. 2013). Sox9b gene-regulating AMH expression, It has been observed that AMH concen- occurs directly in the ooplasm of oocytes, tration is subject to minor fluctuations which appears to favor directional regula- during menstruation cycle, which is not tion of the AMH in the correct place and of clinical importance (van Disseldorp et time. (Rodriguez-Mari et al. 2005) al. 2010; La Marca et al. 2013.) The hor- The research team of Rodriguez-Mari mone maintains its high diagnostic value. (2005), who carried out molecular test- Determination of AMH serum concen- ing on the zebrafish obtained results that tration is used for the basic examination of have confirmed the similarity concerning patients with suspected granular cells can- AMH expression in human granular cells cer (Gustafson et al. 1992; Long et al. 2000). of ovarian follicles, from the fetal live, AMH is used for standard IVF procedures, through reproductive period until the where it constitutes the main diagnostic el- menopause (Lasala et al., 2004). Identi- ement for determining causes for infertility cal AMH expression pattern was deter- (Alvaro Mercadal et al. 2015). Depending mined in the granulosa cells in both test- on the hormone level determined, and the ed cases, with differences of histological use of other diagnostic tools, the cause is nature being determined. The result sug- determined with high likelihood, which gests that genes coding AMH sequence greatly facilitates treatment. originate from a common ancestor to fishes and humans, thus confirming the Diagnostic methods role fulfilled by the AMH in reproductive process. The lack of uniform standards for labora- tory determinations constitutes a disput- Clinical studies able issue. Results obtained differ mark- edly, and depend on the applied method Determination of the AMH level in hu- and laboratory tools. Clinical centers es- mans is increasingly commonly applied tablish own norms used to compare the in highly developed countries. In clinical obtained results, yet different sensitivity practice, determination of AMH serum of applied systems disables comparison concentration is applied primarily for the of results in the global aspect. procedures of assisted reproduction per- The Beckman-Coulter Gen-II system formed in larger clinical centers. utilizes the developed DSL antibodies AMH constitutes a stable marker re- (Li et al. 2012; Han et al. 2014), howev- flecting normal prenatal sexual develop- er, a precise determination according to ment (Josso et al. 2012; Rey and Grin- the rhAMHImmunotech curve requires spon 2011). The diagnostic value of AMH repetition of the procedure to eliminate further includes postnatal developmental additional reaction with the comple- disorders, in particular of boys at prebu- ment. Results of AMH determinations pertal age (Grinspon and Rey 2010; Rey turned out to be approx. 22–40% high- et al. 2013; Rohayem et al. 2015). er in comparison to the results with the AMH is widely used for determina- use of previously used, I generation sys- tion of ovarian reserve in women at re- tem (Wallace et al. 2011).Widely used 336 Małgorzata Jusiakowska-Piputa, Maria Kaczmarek is the Ultrasensitive picoAMH ELISA pression. This hormone, indispensable system by Anshlabs (2013), as well as for the process of sexual formation and a version of this system-analysis with regulation of male and female embryo, dried blood (Gassner and Jung 2014) by acts according to different signal pat- the same company (Roberts et al. 2016), terns. In those processes, cascades of bio- as well as Beckman Coulter Access AMH chemical reactions are activated, includ- (Pearson et al. 2016). Laboratory diag- ing transcription factors, cofactors, signal nosticians value the Roche Elecsys prod- proteins and genes themselves. Positively uct, which was introduced to the marked or negatively coupled interaction loops in in 2014. It is a modern, fully automatic biological processes realize genetic pat- diagnostic system, which utilizes elec- tern for differentiation, development and trochemiluminescence effect (Gassner maintaining of the reproductive potential et al. 2014). in the adult life. The process of AMH value determina- This conservative regulatory mecha- tion has been abbreviated to 18 minutes. nism, with the important role of AMH, In June 2013, during the ESHRE Con- is observed in the majority of Vertebrata. gress (European Society of Reproduction A more extensive use of AMH diag- and Embryology), the Backman Coulter nostic value in the future may contribute company applied for an improvement of to better understanding of processes as- the diagnostic value of AMH by means sociated with dysfunction of the repro- of proper preparation of samples with ductive system and fertility disorders. buffers or freezing after their collection and prior to determination. Establishing Authors’ contributions international standards for AMH consti- tutes the current challenge in the clinical Both authors contributed equally to this practice. manuscript.
Conclusions Conflict of interest
Application of AMH in clinical practice The authors declare that there is no con- appears to have a wide perspective of de- flict of interest regarding the publication velopment. The AMH diagnostic value of this article. enables an insight into developmental processes, both during prenatal life as Corresponding author well as after the birth. It is of particular significance in woman reproductive peri- Małgorzata Jusiakowska-Piputa, De- od, since AMH is the most precise mark- partment of Human Biological Develop- er reflecting biological processes taking ment, Institute of Anthropology, Faculty place in the ovaries. of Biology, Adam Mickiewicz University, The conservative mechanism of sex Umultowska 89, 61-614 Poznań, Poland determination and differentiation during Email address: [email protected] embryogenesis is regulated by activation of expression of genes associated with References chromosome Y, which activates biochem- Al-Asaad I, Chardard D, di Clemente N, ical cascades, including AMH gene ex- Picard JY, Dumond H, Chesnel A, et al. Ovarian activity regulation by anti-Müllerian hormone in early life 337
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