eMJA: McLachlan & Kretser, Male infertility: the case for continued research

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

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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

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