Subfertility in men

Contributed by Mr Anthony Hirsh, consultant in andrology, Whipps Cross & Homerton University Hospitals, London & Bourn Hall Clinic, Cambridge and honorary senior lecturer, Guy's Hospital.

Section 1 Epidemiology and aetiology
Infertility is defined as the failure to conceive after regular unprotected intercourse for two years in the absence of known reproductive pathology (NICE guidelines 2004).

It affects around 9 per cent of couples in the UK. One in 20 men is subfertile and a male factor is diagnosed in almost half of cases of infertility. Causes include impaired semen quality, azoospermia, or inadequate coitus.

Couples where the man is subfertile have a reduced chance of conceiving. Following initial assessment by the GP, early referral to a specialist in clinical andrology or reproductive medicine is recommended.

Specialist treatment of the patient can increase the chances of natural conception in some cases. More often the patient's sperm is used for assisted reproduction with good prospects of biological fatherhood. There is less demand for sperm donation than previously.

Causes of subfertility
The physiological processes that can affect male fertility include spermatogenesis, sperm maturation, seminal plasma secretion, erection, orgasm and ejaculation. Most infertile men have adequate sex hormone levels and sexual function.

Falling sperm counts seen over the last 60 years have occurred in tandem with increases in the incidence of testicular cancer, undescended testes and hypospadias. This is known as the 'testicular dysgenesis syndrome'. One theory is that this syndrome is caused by industrial oestrogens polluting our water supply.

But there is no confirmation that infertility is increasing.

Classification
There are three main causes for subfertility in men. The most common is abnormal semen quality which is found in over 90 per cent of cases. In these patients there are multiple sperm defects, usually of unknown origin, termed oligoasthenoteratozoospermia syndrome (OATS).

The infertility is due to failure of the sperm to fertilise. This is the commonest cause of infertility in humans.

In around 5 per cent of cases, there is no semen deposition because of coital dysfunction.

This may be caused by reduced libido, failure of erection or ejaculation, retrograde ejaculation (bladder neck incompetence), anatomical defect or disability.

In these patients, sperm production and function are usually normal.

About 5 per cent of subfertile men suffer from azoospermia where there is no sperm in the semen. This may be the result of hypothalamic-pituitary failure, primary testicular failure (non-obstructive azoospermia) or post-testicular obstruction (obstructive azoospermia).

Section 2 Making the diagnosis
Semen analyses should be sent to hospitals with infertility services where possible. Semen produced by masturbation after three days' abstinence into a container should be kept warm and presented for analysis within an hour. Non-spermicidal condoms can be used to collect semen during coitus for men with difficulty with or objections to masturbation.

An abnormal result must be confirmed by a second test six weeks later. If the first or repeat analysis is normal no further tests are required.

Clinical assessment
Patient history may reveal an underlying physiological problem. The patient may have a sexual problem such as non-consummation, a known reproductive pathology such as orchidopexy, or orchitis, or a vasectomy. Subfertility can also be caused by a medical condition such as diabetes, previous radiotherapy or chemotherapy, drug abuse, smoking, high alcohol consumption and binge drinking.

The patient should be examined for signs of testosterone deficiency. The risk of testicular cancer is increased in subfertile men, so the testes must be examined. If there is any doubt, the patient should have an ultrasound scan.

Levels of serum follicle stimulating hormone (FSH), luteinising hormone (LH) and testosterone should be measured to determine the cause of azoospermia, with prolactin as a screen for a prolactinoma.

Normal testes and FSH indicate obstructive azoospermia, small testes with high FSH, non-obstructive azoospermia. Very low serum FSH, LH and testosterone levels suggest gonadotrophin deficiency.

SEMEN ANALYSIS RESULTS
Measurement Minimum value Term for abnormality
Volume 2.0 ml hypospermia 2.0 ml hypospermia
Sperm concentration (count)
20 million/ml oligozoospermia
Progressive motility 25% grade A (rapid) or 50% grade A + B (rapid + slow) asthenozoospermia
Morphology (strict criteria) 5–15% normal forms teratozoospermia
White blood cells 1 million/ml leucocytospermia

Section 3 Primary care management
Most men with erectile dysfunction respond to PDE5 inhibitors, which do not adversely affect sperm. Lubricants can be toxic to sperm. Sperm can survive in the female tract for seven days and oocytes have a 6-24-hour window for fertilisation.

The best chance of natural conception results from coitus two to six days before ovum release. Delaying coitus until ovulation may miss the best days. NICE recommends coitus on alternate days throughout the cycle.

Lifestyle adjustment
Low sperm producers have smaller testes that are sensitive to external influences. Semen quality can be reduced over a period of months after pyrexia or after binge drinking.

Patients should be advised to make lifestyle changes that can enhance sperm output. These include losing weight, not smoking or drinking and avoiding recreational drugs. The patient should avoid wearing tight underpants or taking saunas. They should also avoid exposure to chemicals or herbicides and should have a review of any prescribed medication.

Improving sperm output may reduce the complexity of future assisted reproduction. Stopping binge-drinking can lead to re-appearance of sperm in azoospermic men.

Drugs and male infertility
There are a number of drugs that can contribute to infertility (see box below). A drug that is well known to reduce sperm counts and fertility is sulfasalazine. The effect is reversible on withdrawal or substitution. Fertility returns after six to 12 months.

Anabolic steroid abuse inhibits gonadotrophin secretion leading to azoospermia. This can be reversible, but long-term steroid abuse may shut down the hypothalamic-pituitary axis for months or years causing hypogonadism.

Couples seeking help for infertility prefer to conceive naturally. Around 2 per cent of subfertile men can achieve this with the help of specific treatment.

Gonadotrophin therapy for pituitary failure, reconstructive surgery for selected cases of obstructive azoospermia, and sympathomimetics for retrograde ejaculation can improve the chance of natural conception by returning a few normal spermatozoa to the semen.

Abnormal semen quality
While appreciable counts of active spermatozoa are often ejaculated in OATS, there is no therapy to improve the chance of pregnancy for the couple.

Sperm dysfunction is linked to abnormal morphology, DNA fragmentation, free oxygen radicals in the semen, and impaired spermatogenesis.

Correction of a varicocele, gonadotrophin injections, treatment with anti-oestrogens such as tamoxifen or antioxidants such as vitamin E or selenium may improve the sperm count.

However, natural conceptions are rare in the partners of men with OATS, as the spermatozoa remain dysfunctional and these treatments are no longer recommended.

Antibiotics for a semen infection can lead to natural pregnancy.

DRUGS THAT IMPAIR MALE FERTILITY
Reduced spermatogenesis sulfasalazine, methotrexate,
nitrofurantoin, colchicine,
chemotherapy
Pituitary suppressiontestosterone injections, GnRH
analogues
Anti-androgenic effects
cimetidine, spironolactone
Ejaculation failurealpha-blockers, antidepressants,
phenothiazines
Erectile dysfunctionbeta-blockers, thiazide diuretics,
metoclopramide
Drugs of abuse

steroids, cannabis, heroin, cocaine 

 

Microsurgical reversal of vasectomy

Section 4 Assisted reproduction and surgery
The technique of assisted reproduction that is used usually depends on the quantity and quality of sperm that can be purified from the semen.

IVF treatment
The best chance for a live birth for the partners of men with OATS is offered by IVF with intracytoplasmic sperm injection (ICSI). ICSI offers the best chance of biological fatherhood for nearly all infertile men because only one live sperm per oocyte is required. The live birth rate is 25 per cent, and most PCTs will fund one or two cycles.

Intra-uterine insemination (IUI) without hormonal stimulation is recommended for men with mild male factor subfertility, where several million spermatozoa are available. The success rate is 8 per cent per cycle. Most PCTs will fund six IUI cycles. Minor procedures to recover sperm under local or general anaesthesia are used for men with azoospermia, ejaculatory dysfunction or if only non-viable spermatozoa are ejaculated.

Azoospermia treatments
Patients with hypothalamic-pituitary failure such as those with Kallman's syndrome can be treated with gonadotrophin injections. These offer a high chance of natural conception, but in post-pubertal patients a tumour of this critical region must be excluded by MRI.

Reconstructive surgery for post-infective epididymal obstruction and vasectomy reversal offers a 25-50 per cent chance of natural pregnancy.

Irreversible obstructions include unsuccessful vasectomy reversal and congenital bilateral absence of the vas deferens in which 66 per cent of patients carry a cystic fibrosis mutation.

Men with non-obstructive azoospermia have no potential for natural fertility, but 50 per cent have foci of spermatogenesis, including some of the 30 per cent with Klinefelter's syndrome. Precautions against transmitting genetic diseases, such as karyotyping, screening and testing for cystic fibrosis mutations and genetic counselling, should be considered.

Coital dysfunction
Coital dysfunction causes infertility in men whose spermatozoa are usually functionally normal through a failure to deliver them. Appropriate therapy such as sildenafil for erectile dysfunction, and imipramine or ephedrine for retrograde ejaculation can lead to natural pregnancies.

Also, assisted reproduction techniques can make use of sperm isolated from the semen or urine after self-stimulation in cases of hypospadias or retrograde ejaculation. Penile vibratory or rectal electrical stimulation of ejaculation can also be used in cases of spinal cord injury, depending on the level of injury and sperm quality.

If ejaculation cannot be induced artificially, surgical sperm recovery from the vas deferens or the testis is indicated.

In many cases of ejaculation failure as a result of upper spinal cord injury, couples can undertake penile vibratory stimulation at home with vaginal insertion of semen. This can result in pregnancy because the sperm is usually functionally normal.

Prognosis
The fertility prospects for men who need radiotherapy or chemotherapy for cancer have been improved by a wider availability of pre-treatment sperm banking and by a refinement of treatment regimens.

The future fertility of boys who have operations for one undescended testis is almost normal, but is reduced in 50 per cent of patients after bilateral orchidopexy.

Varicoceles occur in 30 per cent of men with semen abnormalities, but there is little evidence to show that surgical repair or embolisation improves their fertility.

However, correction of large varicoceles is recommended to preserve the future fertility of adolescents. This may also return sperm to the semen transiently in cases of non-obstructive azoospermia, and this can be used for IVF-ICSI.

Future developments
The proportion of subfertile men who can be successfully treated remains low, since the largest diagnostic category of OATS remains stubbornly resistant to therapy. Sperm dysfunction is therefore a formidable challenge for research.

Significant advances in assisted reproduction have replaced the need to consider sperm donation for all infertile couples except for the one in 200 infertile men who have no sperm.

Resources

  • Balen A, Rutherford A. Management of infertility. BMJ 2007; 335: 608-11.
  • European Association of Urology guidelines on male infertility: www.uroweb.org/professional-resources/guidelines
  • Hirsh A. Male subfertility. BMJ 2003; 327: 669-72.
  • Hirsh A. Management of infertile men in the assisted conception unit. In: Brinsden PR (ed). Bourn Hall Textbook of IVF. 3rd ed. Taylor & Francis, London, 2005.
  • Hull M, Glazener C, Kelly N et al. Population study of causes, treatment, & outcome of infertility. BMJ 1985; 291: 1,693-7.
  • NICE. Fertility: assessment and treatment for people with fertility problems. Clinical Guideline 11. NICE, London, 2004.

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