REVIEW
Male infertility
Navdeep Ghuman
Mythili Ramalingam
Abstract
It is estimated that one in seven couples in the United Kingdom (UK)
experience some difficulty conceiving at some point in their reproduc-
tive life. The true incidence of male infertility is unknown due to vari-
ability in the prevalence of infertility reported from different countries.
A sub-optimal semen result has been reported in 30e50% of sub-
fertile couples: which could be either low sperm count, poor sperm
motility or sperm with abnormal size and shape (morphology). In
more than 50% of cases of male infertility, the aetiology remains un-
known and the infertility is classified as idiopathic. It is vital to establish
the cause in order to streamline the investigation and management.
Keywords intracytoplasmic sperm injection; male infertility; semen
analysis
Introduction
The true prevalence of male sub-fertility is difficult to estimate
due to lack of population based epidemiological studies in the
prevalence of male infertility. The NICE guidelines (NICE CG no
156) has quoted that 30e50% cases of infertility are due to male
factors. In the UK, low sperm count or quality is considered to be
the cause of infertility in about 20% of couples, and is also a
contributory factor in another 25% of couples. Although several
treatable conditions affect spermatogenesis and lead to male sub-
fertility, many aspects of male infertility are still unclear. Diag-
nostic work-up of male sub-fertility had come a long way from
semen analysis to a comprehensive approach which includes: a
detailed clinical history, physical examination, endocrines
assessment, genetic testing and sperm function studies in addi-
tion to routine semen analysis.
Spermatogenesis
At about sixth week of human embryonic development, undif-
ferentiated primordial gonads are formed from somatic mesen-
chymal tissue. These cells in the gonads differentiate into support
cells and hormone producing cells whereas germ cells migrate to
the gonads from yolk sac. The sex determining region of Y
chromosome gets activated during the development and kick
start the synthesis of a protein named testicular determining
factor (TDF). This in turn causes testicular development and
testosterone synthesis by Leydig cells. Mullerian inhibiting factor
from testis prevent the development of Mullerian ducts and
Navdeep Ghuman MBBS is a Clinical Fellow in Reproductive
Medicine at Ninewells Hospital, Dundee, Scotland, United Kingdom.
Conflicts of interest: none declared.
Mythili Ramalingam MBBS MRCOG is a Consultant Obstetrician and
Gynaecologist at Ninewells Hospital, Dundee, Scotland, United
Kingdom. Conflicts of interest: none declared.
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allows the Wolffian duct to develop into epididymis, vas deferens
and seminal vesicles. The germ cells or spermatogonia in the
seminiferous tubules undergo mitosis and meiosis to produce
mature but non-motile spermatozoa, which takes around 74
days. Spermatozoa acquire motility in epididymis and this pro-
cess of spermatogenesis including the transport in ductal system
takes 3 months.
Aetiology
Conditions leading to male infertility can be broadly classified as
below (Figure 1)

Hypothalamic-hypophyseal tract

Testicular disorders

Disorders of the seminal tract

Immunological

Psychosomatic

Previous treatments for cancers (chemotherapy) and other
medicines like testosterone supplements, anabolic steroids,
antifungals like ketoconazole and some antihypertensives.
Diagnostic work-up
The diagnostic workflow for male subfertility should follow a
systematic approach to ascertain the impact of past factors
influencing present fertility status. A thorough medical history
and physical examination should be followed by semen analysis
and hormonal profile. Further investigations such as chromo-
somal analysis and sperm function tests may be necessary
depending upon the results of the initial investigations.
Clinical history
The medical history should pay particular attention to history of
undescended testes, pubertal development delay, genital surgery
or infection, fertility in the current or previous relationships and
coital frequency, erection or ejaculation problems (Table 1)
Physical examination
Examination should look for evidence of sexually transmitted
diseases, conditions of testis, epididymis and presence of
hernias.
General physical examination should look for the presence of
male pattern escutcheon, distribution and density of axillary hair,
pubic hair and beard. Presence of small testes, phallus, and pros-
tate, scant pubic and axillary hair, and disproportionately long
arms and legs because of delayed epiphyseal closure (arm span 5
cm greater than height) are suggestive of Klinefelter’s syndrome. A
reduced male musculature, gynaecomastia and persistently high-
pitched voice are suggestive of hypogonadism before puberty.
Testicular examination
Testicular volume should be measured using Prader orchid-
ometer which consist of a string of twelve numbered wooden or
plastic beads of increasing size from about 1 to 25 ml. As
germinal tissue approximately forms 85% of testicular mass,
reduced germinal tissue is associated with reduced testicular
volume and soft consistency. Although ethnic and racial origin
influences testicular size, testicular growth is an indicator of
pubertal progression. A testicular volume of <4 ml is prepuber-
tal, 4e15 ml are considered peri-pubertal and 12e25 ml are taken
as adult size testis.
1 Ó 2017 Elsevier Ltd. All rights reserved.

Causes of male infertility
Male infertility
Hypothalamic
hypophyseal
Hyperprolactinaemia
Kallmann syndrome
Haemochromatosis Testicular
Pituitary tumours disorders
Chronic illness
Infection
Clinefelter syndrome
Testicular atrophy
Y chromosome deletions
Systemic disorders
Figure 1
Scrotal examination
Scrotal examination should look for any masses, scars of previ-
ous surgeries, varicocele and presence of palpable epididymis.
The presence of a varicocele should be confirmed with the man
standing and performing a Valsalva manoeuvre. Length of
stretched penis ranges from 10 to 17 cm in adults and 4e8 cm in
prepuberty. Examination should also look for the presence of
hernias and if there is any evidence of sexually transmitted dis-
eases, then further investigations should be considered.
Testicular ultrasound
Testicular ultrasound should ideally be performed with high
resolution 7.5e12 MHz linear transducer. It provides objective
evidence of testicular volume which can be 15% more precise
than palpation. Ultrasound improves the detection of testicular
(hydrocele, haematocele, spermatocele, testicular tumours) and
epididymal pathologies. The evidence of blood reflux on duplex
ultrasonography along with increased venous diameter on Val-
salva manoeuvre provides objective evidence of a possible clin-
ically significant varicocele. Epididymal caput size greater than
7.5 mm in diameter provides objective evidence for possible
obstruction. Further, trans-rectal ultrasound for prostrate and
seminal pathologies may be considered in cases of obstruction.
There is an argument in favour of carrying out routine testicular
ultrasound in sub-fertile men, because an increased risk of
testicular tumours (1 in 200e300 men) has been reported in this
group of men. Most often these tumours may not be palpable.
Ultrasonography improves the detection rate of scrotal pathol-
ogies; the detection rate is described in Table 2.
Semen analysis
Semen analysis is a primary tool to assess male fertility potential.
WHO 2010 standards for assessing semen quality are referred to
as ‘reference’ values as opposed to ‘normal’ values because these
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REVIEW
Psychosomatic
disorders
Immunological
disorders
Seminal tract
Autoimmunity to sperm
disorders
Retrograde ejaculation
Obstructive azoospermia
standards are derived from a population of fertile men. These
have been elaborated in detail in Tables 3 and 4. Semen
assessment using WHO reference values is only valid if WHO
described methodology is used for testing. It has been suggested
that although WHO criteria has a sensitivity of 89.6% but, it has
low specificity to detect true semen abnormalities. Performing a
second semen analysis will falsely identify 2% of men as
abnormal as opposed to a figure of 10% with a single semen
analysis. Ideally the second analysis should be scheduled at an
interval of three months from the first abnormal one as that is the
length of the sperm formation cycle. If this delay seems to cause
anxiety to male partner, then the test may be repeated in 6e8-
week time. In case of azoospermia second sperm test should be
performed in 2e4 weeks time.
Endocrinology profile
Hormone testing is the backbone of andrology work-up and
should be done when two semen analysis show severe oligo-
zoospermia or azoospermia. Testing for serum Follicle stimu-
lating hormone (FSH), Luteinising hormone (LH) and
testosterone can provide important input in differentiating hyper
gonadotrophic hypogonadism (primary testicular failure) from
Hypogonadotrophic hypogonadism (hypothalamic-pituitary
failure).
FSH level testing is more likely to be accurate on single blood
sample testing as FSH has a longer half life. Measurements of LH
on single sample may be erroneous on the other hand because of
its pulsatile release and shorter half life. As circulatory testos-
terone levels are highest in morning hours, it should be ideally
tested in the morning. Total circulatory testosterone level should
always be interpreted in light of clinical symptoms and along
with FSH and LH levels as these levels are influenced by varia-
tions in sex hormone binding globulin (SHBG). Increased SHBG
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 REVIEW
Components of male infertility history
Medical history Recent pyrexial illness
Systemic illness e diabetes mellitus, cancer,
infection
Genetic disorders e cystic fibrosis, Klinefelter
syndrome
Surgical history Undescended testes, orchidopexy
Hernia repair
Testicular trauma, torsion
Pelvic, bladder or retroperitoneal surgery
Fertility history Previous pregnancies e with current and
previous partners
Duration of infertility
Previous infertility treatments
Sexual history Erection or ejaculation problems
Frequency of intercourse
Medication Nitrofurantoin, cimetidine, sulfasalazine,
spironolactone, a -adrenergic blockers,
methotrexate, colchicine, amiodarone,
antidepressants, phenothiazines,
chemotherapy
Social history Alcohol, smoking, anabolic steroids,
recreational drugs
Exposure to ionising radiation
Chronic heat exposure
Aniline dyes
Pesticides
Lead exposure
Developmental Onset of puberty, history of cryptorchidism,
history history of anosmia/hyposmia, history of
galactorrhoea
Androgen deficiency Ejaculation problems, loss of libido, change in
shaving frequency, loss of body hair, loss of
muscle mass, breast tissue development,
voice change, fatigue, poor ability to
concentrate
Infection history Mumps, sexually transmitted diseases,
prostatitis
Table 1
levels associated with hyperthyroidism, liver disease, severe
androgen deficiency and oestrogen excess might lead to normal
total testosterone levels in spite of low free testosterone. In spite
of low production of testosterone, 40% of Klinefelter’s patients
may be tested to have normal range testosterone levels due to
increased SHBG levels following androgen excess.
Conversely testosterone levels may be falsely sub normal in
conditions causing low SHBG such as obesity, hypothyroidism
and acromegaly. If there are difficulties in interpreting the free
testosterone levels, free androgen index can be used as an
adjuvant in addition to testosterone. Primary testicular sper-
matogenic failure leads to compensatory elevated levels of FSH
along with normal to raised LH levels and low to normal
testosterone. The severity of the germ cell compartment defect is
positively correlated to the level of FSH. In cases of progressive
hypergonadotrophic hypogonadism, FSH levels are usually
increased well in advance of increased LH levels. Inhibin B is
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better predictor of Sertoli cell function but is expensive and not
readily available.
Low levels of FSH, LH and testosterone reflect hypothalamic/
pituitary dysfunction. Low volume testis is usually seen in
congenital hypothalamic and pituitary disorders while in post
pubertal patients, secondary impairment of hypothalamic and
pituitary functions has less pronounced impact on size of testis.
This group of patients warrants substitution with gonadotrophins
(usually hCG and FSH) and has excellent prognosis. Studies have
shown normalization of testicular function in 80% of cases with
50e70% pregnancy rates. A high prolactin level is suggestive of a
possible micro or macro-adenoma and may be another treatable
cause of male sub-fertility.
The possibility of androgen substance abuse should be
explored in well androgenised males with low FSH and LH levels.
Testosterone levels may range from low-normal-high depending
upon level of substance abuse.
Normal FSH, LH and testosterone levels reflect the possibility
of post-testicular factors, meiotic arrest of spermatogenesis or
idiopathic male infertility. Possibility of retrograde ejaculation by
examining urine for sperms should be excluded. Post-testicular
obstruction can present as severe oligo to azoospermia and
may be at different levels of the seminal duct, the epididymis, the
prostate, or the seminal vesicles.
Genetic testing
In males with severe male factor infertility, chromosomal
anomalies have been observed 10e15 times higher than in
normal male population. Therefore, additional genetic in-
vestigations including karyotype, screening for specific defects
on Y chromosome such as azoospermia factor (AZF) deletions
and testing for cystic fibrosis trans-membrane conductance
regulator (CFTR) mutations should be considered in severe male
factor subfertility (sperm concentration <5 million/ml). Genetic
testing for FSH receptor defect and epigenetic markers of sper-
matozoa are presently at experimental stage and are not yet
clinically recommended. The most common numeric chromo-
somal disorder is Klinefelter’s syndrome affecting 1 in 600 males.
Klinefelter’s syndrome is seen in 14% of azoospermic males and
is clinically characterized by high gonadotrophin levels and small
sized testicles. The success rates with surgical sperm extraction
in Klinefelter’s syndrome depend upon male age and can go up to
50% in younger males.
Clinically manifested cases of cystic fibrosis, infertility can be
as high as 95% of cases and is usually due to congenital bilateral
absence of vas deferens (CBAVD). The chances of successful
surgical sperm retrieval are high in these cases as testicular
function is normal, but genetic counselling should be offered to
these couples prior to treatment. AZF deletions may be present in
2% of azoospermic male and 10e12% of severely oligospermic
males. The most frequently occurring deletion is AZFc account-
ing for 80% of AZF deletion cases and positive recovery of
sperms with surgical sperm retrieval techniques can reach up to
50%. On the other hand, AZFa deletions are less common but
more often associated with total atrophy of germ cell compart-
ment leading to negligible chances of sperm recovery on SSR.
Importance of genetic counselling should be emphasised to
couples with AZF deletions prior to treatment because of trans-
mission of deletions to male offspring.
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 REVIEW

Assessment of ROS
Detection rates of scrotal pathologies
Sperm proteomics
Scrotal pathology Percentage detected
Sperm viability testing

Varicocele 18.5% Testicular biopsy

Epididymal pathologies 14.0% Testicular biopsies in infertile males are routinely not recom-
Spermatocele 5.2% mended, but a biopsy taken for surgical sperm retrieval can be
Hydrocele 9.9% sent for histopathological examination to evaluate spermatogenic
Hyper- and hypoechogenic lesions 21.4% capacity of testis.
Testicular cysts 1.1%
Testicular tumours 0.5% Therapeutic options
Lifestyle modifications
Table 2
Vaginal intercourse every 2e3 days maximise odds of natural
conception and should be recommended especially as timed in-
tercourse may be emotionally stressful. Excessive alcohol is
WHO (2010) reference values for human semen considered detrimental to semen quality but consumption of 3e4
characteristics units of alcohol per day are unlikely to affect semen quality.
Parameter Lower reference limit Similarly smoking has negative association with sperm parame-
ters while its impact on male fertility is uncertain, and it is
WHO reference values for human semen characteristics of fertile men advisable to stop smoking because of its overall health benefits.
(2010) There is no association between the excessive use of caffeinated
Semen volume (ml) 1.5 (1.4e1.7) beverages and male sub-fertility. An association between
Total sperm number (106 per ejaculate) 39 (33e46) elevated scrotal temperature and poor semen quality has been
Sperm concentration (106 per ml) 15 (12e16) described, but that it is uncertain whether wearing loose-fitting
Total motility (PR þ NP, %) 40 (38e42) underwear improves fertility.
Progressive motility (PR, %) 32 (31e34)
Vitality (live spermatozoa, %) 58 (55e63) Medical treatment
Sperm morphology (normal forms, %) 4 (3.0e4.0) Gonadotrophin therapy has been proved to be effective in pa-
Other consensus threshold values tients with hypogonadotrophic hypogonadism except in crypt-
pH 7.2 orchidism. Human chorionic gonadotrophin (hCG) is advocated
Peroxidase-positive leucocytes (106 per ml) <1.0 initially for 3e6 months to normalise intra-testicular testos-
MAR test (motile spermatozoa with bound <50 terone. Following normalisation of testosterone, a combination
particles, %) of FSH and LH is utilised to kick start sperm production. Pulsatile
Immunobead test (motile spermatozoa with <50 gonadotrophin-releasing hormone (GnRH) may be as effective as
bound beads, %) hCG and hMG in enhancing sperm production in men with
Seminal zinc (mmol/ejaculate) 2.4 hypogonadotrophic hypogonadism, but its widespread avail-
Seminal fructose (mmol/ejaculate) 13 ability is questionable. Gonadotrophins do not confer benefit in
Seminal neutral glucosidase (mU/ejaculate) 20 unexplained male sub-fertility. Similarly selective oestrogen re-
ceptor modulators (clomiphene citrate and tamoxifen), kinin
Table 3 enhancing drugs and bromocriptine are not recommended in
unexplained male sub-fertility cases. Treatment with anti oxi-
dants like vitamin C, vitamin D and glutathione have been re-
Sperm function tests ported to improve semen parameters but there are no data
Sperm function tests vary in their ability to detect defects in the available on improved pregnancy rates. Alpha blockers like
complex processes leading to fertilisation, therefore are not bunazosin and mast cell blockers have seen to improve semen
currently recommended in routine clinical practice. . Computer parameters but need further evaluation before they can be
assisted semen analysis (CASA) is more commonly used and this considered as therapeutic options. NICE CG156 (2013) recom-
has not been found to be better predictive than the standard tests. mend that men with leucocytes in their semen should not be
DNA fragmentation test aimed to analyse DNA integrity using offered antibiotic treatment unless there is an identified infection
TUNEL, Comet or flow chromatin analysis does not provide because there is no evidence that treatment with antibiotics im-
harmonious results thus limiting their utility in clinical practice. proves pregnancy rates.
A post coital test evaluates sperm-cervical mucus interaction but
is found not have much clinical significance. Other sperm func- Treatment for ejaculatory dysfunction
tion tests still needing validation and approval for routine clinical Penile electro-vibration by initiating reflex spinal cord activity
practice are: and transrectal electro-ejaculation by stimulating nerves

Tests of sperm capacitation responsible for ejaculation may be used in anejaculatory patients

Tests of hemizona and zona pellucida binding to retrieve sperms. Medical treatment of anejaculation is not

Sperm penetration assay or sperm capacitation index or generally recommended as treatment of first choice. Medical
zona-free hamster oocyte penetration assay treatment including alpha agonist to increase sympathetic tone of

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 REVIEW
Definitions relating to semen quality (World Health Organization, 2010)
Term
Asthenozoospermia
Asthenoteratozoospermia
Azoospermia
Cryptozoospermia
Haemospermia (haematospermia)
Leukospermia (leukocytospermia,
pyospermia)
Necrozoospermia
Normozoospermia
Oligoasthenozoospermia
Oligoasthenoteratozoospermia
Oligoteratozoospermia
Oligozoospermia
Teratozoospermia
Table 4
bladder and anti-cholinergic to reduce para-sympathetic supply
can be used in cases of retrograde ejaculation. Penile electro-
vibration and recovery of sperms from buffered urine may be
used as second line intervention following failed medical therapy
for retrograde ejaculation. If these modalities fail to recover
motile sperm, then as an alternative, surgical sperm retrieval can
be used in ejaculatory dysfunction. Anxiolytic drugs and/or sil-
denafil may also be helpful in cases of ejaculation failure asso-
ciated with erectile dysfunction caused by psychogenic disorders.
Surgical options for obstructive azoospermia
Presence of azoospermia in association with normal testicular
volume and hormonal profile indicate the possibility of obstruc-
tive azoospermia. The success of corrective surgery depends upon
site of obstruction, duration of obstruction and expertise of
operator. The patency rates and pregnancy rates of vasectomy
reversal have been estimated to be up to 97% and 75%
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Definition
Percentage of progressively motile (PR)
spermatozoa below the lower reference limit
Percentages of both progressively motile (PR)
and morphologically normal spermatozoa
below the lower reference limits
No spermatozoa in the ejaculate
Spermatozoa absent from fresh preparations
but observed in a centrifuged pellet
Presence of erythrocytes in the ejaculate
Presence of leukocytes in the ejaculate
above the threshold value
Low percentage of live, and high percentage
of immotile, spermatozoa in the ejaculate
Total number (or concentration, depending
on outcome reported)* of spermatozoa, and
percentages of progressively motile (PR) and
morphologically normal spermatozoa, equal to
or above the lower reference limits
Total number (or concentration, depending on
outcome reported)* of spermatozoa, and
percentage of progressively motile (PR)
spermatozoa, below the lower reference limits
Total number (or concentration, depending on
outcome reported)* of spermatozoa, and percentages
of both progressively motile (PR) and morphologically
normal spermatozoa, below the lower reference limits
Total number (or concentration, depending on
outcome reported)* of spermatozoa, and percentage
of morphologically normal spermatozoa, below the
lower reference limits
Total number (or concentration) of spermatozoa
below the lower reference limit
Percentage of morphologically normal spermatozoa
below the lower reference limit
respectively if reversal procedure is performed within 3 years of
vasectomy. However, the respective figures are 80% and 55% if
vasectomy reversal has been attempted after 3e8 years. Consid-
eration should be given to recovery and cryopreservation of
sperms for ART at time of reconstructive surgery to avoid repeat
surgery at a later date. It might be reasonable to discuss assisted
reproduction with couples who fail to conceive within 12e18
months following corrective surgery as presence of sperms should
be evident within 6e12 months.
In the light of presently available evidence, varicocele repair is
not recommended.
Surgical sperm retrieval (SSR)
Recent advances in surgical sperm retrieval techniques have
provided an opportunity of biological paternity to azoospermic
men. Many procedures with the aim to retrieve sperms from
epididymis and testis are offered to men with non-obstructive
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 REVIEW
azoospermia, idiopathic azoospermia and obstructive azoo-
spermia. SSR may be planned along with oocyte retrieval during
Intra-cytoplasmic sperm injection (ICSI) treatment (fresh
approach) or performed electively before ICSI treatment with an
intention to cryo-preserve the retrieved sperms for treatment at a
later date (frozen approach). Frozen approach is widely preferred
by most experts because of its logistical advantages. Moreover,
medical literature reports similar fertilisation and pregnancy
rates with fresh and frozen sperms. There always remains a
possibility to repeat the SSR procedure if no viable sperms sur-
vive freeze and thaw process, especially if only few sperms were
recovered at the initial procedure. The choice of procedure de-
pends upon underlying cause, degree of invasiveness and phy-
sician’s preference.
Percutaneous epididymal sperm aspiration (PESA): PESA in-
volves the aspiration of epididymal fluid using a butterfly needle
passed percutaneously through scrotal skin into head of epidid-
ymis and a syringe to create negative suction pressure once
epididymis is stabilised between surgeon’s thumb and forefinger.
Testicular sperm extraction (TESE): this procedure involves the
insertion of large bore (14e18 gauge) butterfly needle through
the scrotal skin in relatively avascular anteriomedial or anterio-
lateral testicular lower pole once testis has been stabilised. While
gently aspirating the syringe to create a negative pressure, the
needle is withdrawn in an attempt to aspirate the tubules within
the testis. Different sections of testis may be sampled through
same puncture in tunica albuginea before completely with-
drawing the needle. Often the testicular tissue needs mechanical
disruption or enzymatic treatment of seminiferous tubules to
liberate sperms and hence results are not readily available in the
operative room.
Micro dissection TESE/microsurgical epididymal sperm aspi-
ration (MESA): both micro dissection (TESE and MESA) require
surgical exposure of testicle and epididymis respectively. Under
10e15 fold optical magnification using operative microscope, the
seminiferous tubules are more likely to have sperms which can
be extracted (the tubules with sperm production appear larger
and more opaque). By targeting the tubules with sperm pro-
duction, the yield of sperms retrieved can be improved with
limited amount of testicular tissue disruption and less scarring of
testicular tissue due to meticulous haemostasis. Average opera-
tive time is longer with micro dissection TESE as compared to
conventional TESE and requires advanced surgical expertise.
Assisted conception
Intrauterine insemination (IUI)
Intrauterine insemination (IUI) which was once used widely for
male factor sub-fertility is no longer recommended to have any
role in management of male infertility. The success rates can
vary between 4 and 11%.
ICSI
The technique of Intracytoplasmic sperm injection has revolu-
tionised the treatment for male factor subfertility. Successful
pregnancy has been reported even with injection of immature
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sperm cells. A small but statistically significant increased risk of
certain genetic and developmental defects (0.5%) observed in off
springs born from ICSI treatment should be discussed with cou-
ples. Although it is uncertain whether this risk associated with
ICSI is related to procedure or because of inherent sperm ab-
normalities which lead to ICSI treatment in first place. It is
imperative that the children being born through ICSI and other
ART continue to be monitored for developmental problems.
Several methods including Intracytoplasmic morphologically
selected sperm injection (IMSI) and Physiological Intra-
cytoplasmic sperm injection (PICSI) have been developed to
improve the sperm selection for ICSI.
Intracytoplasmic morphologically selected sperm
injection (IMSI)
IMSI is a modified ICSI technique primarily based on motile
sperm organelle morphology examination under 6000-fold
magnification or more in comparison to 400-fold magnification
used for conventional ICSI. High magnification in IMSI enables
recognition of subtle defects in sperm organelles such as the
acrosome, mitochondria, and also reveals critical details in
sperm morphology, especially that of the nucleus, thus allowing
selection of highest quality sperm for ICSI. This selection of
morphologically good quality sperm has been demonstrated to
have positive impact in increasing fertilisation rate and reducing
miscarriage rate though further studies are needed to demon-
strate its efficacy and validity to be used routinely.
Physiological Intracytoplasmic sperm injection (PICSI)
During in vivo spermiogenesis, sperm plasma membrane de-
velops receptors for hyaluronic acid (HA), an important
component of the extracellular matrix (ECM) of the cumulus
oophorus. This physiologic selector role of hyaluronic acid is
well demonstrated in vitro as well. It has been proposed that
sperms having greater affinity and binding for HA in vitro have
completed their plasma membrane remodelling, cytoplasmic
extrusion, nuclear maturation and have reduced risk of chro-
mosomal imbalance. Large multicentre trials are ongoing in the
United Kingdom to authenticate the efficacy and validity of this
technique.
Oocyte activation by calcium ionophores
Despite recent advances in sperm microinjection techniques
fertilisation failure is encountered in 1e5% of ICSI cycles. It is
well established that oocyte activation at fertilization is caused
by Caþ2 increase in oocyte cytosol. It has been recently proposed
that sperm specific protein Phospholipase C zeta (PLC zeta)
introduced in oocyte following membrane fusion is the factor
responsible for oocyte activation by generating series of intra-
cellular Caþ2 oscillations in oocyte. PLC zeta deficit sperms may
result in failed fertilisation and poor early embryo development.
Oocyte activation may be artificially facilitated by calcium ion-
ophores in these cases, but this is at present only offered in
research settings.
Sperm cryopreservation
This process involves the cooling and subsequent storage of
sperm at very low temperature in liquid nitrogen. Variability in
the success of the freezing and thawing process occurs between
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 REVIEW
individuals as well as between each semen sample. Cryopreser-
vation of sperm was initially offered for a period of 10 years, and
storage can be continued beyond 10 years (up to a maximum of
55 years) to men where there is a risk of significant infertility.
Sperm freeze may be considered as a backup for treatment in
primary hypogonadism especially if delay in treatment is antici-
pated, prior to cancer treatment, or where there are concerns
with sample production or inability to be physically present for
sample production on the day of treatment.
Donor sperm treatment
This option can be considered in the following situations:

cases of azoospermia where corrective surgery and/or SSR
fails to retrieve sperms,

some cases of severe oligozoospermia with persistent
failed fertilisation and poor embryo development with
underlying poor sperm functional ability,

severe ejaculatory and sexual dysfunction not amenable to
medical treatment

and when there is a significant genetic problem which
could be inherited from the male.
Sperm donors are rigorously screened for sexually transmitted
diseases and genetic conditions. The semen sample is then
quarantined for 6 months before using for any treatment. The
decision to use donor sperm, whether from a known or unknown
donor, can be complicated and difficult for a couple. Counselling
may be helpful to help both partners discuss their feelings and
the potential implications of using donor sperm.
Adoption
Some couples may consider adopting a child. A healthcare pro-
vider or social worker can suggest resources for couples who
decide to pursue this option.
Some couples may even decide to remain childless. Couples
often benefit from counselling after they decide to stop infertility
treatments.
Emotional impact of male infertility
For most men, the initial appointment at the fertility clinic is the
first time they have had to answer personal questions and to be
examined intimately. It is to be noted that most men are usually
unable to share their thoughts with anyone else. The psycho-
logical and social issues associated with the diagnosis and
treatment of male infertility cannot be underestimated. It is
absolutely vital to provide appropriate support and counselling
with locally available resources.
Controversies in the management of male infertility
Male age and male fertility
Most researchers agree that advancing male age is associated
with deterioration in semen quality especially semen volume and
motility, while morphology and concentration largely remain
unaffected. Although plethora of medical literature confirms the
negative effect of advancing maternal age on pregnancy rates and
miscarriage rates, but the evidence of association of paternal age
and these reproductive outcomes is limited and inconclusive.
Association of structural congenital malformations at birth with
advancing paternal age has been reported by some researchers.
Neuro-cognitive disorders like schizophrenia, autism and bipolar
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE --:-
Please cite this article in press as: Ghuman N, Ramalingam M, Male infertility, Obstetrics, Gynaecology and Reproductive Medicine (2017),
https://doi.org/10.1016/j.ogrm.2017.10.007
disorders have been linked to advanced paternal age especially
after 50s.
Genital infections
WHO defines leukocytospermia as greater than one million
leukocytes per millilitre of semen. Several studies have sup-
ported an association between presence of high concentration of
leucocytes and deterioration of semen quality secondary to
reactive oxygen species from the activated leucocytes. However
research shows that treatment with antibiotics fails to improve
semen parameters. Moreover, it may be difficult to distinguish
between immature germ cells and leucocytes on routine semen
analysis. NICE 2013 (CG 156) guidelines recommend that men
with leucocytes in their semen should not be offered antibiotic
treatment unless there is an identified infection because there is
no evidence that treatment with antibiotics improves pregnancy
rates.
Sperm autoantibodies
Antibodies against sperms develop when relative isolation of
testis from the vascular compartment is disrupted (blood-testic-
ular barrier) as a result of testicular trauma, infection, torsion
and surgery such as vasectomy. Among infertile men, the inci-
dence of these anti sperm antibodies varies between 8% and
21% and these autoantibodies account for 3% of male factor
infertility. Diagnosis of anti sperm antibodies is by mixed anti-
globulin reaction (MAR) test or the immunobead test (IBT).
There are three types of ASAB: IgG and IgM are mainly found in
the serum whereas IgA is found locally in the genital tract.
Impaired sperm motility leads to reduced sperm penetration in
the cervical mucus and affect the capacitation and acrosomal
reaction, thus interfering with sperm oocyte interaction which
have been attributed to ASAB. Although the detection of ASAB is
not diagnostic of infertility, few studies have suggested that
infertility from ASAB is possible if more than 50% of sperm are
bound to the sperm antibodies. Immunosuppressant therapy
with corticosteroids does not improve pregnancy rates and may
be associated with significant side effects including dyspepsia,
facial flushing, weight gain and rare complications such as
aseptic necrosis of the hip. NICE (2013) recommend that men
should be informed that the significance of anti sperm antibodies
is unclear and the effectiveness of systemic corticosteroids is
uncertain.
Varicocele
Dilated veins of pampiniform plexus or varicoceles are linked
to having adverse influence on semen quality attributed to
raised scrotal temperature secondary to internal spermatic vein
reflux. Incidence of varicocele has been estimated to be twice
as high as in general adult male population. Surgery for vari-
cocele in the form of varicocelectomy is not justified for
fertility treatment.
Undescended testes
Undescended testis or cryptorchidism affects 2e4% of term
newborn boys and incidence can reach up to 21% in premature
male babies. In 10% cases both testis are involved. About half of
the undescended testes descend to the scrotum in first 3 months
of life thereby reducing the true incidence of cryptorchidism to
7 Ó 2017 Elsevier Ltd. All rights reserved.
 REVIEW

1e2%. Its aetiology is multifactorial, as 14% of the males having
undescended testis also have another male relative with this
condition. The mal-descent may occur in the transabdominal or
inguinal phase and may be due to endocrine disruption, defective
anti-mullerian regulation of abdominal descent and gene deletion
expressed on Leydig cells affecting the androgen production. The
most important long-term complications of undescended testes
include infertility and testicular cancer in addition to psycho-
logical consequences. This makes males with cryptorchidism to
be over represented in fertility clinics. Orchidopexy performed at
the early age between 6 and 12 months can result in a catch up of
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
serious complication of orchidopexy. Although hormonal treat-
ment with human chorionic gonadotrophin (hCG) helps in
testicular descent in 15e20% cases, one-fifth of these re-ascend
later on.
Future perspective
During the past few years a considerable progress has been made
to derive male germ cells from embryonic pluripotent stem cells.
Stem cells are considered as potentially new therapeutic agents
for the treatment of male infertility. In-vitro derived sperms
provide the possibility of having genetically related children for
people who currently cannot produce sperm on their own. Sci-
entists are concerned that the very complex process needed to
generate them has great potential for chromosome abnormalities
and other severe genetic problems. A
FURTHER READING
Human fertilisation and embryo authority (HFEA). www.hfea.gov.uk.
National Institute of Clinical Excellence (NICE) clinical guideline no
156: assessment and treatment of people with fertility problems,
February 2013.
World Health Organisation (WHO) laboratory manual for the exami-
nation and the processing of human semen. 5th edn, 2010.
Practice points
C Poor semen quality contributes to the sub-fertility in 30e50% of
couples undergoing IVF.
C A male infertility evaluation must go far beyond a simple semen
analysis, as it has to be complemented by a comprehensive his-
tory taking, physical examination, and relevant endocrine, ge-
netic, and other investigations.
C Men with hypogonadotrophic hypogonadism should be offered
gonadotrophins drugs which are effective in improving fertility.
C There is no role for IUI with partner’s sperm for male factor
infertility except for couples with physical, ethical or moral ob-
jection to IVF/ICSI.
C Surgical sperm retrieval in the form of PESA, TESE and open
testicular biopsy are performed to obtain sperm for ICSI.
C ICSI has revolutionised the treatment of male infertility with newer
advancements like IMSI and PICSI.
C Sperm cryopreservation is commonly used for fertility preserva-
tion in men before gonadotoxic therapy.
C Embryonic stem cells are considered as potentially new thera-
peutic agents for the treatment of male infertility.

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE --:- 8 Ó 2017 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Ghuman N, Ramalingam M, Male infertility, Obstetrics, Gynaecology and Reproductive Medicine (2017),
https://doi.org/10.1016/j.ogrm.2017.10.007