Causes of Male Infertility

Causes of male infertility can be classified in a number of different ways:

 anatomically: pre-testicular, testicular and post-testicular

 pathophysiologically (Table 1)
 according to the associated factors (Table 3)

Pathophysiological classification of male infertility

Hypothalamic pituitary disease (secondary hypogonadism) (1–2%)
Testicular disease (primary hypogonadism) (30–40%)
Sperm transport problems (10–20%)
Unexplained (40–50%)

Causes of male infertility using pathophysiological classification

Hypothalamic pituitary disease
Congenital Congenital GnRH deficiency (Kallmann's syndrome)
Genetic disorders that affect multiple organs (e.g. Prader–Willi and
Laurence–Moon–Biedl syndromes)
Haemochromatosis
Acquired Pitutatary and hypothalamic tumours
Trauma (surgery, irradiation)
Vascular
Infiltrative disorders (sarcoidosis, tuberculosis)
Drugs/hormonal (↑prolactin, ↑testosterone, ↑estrogen)
Systematic disorders (chronic illness, malnutrition, morbid obesity)
Testicular disease
Congenital Kleinefelter’s syndrome
Cryptorchidism
Y chromosome deletions
Defective androgen synthesis or response (5a-reductase deficiency,
androgen insensitivity)
Acquired Varicocele
Infection
Drugs
Environmental toxins
Smoking
Hyperthermia
 Antisperm antibodies
Systematic disorders
Sperm transport Epididymis
problems Vas Deferens
Seminal vesicles and prostate?
Defective ejaculation
Unexplained Unexplained

Male infertility associated factors (and percentage of distribution in 10 469 patients)*

Idiopathic male infertility 31%
Varicocele 15.6%
Hypogonadism 8.9%
Urogenital infection 8.0%
Maldescended testes 7.8%
Disturbance of semen deposition and sexual factors 5.9%
Immunological factors 4.5%
General and systemic disease 3.1%
Obstructions 1.7%
Others 5.5%

Congenital Disorders
Hypogonadism is a combination of impaired spermatogenesis and testosterone production in the
testicles after puberty. Men with infertility from hypogonadism present with impaired semen
analysis and decreased testicular volume.

Hypergonadotrophic hypogonadism (primary testicular failure) is more common than

hypogonadotrophic hypogonadism (secondary testicular failure.)

Hypothalamic–pituitary disease (secondary hypogonadism)

Congenital or acquired disorders can cause gonadotrophin-releasing hormone (GnRH) or

gonadotrophin deficiency and, therefore, infertility.

Congenital disorders

Idiopathic hypogonadotrophic hypogonadism (commonly known as hypo-hypo) is characterized by

isolated gonadotrophin deficiency. Hypo–hypo can be caused by either anatomic or functional
problems. This results in sexual underdevelopment, eunuchoidal body habitus and sometimes
anosmia (Kallmann's syndrome).
More than half of patients with Kallmann syndrome have associated somatic stigmata, most
commonly, nerve deafness, colour blindness, mid-line cranio-facial deformities such as cleft palate
or harelip, and renal abnormalities. Most are of normal or above average stature. Females may
present with primary amenorrhoea; males with cryptorchidism.

Other genetic disorders of gonadotrophin secretion include haemochromatosis, the Prader–Willi

syndrome and the Laurence–Moon–Biedl syndrome.

Chromosomal abnormalities

Infertile men with poor semen (i.e. low count, low motility and morphology) have increased
frequency of chromosomal abnormalities.

A sperm count of ≤10 million/ml have a ten-times higher incidence of autosomal abnormalities (4%),
which are numerical or structural (translocations). In a large series of infertile men (Vincent MC et al
2002) the incidence of chromosomal abnormality was 5.8%. Sex chromosome abnormality was 4.2%
and autosomal was 1.5% (Johnson MD 1998).

Acquired Disorders
GnRH neuron destruction or hypothalamic-pituitary circulation interruption can be due to pituitary
macroadenomas (mainly prolactinomas), craniopharyngiomas as well as the surgical therapy of the
above. Less common causes include vascular lesions and infiltrative disorders such as sarcoidosis and
tuberculosis.

Functional inhibition of GnRH or gonadotrophin secretion can be caused by hyperprolactinaemia,

androgen, estrogen, or cortisol excess. Any cause of hyperprolactinaemia, drugs, hypothyroidism,
prolactinomas may be incriminated. Androgen excess may be due to the abuse of anabolic steroids
or due to congenital adrenal hyperplasia or tumors of the testis or adrenal glands.

Estrogen excess may be due to estrogen producing testicular tumors. Any serious systemic illness or
chronic nutritional deficiency can cause hypo-hypo and infertility. Massive obesity has a similar
effect.

Testicular Disease
Primary hypogonadism (hypergonadotrophic) can also be due to congenital or acquired pathology.

Congenital causes
Klinefelter's Klinefelter's syndrome has an incidence of one in 500–1000 in newborn males.
syndrome An extra X chromosome (XXY) is the most frequent reason although cases of
chromosomal mosaicism (e.g. XY/XXY) have been described. These men are tall,
with cognitive and behavioural difficulties being common
Cryptorchidism Cryptorchidism is failure of descent of the testes into the scrotum during fetal
development. This may result in the testes being within the abdomen, inguinal
canal, or other location. Both unilateral and bilateral cryptorchidism, are
associated with impaired spermatogenesis and an increased risk of testicular
 tumours. (Relative risk of testicular cancer 7.5 compared with the general
population.) Remember, the testes are more retractile to start with. If they are
permanently in the scrotum by the end of the first year of life then there is no
problem
Y chromosome Y chromosome deletions are increasingly recognised as a genetic cause of azoo-
deletions and severe oligozoospermia. Up to 20% of infertile men may have
microdeletions in the long arm of the Y chromosome, (many to the Yq11 region
of the chromosome, most commonly the AZFc region of Yq11). Testicular
biopsies in these cases show severe reduction is spermatogenesis, germinal
arrest, or Sertoli cell-only syndrome. These deletions may also be detectable in
men with disorders such as cryptorchidism, varicocele, and obstructive lesions of
the vas deferens. The deletions, therefore, may cause abnormalities in testicular
development as well as spermatogenesis
Defective Defective androgen synthesis or response, congenital androgen insensitivity and
androgen 5α-reductase deficiency should be included here. Reifenstein's syndrome is
synthesis partial androgen insensitivity characterised by varying degrees of ambiguous
external genitalia, hypogonadism, and infertility. 5α-reductase deficiency
presents as pseudohermaphroditism with increased virilisation at puberty, small
phallus, severe hypospadias and cryptorchidism

Acquired Causes

Varicoceles
Varicoceles are dilatations of the pampiniform plexus of spermatic veins in the scrotum.
Left-sided varicoceles are ten times more common than right-sided ones, perhaps because of a
longer left spermatic vein and the right-angle insertion into the left renal vein, which cause a higher
hydrostatic pressure and dilatation in the left spermatic vein.
Varicoceles are found in 11.7% of adult men and 25.4% in men with abnormal semen analysis. The
reversibility of infertility with surgery is controversial and the 2013 NICE guidelines recommend
that men should not be offered surgery to improve fertiltiy, as it does not improve pregnancy rates
However, the European Association of Urology Guideline on Male Infertility (2012) does suggest
that DNA damage may improve after varicoceles ligation.
Infection/viral orchitis
Infection viral orchitis, especially mumps, is a well-recognised cause of infertility.
While rare before puberty, clinical orchitis occurs in 15–25% of adult men.
In mumps and other viral causes of orchitis (echovirus and arbovirus) sperm production problems
are much more common than androgen deficiency.
Other infectious causes of orchitis include sexually transmitted diseases, such as gonorrhoea and
chlamydia, as well as tuberculosis and leprosy.
Drugs
Many drugs are associated with impaired spermatogenesis and/or Leydig cell dysfunction.
The alkylating drugs (cyclophosphamide and chlorambucil), antiandrogens (flutamide, cyproterone,
spironolactone, ketoconazole, and cimetidine) cause testicular dysfunction by inhibiting testicular
androgen production or action.
Environmental toxins
Environmental toxins may be an underappreciated cause of subfertility.
The pesticide dibromochloropropane is a well-known cause, as are lead, cadmium and mercury.
The possibility that chemicals with estrogenic or antiandrogenic activity, including insecticides and
fungicides, may lower sperm counts has attracted much attention, although direct proof of an
effect in men is lacking.
Radiation should also be included here.
Smoking
In a meta-analysis of 20 observational studies, men who smoked cigarettes were more likely to
have low sperm counts.
Prolonged hyperthermia
High testicular temperature may explain the infertility associated with varicoceles and spinal cord
injuries.
Studies in rodents and non-human primates have shown that small increases in testicular
temperature accelerate germ cell loss.
However human data on this topic are lacking.
Antisperm antibodies
Some infertile men have antisperm antibodies, which presumably could impair spermatogenesis.
These antibodies can occur spontaneously or after some testicular injury (vasectomy included).
DNA fragmentation
Oligospermic men have increased DNA damage in spermatozoa, which reduces the chances of
natural conception, as well as assisted reproductive techniques. There is increased early pregnancy
loss.
Systemic disorders
Chronic renal insufficiency, cirrhosis, or malnutrition may cause hypogonadism.
Infertility is common in men with sickle cell anaemia, presumably due to ischaemia inside the
testes.
Sperm motility and morphology abnormalities have been reported in men with celiac disease.

Sperm Transport Problems

Epididymis

The epididymis is the site of sperm maturation. Its absence, obstruction or dysfunction leads to
infertility even though testicular sperm production is normal.

Drugs (e.g. triptolide), chemical toxins (chlorhydrin) or intrauterine exposure to estrogens may cause
epididymal dysfunction.

It is presumed that some men with isolated asthenozoospermia have epididymal function defects.
Vas deferens

The vas deferens transports sperm from the epididymis to the urethra. 1–2% of infertile men have
congenital absence of the vas deferens. Most are carriers of cystic fibrosis mutations.

Obstruction may result from infection (gonorrhoea, chlamydia, tuberculosis). Vasectomy, may be
reversible, but some men have an immune response and remain infertile despite adequate
reanastomosis.

Another genetic defect that may lead to abnormal transport of sperm is Young's syndrome
(bronchiectasis, rhinosinusitis, reduced fertility) in which inspissated secretions within the vas
deferens and epididymis interfere with transport of sperm and produce secretions that contribute to
the spermatic fluid.

It is unknown if abnormal function can cause subfertility.

Seminal vesicles and prostate

The seminal vesicles and prostate produce secretions that contribute to the spermatic fluid. It is
unknown if abnormal function can cause subfertility.

Defective ejaculation

Spinal cord or autonomic disease (e.g. diabetes) can interfere with normal ejaculation.

Erectile dysfunction and premature ejaculation may be contributing factors.

Unexplained Male Infertility

Oligo-astheno-teratozoospermia syndrome (OATS) is the most common diagnosis and is classified as

unexplained infertility.

Environment pollution, genetic aberrations and reactive oxygen species (ROS) are forerunners in the
most possible causes of unexplained male infertility.

Environment pollution

Men exposed to pesticides have higher serum estradiol concentrations, and men exposed to
solvents had lower LH concentrations with impaired androgen production. This leads to lower
testosterone:estradiol ratio and impaired spermatogenesis (Oliva et al 2001).

Genetic aberrations

Our understanding of spermatogenic genetic infertility is gradually widening with the advances in
molecular diagnostic technology. An exciting pilot study detecting genetic variants single-nucleotide
polymorphisms (SNPs) in men with oligozoospermia and azoospermia identified 21 novel
SNPs related to male infertility. This is very promising and further, larger studies are required to give
insight in male spermatogenic infertility (Ferlin et al 2007), Aston et al 2009)

Reactive oxygen species (ROS) and oxidative stress

ROS (H2O2 – hydrogen peroxide, OH-hydroxyl radicals, O2-oxide anions) are normal metabolites of
sperm metabolism and leucocytes in the semen.

At low levels, ROS enhance sperm capacitation, sperm hyperactivation and promote acrosomal
reaction. At higher levels, ROS damage the sperm membrane reducing sperm motility, acrosomal
reaction and zona pellucida binding of the spermatozoa. In addition, ROS directly damage the sperm
DNA (DNA fragmentation) leading to failure of conception and miscarriages.

Antioxidant therapy, i.e.vitamin E, vitamin C, folate, lycopene, zinc, selenium and garlic have shown
to significantly increase pregnancy rates for couples where the men have higher levels of ROS and
sperm damage (Tremelen 2008).

A Cochrane analysis showed a significantly higher birth rate in subfertile men taking oral
antioxidants compared to men taking the control (Showell 2011).

Empirical treatments

Empirical treatments like antiandrogens, androgens, gonadotrophins, hCG, aromatase inhibitors,

corticosteroids, bromocriptine, α-blockers and magnesium supplements have no scientific evidence
and are not effective in the treatment of OAT syndrome. Recommendation for medical treatment of
male infertility is only for cases of hypogonadotrophic hypogonadism.

Evaluation of Male Infertility

History Taking

A detailed history gives us important information about the following:

Developmental Testicular descent

Puberty
Change in shaving frequency
Loss of body hair
Infections Mumps
Sexually transmitted diseases
Prostatitis
Sinopulmonary symptoms
Surgical Hernia repair
Vasectomy
Drugs/environmental Alcohol
Anabolic steroids
Chemotherapy
Drugs that cause hyperprolactinaemia
Exposure to toxic chemicals (e.g. pesticides)
Radiation
Sexual history Libido
Frequency of intercourse
Previous fertility assessment
Chronic medical illness Any

Physical Examination

General Increased body fat and decreased muscle mass may suggest androgen
appearance deficiency
Arm span more than 5 cm greater than height may suggest androgen deficiency
starting before puberty (delayed closure of the epiphyses)
Skin Loss of pubic, axillary and facial hair
Decreased oiliness of the skin
Fine facial wrinkling (suggesting long-standing androgen deficiency)
External
genitalia Examination of the scrotum can reveal
absence of the vas, epididymal enlargement
or varicocele
The presence of a varicocele should be
confirmed with the man standing and
performing a Valsalva maneuver
Decreased testicular size is assessed by
experience or by the Prader orchidometer
Look for hernias
This consists of a collection of ellipsoids with
volumes from 1 to 35 ml
Testicular volume below 15 ml is considered
small
Breasts gynecomastia suggests increased estrogens
Incomplete sexual development can be recognised by examining the phallus
and testes and using a Tanner puberty table
Undescended testicle
Tanner puberty table

Tanner stages of puberty in normal adolescent boys

Stage of Age Genitalia Serum testosterone

puberty (years) (ng/dl)

1 Prepubertal 27

2 11.6 ± Testes and scrotum begin to enlarge. Change in 251

1.1 texture and reddening of scrotal skin

3 12.9 ± Beginning growth of the penis mainly in length. 336

1.0 Scrotum and testes continue to grow

4 13.8 ± Further growth of penis. Further darkening of scrotal 525

1.0 skin

5 14.9 ±
Adult size 571
1.0

Semen analysis

The semen analysis should be performed according to the World Health Organization (WHO)
Laboratory Manual for Human Semen and Sperm Cervical Mucus Interaction. The sample should be
collected after 2–7 days of sexual abstinence, preferably at the fertility clinic by masturbation.

If this is not possible, then samples can be collected with condoms without chemical additives and
delivered to the laboratory within an hour of collection.

If routine semen analysis is abnormal, it should be repeated. It does not always distinguish fertile
from infertile men.

Semen analyses from 4500 men from 14 countries in four continents were obtained from
retrospective and prospective analyses on fertile men, men with unknown fertility and men selected
as normozoospermic. Men whose partners had time to pregnancy of <12 months were chosen as
individuals to provide the reference values.

The fertile ranges were a total sperm count of 39 million per ejaculate, sperm concentration of 15
million/ml, vitality of 58%, progressive motility of 32% and morphological normal forms of 4%.
WHO reference values for human semen characteristics of fertile men
Parameter Lower reference limit

Semen volume (ml) 1.5 (1.4–1.7)

Total sperm number (106 per ejaculate) 39 (33–46)

Sperm concentration (106 per ml) 15 (12–16)

Total motility (PR+NP [%]) 40 (38–42)

Progressive motility (PR [%]) 32 (31–34)

Vitality (live spermatozoa [%]) 58 (55–63)

Sperm morphology (normal forms [%]) 4 (3.0–4.0)

Other consensus threshold values

pH ≥7.2

Peroxidase-positive leucocytes (106 per ml) <1.0

MAR test (motile spermatozoa with bound particles [%]) <50

Immunobead test (motile spermatozoa with bound beads [%]) <50

Seminal zinc (µmol/ejaculate) ≥2.4

Seminal fructose (µmol/ejaculate) ≥13

Seminal neutral glucosidase (mU/ejaculate) ≥20

Semen analysis explanation

Semen volume

Semen volume is normally 1.4–1.7 ml. A low volume in the presence of azoospermia or severe
oligozoospermia suggests genital tract obstruction.

Congenital absence of vas deferens is diagnosed by physical examination and low semen pH.
Ejaculatory duct obstruction is diagnosed by the finding of dilated seminal vesicles on transrectal
ultrasonography. Retrograde ejaculation should be suspected in cases of neuropathic disorders,
including urogenital tract surgery, sympathetic denervation and diabetes.
Sperm concentration

Sperm concentration is normally above 12 million/ml. If no spermatozoa are seen, the semen should
be centrifuged and the pellet examined for the presence of spermatozoa, before the diagnosis of
azoospermia is reached. The presence of any sperm in the pellet will allow for intracytoplasmic
sperm injection (Intracytoplasmic sperm injection). For IVF, 10 million/ml or even less can be
satisfactory. Round cells may be leucocytes, immature germ cells or degenerating epithelial cells.
Leucocytes can be seen microscopically, with more than 1 million/ml indicating infection.

Sperm motility

Total sperm motility should be above 38%. Progressive motility should be 31% and above.

Agglutination suggests autoimmunity, which should be confirmed by tests for sperm surface
antibodies (mixed antiglobulin reaction). If sperm motility is poor, sperm vitality can be assessed by
the hypoosmotic swelling test to determine if the immotile spermatozoa are dead.

Sperm morphology

Sperm morphology is assessed microscopically on examination of a dried, fixed and stained drop of
semen smear. The morphology of the spermatozoa are assessed according to strict criteria.

Characteristics of a normal human spermatozoan according to the strict criteria include:

 smooth oval head

 a well-defined acrosome covering 40%–70% of the head
 a slender axially attached mid piece, 1.5-times the head length
 a uniform tail, thinner than the mid piece, eight to ten times longer than the head

Specialized semen analyses

Sperm agglutination tests (immunobead tests) are now routinely performed because a positive
agglutination test shall decide if ICSI is appropriate.

Biochemistry tests, zona-free hamster oocyte penetration tests and computer-assisted sperm
analysis are no longer used. Future developments in the investigation of male infertility include the
sperm DNA fragmentation index (DNAFI) and sperm aneuploidy tests. These tests not only give
therapeutic options but can be very helpful in counselling patients. Assisted reproductive techniques
have now taken precedence in male infertility treatment.

Impact of WHO's 2010 reference values for human semen

The new reference values are markedly lower than previous values. Previously diagnosed infertile
men would be now fertile. Though the reference values are from controlled time to pregnancy (TTP)
groups from different parts of the world, they are somewhat biased as they are limited to the
population analysed and the biases in laboratory methods in spite of standardised WHO criteria
Endocrine tests

Endocrine tests

If repeated semen analyses demonstrate severe oligozoospermia (<5 million spermatozoa/ml) or

azoospermia, then basal serum FSH, LH, and testosterone:estradiol ratio (t:E) should be measured. If
the t:E ratio is <10, then antiestrogen therapy may be beneficial to improve the semen analysis.

Serum testosterone

Low serum FSH, LH and low testosterone warrants gonadotrophin treatment (hCG and combination
of FSH with LH). Testosterone suppresses the endogenous LH, which in turn affects
spermatogenesis. Testosterone therapy has to be titrated with serum levels, which is difficult with
available preparations.

Serum LH and FSH

If serum concentrations of FSH, LH, and testosterone are normal and the man has azoospermia, a
postejaculatory urine sample will provide evidence about retrograde ejaculation if sperm are seen in
the urine. If spermatozoa are not present in the postejaculatory urine, the man has obstructive
azoospermia or impaired spermatogenesis. When testosterone is low, high FSH and LH indicate
primary hypogonadism while normal values indicate secondary hypogonadism. Men with low sperm
counts and low LH who are well-androgenised should be suspected of anabolic steroid abuse.

The serum testosterone can be low, normal, or high depending upon the specific substance taken.
Sperm production recovers in most men when they stop using anabolic steroids; however, this
process can take years.

Prolactin

Prolactin should be measured in men who complain of reduced libido and have low serum
testosterone.

Low serum inhibin B may be a more sensitive indicator of primary testicular dysfunction than high
FSH.

Treatment of Male Infertility

Many treatments have initially been reported to improve male fertility only to be later proven
ineffective.
There are two main reasons for this; firstly, the use of semen quality as the outcome measure, and
secondly, the noninclusion of controls. Pregnancy should be the main outcome in male fertility
studies because semen quality can show considerable background variability.

A control group should be included, as it is possible for untreated men with severe deficiencies in
their semen analysis to make their partners pregnant.

Specific treatment

Specific treatment is possible only in cases of hypo–hypo. If this results from hyperprolactinaemia,
lowering the serum prolactin concentration should be all that is required.

Relevant medication should be stopped. Dopamine agonist, such as cabergoline or bromocriptine

should be used for adenomas.

Normal spermatogenesis takes 3 months, so restoration of a normal sperm count does not occur for
up to 6 months (or more) after serum prolactin and testosterone have normalised.

If serum testosterone does not increase to normal within 6 months of prolactin normalisation, hCG
or pulsatile GnRH is indicated.

Artificial reproductive techniques have surpassed medical treatments and have increased the
pregnancy rates in partners of men with OATS.

Assisted reproductive techniques

Assisted reproductive techniques (ART) are used for the treatment of men with moderate or severe
oligozoospermia and azoospermia.

ICSI is the main revolution in male infertility in men with low sperm count, low sperm motility, low
strict sperm morphology and sperm agglutination. A normal-looking spermatozoa is immobilised by
teasing the tail and injected in the cytoplasm of the oocyte.

Intrauterine insemination

Intrauterine insemination consists of centrifugation and the swim-up technique of the ejaculate in
order to remove non-motile cells, debris and prostaglandins. This concentrates motile sperm in a
small volume of culture medium. The motile sperm are then injected into the uterine cavity with a
soft catheter.

The other method used is the density gradient technique, which also separates motile spermatozoa
from leucocytes and bacteria, thus reducing the reactive oxygen species damage to the sperm DNA.
No trials are available as to which method is superior.

The insemination is timed just prior to ovulation, using home urine LH kits. Intrauterine insemination
is frequently combined with ovulation induction.

In couples diagnosed with male infertility, intrauterine insemination more than doubles the
pregnancy rate compared with intracervical insemination or timed natural cycles (OR: 2.2; 95% CI:
1.4–3.4).
The overall pregnancy rates and live birth rates remain low with intrauterine insemination in natural
or ovulation-enhanced cycles in male infertility.

In vitro fertilization

IVF is the stimulation of the ovaries with gonadotrophins and the aspiration of several oocytes from
ovarian follicles.

The main indication for IVF used to be tubal infertility in women with tubal blockage. However,
greater understanding of the pathophysiology of infertility and conception, along with rapid
advances in laboratory techniques, has increased the scope for IVF and ICSI as a therapeutic option
for conception for a wide range of indications.

Intracytoplasmic sperm injection

Intracytoplasmic sperm injection (ICSI) involves the direct injection of a single spermatozoon into the
cytoplasm of an oocyte.

It has revolutionized the treatment of men with very severe oligozoospermia, asthenozoospermia
and teratozoospermia. When there are no sperm in the ejaculate, ICSI can be performed with
spermatozoa isolated from testicular biopsies or fine needle aspirates. Successful pregnancy has
been reported even with injection of immature sperm cells, such as elongated spermatids.

The possibility of spermatozoa from men with severe sperm abnormalities and genetic disorders to
fertilise human oocytes raises the concern over the frequency of chromosomal abnormalities and
congenital malformations in live births following ICSI. In men with Klinefelter's syndrome and those
with Y microdeletions, their offspring might carry the same gene or have an increased risk of sex
chromosome aneuploidy.

Sperm selection for ICSI is dependent on the morphological features of spermatozoa. In infertile men
with OAT and surgically retrieved spermatozoa (i.e. PESA, MESA, TESA or testicular biopsy), sperm
selection is dependent on strict morphology as this shows better predictive value for IVF results
compared with the classical WHO criteria (4% strict morphology). The lower the strict morphology,
the higher the failure rates of fertilisation of oocytes with IVF (Menkveld et al 1991). Hence, strict
morphology is very helpful in counselling patients for ICSI as it helps to avoid the frustrations of
failed or poor fertilisation with IVF.

Donor insemination
Donor insemination is the alternative for many couples, including those who failed to conceive with
ART, single woman parent and female same-sex couples.
Pregnancy rates were as high as 50% with fresh donor sperms. Since the screening of donors for
sexually transmitted diseases, quarantine and storage of frozen semen, the pregnancy rates have
since gone down.

For women receiving frozen donor semen (intrauterine insemination) in 2008 the percentage of
cylces started that resulted in a live birth (national average) was:

 15.8% for women aged under 35 years (237/1497)

 11.0% for women aged 35-39 years (154/1394)
 4.7% for women aged 40-42 years (23/492)
 1.2% for women aged 43-44 years (2/172)
 0% for women aged over 44 years (0/46)

Figures in brackets are intrauterine insemination cycles resulting in a live birth rate/intrauterine
insemination cycles started (HFEA 2009).

Children born from pregnancies resulting from donor insemination grow and develop normally, both
physically and psychologically. This alternative, together with adoption and childlessness, should be
offered to all couples with male factor infertility.

From April 2005, children conceived using donor sperm (or eggs) are able to trace their biological
parent in the same way as children who are adopted.

Genital infections

The presence of increased leucocytes in the semen may decrease the functional capacity of the
sperm by the release of reactive oxygen species.

These men are sometimes labelled as having chronic prostatitis, but specific organisms are rarely
identified at culture.

The poor results of antibiotic treatment make it difficult to demonstrate a causal relationship
between genital infections and male infertility.

However, infections can lead to obstruction of the epididymis and vas deferens.

Sperm autoimmunity
Antisperm antibodies are produced after trauma, operations such as vasectomy and infection of the
genital tract. Autoimmunity to spermatozoa occurs due to a breach in the blood–testicular barrier.
Diagnosis of antisperm antibodies is by mixed antiglobulin reaction (MAR test) or the immunobead
test (IBT).

There are three types of antisperm antibodies. IgG and IgM are mainly found in the serum whereas
IgA is found locally in the genital tract. They impair sperm motility, reduce sperm penetration in the
cervical mucous, and affect the capacitation and acrosomal reaction interfering with sperm oocyte
interaction.
Detection of antisperm antibodies is not diagnostic of infertility from this. Infertility from antisperm
antibodies is probable if more than 50% of sperm are bound to the sperm antibodies.

Immunosuppressant therapy (i.e. corticosteroids) is very controversial for a number of reasons. In

placebo/double-blind crossover trials there is no agreement with the results (pregnancy rates),
dosage of corticosteroids and the duration of treatment. Secondly there were significant side effects
to show improvement in antisperm antibodies suppression (Cushingoid features with decreased
bone mineral density occurred in 60% of patients).

ICSI is the treatment of choice at present

Retrograde ejaculation

Retrograde ejaculation can be treated with intrauterine insemination using the male partner's
spermatozoa collected after alkalinisation of the urine and washing of the sperm.

Alternatively, the spermatozoa can be used for IVF or ICSI.

Varicocele

A varicocele is a collection of enlarged veins in the scrotum. It occurs next to and above one or both
of the testes and effects approximately one in seven men.

Normally, you can not see or feel the veins in the spermatic cord that carry the blood from the
testes; however, if the patient has a varicocele the veins become bigger (they enlarge or dilate),
making them more prominent, similar to varicose veins of the legs. While there is a higher rate of
infertility in men with a varicocele compared to those without, most men with varicoceles are not
infertile.

For detailed information on varioceles visit the varicocele section of the Patient UK website.

The causal relationship between varicocele and male infertility has been ascribed to increased
testicular temperature. In a WHO study of over 9000 male partners of infertile couples, a varicocele
was significantly more common in men with abnormal semen (25.4%) than in men with normal
semen (11.7%).

In a prospective multi-centre WHO trial to compare immediate varicocele ligation with operation
deferred for 1 year, 248 couples from 12 countries participated. The first-year cumulative pregnancy
rates were 34.8% in the immediate operation group and 16.7% in the delayed operation group
(p<0.003).

In addition to the markedly higher pregnancy rate, sperm concentration was significantly improved
at 3, 6, 9 and 12 months after surgery (all p<0.001).

These findings suggest that varicocele ligation is approximately 2.5 times more effective than
delayed operation. However, there were considerable loss to follow-up, particularly in the group of
men randomised to delayed operation. The Cochrane meta-analyses, however, have reported no
benefit of varicocele repair.

As previously mentioned the 2013 NICE guideline recommends (Grade A) men should not be offered
surgery for varicoceles.

Obstructive azoospermia

Obstructive azoospermia is suggested by the combination of azoospermia or severe

oligozoospermia, normal size testes, normal serum FSH, normal serum LH and normal serum
testosterone. Both surgery and ART may be options for such patients. Obstruction of the epididymis
can be treated by end-to-end anastomosis of the epididymal duct to epididymal duct or to vas.

The results are variable and depend on the site of reanastomosis, the skill of the operator, and the
duration of obstruction. Results are better with vasectomy reversals, with a pregnancy rate of over
50%, however this is very much dependant on the skill, experience and the surgical technique of the
urology surgeon. The longer it has been since vasectomy, the poorer the pregnancy rate.

Vasectomy reversal has been found to be more successful and cost-effective than microsurgical
epididymal sperm aspiration followed by IVF or ICSI. In contrast, for obstruction due to other
epididymal lesions, the results of surgical anastomosis are not as good as those with aspiration and
ICSI. Secondly, reversal of vasectomy is associated with anti-sperm antibodies (60-80%) in
the majority of vasectomy patients.

ART can be combined with the use of spermatozoa obtained by aspiration from the epididymis or
from the testes by biopsy or fine needle aspiration. Thus, men previously classified as sterile can
now be fertile.

Men with congenital bilateral absence of the vas may be cystic fibrosis carriers and there is a
possibility they will have children with cystic fibrosis. Such men and their partners should have
genetic screening and counselling.

Undescended testes (cryptorchidism)

The incidence of undescended testes is 2 – 5% in newborn baby boys and is more common in
preterm boys. The incidence decreases to 1 – 2% spontaneously at 3 months of age.

Aetiology is multifactorial. The maldescent may occur in the transabdominal or inguinal phase and
may be due to endocrine disruption, defective anti-mullerian regulation of abdominal descent, gene
deletion expressed on Leydig cells affecting androgen production and other gene deletions.
Undescended testes cause infertility and increases the risk of malignancy.

Orchidopexy at the early age of 9 months can result in a catch up growth (versus orchidopexy at 3
years of age) and may possibly improve spermatogenesis. Orchidopexy also reduces incidence of
malignancy. Testicular atrophy due to vascular damage is a severe complication of orchidopexy.
Hormonal treatment with hCG or GnRH helps a small percentage in the descent but a fifth re-ascend
later and hCG causes apoptosis of germ cells affecting future spermatogenesis. Hormone treatment,
therefore, has no place in the treatment of maldescended testes.

Empirical treatments

Many empirical treatments, such as anti-estrogens (clomifene and tamoxifene), zinc, pentoxifylline,
vitamin E, gonadotrophins, alpha-adrenergic agonists and kallikrein, have been used for male
infertility. When placebo-controlled prospective randomised trials have been performed, none of
these methods has been proven clinically effective in idiopathic oligospermia or azoospermia.

The common recommendation to subfertile men – to wear boxer underwear and not to take hot
showers or baths – also has little evidence in support. A study of men who wore tight athletic
supporters lined with polyester for 12 months found no impairment in semen quality. No change in
semen parameters were found in men taking frequent saunas or hot baths.

Summary

 No treatment is currently available in cases where the seminiferous tubules have been severely
damaged, such as in cases of Klinefelter's syndrome, microdeletions of the Y chromosome and
Sertoli cell-only syndrome. Fertility has been achieved in patients with Klinefelter's syndrome
and Sertoli cell-only syndrome using sperm retrieval and intracytoplasmic sperm injection.
However, there are important genetic implications of these procedures.
 In the future, germ cell transplantation may become a feasible treatment for male infertility.
Mouse germ cells have been used to initiate normal spermatogenesis in mice depleted of germ
cells due to genetic mutation or after chemotherapy, and have resulted in normal offspring
following mating with females. Successful germ cell transplants have been achieved from mouse
to mouse, rat to rat, and rat to immune-compromised mouse.
 Ectopic grafting of testis tissue from diverse donor species, including primates, into a mouse
host has opened an additional possibility to study spermatogenesis and to study toxicants or
drugs with the potential to enhance or suppress male fertility without the necessity of
performing experiments in the target species. This possibility, not the only one in the rapidly
advancing field of reproductive medicine, raises serious social and ethical issues.
 Artificial synthesis of spermatozoa by the Newcastle Group raises further issues – are we ready
for this?