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Why male fertility is about more than just sperm count

Continuing our series on fertility Dr Chris Ford and Dr Uma Gordon look at couples seeking treatment where male factor is the primary diagnosis

For at least a quarter of couples who seek specialist help for infertility, male factor is the primary diagnosis. In about 94 per cent of these couples the men are potentially fertile and their management must be based on an imprecise estimate of their chance of conception.

Many men find it hard to accept their semen is inadequate. Stress may be exacerbated by an uncertain diagnosis so a sensitive explanation is essential. Fortunately, assisted reproduction in the form of intracytoplasmic sperm injection (ICSI) is now an effective, if expensive, treatment.

The causes of male sub-fertility remain unknown in most cases. Some lifestyle factors have been shown to have an adverse effect. Smoking decreases sperm count and passive exposure decreases female fertility. Heavy alcohol use reduces libido and erectile function, but may also have direct effects on fertility.

Other recreational drugs also have reported adverse effects and some anabolic steroids or body supplements used by body builders suppress spermatogenesis. Occupational exposure to chemicals, notably solvents and heavy metals, is potentially harmful, although risk can be minimised with precautions.

For optimal spermatogenesis the testes should be below body temperature. Tight clothing or prolonged exposure to heat should be avoided. Some therapeutic interventions such as anti-cancer medications and radiation kill germ cells and may stop spermatogenesis permanently. Sulphasalazine has a well-established but reversible contraceptive effect while calcium channel blockers, ?-blockers, antibiotics such as high-dose nitrofurantoin or tetracyclines, cimetidine, colchicines and allopurinol have reported adverse effects on fertility. Alternatives to these drugs should be considered.

Evidence for genetic aetiologies of male infertility is increasing. Severe oligozoospermia and azoospermia may be due to sex chromosome abnormalities or microdeletions of the Y chromosome. Azoospermia can result from congenital absence of the vas deferens because of mutations in the cystic fibrosis gene (CFTR). The prevalence of familial associations of subfertility suggests other genetic factors remain to be identified.

Hypogonadotropic hypogonadism and other endocrine disorders are rare but medically treatable. Erectile or other sexual dysfunction may prevent proper or correctly timed intercourse.

Otherwise the area is rich in controversy: a visible or palpable varicocele deserves a specialist opinion, whether they impair semen quality or whether surgery is worthwhile remains unresolved. The importance of chronic infection and high leukocyte numbers in semen are the subject of conflicting reports. Infection and other trauma are thought to break down immune barriers and lead to the formation of antisperm antibodies.

How is a diagnosis made?

Physical examination and history taking are essential and can provide useful information, but the classification of male subfertility relies heavily on semen analysis. A qualified laboratory that participates in the national quality control scheme should do this and should include a test for antisperm antibodies.

Some simple but important facts need to be explained to the patient. Men should abstain from ejaculation for two to five days before the sample is produced. Shorter periods result in low sperm numbers while more prolonged abstinence leads to poor motility and morphology.

Sometimes men fail to collect the initial sperm-rich fraction of their ejaculate and it is important that they report this. If the sample is produced at home it must not be exposed to high or low temperatures and should be taken to the laboratory without delay. Any delay should be specifically documented. The Royal College of Gynaecologists recommends analysis be repeated because even the most fertile men can occasionally produce ejaculates in the severely subfertile range. At least six weeks should be allowed between tests. Semen analysis techniques vary and published values must be adjusted to fit local practice.

What are the referral criteria?

In men with moderate alcohol intake, smoking or other lifestyle factors, it is important to advocate the necessary changes and be aware it could take up to three months for any improvement in sperm parameters. For most GPs the options are to refer the couple for specialist help or to reassure them, give advice on the timing of intercourse and encourage them to keep trying.

The decision for referral is generally based on the following principles, assuming that the woman is normal. Couples who have been trying to conceive for more than three years have a very low chance of a natural pregnancy, even with excellent semen, and should be referred immediately. Since age is the most important prognostic factor for success, earlier referral is indicated where the woman is 35 or older.

Where infertility is less prolonged, the couple should be referred immediately if the ejaculate consistently contains no sperm (azoospermia) or less than five million per ml (severe oligozoospermia). Consider follicle stimulating hormone (FSH), luteinising hormone (LH) and testosterone assays while patients are waiting for the specialist appointment.

Once more motile sperm are present, natural conception is possible and patients will want to know the likelihood that it will be achieved in an acceptable timescale. Decisions are often based on the WHO reference ranges (shown by large arrows in the figure left), but the use of a sharp cut-off in this way is over-simplistic.

The true situation is illustrated better by a study that tried to distinguish fertile and infertile couples with normal female partners based on sperm concentration, per cent motility and per cent normal morphology. Each parameter was divided into fertile, subfertile and borderline ranges (green, red and amber respectively in the figure). Classification was imperfect (as shown by the figures in square brackets). Fertility of couples with semen in the borderline range was only slightly less than those in the fertile range (around 50 per cent versus around 60 per cent).

Unless the woman's age is a pressing factor, couples with borderline semen quality can be advised that although their chance of success may be a little less than normal, it remains good. Immediate referral to a specialist clinic is only required if more than one parameter is abnormal or if a single parameter is severely abnormal.

What happens after referral?

Medical management has a limited place except in patients with hypogonadotropic hypogonadism. Weekly injections of gonadotropins can promote testicular growth and initiate sperm production over a period of several months. Antisperm antibodies were in the past managed using high-dose steroids, which led to complications such as hypertension and aseptic necrosis of the femoral neck. These patients are now directly referred for ICSI.

Management in secondary and tertiary care will depend on the extent of sperm impairment along with a full discussion of the options available and costs involved. In mild to moderate sperm impairment up to six cycles of intrauterine insemination can be attempted before ICSI treatment. In severe cases of oligozoospermia, ICSI is the only option, with success rates comparable with conventional in-vitro fertilisation.

In men with obstructive azoospermia, such as past infection or failed vasectomy reversal, surgical sperm recovery (SSR) is very successful. Using simple needle aspiration from the epididymis or testicular biopsies, sperm can be recovered in almost all cases

and cryopreserved for several cycles of ICSI.

But in non-obstructive azoospermia with testicular failure, the prognosis is much poorer with sperm recovery rates varying from 20 to 60 per cent.

Only a small amount of sperm may be recovered, suitable for one or two cycles of ICSI treatment. In these men, counselling is necessary and the option of donor sperm discussed. Donor insemination is less expensive, offering pregnancy rates of 10 per cent per cycle in women under 40.

The follow-up of ICSI children has been closely monitored and most of these studies have been reassuring. But in view of the concerns raised with a few studies, detailed discussion with couples is necessary along with continued surveillance of the children.

Chris Ford is a senior research fellow in reproductive medicine and Uma Gordon is a subspecialist in reproductive medicine and surgery, both at the Centre for Reproductive Medicine, Bristol

Reference

1 Guzick DS et al. Sperm morphology, motility and concentration in fertile and infertile men. N Engl J Med, 2001;345:1388-93

Further information

Campbell AJ, Irvine DS. Male infertility and intracytoplasmic sperm injection (ICSI). Br Med Bull 2000;56:616-29

Gordon UD. Assisted conception in the azoospermic male. Hum Fert, 2002;5 (Suppl):S9-S14

Hirsh A. ABC of Subfertility. Male subfertility. BMJ, 2003;327:669-72

Braude P, Taylor A. ABC of subfertility. London: BMJ Books, 2004

Useful websites

www.repromed.org.uk

www.mattersonline.net

www.nice.org.uk/

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