AZOOSPERMIA I: SPERM PRODUCTION PROBLEMS—GENETICS
It is thought that a significant proportion of male infertility is due to underlying genetic causes. Currently, genetic testing for male infertility is based mainly on abnormalities of sperm concentration. However, it is clear that the epididymis plays a large role in the development of sperm motility and that 200 to 300 genes control sperm motility. Thus, as our knowledge of genomics develops, genetic testing for abnormal motility will also become routine in the future.
Genetic defects are generally divided into three categories. The simplest
are point mutations in single genes that follow the rules of mendelian
genetics. The second category of genetic defects are the chromosomal disorders
in which changes in whole segments of chromosomes occur that are classified as
either structural or numerical in type. As a consequence of structural defects,
there is a loss (deletion), gain (duplication), or exchange (balanced defect)
of genetic material. Numerical chromosomal defects result in extra or missing
chromosomes. The third category is polygenic or multifactorial genetic defects.
These are the most common defects and include most disorders of human biology.
A fourth, rare category of mutations exists, termed mitochondrial disorders, consisting
of mutations in nonchromosomal DNA within these subcellular organelles.
From 2% to 15% of infertile men with azoospermia (no sperm count) or
severe oligospermia (low sperm counts) harbor a chromosomal abnormality on
either the sex chromosomes or autosomes. A blood test for cytogenetic analysis
(karyotype) can determine if such a genetic anomaly is present. Patients at
risk for abnormal cytogenetic findings include men with small, atrophic testes,
elevated follicle-stimulating hormone (FSH, see Plate 1-4) values, and
azoospermia. Klinefelter syndrome (47,XXY) is the most frequently detected sex
chromosomal abnormality among infertile men (see Plate 1-7).
Other genetic causes of low sperm concentrations include XYY syndrome
typically associated with tall stature, decreased intelligence, higher risk of
leukemia, and aggressive, often antisocial behavior. Chromosomal translocations
or inversions are also an infrequent cause of male infertility and low sperm
counts. When segments of chromosomes are exchanged, a translocation results.
When a chromosome breaks in two places and the material between the breakpoints
reverses orientation, an inversion results. Such exchanges may either interrupt
important genes at the breakpoint or interfere with normal chromosome pairing
during meiosis because of imbalances in chromosomal mass. Many translocations
have been associated with male infertility. In particular, reciprocal and
robertsonian translocations (in which material from chromosomes 13, 14, 15, 21,
and 22 are involved) are eightfold more common in infertile men than in normal
males. In addition, syndromes such as myotonic dystrophy, Noonan syndrome,
46,XX male syndrome and mixed gonadal dysgenesis, sickle cell anemia,
congenital adrenal hyperplasia, Kallmann syndrome (see Plate 3-17),
Prader-Willi syndrome, and Kennedy disease are rare but well-described genetic
causes of male infertility.
Before its firm association with male fertility, the Y chromosome was
widely considered a genetic black hole, an evolved, broken remnant of the X
chromosome. It was apparent that the Y harbored the male sex-determining region (testis-determining region, SRY ), but it
was also home to gene regions that govern stature, tooth enamel, and hairy ears
as well as “junk” genes. Now that the genome of the human Y is known, it is
clear that this chromosome is structurally unique as a fertility chromosome.
The postulation that deletions in the long arm of the Y chromosome cause azo-
ospermia was made in 1976 and this theoretical region was termed the
Azoospermia Factor (AZF). Currently, the positional patterns of deletions
(termed microdeletions) in the AZF region are used to subdivide this
region into AZFa, b, c subregions. As many as 7% of men with oligospermia and 15% of azoospermic men have small, underlying
deletions in one or more gene regions on the long arm of the Y chromosome (Yq).
Deletion of the DAZ (deleted in azoospermia) gene in the AZFc region is the
most commonly observed microdeletion in infertile men. Fertility is possible in
many men with these deletions with in vitro fertilization and intracytoplasmic
sperm injection. A polymerase chain reaction–based blood test can examine the Y
chromosome from peripheral leukocytes for these gene deletions and is
recommended for men with low or no sperm
counts and small, atrophic testes.
