Testicular Anti-Müllerian Hormone: Clinical Applications in DSD

Nathalie Josso; Rodolfo Rey; Jean-Yves Picard

doi:10.1055/s-0032-1324719

Seminars in Reproductive Medicine, Table of Contents

Semin Reprod Med 2012; 30(05): 364-373
DOI: 10.1055/s-0032-1324719

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Testicular Anti-Müllerian Hormone: Clinical Applications in DSD

Nathalie Josso

¹INSERM. U782, Université Paris-Sud, Clamart, France

,

Rodolfo Rey

²Centro de Investigaciones Endocrinológicas (CEDIE-CONICET), Hospital de Niños “R. Gutiérrez,” Buenos Aires, Argentina

³Departamento de Histología, Embriología, Biología Celular y Genética, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina

,

Jean-Yves Picard

¹INSERM. U782, Université Paris-Sud, Clamart, France

› Author Affiliations

Abstract

Male fetal sexual differentiation of the genitalia is driven by Leydig cell-secreted androgens and Sertoli cell-secreted anti-Müllerian hormone (AMH). Disorders of sex development (DSD) may be due to abnormal morphogenesis of genital primordia or to defective testicular hormone secretion or action. In dysgenetic DSD, due to an early fetal-onset primary hypogonadism affecting Leydig and Sertoli cells, the fetal gonads are incapable of producing normal levels of androgens and AMH. In non-dysgenetic DSD, either Leydig cells or Sertoli cells are affected but not both. Persistent Müllerian duct syndrome (PMDS) may result from Sertoli cell-specific dysfunction due to mutations in the AMH gene; these patients have Fallopian tubes and uterus, but male external genitalia. In DSD due to insensitivity to testicular hormones, fetal Leydig and Sertoli cell function is normal. Defective androgen action is associated with female or ambiguous genitalia whereas insensitivity to AMH results in PMDS with normal serum AMH. Clinical and biological features of PMDS due to mutations in the genes coding for AMH or the AMH receptor, as well as genetic aspects and clinical management are discussed.

Keywords

testis differentiation - steroidogenesis - ambiguous genitalia

Full Text

References

References
1 Racine C, Rey R, Forest MG , et al. Receptors for anti-müllerian hormone on Leydig cells are responsible for its effects on steroidogenesis and cell differentiation. Proc Natl Acad Sci U S A 1998; 95 (2) 594-599
2 Durlinger AL, Visser JA, Themmen AP. Regulation of ovarian function: the role of anti-Müllerian hormone. Reproduction 2002; 124 (5) 601-609
3 Bergadá I, Milani C, Bedecarrás P , et al. Time course of the serum gonadotropin surge, inhibins, and anti-Müllerian hormone in normal newborn males during the first month of life. J Clin Endocrinol Metab 2006; 91 (10) 4092-4098
4 Guibourdenche J, Lucidarme N, Chevenne D , et al. Anti-Müllerian hormone levels in serum from human foetuses and children: pattern and clinical interest. Mol Cell Endocrinol 2003; 211 (1-2) 55-63
5 Aksglaede L, Sørensen K, Boas M , et al. Changes in anti-Müllerian hormone (AMH) throughout the life span: a population-based study of 1027 healthy males from birth (cord blood) to the age of 69 years. J Clin Endocrinol Metab 2010; 95 (12) 5357-5364
6 Grinspon RP, Bedecarrás P, Ballerini MG , et al; LAREP Group. Early onset of primary hypogonadism revealed by serum anti-Müllerian hormone determination during infancy and childhood in trisomy 21. Int J Androl 2011; 34 (5 Pt 2) e487-e498
7 Nelson SM, Messow MC, McConnachie A , et al. External validation of nomogram for the decline in serum anti-Müllerian hormone in women: a population study of 15,834 infertility patients. Reprod Biomed Online 2011; 23 (2) 204-206
8 Nelson SM, La Marca A. The journey from the old to the new AMH assay: how to avoid getting lost in the values. Reprod Biomed Online 2011; 23 (4) 411-420
9 Cate RL, Mattaliano RJ, Hession C , et al. Isolation of the bovine and human genes for Müllerian inhibiting substance and expression of the human gene in animal cells. Cell 1986; 45 (5) 685-698
10 Pepinsky RB, Sinclair LK, Chow EP , et al. Proteolytic processing of mullerian inhibiting substance produces a transforming growth factor-beta-like fragment. J Biol Chem 1988; 263 (35) 18961-18964
11 di Clemente N, Jamin SP, Lugovskoy A , et al. Processing of anti-mullerian hormone regulates receptor activation by a mechanism distinct from TGF-β. Mol Endocrinol 2010; 24 (11) 2193-2206
12 Vigier B, Picard JY, Tran D, Legeai L, Josso N. Production of anti-Müllerian hormone: another homology between Sertoli and granulosa cells. Endocrinology 1984; 114 (4) 1315-1320
13 Rey R, Sabourin JC, Venara M , et al. Anti-Müllerian hormone is a specific marker of sertoli- and granulosa-cell origin in gonadal tumors. Hum Pathol 2000; 31 (10) 1202-1208
14 Visser JA, de Jong FH, Laven JSE, Themmen APN. Anti-Müllerian hormone: a new marker for ovarian function. Reproduction 2006; 131 (1) 1-9
15 De Santa Barbara P, Bonneaud N, Boizet B , et al. Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Müllerian hormone gene. Mol Cell Biol 1998; 18 (11) 6653-6665
16 Arango NA, Lovell-Badge R, Behringer RR. Targeted mutagenesis of the endogenous mouse Mis gene promoter: in vivo definition of genetic pathways of vertebrate sexual development. Cell 1999; 99 (4) 409-419
17 Shen WH, Moore CC, Ikeda Y, Parker KL, Ingraham HA. Nuclear receptor steroidogenic factor 1 regulates the müllerian inhibiting substance gene: a link to the sex determination cascade. Cell 1994; 77 (5) 651-661
18 Watanabe K, Clarke TR, Lane AH, Wang X, Donahoe PK. Endogenous expression of Müllerian inhibiting substance in early postnatal rat sertoli cells requires multiple steroidogenic factor-1 and GATA-4-binding sites. Proc Natl Acad Sci U S A 2000; 97 (4) 1624-1629
19 Viger RS, Mertineit C, Trasler JM, Nemer M. Transcription factor GATA-4 is expressed in a sexually dimorphic pattern during mouse gonadal development and is a potent activator of the Müllerian inhibiting substance promoter. Development 1998; 125 (14) 2665-2675
20 Hossain A, Saunders GF. Role of Wilms tumor 1 (WT1) in the transcriptional regulation of the Mullerian-inhibiting substance promoter. Biol Reprod 2003; 69 (6) 1808-1814
21 Lukas-Croisier C, Lasala C, Nicaud J , et al. Follicle-stimulating hormone increases testicular Anti-Mullerian hormone (AMH) production through sertoli cell proliferation and a nonclassical cyclic adenosine 5′-monophosphate-mediated activation of the AMH Gene. Mol Endocrinol 2003; 17 (4) 550-561
22 Rey RA, Venara M, Coutant R , et al. Unexpected mosaicism of R201H-GNAS1 mutant-bearing cells in the testes underlie macro-orchidism without sexual precocity in McCune-Albright syndrome. Hum Mol Genet 2006; 15 (24) 3538-3543
23 Lasala C, Schteingart HF, Arouche N , et al. SOX9 and SF1 are involved in cyclic AMP-mediated upregulation of anti-Mullerian gene expression in the testicular prepubertal Sertoli cell line SMAT1. Am J Physiol Endocrinol Metab 2011; 301 (3) E539-E547
24 Rey R, Lordereau-Richard I, Carel JC , et al. Anti-müllerian hormone and testosterone serum levels are inversely during normal and precocious pubertal development. J Clin Endocrinol Metab 1993; 77 (5) 1220-1226
25 Al-Attar L, Noël K, Dutertre M , et al. Hormonal and cellular regulation of Sertoli cell anti-Müllerian hormone production in the postnatal mouse. J Clin Invest 1997; 100 (6) 1335-1343
26 Grinspon RP, Rey RA. Anti-müllerian hormone and sertoli cell function in paediatric male hypogonadism. Horm Res Paediatr 2010; 73 (2) 81-92
27 Berensztein EB, Baquedano MS, Gonzalez CR , et al. Expression of aromatase, estrogen receptor alpha and beta, androgen receptor, and cytochrome P-450scc in the human early prepubertal testis. Pediatr Res 2006; 60 (6) 740-744
28 Chemes HE, Rey RA, Nistal M , et al. Physiological androgen insensitivity of the fetal, neonatal, and early infantile testis is explained by the ontogeny of the androgen receptor expression in Sertoli cells. J Clin Endocrinol Metab 2008; 93 (11) 4408-4412
29 Boukari K, Meduri G, Brailly-Tabard S , et al. Lack of androgen receptor expression in Sertoli cells accounts for the absence of anti-Mullerian hormone repression during early human testis development. J Clin Endocrinol Metab 2009; 94 (5) 1818-1825
30 Rey RA, Codner E, Iñíguez G , et al. Low risk of impaired testicular Sertoli and Leydig cell functions in boys with isolated hypospadias. J Clin Endocrinol Metab 2005; 90 (11) 6035-6040
31 Feyaerts A, Forest MG, Morel Y , et al. Endocrine screening in 32 consecutive patients with hypospadias. J Urol 2002; 168 (2) 720-725 , discussion 725
32 Josso N. Paediatric applications of anti-müllerian hormone research. 1992 Andrea Prader Lecture. Horm Res 1995; 43 (6) 243-248
33 Lee MM, Donahoe PK, Silverman BL , et al. Measurements of serum müllerian inhibiting substance in the evaluation of children with nonpalpable gonads. N Engl J Med 1997; 336 (21) 1480-1486
34 Rey RA, Belville C, Nihoul-Fékété C , et al. Evaluation of gonadal function in 107 intersex patients by means of serum antimüllerian hormone measurement. J Clin Endocrinol Metab 1999; 84 (2) 627-631
35 Morel Y, Rey R, Teinturier C , et al. Aetiological diagnosis of male sex ambiguity: a collaborative study. Eur J Pediatr 2002; 161 (1) 49-59
36 Plotton I, Gay CL, Bertrand AM , et al. AMH determination is essential for the management of 46,XY DSD patients. Pediatr Res 2009; 72 (suppl. 3) 365
37 Hagen CP, Aksglaede L, Sørensen K , et al. Serum levels of anti-Müllerian hormone as a marker of ovarian function in 926 healthy females from birth to adulthood and in 172 Turner syndrome patients. J Clin Endocrinol Metab 2010; 95 (11) 5003-5010
38 Adamsbaum C, Rolland Y, Josso N, Kalifa G. Radiological findings in three cases of persistent müllerian duct syndrome. Pediatr Radiol 1993; 23 (1) 55-56
39 Gutte AA, Pendharkar PS, Sorte SZ. Transverse testicular ectopia associated with persistent Mullerian duct syndrome - the role of imaging. Br J Radiol 2008; 81 (967) e176-e178
40 El-Gohary MA. Laparoscopic management of persistent müllerian duct syndrome. Pediatr Surg Int 2003; 19 (7) 533-536
41 Lang-Muritano M, Biason-Lauber A, Gitzelmann C, Belville C, Picard Y, Schoenle EJ. A novel mutation in the anti-müllerian hormone gene as cause of persistent müllerian duct syndrome. Eur J Pediatr 2001; 160 (11) 652-654
42 Asthana S, Deo SV, Shukla NK, Raina V, Kumar L. Persistent Mullerian duct syndrome presenting with bilateral intra-abdominal gonadal tumours and obstructive uropathy. Clin Oncol (R Coll Radiol) 2001; 13 (4) 304-306
43 Berkmen F. Persistent müllerian duct syndrome with or without transverse testicular ectopia and testis tumours. Br J Urol 1997; 79 (1) 122-126
44 Bucci S, Liguori G, Buttazzi L, Bussani R, Trombetta C. Bilateral testicular carcinoma in patient with the persistent müllerian duct syndrome. J Urol 2002; 167 (4) 1790
45 Prakash N, Khurana A, Narula B. Persistent Müllerian duct syndrome. Indian J Pathol Microbiol 2009; 52 (4) 546-548
46 Chiang CY, Tsai JW, Wang HP, Sung YZ, Chang LC. Hernia uterine inguinale and seminoma in persistent Müllerian duct syndrome. Int J Surg Pathol 2010; 18 (5) 440-442
47 Shinmura Y, Yokoi T, Tsutsui Y. A case of clear cell adenocarcinoma of the müllerian duct in persistent müllerian duct syndrome: the first reported case. Am J Surg Pathol 2002; 26 (9) 1231-1234
48 Dekker HM, de Jong IJ, Sanders J, Wolf RF. Persistent Müllerian duct syndrome. Radiographics 2003; 23 (2) 309-313
49 Romero FR, Fucs M, Castro MG, Garcia CR, Fernandes RdeC, Perez MD. Adenocarcinoma of persistent müllerian duct remnants: case report and differential diagnosis. Urology 2005; 66 (1) 194-195
50 Gricourt S, Treton D, Renard-Pennat R , et al. Novel anti-mullerian hormone mutation revealed by haematospermia in a 60-year-old patient. Clin Endocrinol (Oxf) 2011; 74 (3) 404-405
51 Martin EL, Bennett AH, Cromie WJ. Persistent müllerian duct syndrome with transverse testicular ectopia and spermatogenesis. J Urol 1992; 147 (6) 1615-1617
52 Miller A, Hong MK, Hutson JM. The broad ligament: a review of its anatomy and development in different species and hormonal environments. Clin Anat 2004; 17 (3) 244-251
53 Naouar S, Maazoun K, Sahnoun L , et al. Transverse testicular ectopia: a three-case report and review of the literature. Urology 2008; 71 (6) 1070-1073
54 Abduljabbar MA, Taheini K, Picard JY, Cate RL, Josso N. Mutations of the AMH type II receptor in two extended families with persistent Müllerian duct syndrome: lack of phenotype/genotype correlation. Horm Res Paediatr 2012; 77 (5) 291-297
55 Chaabane W, Jarboui L, Sahnoun A , et al. Persistent Müllerian duct syndrome with torsion of a transverse testicular ectopia: first reported case. Urology 2010; 76 (1) 65-66
56 Imbeaud S, Rey R, Berta P , et al. Testicular degeneration in three patients with the persistent müllerian duct syndrome. Eur J Pediatr 1995; 154 (3) 187-190
57 Josso N, Fékété CN, Cachin O, Nezelof C, Rappaport R. Persistence of Müllerian ducts in male pseudohermaphroditism, and its relationship to cryptorchidism. Clin Endocrinol (Oxf) 1983; 19 (2) 247-258
58 Farag TI. Familial persistent müllerian duct syndrome in Kuwait and neighboring populations. Am J Med Genet 1993; 47 (3) 432-434
59 Vandersteen DR, Chaumeton AK, Ireland K, Tank ES. Surgical management of persistent müllerian duct syndrome. Urology 1997; 49 (6) 941-945
60 Lindgren BW, Franco I, Blick S , et al. Laparoscopic Fowler-Stephens orchiopexy for the high abdominal testis. J Urol 1999; 162 (3 Pt 2) 990-993 , discussion 994
61 Brandli DW, Akbal C, Eugsster E, Hadad N, Havlik RJ, Kaefer M. Persistent Mullerian duct syndrome with bilateral abdominal testis: surgical approach and review of the literature. J Pediatr Urol 2005; 1 (6) 423-427
62 Josso N, Belville C, di Clemente N, Picard JY. AMH and AMH receptor defects in persistent Müllerian duct syndrome. Hum Reprod Update 2005; 11 (4) 351-356
63 Belville C, Van Vlijmen H, Ehrenfels C , et al. Mutations of the anti-mullerian hormone gene in patients with persistent mullerian duct syndrome: biosynthesis, secretion, and processing of the abnormal proteins and analysis using a three-dimensional model. Mol Endocrinol 2004; 18 (3) 708-721
64 Cohen-Haguenauer O, Picard JY, Mattéi MG , et al. Mapping of the gene for anti-müllerian hormone to the short arm of human chromosome 19. Cytogenet Cell Genet 1987; 44 (1) 2-6
65 Sloan WR, Walsh PC. Familial persistent Müllerian duct syndrome. J Urol 1976; 115 (4) 459-461
66 Naguib KK, Teebi AS, Farag TI, al-Awadi SA, el-Khalifa MY, el-Sayed Mahfouz. Familial uterine hernia syndrome: report of an Arab family with four affected males. Am J Med Genet 1989; 33 (2) 180-181
67 Knebelmann B, Boussin L, Guerrier D , et al. Anti-Müllerian hormone Bruxelles: a nonsense mutation associated with the persistent Müllerian duct syndrome. Proc Natl Acad Sci U S A 1991; 88 (9) 3767-3771
68 Mazen I, Abdel Hamid MS, El-Gammal M, Aref A, Amr K. AMH gene mutations in two Egyptian families with persistent müllerian duct syndrome. Sex Dev 2011; 5 (6) 277-280
69 Menabò S, Balsamo A, Nicoletti A , et al. Three novel AMH gene mutations in a patient with persistent mullerian duct syndrome and normal AMH serum dosage. Horm Res 2008; 70 (2) 124-128
70 Nishio R, Fuse H, Akashi T, Furuya Y. Persistent Müllerian duct syndrome: a surgical approach. Arch Androl 2003; 49 (6) 479-482
71 Takahashi C, Fujito A, Kazuka M, Sugiyama R, Ito H, Isaka K. Anti-Müllerian hormone substance from follicular fluid is positively associated with success in oocyte fertilization during in vitro fertilization. Fertil Steril 2008; 89 (3) 586-591
72 Wu HC, Chen JH, Lu HF, Shen WC. Persistent müllerian duct syndrome wtih seminoma: CT findings. AJR Am J Roentgenol 2000; 174 (1) 102-104
73 Gökce MI, Burgu B, Aydoğdu O, Fitöz S, Soygür T. Transverse testicular ectopia associated with persistent Müllerian duct syndrome: another entity in which magnetic resonance imaging is unreliable. Urology 2010; 76 (6) 1475-1477
74 Odi TO, Abdur-Rahman LO, Nasir AA. Persistent Mullerian duct syndrome: a case report and review of the literature. Afr J Paediatr Surg 2010; 7 (3) 191-193
75 Macedo Jr A, Barroso Jr U, Ottoni SL, Ortiz V. Transverse testicular ectopia and persistent Müllerian duct syndrome. J Pediatr Urol 2009; 5 (3) 234-236
76 Wuerstle M, Lesser T, Hurwitz R, Applebaum H, Lee SL. Persistent mullerian duct syndrome and transverse testicular ectopia: embryology, presentation, and management. J Pediatr Surg 2007; 42 (12) 2116-2119
77 Costa E, Domenice S, Sireilli M, Inacio M, Mendonca B. DSD due to 5α-reductase 2 deficiency—from diagnosis to long-term outcome. Semin Reprod Med 2012; 30 (5) 427-431
78 Stuchi-Perez EG, Hackel C, Oliveira LE , et al. Diagnosis of 5alpha-reductase type 2 deficiency: contribution of anti-Müllerian hormone evaluation. J Pediatr Endocrinol Metab 2005; 18 (12) 1383-1389
79 Hughes I, Werner R, Bunch T, Hiort O. Androgen insensitivity syndrome. Semin Reprod Med 2012; 30 (5) 432-442
80 Bouvattier C, Carel JC, Lecointre C , et al. Postnatal changes of T, LH, and FSH in 46,XY infants with mutations in the AR gene. J Clin Endocrinol Metab 2002; 87 (1) 29-32
81 Rey R, Mebarki F, Forest MG , et al. Anti-müllerian hormone in children with androgen insensitivity. J Clin Endocrinol Metab 1994; 79 (4) 960-964
82 Baarends WM, van Helmond MJ, Post M , et al. A novel member of the transmembrane serine/threonine kinase receptor family is specifically expressed in the gonads and in mesenchymal cells adjacent to the müllerian duct. Development 1994; 120 (1) 189-197
83 di Clemente N, Wilson C, Faure E , et al. Cloning, expression, and alternative splicing of the receptor for anti-Müllerian hormone. Mol Endocrinol 1994; 8 (8) 1006-1020
84 Jamin SP, Arango NA, Mishina Y, Hanks MC, Behringer RR. Requirement of Bmpr1a for Müllerian duct regression during male sexual development. Nat Genet 2002; 32 (3) 408-410
85 Imbeaud S, Faure E, Lamarre I , et al. Insensitivity to anti-müllerian hormone due to a mutation in the human anti-müllerian hormone receptor. Nat Genet 1995; 11 (4) 382-388
86 Hoshiya M, Christian BP, Cromie WJ , et al. Persistent Mullerian duct syndrome caused by both a 27-bp deletion and a novel splice mutation in the MIS type II receptor gene. Birth Defects Res A Clin Mol Teratol 2003; 67 (10) 868-874
87 Klosowski S, Abriak A, Morisot C , et al. [Jejunal atresia and persistent mullerian duct syndrome]. Arch Pediatr 1997; 4 (12) 1264-1265
88 Josso N, Clemente N. Transduction pathway of anti-Müllerian hormone, a sex-specific member of the TGF-beta family. Trends Endocrinol Metab 2003; 14 (2) 91-97
89 Kobayashi A, Stewart CA, Wang Y , et al. β-Catenin is essential for Müllerian duct regression during male sexual differentiation. Development 2011; 138 (10) 1967-1975
90 Tanwar PS, Zhang L, Tanaka Y, Taketo MM, Donahoe PK, Teixeira JM. Focal Mullerian duct retention in male mice with constitutively activated beta-catenin expression in the Mullerian duct mesenchyme. Proc Natl Acad Sci U S A 2010; 107 (37) 16142-16147
91 Bellini C, Bonioli E, Josso N , et al. Persistence of Müllerian derivatives and intestinal lymphangiectasis in two newborn brothers: confirmation of the Urioste syndrome. Am J Med Genet 2001; 104 (1) 69-74
92 Van Maldergem L, Bachy A, Feldman D , et al. Syndrome of lipoatrophic diabetes, vitamin D resistant rickets, and persistent Müllerian ducts in a Turkish boy born to consanguineous parents. Am J Med Genet 1996; 64 (3) 506-513
93 Bashamboo A, Ledig S, Wieacker P, Achermann JC, McElreavey K. New technologies for the identification of novel genetic markers of disorders of sex development (DSD). Sex Dev 2010; 4 (4–5) 213-224
94 Hughes IA, Houk C, Ahmed SF, Lee PA ; LWPES Consensus Group; ESPE Consensus Group. Consensus statement on management of intersex disorders. Arch Dis Child 2006; 91 (7) 554-563