Male factor infertility

The male partner is directly responsible for 25% of cases of infertility and is thought to play a contributory role in another 25%. Male factor infertility implies a lack of sufficient numbers of competent sperm, resulting in failure to fertilize the normal ovum. The World Health Organization (WHO) has proposed a set of criteria for normal semen parameters (Table 45.5). This is useful as a point of reference for results from different laboratories. A list of underlying factors responsible for male infertility compiled by the WHO is shown in Table 45.6. This classification needs to be updated in the light of recent scientific advances, especially in the genetic causes of defective sper-matogenesis. Some of the common causes are discussed below.

Table 45.5 Reference values for semen analysis

Parameter

Normal value

Volume

2.0 ml or more

PH

7.2-7.8

Sperm concentration

20 x 106/ml or more

Motility

50% or more with progressive

motility (Grade a or b)*

Morphology

15-30%+

Viability

75% or more live

White blood cells

Fewer than 1 x 106/ml

* Grade a: rapid progressive motility; Grade b: slow or sluggish motility.

+ Currently being reassessed by WHO. In the interim the proportion of normal forms accepted by laboratories in the UK is either the earlier WHO limit of 30 or 15% based on strict morphological criteria.

* Grade a: rapid progressive motility; Grade b: slow or sluggish motility.

+ Currently being reassessed by WHO. In the interim the proportion of normal forms accepted by laboratories in the UK is either the earlier WHO limit of 30 or 15% based on strict morphological criteria.

Adapted from: World Health Organization, 1999.

IDIOPATHIC IMPAIRMENT OF SEMEN QUALITY

In the majority of cases of male infertility the cause of impaired semen parameters is unknown. Azoospermia (absence of sperm) or significant oligozoospermia (sperm concentration <20 million per ml) may be associated with small soft testes and raised FSH levels. Histolog-ical changes within the tubules, such as the absence or reduced number of germ cells may be patchy and non-specific.

Asthenozoospermia implies impaired motility (less than 50%). Absent or very poor motility in sperm may be caused by structural abnormalities such as the absence of dynein arms, radial spokes or nexin bridges and dys-plasia of the fibrous sheath. Similar defects are seen within respiratory cilia in the Immotile Cilia Syndrome comprising respiratory infection, sinusitis and bronchiectasis. The presence of situs inversus in these men leads to a diagnosis of Kartgener's Syndrome.

Teratozoospermia is the term used to describe abnormal sperm morphology on microscopy. Although the assessment is inevitably subjective, observance of strict criteria can lead to a degree of consistency of reporting, at least within each laboratory. Morphology is believed to reflect maturity and functional integrity of sperm and has been related to acrosomal defects and sperm motility.

Table 45.6 Causes of male infertility

Cause

Prevalence (%)

No demonstrable cause

12.6

Varicocoele

11.2

Idiopathic oligozoospermia

11.2

Accessory gland infection

6.9

Idiopathic teratozoospermia

5.9

Idiopathic asthenozoospermia

3.9

Isolated seminal plasma abnormalities

3.5

Suspected immunological infertility

3.0

Congenital abnormalities

1.7

Systemic diseases

1.4

Sexual inadequacy

1.3

Obstructive azoospermia

0.9

Idiopathic necrozoospermia

0.8

Ejaculatory inadequacy

0.7

Hyperprolactinaemia

0.6

Iatrogenic causes

0.5

Karyotype abnormalities

0.1

Partial obstruction to ejaculatory duct

0.1

Retrograde ejaculation

0.1

Immotile cilia syndrome

<0.1

Pituitary lesions

<0.1

Gonadotrophin deficiency

<0.1

Adapted from: Rowe et al. 1993.

Adapted from: Rowe et al. 1993.

VARICOCELE

A varicocele is a group of dilated veins in the pampiniform plexus of the spermatic cord. On examination, it is visible as a tangle of distended blood vessels in the scrotum. Usually left sided, varicoceles develop at puberty and affect 15% of otherwise healthy men (Evers and Collins, 2003). Observational data (WHO, 1992) have suggested that clinically detectable varicoceles are present in 12% of normal men and 25% of men with semen abnormalities. Spermatogenesis is believed to be prejudiced by impaired vascular drainage from the testis due to increased scro-tal temperature, hypoxia, raised testicular pressure and reflux of adrenal metabolites (Evers and Collins, 2003). However, the presence of varicoceles in fertile men with normal sperm counts has led some workers to question the presence of a causal association.

GENETIC CAUSES

Chromosomal abnormalities have been detected in 2.18.9% of men attending infertility clinics and are related to the severity of the male factor problem. Azoosper-mia is associated with karyotypic abnormalities in 15% of cases, of which 90% are 47XXY (Klinefelter's Syndrome). Structural abnormalities of the Y chromosome, such as deletion of the distal fluorescent heterochromatin, may also be responsible for impaired spermatogenesis. Deletions affecting a family of genes on the Y chromosome have been found in 10% cases of non-obstructive azoospermia and some cases of severe oligozoospermia. Microdeletions have been found in three non-overlapping regions of the Y chromosome, AZF a-b-c. The commonest abnormality reported in the literature is a microdeletion in the AZFc region encompassing the DAZ gene (Hargreave, 2000).

CRYPTORCHIDISM

Undescended testes which remain untreated at 2 years of birth are likely to be histologically abnormal. Delay in surgical correction is associated with reduced fertility and a 4 to 10-fold increase in the risk of testicular cancer.

ORCHITIS

Symptomatic orchitis complicates 27-30% of cases of mumps in males. In 17% orchitis is bilateral and causes atrophy of the seminiferous tubules. Fertility is affected if bilateral orchitis occurs after puberty.

OCCUPATIONAL AND ENVIRONMENTAL FACTORS

Toxic effects of radiation, drugs, and chemicals can affect the rapidly dividing germ cells which are the precursors of spermatozoa. A number of heavy metals, chemicals and

Table 45.7 Therapeutic drugs interfering with male infertility

Drug

Action

Cancer Alkylating agents cause irreversible damage chemotherapy Hormone High-dose corticosteroids, androgens, treatment anti-androgens, oestrogens and LHRH

agonist

Cimetidine May competitively inhibit androgen effect on the receptor

Sulphasalazine Can cause impairment of sperm quality by direct toxicity

Spironolactone Antagonizes the action of androgen in some tissues

Nitrofurantoin May cause impairment of sperm quality by direct toxicity Niradozole May cause temporary depression of spermatogenesis Colchicine Cause depression of fertility by direct toxicity to spermatogenesis

Adapted from: Rowe et al. 1993.

pesticides have been associated with deranged spermato-genesis. Tobacco, cannabis, alcohol and lifestyle factors such as wearing tight underwear have also been linked with male infertility. Evidence regarding some of these associations is conflicting.

LATROGENIC

A number of commonly used drugs can impair semen quality. They are listed in Table 45.7, along with their mechanisms of action.

GENITAL TRACT OBSTRUCTION

Azoospermia in the presence of normal testicular volume and normal FSH suggests the possibility of genital tract obstruction. Previous vasectomy and congenital abnormalities are the principal causes, although infections such as tuberculosis and gonorrhoea predominate in some parts of the world. Congenital causes of obstruction of the male genital tract include agenesis or malformations of the Wolfian ducts affecting the epididymis and seminal vesicles. Congenital bilateral absence of the vas deferens (CBAVD) occurs in 2% of cases of obstructive azoospermia and is commonly associated with cystic fibro-sis (Hargreave 2000). Young's Syndrome is characterized by obstruction at the junction of the caput and the body of the epididymis, chronic lung infection and bronchiectasis.

MALE ACCESSORY GLAND INFECTION

Infections caused by gram negative enterococci, chlamy-dia, and gonococcus can present with urethral discharge, painful ejaculation, dysuria, haematospermia, tenderness of the epididymis and prostate. Confirmation is by semen culture, urethral swabs and the presence of more than 1 million polymorphonuclear leucocytes per ml of semen. Theroleof subclinical infection in thegenesis of maleinfer-tility is unclear and there is little consensus on appropriate criteria for diagnosis.

HYPOGONADOTROPHIC HYPOGONADISM

Hypogonadotrophic hypogonadism is a rare condition caused by congenital or acquired hypothalamic and pituitary failure. Where the condition is congenital, evidence of androgen deficiency usually leads to a diagnosis at puberty. A complete absence of GnRH results in absence of secondary sexual characteristics and total testicular failure. Many affected men have anosmia (Kallman's syndrome). Manifestations are less profound in men with partial deficiency. A diagnosis of hypogonadotrophic hypog-onadism is confirmed by low or undetectable levels of gonadotrophins (LH and FSH) and testosterone. Trauma, tumours or chronic inflammation can cause adult onset hypothalamic hypogonadism presenting with infertility.

COITAL DYSFUNCTION

Infertility in the male can be due to problems with intercourse. Causes of coital dysfunction in men are shown in Table 45.8.

Table 45.8 Coital dysfunction

Problem

Cause

Ejaculatory failure Spinal cord injury Medical disorders: Diabetes mellitus Multiple sclerosis Chronic renal failure Erectile or ejaculatory Depression problems Alcohol abuse

Medication: Adrenergic blocking agents Antihypertensives Psychotropic agents Psychosexual Loss of libido Hyperprolactinaemia

Retrograde Transurethral prostatectomy ejaculation Retroperitoneal lymph node dissection Neuropathy: Diabetic

Injury to lumbar sympathetic nerves Damage to bladder neck

Adapted from: Templeton et al. Management of infertility for the MRCOG and beyond RCOG, 2000.

IMMUNOLOGICAL CAUSES

Antisperm antibodies are detected in one in six men attending infertility clinics. They are IgG or IgA isotypes and may be present in serum, seminal fluid or bound to various sites on the spermatozoa. Risk factors for the development of antisperm antibodies include reversal of vasectomy, prior infection such as epididymitis, sexually transmitted diseases and orchitis. Their effect on infertility is unclear. It is believed that antisperm antibodies can affect with sperm motility, cause acrosomal reaction abnormalities and inhibit zona pellucida binding. Antisperm antibodies are also present in fertile men and current techniques do not allow a meaningful way of separating different epitopes (Paradisi et al. 1995).

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