*Centro de Atendimento Materno-Fetal, Aracatuba Sao Paulo, Brazil;  ^#Nashville, TN

Synonyms: testicular feminization syndrome^,[2].

Definition: Defects of androgen receptor gene lead to testicular feminization syndrome, which is one of the most common etiology of male pseudohermaphroditism1.

Prevalence: rare. Many affected kindreds have been diagnosed, but in the majority, defects in testosterone or its conversion to dihydrotestosterone are the source of the anomaly[3].

Etiology: Androgen insensitivity syndrome presents a defect in the androgen receptor gene, leading to abnormal development or no-development of both internal and external male structures in 46, XY individuals[4]. The androgen receptor gene is located on the X-chromosome at Xq11-12 and is coded for a protein with a molecular mass of approximately 110 kDa. Only one androgen receptor cDNA was identified, despite two different ligands[5].

Pathogenesis: Male pseudohermaphroditism is a sex differentiation disorder, in which the gonads are testes, but the internal and/or external genitalia are incompletely masculinized. Androgens are important steroid hormones for expression of the male phenotype, being responsible for male sexual differentiation, development and maintenance of secondary male characteristics, and initiation and maintenance of spermatogenesis. The two most important androgens are testosterone and 5-a-dihydrotestosterone. Each androgen has its specific function during male sexual differentiation: testosterone is responsible for the development and differentiation of structures derived from the Wolffian duct and 5-a-dihydrotestosterone (a metabolite of testosterone) is the active ligand in the urogenital sinus and tubercle and their derived structures.

Male pseudohermaphroditism is classified to subtypes according to etiological factors: (1) testicular unresponsiveness to hCG and LH; (2) defect in testosterone biosynthesis; (3) end-organ resistance to androgen; (4) defects in the intracellular metabolism of testosterone; (5) aberrations in testicular organogenesis; (6) defects in anti-Mullerian hormone[6]. The end-organ resistance to androgens has been designated as androgen insensitivity syndrome, in which there is a defect in the androgen receptor. The actions of androgens are mediated by this androgen receptor. This ligand dependent transcription factor belongs to the superfamily of nuclear receptors, including those for the other steroid hormones, and is distinct from other forms of male pseudohermaphroditism like 17-b-hydroxy-steroid dehydrogenase type 3 deficiency, Leydig cell hypoplasia due to inactivating LH receptor mutations or 5-a-reductase type 2 deficiency2. There are 2 types of androgen insensitivity syndrome: complete and partial.

Diagnosis: Several different phenotypes can occur in the androgen insensitivity syndrome, ranging from individuals with predominantly a female appearance to persons with ambiguous genitalia, or individuals with a predominantly male phenotype. Cases of mild undervirilisation present perineoscrotal hypospadias with cryptorchidism and micropenis and cases of marked undervirilisation present clitoromegaly and partial labial fusion[8]^,[9],[10]. At puberty, elevated LH, testosterone and estradiol levels are observed. Individuals with mild symptoms of undervirilization, infertility has been described 2. The diagnosis of androgen insensitivity can be obtained by polymerase chain reaction and denaturing gradient gel electrophoresis[11] on material obtained either by amniocentesis or chorionic villus biopsy.

Sonographic findings: Ambiguous genitalia.

Differential diagnosis:

• Cases of male pseudo-hermaphroditism

• Congenital adrenal hyperplasia

Associated anomalies: There is a study that shown Down syndrome[12] in association with features of the androgen insensitivity Syndrome[13]. Abnormal androgen receptor structure and function has been associated with spinal and bulbar muscular atrophy and prostate cancer2.

Prognosis: Depends on the etiology.

Recurrence risk:  Depends on the etiology.

Management:  Gonadectomy must be made due to the potential of malignization of the testes. Laparoscopy gonadectomy can be considered for the removal of gonads, which presents reduced morbidity, shorter hospital stay and safety[14]. Neovaginoplasty can be necessary. Psycho-emotional support must be offered.

[1] Wu MH, Hsieh MF, Yau MP, Hsu CC.Bilateral laparoscopic gonadectomy for testicular feminization syndrome. Kaohsiung J Med Sci 1997 Aug;13(8):511-5

[2] De Bellis A, Quigley CA, Marschke KB, el-Awady MK, Lane MV, Smith EP, Sar M, Characterization of mutant androgen receptors causing partial androgen insensitivity syndrome. J Clin Endocrinol Metab 1994 Mar; 78(3): 513-22

[3] Buyse, ML. Birth Defects Enciclopedia.Pag 120.

[4] Lundberg Giwercman Y, Nikoshkov A, Lindsten K, Bystrom B, Pousette A, Knudtzon J, Alm J, Wedell A.Response to treatment in patients with partial androgen insensitivity due to mutations in the DNA-binding domain of the androgen receptor. Horm Res 2000; 53(2):83-8

[5] Radmayr C, Culig Z, Hobisch A, Corvin S, Bartsch G, Klocker H.Analysis of a mutant androgen receptor offers a treatment modality in a patient with partial androgen insensitivity syndrome. Eur Urol 1998; 33(2): 222-6

[6] Fukutani K.Male pseudohermaphroditism. Nippon Rinsho 1997 Nov;55(11):2920-4

[7] Brinkmann AO.Molecular basis of androgen insensitivity. Mol Cell Endocrinol 2001 Jun 20;179(1-):1059

[8] Evans BA, Hughes IA, Bevan CL, Patterson MN, Gregory JW.Phenotypic diversity in siblings with partial androgen insensitivity syndrome.Arch Dis Child 1997 Jun;76(6):529-31

[9] Batch JA, Davies HR, Evans BA, Hughes IA, Patterson MN.Phenotypic variation and detection of carrier status in the partial androgen insensitivity syndrome.Arch Dis Child 1993 Apr;68(4):453-7

[10] Melo KF, Latronico AC, Costa EM, Billerbeck AE, Mendonca BB, Arnhold IJ. A novel point mutation (R840S) in the androgen receptor in a Brazilian familwith partial androgen insensitivity syndrome.Hum Mutat 1999 Oct;14(4):353

[11] De Bellis A, Quigley CA, Marschke KB, el-Awady MK, Lane MV, Smith EP, Sar M, Characterization of mutant androgen receptors causing partial androgen insensitivity syndrome. J Clin Endocrinol Metab 1994 Mar;78(3):513-22

[12] Viner RM, Shimura N, Brown BD, Green AJ, Hughes IA. Down syndrome in association with features of the androgen insensitivity syndrome. J Med Genet 1996 Jul;33(7):574-7

[13] Viner RM, Shimura N, Brown BD, Green AJ, Hughes IA.Down syndrome in association with features of the androgen insensitivity syndrome.J Med Genet 1996 Jul;33(7):574-7

[14]Kriplani A, Abbi M, Ammini AC, Kriplani AK, Kucheria K, Takkar D.Laparoscopic gonadectomy in male pseudohermaphrodites.Eur J Obstet Gynecol Reprod Biol 1998 Oct;81(1):37-41