46,XX Dsd (Female Pseudohermaphrodites)
46,XX disorders of sex development (DSD) are characterized by a 46,XX genotype, nonpalpable gonads or normal ovaries, and variable degrees of virilization of the external genitalia.
Congenital Adrenal Hyperplasia
CAH is the most common cause of female ambiguous genitalia or pseudohermaphroditism and accounts for approximately 70% of all patients with ambiguous genitalia. CAH accounts for >95% of the cases of female pseudohermaphroditism, with exposure to maternal androgens accounting for the remaining 5%. Mutations in one of five genes result in impaired cortisol secretion, which in turn causes excess secretion of adrenocorticotropic hormone (ACTH) and consequently adrenal hyperplasia (Speiser, 2007). Four of the five genes code for enzymes necessary for steroid hormone synthesis, and the fifth encodes for an intracellular cholesterol transport protein (StAR) (Figure 43–9). Deficiencies in 21α-hydroxylase and 11β-hydroxylase result in masculinization of the female fetus, while they have no effects on the genitalia of the male fetuses. In contrast, infants with deficiencies in 3β-hydroxysteroid dehydrogenase, 17α-hydroxylase, and StAR have defects in both the synthesis of cortisol and steroid hormones. Affected males have varying degree of ambiguous genitalia due to deficiency in testosterone synthesis, while affected females may or may not be virilized.
21α-Hydroxylase deficiency is the most common cause of CAH, accounting for 90% of cases. The metabolites 17-hydroxyprogesterone and 17-hydroxypregnelone, which build up above the 21α-hydroxylase deficiency, are metabolized to androgens, resulting in virilization of the female external genitalia. Three forms of 21α-hydroxylase deficiency exist: classic, simple virilizing, and nonclassic. Each of these disorders is characterized by the activity level of the gene. Patients with the classic disease have both virilization and salt wasting, those with simple virilizing have masculinization without salt losing, and the nonclassic patients present after puberty with virilization.
In general, the classic form of 21α-hydroxylase deficiency exhibits the more severe forms of virilization (Figure 43–13). Impaired cortisol and aldosterone secretion leads to electrolytes and fluid losses, producing hyponatremia, hyperkalemia, acidosis, increased plasma renin, dehydration, and eventual vascular collapse unless recognized and treated. In affected males, deficiency in 21α-hydroxylase does not result in abnormal genitalia, and consequently, salt loss may occur unnoticed. Aggressive fluid resuscitation with normal saline should be instituted immediately and repeat serum electrolyte measurement should be obtained to monitor the progress of the resuscitation. Diagnosis is based on an elevated level of 17-hydroxyprogesterone in the urine and blood. After diagnosis and stabilization, replacement therapy should be instituted with glucocorticoids, mineralocorticoids, and salt. Regular measurement of serum electrolytes, renin, and ACTH helps to monitor the adequacy of hormonal replacement. Untreated patients with 21α-hydroxylase deficiency exhibit excessive growth, virilization, advanced bone age, and early closure of epiphyseal growth plates (Hughes, 2007).
Patient with severe masculinization from congenital adrenal hyperplasia.
11β-Hydroxylase deficiency accounts for most of the remaining cases of CAH (approximately 9%). Patients with 11β-hydroxylase accumulate 17-hydroxyprogesterone as well as DOC and 11-deoxycortisol, which results in salt accumulation leading to hypertension. Patients with 11β-hydroxylase deficiency are more likely to present with hypertension secondary to the salt-retaining metabolites DOC and 11-deoxycortisol, in contrast to the hypovolemic shock associated with 21α-hydroxylase deficiency. Hypokalemia is also common secondary to an increase in mineralocorticoid activity.
Since CAH is hereditary, it is possible to counsel and offer treatment to families wishing further children. Maternal treatment with dexamethasone prior to the 10th week of gestation can significantly reduce the risk of masculinization of the female fetus (Miller, 1998). Standard prenatal treatment is 20 mg/kg two times daily beginning as soon as the pregnancy is confirmed (5th week of gestation) in a family with a positive history of CAH. At 9–10 weeks' gestation, chorionic villus sampling can confirm karyotype and test for the presence of the gene CYP 21, which is present in 21α-hydroxylase deficiency (90% of CAH cases). If the karyotype is XY or the CAH gene CYP 21 is not present, the maternal dexamethasone treatment is stopped. Statistically, 50% of the fetuses will be male, and of the females, only 25% will be affected secondary to the recessive inheritance pattern of 21α-hydroxylase deficiency. Unfortunately, this will result in unnecessary prenatal steroid exposure in seven of eight fetuses with unknown long-term health consequences, such as hypertension. Although the short-term success of decreasing female virilization has been documented, long-term follow-up of fetuses exposed to steroids needs to be documented.
Maternal Hormonal Sources of Virilization
Maternal tumors are a rare cause of virilization of the female fetus. The most common type are luteomas of the ovary, which also virilize the mother. Diagnosis can be made by maternal blood samples and imaging studies (sonogram and magnetic resonance imaging). Maternal ingestion of medication is another rare cause of abnormalities in genital development (Table 43–6). Progesterone is a common agent being used early in pregnancy to prevent abortions as well as during in vitro fertilization treatments.
Table 43–6. Drugs that May Induce Disorder of Sex Development If Taken during Pregnancy.
The female fetus that is exposed to high concentrations of progesterone can virilize secondary to direct action of progesterone on the AR. In the male fetus, hypospadias can develop by progesterone-inhibiting testosterone synthesis and downregulating the AR. A prenatal history of progesterone exposure should be elicited in the differential diagnosis of patients with abnormalities of the external genitalia.
46,Xy Dsd (Male Pseudohermaphrodites)
46,XY DSD are characterized by a 46,XY genotype, normal testes (usual palpable), and partial or complete masculinization of the external genitalia. The differential diagnosis is outlined in Figure 43–14.
Differential diagnosis of patients with male pseudohermaphroditism. 17α-D, 17(α)-hydroxylase; DHEA, dehydroepiandrosterone; GU, genitourinary; hCG, human chorionic gonadotropin; HSD, hydroxy-steroid dehydrogenase; LH, luteinizing hormone; StAR, steroidogenic acute regulatory protein; T/DHT, testosterone/dihydrotestosterone.
Two forms of androgen resistance related to male pseudohermaphrodites are complete androgen insensitivity and partial androgen insensitivity.
Complete Androgen Insensitivity
Androgen resistance ranges from partial to complete due to a defect in the AR. Patients with complete androgen resistance or androgen insensitivity syndrome (AIS) (previously called testicular feminization) have a 46,XY karyotype but have unambiguous female external genitalia, hypoplastic labia majora, a blind vaginal pouch, and an absent uterus (Wisniewski et al, 2000). Since a functional AR is necessary for the development of axillary and pubic hair, complete AIS patients have sparse to nonexistent hair growth in these areas. Complete AIS patients either inherit the disease by an X-linked recessive pattern or develop a spontaneous mutation that renders the AR nonfunctional. Patients with complete AIS appear to identify as females. Presumably, the functional defect in the AR also exists in the brain, preventing “masculinization.” There is not enough long-term follow-up to assess issues with sexual identity in these patients.
Complete androgen resistance should be suspected in phenotypic females who present with an inguinal hernia that contains a testis (approximately 1% of all prepubertal females undergoing hernia repair) (Oakes et al, 2008). The most common presentation for complete AIS is amenorrhea in adolescent females. Breast development occurs in AIS patients secondary to the peripheral conversion of testosterone to estradiol from aromatase enzyme. After puberty, the testes have approximately a 10% risk of developing cancer, the most common tumor being a seminomatous germ cell. Because of the significantly increased cancer risk, removal of the gonads is recommended after postpubertal breast development. Alternatively, the gonads can be removed at the time of diagnosis, with estrogen replacement therapy initiated in the pubertal time period. Since the vagina may be inadequate in length, some patients may need augmentation procedures. Self-vaginal dilation is the most common technique, followed by vaginal augmentation procedures using skin grafts or bowel.
Partial Androgen Insensitivity
In contrast to complete AIS, patients with partial androgen resistance may have external genitalia ranging from mild to severe hypospadias (with or without cryptorchidism) to micropenis or clitorimegaly with partial labial fusion (Figure 43–15) (Griffin et al, 1995). The testes may be located in the labia, inguinal canal, or abdomen. The testes are histologically normal before puberty. However, after puberty, spermatogenesis is usually absent and there is Leydig cell hyperplasia. The testes are predisposed to malignant transformation in 4–9% of the patients (Fallat and Donahoe, 2006).
Partial androgen receptor defect resulting in severe hypospadias with curvature (A) and a small phallus (B).
The defect in partial androgen resistance is typically due to a single base pair mutation in the AR. Inheritance may be X-linked, autosomal recessive, or from a spontaneous mutation. Interestingly, the same genetic defect within a family may have a different phenotypic expression. The variability of phenotypic expression makes counseling difficult in affected families.
In patients with partial androgen resistance, the sex of rearing depends on the degree of androgen resistance and the degree of genital ambiguity. In patients who respond to high-dose androgen therapy (2 mg/kg initially followed by 4 mg/kg) with phallic growth, the sex of rearing as male has been successful. Genital reconstruction repairing the hypospadias and undescended testes is performed at an early age. Patients who have a poor response to androgen stimulation fall into a difficult category of intersex. In the past, patients who were raised as females had feminizing genital surgery and gonadectomy typically in the first year of life. At the time of puberty, estrogen replacement is instituted. Presumably in partial androgen insensitivity, sexual identity is influenced by the effects of androgens on central imprinting. A discord may exist between the external genitalia that partially responds to androgen stimulation and the effects of androgens on determining sexual identity in the brain (Zucker, 2003). The fact that some patients with severe hypospadias and a small phallus have had difficulty with sexual identity in adulthood makes sex assignment difficult. Presently, it seems reasonable to delay irreversible surgery until after the patient has developed a sexual identity and can drive the decision for reconstructive surgery.
5a-Reductase Type 2 Deficiency
5α-Reductase type 2 deficiency is an autosomal recessive transmitted disorder affecting the formation of the male genitalia (Wilson et al, 1993). 5α-Reductase is responsible for the conversion of the less potent testosterone to the five to ten times more potent DHT. Type 2 5α-reductase predominates in the tissue of the external genitalia and the prostate, whereas type 1 5α-reductase localizes to the skin and nongenital tissues. Numerous mutations have been described in the 5α-reductase type 2 gene consistent with the variation in clinical spectrum seen in patients with this defect. Immunohistochemical localization of 5α-reductase type 2 reveals that the enzyme is located in the midline urethral seam (Figure 43–16) (Kim et al, 2002). The midline seam localization is consistent with the formation of hypospadias in patients with 5a-reductase type 2 gene defects in that the epithelial edges of the urethral seam would fail to fuse, resulting in hypospadias.
Immunohistochemical localization of 5α-reductase type 2 (A–D) and the androgen receptor (AR) (E–H) in the same human fetal penis at 16.5 weeks of gestation (reduced from 25×). Note the strong expression of 5α-reductase type 2 along the urethral seam area (arrows).
Clinically, patients with 5α-reductase type 2 present with a small phallus, severe hypospadias, bifid scrotum, and a residual prostatic utricle or blind-ending vaginal pouch (Figure 43–17). The testes are often undescended in the inguinal canal. Untreated patients will typically virilize during puberty when elevated levels of the less potent testosterone either overwhelm the functioning androgen gene or the functioning 5α-reductase type 1 enzyme cross-reacts with the excess testosterone, converting it to DHT.
A patient with 5α-reductase type 2 deficiency. Note severe hypospadias with a small phallus, bifid scrotum, and visible prostatic utricle or blind-ending vaginal pouch.
Sexual identity appears to be intact for karyotype XY males with 5α-reductase type 2 deficiency, presumably from an intact masculinization of the brain. In specific geographic areas such as the Dominican Republic, where the incidence of 5α-reductase type 2 deficiency is relatively high, it is generally accepted that these children will change from an initial “in-between” sex to a male sexual identity at the time of puberty.
The diagnosis of 5α-reductase type 2 deficiency should be considered in severe phenotypes of hypospadias, especially with associated scrotal anomalies and undescended testes. Diagnosis is based on an increase in ratio of testosterone to DHT. Since these patients have a small phallus, attempts at enlargement with DHT cream are reasonable, although DHT is difficult to obtain in the United States. Reconstructive surgery for the hypospadias and undescended testes is indicated. Fertility has not been reported in patients with 5α-reductase type 2, although sperm production has been documented.
Persistent MüLlerian Duct Syndrome
Müllerian-inhibiting substance or factor (anti-Müllerian duct hormone) causes regression of the structures that would have formed the uterus, fallopian tube, and upper part of the vagina. Defects in the MIS gene or MIS receptor result in retained Müllerian structures typically inherited as an autosomal recessive defect. Male siblings of affected patients, especially with cryptorchidism, should undergo screening; they have a 25% chance of being affected (Rey et al, 1999).
Clinically, patients with persistent Müllerian duct syndrome present, unexpectedly, at the time of surgery for cryptorchidism (Figure 43–18). Hence, the alternate name for persistent Müllerian duct syndrome is hernia uterine inguinale. Within the hernia sac, a fallopian tube, uterus, or both are found attached to the testicular cord structures. What makes the treatment difficult is that these structures and hence the diagnosis are found unexpectedly at the time of surgery for cryptorchidism. If persistent Müllerian duct structures are found during orchiopexy, it is reasonable to abort the procedure until a correct diagnosis can be determined. At the initial exploration, a clear description of gonad and surrounding Müllerian structures should be documented, with a biopsy specimen of the gonad taken and a karyotype obtained.
Hernia uterine inguinale or persistent Müllerian duct syndrome. Note the presence of a fallopian tube (black arrow) and uterus attached (white arrow) to the testicular cord structures.
Once a definitive diagnosis is made, reconstructive surgery can then be performed. Separation of inappropriate Müllerian structures from the cord without disturbing the vas deferens, the testicular artery, or both is the goal; however, this may be impossible if the vas runs through the Müllerian structures, which is a common outcome. Fertility is usually impaired in patients with persistent Müllerian duct syndrome even though testosterone levels may be normal. Whether this is a consequence of primary gonadal dysfunction or secondary to the cryptorchid testes is controversial. Efforts should be made to remove the Müllerian structures and deliver the testes into the scrotum or at least a palpable position in the groin for subsequent cancer surveillance. Testes cancer has been reported in 2–10% of patients. In patients where the testes remains in the abdomen or cannot be separated from the Müllerian structures, orchiectomy is indicated.
Abnormal Gonadal Function Syndromes
45,X Dsd (Turner's Syndrome)
Turner's syndrome is relatively common, occurring in 1 in every 2000 female births. The genotype in patients with Turner's syndrome is a complete or mosaic X monosomy, 45,X, or 45,X/46,XX) (Loscalzo, 2008). Turner stigmata consist of a web neck, shield chest, aortic valve defects, coarctation of the aorta, horseshoe kidney, short stature, and absent puberty. During fetal development in patients with Turner's syndrome, the ovaries develop but subsequently degenerate to streak gonads. The streak gonads are not at risk for cancer (unless Y chromatin material is present) and therefore do not need to be removed. Therapy is directed toward growth augmentation with growth hormone therapy in childhood. Subsequently, estrogen replacement is begun in late adolescence so as not to interfere with maximum growth.
46,XX Dsd Complete Gonadal Dysgenesis
Patients with 46,XX complete gonadal dysgenesis are typically diagnosed following a workup for delayed puberty or primary amenorrhea. Patients have a normal female phenotype without the stigmata of Turner's syndrome, normal external and internal Müllerian structures, and bilateral streak gonads. Sexual identity is female. Unlike patients with 46,XY gonadal dysgenesis, risk of tumor formation is rare and treatment is directed at hormonal replacement, with removal of the streaks gonads unnecessary.
46,Xy Dsd Gonadal Dysgenesis (Swyer's Syndrome)
Patients with 46,XY gonadal dysgenesis are characterized by absent testicular function in the presence of a Y chromosome. Classically, patients with 46,XY gonadal dysgenesis have a female phenotype. Patients come to medical attention if the prenatal karyotype (XY) is discordant with the child's phenotype (female), delayed puberty, amenorrhea, or precocious puberty from a hormonally functional gonadal tumor. The incidence of gonadal tumors is as high as 60%, with gonadoblastoma being the most common, although dysgerminomas, seminomas, and nonseminomatous germ cell tumors have also been reported.
In pure XY gonadal dysgenesis, Müllerian duct structures usually are present secondary to failure of MIS secretion, and Wolffian duct structures are vestigial or absent secondary to lack of testosterone secretion. Laboratory analysis reveals female levels of baseline testosterone with no increase in response to hCG stimulation. Surgical exploration reveals streak gonads, fallopian tubes, and a uterus. With a 60% chance of tumor, the gonads need to be removed once the diagnosis is confirmed. These patients should be raised as females with estrogen replacement at the time of puberty.
45,X/46,Xy Dsd (Mixed Gonadal Dysgenesis)
Patients with mixed gonadal dysgenesis usually have a 45,X/46,XY, 46,XY, or other mosaic karyotype. They typically have one streak and one dysgenetic testis. Most children with mixed gonadal dysgenesis have incomplete virilization resulting in ambiguous genitalia or hypospadias with cryptorchidism. The other classic presentation is a mosaic genotype diagnosed on prenatal amniocentesis (Chang et al, 1990). Interestingly, the subsequent phenotype of patients with a prenatal karyotype of 45,X/46,XY is 90% normal male external genitalia. However, with a prenatal genotype of 45,X/46,XY, the patient is at risk for progressive gonadal changes leading to fibrosis and decreased fertility and low testosterone levels. The incidence of gonadal tumors does not seem to be increased. Most notably, 20% of these children have mental retardation or autism.
In patients who present with ambiguous genitalia, one gonad is typically palpable in the scrotum or inguinal canal and the other gonad (streak) is nonpalpable. The phallus size is typically small with a proximal or more severe hypospadias (Figure 43–19). Testosterone levels are normal with an appropriate response to hCG. MIS levels are usually normal. At surgery, the dysgenetic gonad (streak) may grossly appear normal but have microscopic abnormalities such as hypoplastic tubules surrounded by ovarian or fibrotic stroma. Variable Müllerian duct structures, such as fallopian tubes and uterus, are present depending on the degree of gonadal dysgenesis. On biopsy, the contralateral gonad in the scrotum or inguinal canal is either a normal or dysgenetic testis. In patients with mixed gonadal dysgenesis, the risk of gonadoblastoma is 15–30% (Levin, 2000). Gonadoblastoma is a steroid hormone–secreting gonadal tumor composed of large germ cells, Sertoli cells, and stromal derivatives. The incidence of gonadoblastoma appears to be higher in more undervirilized patients and the most common associated karyotype is 46,XY. Sixty percent of gonadoblastomas arise in an indeterminate gonad, 22% in streak gonads, and 18% in dysgenetic cryptorchid testis. Two cases occurring in a testis located in the scrotum have been reported. One-third of the patients have bilateral disease. Sixty percent of gonadoblastomas are associated with subsequent malignant germ cell tumor (germinoma, seminoma, and dysgerminoma but also embryonal teratoma, embryonal carcinoma, endodermal sinus tumor, or choriocarcinoma). Metastases develop in 10% of patients with germinomas arising within the gonadoblastoma.
Presentation of mixed gonadal dysgenesis with ambiguous genitalia and a unilateral palpable gonad on the right side.
In children who are undervirilized, female sex assignment is an option, and the streak and dysgenetic gonads should be removed at the time of diagnosis due to increased risk of malignancy. Hormonal replacement with estrogen will be necessary during adolescence. If male gender is assigned, management of the scrotal testis is controversial, ranging from serial observation to surveillance biopsy. In the virilized patients who are raised as males, the testis will inevitably reveal poor hormonal and fertility potential (Woodhouse, 2001). These patients will require testosterone supplementation in adulthood (Birnbacher et al, 1999).
In 5% of patients, mixed gonadal dysgenesis is associated with Wilms' tumor, ambiguous genitalia, and progressive glomerulopathy known as the Denys-Drash syndrome. Wilms' tumor occurs in the first 2 years of life and is often bilateral. Classic presentation is an infant with ambiguous genitalia, hypertension, and nephrotic syndrome.
17b-Hydroxysteroid Dehydrogenase Deficiency
Patients with a defect in the enzyme 17β-hydroxysteroid dehydrogenase do not efficiently convert androstenedione to testosterone. 17β-Hydroxysteroid dehydrogenase is predominantly located in the testes. The rare disorder of 17β-hydroxysteroid dehydrogenase deficiency is inherited via an autosomal recessive pattern. This disorder is indigenous to the Arab population of the Gaza strip in the Middle East. Clinical presentation in a patient with XY genotype is mild virilization of the external genitalia, with clitoral hypertrophy, and a blind-ending utricle (vagina). The testes are undescended in the abdomen or inguinal canal or descended into the labioscrotal folds. If the virilization is mild, the diagnosis becomes apparent at puberty, with penile growth and male secondary sexual characteristics. At puberty, the increased levels of androstenedione are converted by nongenital, nonmutant 17α-hydroxysteroid dehydrogenase to testosterone. These patients may also present with gynecomastia at puberty by the peripheral conversion of androstenedione to estradiol by aromatase. Diagnosis is based on an increased ratio of androstenedione to testosterone postpubertal or in the prepubertal state in response to an hCG-stimulation test.
If the diagnosis is suspected in infancy, treatment with testosterone, reconstruction of the hypospadias, and male sex assignment are indicated. At puberty in the Gaza strip, gender conversion from female to male is common practice. Long-term outcomes of patients raised as females initially and reassigned to males at puberty await documentation.
Ovotesticular Dsd (True Hermaphroditism)
True hermaphroditism is defined as the presence of both ovarian and testicular tissue within the same individual (Figure 43–20). The most common karyotype in patients with true hermaphroditism is 46,XX (predominately in African Americans), followed by 46,XY/46,XX mosaicism. The latter karyotype in a patient with ambiguous genitalia strongly suggests the diagnosis of true hermaphroditism. Only 7% of patients with this disorder have a 46,XY karyotype. Interestingly, not all true hermaphrodites express the SRY gene, suggesting that non-SRY genes play a role in the development of the testes in these patients.
Finding at the time of surgical exploration in a true hermaphrodite. On the patient's right side, note the testes, and on the left, note the fallopian tube, uterus, and biopsy-proven ovary.
In patients with true hermaphroditism, the gonads are a combination of ovotestis, ovaries, or testis. The most common configuration is ovotestis/ovary in 35%, followed by bilateral ovotestis in 25%, ovary/testes in 25%, and ovotestis/testes in the remaining 15%. One or both gonads are palpable in at least 60% of the patients. For unexplained reasons, the testis is more likely to be found on the right side. The testis and ovaries are located in their respective normal position, and the level of descent of the ovotestis is dependent on the amount of testicular tissue. While ovarian histology and function may be normal, testicular histology and function is usually abnormal. Ovotestis can be bilobar in configuration, with the ovarian and testicular tissue relatively separate, or the ovarian and testicular tissue may be intermingled and difficult to surgically separate. At the time of diagnosis, deep biopsies are necessary to determine the histologic status of the gonad. The internal structures tend to correlate with the type of gonad. Approximately 80% of true hermaphrodites will have a functional or rudimentary uterus. The uterus may be found in the abdomen or associated with an inguinal hernia. In patients with normal uterine structures and ovarian histology, fertility and normal pregnancies have been reported.
The external genitalia are usually ambiguous, although 60% of patients are masculinized, with a well-developed hypospadiac phallus. The hypospadias can be severe perineal or penile scrotal with incomplete fusion of the labioscrotal folds. The degree of masculinization is dependent on the amount of functional testicular tissue present. In childhood, testicular tissue has been documented to have normal spermatogonia. With maturation, however, testicular fibrosis occurs, with fertility in males a rare event. Testicular tumor is uncommon, occurring only in 1–2% of the patients.
The diagnosis of true hermaphroditism should be suspected in patients with virilized ambiguous genitalia who have a 46,XX (African American) or mosaic genotype 46,XX/46,XY associated with the finding of Müllerian structures. Diagnosis is confirmed by gonadal biopsy confirming the presence of both ovarian and testicular tissue. After a decision regarding sex gender assignment has been made, gonadal tissue inappropriate for sex gender assignment should be removed. In patients who are raised as females, removal of all functioning testicular tissue is critical to prevent virilization at puberty. Surgical correction of the urogenital sinus to expose the vagina is necessary. In patients raised as males—who account for approximately 30% of all true hermaphrodites—the hypospadias and undescended testes should be reconstructed. In males, since testicular failure is common at puberty, testosterone supplementation may be required.
Unclassified Forms of Abnormal Sexual Development
Hypospadias except in the most severe situation is not a form of DSD (intersex) (Figure 43–21) (Baskin and Ebbers, 2006). The etiology can be defined in less than 5% of patients. This leaves most cases without a defined etiology. The variable expression of the AR in the ventral versus the dorsal urethra may play a role in the etiology of hypospadias (Figure 43–22) (Baskin et al, 1998; Kim et al, 2002). Recent theories suggest an abnormality in closure of the midline urethral seam. Another possible etiology explaining the increase in incidence of hypospadias in western countries over the last 25 years is an increase in exposure to environmental endocrine disruptors (Baskin et al, 2001).
The spectrum of hypospadias, which is not an ambiguous or intersex condition. A: Anterior, where the meatus is on the inferior surface of the glans penis. B: Coronal, where the meatus is in the balanopenile furrow. C: Distal, on the distal third of the shaft. D: Penoscrotal, at the base of the shaft in front of the scrotum. E: Scrotal, on the scrotum or between the genital swellings. F: Perineal, where the meatus is behind the scrotum or genital swellings.
Androgen receptor (AR) expression in the human fetal penis at 16.5 weeks. A greater density of AR-positive cells is seen in the ventral portion of the urethral epithelium in the distal glans (A), midglans (B), and proximal glans (C). In the distal (E), mid (F), and proximal (G) shaft of the penis, all portions of the urethral epithelium show the same density of expression. Three-dimensional reconstruction was performed to demonstrate the urethral AR expression pattern (D). Note the weaker density of AR in the dorsal aspect of the glanular urethra.
In controlled studies, most patients with hypospadias undergo successful surgical reconstruction and have acceptable long-term outcomes. Patients with hypospadias have an unambiguous male sexual identity. In severe forms of hypospadias with perineal or scrotal urethral openings, severe curvature and the phallus buried within the scrotum are the critical issues confirming the correct diagnosis. This is also the case for patients with hypospadias and a nonpalpable or undescended testis. If any doubt exists, patients with severe hypospadias, hypospadias in association with an undescended testis, or both, a karyotype should be checked to document genotype (McAleer and Kaplan, 2001). In severe cases of hypospadias where penile size is difficult to assess secondary to severe chordee, an hCG stimulation will assess the gonadal axis and confirm an intact AR by eliciting penile growth.
A penis less than 2.5 cm in stretched penile length without hypospadias in a full-term male is defined as micropenis (Figure 43–23 and Table 43–4). Micropenis can be caused by multiple etiologies, the most common being fetal testosterone deficiency followed by partial defects in the AR or 5α-reductase enzyme (Table 43–7). Fetal testosterone synthesis can be divided into two categories: (1) primary testicular failure (Leydig cell) and (2) central failure. Central failure can be from congenital hypopituitarism or isolated gonadotropin deficiency. Patients with decreased fetal testosterone production either from (Fallat and Donahoe, 2006) Leydig cell failure or lack of Leydig cell stimulation from gonadotropin deficiency respond to treatment with supplementary testosterone enanthate intramuscular injections 25–50 mg each month for 3 consecutive months.
Micropenis. Normal corporeal bodies are palpable within the foreskin. The urethral meatus is at a terminal position within the glans. Stretched penile length is <2.5 cm in this full-term infant.
Table 43–7. Etiologies of Micropenis. ||Download (.pdf)
Table 43–7. Etiologies of Micropenis.
Deficient testosterone secretion
Primary hypogonadism (“Bum Gonads”)
Gonadal dysgenesis (partial)
LH receptor defects (partial)
Testosterone synthesis defects (partial)
Defects in testosterone action
Androgen receptor defects (partial)
Growth hormone/insulin growth factor-1 deficiency
Fetal hydantoin syndrome
Long-term outcomes of patients with micropenis have documented that final adult penile length is normal for >90% of patients treated with multiple short courses of testosterone enanthate. In addition, patients with micropenis identified with the male gender had normal erections, ejaculation, and orgasm. In rare patient who does not respond to testosterone stimulation, gender conversion to female had been advocated in the past. Presently, gender conversion would not be considered based solely on the small phallus size.
Reassignment to the female gender with removal of the gonads and feminizing genitoplasty in patients with penile agenesis, iatrogenic penile amputation, or circumcision injury had been standard treatment. In complete penile agenesis, the testicles are normal, corporeal bodies are absent, and the urethra opens into the anterior rectum or perineum. These patients have normal prenatal androgen levels, and hence, the brain has received signals for male gender identity (Wisniewski et al, 2001). The same is true for the rare patient who has a severe penile injury during circumcision. As in micropenis, gender conversion would now not be considered based solely on the absence or small size of the phallus. Penile reconstruction, although not technically ideal, may provide the best overall outcome.
Cloacal and Exstrophy Anomalies
In the past, patients with the most severe and rare form of lower abdominal congenital malformation, cloacal exstrophy (incidence of 1 in 200,000 live births), were usually left to die. Significant problems associated with surgical reconstruction of cloacal exstrophy include omphalocele; numerous gastrointestinal anomalies such as short gut, malrotation, duplication, duodenal atresia, and Meckel's diverticulum; and significant genitourinary anomalies such as separate bladder halves, upper-tract renal anomalies, and bifid genitalia. Patients with cloacal exstrophy can also have neurologic and orthopedic anomalies such as tethered cord, myelomeningocele, lower extremity paralysis, club-foot, and hip dislocation.
Historically, newborn males with cloacal exstrophy (Figure 43–24) were often gender converted to female as a result of inadequate genital development and the poor prognosis for surgically developing a normal male phenotype. In rearing genetic males as females, although the surgical reconstruction can match the assigned female phenotype, a new set of issues was created, such as the need for hormonal replacement with estrogen during adolescence and the issue of a nonmenstruating infertile female. In addition, the fetal and neonatal androgen imprinting on the brain does not seem to be reversible.
A: Male with cloacal exstrophy. B: Female with cloacal exstrophy. In the male, note the split scrotal appearance and the small hemiphallus (arrow). In the female, the clitoral bodies/genitalia are not visible.
Because some of these XY, gender-converted females have self-reassigned their sex during adolescence to coincide with their genetic karyotype, there has been reevaluation of the practice of rearing genetic males as females. With the exact determinates of sexual identity not completely defined, a pragmatic approach is to delay any irreversible surgery such as orchiectomy or phallic removal/reduction in these patients. With modern surgical techniques and a multidisciplinary approach to their care, children with this complex disorder can have a normal sexual identity.