31.10 Androgen Insensitivity Syndrome (Testicular Feminization Syndrome)

•Clitroplasty

•Vaginoplasty depending on the level of entry of the vaginal opening into the urogenital sinus.

•Labioplasty

31.10Androgen Insensitivity Syndrome (Testicular Feminization Syndrome)

•Androgen insensitivity syndrome affects males.

•There are two types of androgen insensitivity syndrome:

–Complete androgen insensitivity syndrome

–Partial androgen insensitivity syndrome

•Partial androgen insensitivity syndrome results in ambiguous genitalia and there is no consensus whether to raise a child with this syndrome as a male or female.

•Complete androgen insensitivity syndrome causes a genetically male to have an incompletely developed and often blind ended vagina, clitoris and breasts.

•Patients with complete androgen insensitivity syndrome are raised as females.

•Patients with complete androgen insensitivity syndrome do not have a uterus or ovaries and are infertile.

•Syndromes of androgen insensitivity involve a failure of the end organ (external genitalia and prostate) in a 46,XY gonadal male fetus to respond to appropriately produced levels of dihydrotestosterone (DHT), resulting in testicular feminization.

•Currently, the basic pathophysiology of the lack of androgen effect on the genitalia is understood more fully.

–Some patients are receptor-negative; their cytosol receptors cannot bind DHT.

–Another variant is receptor-positive, in which receptors apparently permit DHT binding, but DHT does not lead to normal differentiation toward the male phenotype.

–Assays of genital skin fibroblasts elucidate the difference between receptor-negative and receptor-positive types.

•Inheritance of this syndrome appears to be X-linked.

•Complete androgen insensitivity presents in infancy only if the child has a shallow blind-ending vagina, reflecting the lack of internal müllerian development expected in an XY patient whose testes manufacture MIS at reference range levels.

•Inguinal hernias are common in testicular feminization, and an occasional case is detected during inguinal herniorrhaphy when a gonad is present in the hernia and a fallopian tube cannot be seen (Figs. 31.23, 31.24, 31.25, 31.26, and 31.27).

•Failure to identify an internal müllerian structure in a phenotypic female with an inguinal hernia should always raise the possibility of testicular feminization.

•If not detected in this fashion, diagnosis usually is not made until puberty, when the patient presents with amenorrhea.

•Although these characteristics are not noted early in life, these girls exhibit a body hair deficiency as they age, and their breasts, although well formed, characteristically are deficient in stroma.

•Despite a 46,XY karyotype and gonads with the typical appearance of testes (perhaps altered similarly to those with cryptorchidism), a feminine gender assignment is unquestionable because of the completely feminine phenotype and because end-organ failure prevents endocrinologically produced masculinization.

•Confirmation of the diagnosis is crucial because the syndrome is associated with a significant incidence of gonadal malignancies.

•Malignant tumors are termed germinomas or, more properly, seminomas because the tumors arise in a testis.

–The youngest reported age of occurrence of malignant tumor was 14 years.

–Overall frequency of gonadal malignancies is approximately 6 %, with incidence rising to more than 30 % by age 50 years.

Fig. 31.25 A clinical photograph showing a female patient who was found to have complete androgen insensitivity syndrome at the time of herniotomy. Note the normal looking testis in the hernial sac

–Sertoli cell and Leydig cell tumors have been reported also.

–Tubular cell adenomas, also fairly frequent, have a potential for malignancy because neoplastic transformation has been reported.

•Disagreement exists on the best timing for gonadectomy.

–There are those who advocate delayed gonad removal after puberty.

–Others advocate early gonadectomy because morbidity is minimal in a young child.

•Pubertal changes are induced easily with hormone replacement, a requirement for all patients following gonadectomy.

•Although a vaginoplasty later may be required, many of these girls have an adequate vagina, requiring no therapy or possibly only vaginal dilation.

•Complete androgen insensitivity syndrome:

–This is seen in a 46XY male.

–CAIS occurs at a frequency of 1 in 20,000 to 1 in 64,000 male births.

–It results from failure of the end organ (external genitalia and prostate) to respond appropriately to dihydrotesteterone (DHT).

–There are two subtypes of complete androgen insensitivity syndrome:

•Receptor-negative type: These patients are receptor negative and the main problem is that their cytosol receptors cannot bind DHT.

•Receptor-positive type: These patients are receptor positive but in spite of DHT binding to its receptors it does not lead to normal differentiation of the external genitalia toward the male phenotype.

–This can be diagnosed based on assays of genital skin fibroblasts.

–Complete androgen insensitivity syndrome is inherited as X-linked.

–The gonads are symmetrical and exclusively testicular tissue (seminiferous

Figs. 31.26 and 31.27 Clinical photographs showing a hernia sac containing a normal looking testis in a female patient who was found to have complete androgen insen-

sitivity syndrome at the time of herniotomy. Note the normal looking testis

tubules with no spermatogenesis and increased numbers of Leydig cells).

–The Wolffian ducts develop in half of these cases, while all Müllerian structures regress.

–Phenotypically, patients are normal, tall and hairless females with feminine external genitalia and a very short and shallow utricle.

–At the time of puberty, normal breasts develop due to peripheral conversion of testosterone to estrogen.

–Axillary and pubic hair is absent or scanty, with slight vulval hair development.

–Amenorrhoea is the rule.

–A large number of patients with complete androgen insensitivity syndrome present with inguinal hernias and sometimes the diagnosis is made during inguinal herniorrhaphy when a gonad is present in the hernial sac.

–Failure to identify an internal Müllerian structure in a phenotypic female with an inguinal hernia should always raise the possibility of testicular feminization syndrome (Figs. 31.28, 31.29, 31.30, 31.31, 31.32, 31.33 and 31.34).

–The other presentation of complete androgen insensitivity syndrome is at puberty, when the patient presents with amenorrhea.

–Despite a 46XY karyotype and gonads with the typical appearance of testes, these patients are raised as females because of the completely feminine phenotype.

–It is important to establish the diagnosis in these patients because of the associated risk of gonadal malignancies.

–The diagnosis after puberty can be made by the presence of a male androgen and gonadotrophin profile in a phenotypically female patient.

–A prepubertal diagnosis is more difficult and requires an hCG stimulation test and PCR characterization of the androgenreceptor gene in DNA obtained from a venous blood sample.

–The gonads are at low risk of malignancy because of the cryptorchidism (2 %).

–As the risk starts after puberty a gonadectomy at puberty allows the spontaneous onset of puberty to be followed by estrogen therapy.

–A prepubertal gonadectomy can be done if the condition is causing discomfort or hernia formation, or if the gene mutation has not been characterized, to avoid virilization at the time of puberty.

–Gonadoblastomas are the commonest malignant tumors in these patients.

–Other tumors include: Sertoli cell and Leydig cell tumors and tubular cell adenomas.

–The management of these patients include and early or delayed gonadectomy.

–The timing for gonadectomy is still controversial.

–There are those who recommend gonadectomy after puberty.

–In contrast, others recommend early gonadectomy because morbidity is minimal in a young child. This also avoid the potential risk of loss of some of these patients during follow-ups.

–Hormone replacement is important in these patients at puberty to induce secondary female sexual characteristics.

–These patients may have a small vagina and a vaginoplasty may be required later in life.

–Others have an adequate vagina, requiring no vaginoplasty or possibly only vaginal dilation.

•Partial (incomplete) androgen insensitivity syndrome (PAIS) (Figs. 31.35 and 31.36):

–An incomplete form of androgen insensitivity also occurs.

–In the Partial Androgen Insensitivity Syndrome (PAIS), the genitals can vary from mostly female to almost completely male.

–Some people with PAIS think of themselves as girls/women, others regard themselves as boys/men, and some consider themselves mixed-gender.

–These patients demonstrate a spectrum of external genitalia ranging from:

•Very feminine (Lubs syndrome)

•Increasingly masculine (GilbertDreyfus syndrome)

•Most masculine (Reifenstein syndrome)

–They may present only with micropenis or cliteromegaly and causes a problem with gender assignment.

Figs. 31.32, 31.33, and 31.34 Clinical intraoperative photographs showing a patient with testicular feminizing syndrome with bilateral intraabdominal undescended tes-

tes found at the time of inguinal herniotomy. Note also the bilateral gonadectomy done early for two patients with testicular feminizing syndromes

–A diagnosis of incomplete androgen insensitivity is suggested by elevated LH levels, with reference range levels of plasma DHT and 5-alpha-reductase activity in genital skin fibroblasts.

–Exogenously administered androgens do not cause adequate virilization; therefore, incomplete androgen insensitivity raises little question regarding the preferred sex with which to rear the child.

–Partial androgen insensitivity syndrome results in ambiguous genitalia and there is no consensus regarding whether to raise a child with this form as male or female.

–An early gonadectomy and feminizing genitoplasty are recommended in infancy by some authors.

–In recent years the tendency has been to postpone surgery until the child has expressed a clear gender preference and is old enough to participate actively in decisions about his/her medical treatment.

–Nearly one third of patients develop a dysgerminoma or gonadoblastoma; therefore, gonadectomy becomes important as soon as the diagnosis is recognized.

–The diagnosis of incomplete androgen insensitivity syndrome is suggested by:

•Elevated LH levels.

•Normal levels of plasma DHT.

•Normal 5-alpha–reductase activity in genital skin fibroblasts.

– These patients are managed with (Figs. 31.37 and 31.38):

•Early gonadectomy

•Clitroplasty

•Feminizing genitoplasty

•Hormonal replacement at puberty to induce female secondary sexual characteristics.

•Patients who are assigned as males will require hormonal treatment to virilize their body.

–Mild androgen insensitivity syndrome is also described.

•This is a condition which mildly affects a genetic male’s ability to recognize androgens.

•It is considered a form of androgen insensitivity syndrome and is considered the least severe form.

•While men generally do not need any specialized medical care related to this form, mild androgen insensitivity syndrome may result in gynecomastia and hypospadias.

•Removal of gynecomastia and repair of hypospadias can be performed.

•Men with mild androgen insensitivity syndrome may have reduced fertility.

31.11Deficiency of MIS (Persistent Müllerian Duct Syndrome)

•Persistent Müllerian duct syndrome (PMDS) is also called hernia uterine inguinale.

•It is a rare condition and results from either a complete failure of the testes to produce

Müllerian Inhibiting Hormone or substance (MIH, MIS) or a failure of the Müllerian duct to respond to its secretion.

•This is seen in males with normal 46XY chromosomes.

•Both Wolffian and Müllerian ducts develop.

•These patients have normal external genitalia and usually present with undescended testes or inguinal hernia (Fig. 31.39).

•Isolated MIS deficiency is a rare syndrome and usually does not present in the newborn period because the genitalia appear to be those of a male with undescended testes.

•The most common presentation is a phenotypic male with an inguinal hernia on one side and an impalpable contralateral gonad.

Fig. 31.39 A clinical photograph of a patient with normal looking external genitalia and undescended right testis who was found to have deficiency of MIS

•At the time of herniotomy or orchidopexy, a uterus and fallopian tube is found in the hernial sac (Fig. 31.40).

•A vas deferens is presents bilaterally, usually running close to the uterus.

•To avoid damage to the vas, care must be taken at the time of Müllerian remnants excision.

•Sometimes, the vas deferens ends blindly.

•Abnormalities in the attachment of the epididymis to the testis are also reported.

•Appropriate surgical management attempts to bring the testes into the scrotum based on the rationale that testis tumors may occur later.

•The incidence of malignancy is unknown.

•A primary or staged orchidopexy is all that is required.

•Inguinal hernia should be repaired when present.

•Surgical removal of the Müllerian duct derivatives is controversial, as malignancy in retained Müllerian structures is extremely rare and the potential fertility can be compromised by a surgical attempt to remove the Müllerian derivatives.

•The surgical management includes:

–Orchidopexy. This may necessitates division of the uterus to lengthen the vas.

–A transverse testicular ectopia may be associated with this condition. In this, both testes are found on the same side.

–Excision of Müllerian remnants.

•This is still controversial

•This is not a simple procedure and care should be taken to avoid injury to the vas.

Fig. 31.40 A clinical intraoperative photograph of a patient with persistent Mullerian duct syndrome. Note the presence of a uterus, two fallopian tubes and two testes but no ovaries. This results from deficiency of MIS

FALLOPIAN

TUBES

FALLOPIAN TUBES

•Removal of Müllerian remnants is unnecessary, since the remnants rarely produce symptoms and an extremely rare risk of subsequent malignancy.

31.125-Alpha-Reductase Deficiency

•This is an autosomal recessive condition caused by a mutation of the 5-alpha reductase type 2 gene.

•5-alpha reductase enzyme is important for the conversion of testosterone to dihydrotestesterone (DHT).

Deficiency of MIS (Persistent Müllerian Duct Syndrome)

•The karyotype is 46XY

•Normal male external genitalia

•Results from complete failure of the testes to produce Müllerian Inhibiting Hormone or substance (MIH, MIS) or a failure of the Müllerian duct to respond to its secretion

•Both Wolffian and Müllerian ducts develop.

•Usually present with undescended testes or inguinal hernia

•There is a uterus, two fallopian tubes and two testes with two vas deference but no ovaries

•A transverse testicular ectopia may be associated with this condition where both testes are found on the same side

•The treatment is a primary or staged orchidopexy

•Excision of Müllerian remnants is controversial

•This is seen in males with a 46XY chromosomes.

•These patients have normal testes but lacks the enzyme 5-alpha reductase in the cells of the external genitalia and urogenital sinus.

•The fetus is born with minimally virilized external genitalia (pseudovaginal perineoscrotal hypospadias).

•A 46,XY fetus with normal testes but lacking the enzyme 5-alpha reductase in the cells of the external genitalia and urogenital sinus cannot produce DHT.

•Therefore, the fetus is born with minimally virilized external genitalia (e.g., pseudovaginal perineoscrotal hypospadias), though the fetus usually has a degree of phallic enlargement, reflecting the direct action of testosterone.

•The fetus usually has a degree of phallic enlargement as a result of the direct action of testosterone.

•The striking feature in these patients is the extreme virilization at puberty. This is most likely caused by direct action of testosterone on the phallus. There will be increase in the penile size as well as the muscle mass and a masculine voice.

•The main features that do not develop are the ones depend on DHT (prostatic enlargement, facial hair, acne).

•There is a spectrum of 5-alpha-reductase deficiency which probably accounts for some of the variation in the phenotypes seen.

•These patients are fertile with the ability to have children.

•The diagnosis of 5-alpha-reductase deficiency can be confirmed as follows:

–A patient with a 46XY karyotype.

–A high ratio of serum testosterone to DHT.

5-Alpha-Reductase Deficiency

•An autosomal recessive condition

•Karyotype is 46XY

•Caused by a mutation of the 5-alpha reductase type 2 gene

•They have normal testes but lacks the enzyme 5-alpha reductase

•5-alpha reductase enzyme is important for the conversion of testosterone to dihydrotestosterone (DHT)