31.15 Ovotestis Disorders of Sexual Development

31.15Ovotestis Disorders

of Sexual Development

•This refers to a rare condition in which the histology of a gonad contains both ovarian and testicular tissues (Figs. 31.41 and 31.42).

•A diagnosis of Ovotestis-DSD is based solely on the presence of ovarian and testicular tissue in the gonad and not on the characteristics of the internal and external genitalia.

•This was formerly known as true hermaphroditism.

•They account for less than 10 % of DSD cases.

•The appearance of the genitalia varies widely in this condition.

•Although ambiguity is the rule, the tendency is toward masculinization.

•Presentation:

–In the neonatal period, these patients usually presents with ambiguous genitalia.

–Although some cases of ovotestis DSD are diagnosed in the newborn period, only 20 % are diagnosed prior to age 5 years.

–Most cases of ovotestis DSD are diagnosed in the pubertal period when the young male begins to experience feminization.

–Inguinal hernia and cryptorchidism are common in these patients.

•The peripheral karyotype is also variable in these patients and include:

–46,XX ovotesticular DSD. This is the most common karyotype, seen in 60–80 % of patients.

–46, XY ovotesticular DSD. This karyotype is found in about 10–15 % of patients.

–46,XX/46,XY peripheral karyotype

•A translocation of the gene coding for HY antigen from a Y chromosome to either an X chromosome or an autosome presumably explains the testicular material in a patient with a 46,XX karyotype.

Fig. 31.42 A clinical intraoperative photograph of a patient with ovotesticular DSD. Note the presence of a fallopian tube and a vas

VAS DEFERENCE

FALLOPIAN

TUBE

•More problematic is how a patient with a 46,XY karyotype can have ovarian tissue, given that two X chromosomes are believed to be necessary to normal ovarian development. Possibly, unidentified XX cell lines are present in these patients.

•The gonads in these patients may be:

–Ovotestis on both sides

–A combination of an ovary on one side and a testis or ovotestis on the other side.

–Ovotestes on both sides are the most frequent gonad present (60 %), followed by the ovary and then the testis (9 %).

–When an ovotestis is present, one third of the patients exhibit bilateral ovotestes.

–A testicle, when present, is more likely to exist on the right (57.4 %), and an ovary, when present, is more commonly seen on the left (62 %).

–A palpable gonad is present in 61 % of patients; of these, 60 % are found to be an ovotestis.

–In 80 % of patients with ovotestes, testicular and ovarian tissues are aligned in an end-to-end fashion, emphasizing the need for a long longitudinal biopsy.

–In 20 % of patients with ovotestes, testicular tissue is found in the hilar region of the gonad, reemphasizing the need for an adequate and deep biopsy.

–An ovary, when found, is situated most commonly in the normal anatomic intraabdominal position, and extremely rare an ovary can be found in the hemiscrotum.

–The least common gonad in ovotesticular DSD is the testis; when present, a testis is found approximately two thirds of the time in the scrotum, emphasizing that normal testicular tissue is most likely to descend fully.

–Ovotestes may present with either a fallopian tube or a vas deferens but usually not with both.

–If a fallopian tube has a fimbriated end, the end is closed in most patients, perhaps contributing to the usual lack of fertility.

–Although fertility is rare in this setting, it has been reported.

–Gonadal tumors also are rare but have been reported.

•The anatomical location of these gonads is variable:

–The ovotestis tends to be anatomically located in:

•A normal ovarian position

•In the labioscrotal fold

•In the inguinal canal

•At the internal inguinal ring

–Ovaries, when found, can occupy the normal abdominal position, although they may occasionally be found at the internal inguinal ring.

•Interestingly, ovaries occur more commonly on the left side than the right.

•The testes are usually found in the scrotum, although they can be found at any level along the path of embryonic descent from abdomen to scrotum, frequently presenting as inguinal hernias.

–Many patients with ovotesticular disorder of sexual development have a uterus.

–Internal duct development usually corresponds to the adjacent gonad so that:

•Müllerian duct structures are usually seen on the gonad side(s) not containing testicular tissue.

•Wolffian duct structures are usually seen on the gonad side(s) containing functioning testicular tissue.

•Ovotestes are usually made up of ovarian part and testicular part with connective tissue between then. This is important surgically when separating the ovarian components from the testicular components. However, on rare occasions, it is difficult to separate the two.

•Most patients with ovotestes DSD are reared as males due to the size of the phallus but male reproductive potential in these individuals is rare.

•This is not the case in those who are assigned a female gender with 46,XX chromosomes who have fertility potential.

•They also have varying degrees of labioscrotal fusion and/or hypospadias which needs correction.

•Most cases of ovotesticular DSDs are diagnosed during the adolescent period and because of functioning normal ovarian tissue, most of them experience breast development

at puberty, and approximately two-thirds of those with a 46,XX peripheral karyotype menstruate.

•Patients with ovotestes DSD are at risk of gonadal tumors which occur in 2.6 % of the cases.

–The testis or testicular part of an ovotestis is likely to be dysgenetic with a risk of developing dysgerminomas, seminomas, gonadoblastomas, and yolk sac carcinomas.

–The risk is more in those with 46,XY karyotype.

–Benign tumors, including mucinous cystadenomas, benign teratomas, and Brenner tumors, have also been reported in these patients.

•Investigations:

–Chromosomal analysis

–Hormonal evaluation

•Serum 17-hydroxyprogesterone:

–Patients with ovotesticular DSD have normal levels of this hormone which differentiate them from those with congenital adrenal hyperplasia.

•Basal and stimulated serum androgens:

–The presence of functional testicular tissue can be determined with the use of a human chorionic gonadotropin (HCG) stimulation test.

–In this test, basal levels of testosterone, dehydroepiandrosterone sulfate, androstenedione, and dihydrotestosterone (DHT) are measured.

–HCG (3,000–5,000 IU/m2/d IM) is then administered for 5 days.

–On the day 6, the serum hormone levels tests are repeated.

–A rise in serum testosterone demonstrates the presence of functioning Leydig cells.

–Elevated testosterone precursors may suggest a specific defect of testosterone synthesis.

–Failure of testosterone to reduce to DHT may suggest a 5-alpha reductase deficiency.

•Basal and stimulated estrogen levels:

–The presence of functional ovarian tissue can be determined with the use

of gonadotropin or clomiphene citrate administration.

–An estradiol response to gonadotropin stimulation is a reliable test to differentiate ovotesticular disorder of sexual development from other disorders.

–Radiological evaluation:

•A scrotal ultrasonography is used to detect occult gonads.

•A genitogram is used to evaluate the structure of the urethra and to confirm the presence of a vagina and uterus (Fig. 31.43).

•An intravenous pyelogram is important to rule out any associated urinary tract anomalies.

•Abdominal and pelvic ultrasonography, CT scan, or MRI are useful in delineating the gonads and duct structures.

•Management:

–The main point in the management of these patient is gender assignment.

–This must take in consideration two main points:

•The potential for normal sexual function

•The potential for future reproductive function

–It is important to establish histological confirmation with a gonadal biopsy which can bedoneviaalaparotomyorLaparoscopically.

–Surgery in these patients should be planned with the previous two goals in mind and conservative gonadal surgery is the procedure of choice.

–Ovotestes frequently can be separated into ovarian and testicular components and partial resection of ovotestes is feasible in a

Fig. 31.43 A genitogram showing a normal looking vagina in a patient with ovotesticular DSD

large number of these patients which should be guided by intraoperative histologic confirmation (Fig. 31.44).

–It allows preservation of gonadal tissue concordant with sex of rearing, and removal of all discordant tissue.

–The ovarian tissue can be preserved in people who are given a female sex assignment. Frequently, these patients demonstrate normal ovarian function and potential for reproduction.

–The aim is to preserve the gonadal tissue that is concordant with sex of rearing, and excision of all other tissue.

–Cystoscopy may be used to determine the position of entry of the vagina into the urethra or urogenital sinus.

–Prophylactic gonadectomy should be considered in those who manifest signs of virilization or are at an increased risk of gonadal malignancy.

–Hormone replacement might be required for those with pubertal delay.

–The following operative procedures are indicated in patients with ovotestes DSD depending on the sex of rearing:

•Excision of intra-abdominal testis or streak gonads in those with Y chromosome-DNA because of increased risk of malignant transformation.

•Excision of wolffian structures and testicular tissue if the patient has been given a female gender assignment.

•Excision of Müllerian structures and ovarian tissue if the patient has been given a male gender assignment.

•Orchiopexy to treat an undescended testis in a patient with male gender assignment.

•Clitoral recession, vaginoplasty, and labioscrotal reduction are necessary for people with ovotesticular DSD who are given a female sex assignment.

•These feminizing procedures should be performed as early as possible as a 1-stage procedure.

•Correction of penile deviation and hypospadias should be done in those given a male gender assignment.

31.16Other Rare Disorders of Sexual Development

17β-Hydroxysteroid dehydrogenase deficiency:

•This condition is characterized by impaired androgen and estrogen synthesis in both males and females.

•The end result is:

–Pseudohermaphroditism/undervirilization in males.

–Excessive virilization of females.

Fig. 31.44 A clinical intraoperative photograph of a patient with ovotesticular DSD. Note the presence of an ovotestis on this side

Aromatase deficiency:

•Aromatase is the enzyme that catalyzes conversion of androgens into estrogens.

•As a result of this enzyme deficiency, there will be androgen excess and estrogen deficiency.

•This results in inappropriate virilization of females.

•They have normal female external genitalia.

•They may have cliteromegaly.

•These female patients can present:

–During childhood and adolescence with cystic ovaries

–At puberty with:

•Primary amenorrhea

•Failure of breast development

•Virilization

•Hypergonadotrophic hypogonadism

•The chromosomal karyotype is 47, XXX.

•It is a common condition affecting 1 in 1,000 females.

•It is a benign condition and generally does not cause health issues or abnormal development.

Aromatase excess syndrome:

•This is also called familial hyperestrogenism.

•In this condition, there is excessive estrogen production.

•It is seen in males and females.

•In males, it will result in feminization without pseudohermaphroditism.

–A normal male external genitalia at birth.

–Female secondary sexual characteristics at puberty.

•In females, it will lead to hyperfeminization.

Klinefelter syndrome:

•This condition is seen in males born with at least one extra female chromosome.

•It is also called XXY syndrome.

•The chromosomal karyotype is 47, XXY.

•Though the most common chromosomal variation is 47, XXY, other variations may also be 48, XXXY or 49, XXXXY.

•It is a common occurrence, affecting 1 in 500 to 1,000 men.

•While some men may have no issues related to the syndrome, others may experience:

–Gynecomastia

–Micropenis

–Cognitive difficulties

–Hypogonadism

–Reduced fertility/infertility

–Little or no facial hair.

•Testosterone therapy may be pursued by men who desire a more masculine appearance and those with gynecomastia may opt to undergo a reduction mammoplasty.

•Men who wish to father children may be able to do so with the help of IVF.

Triple X syndrome:

•A condition that occurs in a female born with an extra female chromosome.

Aphallia:

•This is a rare congenital condition where a male is born without a penis or where a female is born without a clitoris.

•It should not be confused with intentional or accidental amputation of the genitalia.

Aposthia:

•A congenital defect where a male is born without a foreskin.

Diphallia:

•This is also known as penile duplication, diphallic terata, and diphallasparatus.

•This is extremely rare.

•It is characterized by a male born with two penises.

•The penises may be side by side or one on top of the other.

•The penises may be of equal size or with one penis being distinctively larger than the other.

•Both penises may be suitable for urination and intercourse.

•Men with diphallia may be sterile.

Micropenis:

•This is also known as microphallus.

•It is defined as a penis that measures 3 in. (7.62 cm) or less in length when erect.

•It is a common condition, occurring in 1 in 200 men.

•Micropenis may be the result of undervirilization during fetal development or may be caused by an underlying intersex condition, such as mild androgen insensitivity syndrome, partial androgen insensitivity syndrome, or Klinefelter syndrome.

•It may also be considered a natural variation of penis size.

Fig. 31.45 A genitogram showing a double vagina

•While the majority of men have no issues with having a micropenis, some may opt to use a prosthetic penis or undergo penile enlargement to increase the size of their penis.

Uterus didelphys:

•This is also known as double uterus.

•It is seen in a female born with two uteri.

•It is often accompanied by two vaginas (Fig. 31.45).

•This is a benign condition and females with uterus didelphys usually have normal sex lives and pregnancies.

Bilateral vanishing testes:

•‘Bilateral vanishing testes’ implies absent gonads that could be due to mutation, exposure to a teratogen, or bilateral torsion (Figs. 31.46 and 31.47).

•The karyotype is typically 46,XY.

•The phenotype shows a male with undescended testes.

•Laparoscopy can detect rudimentary cord structures with no recognizable testicular tissue histologically.

•These patients will require androgen replacement and testicular prostheses.

•Embryonic testicular regression syndrome is a variant of bilateral vanishing testes in which the testicular function is lost early in embryonic life. This results in individuals with ambiguous genitalia.

ATROPHIC

TESTIS

ATROPHIC

TESTIS

ATROPHIC

TESTIS

Figs. 31.46 and 31.47 Clinical intraoperative photographs showing unilateral and bilateral atrophic testes. These are usually secondary to intrauterine torsion of testes. Note the presence of a vas

Fig. 31.48 A clinical photograph showing cliteromegaly. Note the normal external genitalia

Clitoromegaly:

•A clitoris that is considered larger than average (Fig. 31.48).