Section 1: Epidemiology and aetiology
Subfertility is defined as failure of conception after 12 months of regular unprotected intercourse. Fertility problems affect approximately one in six couples trying to conceive, and a male factor is implicated in around half of these couples.
Approximately 10% of males will fail to conceive after a year of trying.
Perhaps surprisingly, around 70% of male fertility problems are treatable, but unfortunately this is commonly overlooked. The majority of fertility clinics are gynaecology-led, where the emphasis is on investigating the female partner and carrying out assisted conception.
The investigation and treatment of male-related fertility problems is often missed out completely, and therefore the couple are denied the opportunity of a natural conception.
Male factor treatment may also be cheaper, more successful, and less invasive. Furthermore, a proportion of males with subfertility will have other significant urological or endocrine problems requiring diagnosis and treatment.
The cause of male factor infertility is unknown in around 25% of cases, and may be due to undetected genetic abnormalities.
Approximately 40% of cases are due to varicoceles, which are incompetent valves in the gonadal vein. They are present in around 35% of men seen in a fertility clinic, and are more common on the left side.
A putative pathophysiological mechanism is loss of the normal counter-current mechanism that cools arterial blood to the testis, resulting in lowered sperm parameters.
Some literature suggests that repairing varicoceles improves sperm parameters significantly.1 Research into the repair of varicoceles and improvements in pregnancy rates is mixed, therefore this area remains controversial.2
Genetic factors are also implicated in subfertility. Causes include cryptorchidism (undescended testes); Klinefelter's syndrome; Kallmann's syndrome (low LH and FSH); Kartagener's syndrome (primary ciliary dyskinesia); congenital bilateral absence of vas deferens (changes in the gene responsible for cystic fibrosis cause the vas deferens on both sides to be absent); congenital androgen insensitivity syndrome; 5-alpha-reductase deficiency; persistent Mullerian duct syndrome and changes in the azoospermia factor (AZF) gene.
Other causes include drugs and toxins (see box above), testis injury (post-pubertal bilateral mumps orchitis, torsion, radiotherapy, trauma) and obstruction including infection, previous inguinoscrotal surgery, congenital absence of vas deferens or ejaculatory system (Wolffian duct abnormality), vasectomy and Mullerian prostatic cysts. Ejaculatory disorders are also a cause.
|Drugs and toxins that cause subfertility|
Section 2: Making the diagnosis
A full sexual and reproductive history is vital to ascertain the duration of the problem, method and timing of intercourse, the use of lubricants, previous pregnancies and sexual dysfunction.
A developmental, urological, genitourinary, endocrine and drug history should be taken and include questions on recreational and body-building drugs and lifestyle factors.
Examination should include a general physical examination, gonadal examination (foreskin, position and size of urethral meatus, testicular size, position and consistency, presence of the vas on both sides), epididymis (full or collapsed) and groin scars. A rectal examination by a specialist may be helpful where there is a suspicion of obstruction.
It is reasonable to carry out semen analysis fairly early on, as detection of a severe problem will avoid unnecessary delays. Semen analysis has been standardised by the WHO, and should be collected by masturbation after three to four days of abstinence. It should be delivered to the laboratory within one hour, and repeated if abnormal.
As well as semen volume, its general appearance, viscosity, liquefaction and pH are noted. Microscopy is used to measure sperm concentration and number, motility and morphology. Presence of leucocytes and antisperm antibodies is also checked. The WHO recently updated its reference ranges for semen variables (see table above). The reference ranges have been lowered for volume, count, motility and morphology.
Men with severe oligozoospermia (less than 5 million ml orazoospermia should undergo hormonal evaluation testosterone fsh and lh the most instructive parameter is an level greater than twice upper limit of normal suggests severely impaired spermatogenesis.
Low levels of FSH, LH and testosterone indicate hypogonadotropic hypogonadism. These men have a delay in the onset of puberty, poor secondary sexual characteristics and small firm testes. Treatment includes testosterone replacement but testicular growth and the initiation of spermatogenesis requires gonadotrophin replacement.
Hypogonadotropic hypogonadism can be due to a pituitary tumour. This often presents with a decreased libido, an elevated serum prolactin level and decreased serum testosterone and LH levels.
All severely oligozoospermic and azoospermic men should undergo karyotyping. The incidence of chromosomal abnormalities is approximately 5%. Around 7% of all infertile males, and 23% of those with azoospermia, have deletions in an area of the long arm of the Y chromosome, divided into AZFa, b and c.
A deletion of AZFa predicts no spermatogenesis, whereas microdeletion of AZFc is the most common genetic abnormality in testicular failure, and 70% of men carry sperm in their testicular tissue.
|WHO reference ranges for semen variables|
|New WHO criteria (2009)||Old WHO criteria (1999)|
|Sperm count (million/ml)||>15||>20|
|Total motility (per cent)||>40||>50|
|Morphology (normal forms)||>4%||>15 per cent|
Section 3: Managing the condition
Patients with mildly abnormal semen analysis may benefit from lifestyle adjustments, such as stopping smoking and recreational drugs, limiting caffeine and alcohol, regular (not excessive) exercise, a healthy diet, avoiding excessive heat and limiting stress. Some authorities also recommend nutritional supplements (vitamin C and E, selenium, zinc, folic acid and CoQ10). The use of lubricants should be avoided.
Transurethral resection of ejaculatory ducts: pre-operative (top) and postoperative (above)
The role of medical treatments in male subfertility is uncertain.
On an empirical basis, the WHO and European Association of Urology endorse the use of tamoxifen for idiopathic oligozoospermia, which prevents the negative feedback of estrogens to the hypothalamic-pituitary axis, increasing FSH production and spermatogenesis.
Therefore if the FSH is not elevated, it can be given at a dose of 20mg per day. Some studies have shown a significant improvement in sperm concentration,3 while a meta-analysis did not.4 Clomifene citrate acts in the same way, but has estrogenic effects and is less effective in improving semen quality.
Exogenous testosterone therapy should be avoided as this may cause prolonged azoospermia through a negative feedback mechanism.
In the case of hypogonadotropic hypogonadism, if pregnancy is not desired, then treatment can be testosterone replacement alone. However, in those attempting to have children, hCG and human menopausal gonadtrophin with or without recombinant FSH can be used to stimulate a combination of spermatogenesis and testosterone production.
Oxidative stress plays a part in sperm health, and although there are many studies suggesting benefit, the role of antioxidants is not fully defined.
Varicocele repair is the most common operation performed for male infertility. The best results and the lowest morbidity are achieved by a microsurgical ligation via a small subinguinal incision. One study showed a 69% pregnancy rate at two years.5 It can also be performed via the more invasive inguinal or retroperitoneal (laparascopic) approach. An even less invasive but less successful technique is radiological embolisation of the testicular vein.
Transurethral resection of ejaculatory ducts (TURED) is a treatment for ejaculatory duct obstruction (EDO), which is usually due to either post-inflammatory occlusion of the ejaculatory ducts, or a midline Mullerian cyst within the prostate. This should be suspected in azoospermia associated with a low-volume, low-pH ejaculate.
TURED involves injection of the seminal vesicles with methylene blue, and resection of the ejaculatory ducts.
Vasovasostomy is the most cost-effective treatment following a previous vasectomy. Approximately 4% of men who have had a vasectomy will seek reversal. The highest success rates are achieved by microsurgeons working with an operating microscope.
Epididymovasostomy is carried out for epididymal obstruction, but is a difficult surgical procedure requiring advanced microsurgical skills, and has lower success rates than vaso-vasostomy.
Surgical sperm retrieval techniques include percutaneous epididymal sperm aspiration, which is suitable for when there is a distended epididymal head full of sperm; microsurgical epididymal sperm aspiration, which involves analysis of epididymal fluid during microsurgical reconstruction; testicular sperm aspiration and testicular sperm extraction (TESE), which is a testicular biopsy to remove an area of testicular tissue. Micro-TESE is microscope-assisted extraction of testicular tissue.
Section 4: Prognosis
Intracytoplasmic sperm injection has made paternity possible where sperm count is low (birth rate of up to 35% when the female partner is young).
Where there are no sperm in the ejaculate, approximately 50% of cases of obstruction can be surgically de-obstructed, and in cases of testicular failure, surgical sperm retrieval and microdissection of the testicular tissue can lead to sperm being harvested in situations previously not thought possible (see table below).
|Sperm retrieval rates in poor prognosis groups6-9|
|Clinical pregnancy rate|
|One to two failed biopsies||51%|
|Three to four failed biopsies||23%|
|Pure sertoli cell only||24%|
In non-obstructive azoospermia, suitable sperm can be obtained in 65% of men and can even be retrieved in poor-prognosis groups.6,7,8,9
Section 5: Case study
A 32-year-old man presented to his GP after a year of trying to conceive. General and digital rectal examination were normal, he had normal volume and consistency testes, and both vasa were palpable in the scrotum.
Initial hormonal analysis of his 28-year-old partner was normal. Semen analysis revealed azoospermia. This was confirmed on a second sample.
His GP arranged a male hormone profile (testosterone, FSH and LH), karyotype and Y-microdeletion screen but these were all normal. A cystic fibrosis screen was not required as both vasa were clearly palpable. The couple were referred to a joint andrology/fertility clinic, and review of his semen analysis revealed a volume of 0.3ml and pH of 7.2.
These parameters in the context of azoospermia are suggestive of an EDO, and a transrectal ultrasound scan of the prostate and seminal vesicles was arranged. This revealed dilated seminal vesicles and ejaculatory ducts consistent with EDO.
It was explained to the patient that TURED will restore sperm to the ejaculate in 60% of cases. He was told that the procedure required catheterisation overnight but can be carried out as a day-case and has very few side-effects. He opted to proceed, and he had a smooth recovery.
Semen analysis three months postoperatively revealed a sperm count of 18 million/ml. The couple went on to conceive and did not require any further fertility treatment.
Section 6: Evidence base
There are few randomised trials within the arena of urological intervention for the infertile male. However, there have been a number of studies of varicocele and its treatment, and these are summarised in the meta-analysis below:
- Evers JL, Collins JA. Assessment of efficacy of varicocele repair for male subfertility: a systematic review. Lancet 2003; 361(9372): 1849-52.
There are also large scale studies demonstrating the superior results of microsurgery in reconstruction and vasectomy reversal:
- Belker AM, Thomas AJ Jr, Fuchs EF et al. Results of 1,469 microsurgical vasectomy reversals by the Vasovasostomy Study Group. J Urol 1991; 145(3): 505-11.
- Van Steirteghem A, Nagy P, Joris H et al. The development of intracytoplasmic sperm injection. Hum Reprod 1996; 11 Suppl 1: 59-72.
This article discusses intracytoplasmic sperm injection, which has transformed prognosis in severe male infertility.
- WHO laboratory manual for the examination and processing of human semen. Fifth edition. Department of Reproductive Health and Research, World Health Organization, 2010.
These are guidelines for the examination of semen and sperm parameters. They were updated in 2010 with parameters based on the fifth centile.
- Dohle GR, Colpi GM, Hargreave TB et al. European Association of Urology guidelines on male infertility. The EAU Working Group on Male Infertility. Eur Urol 2005; 48: 703-11.
- Sharlip ID, Jarow JP, Belker AM et al. Best practice policies for male infertility. Fertil Steril 2002; 77(5): 873-82.
- Oehninger SC, Kruger TF. Male Infertility: Diagnosis and Treatment. Informa Healthcare, 2007.
A comprehensive text covering all aspects of male infertility.
This is an excellent website of a world-leading male fertility centre that is full of good information, particularly on the fertility evaluation, medical and surgical treatments and general lifestyle advice.
This webpage from the American Urological Association has an up-to-date comprehensive summary of the optimal evaluation of the infertile male.
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1. Laven JS, Haans LC, Mali WP et al. Fertil Steril 1992; 58(4): 756-62.
2. Evers JL, Collins JA. Lancet 2003; 361(9372): 1849-52.
3. Adamopoulos DA, Pappa A, Billa E et al. Fertil Steril 2003; 80(4): 914-20.
4. Liu PY, Handelsman DJ. Hum Reprod Update 2003; 9(1): 9-23.
5. Goldstein M, Gilbert BR, Dicker AP et al. J Urol 1992; 148: 1808-11.
6. Schiff JD, Palermo GD, Veeck LL et al. J Clin Endocrinol Metab 2005; 90(11): 6263-7.
7. Meseguer M, Garrido N, Remohi J et al. Hum Reprod 2003; 18(6): 1281-5.
8. Ramasamy R, Schlegel PN. J Urol 2007; 177(4): 1447-9.
9. Hung AJ, King P, Schlegel PN. J Urol 2007; 178(2): 608-12.