The Principles of Clinical Cytogenetics - Extra Materials - Springer

Cytogenetics of Infertility 253
genetic disorders that affect reproduction only, and genetic disorders with other effects but which
also are associated with infertility. Although many advances have been made in the field of male
factor infertility, it is estimated that the cause of about 30% of male infertility is still not known (13).
This chapter will provide an overview of causes but provide detail only on cytogenetic and molecular
cytogenetic causes. See Table 5 for information on other genetic causes of male infertility.
The SRY Gene and Genetic Sex
The presence of the SRY (sex-determining region Y) gene on the short arm of the Y chromosome
induces differentiation of precursor cells into Sertoli cells, which express anti-Müllerian hormone.
Anti-Müllerian hormone, which is also known as Müllerian inhibiting substance, causes regression
of Müllerian structures—the Fallopian tubes, uterus, and upper vagina—and the production of testosterone
in the Leydig cells. The Leydig cells are thought to differentiate because of messages from
the Sertoli cells. Testosterone leads to the formation of internal male genitalia, such as epididymis,
vas deferens, seminal vesicles, and ejaculatory duct. The production of dihydrotestosterone results in
the formation of the penis, testes, prostate gland, and urethra. Secretion of insulin-like hormone 3 by
the Leydig cells causes the descent of the testes (14).
About 10% of infertile men have severe defects in sperm production (15), and it is in this group of
men that many of the cytogenetic and genetic disorders are concentrated. Hackstein et al. (16) note
that in the fruit fly Drosophila there is evidence that up to 1500 genes contribute to male fertility.
Much more work remains to be done in humans, in whom several genes have been found to be
involved in early sexual development, but many remain to be discovered.
In general, men with infertility and a normal semen analysis are less likely to have a cytogenetic or
molecular cytogenetic basis for their infertility. However, men with normal spermatozoa concentrations
but whose spermatozoa do not fertilize also have an increased risk of a constitutional chromosome
abnormality. In a study of 400 men who were to undergo intracytoplasmic sperm injection
(ICSI), 6.1% of the azoospermic men and 2.7% of the oligospermic men were found to have constitutional
chromosome abnormalities, and 7.4% of the men with normospermic analysis also had constitutional
cytogenetic abnormalities (17).
Semen Analysis
Semen analysis is usually performed on a sample that has been ejaculated into a specimen
cup. The volume and pH of the semen are measured, and the concentration, morphology, and
motility of the spermatozoa are analyzed under a microscope. Cellular debris is examined to
determine whether an infection is present, and fructose is measured as an indicator of obstruction.
Spermatozoa counts are designated as the number present per milliliter. A normal number
as defined by WHO is 20 × 10 6 sperm/mL of semen (12). However, in a study of 430 couples in
Denmark having unprotected sex, the probability of conception increased with increasing spermatozoa
concentration to 40 × 10 6/ mL. Above that level, there was no additional likelihood of
pregnancy. The authors suggested that the WHO guidelines should be used with caution, as
some men above the normal range could be subfertile (18).
Oligospermia, Nonobstructive Azoospermia and Teratozoospermia
Oligospermia, also called oligozoospermia, is defined as having a low spermatozoa count in an
ejaculate. Azoospermia is the absence of spermatozoa, and teratozoospermia indicates abnormally
formed spermatozoa. The number in terms of concentration, morphology, and motility of spermatozoa
are important factors in achieving conception.
Gunduz et al. (19) performed chromosome analysis on 41 men with azoospermia and 61 men
with oligospermia. Fourteen of the 41 men, or 34.1%, and 2, or 3.3%, of the oligospermic men had
a constitutional chromosome abnormality. The most common abnormality was 47,XXY (19).