Clinical Review – Subfertility in men

  • rowland rees

Contributed by Mr Rowland Rees, consultant urological surgeon, Royal Hampshire County Hospital, Winchester.

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.

Aetiology
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.

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
  • Environmental (smoking, marijuana, alcohol, phytoestrogens, general debility).
  • Antispermatogenic agents (cytotoxic chemotherapies, colchicine, sulphasalazine, nitrofurantoin, amiodarone).
  • Antimotility drugs (propranolol, chlorpromazine, quinine).
  • Anti-androgens: anabolic steroids (including testosterone replacement therapy), spironolactone, cimetidine, cyproterone.

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
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.

Investigations
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 (<5 million/ml) or azoospermia should undergo hormonal evaluation (testosterone, FSH and LH). The most instructive parameter is FSH, and an FSH level greater than twice the 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.

Genetic evaluation
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)
Semen volume >1.5ml >2ml
Sperm count (million/ml) >15 >20
Total motility (per cent) >40 >50
Morphology (normal forms) >4% >15 per cent
Source: www.who.int/reproductivehealth

 

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.

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
Sperm retrieval 
rate
Clinical pregnancy rate
Klinefelter’s syndrome 66% 28%
Post-chemotherapy 53% 22%
One to two failed biopsies 51%
Three to four failed biopsies 23%
Maturation arrest 47%
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.

Investigations
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
Clinical trials

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:

There are also large scale studies demonstrating the superior results of microsurgery in reconstruction and vasectomy reversal:

This article discusses intracytoplasmic sperm injection, which has transformed prognosis in severe male infertility.

Guidelines

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.

Key text

  • Oehninger SC, Kruger TF. Male Infertility: Diagnosis and Treatment. Informa Healthcare, 2007.

A comprehensive text covering all aspects of male infertility.

Online

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.

  • http://www.gponline.com/Clinical/article/1107681/clinical-review-subfertility-men/