Androgen insensitivity revealed by surgery in elderly identical twins
© Springer-Verlag 2009
Received: 6 June 2009
Accepted: 6 August 2009
Published: 25 August 2009
Two elderly identical twin sisters with inguinal hernias and malignant gonadic tumors were diagnosed during surgery as having complete androgen insensitivity syndrome. Androgen insensitivity syndrome, also referred to as testicular feminization, is an X-chromosome-linked genetic condition in which the tissues of a genotypic male are unresponsive to androgens because of an anomaly of the androgen receptor. This results in feminization of the external genitalia. The internal genital organs including the cranial part of the vagina, cervix, uterus, and fallopian tubes are absent because of testicular inhibition during embryonic development. Patients most frequently present as young females with asymptomatic bilateral inguinal hernias. They may undergo normal puberty but have primary amenorrhea. Rarely, the diagnosis may follow a workup for infertility. As in cryptorchidia, the testicles are prone to malignant transformation and require that orchidectomy be performed, usually after puberty.
At the other end of the spectrum, grade 7 patients are those with complete androgen insensitivity. At birth, their external genital organs are unequivocally female. Their internal genital organs are lacking because of physiological inhibition by Mullerian-inhibiting factor secreted in utero by the testes. Remnants of Wolffian structures, such as vestigial vas deferens or epididymis, may sometimes be found but, usually, internal genital organs are limited to the presence of two undescended or partially descended testes. Pubic and axillary hairs are scant or absent at puberty. Pubertal breast development ranging from mild gynecomastia to large breasts can occur with all grades of AIS and tends to be more pronounced with increasing androgen insensitivity. This is due to the loss of feedback resulting in increased pituitary secretion of luteinizing hormone with overstimulation of Leydig cell production of testosterone and estradiol. Testosterone also undergoes aromatization to estradiol in peripheral tissues. Complete androgen insensitivity results in an unequivocally feminine appearance at adult age.
As in cryptorchidia, the testes of patients with androgen insensitivity are prone to malignant transformation. The risk of developing a malignant germ cell tumor (seminoma) rises from 3% at age 20 to 30% at age 50 . Low-grade nongerm cell (Sertoli and Leydig cells) tumors can also develop as well as mixed tumors (hamartomas) containing germ cell, Leydig cell, and Sertoli cell elements. The overall incidence of gonadal neoplasia remains difficult to evaluate, but it is thought that neoplasia very seldom develops before puberty. The overall risk of malignancy is estimated to be 6–9% . Benign tumors develop in 25% of patients. Prevention of testicular cancer mandates orchidectomy in patients with AIS. This can be performed in early childhood or be delayed till after puberty, but usually before age 20.
A frequent mode of presentation of AIS is that of a young woman with normal puberty but with no menstruations and scant/absent pubic and axillary hairs. Up to 1–2% of young girls with asymptomatic bilateral inguinal hernias are thought to have complete androgen insensitivity syndrome . It has been suggested that during bilateral hernia repair in a young girl with herniated gonads, the surgeon should verify the presence of normal Mullerian structures (fimbriae and tubes) by pulling the gonads outwards. Their absence is highly suggestive of the diagnosis. If androgen insensitivity syndrome is suspected, a frozen section biopsy of the gonad should be performed. Evidence of normal testicular tissue at pathology will corroborate the diagnosis. The hernias should be repaired, and the gonads placed subcutaneously below the skin incision to facilitate later orchidectomy. Gonadectomy is not indicated during hernia repair when the diagnosis is first suspected. This decision will be left until later when the patient and her family have been adequately counseled and have given their informed consent . Gynecological evaluation will confirm the absence of a uterus and cervix. Genetic studies will reveal an XY genotype.
Sex assignment can be a significant dilemma facing these patients, their parents, and healthcare professionals. Female assignment remains the most frequently chosen option, but male assignment has gained popularity during the past decade. While assignment of female sex to patients with complete AIS and male sex to those with mild forms of AIS may appear self-evident, the decision becomes very difficult in patients with highly ambiguous external genital organs. This is compounded by the fact that the degree of masculinization and penile growth at puberty is, to a large extent, unpredictable. If male assignment is chosen, the infant will need to undergo repair of hypospadias, closure of midline pouch, and placement of testes in the scrotum if possible. High-dose testosterone can sometimes achieve virilization at puberty. Gynecomastia can be corrected, and the gonads can be removed sometime after puberty to prevent the risk of cancer. If female assignment is chosen, gonadectomy in childhood is performed to halt masculinization and to prevent testicular neoplasia. When necessary, the vaginal opening is enlarged, and the clitoris is reduced. Estrogen is administered at puberty. Vaginal bougienage or surgery may be necessary to lengthen the vagina. In complete AIS, gonadectomy is best postponed till after puberty as the testes also produce estrogens that encourage breast development and female body shape at puberty. More recently, it has been suggested that surgery be delayed until adolescence when the patient is capable of choosing his/her sex. It would seem, however, that to achieve successful gender identification, the decision to rear the child as a girl or a boy should be made as soon as possible after birth. Also, it may be very troubling for a child to discover he is morphologically different from other children.
Androgen insensitivity syndrome also poses a difficult ethical issue. Should the diagnosis be revealed to the patient or should it be concealed on the assumption that it will cause permanent emotional distress to the patient? With the advent of modern information technology, it is likely that a young woman who wants to find out why she is not menstruated or has no pubic/axillary hair will get cued as to her condition simply by browsing on the internet. Nor will she content herself with a vague diagnosis of “idiopathic infertility” given by a healthcare professional. Being told the truth in a frank and sensitive way is probably preferable .
Conflict of interest
There is no actual or potential conflict of interest in relation to this article.
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