Abnormalities Of Male Sexual Differentiation And Development
An undescended testis (cryptorchidism) is the most common genital abnormality seen in male newborn infants. It occurs in 3% of babies. Either one or both testes may be involved. Cryptorchidism occurs when the gubernaculum fails to develop or fails to pull the testes into the scrotum. Androgen activity directs gubernacular development and function, thus gubernacular dysfunction reflects androgen abnormalities. Insufficient androgen activity can result from developmental defects anywhere along the fetal hypothalamic–pituitary–testicular axis. To this point, cryptorchidism can result from any of the following:
• fetal hypothalamic failure to stimulate gonadotropin secretion in the third trimester (Kallmann and Prader Willi syndromes, anencephaly);
• failure of the testes to secrete androgens (gonadal dysgenesis); (iii) failure of testosterone conversion to dihydrotestosterone (DHT) in target tissues (5α-reductase deficiency); or (iv) absence of functioning androgen receptors (androgen insensitivity syndromes) (Table 26.1).
Cryptorchid testes may remain in the inguinal canal (70%), the abdomen or retroperitoneum (25%), or other ectopic locations (5%). Testes remaining in the abdomen or inguinal canal will be exposed to comparatively higher temperatures than those in the scrotum and will cease spermatogenesis in response. They are also prone to neoplastic change. Medical therapy for cryptorchidism involves administration of human chorionic gonadotropin (hCG) or androgens. Surgical therapy is called orchiopexy. Some cryptorchid testes are unresponsive to medications or cannot be brought into the scrotum surgically. These testes are usually removed because they cannot be adequately monitored for the development of a neoplasm.
Inguinal hernia is a forme fruste of cryptorchidism. Here, testicular descent occurs, but the inguinal ring does not close completely after descent. Boys who have an inguinal hernia diagnosed before the age of 15 have twice the risk of developing testicular cancer when com- pared to boys in the general population.
Hypospadias is a very common congenital abnormality seen in male newborn infants. In hypospadias, the urethral meatus opens on to the ventral surface of the penile shaft at sites proximal to the normal location (Fig. 26.1). Embryologically, hypospadias results from a failure of complete ventral closure of the urethral groove. The penile urethra depends on the androgen DHT to differentiate. Therefore, hypospadias can result from deficiencies in testosterone (T) production, from inadequate conversion of T to DHT, or from local deficiencies in androgen recognition (insufficient androgen receptor number or function). There is a non-Mendelian genetic predisposition to hypospadias. If one sibling has a hypospadias, the recurrence risk is 12% in that family. If both the father and a brother are affected, the risk for a second son is 25%.
Cryptorchidism is seen in 16% of boys with hypospadias. If both are present, the child may be a pseudohermaphrodite and chromosomal and hormonal testing should be obtained.
Congenital bilateral absence of the vas deferens
Congenital bilateral absence of the vas deferens (CBAVD) is a rare congenital anomaly found most often in men with cystic fibrosis (CF). It can also occur in the absence of clinically apparent CF. When it does, it is usually associated with mutations in the gene coding for the CF transmembrane receptor (CFTR). The molecular mechanism by which an abnormal transmembrane receptor involved in chloride channels leads either to failure of the vas deferens to differentiate or to its resorption is not known. The presence of CBAVD mandates genetic testing for CF genes.
The presence of at least one additional X chromosome in most of the cells of a man with Kleinfelter syndrome (usually 47XXY) results in hypogonadism and frequent infertility and microorchidism. XXY men are variably affected with other physical (tall stature, gynecomastia) and behavioral (speech and learning) problems. This is the most common sex chromosome aneuploidy in males and may be one of the most common chromosome abnormalities in humans.
Individuals possessing testes, but in the presence of external and/or internal genitalia with a female phenotype are called male pseudohe maphrodites. Gonadal sex does not match genital phenotype. Male pseudohermaphroditism results from an inappropriate fetal hormonal environment. This can be caused by biochemical defects in androgen activity or by abnormal sex chromosome constitution. Pseudohermaphroditism is a rare disorder, but its multiple etiologies have offered the opportunity to further understand the role of steroids in human genital development. A list of the known biochemical defects leading to male pseudohermaphroditism includes:
• Androgen insensitivity syndromes
• 5α-reductase deficiency
• Testosterone biosynthesis defects
• Congenital adrenal hyperplasia (CAH) syndromes
• Impaired androgenization
• Anti-Müllerian hormone defect.
Androgen insensitivity syndromes
The androgen insensitivity syndromes are a group of X-linked recessive traits that produce a spectrum of incompletely virilized phenotypes. The most severe form, complete androgen insensitivity (AI), was originally known as testicular feminization. In complete AI, the intracellular androgen receptor is absent or nonfunctional. Androgen induction of Wolffian duct development does not occur. Müllerian- inhibiting substance (MIS) is produced by the normally functioning testes and the Müllerian ducts regress. The testes descend to the level of the inguinal ring under the influence of MIS. A short vagina forms from the urogenital sinus. At birth, children with complete AI are typically assigned the female sex because there is no trace of androgen activity and the external genitalia clearly appear female. Complete AI is typically diagnosed after puberty when primary amenorrhea becomes apparent. Examination of the complete AI individual reveals a blindending, short vagina and an absent cervix, uterus and ovaries. Breast development is normal, but axillary and pubic hair is scant or absent. Complete AI accounts for about 10% of all cases of primary amenorrhea. In contrast to those individuals with a dysgenetic gonad bearing a Y chromosome, those with complete AI have less than a 5% risk of developing a gonadal tumor. Gonadal tumors that do develop in AI patients rarely appear before age 25. Therefore, gonadectomy is postponed until puberty is complete.
The incomplete androgen insensitivity syndrome (Reifenstein syndrome) is far less common than the complete and is associated with a broad spectrum of phenotypes. These vary from almost complete failure of internal and external genital virilization to complete phenotypic masculinization. Between these extremes exist patients with mild clitoromegaly and slight labial fusion to those with significant genital ambiguity. Recently, several men have been described whose only indication of AI was infertility resulting from low or absent sperm production. Some fertile males who appear undervirilized probably have a mild form of this disorder.
Incomplete AI results from mutations in the androgen receptor gene. The gene encoding the androgen receptor localizes to the q11-12 region of the X chromosome. Defects can occur in the androgen- binding domain of the receptor, the DNA-binding domain of the receptor or in receptor protein production. Identified abnormalities range from complete loss of receptor function to subtle qualitative changes in the transcription of androgen-dependent target genes. There is poor correlation between absolute androgen receptor levels and the degree of masculinization seen in patients with incomplete AI.
The syndrome seen among patients with 5α-reductase deficiency was originally given the name pseudovaginal perineoscrotal hypospadias (PPH). It differs from AI in that masculinization occurs at puberty. At birth, individuals with 5α-reductase deficiency have external genitalia that resemble those of incomplete AI, including hypospadias, varying degrees of failure of the labioscrotal folds to fuse and either a urogenital opening or separate vaginal and urethral openings. The cleft in the scrotum resembles a vagina and most children with 5α-reductase deficiency are raised as girls. In these patients, adrenal steroid production is normal and the karyotype is XY. Measuring blood levels of testosterone and DHT and demonstrating an elevated T: DHT ratio can establish the diagnosis of 5α-reductase deficiency and eliminate the diagnosis of CAH in an incompletely virilized newborn infant (Chapter 27).
Molecular analyses have demonstrated that there are two 5α-reductase genes; mutations in the isoenzyme coded on chromosome 2 (SRD5A2 gene) are responsible for this form of male pseudohermaphroditism. Multiple mutations of SRD5A2 have been identified. The segregation of the same specific defects in unrelated individuals of the same ethnicity suggests common ancestry. Compound heterozygotes are common, suggesting that the gene frequency for SRD5A2 mutations may be fairly high. Women are not clinically affected by 5α-reductase deficiency.
Congenital adrenal hyperplasia syndromes
A group of enzymatic defects of the steroidogenic pathways cause reproductive and metabolic disorders collectively known as the CAH syndromes. Among these, lipoid congenital adrenal hyperplasia (StAR protein deficiency), 3β-hydroxysteroid dehydrogenase deficiency, 17α-hydroxylase deficiency and 17β-hydroxysteroid dehydrogenase deficiency can cause feminization of fetal external genitalia. All are specific enzymatic defects in the steroidogenic pathway common to the testes and adrenal glands and all involve enzymes occurring early in the steroidogenic pathway between cholesterol and testosterone (Chapters 2 and 29). CAH syndromes that cause masculinization in female fetuses are much more common and result from enzymatic defects more distal in the steroidogenic pathways.
Gender assignment in male infants with pseudohermaphroditism requires knowledge of the specific defect. Most are raised as females. Individuals with complete AI (testicular feminization) are raised as females because they unambiguously appear as females at birth. In addition, because they lack functional androgen receptors, AI patients will never be virilized. Males whose incomplete AI presents with ambiguous genitalia are also usually raised as females because predict- able feminization with gynecomastia will occur at puberty. Males with 5α-reductase deficiency have been successfully raised as either females or males. In fact, in cultures with a high frequency of the disorder, children have been raised as females in childhood and males after puberty. Patients with 5α-reductase deficiency who are assigned as females and wish to retain their female gender will need to be gonadectomized to avoid deepening of their voices and a male pattern of muscle development that will occur at puberty. Both will occur in response to pubertal testosterone, a substance to which they can respond. Estrogen and progesterone therapy can be used to produce female secondary sexual development. Patients with 5α-reductase deficiency who are assigned to the male gender require repair of their hypospadias and cryptorchidism. At puberty, spermatogenesis and masculine sexual maturation will occur under the influence of testosterone.
True gonadal dysgenesis is relatively rare in individuals with an XY karyotype. Bilateral dysgenesis of the testes (Swyer syndrome) results in normal, but infantile female external and internal genital development and lack of secondary sexual development at puberty. Fibrous bands appear in place of the testes. Gonadectomy is necessary to prevent the 20–30% risk of tumor formation. Estrogen and progesterone therapy support female secondary sexual development at puberty.