Abnormalities Of Male Sexual Differentiation And
Development
Cryptorchidism
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
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.
Microorchidism
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.
Pseudohermaphroditism
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.
5α-reductase deficiency
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
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.
