Pocket ObGyn – Androgen Insensitivity Syndrome
See Abbreviations
Definition and Epidemiology (J Pediatrc Surg 2005;40:133; J Clin Endocrinol Metab
2001;86:4151)
- Male pseudohermaphroditism from muts in AR & decreased end organ 1.1% incid of CAIS in a premenarcheal child w/ inguinal hernias.
- 1 in 20000–99000 genetic males
Etiology
- 70% of AR muts are X-linked recessive leading to decreased resp to androgens; 30% de novo sporadic muts. Multi
| Androgen abnormality/insensitivity syndromes | |||||
|
Complete |
Incomplete |
Reifenstein |
Infertile |
5a–
reductase |
|
| Inheritance pattern | X-linked
recessive |
X-linked
recessive |
X-linked
recessive |
X-linked
recessive |
Autosomal recessive |
| Spermatogenesis | — | — | — | ¯ | ¯ |
| Müllerian structures | — | — | — | — | — |
| Wolffian
structures |
— | | | | |
| External
genitalia |
| – clitoromegaly Partial
labioscrotal fusion |
– hypospadias | | |
| Breasts | | | Gynecomastia | Gynecomastia | |
| From Griffin JE. Androgen resistance—the clinical and molecular spectrum. N Eng J Med 1992;326:611–618; Kim HH, Laufer MR. Developmental abnormalities of the female reproductive tract. Curr Opin Obstet Gynecol 1994;6:518–525. | |||||
Pathophysiology
- Nml male dev only occur if adequate androgen production acting on target tissues (sex differentiation). Muts in AR leads to a defective resp to androgens at all stages of Production of testosterone occurs at ~8–16 w via placental hCG; after 16 w, fetal LH controls circulating androgens.
- Testosterone (produced by Leydig cells in testes) is responsible for Wolffian dev & formation of the epididymis, vas deferens, & seminal DHT is responsible for formation of male external genitalia & fusion of labioscrotal folds. Androgens control descent of testes into scrotum ® in AIS, testes remain in pelvis.
- Androgens ® secondary male sex characteristics at puberty (axillary & pubic hair) & spermatogenesis. MIS is produced normally by Sertoli cells in testes causing regression of Müllerian ducts ® no uterus, oviducts, & upper
Figure 6.5 The major pathways of male and female sexual differentiation
TDF, testis-determining factor; MIF, Müllerian inhibitory factor; T, testosterone (From Ostrer H. Genetics of Sexual Differentiation. Glob. libr. women’s med., (ISSN: 1756–2228) 2008. doi:10.3843/GLOWM.10347)
Clinical Manifestations
- Karyotype 46XY
- Male pseudohermaphroditism: Variety of phenotypes ranging from male infertility to nml female external May present w/ ambiguous genitalia or infantile male genitalia. + MIS ® short vagina, absent uterus & cervix.
- Primary amenorrhea/infertility
- CAIS: No activity at the AR ® nml female Nml breast dev w/ pale areola (estrogens produced by testes & circulating androgens fail to antagonize estrogens). Sparse or absent pubic & axillary hair (vellus hair only, if present). Nml or slightly advanced height, however decreased bone density. 50% w/ inguinal hernias: Gonads (testes) intra-abdominal or in the inguinal rings. Serum testosterone in the range of pubertal male. No issues regarding gender identity or sexual preference given they are not exposed to male androgen levels ® brain dev along w/ physical dev is female.
- PAIS: Varying degrees of female virilization or male feminization due to differing degrees of AR Labial fusion, bifid scrotum, hypospadias, micropenis, &/ or clitromegaly. Blind vas deferens. Testes in labioscrotal folds. Nml breasts & pubic & axillary hair. Higher rates of bisexuality, homosexuality, & gender identity d/o.
- Mild AIS: Phenotypic & genotypic Male infertility (oligospermia w/ nml T & LH). Gynecomastia in young men. Minor hypospadias.
Physical Exam
- Female infant or toddler w/ an inguinal hernia ® attempt to pass a sterile Q-tip into vagina (consider exam under anesthesia in toddlers). Consider
- Adol ® full physical exam (note breast dev, pubic & axillary hair, & external genitalia including hymenal anatomy), rectal exam to r/o lower vaginal
Diagnostic Workup/Studies
- CAIS: T & Diff:
MRKH syn or Müllerian agenesis; distinguish by karyotype; XX genetic females; nml testosterone; presence of pubic & axillary hair (absent in CAIS)
Swyer syn = XY complete gonadal dysgenesis. No breast dev & short stature; XY genetic males.
- PAIS: Nml T & LH (Clin Endocrinol Metab 2006;20:577), MRI (gold std) or pelvic US to document internal anatomy, localize testes, r/o testicular tumors, karyotype, genetic counseling for
Differential diagnoses (DDx) Partial gonadal dysgenesis
17b-hydroxysteroid dehydrogenase deficiency 5a-reductase deficiency
Mixed gonadal dysgenesis w/ mosaic Turner syn (45XO/46XY) Defect in LH receptor
Treatment
- Prophylactic gonadectomy in CAIS b/c of rate of malig degeneration & formation of dysgerminomas/gonadoblastomas after pubertal dev, then estrogen replacement
- Incid of 5% malig in CAIS, 5.5% in overall AIS pop; as high as 50% in PAIS if gonads in nonscrotal position (intra-abdominal location inc risk for malig). If dx prior to puberty, serial US monitoring for pelvic masses (Acta Endocrinol 1990;123416; Int J Gynecol Pathol 1991;10:126; J Clin Endocrinol Metab 2005;90:5295)
Rate of malig in pts w/ AIS prior to puberty is 0.8% (CAIS) & 5.5% (overall)
(Endocrine Rev 2006;27:468; J Pathol 2006;208:518)
- Hormone replacement
CAIS ® estrogen replacement during late adolescence/early adulthood to aid final Tanner 5 breast dev, help build bone,Vit D, regular weight-bearing exercise; DEXA or bisphosphonates prn
PAIS ® large doses of androgens to promote phallic growth
- ± vaginal dilators for increased vaginal length; d/c once regular vaginal intercourse
- ± genital reconstructive Surg when pt voices desire to proceed
- Multidisciplinary support including a mental health provider, social worker, geneticist