CASE REPORT. a Endocrinology Unit, IRCCS Policlinico San Donato, San Donato Milanese, Milan; b Department of Medical-Surgical Sciences,
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1 CASE REPORT Gonadal structures in a fetus with complete androgen insensitivity syndrome and persistent M ullerian derivatives: comparison with normal fetal development Sabrina Corbetta, M.D., Ph.D., a,b Marina Muzza, Ph.D., c,d Laura Avagliano, M.D., Ph.D., e,f Gaetano Bulfamante, M.D., e,f Luigi Gaetti, M.D., g Cristina Eller-Vainicher, M.D., c Paolo Beck-Peccoz, M.D., c,d and Anna Spada, M.D., Ph.D. c,d a Endocrinology Unit, IRCCS Policlinico San Donato, San Donato Milanese, Milan; b Department of Medical-Surgical Sciences, University of Milan, San Donato Milanese, Milan; c Endocrine Unit, IRCCS Fondazione Ca 0 Granda Policlinico, Milan; d Department of Medical Sciences, University of Milan, Milan; e Prenatal and Neonatal Pathology Unit, A.O. S.Paolo, and IRCCS Fondazione Ca 0 Granda Policlinico, Milan; f Department of Medicine, Surgery and Dentistry, University of Milan, Milan; and g Pathology Unit, Ospedale Mantova, Mantua, Italy Objective: To report a case of complete androgen insensitivity syndrome (CAIS) with M ullerian duct persistence. Design: Case report. Setting: Academic hospital. Patient(s): A case of CAIS at 20 weeks gestational age, and three male and one female 20-week-old fetuses for comparison. Intervention(s): DNA screening for androgen receptor (AR), antim ullerian hormone (AMH), and AMH receptor type 2(AMHR2) gene mutations, and morphologic examination of Wolffian and M ullerian derivatives and immunohistochemistry for AMH, AMHR2, and bone morphogenetic protein receptor type 1A (BMPR1A) in aborted fetuses. Main Outcome Measure(s): Histopathologic, genetic, and immunohistochemical studies. Result(s): A novel mutation of AR (D767V) was identified in the index fetus. The CAIS case showed Wolffian duct degeneration, Leydig cell hyperplasia, and normally developed Sertoli cells. No AMH and AMHR2 gene sequence alterations were observed in the CAIS case, and the uterus and vagina were developed to a similar extent as found in the normal female 20-week-old fetus. The CAIS testes expressed more abundant AMH and showed fewer AMHR2- positive peritubular mesenchymal cells than the normal male testes, but BMPR1A stained similarly. Conclusion(s): Our study indicates that testes differentiation and development as well as the expression patterns of AMH, AMHR2, and BMPR1A are independent from AR function, at least up to the second trimester. The mechanisms by which the lack of functional androgen interferes with AMH action and M ullerian duct regression remain undefined. (Fertil Steril Ò 2011;95:1119.e9 e14. Ó2011 by American Society for Reproductive Medicine.) Key Words: AMH, AMHR2, androgen receptor, M ullerian structures, testis Received June 22, 2010; revised August 8, 2010; accepted September 16, 2010; published online October 25, S.C. has nothing to disclose. M.M. has nothing to disclose. L.A. has nothing to disclose. G.B. has nothing to disclose. L.G. has nothing to disclose. C.E-V. has nothing to disclose. P.B-P. has nothing to disclose. A.S. has nothing to disclose. Supported by the University of Milan Foundation. Reprint requests: Sabrina Corbetta, M.D., Ph.D., Endocrinology and Diabetology Unit, Department of Medical-Surgical Sciences, University of Milan, IRCCS Policlinico S. Donato, Via Morandi 30, S. Donato M.se (MI), Italy ( sabrina.corbetta@unimi.it). The androgen receptor (AR) mediates the action of testosterone and dihydrotestosterone on the male sexual differentiation. Mutations in the AR gene (MIM ) cause androgen insensitivity syndrome (MIM ), an X-linked condition with a minimal incidence of 1:99,000 (1). Clinically, androgen insensitivity syndrome ranges from a complete form (CAIS), characterized by a normal female external phenotype, a blind-end vagina, and intra-abdominal testes, to a partial form (PAIS) with a variable ambiguity of genitalia (2). To date, over 800 different AR mutations have been reported in androgen insensitivity syndrome ( In these individuals, M ullerian derivatives are usually absent because the production of antim ullerian hormone (AMH) by the testes is preserved. However, some M ullerian remnants have been observed in sporadic patients with CAIS (3 9). Commonly, patients with androgen insensitivity syndrome are diagnosed in childhood for intra-abdominal testis or in postpubertal age for primary amenorrhea. Therefore, testicular development has been investigated in childhood, and at prepubertal and postpubertal ages. Here, we describe the gonadal structures of a 20-week-old fetus with CAIS, which presented with M ullerian derivative development similar to that found in an age-matched female fetus, in the presence of a normal sequence and expression of AMH and other key genes involved in M ullerian duct regression /$36.00 Fertility and Sterility â Vol. 95, No. 3, March 1, e9 doi: /j.fertnstert Copyright ª2011 American Society for Reproductive Medicine, Published by Elsevier Inc.
2 FIGURE 1 Particulars of body examination during fetal autopsies. (A) Typically female external genitalia (E) with abdominal gonad (G) and increased volume. (B, C) Histologic examination of the paratesticular area revealing degenerative involution of Wolffian and M ullerian ducts. (D) Gonad examination showing normal fetal testis with normal tubular structures (T). The number and size of Leydig cells (L) were increased in (E) CAIS compared with (F) the normal control male. (Magnification: 40; stain: hematoxylin and eosin). Corbetta. Testicular development in fetal CAIS. Fertil Steril CASE REPORT The case was a fetus aborted at 20 weeks for a sex development disorder: the chorionic villous culture at 12 weeks of gestational age showed a 46,XY karyotype, but the morphologic ultrasound examination at 18 weeks revealed external female genitalia. The gestational age was determined by the date of the last menstrual period and was confirmed by a first trimester ultrasound (according to embryo crown-rump length). Termination of the pregnancy was performed after genetic counseling. Informed consent for the fetal tissue examination and DNA sequencing was obtained. The study was approved by the local ethics committee. MATERIALS AND METHODS Tissue Collection Complete postmortem fetal examination was performed according to international criteria (10). Fetal gonads and internal genitalia were obtained from the index case and from four gestational agematched normal fetuses (one female and three male fetuses). No fetal abnormalities, except in the index case, were present. The control tissues were obtained after legal voluntary terminations of pregnancy, according to Italian legislation. Informed consent of the mothers was obtained before procurement of the tissues, in accordance with guidelines outlined by the San Paolo Hospital ethics committee. Molecular Analysis The DNA of the fetus was obtained from the formalin-fixed, paraffin-embedded liver and was extracted by a commercial kit (Puregene; Gentra Systems, Minneapolis, MN). Exons 1 to 8 of the AR gene (11), and the hot spots of the AMH gene (exons 1 and 5) and AMHR2 gene (exon 10) (12) were amplified by polymerase chain reaction (PCR) (amplification conditions and primers available on request). Direct sequencing of each PCR product was 1119.e10 Corbetta et al. Testicular development in fetal CAIS Vol. 95, No. 3, March 1, 2011
3 FIGURE 2 Internal genitalia reconstruction of fetus with complete androgen insensitivity syndrome (CAIS). Vaginal epithelium: (A) index case and (B) normal female control. Insets show the histologic finding of vaginal epithelium (magnification: 20; stain: hematoxylin and eosin). Uterine epithelium: (C) CAIS and (D) female control. (Magnification: 60; stain: H&E.) Specific immunostaining in the uterine sections: In CAIS case, (E) antim ullerian hormone receptor type 2 (AMHR2) and (G) bone morphogenetic protein receptor, type IA (BMPR1A). In normal female fetus, (F) AMHR2 and (H) BMPR1A. Ut, uterus; Va, vagina. Corbetta. Testicular development in fetal CAIS. Fertil Steril performed and run on an ABI PRISM 310 Genetic Analyzer (Applied Biosystems, Foster City, CA). Histologic Analysis and Immunohistochemistry Formalin-fixed, paraffin-embedded fetal samples were processed for conventional histopathologic examination. Immunohistochemical studies were performed by use of the Novolynk Polymer Detection System (Novocastra Laboratories Ltd, Newcastle, UK) with monoclonal antibody raised against AMH (MIS [C-20: sc 6886]; Santa Cruz Biotechnology, Santa Cruz, CA], antim ullerian hormone receptor type 2 (AMHR2) (Abcam, Cambridge, U.K.), and bone morphogenetic protein receptor, type 1A (BMPR1A) (Abcam) at a concentration of 1:200, 1:100, and 1:100, respectively. RESULTS Morphology and Histologic Analysis Fetal growth was normal, and no major malformations were found in the extragenital structures. Examination of the fetus showed external female genitalia (Fig. 1A). Two enlarged testes of maximal diameter 12 mm (vs. 6 mm in normal age-matched male fetuses) were found in abdomen. Normally developed M ullerian structures were observed (see Fig. 1A). The histologic examination showed Fertility and Sterility â 1119.e11
4 FIGURE 3 Immunohistochemical analysis for antim ullerian hormone (AMH), antim ullerian hormone receptor type 2 (AMHR2), and bone morphogenetic protein receptor, type IA (BMPR1A) in testis sections from fetus with complete androgen insensitivity syndrome (CAIS) (left) and normal male fetus (right). (A, B) AMH showed a strong reaction in CAIS and in normal Sertoli cells (magnification: 10). (C, D) AMHR2 had a peritubular distribution (magnification: 20), but AMHR2-positive mesenchymal cells (arrows) were less represented in (C) CAIS than in (D) normal testis. (E, F) BMPR1A was expressed in Leydig cells of the (E) CAIS testis as well as of the (F) normal male control. Corbetta. Testicular development in fetal CAIS. Fertil Steril differentiated testes, with normally developed tubular structures, Sertoli cells, and rare spermatogonia (see Fig. 1D). In comparison with the normal male 20-week-old fetuses used for control, the CAIS testes showed diffuse hypertrophy and hyperplasia of Leydig cells (see Fig. 1E and F), and the intertubular mesenchymal tissue was reduced. Screening of the paratesticular area revealed Wolffian duct derivatives with degenerative involution (see Fig. 1B). At the opposite testis poles, fallopian tube remnants were observed (see Fig. 1C). A complete uterus and vagina were present; they appeared to have developed to a similar extent in the CAIS case and the normal female fetus (Fig. 2). Both index case and normal female fetal vaginas showed a developing malpighian epithelium (see Fig. 2A and B). In the uterine cavity of the CAIS fetus, the epithelium showed an immature malpighian epithelium (basaloidlike), but it was columnar and pseudostratified in the uterus of the control (see Fig. 2C and D). The myometrium was organizing in both the index and control cases. Direct Sequence Analysis of AR, AMH, and AMHR2 Genes Direct sequencing analysis of the proband AR gene revealed a novel missense mutation in exon 5, the ligand-binding domain. An A to 1119.e12 Corbetta et al. Testicular development in fetal CAIS Vol. 95, No. 3, March 1, 2011
5 T transition was detected at nucleotide 2662, resulting in an aspartic acid to valine substitution in codon 767. This mutation has not previously been identified. However, the database ( reports a different change affecting the same residue (i.e., D767E). The direct sequencing analysis of the hot spots of both AMH and AMHR2 genes in the proband did not detect any variants. Immunohistochemistry Positive staining for AMH confined to the cytoplasm was detected in Sertoli cells from both the index case and the 20-week-old normal male fetuses, although AMH expression was higher in the CAIS fetus than in the controls (Fig. 3A and B). Uterus section from the CAIS fetus and the normal female fetus showed a similar positive immunostaining for AMHR2 in the mesenchymal cells (see Fig. 2E and F), but no specific staining for BMPR1A could be detected in any uterine samples (see Fig. 2G and H). We found that AMHR2 protein was expressed in the testes mesenchymal peritubular cells with a lower positivity in CAIS tissue (see Fig. 3C and D). We detected BMPR1A immunostaining at a high level in the Leydig cells of both the CAIS fetus and the controls (see Fig. 3E and F). DISCUSSION Our study describes the gonadal phenotype of a fetus with CAIS due to a novel AR mutation associated with persistence of normally developed M ullerian derivatives. Very few data, if any, concerning human fetal gonadal development in the absence of androgen action are available. The histologic features of the CAIS testis showed seminiferous tubules, Sertoli cells, and rare spermatogonia appropriate for the gestational age, suggesting that androgens are not essential for testes differentiation and development up to the second trimester. The CAIS testis was characterized by a dramatic increase in the size and number of Leydig cells. It is worth noting that Leydig cell hyperplasia is not a feature of AR knockout mice (13), but it is typically present in persistent M ullerian duct syndrome due to AMH or AMHR2 gene mutations (12). In our CAIS case, the uterus and vagina were present and appeared to have developed to a similar extent as found in the normal 20-week-old female fetus. Some M ullerian remnants have been observed in sporadic patients with CAIS (3 9), although AMH synthesis and function are supposed to be normal in CAIS due to normal Sertoli cell differentiation. The pathogenesis of these M ullerian structures and CAIS coexistence is unclear. Explanations proposed for the persistence of M ullerian structures in CAIS did not seem to account for the normal development of M ullerian derivatives in the index case. The uterine and vaginal epithelial cells did not present with signs of diethylstilbestrol exposure, excluding an unopposed estrogenic environment interfering with AMH action (4). The M ullerian derivatives were tightly tethered to the testis, allowing AMH paracrine action. Finally, consistent with the absence of gene mutations, the CAIS Sertoli cells positively stained for AMH, and uterine mesenchymal cells, the targets of AMH action, expressed AMHR2 protein. Conversely, BMPR1A, the most likely AMH type 1 receptor, whose conditional male knockout mice exhibit persistent M ullerian ducts (14), was absent in the uterine sections from both CAIS and normal female fetuses. Moreover, BMPR1A, which was expressed in the Leydig cells, did not colocalize with AMHR2, further bringing into question the role of BMPR1A in human gonad differentiation. The CAIS fetus showed elevated AMH expression in Sertoli cells associated with reduced peritubular mesenchymal cells positive for AMHR2. The AMH induction as well as the Leydig cell hyperplasia are in line with the phenotype of persistent M ullerian duct syndrome in humans and animal models, which occurs due to inactivated AMH and AMHR2 gene mutations, but the reduced AMHR2 expression remains unexplained. Nonetheless, it could be speculated that AR inactivation might down-regulate AMHR2 expression, as has been reported in adult testes exposed in utero to anti-androgens (15). Alternatively, AR deficiency might inhibit peritubular mesenchymal cells differentiation/proliferation, thus determining a condition of resistance to AMH. Our study suffers from some limits. Unfortunately, this natural human AR knockout model was studied at 20 weeks gestational age when the gonads and genital structures are fully committed to their form. Accordingly, the correct timing of the expression patterns of the genes involved in M ullerian structure regression could not be tested in our model. Our study clearly showed that testes differentiation and development as well as the expression pattern of AMH, AMHR2, and BMPR1A are independent from AR function, at least up to the second trimester. The mechanism by which the lack of functional androgen interferes with AMH action and M ullerian ducts regression remains undefined. Acknowledgments: The authors thank Ms. Patrizia Doi for technical assistance with the study. REFERENCES 1. Boehmer ALM, Br uggenwirth H, van Assendelft C, Otten BJ, Verleun-Mooijman MCT, Niermeijer MF, et al. Genotypes versus phenotype in families with androgen insensitivity syndrome. J Clin Endocrinol Metab 2001;86: Quigley CA, De Bellis A, Marschke KB, el- Awady MK, Wilson EM, French FS. Androgen receptor defects: historical, clinical, and molecular perspectives. Endocr Rev 1995;16: Oka M, Katabuchi H, Munemura M, Mizumoto J, Maeyama M. An unusual case of male pseudohermaphroditism: complete testicular feminization associated with incomplete differentiation of the m ullerian duct. Fertil Steril 1984;41: Dodge ST, Finkelston MS, Miyazawa K. Testicular feminization with incomplete m ullerian regression. Fertil Steril 1985;43: Ulloa-Aguirre A, Mendez JP, Angeles A, Fernandez del Castillo C, Chavez B, Perez-Palacios G. The presence of m ullerian remnants in the complete androgen insensitivity syndrome: a steroid hormonemediated defect? Fertil Steril 1986;45: Heller DS, Ranzini A, Futterweit W, Dottino P, Deligdisch L. M ullerian remnants in complete androgen insensitivity syndrome. Int J Fertil 1992;37: Damiani D, Mascolli MA, Almeida MJ, Jaubert F, Fellous M, Dichtchekenian V, et al. Persistence of m ullerian remnants in complete androgen insensitivity syndrome. J Pediatr Endocrinol Metab 2002;15: Van YH, Lin JL, Huang SF, Luo CC, Hwang CS, Lo FS. Novel point mutations in complete androgen insensitivity syndrome with incomplete m ullerian regression: two Taiwanese patients. Eur J Pediatr 2003;162: Galani A, Sofocleous C, Karahaliou F, Papathanasiou A, Kitsiou-Tzeli S, Kalpini- Mavrou A. Sex-reversed phenotype in association with two novel mutations c.2494dela and c.t3004c in the ligand-binding domain of the androgen receptor gene. Fertil Steril 2008;90: Gilbert-Barness E, Debich-Spicer D. Handbook of pediatric autopsy pathology. Totowa, NJ: Humana Press, Lubahn DB, Brown TR, Simental JA, Higgs HN, Migeon CJ, Wilson EM, et al. Sequence of the intron/exon junctions of the coding region of the human androgen receptor gene and identification of Fertility and Sterility â 1119.e13
6 a point mutation in a family with complete androgen insensitivity. Proc Natl Acad Sci USA 1989;86: Josso N, Belville C, Di Clemente N, Picard JY. AMH and AMH receptor defects in persistent m ullerian duct syndrome. Hum Reprod Update 2005;11: Wang R-S, Yeh S, Tzeng C-R, Chang C. Androgen receptor roles in spermatogenesis and fertility: lessons from testicular cell-specific androgen receptor knockout mice. Endocr Rev 2009;30: Jamin SP, Arango NA, Mishina Y, Hanks MC, Behringer RR. Requirement of BMPR1A for m ullerian duct regression during male sexual development. Nat Genet 2002;32: Benbrahim-Tallaa L, Siddeek B, Bozec A, Tronchon V, Florin A, Friry C, et al. Alterations of Sertoli cell activity in the long-term testicular germ cell death process induced by fetal androgen disruption. J Endocrinol 2008;196: e14 Corbetta et al. Testicular development in fetal CAIS Vol. 95, No. 3, March 1, 2011
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