INTERSEX: MALE PSEUDOHERMAPHRODITISM I GONADAL
The pseudohermaphrodite is an individual with the gonads of only one sex but with genitalia (internal and external) and secondary sex characters exhibiting sexual ambiguity. Such a simple classiﬁcation of intersex is based purely on phenotype or morphology, without regard to genetic etiology. Factors that contribute to such disordered development include (1) gene mutations, (2) abnormal maternal hormonal inﬂuences, and (3) abnormal hormonal inﬂuences from the embryonic gonad, adrenal, or other endocrine organ. The type and degree of disordered development depend on the intensity and timing of these inﬂuences during embryonic life.
Male pseudohermaphrodites have varying degrees of female internal or external genitalia but have gonads that are testes. Although genetically male, they are often raised as female; the onset of puberty with growth of the penis, hair, and voice change usually precipitates the medical evaluation for intersex. Simple penile hypospadias is a very elementary form of male pseudohermaphroditism. In more severe forms, müllerian structures can develop to various degrees, and in most instances a biﬁd scrotum appearing as labial folds co ceals a rudimentary blind pouch or well-developed vaginal cavity. The testes may lie intraabdominally, within the canal, or may have descended into a biﬁd scrotum. When the sex of the infant is unclear, exploratory surgery and gonadal biopsy to determine gonadal as well as genetic sex is advisable during infancy. Most male pseudohermaphrodites develop emotionally as males during puberty, which has led clinicians to perform gender correction procedures before puberty, including release of penile chordee, construction of a penile urethra, orchiopexy and, in some instances, excision of the vagina, uterus, and fallopian tubes.
Milder forms of male pseudohermaphroditism include Klinefelter syndrome (47,XXY; 48,XXXY and mosaics), Kallmann syndrome (gonadotropin-releasing hormone deﬁciency and anosmia), micropenis, and distal hypospadias. Aphallia is a birth defect in which the penis or clitoris is congenitally absent. It is a rare condition, with fewer than 100 cases reported. Its cause is not entirely clear, but it appears to be due to a failure of the fetal genital tubercle to form between 3 and 6 weeks after conception. Anatomically, the urethra opens on the perineum. Although aphallia can occur in both males and females, it is considered more troublesome in males and engenders controversy about the role of gender reassignment surgery.
There are several forms of gonadal dysgenesis that may also result in male pseudohermaphroditism. The term pure gonadal dysgenesis describes conditions with normal sex chromosomes (e.g., 46,XX or 46,XY), as opposed to gonadal dysgenesis in which the genetic constitution involves missing or truncated sex chromosomes. (e.g., Turner syndrome, 45,X). Mixed gonadal dysgenesis involves a genetic mixture of sex chromosomes (e.g., 46,XY/45,X). In this condition, there is a streak gonad that develops on one side, with a partially developed testis on the opposite side, and it can be associated with ambiguous genitalia. Importantly, streak gonads with Y chromosome–containing cells have a high likelihood of developing cancer, especially gonadoblastoma. In Swyer syndrome, an example of 46,XY pure gonadal dysgenesis, there is atypical formation of both gonads early in gestation. In complete gonadal dysgenesis, the gonads do not function at all, resulting in a female appearance of the external genitalia. In partial gonadal dysgenesis, the testes function, but not at normal levels, resulting in a male with ambiguous genitalia. Because the adrenal glands can make small amounts of androgens and are unaffected, pubic hair develops in most patients, although it often remains sparse. In complete forms such as Swyer syndrome, the diagnosis is often made due to delayed puberty. A karyotype reveals XY, and pelvic imaging demonstrates a uterus (no müllerian inhibiting substance present) but no ovaries (streak gonads are not usually seen). The absence of breasts and the presence of a uterus exclude the possibility of androgen insensitivity.
Another condition, 5-α-reductase deﬁciency (5- ARD), can be observed in phenotypic females with a normal male karyotype. It is characterized by an absence of the enzyme 5-α-reductase, which converts testosterone to dihydrotestosterone (DHT). DHT is the primary androgen needed for the normal development of male external genitalia during development. Without DHT, prenatal genital development results in a female appearance. Individuals with 5-ARD can have normal male external genitalia, ambiguous genitalia, or normal female genitalia. They are born with testicles and wolfﬁan structures but usually have female sex characteristics.
Because of the normal action of müllerian-inhibiting substance produced by the testis in utero, individuals with 5-ARD lack a uterus and fallopian tubes. Consequently, they are often raised as girls and may develop a female gender identity. Because male puberty depends more strongly on testosterone than on DHT, puberty will be virilizing unless the gonads are removed or a blocking medication is used. As a consequence of virilization at puberty, gender identity issues may result in adulthood. Phenotypic girls will also have primary amenorrhea.
Individuals with 5-ARD are generally capable of producing viable sperm. In individuals with feminized or ambiguous genitalia, there is a tendency toward a macroclitoris or microphallus. This structure may be capable of ejaculations as well as erections; however, assisted reproduction is necessary as intercourse may not be possible.