Male infertility: The case for continued research

Full text

Male infertility: the case for continued
research
Med J Aust 2001; 174 (3): 116-117.
• Article
Editorial
Male infertility: the case for continued research
Even with modern assisted-reproduction technologies, clinical assessment
and basic research on male infertility are essential
MJA 2001; 174: 116-117
IN AUSTRALIA, male infertility affects one man in 20,
contributes to half of all infertility problems in
relationships, and is the underlying reason for 40%
of infertile couples using assisted-reproduction
technologies (ARTs). It is a major health problem,
placing a heavy psychosocial burden on affected
men and their partners and a financial burden on
the community.
Intracytoplasmic sperm injection (ICSI) has
revolutionised infertility practice. Any man with
viable sperm found at any point in the genital tract
can now father his own children. Erroneously, the
media reported this development as signalling that
male infertility was "cured".
Such pronouncements may result in failure to
assess men for infertility and encourage the view
that further research on male infertility can be
scaled back. We strongly disagree. For all men
presenting with an infertility problem, a medical
history should be taken, and an examination and
appropriate investigations carried out. Accurate
diagnosis may prompt alternative, less expensive
treatments that do not expose the female partner
to the risks associated with ART (such as ovarian
hyperstimulation syndrome). For example,

infertility related to a pituitary prolactinoma is best
managed with a dopamine agonist rather than
ICSI. A diagnosis will also satisfy the man's
legitimate desire to understand the reason for his
infertility.
Testicular examination is mandatory: a Prader
orchidometer is used for volume estimation and
careful palpation is performed. A past history of
cryptorchidism is common in infertile men.
Moreover, this condition and infertility are primary
risk factors for testicular cancer.1 It is also
important to detect and treat androgen deficiency,
which is more common in infertile men, to improve
quality of life and prevent long-term sequelae such
as osteoporosis. Erectile dysfunction and
infrequent or poorly timed intercourse may be
remediable with specific therapy or counselling.
Deficiency of pituitary gonadotropins, although
rare (occurring in less than 1% of infertile men),
must be considered in the diagnostic work-up, as
infertility resulting from this condition is amenable
to gonadotropin therapy.
Of the identifiable causes of male infertility,
obstruction is the most common. Obstruction is
increasingly managed with ICSI because surgery is
either impossible or compares poorly. Examples
include bilateral congenital absence of the vas
(BCAV), epididymal or ejaculatory duct
obstruction, and vasectomy-related infertility (the
largest single group). Surgical reversal of
vasectomy offers only a 50% prospect of restoring
fertility. As men rarely store sperm before
vasectomy, couples who are infertile as a result of
the procedure now generally opt for ART with

testicular or epididymal sperm (particularly since
the removal of the Medicare rebate for vas
reversal2). Sperm autoimmunity affecting sperm
motility, vitality or function is now managed by
ICSI rather than immunosuppressive drug therapy.
In about 60% of infertile men no cause is found for
low sperm counts or inadequate production of
sperm with normal motility, morphology and
function. Such conditions, collectively termed
"seminiferous tubule failure" (STF), include a
number of distinct disorders characterised by poor
semen quality. Varicoceles are certainly more
common in men with STF (25%-35%) than men in
the general population (10%-15%), but there is no
firm evidence that semen quality or fertility is
improved by varicocele removal.
In 6%-10% of men with azoospermia or severe
oligospermia (ie, sperm densities of <5 million/mL;
normal, >20 million/mL), there are microdeletions
in the long arm (Yq) of the Y chromosome,
suggesting a genetic basis for STF. The Yq11
region includes a number of testis-specific genes
and gene families thought to be important in
spermatogenesis. The detection of Yq11 deletions
provides a definitive diagnosis of STF, and the
demonstration that these deletions are passed on
to male offspring conceived by ICSI has
emphasised the importance of genetic evaluations
in men considering the use of ICSI.3,4
In the majority of remaining men with STF, other
genetic lesions are likely. An autosomal-recessive
pattern of transmission is a possibility in families
with a history of involuntary infertility.5 Mutations

of the androgen receptor gene (on the X
chromosome) may be associated with male
infertility and poor spermatogenesis. There are
numerous animal models of single-gene defects
associated with specific impairment of
spermatogenesis, and, although such evidence is
lacking in humans, it seems extremely likely that
single-gene and polygene defects will be found to
be an important cause of infertility.
Severely infertile men with STF are known to have
an increased incidence of chromosomal aneuploidy
(sex-chromosome mosaicism or autosomal
translocations).6 These abnormalities may affect
the health of offspring conceived with the use of
ICSI. Although male karyotyping is routine before
ICSI, there is accumulating evidence that, even
when karyotype is normal, there is a roughly
threefold increased risk of Klinefelter's syndrome
and autosomal translocations in the offspring of
these men.7 As mutations of the cystic fibrosis
gene are the most common cause of BCAV, routine
screening of female partners before ICSI is
essential to avoid the possibility of cystic fibrosis in
offspring.8 Such examples show the added
complexities of clinical practice with ICSI and the
important role of genetic counselling in the
management of couples in which the male partner
is infertile.
The alleged decline in sperm counts over the past
40 years and differences in sperm counts between
geographical regions have led to speculation that
environmental factors may adversely affect male
reproductive potential. However, Australian data
do not support the contention that sperm counts

are falling.9 Environmental oestrogens are often
cited as male reproductive toxicants, but it is
notable that in the large number of males exposed
to high levels of diethylstilboestrol during gestation
fertility appears unaffected, although there is an
increased incidence of epididymal cysts and
abnormalities.10 A great deal of research is needed
to identify other possible toxic substances — a
daunting task when one considers the enormous
number of chemicals in industry and the
environment.
ICSI is a "bypass" procedure, not a treatment — it
can help some, but by no means all, infertile men.
The ICSI revolution must not distract practitioners
(particularly gynaecologists lacking training in
clinical andrology) from the appropriate clinical
management of male infertility or obscure the need
for continued basic and clinical research that may
ultimately provide specific treatment or prevention
strategies.
Robert I McLachlan
Principal Research Fellow
Prince Henry's Institute of Medical Research
David M de Kretser
Professor, Monash Institute of Reproduction and
Development
Australian Centre for Excellence in Male Reproductive
Health
Monash University, Melbourne, VIC
rob.mclachlanATmed.monash.edu.au
1. Moller H, Skakkebaek NE. Risk of testicular
cancer in subfertile men: case-control

study. BMJ 1999; 318: 559-562.
2. Jequier AM. Vasectomy related infertility: a
major and costly medical problem. Hum
Reprod 1998; 13: 1757-1759.
3. Krausz C, Quintana-Murci L, McElreavey K.
What is the clinical prognostic value of Y
chromosome microdeletion analysis? Hum
Reprod 2000; 15: 1431-1434.
4. Cram D, Ma K, Bhasin S, et al. Y chromosome
analysis of infertile men and their sons
conceived through intracytoplasmic sperm
injection: vertical transmission of deletions and
rarity of de novo deletions. Fertil Steril 2000;
74: 909-915.
5. Lilford R, Jones AM, Bishop DT, et al. Case-
control study of whether subfertility in men is
familial. BMJ1994; 309: 570-573.
6. Peschka B, Leygraaf J, Van der Ven K, et al.
Type and frequency of chromosome aberrations
in 781 couples undergoing intracytoplasmic
sperm injection. Hum Reprod 1999; 14: 2257-
2263.
7. Bonduelle M, Camus M, De Vos A, et al. Seven
years of intracytoplasmic sperm injection and
follow-up of 1987 subsequent children. Hum
Reprod 1999; 14: 243-264.
8. Lissens W, Mercier B, Tournaye H, et al. Cystic
fibrosis and infertility caused by congenital
bilateral absence of the vas deferens and
related clinical entities. Hum Reprod 1996;
11(Suppl 4): 55-78.
9. Handelsman DJ. Sperm output of healthy men
in Australia: magnitude of bias due to self-
selected volunteers. Hum Reprod 1997; 12:
2701-2705.
10. Wilcox AJ, Baird DD, Weinberg CR, et al.

Fertility in men exposed prenatally to
diethylstilbestrol. N Engl J Med 1995; 332:
1411-1416.
Make a comment