Keywords

Androgen insensitivity syndrome, X-linked recessive disorder, testosterone, primary amenorrhea, hormone replacement therapy

Androgen insensitivity syndrome (AIS) is defined as female or ambiguous phenotype in a 46,XY male with testes as internal gonads and normal testosterone production and metabolism.¹ It is an X-linked recessive disorder with an incidence of 1:20,000-64,000 male births. This genetic disorder is caused by mutation of the androgen receptor gene located on X chromosome resulting in complete loss of the androgen to bind to its receptor.² It is generally accepted that defects in the androgen receptor gene prevent the normal development of both internal and external genital structures in 46,XY individuals, causing a variety of phenotypes ranging from male infertility to completely normal female external genitalia. Precise diagnosis requires clinical, hormonal and molecular investigation and is of great importance for appropriate gender assignment and management in general. The complexity of phenotypic presentation of AIS with genotype-phenotype variability of identical mutations complicates both the diagnostic procedure and genetic counseling of the affected families. In complete AIS patients are complete women phenotypically with breast development, normal external genitalia, vagina of varied depth, absent uterus as a result of normal anti-mullerian hormone action and sparse to complete absence of axillary and pubic hairs. Partial androgen insensitivity present as male infertility to ambiguous external genitalia. Internal gonads are testis which may be intra-abdominally, inguinal or labial. Management includes detailed psychological counseling about the sexual mentation and infertility. In view of a high incidence of gonadal malignancy associated with dysgenetic gonads; gonadectomy is advocated.

Case Report

A 22-year-old unmarried girl presented to Endocrine OPD of Post Graduate Institute of Medical Sciences with complaint of primary amenorrhea. There was no history of prior medical consultation for it in past. There was no other positive relevant medical history.

On examination, her vitals were stable, height - 168 cm, weight - 95 kg, body mass index (BMI) - 33.6 kg/m². Patient had well-developed breasts (Tanner stage 4), with sparse axillary and pubic hair as shown in Figure 1.

On local examination, external genitalia were normal, per speculum vagina 3-4 cm long with normal rugae and ending in blind pouch, cervix was not visualized. Uterus and adnexa could not be revealed on per vaginal and per rectum examination. Routine blood investigations were normal. Serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were 19.54 mIU/mL (1.9-12.5) and 2.24 mIU/mL (1.4-11.5). Serum testosterone and 5α-dihydrotestosterone (5α-DHT) levels were raised 448.03 ng/dL (14-76) and 554.32 pg/mL (24-368), respectively. Karyotype revealed normal male karyotype (46,XY). USG revealed absence of uterus and ovaries. Magnetic resonance imaging (MRI) pelvis and abdomen showed an oval mass on right and left posterolateral aspect of urinary bladder, which appeared to be testis with absence of uterus and ovaries. Prostate and seminal vesicles were not seen (Fig. 2). In view of elevated testosterone, 5α-testosterone and LH with 46,XY karyotype and presence of bilateral intra-abdominal testis, a diagnosis of complete AIS was made. Since patient was reared as a female, so after discussion with patient and parents, in view of risk of malignancy of intra-abdominal testis, and after explaining risk and taking proper consent gonadectomy was planned and performed. After that patient was put on hormone replacement therapy.

Discussion

Primary amenorrhea is the failure of menses to occur by age 16 years, in the presence of normal growth and secondary sexual characteristics. If by age 13, menses has not occurred and the onset of puberty, such as breast development, is absent, a work-up for primary amenorrhea should start. The relative prevalence of primary amenorrhea includes hypergonadotropic hypogonadism (48.5% of cases), hypogonadotropic hypogonadism (27.8%) and eugonadism (pubertal delay with normal gonadotropins; 23.7%).³ Out of all, androgen insensitivity contributes 1.5% only.

AIS is an X-linked disease characterized by variable defects in virilization of 46,XY individuals due to loss-of-function mutations in the androgen receptor gene. Androgens exert their effects by mediating the differentiation and development of the normal male phenotype via a single receptor protein, the androgen receptor.⁴

The most common causes of AIS are the point mutations in the androgen receptor gene resulting in a defective receptor protein, which is unable to bind hormone or bind to DNA.⁵ This alteration in the gene blocks the body’s response to androgen during fetal development and after birth. The body can respond to feminizing hormones (estrogen), but not androgen. The clinical phenotypes of AIS are variable and are classified into three main categories: complete IAS (CAIS), partial IAS (PAIS) and mild IAS (MAIS) form, the designations reflecting the severity of androgen resistance.

Individuals affected by CAIS present with normal female external genitalia with a short blind ending vagina. Subjects with CAIS are born unambiguously female and are not suspected of being abnormal until the onset of puberty, when breast development is normal but pubic and axillary hair is not developed and menses do not occur. All the above features were present in our case. Like in our case most of the cases are diagnosed in the post-pubertal stage due to primary amenorrhea. A recent retrospective study of 9 post-pubertal individuals with CAIS suggests that these individuals enter puberty at an age closer to that of females.⁶

In contrast, PAIS patients present with genital ambiguity. Such individuals with predominantly female external genitalia have mild clitoromegaly, some fusion of the labia and pubic hair at puberty, while those of predominantly male appearance of external genitalia exhibit micropenis, perineal hypospadias and cryptorchidism (also called Reifenstein syndrome).⁷ Because of variability of clinical manifestations and the existence of subtle or atypical forms of androgen resistance such as male infertility, the prevalence of partial forms of AIS is unknown. At puberty, elevated LH, testosterone and estradiol levels are observed, but in general, the degree of undervirilization is less as compared with individuals with CAIS.

At puberty MAIS takes two phenotypic forms, both presenting with various degrees of gynecomastia, high-pitched voice, sparse sexual hair and impotence. In one form of MAIS, spermatogenesis and fertility are impaired, while in another spermatogenesis is normal or sufficient to preserve fertility.⁸

In patients with clinically suspecting CAIS one should do serum LH, FSH, testosterone, 5α-DHT with karyotype and ultrasonography. Laparoscopy should be done in all such patients to examine internal genital organs. Measurement of serum 17-hydroxyprogesterone and its sulfate should be done to detect testosterone biosynthetic defects.⁹ Successful management of patients with this condition requires counseling, gonadectomy, vaginal enlargement and estrogen replacement. Gonadectomy is best delayed until after puberty is completed as pubertal development generally proceeds more smoothly in response to endogenous hormonal production¹⁰ and the overall risk of gonadal tumor development is 3.6% and 33% at the age of 25 years and 50 years, respectively. Once the testes have been removed, estrogen needs to be taken in order to maintain feminity.

Conclusion

Androgen insensitivity syndrome, although very rare, is extremely distressing to the concerned individual and requires expert and sympathetic handling. Patients can be helped to achieve an excellent quality-of-life as a female by a multispecialty approach including gonadectomy, surgical correction, detailed and repeated psychological counseling along with estrogen replacement.

References

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