review article anti-müllerian hormone: a valuable addition...

Hindawi Publishing CorporationInternational Journal of EndocrinologyVolume 2013 Article ID 674105 12 pageshttpdxdoiorg1011552013674105

Review ArticleAnti-Muumlllerian Hormone A Valuable Addition tothe Toolbox of the Pediatric Endocrinologist

Nathalie Josso1 Rodolfo A Rey23 and Jean-Yves Picard1

1 INSERM U782 Universite Paris-Sud UMR-S0782 92140 Clamart France2 Centro de Investigaciones Endocrinologicas ldquoDr Cesar Bergadardquo (CEDIE) CONICET-FEI-Division de EndocrinologıaHospital de Ninos ldquoR Gutierrezrdquo C1425EFD Buenos Aires Argentina

3Departamento de Histologıa Embriologıa Biologıa Celular y Genetica Facultad de MedicinaUniversidad de Buenos Aires C1121ABG Buenos Aires Argentina

Correspondence should be addressed to Nathalie Josso nathaliejossou-psudfr

Received 31 May 2013 Accepted 7 October 2013

Academic Editor Volker Ziller

Copyright copy 2013 Nathalie Josso et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Anti-Mullerian hormone (AMH) secreted by immature Sertoli cells provokes the regression of male fetal Mullerian ducts FSHstimulates AMHproduction during puberty AMH is downregulated by intratesticular testosterone andmeiotic germ cells In boysAMH determination is useful in the clinical setting Serum AMH which is low in infants with congenital central hypogonadismincreases with FSH treatment AMH is also low in patients with primary hypogonadism for instance inDown syndrome from earlypostnatal life and in Klinefelter syndrome from midpuberty In boys with nonpalpable gonads AMH determination without theneed for a stimulation test is useful to distinguish between bilaterally abdominal gonads and anorchism In patients with disordersof sex development (DSD) serum AMH determination helps as a first line test to orientate the etiologic diagnosis low AMH isindicative of dysgenetic DSD whereas normal AMH is suggestive of androgen synthesis or action defects Finally in patients withpersistent Mullerian duct syndrome (PMDS) undetectable serum AMH drives the genetic search to mutations in the AMH genewhereas normal or high AMH is indicative of an end organ defect due to AMH receptor gene defects

1 Introduction

Anti-Mullerian hormone (AMH) also known as Mullerianinhibiting substance (MIS) or factor (MIF) is a member ofthe transforming growth factor-120573 (TGF-120573) secreted essen-tially by fetal and prepubertal Sertoli cells and to a lesseramount by granulosa cells of small follicles AMHplays a bio-logical major role in shaping the male reproductive tract bytriggering the regression of male fetal Mullerian ducts whileandrogens secreted by the Leydig cells present in the intersti-tial tissue are responsible for the stabilization of theWolffianducts and their differentiation into male accessory organs aswell as for the virilization of the urogenital sinus and theexternal genitalia In males lacking AMH the persistence ofMullerian derivatives coexists with the development of nor-mal male external genitalia It follows that clinical applica-tions of AMH in pediatric endocrinology are essentially diag-nostic and restricted to boys In recent years AMHhas gained

great importance in gynecology and obstetrics due to itsvalue as a marker of ovarian reserve but this clinical applica-tion does not concern pediatricians and will not be consid-ered here Several AMH ELISA kits are commercially avail-able as discussed elsewhere in this issue

2 Ontogeny and Regulation ofTesticular AMH Production

AMH is a homodimeric glycoprotein member of the TGF-120573 family It is initially secreted as a precursor subsequentlycleaved to yield 110 kDa N-terminal and 25-kDa C-terminalhomodimers which remain associated as a biologically activenoncovalent complex [1] Dissociation of the noncovalentcomplex occurs at the time of binding to type II AMH recep-tor and is required for biological activity [2]Themajor site ofAMH production is the immature Sertoli cell In the late fetal

2 International Journal of Endocrinology

Gonadotroph

Leydig cell

Sertoli cell

GnRH

LH FSH

AMH

LH-R

FSH-R

T

AR

_+

AIS (puberty)

GnRH

LH FSH

AMH

LH-R

FSH-R

T

AR

_+

Leydig cell aplasiaT synthesis defects

GnRH

LH FSH

AMH

LH-R

FSH-R

T

AR

_+

Normal pubertyPrecocious puberty

GnRH

LH FSH

AMH

LH-R

FSH-R

T

AR

_+

Centralhypogonadism

GnRH

LH FSH

AMH

LH-R

FSH-R

T

AR

_+

Childhood

I II III IV V

Foetusmdash0ndash6 months

timestimes

Figure 1 Regulation of testicular AMH secretion by gonadotropins and androgens In general the hypothalamus regulates LH and FSHsecretion by the gonadotroph through the gonadotropin-releasing hormone (GnRH) LH acts on the LH receptor (LH-R) present in Leydigcells inducing testosterone (T) secretion FSH acts on the FSH receptor (FSH-R) present in Sertoli cellsThe hypothalamic-pituitary-gonadalaxis is active in the foetus and early infancy is quiescent during childhood and is reactivated at puberty FSH is a moderate inducer of AMHsecretion whereas T acting through the androgen receptor (AR) is a potent inhibitor of AMHproduction In the normal foetus and infant aswell as in patients with the androgen insensitivity syndrome (AIS) the lack of AR expression results in high AMH production by Sertoli cells(I) During childhood there is a physiologic hypogonadotropic state resulting in very low T AMH levels remain high but somewhat lowerprobably due to the lack of FSH stimulus (II) In normal or precocious puberty T prevails over FSH resulting in AMH inhibition (III) Incongenital central hypogonadism AMH is lower than in the normal boy because of the longstanding lack of FSH from foetal life however atpubertal age the inhibitory effect of T is also absent and AMH remains higher than in normal puberty (IV) In Leydig cell-specific primaryhypogonadism (Leydig cell aplasia or hypoplasia due to LH-R defects or defects of steroidogenesis) the inhibitory effect of androgens isabsent and AMH levels are high The orange area represents the testis Thickness of lines is in correlation with hormone effect on its targetFrom [5] Copyright Karger AG 2010 with permission

and postnatal ovary it is also produced by granulosa cells ofdeveloping follicles essentially preantral and small antral fol-licles [3 4]

In the male AMH is a specific functional marker of theimmature Sertoli cell AMH expression is initiated at the timeof fetal differentiation of the seminiferous cords by the end ofthe 7th embryonic week and remains at high levels until theonset of puberty except for a transient decline in the perinatalperiod [6 7] AMH expression is triggered by SOX9 whichbinds to the AMH promoter subsequently SF1 GATA4 andWT1 further increase AMH promoter activity (reviewed in[8]) The onset of AMH expression and its basal expressionlevel throughout life are independent of gonadotropinsHowever FSH stimulates testicular AMHproduction by bothinducing Sertoli cell proliferation and upregulating AMHtranscription [9] The latter is mainly mediated by the clas-sical pathway involving Gs120572 and adenylyl cyclase increase ofcyclic AMP levels which stimulates protein kinase A (PKA)activity subsequently involving transcription factors SOX9SF1 GATA4 NF120581B and AP2 [10ndash12] During puberty AMHproduction is inhibited by the increase of intratesticulartestosterone concentration and the onset of germ cell meiosis

(Figure 1) (reviewed in [13 14]) The inhibitory effect ofandrogens onAMHovercomes the positive effect of FSHafterpubertal onset On the contrary androgens cannot inhibitAMH production in the fetal and neonatal testis whereSertoli cells do not yet express the androgen receptor [15ndash17]

3 AMH in Boys with Hypogonadism

Gonadotropin and testosterone which are high in the 3ndash6months after birth normally decrease to very low levels untilthe onset of puberty Therefore their usefulness as markersof the function of the hypothalamo-pituitary-gonadal axisin the boy is limited On the contrary AMH determinationis extremely useful since Sertoli cells remain active duringinfancy and childhood [18 19] Serum AMH reliably reflectsthe presence and function of testes in prepubertal boys with-out the need for any stimulation test [18 20 21] In this sec-tion we address how the different disorders causing hypogo-nadism affect AMH testicular production

31 Central Hypogonadism Serum AMH is low in infantswith congenital central hypogonadism Treatment with FSH

International Journal of Endocrinology 3

rhFSH + hCG

T (ngdL)302 plusmn 25


Seru

m A

MH

(pm

olL

)

0

250

500

750

1000

0 10 20 30 60 90Days

rhFSH

T (ngdL)31 plusmn 5

T (ngdL)39 plusmn 8

Patients with congenital central hypogonadism

150 Ud 150 Ud

lowastlowastlowast

lowastlowastlowast

lowastlowastlowast

lowastlowast

lowast

1500 U 2wk

Figure 2 AMH levels in central hypogonadism Serum AMH waslow for Tanner stage I (prepubertal) in patients with previouslyuntreated central hypogonadism Initial treatment with recombi-nant human FSH (rhFSH) during 30 days resulted in an elevationof serum AMH in all 8 patients while testosterone (T) remained atprepubertal levels Shaded area represents normal AMH for TannerI stage according to T levels observed in these patients Subsequentaddition of hCG treatment resulted in an elevation of T whichprovoked a decline in serum AMH Shaded area represents AMHvalues for Tanner IV-V stages according to T levels observed inthe treated patients From [5] Copyright Karger AG 2010 withpermission

results in an elevation in serum AMH in correlation with anincrease in testis volume [22] In patients of pubertal age withuntreated congenital central hypogonadism serum AMHis elevated for agemdashbecause the insufficient testosteroneproduction is unable to downregulate AMH but lower thanexpected for patientrsquos Tanner stage [23 24]mdashreflecting thelack of FSH stimulus FSH treatment results in an increase inserumAMH subsequent treatmentwith hCG induces andro-gen production which provokes a physiological decline inAMH (Figure 2) Interestingly inhibition of AMH does notoccur when patients are treated with exogenous testosteronewhich reflects that intratesticular testosterone levels remainlow [24]

32 Primary Hypogonadism In patients with sex-chro-mosome aneuploidies resulting in Klinefelter syndrome(47XXY) no overt signs of hypogonadism are evident duringinfancy and childhood AMH inhibin B and FSH levelsare normal However from midpuberty Sertoli cell functiondeteriorates progressively resulting in extremely lowor unde-tectable AMH and inhibin B levels very high FSH and smalltestis volume [25]

Unlike Klinefelter syndrome the somatic aneuploidy ofTrisomy 21 (Down syndrome) results in early-onset primaryhypogonadism in a large proportion of cases Serum AMH islow from infancy [22]

Patients with Prader-Willi syndrome have hypogonadismleading to small genitalia and arrested pubertal development

classically attributed to hypothalamic dysfunction Howeverrecent investigations have demonstrated that the disordermay also be due to primary hypogonadism with low AMHand testosterone levels associated with normal to moderatelyelevated gonadotropins [26ndash28] or to a combined form ofhypogonadism with low testicular hormones and inade-quately normal gonadotropins [27 29]

The X-linked form of adrenal hypoplasia congenita asso-ciated with hypogonadism resulting from mutations in theDAX1 gene is another example of combined (central + pri-mary) hypogonadism These patients have low serum AMHand inhibin B and defective androgen response to hCGindicative of a primary testicular failure At pubertal agegonadotropin levels remain inadequately normal in spite ofthe lack of negative feedback resulting from low inhibin B andtestosterone which indicates that gonadotrope function isalso impaired [30]

33 Cryptorchidism Cryptorchidism is a sign that can bepresent in many disorders of different etiologies most ofwhich remain elusive [31 32] Dissociated testicular dysfunc-tion primarily affecting the tubular compartment seems to bethe underlying pathophysiology in cases presenting with lowAMH [33] and inhibin B [34] but with normal testosteroneand INSL3 [35] during early infancy and childhood In othercases no significant changes in hormone levels could bedetected [36] The apparently contradictory results are mostprobably due to the heterogeneity of the cryptorchid patientswith underlying conditions of different etiologies and prog-noses Bilateral cryptorchidism with nonpalpable gonadsshould be distinguished from anorchia Vanishing or regres-sion of testicular tissue occurring in late fetal life oncesex differentiation has occurred is associated with malegenitalia micropenis and hypoplastic scrotum Later inpostnatal life anorchia should be distinguished from bilateralcryptorchidism with abdominal testes Serum AMH is unde-tectable in anorchid boys but detectable in boys with abdom-inal gonads (Figure 3) [20 21 37]

In Noonan syndrome cryptorchidism occurs in approx-imately 23 of the cases During childhood reproductivehormones are within the expected range Pubertal onset isdelayed by mid- to late puberty gonadotropin levels increaseover the normal range and AMH and inhibin B decline tosubnormal levels in patients with a history of cryptorchidismbut remain within normal levels in those with descendedtestes [38]

4 AMH in Disorders of Sexual Differentiation

Thedevelopment and differentiation of the sex organs duringfetal life involve three successive steps (1) the early mor-phogenesis of the gonadal and genital primordia which isidentical in XY and XX embryos (2) the differentiation of thegonadal ridge into a testis or an ovary (3) the differentiationof the primordia of the internal and external genitalia whichare virilized by the action of androgens and AMH or femi-nized in their absence


0

500

1000

1500

2000

Bilateral cryptorchidismAnorchia

AMH

(pm

olL

)

Age (years) 0 2 4 6 8 10 12 14 16 18 20

Figure 3 Serum AMH levels are useful to distinguish betweenbilateral cryptorchidism with abdominal testes and anorchismSerum AMH is undetectable in anorchid patients in patients withbilaterally abdominal testes serum AMH is always detectable rang-ing from subnormal to normal values according to the functionalstatus of the gonads Shaded area represents the normal serumAMHrange (3thndash97th centiles) according to [22]

Based on the recognition of the cause of abnormal sexorgan development in patients bearing a Y chromosome(Table 1) disorders of sex development (DSD)may be dividedinto (a) malformative DSD where abnormal morphogenesisof the genital primordia occurs in early embryonic life (b)dysgenetic DSD due to abnormal gonadal differentiationresulting in insufficient secretion of androgens and AMHand (c) nondysgenetic DSD in which the abnormal sex hor-mone-dependent genital differentiation results from specificdefects in the production or action of androgens or AMH

41 AMH in Malformative DSD Defects in the early mor-phogenesis of the Mullerian orWolffian ducts the urogenitalsinus or the primordia of the external genitalia for examplecloacal malformations isolated hypospadias or aphalliausually occur in eugonadal patients Therefore serum AMHand testosterone levels are within the expected range for sexand age From a practical standpoint nonendocrine relatedDSD should be considered when there is inconsistency inthe development of the different elements of the genitaliaFor instance isolated hypospadias with no other signs ofhypovirilization in patients with normal AMHand androgenlevels is most probably due to early morphogenetic defects[39 40] In most cases endocrine-unrelated malformationsof the genitalia are associated with other somatic dysmorphicfeatures like in Robinow syndrome due to ROR2 mutationsPallister-Hall syndrome due to GLI3 mutations or manyother polymalformative associations of unknown etiologyldquoIdiopathicrdquo persistence of Mullerian derivatives (PMDS) inpatients with a normal AMH level mutation-free AMH andAMH receptor genes may belong to the same category (seebelow)

42 AMH in Dysgenetic DSD Gonadal dysgenesis estab-lished in the first trimester of fetal life represents the earliestform of primary hypogonadism and prevents the normalhormone-driven differentiation of the sex organs In thefetus carrying a Y chromosome gonadal dysgenesis results infemale or ambiguous genitalia reflecting the degree of testic-ular hormone deficiency SerumAMH is low or undetectabledepending on the amount of testicular tissue remaining [41](Table 1 and Figure 4) Serum AMH observed in a newbornwith ambiguous genitalia should be compared with referencelevels for the adequate age period to avoid overdiagnosis ofdysgenetic DSD AMH levels are transiently lower during thefirst 2-3 weeks after birth in the normal newborn [6 7 22]when in doubt a repeat measurement to assess the evolutionof serum AMHmay be helpful [42]

In 45X or 45X46XX patients gonads are reduced tofibrous streaks or develop into dysgenetic ovaries SerumAMH levels reflect the amount of small follicles present inthese gonads and predict the occurrence of spontaneouspubertal onset [43]

Ovotesticular DSD is a particular type of gonadal dysgen-esis where both testicular and ovarian tissues are presentThemost frequent karyotypes are 46XX or mosaicism includingat least one XY lineage The degree of virilization is usuallycommensurate with the amount of testicular tissue In XXpatients the differential diagnoses are congenital adrenalhyperplasia aromatase deficiency and androgen-secretingtumors An increased level of serum AMH is specific ofovotesticular DSD [41] in the other conditions serum AMHis in the female range In contrast androgen assay is notuseful for diagnosis since androgens are always above normalfemale levels

43 AMH in DSD due to Defects in Androgen Synthesis orAction While gonadal dysgenesis affects the production ofboth androgens and AMH DSD may also result from a spe-cific defect impairing the endocrine function of Leydig cellsIn this case there is a ldquodissociatedrdquo or ldquocell-specificrdquo form offetal-onset primary hypogonadism (reviewed in [5]) asopposed to gonadal dysgenesis leading to whole gonadalfailure Deficiency of androgen synthesis results in the occur-rence of female or ambiguous external genitalia and nouterus

431 Leydig Cell AplasiaHypoplasia and Steroidogenic Pro-tein Defects Leydig cell aplasia due to inactivating muta-tions of the LHCG receptor and defects in proteins orenzymes involved in testicular steroidogenesis result in com-plete lack or insufficiency of androgen production by thetestes Consequently hypovirilization or feminization of gen-italia occurs as in dysgenetic DSD Both dissociated primaryhypogonadism specifically affecting Leydig cells and dysge-netic DSD have low testosterone levels in serum yet it is pos-sible to distinguish them bymeasuring AMHWhile AMH islow or undetectable in dysgenetic DSD as described above itis normalhigh in steroidogenic defects because the androgeninhibitory effect on AMH is lacking and the elevation ofserum FSH upregulates AMH secretion [41] particularly in


Table 1 Etiopathogenic classification of disorders of sex development (DSD) in patients with a Y chromosome

Etiopathogenic classification Serum AMH Serum T(A) Malformative DSD

Defective morphogenesis of the wolffian ductsCongenital absence of the vas deferens (Cystic Fibrosis) Normal Normal

Defective morphogenesis of the urogenital sinus and of the primordia of theexternal genitalia

Cloacal malformations aphallia and isolated hypospadias Normal Normal(B) Primary hypogonadism (early fetal-onset)(B1) Dysgenetic DSD whole testicular dysfunction

Complete gonadal dysgenesisY chromosome aberrationsDSS duplications 9p deletions (DMRT12) 1p duplication (WNT4)Gene mutations SRY CBX2 SF1 WT1 SOX9 DHH MAMLD1 TSPYL1DHCR7 and so forth Undetectable Undetectable

Partial gonadal dysgenesisSame as complete gonadal dysgenesis Low Low

Asymmetric gonadal differentiation45X46XY an other mosaicism or Y chromosome aberrations Low Low

Ovotesticular gonadal differentiation46XX46XY an other mosaicism Low Low

(B2) Nondysgenetic DSD cell-specific dysfunctionLeydig cell dysfunction

Mutations in LHCG-R StAR P450scc P450c17 POR cytochrome b53120573-HSD and 17120573-HSD

High in neonates andin pubertal agenormal in childhood

Lowundetectable

Sertoli cell dysfunctionAMH gene mutations Lowundetectable Normal

(C) End-organ failure(C1) Androgen end-organ failure

Impaired DHT production5120572-Reductase gene mutations Normal Normal

Androgen insensitivity syndrome (AIS)

Androgen receptor mutations

Partial AIS high inneonates normal inchildhood andinadequately high atpubertal ageComplete AISnormallow inneonates normal inchildhood and veryhigh at pubertal age

Normalhigh

(C2) AMH end-organ failureAMHR-II mutations Normal Normal

3120573-HSD 3120573-hydroxysteroid dehydrogenase 17120573-HSD 17120573-hydroxysteroid dehydrogenase AGD asymmetric gonadal differentiation AMH Anti-Mullerianhormone AMHR2 Anti-Mullerian hormone receptor type 2

the first 3ndash6 months after birth and at pubertal age in thosecaseswhere gonadectomyhas not yet been performed (Table 1and Figure 4) It should be noted that AMHmay bewithin thenormal male range in these patients during childhood

432 Deficiency of 5120572-Reductase Steroid 5120572-reductase isthe key enzyme for the conversion of testosterone to dihy-drotestosterone (DHT) The androgen receptor has a higheraffinity for DHT than for testosterone In the absence of


2500

2000

1500

1000

500

LCD

CAIS

PAIS

PTD

CGD TH LCD

CAIS

PAIS

PTD

CGD TH LCD

CAIS

PAIS

PTD

CGD

Seru

m A

MH

(pm

olL

)

lt1 yr 1ndash9 yr gt9 yr

(a)

3500

2800

2100

1400

700

00 4 8 12 16 20 24 32 40 48

Age (yr)

Seru

m A

MH

(pm

olL

)

LCDCAISPAIS

(b)

Figure 4 Serum AMH in disorders of sex development (DSD) (a) Serum AMH levels in patients with DSD LCD Leydig cell defectsincluding Leydig cell aplasia or hypoplasia and steroidogenic enzyme mutations CAIS complete androgen insensitivity syndrome PAISpartial androgen insensitivity syndrome PTD partial testicular dysgenesis including asymmetrical gonadal differentiation CGD completegonadal dysgenesis TH true hermaphroditism or ovotesticular DSD The shaded areas represent the normal levels Data is obtained from[41] Copyright The Endocrine Society 1999 (b) Serum AMH levels in patients with DSD due to defects in androgen production (Leydigcell defects LCD) or action (complete or partial androgen insensitivity syndrome AIS) The shaded area represents the normal levels Datais obtained from [44] Copyright The Endocrine Society 1994 with permission

5120572-reductase activity the Wolffian ducts differentiate nor-mally because the adjacent testes supply sufficiently highlocal testosterone concentrations Conversely more distantandrogen-dependent organs like the urogenital sinus and theexternal genitalia need testosterone conversion to DHT foradequate virilization The Mullerian ducts regress normallybecause Sertoli cell AMH production is not affected Testos-terone levels are normal and serum AMH is also withinthe normal male range Because there are normal testicularandrogen concentration and androgen receptor expressionand FSH is not elevated serumAMH is not increased in thesepatients [45] (Table 1)

433 Androgen Insensitivity Syndrome (AIS) Androgeninsensitivity due to mutations in the androgen receptor is themost frequent cause of lack of virilization in eugonadal XYpatients The testes differentiate normally and both Sertoliand Leydig cells are functionally normal from an endocrinestandpoint Owing to end-organ insensitivity to androgensWolffian ducts regress and the urogenital sinus and the exter-nal genitalia fail to virilize Mullerian ducts do not developreflecting normal AMH activity Complete AIS results in afemale external phenotype whereas partial AIS presents withambiguous genitalia

Thepituitary-gonadal axis shows different features duringthe first three months of life in complete and partial AISIn the newborn with complete AIS FSH remains low whichprobably explains why serumAMH is not as high as expected[46] Conversely in partial AIS gonadotropins as well asAMH are elevated (Table 1 and Figure 4) [44 46] As in DSD

80

60

40

20

0AMH AMHR-II

Num

ber

PMDS familiesWith recurrent alleles

Figure 5 Recurrent alleles in families with persistent Mullerianduct syndrome (PMDS) Number of PMDS families and numberof families with recurrent alleles PMDS persistent Mullerian ductsyndrome AMH anti-Mullerian hormone gene AMHR-II anti-Mullerian hormone receptor type II gene

due to defects of steroid synthesis serum AMH remainswithin the normal male range during childhood [41] Atpubertal age provided gonadectomyhas not been performeda difference is again observed between partial and completeAIS In complete AIS serum AMH increases to abnormallyhigh levels whereas in partial AIS the elevation of intrat-esticular testosterone concentration is capable of inducing


C-terminal

V12G

L70P

L118P

F148L Y167C

R194CA206D V477A

C488Y

H506QC525Y

R123W

G101V G101R Q496H

P151S R302Q

P151A

R377C

C188G

T193I R302P

V174G

A120P L339P

L426R

L536FC557SR560P

R191Stop E382StopQ128Stop

R40Stop

d27-28

d1129-1130d2277

d219

E466StopW121Stop

d353-354

W494Stop

May 2013

d-216

A314G

G533V

R95Stop

AMH gene

lowast

lowast lowast lowast

05 kbp

ATG rarr ATT

d353ndash356

+C (213ndash218)

ndash2292d1074ndash1087

+23 bp (2349)

Figure 6 Mutations of the AMH gene in PMDS Exons are shaded All recurrent mutations are indicated in red Missense mutations are inyellow boxes note that the first mutation destroys the translation initiation site Asterisks represent splice mutations the red asterisk at thebeginning of the second intron indicates a mutation detected in three different families all fromNorthern Europe Deletions (marked ldquodrdquo) arein green boxes insertions (marked ldquo+rdquo) are in blue boxes and nonsense mutations are in white boxes A deletion mutation in the promoteris shown C-terminal coding for bioactive C-terminal domain of the AMHmolecule Base numbering is from major transcription initiationsite minus10 bp from A of ATG

an incomplete inhibition of AMH expression NonethelessAMH levels are inadequately high for the concomitant circu-lating testosterone [41]

44 AMH in the PersistentMullerianDuct Syndrome (PMDS)PMDS is characterized by the persistence of Mullerian ductderivatives uterus Fallopian tubes and upper vagina in oth-erwise normally virilized 46XYmales Approximately 85ofcases are due to mutations of the AMH or AMHR-II gene inroughly equal proportions 15 are idiopathic All the infor-mation provided is current up to May 2013

441 AMH Deficiency PMDS due to AMH Gene Mutations

Clinical and Anatomical Features Because of their normalexternal male phenotype patients are assigned at birth to themale gender without hesitation in spite of the fact that one orboth testes are not palpable in the scrotum When cryp-torchidism is unilateral the contralateral scrotal sac containsa hernia in addition to the testis Preoperative diagnosis ofPMDS is best reached by laparoscopy [47 48] Howeverunless an elder brother has been diagnosed with the con-dition persistence of Mullerian derivatives is usually dis-covered unexpectedly during a surgical procedure for cryp-torchidism andor hernia repair

Testes and the vasa deferentia adhere to thewalls of uterusand vagina [49] Their location depends upon the mobility

of the Mullerian structures Often the broad ligament whichanchors the uterus to the pelvis is abnormally thin allowingthe Mullerian derivatives to follow one testis through theinguinal canal and into the scrotum resulting in ldquoherniauteri inguinalisrdquo The testis on the opposite side may alreadybe present in the same hemiscrotum a condition known asldquotransverse testicular ectopiardquo this rare condition is associatedwith PMDS in 30 of cases [50] Very rarely transverse tes-ticular ectopia is the only anatomical abnormality observedin patients homozygous for an AMH or AMHR-II mutationno Mullerian derivatives can be detected [51]

The PMDS testis is only loosely anchored to the bottomof the processus vaginalis the gubernaculum is long and thinresembling the round ligament of the uterus and exposing themobile testis to an increased risk of torsion [52] and subse-quent degeneration [53] Alternatively the Mullerian deriva-tivesmay remain anchored in the pelvis preventing testiculardescent [54] and giving rise to bilateral cryptorchidism Thepresence of these midline structures may be missed if cureis attempted through inguinal incisions The apparent risein the incidence of PMDS over recent years may be due tothe increased use of laparoscopy in patients presenting withbilateral impalpable testes

Prognosis Pubertal development is normal however incon-trovertible evidence of paternity is lacking Infertility mayresult from aplasia of the epididymis or germ cell degenera-tion due to long standing cryptorchidism However excising


0

10

20

30

40

50

AMHAMHR-II

Fam

ilies

()

(23)

(27)

(11)(8)

(15)

(6)

(13)(12)

(1) (2) (2)(4)

N E

urop

e

S E

urop

e

Afr

ica

ME

Asia

USA

Latin

Am

Figure 7 Ethnic origin of PMDS families Results are expressedas percentages of total number of families with respectively AMHor AMHR-II mutations The number of families is shown betweenparentheses Differences between AMH and AMHR-II mutationsare not statistically significant the predominance of NorthernEurope merely reflects a recruitment bias N Europe NorthernEurope (including Northern France) S Europe Southern Europe(including Southern France) Africa (mostlyMaghreb)MEMiddleEast (includes Turkey Afghanistan and Pakistan as per Wikipediadefinition) Latin Am Latin America (includesMexico Central andSouth America)

the uterus to allow abdominal testes to descend into thescrotum carries significant risks to testicular blood supplyMost authors recommend partial hysterectomy limited to thefundus and proximal Fallopian tubes or the simple divisionof Mullerian structures in the midline Later in the case ofejaculatory duct defects intracytoplasmic sperm injectionmay be helpful Orchiectomy is required if the testis cannot bebrought down because of a 15 risk of cancer an incidenceapparently not higher than that for other abdominal unde-scended testes (reviewed in [55 56]) AMH mutations areasymptomatic in young girls

Biological Features Testosterone and gonadotropin levels arenormal for age Serum AMH levels are generally very low orundetectable in prepubertal patients [57] due to instabilityof the mutant protein This is not restricted to mutationscoding for the bioactive C-terminus [58] a 3D model of theC-terminus has been generated using BMP2 and BMP7 astemplates providing insights into the impact of 31015840 mutationsupon secretion and action One single mutation suspectedof disturbing the interaction of the molecule with its type Ireceptor ALK3 coexisted with a normal serum AMH con-centration [58]Thus a normal serumAMH albeit very raredoes not absolutely rule out the possibility of a pathogenicAMH gene mutation however this hypothesis cannot beentertained unless the AMHR-II gene has been totally exon-erated

Type Ireceptor

AMHRII

Receptor signalingcomplex

P P

Smad158PSmad4

P

Translocate to nucleusTurn on AMH responsive genes

Mature AMH

AMH intracellular signaling

Figure 8 Signaling pathway of the AMH protein Model showinghow processing of AMH may regulate the assembly of the recep-tor signaling complex Cleavage of full-length AMH results in aconformational change in the C-terminal domain indicated by theshape and color change which allows binding of AMRH-II Bindingof AMHRII induces dissociation of the proregion via a negativeallosteric interaction between the receptor- and proregion-bindingsites on theC-terminal dimer indicated by the shape change Resultspresented in this paper are consistent with proregion dissociationoccurring before type I receptor engagement but this has not beenproven Type I and II receptor-binding sites on theC-terminal dimerare indicated by either a I or a II black labels indicate sites on thefront of the dimer and white labels indicate sites on the back ofthe dimer From [2] Copyright The Endocrine Society 2010 withpermission

Molecular Genetics The human AMH gene first cloned in1986 [59] contains 5 exons The 31015840 end of the last one isextremely GC rich and shows homology to other membersof the TGF-szlig family it codes for the bioactive C-terminaldomain of the AMH molecule The gene is located onthe short arm of chromosome 19 [60] PMDS is usuallytransmitted as an autosomal recessive trait AMH mutationsare responsible for 52 of the PMDS cases in which geneticdefects have been detectedThefirst reportedAMHmutationa nonsensemutation of the 5th exonwas discovered in 1991 ina Moroccan family [61] At the time of writing May 2013 65families with AMHmutations (Figure 5) representing a totalof 54 different alleles have been identified (Figure 6) Exceptfor exon 4 all exons coding both the inactive N-terminalproregion and the bioactive C-terminal mature protein areaffected All types of mutations are represented 63 arehomozygous There is no true hotspot though 17 abnormalalleles have been detected inmore than one familyThe ethnicorigin of patientswith documentedAMHmutations is shownin Figure 7 The high proportion of European families iscertainly due to a recruitment bias

442 Insensitivity to AMH PMDS due to AMH ReceptorMutations Like other members of the TGF-szlig family AMHuses two types of membrane-bound serinethreonine kinasereceptors for signal transduction The AMH type II receptorcloned in 1994 [62 63] binds specifically to AMH and then


Extracellular domain

Transmembrane domain Intracellular domain

R97StopR80Stop R172StopR407Stop

d1692

Q371Stop Q502StopR178StopQ384Stop

d5998-5999

G40Stop

d92

D491H

V458A C500YR303WG142V

R504CR406Q

R54CH282Q

R59CG265R R342W

R471HE28Q

A118T

L249FH254Q

I257MI257T

G328DG345AS346L

D426G

D409Y

R504HM76V

W8Stop

May 2013

AMHR-II gene

05 kbp


middot middot middot

ATG rarr ACGATG rarr ATA

d84ndash87d863-864 d5079-5080

d6315ndash6323

d6331ndash6357

Figure 9 Mutations of AMHR-II gene in PMDS Same representation as in Figure 6 All recurrent mutations are indicated in red Asterisksrepresent splice mutations Missense mutations are represented in yellow boxes deletions (marked ldquodrdquo) in green boxes and nonsensemutations in white boxes The deletion of 27 bases between bases 6331 and 6357 (d6331ndash6357 in exon 10) is extremely frequent it is present in21 of all PMDS families and in 44 of those with receptor mutations Base numbering is from transcription initiation site minus78 bp from Aof ATG

recruits type I receptor which phosphorylates intracytoplas-mic proteins the SMADs allowing them to enter the nucleusto interact with target genes (Figure 8)

ALK2ACVR1 [64 65] ALK3BMPR1A [66] andALK6BMPR1B [67] all type I receptors of the BMPfamily have been found to interact with the AMH type IIreceptor ALK2ACVR1 [65] and ALK3BMPR1A [66] havebeen shown to function redundantly in transducing AMHsignal to provoke Mullerian duct regression ConverselyALK6BMPR1B disruption does not affect Mullerian ductregression in male mice [64] and in the immature Sertolicell line SMAT1 ALK6BMPR1B inhibits AMH action [68]

Mutations of type II receptor AMHR-II are responsiblefor 48 of PMDS cases with documented genetic abnormal-ities (Figure 5) Clinical and biological features do not differfrom those described above for AMH mutations apart fromthe fact that serum AMH level is lownormal AMH assaycannot discriminate between AMH and AMHR-II mutationsin adulthood because in both instances AMH levels are lowEven in childhood a normal AMH level is not specific forAMHR-IImutations since approximately 15of PMDS casesare not associated with either AMH or AMHR-II mutations

The AMHR-II gene is composed of 11 exons the first 3coding for the receptor extracellular domain exon 4 for mostof the transmembrane domain and the rest for the intracellu-lar domain where the kinase consensus elements are locatedThe gene has been mapped to the long arm of chromosome12 [69] The first AMHR-II mutation in PMDS a splicemutation was reported in 1995 [69] Since then 59 familiesharboring a total of 49 abnormal AMHR-II alleles have beenstudied in our laboratory and an additional one has been

reported in Boston (Figure 9) [70] All exons except exon4 may be affected A 27-base deletion in exon 10 is presentin approximately half the families with receptor mutationsnearly all of Northern European origin suggesting a foundereffect Other recurrent mutations are much less frequentapart from the nonsense R407Stop in exon 9 detected in 5cases

In approximately 15 of PMDS cases all with a normallevel of serum AMH both the AMH and AMHR-II genesincluding their proximal promoters and intronic sequencesare free of mutations Several were born small andor pre-sented with various other congenital defects such as jejunalatresia [71] Mutations of the AMH type I receptors or cyto-plasmic downstream effectors [72] are unlikely since these areshared with the BMPs and required for normal embryonicdevelopment Inactivation [73] or dysregulation [74] of szlig-catenin or dysfunction of other factors capable of interferingwith AMH action might be involved

5 Concluding Remarks

Assay of serum AMH now provides the pediatric endocri-nologist with a new tool for investigating the function of theprepubertal testis without the need for hCG stimulationTheassessment of both serumAMH amarker of Sertoli cell func-tion and serum testosterone reflecting Leydig cell functionis a simple and useful tool for the clinician In DSD patientswhen both hormones are below the normalmale range testic-ular dysgenesis should be suspected AMH in the male rangeand low testosterone indicate Leydig cell-specific disorders


When both hormones are within or above the male rangeandrogen target organ defects are most likely Finally PMDSis a rare etiology of cryptorchidism in boys with virilizedexternal genitalia in these cases low or undetectable serumAMH predicts mutations in the AMH gene while normalserum AMH drives attention to the AMHR-II gene In boyswith normally virilized genitalia serum AMH helps in theassessment of the existence and function of testes Unde-tectable AMH is indicative of anorchia whereas low AMHindicates primary or central hypogonadism

Abbreviations

AIS Androgen insensitivity syndromeAMH Anti-Mullerian hormoneAMHR-II AMH receptor type 2DSD Disorders of sex developmenthCG Human chorionic gonadotropinPMDS Persistent Mullerian duct syndrome

References

[1] R B Pepinsky L K Sinclair E P Chow et al ldquoProteolyticprocessing of Mullerian inhibiting substance produces a trans-forming growth factor-120573-like fragmentrdquo Journal of BiologicalChemistry vol 263 no 35 pp 18961ndash18964 1988

[2] N di Clemente S P Jamin A Lugovskoy et al ldquoProcessingof anti-Mullerian hormone regulates receptor activation by amechanism distinct from TGF-120573rdquo Molecular Endocrinologyvol 24 no 11 pp 2193ndash2206 2010

[3] B Vigier J Y Picard and D Tran ldquoProduction of anti-Mul-lerian hormone another homology between Sertoli and granu-losa cellsrdquo Endocrinology vol 114 no 4 pp 1315ndash1320 1984

[4] R Rey J-C Sabourin M Venara et al ldquoAnti-Mullerian hor-mone is a specific marker of sertoli- and granulosa-cell originin gonadal tumorsrdquo Human Pathology vol 31 no 10 pp 1202ndash1208 2000

[5] R P Grinspon andRA Rey ldquoAnti-Mullerian hormone and ser-toli cell function in paediatric male hypogonadismrdquo HormoneResearch in Paediatrics vol 73 no 2 pp 81ndash92 2010

[6] I Bergada C Milani P Bedecarras et al ldquoTime course of theserum gonadotropin surge inhibins and anti-Mullerian hor-mone in normal newborn males during the first month of liferdquoJournal of Clinical Endocrinology amp Metabolism vol 91 no 10pp 4092ndash4098 2006

[7] L Aksglaede K Soslashrensen M Boas et al ldquoChanges inAnti-Mullerian Hormone (AMH) throughout the life span apopulation-based study of 1027 healthy males from birth (cordblood) to the age of 69 yearsrdquo Journal of Clinical Endocrinologyamp Metabolism vol 95 no 12 pp 5357ndash5364 2010

[8] N Josso R Rey and J Y Picard ldquoTesticular anti-Mullerian hor-mone clinical applications in DSDrdquo Seminars in ReproductiveMedicine vol 30 no 05 pp 364ndash373 2012

[9] C Lasala D Carre-Eusebe J-Y Picard and R Rey ldquoSubcellularandmolecularmechanisms regulating anti-Mullerian hormonegene expression in mammalian and nonmammalian speciesrdquoDNA and Cell Biology vol 23 no 9 pp 572ndash585 2004

[10] C Lukas-Croisier C Lasala J Nicaud et al ldquoFollicle-stim-ulating hormone increases testicular Anti-Mullerian Hormone

(AMH) production through Sertoli cell proliferation and a non-classical cyclic adenosine 51015840-monophosphate-mediated activa-tion of the AMH generdquo Molecular Endocrinology vol 17 no 4pp 550ndash561 2003

[11] R A Rey M Venara R Coutant et al ldquoUnexpected mosaicismof R201H-GNAS1 mutant-bearing cells in the testes underliemacro-orchidismwithout sexual precocity inMcCune-AlbrightsyndromerdquoHumanMolecular Genetics vol 15 no 24 pp 3538ndash3543 2006

[12] C Lasala H F Schteingart N Arouche et al ldquoSOX9 andSF1 are involved in cyclic AMP-mediated upregulationof anti-Mullerian gene expression in the testicular prepubertal Sertolicell line SMAT1rdquoAmerican Journal of Physiology Endocrinologyand Metabolism vol 301 no 3 pp E539ndashE547 2011

[13] R Rey ldquoEndocrine paracrine and cellular regulation of postna-tal anti-Mullerian hormone secretion by Sertoli cellsrdquo Trends inEndocrinology and Metabolism vol 9 no 7 pp 271ndash276 1998

[14] R A Rey M Musse M Venara and H E Chemes ldquoOntogenyof the androgen receptor expression in the fetal and postnataltestis its relevance on sertoli cell maturation and the onset ofadult spermatogenesisrdquoMicroscopyResearch andTechnique vol72 no 11 pp 787ndash795 2009

[15] E B Berensztein M S Baquedano C R Gonzalez et alldquoExpression of aromatase estrogen receptor 120572 and 120573 androgenreceptor and cytochrome P-450scc in the human early prepu-bertal testisrdquo Pediatric Research vol 60 no 6 pp 740ndash7442006

[16] H E Chemes R A Rey M Nistal et al ldquoPhysiologicalandrogen insensitivity of the fetal neonatal and early infantiletestis is explained by the ontogeny of the androgen receptorexpression in Sertoli cellsrdquo Journal of Clinical Endocrinology ampMetabolism vol 93 no 11 pp 4408ndash4412 2008

[17] K Boukari G Meduri S Brailly-Tabard et al ldquoLack of andro-gen receptor expression in Sertoli cells accounts for the absenceof anti-Mullerian hormone repression during early humantestis developmentrdquo Journal of Clinical Endocrinology ampMetab-olism vol 94 no 5 pp 1818ndash1825 2009

[18] R Rey ldquoAssessment of seminiferous tubule function (anti-Mullerian hormone)rdquo Best Practice and Research vol 14 no 3pp 399ndash408 2000

[19] M M Lee M Misra P K Donahoe and D T MacLaughlinldquoMISAMH in the assessment of cryptorchidism and intersexconditionsrdquo Molecular and Cellular Endocrinology vol 211 no1-2 pp 91ndash98 2003

[20] MM Lee P K Donahoe B L Silverman et al ldquoMeasurementsof serum Mullerian inhibiting substance in the evaluation ofchildren with nonpalpable gonadsrdquoTheNew England Journal ofMedicine vol 336 no 21 pp 1480ndash1486 1997

[21] N Josso ldquoPaediatric applications of anti-Mullerian hormoneresearch 1992 Andrea Prader Lecturerdquo Hormone Research vol43 no 6 pp 243ndash248 1995

[22] R P Grinspon P Bedecarras M G Ballerini et al ldquoEarly onsetof primary hypogonadism revealed by serum anti-Mullerianhormone determination during infancy and childhood in tri-somy 21rdquo International Journal of Andrology vol 34 no 5 ppe487ndashe498 2011

[23] J Young R Rey B Couzinet P Chanson N Josso and GSchaison ldquoAntimullerian hormone in patients with hypogo-nadotropic hypogonadismrdquo Journal of Clinical Endocrinology ampMetabolism vol 84 no 8 pp 2696ndash2699 1999

[24] J Young P Chanson S Salenave et al ldquoTesticular anti-Mullerian hormone secretion is stimulated by recombinant


human FSH in patients with congenital hypogonadotropichypogonadismrdquo Journal of Clinical Endocrinology amp Metabo-lism vol 90 no 2 pp 724ndash728 2005

[25] M G Bastida R A Rey I Bergada et al ldquoEstablishment of tes-ticular endocrine function impairment during childhood andpuberty in boyswithKlinefelter syndromerdquoClinical Endocrinol-ogy vol 67 no 6 pp 863ndash870 2007

[26] H J Hirsch T Eldar-Geva F Benarroch O Rubinstein and VGross-Tsur ldquoPrimary testicular dysfunction is a major contrib-utor to abnormal pubertal development in males with Prader-Willi syndromerdquo Journal of Clinical Endocrinology amp Metab-olism vol 94 no 7 pp 2262ndash2268 2009

[27] A F Radicioni G di Giorgio G Grugni et al ldquoMultiple formsof hypogonadism of central peripheral or combined origin inmales with Prader-Willi syndromerdquo Clinical Endocrinology vol76 no 1 pp 72ndash77 2012

[28] E P C Siemensma R F A de Lind van Wijngaarden B JOtten F H de Jong and A C S Hokken-Koelega ldquoTesticularfailure in boys with Prader-Willi syndrome longitudinal studiesof reproductive hormonesrdquo Journal of Clinical Endocrinology ampMetabolism vol 97 no 3 pp E452ndashE459 2012

[29] U Eiholzer D lrsquoAllemand V Rousson et al ldquoHypothalamicand gonadal components of hypogonadism in boyswith Prader-Labhart-Willi syndromerdquo Journal of Clinical Endocrinology ampMetabolism vol 91 no 3 pp 892ndash898 2006

[30] I Bergada L Andreone P Bedecarras et al ldquoSeminiferoustubule function in delayed-onset X-linked adrenal hypopla-sia congenita associated with incomplete hypogonadotrophichypogonadismrdquo Clinical Endocrinology vol 68 no 2 pp 240ndash246 2008

[31] A Ferlin D Zuccarello B Zuccarello M R Chirico G FZanon and C Foresta ldquoGenetic alterations associated withcryptorchidismrdquo Journal of the American Medical Associationvol 300 no 19 pp 2271ndash2276 2008

[32] H E Virtanen and J Toppari ldquoEpidemiology and pathogenesisof cryptorchidismrdquo Human Reproduction Update vol 14 no 1pp 49ndash58 2008

[33] M Misra D T MacLaughlin P K Donahoe M M Lee andM Massachusetts ldquoMeasurement of Mullerian inhibiting sub-stance facilitates management of boys with microphallus andcryptorchidismrdquo Journal of Clinical Endocrinology amp Metabo-lism vol 87 no 8 pp 3598ndash3602 2002

[34] A-M Suomi K M Main M Kaleva et al ldquoHormonalchanges in 3-month-old cryptorchid boysrdquo Journal of ClinicalEndocrinology amp Metabolism vol 91 no 3 pp 953ndash958 2006

[35] K Bay H E Virtanen S Hartung et al ldquoInsulin-like factor 3levels in cord blood and serum from children effects of agepostnatal hypothalamic-pituitary-gonadal axis activation andcryptorchidismrdquo Journal of Clinical Endocrinology amp Metabo-lism vol 92 no 10 pp 4020ndash4027 2007

[36] C Kollin J B Stukenborg M Nurmio et al ldquoBoys with unde-scended testes endocrine volumetric and morphometric stud-ies on testicular function before and after orchidopexy at ninemonths or three years of agerdquo Journal of Clinical Endocrinologyamp Metabolism vol 97 pp 4588ndash4595 2012

[37] R P Grinspon M G Ropelato P Bedecarras et alldquoGonadotrophin secretion pattern in anorchid boys from birthto pubertal age pathophysiological aspects and diagnosticusefulnessrdquo Clinical Endocrinology vol 76 no 5 pp 698ndash7052012

[38] C Ankarberg-Lindgren O Westphal and J Dahlgren ldquoTes-ticular size development and reproductive hormones in boys

and adult males with Noonan syndrome a longitudinal studyrdquoEuropean Journal of Endocrinology vol 165 no 1 pp 137ndash1442011

[39] A Feyaerts M G Forest Y Morel et al ldquoEndocrine screeningin 32 consecutive patients with hypospadiasrdquo Journal of Urologyvol 168 no 2 pp 720ndash725 2002

[40] R A Rey E Codner G Inıguez et al ldquoLow risk of impairedtesticular sertoli and leydig cell functions in boys with isolatedhypospadiasrdquo Journal of Clinical Endocrinology amp Metabolismvol 90 no 11 pp 6035ndash6040 2005

[41] R A Rey C Belville C Nihoul-Fekete et al ldquoEvaluation ofgonadal function in 107 intersex patients by means of serumantimullerian hormone measurementrdquo Journal of ClinicalEndocrinology amp Metabolism vol 84 pp 627ndash631 1999

[42] I Plotton C L Gay AM Bertrand et al ldquoAMHdeterminationis essential for the management of 46 XY DSD patientsrdquoPediatric Research vol 72 supplement 3 p 365 2009

[43] C P Hagen L Aksglaede K Soslashrensen et al ldquoSerum levelsof anti-Mullerian hormone as a marker of ovarian functionin 926 healthy females from birth to adulthood and in 172turner syndrome patientsrdquo Journal of Clinical Endocrinology ampMetabolism vol 95 no 11 pp 5003ndash5010 2010

[44] R Rey FMebarkiM G Forest et al ldquoAnti-Mullerian hormonein children with androgen insensitivityrdquo Journal of ClinicalEndocrinology amp Metabolism vol 79 no 4 pp 960ndash964 1994

[45] E G Stuchi-Perez C Hackel L E C Oliveira et al ldquoDiag-nosis of 5120572-reductase type 2 deficiency contribution of anti-Mullerian hormone evaluationrdquo Journal of Pediatric Endocrinol-ogy and Metabolism vol 18 no 12 pp 1383ndash1389 2005

[46] C Bouvattier J-C Carel C Lecointre et al ldquoPostnatal changesof T LH and FSH in 46XY infants with mutations in the ARgenerdquo Journal of Clinical Endocrinology amp Metabolism vol 87no 1 pp 29ndash32 2002

[47] M Lang-Muritano A Biason-Lauber C Gitzelmann CBelville Y Picard and E J Schoenle ldquoA novel mutation in theanti-Mullerian hormone gene as cause of persistent Mullerianduct syndromerdquo European Journal of Pediatrics vol 160 no 11pp 652ndash654 2001

[48] M A El-Gohary ldquoLaparoscopic management of persistentMullerian duct syndromerdquo Pediatric Surgery International vol19 no 7 pp 533ndash536 2003

[49] E L Martin A H Bennett and W J Cromie ldquoPersistentMullerian duct syndrome with transverse testicular ectopia andspermatogenesisrdquo Journal of Urology vol 147 no 6 pp 1615ndash1617 1992

[50] S Naouar KMaazoun L Sahnoun et al ldquoTransverse testicularectopia a three-case report and review of the literaturerdquoUrology vol 71 no 6 pp 1070ndash1073 2008

[51] M Abduljabbar K Taheini J Y Picard et al ldquoMutations of theAMH type II receptor in two extended families with persistentMullerian duct syndrome lack of phenotypegenotype correla-tionrdquoHormoneResearch in Paediatrics vol 77 pp 291ndash297 2012

[52] W Chaabane L Jarboui A Sahnoun et al ldquoPersistent Mul-lerian duct syndrome with torsion of a transverse testicularectopia first reported caserdquo Urology vol 76 no 1 pp 65ndash662010

[53] S Imbeaud R Rey P Berta et al ldquoTesticular degeneration inthree patients with the persistent Mullerian duct syndromerdquoEuropean Journal of Pediatrics vol 154 no 3 pp 187ndash190 1995

[54] N Josso C Fekete and O Cachin ldquoPersistence of Mullerianducts in male pseudohermaphroditism and its relationship to


cryptorchidismrdquo Clinical Endocrinology vol 19 no 2 pp 247ndash258 1983

[55] D R Vandersteen A K Chaumeton K Ireland and E S TankldquoSurgical management of persistent Mullerian duct syndromerdquoUrology vol 49 no 6 pp 941ndash945 1997

[56] DW Brandli C Akbal E Eugsster N Hadad R J Havlik andM Kaefer ldquoPersistent Mullerian duct syndrome with bilateralabdominal testis surgical approach and review of the literaturerdquoJournal of Pediatric Urology vol 1 no 6 pp 423ndash427 2005

[57] N Josso C Belville N di Clemente and J-Y Picard ldquoAMHandAMH receptor defects in persistent Mullerian duct syndromerdquoHuman Reproduction Update vol 11 no 4 pp 351ndash356 2005

[58] C Belville H van Vlijmen C Ehrenfels et al ldquoMutations ofthe anti-Mullerian hormone gene in patients with persistentMullerian duct syndrome biosynthesis secretion and pro-cessing of the abnormal proteins and analysis using a three-dimensional modelrdquoMolecular Endocrinology vol 18 no 3 pp708ndash721 2004

[59] R L Cate R J Mattaliano and C Hession ldquoIsolation of thebovine andhuman genes forMullerian inhibiting substance andexpression of the human gene in animal cellsrdquo Cell vol 45 no5 pp 685ndash698 1986

[60] OCohen-Haguenauer J Y Picard andM-GMattei ldquoMappingof the gene for anti-Mullerian hormone to the short arm ofhuman chromosome 19rdquo Cytogenetics and Cell Genetics vol 44no 1 pp 2ndash6 1987

[61] B Knebelmann L Boussin D Guerrier et al ldquoAnti-Mullerianhormone bruxelles a nonsense mutation associated withthe persistent Mullerian duct syndromerdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 88 no 9 pp 3767ndash3771 1991

[62] W M Baarends M J L van Helmond M Post et al ldquoA novelmember of the transmembrane serinethreonine kinase recep-tor family is specifically expressed in the gonads and in mes-enchymal cells adjacent to the Mullerian ductrdquo Developmentvol 120 no 1 pp 189ndash197 1994

[63] N di Clemente CWilson E Faure et al ldquoCloning expressionand alternative splicing of the receptor for anti-Mullerian hor-monerdquo Molecular Endocrinology vol 8 no 8 pp 1006ndash10201994

[64] T R Clarke Y Hoshiya S E Yi X Liu K M Lyons and PK Donahoe ldquoMullerian inhibiting substance signaling uses aBone Morphogenetic Protein (BMP)-like pathway mediated byALK2 and induces Smad6 expressionrdquo Molecular Endocrinol-ogy vol 15 no 6 pp 946ndash959 2001

[65] G D Orvis S P Jamin K M Kwan et al ldquoFunctional redun-dancy of TGF-beta family type i receptors and receptor-smadsin mediating anti-Mullerian hormone-induced Mullerian ductregression in the mouserdquo Biology of Reproduction vol 78 no 6pp 994ndash1001 2008

[66] S P Jamin N A Arango Y Mishina M C Hanks and R RBehringer ldquoRequirement of Bmpr1a for Mullerian duct regres-sion during male sexual developmentrdquo Nature Genetics vol 32no 3 pp 408ndash410 2002

[67] L Gouedard Y-G Chen L Thevenet et al ldquoEngagement ofbonemorphogenetic protein type IB receptor and Smad1 signal-ing by anti-Mullerian hormone and its type II receptorrdquo Journalof Biological Chemistry vol 275 no 36 pp 27973ndash27978 2000

[68] C Belville S P Jamin J-Y Picard N Josso andN di ClementeldquoRole of type I receptors for anti-Mullerian hormone in theSMAT-1 Sertoli cell linerdquo Oncogene vol 24 no 31 pp 4984ndash4992 2005

[69] S Imbeaud E Faure I Lamarre et al ldquoInsensitivity to anti-Mullerian hormone due to a mutation in the human anti-Mullerian hormone receptorrdquoNature Genetics vol 11 no 4 pp382ndash388 1995

[70] M Hoshiya B P Christian W J Cromie et al ldquoPersistentMullerian duct syndrome caused by both a 27-bp deletion anda novel splice mutation in the MIS type II receptor generdquo BirthDefects Research A vol 67 no 10 pp 868ndash874 2003

[71] S Klosowski A Abriak C Morisot et al ldquoJejunal atresia andpersistent Mullerian duct syndromerdquo Archives de Pediatrie vol4 no 12 pp 1264ndash1265 1997

[72] N Josso and N di Clemente ldquoTransduction pathway of anti-Mullerian hormone a sex-specific member of the TGF-120573 fam-ilyrdquo Trends in Endocrinology and Metabolism vol 14 no 2 pp91ndash97 2003

[73] A Kobayashi C Allison Stewart Y Wang et al ldquo120573-catenin isessential for Mullerian duct regression during male sexual dif-ferentiationrdquo Development vol 138 no 10 pp 1967ndash1975 2011

[74] P S Tanwar L Zhang Y Tanaka M M Taketo P K Donahoeand J M Teixeira ldquoFocal Mullerian duct retention in malemice with constitutively activated 120573-catenin expression in theMullerian duct mesenchymerdquo Proceedings of the National Acad-emy of Sciences of the United States of America vol 107 no 37pp 16142ndash16147 2010

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Gonadotroph

Leydig cell

Sertoli cell

GnRH

LH FSH

AMH

LH-R

FSH-R

T

AR

_+

AIS (puberty)

GnRH

LH FSH

AMH

LH-R

FSH-R

T

AR

_+

Leydig cell aplasiaT synthesis defects

GnRH

LH FSH

AMH

LH-R

FSH-R

T

AR

_+

Normal pubertyPrecocious puberty

GnRH

LH FSH

AMH

LH-R

FSH-R

T

AR

_+

Centralhypogonadism

GnRH

LH FSH

AMH

LH-R

FSH-R

T

AR

_+

Childhood

I II III IV V

Foetusmdash0ndash6 months

timestimes

Figure 1 Regulation of testicular AMH secretion by gonadotropins and androgens In general the hypothalamus regulates LH and FSHsecretion by the gonadotroph through the gonadotropin-releasing hormone (GnRH) LH acts on the LH receptor (LH-R) present in Leydigcells inducing testosterone (T) secretion FSH acts on the FSH receptor (FSH-R) present in Sertoli cellsThe hypothalamic-pituitary-gonadalaxis is active in the foetus and early infancy is quiescent during childhood and is reactivated at puberty FSH is a moderate inducer of AMHsecretion whereas T acting through the androgen receptor (AR) is a potent inhibitor of AMHproduction In the normal foetus and infant aswell as in patients with the androgen insensitivity syndrome (AIS) the lack of AR expression results in high AMH production by Sertoli cells(I) During childhood there is a physiologic hypogonadotropic state resulting in very low T AMH levels remain high but somewhat lowerprobably due to the lack of FSH stimulus (II) In normal or precocious puberty T prevails over FSH resulting in AMH inhibition (III) Incongenital central hypogonadism AMH is lower than in the normal boy because of the longstanding lack of FSH from foetal life however atpubertal age the inhibitory effect of T is also absent and AMH remains higher than in normal puberty (IV) In Leydig cell-specific primaryhypogonadism (Leydig cell aplasia or hypoplasia due to LH-R defects or defects of steroidogenesis) the inhibitory effect of androgens isabsent and AMH levels are high The orange area represents the testis Thickness of lines is in correlation with hormone effect on its targetFrom [5] Copyright Karger AG 2010 with permission

and postnatal ovary it is also produced by granulosa cells ofdeveloping follicles essentially preantral and small antral fol-licles [3 4]

In the male AMH is a specific functional marker of theimmature Sertoli cell AMH expression is initiated at the timeof fetal differentiation of the seminiferous cords by the end ofthe 7th embryonic week and remains at high levels until theonset of puberty except for a transient decline in the perinatalperiod [6 7] AMH expression is triggered by SOX9 whichbinds to the AMH promoter subsequently SF1 GATA4 andWT1 further increase AMH promoter activity (reviewed in[8]) The onset of AMH expression and its basal expressionlevel throughout life are independent of gonadotropinsHowever FSH stimulates testicular AMHproduction by bothinducing Sertoli cell proliferation and upregulating AMHtranscription [9] The latter is mainly mediated by the clas-sical pathway involving Gs120572 and adenylyl cyclase increase ofcyclic AMP levels which stimulates protein kinase A (PKA)activity subsequently involving transcription factors SOX9SF1 GATA4 NF120581B and AP2 [10ndash12] During puberty AMHproduction is inhibited by the increase of intratesticulartestosterone concentration and the onset of germ cell meiosis

(Figure 1) (reviewed in [13 14]) The inhibitory effect ofandrogens onAMHovercomes the positive effect of FSHafterpubertal onset On the contrary androgens cannot inhibitAMH production in the fetal and neonatal testis whereSertoli cells do not yet express the androgen receptor [15ndash17]

3 AMH in Boys with Hypogonadism

Gonadotropin and testosterone which are high in the 3ndash6months after birth normally decrease to very low levels untilthe onset of puberty Therefore their usefulness as markersof the function of the hypothalamo-pituitary-gonadal axisin the boy is limited On the contrary AMH determinationis extremely useful since Sertoli cells remain active duringinfancy and childhood [18 19] Serum AMH reliably reflectsthe presence and function of testes in prepubertal boys with-out the need for any stimulation test [18 20 21] In this sec-tion we address how the different disorders causing hypogo-nadism affect AMH testicular production

31 Central Hypogonadism Serum AMH is low in infantswith congenital central hypogonadism Treatment with FSH


rhFSH + hCG



Seru

m A

MH

(pm

olL

)

0

250

500

750

1000

0 10 20 30 60 90Days

rhFSH

T (ngdL)31 plusmn 5

T (ngdL)39 plusmn 8


150 Ud 150 Ud

lowastlowastlowast

lowastlowastlowast

lowastlowastlowast

lowastlowast

lowast

1500 U 2wk













0

500

1000

1500

2000


AMH

(pm

olL

)

Age (years) 0 2 4 6 8 10 12 14 16 18 20






















Lowundetectable







Normalhigh






2500

2000

1500

1000

500

LCD

CAIS

PAIS

PTD

CGD TH LCD

CAIS

PAIS

PTD

CGD TH LCD

CAIS

PAIS

PTD

CGD

Seru

m A

MH

(pm

olL

)


(a)

3500

2800

2100

1400

700

00 4 8 12 16 20 24 32 40 48

Age (yr)

Seru

m A

MH

(pm

olL

)

LCDCAISPAIS

(b)





80

60

40

20

0AMH AMHR-II

Num

ber





C-terminal

V12G

L70P

L118P

F148L Y167C

R194CA206D V477A

C488Y

H506QC525Y

R123W

G101V G101R Q496H

P151S R302Q

P151A

R377C

C188G

T193I R302P

V174G

A120P L339P

L426R

L536FC557SR560P


R40Stop

d27-28

d1129-1130d2277

d219

E466StopW121Stop

d353-354

W494Stop

May 2013

d-216

A314G

G533V

R95Stop

AMH gene

lowast


05 kbp

ATG rarr ATT

d353ndash356

+C (213ndash218)


+23 bp (2349)











0

10

20

30

40

50

AMHAMHR-II

Fam

ilies

()

(23)

(27)

(11)(8)

(15)

(6)

(13)(12)

(1) (2) (2)(4)

N E

urop

e

S E

urop

e

Afr

ica

ME

Asia

USA

Latin

Am




Type Ireceptor

AMHRII


P P

Smad158PSmad4

P


Mature AMH









d1692


d5998-5999

G40Stop

d92

D491H

V458A C500YR303WG142V

R504CR406Q

R54CH282Q

R59CG265R R342W

R471HE28Q

A118T

L249FH254Q

I257MI257T

G328DG345AS346L

D426G

D409Y

R504HM76V

W8Stop

May 2013

AMHR-II gene

05 kbp




d84ndash87d863-864 d5079-5080

d6315ndash6323

d6331ndash6357












Abbreviations


References






















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















rhFSH + hCG



Seru

m A

MH

(pm

olL

)

0

250

500

750

1000

0 10 20 30 60 90Days

rhFSH

T (ngdL)31 plusmn 5

T (ngdL)39 plusmn 8


150 Ud 150 Ud

lowastlowastlowast

lowastlowastlowast

lowastlowastlowast

lowastlowast

lowast

1500 U 2wk













0

500

1000

1500

2000


AMH

(pm

olL

)

Age (years) 0 2 4 6 8 10 12 14 16 18 20






















Lowundetectable







Normalhigh






2500

2000

1500

1000

500

LCD

CAIS

PAIS

PTD

CGD TH LCD

CAIS

PAIS

PTD

CGD TH LCD

CAIS

PAIS

PTD

CGD

Seru

m A

MH

(pm

olL

)


(a)

3500

2800

2100

1400

700

00 4 8 12 16 20 24 32 40 48

Age (yr)

Seru

m A

MH

(pm

olL

)

LCDCAISPAIS

(b)





80

60

40

20

0AMH AMHR-II

Num

ber





C-terminal

V12G

L70P

L118P

F148L Y167C

R194CA206D V477A

C488Y

H506QC525Y

R123W

G101V G101R Q496H

P151S R302Q

P151A

R377C

C188G

T193I R302P

V174G

A120P L339P

L426R

L536FC557SR560P


R40Stop

d27-28

d1129-1130d2277

d219

E466StopW121Stop

d353-354

W494Stop

May 2013

d-216

A314G

G533V

R95Stop

AMH gene

lowast


05 kbp

ATG rarr ATT

d353ndash356

+C (213ndash218)


+23 bp (2349)











0

10

20

30

40

50

AMHAMHR-II

Fam

ilies

()

(23)

(27)

(11)(8)

(15)

(6)

(13)(12)

(1) (2) (2)(4)

N E

urop

e

S E

urop

e

Afr

ica

ME

Asia

USA

Latin

Am




Type Ireceptor

AMHRII


P P

Smad158PSmad4

P


Mature AMH









d1692


d5998-5999

G40Stop

d92

D491H

V458A C500YR303WG142V

R504CR406Q

R54CH282Q

R59CG265R R342W

R471HE28Q

A118T

L249FH254Q

I257MI257T

G328DG345AS346L

D426G

D409Y

R504HM76V

W8Stop

May 2013

AMHR-II gene

05 kbp




d84ndash87d863-864 d5079-5080

d6315ndash6323

d6331ndash6357












Abbreviations


References






















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















0

500

1000

1500

2000


AMH

(pm

olL

)

Age (years) 0 2 4 6 8 10 12 14 16 18 20






















Lowundetectable







Normalhigh






2500

2000

1500

1000

500

LCD

CAIS

PAIS

PTD

CGD TH LCD

CAIS

PAIS

PTD

CGD TH LCD

CAIS

PAIS

PTD

CGD

Seru

m A

MH

(pm

olL

)


(a)

3500

2800

2100

1400

700

00 4 8 12 16 20 24 32 40 48

Age (yr)

Seru

m A

MH

(pm

olL

)

LCDCAISPAIS

(b)





80

60

40

20

0AMH AMHR-II

Num

ber





C-terminal

V12G

L70P

L118P

F148L Y167C

R194CA206D V477A

C488Y

H506QC525Y

R123W

G101V G101R Q496H

P151S R302Q

P151A

R377C

C188G

T193I R302P

V174G

A120P L339P

L426R

L536FC557SR560P


R40Stop

d27-28

d1129-1130d2277

d219

E466StopW121Stop

d353-354

W494Stop

May 2013

d-216

A314G

G533V

R95Stop

AMH gene

lowast


05 kbp

ATG rarr ATT

d353ndash356

+C (213ndash218)


+23 bp (2349)











0

10

20

30

40

50

AMHAMHR-II

Fam

ilies

()

(23)

(27)

(11)(8)

(15)

(6)

(13)(12)

(1) (2) (2)(4)

N E

urop

e

S E

urop

e

Afr

ica

ME

Asia

USA

Latin

Am




Type Ireceptor

AMHRII


P P

Smad158PSmad4

P


Mature AMH









d1692


d5998-5999

G40Stop

d92

D491H

V458A C500YR303WG142V

R504CR406Q

R54CH282Q

R59CG265R R342W

R471HE28Q

A118T

L249FH254Q

I257MI257T

G328DG345AS346L

D426G

D409Y

R504HM76V

W8Stop

May 2013

AMHR-II gene

05 kbp




d84ndash87d863-864 d5079-5080

d6315ndash6323

d6331ndash6357












Abbreviations


References






















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





























Lowundetectable







Normalhigh






2500

2000

1500

1000

500

LCD

CAIS

PAIS

PTD

CGD TH LCD

CAIS

PAIS

PTD

CGD TH LCD

CAIS

PAIS

PTD

CGD

Seru

m A

MH

(pm

olL

)


(a)

3500

2800

2100

1400

700

00 4 8 12 16 20 24 32 40 48

Age (yr)

Seru

m A

MH

(pm

olL

)

LCDCAISPAIS

(b)





80

60

40

20

0AMH AMHR-II

Num

ber





C-terminal

V12G

L70P

L118P

F148L Y167C

R194CA206D V477A

C488Y

H506QC525Y

R123W

G101V G101R Q496H

P151S R302Q

P151A

R377C

C188G

T193I R302P

V174G

A120P L339P

L426R

L536FC557SR560P


R40Stop

d27-28

d1129-1130d2277

d219

E466StopW121Stop

d353-354

W494Stop

May 2013

d-216

A314G

G533V

R95Stop

AMH gene

lowast


05 kbp

ATG rarr ATT

d353ndash356

+C (213ndash218)


+23 bp (2349)











0

10

20

30

40

50

AMHAMHR-II

Fam

ilies

()

(23)

(27)

(11)(8)

(15)

(6)

(13)(12)

(1) (2) (2)(4)

N E

urop

e

S E

urop

e

Afr

ica

ME

Asia

USA

Latin

Am




Type Ireceptor

AMHRII


P P

Smad158PSmad4

P


Mature AMH









d1692


d5998-5999

G40Stop

d92

D491H

V458A C500YR303WG142V

R504CR406Q

R54CH282Q

R59CG265R R342W

R471HE28Q

A118T

L249FH254Q

I257MI257T

G328DG345AS346L

D426G

D409Y

R504HM76V

W8Stop

May 2013

AMHR-II gene

05 kbp




d84ndash87d863-864 d5079-5080

d6315ndash6323

d6331ndash6357












Abbreviations


References






















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















2500

2000

1500

1000

500

LCD

CAIS

PAIS

PTD

CGD TH LCD

CAIS

PAIS

PTD

CGD TH LCD

CAIS

PAIS

PTD

CGD

Seru

m A

MH

(pm

olL

)


(a)

3500

2800

2100

1400

700

00 4 8 12 16 20 24 32 40 48

Age (yr)

Seru

m A

MH

(pm

olL

)

LCDCAISPAIS

(b)





80

60

40

20

0AMH AMHR-II

Num

ber





C-terminal

V12G

L70P

L118P

F148L Y167C

R194CA206D V477A

C488Y

H506QC525Y

R123W

G101V G101R Q496H

P151S R302Q

P151A

R377C

C188G

T193I R302P

V174G

A120P L339P

L426R

L536FC557SR560P


R40Stop

d27-28

d1129-1130d2277

d219

E466StopW121Stop

d353-354

W494Stop

May 2013

d-216

A314G

G533V

R95Stop

AMH gene

lowast


05 kbp

ATG rarr ATT

d353ndash356

+C (213ndash218)


+23 bp (2349)











0

10

20

30

40

50

AMHAMHR-II

Fam

ilies

()

(23)

(27)

(11)(8)

(15)

(6)

(13)(12)

(1) (2) (2)(4)

N E

urop

e

S E

urop

e

Afr

ica

ME

Asia

USA

Latin

Am




Type Ireceptor

AMHRII


P P

Smad158PSmad4

P


Mature AMH









d1692


d5998-5999

G40Stop

d92

D491H

V458A C500YR303WG142V

R504CR406Q

R54CH282Q

R59CG265R R342W

R471HE28Q

A118T

L249FH254Q

I257MI257T

G328DG345AS346L

D426G

D409Y

R504HM76V

W8Stop

May 2013

AMHR-II gene

05 kbp




d84ndash87d863-864 d5079-5080

d6315ndash6323

d6331ndash6357












Abbreviations


References






















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















C-terminal

V12G

L70P

L118P

F148L Y167C

R194CA206D V477A

C488Y

H506QC525Y

R123W

G101V G101R Q496H

P151S R302Q

P151A

R377C

C188G

T193I R302P

V174G

A120P L339P

L426R

L536FC557SR560P


R40Stop

d27-28

d1129-1130d2277

d219

E466StopW121Stop

d353-354

W494Stop

May 2013

d-216

A314G

G533V

R95Stop

AMH gene

lowast


05 kbp

ATG rarr ATT

d353ndash356

+C (213ndash218)


+23 bp (2349)











0

10

20

30

40

50

AMHAMHR-II

Fam

ilies

()

(23)

(27)

(11)(8)

(15)

(6)

(13)(12)

(1) (2) (2)(4)

N E

urop

e

S E

urop

e

Afr

ica

ME

Asia

USA

Latin

Am




Type Ireceptor

AMHRII


P P

Smad158PSmad4

P


Mature AMH









d1692


d5998-5999

G40Stop

d92

D491H

V458A C500YR303WG142V

R504CR406Q

R54CH282Q

R59CG265R R342W

R471HE28Q

A118T

L249FH254Q

I257MI257T

G328DG345AS346L

D426G

D409Y

R504HM76V

W8Stop

May 2013

AMHR-II gene

05 kbp




d84ndash87d863-864 d5079-5080

d6315ndash6323

d6331ndash6357












Abbreviations


References






















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















0

10

20

30

40

50

AMHAMHR-II

Fam

ilies

()

(23)

(27)

(11)(8)

(15)

(6)

(13)(12)

(1) (2) (2)(4)

N E

urop

e

S E

urop

e

Afr

ica

ME

Asia

USA

Latin

Am




Type Ireceptor

AMHRII


P P

Smad158PSmad4

P


Mature AMH









d1692


d5998-5999

G40Stop

d92

D491H

V458A C500YR303WG142V

R504CR406Q

R54CH282Q

R59CG265R R342W

R471HE28Q

A118T

L249FH254Q

I257MI257T

G328DG345AS346L

D426G

D409Y

R504HM76V

W8Stop

May 2013

AMHR-II gene

05 kbp




d84ndash87d863-864 d5079-5080

d6315ndash6323

d6331ndash6357












Abbreviations


References






















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















d1692


d5998-5999

G40Stop

d92

D491H

V458A C500YR303WG142V

R504CR406Q

R54CH282Q

R59CG265R R342W

R471HE28Q

A118T

L249FH254Q

I257MI257T

G328DG345AS346L

D426G

D409Y

R504HM76V

W8Stop

May 2013

AMHR-II gene

05 kbp




d84ndash87d863-864 d5079-5080

d6315ndash6323

d6331ndash6357












Abbreviations


References






















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















Abbreviations


References






















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of












































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article anti-müllerian hormone: a valuable addition...

Documents