DOI: 10.1111/j.1744-4667.2012.00145.x 2013;15:1–9
The Obstetrician & Gynaecologist
Review
http://onlinetog.org
Assessment of the infertile male
Stamatios Karavolos BSc MBBS MRCOG,a,* Jane Stewart MD BSc MBChB FRCOG,b Isaac Evbuomwan MD MRCOG,
c
Kevin McEleny BM BSc PhD FRCS (Urol),d Ian Aird MBChB FRCOGe
a
Specialty Registrar, Obstetrics and Gynaecology, The Gateshead Fertility Unit, Queen Elizabeth Hospital, Gateshead NE9 6SX, UK
b
Consultant Gynaecologist, Subspecialist in Reproductive Medicine, Newcastle Fertility Centre at Life, International Centre for Life, Times Square,
Newcastle upon Tyne NE1 4EP, UK
c
Consultant Obstetrician and Gynaecologist, The Gateshead Fertility Unit, Queen Elizabeth Hospital, Gateshead NE9 6SX, UK
d
Consultant Andrologist, Newcastle Fertility Centre at Life, International Centre for Life, Times Square, Newcastle upon Tyne NE1 4EP, UK
e
Consultant Obstetrician and Gynaecologist, The Gateshead Fertility Unit, Queen Elizabeth Hospital, Gateshead NE9 6SX, UK
*Correspondence: Stamatios Karavolos. Email:
Accepted on 15 March 2012
Key content conception, there are concerns regarding its potential to transmit
Male factors alone account for up to 30% of subfertile couples genetic defects.
undergoing in vitro fertilisation.
Learning objectives
Male infertility may be due to problems with sperm production or
To review appropriate practice in the assessment and investigation
transport and also sexual dysfunction. The underlying cause in
of the infertile male.
most cases is idiopathic.
To critically appraise the currently available investigations for male
Modifiable lifestyle factors can have an impact on male fertility,
fertility.
but medical treatments have a limited value in enhancing semen To summarise the treatment options for subfertile men.
quality. Most treatments are based on assisted fertilisation
techniques, rather than treatment of the underlying cause. Ethical issues
The number and quality of sperm that can be recovered, either Does ICSI propagate genetic causes of male infertility?
from the ejaculate or surgically, determines the available options Could there ever be a role for the use of artificial sperm in assisted
for assisted conception. reproduction?
Intracytoplasmic sperm injection (ICSI) is considered relatively
Keywords: in vitro fertilisation / infertility / intracytoplasmic sperm
safe; however, because of the ability to bypass natural barriers to
injection / male / semen analysis
Please cite this paper as: Karavolos S, Stewart J, Evbuomwan I, McEleny K, Aird I. Assessment of the infertile male. The Obstetrician & Gynaecologist 2013;15:1–9.
dependent upon numerous factors, such as coital
Introduction
frequency, and do not necessarily reflect biological fertility.
It is estimated that one in seven couples in the UK experience Studies in the early 1990s suggested a possible decline in
some difficulty conceiving at some point in their semen quality,6 however, subsequent reports suggest that this
reproductive life.1 Sixteen percent of couples will fail to finding is not universal.7 Demographic data on UK fertility
conceive after 1 year of trying.1 A male factor alone is rates provide evidence to suggest that male infertility is
thought to contribute in up to 30% of these cases, with a increasing.8 This, however, may be the result of increasing
combination of male and female factors affecting up to 40% publicity of available treatments and thus reflect an
of all infertile couples undergoing assisted reproduction.2–4 increasing willingness of couples to seek advice and
‘Normal’ reference values for semen quality were first treatment. Long-term data from the Human Fertilisation
published by McLeod5 in 1951. For several decades male and Embryology Authority (HFEA)9 analysing male factors
infertility was considered an idiopathic and incurable as a cause for referral to fertility centres, has shown that the
condition, however, with advances in assisted reproductive percentage of infertility attributable to male factors appears
technologies, effective treatments have now been developed to have increased from 27.6% in 2000 to 32.5% in 2006, but
and research into factors affecting sperm quality is increasing. since then it averages at approximately 30%.4 The evidence
that sperm counts may be declining has been linked to the
theory of testicular dysgenesis syndrome (TDS), which
Epidemiology of male infertility
comprises a developmental disorder with increased rates of
It is difficult to estimate the prevalence of male infertility in testicular cancer, undescended testes and congenital
the general population, as reported fertility rates are malformations.10 This may be due to environmental
ª 2013 Royal College of Obstetricians and Gynaecologists 1
, Assessment of the infertile male
factors. However, the validity of this theory has recently reduction divisions (meiosis I and II) to form spermatids. By
been questioned.11 the process of spermiogenesis, spermatids transform into
mature cytoplasm-free sperm with condensed DNA in the
head, an apical acrosome and a tail. Normal spermatogenesis
Box 1. Main causes of male factor infertility
is under the influence of follicular stimulating hormone
Pretesticular: (FSH) and testosterone. FSH binds to Sertoli cells
Hypothalamic disease
and increases spermatogonial number and maturation to
‐ Gonadotrophin deficiency (Kallman syndrome) spermatocytes, but it is unable to complete spermatogenesis
Pituitary disease alone. Luteinising hormone (LH) is necessary for testosterone
production by the Leydig cells, and plays an essential role in
‐ Pituitary insufficiency (tumours, radiation, surgery)
‐ Hyperprolactinaemia spermatid maturation. The entire spermatogenic process,
‐ Exogenous hormones (anabolic steroids, glucocorticoid excess, including transit in the ductal testicular system takes
hyper- or hypothyroidism) approximately 3 months.12 This is important to bear in
Testicular: mind when advising individuals on the potential effect of
Congenital lifestyle changes on semen quality improvement.
Genetic
‐ Chromosomal (Kleinfelter syndrome 47, XXY) Causes of male infertility
‐ Y chromosome microdeletions
‐ Noonan syndrome (male Turner syndrome 45, XO) Causes of male factor infertility can be classified into
pretesticular, testicular and post-testicular (Box 1).
Other
Conditions that act at the pretesticular level tend to be
‐ Cryptorchidism hormonal in nature and most of these can be treated with
Acquired hormone manipulation. Causes at the testicular level are
‐ Injury (orchitis, torsion, trauma)
largely irreversible, but can be treated with assisted
‐ Varicocele reproductive technology (ART), if sperm is retrievable.
‐ Systemic disease (renal failure, liver failure) Post-testicular causes can be treated with microsurgery or
‐ Chemotherapy, radiotherapy with ART. It is estimated that in about 50% of men with poor
‐ Testicular tumours
‐ Idiopathic semen quality, no cause for this will be identified.13
Post-testicular (obstruction):
Male age
Congenital
Male age has been shown to have an impact on fertility and
‐ Cystic fibrosis, congenital absence of the vas deferens (CAVD) offspring health.14 A UK study15 has shown that paternal age
‐ Young’s syndrome
of >35 years halves the chance of achieving a pregnancy
Acquired compared with a paternal age of <25 years. The effect of age
‐ Vasectomy on male fertility is more noticeable after the age of 50,16 with
‐ Infection (chlamydia, gonorrhoea) studies showing a concomitant increase in adverse outcome
‐ Iatrogenic vasal injury in the offspring.17,18 For this reason, the age of semen donors
Disorders of sperm function or motility is limited to 40 or 45 years in some countries.19
‐ Immotile cilia syndrome
‐ Maturation defects Environmental, occupational and lifestyle factors
‐ Immunological infertility There is increasing evidence from epidemiological studies
‐ Globozoospermia
that occupational exposures to certain chemicals can affect
Sexual dysfunction semen quality.20,21 More than 104 000 such chemicals and
‐ Timing and frequency physical agents have been identified.1 These include heat,
‐ Erectile/ ejaculatory dysfunction X-rays, heavy metals (lead, mercury), glycol ethers (highly
‐ Diabetes mellitus, multiple sclerosis, spinal cord/pelvic injuries volatile compounds used as solvents)22 and pesticides; a
well documented example being dibromochloropropane
(DBCP),21 a nematocide used in certain crops. The exact
mechanism by which these occupational substances affect
Regulation of spermatogenesis
male fertility remains unclear.
Sperm are formed in the seminiferous tubules, from germinal Despite earlier reports, the level of environmental
cells called spermatogonia. Spermatogonia divide by mitosis estrogens would not appear to be a threat to male
into primary spermatocytes, which in turn undergo two reproductive health.23 Recent observational studies support
2 ª 2013 Royal College of Obstetricians and Gynaecologists
The Obstetrician & Gynaecologist
Review
http://onlinetog.org
Assessment of the infertile male
Stamatios Karavolos BSc MBBS MRCOG,a,* Jane Stewart MD BSc MBChB FRCOG,b Isaac Evbuomwan MD MRCOG,
c
Kevin McEleny BM BSc PhD FRCS (Urol),d Ian Aird MBChB FRCOGe
a
Specialty Registrar, Obstetrics and Gynaecology, The Gateshead Fertility Unit, Queen Elizabeth Hospital, Gateshead NE9 6SX, UK
b
Consultant Gynaecologist, Subspecialist in Reproductive Medicine, Newcastle Fertility Centre at Life, International Centre for Life, Times Square,
Newcastle upon Tyne NE1 4EP, UK
c
Consultant Obstetrician and Gynaecologist, The Gateshead Fertility Unit, Queen Elizabeth Hospital, Gateshead NE9 6SX, UK
d
Consultant Andrologist, Newcastle Fertility Centre at Life, International Centre for Life, Times Square, Newcastle upon Tyne NE1 4EP, UK
e
Consultant Obstetrician and Gynaecologist, The Gateshead Fertility Unit, Queen Elizabeth Hospital, Gateshead NE9 6SX, UK
*Correspondence: Stamatios Karavolos. Email:
Accepted on 15 March 2012
Key content conception, there are concerns regarding its potential to transmit
Male factors alone account for up to 30% of subfertile couples genetic defects.
undergoing in vitro fertilisation.
Learning objectives
Male infertility may be due to problems with sperm production or
To review appropriate practice in the assessment and investigation
transport and also sexual dysfunction. The underlying cause in
of the infertile male.
most cases is idiopathic.
To critically appraise the currently available investigations for male
Modifiable lifestyle factors can have an impact on male fertility,
fertility.
but medical treatments have a limited value in enhancing semen To summarise the treatment options for subfertile men.
quality. Most treatments are based on assisted fertilisation
techniques, rather than treatment of the underlying cause. Ethical issues
The number and quality of sperm that can be recovered, either Does ICSI propagate genetic causes of male infertility?
from the ejaculate or surgically, determines the available options Could there ever be a role for the use of artificial sperm in assisted
for assisted conception. reproduction?
Intracytoplasmic sperm injection (ICSI) is considered relatively
Keywords: in vitro fertilisation / infertility / intracytoplasmic sperm
safe; however, because of the ability to bypass natural barriers to
injection / male / semen analysis
Please cite this paper as: Karavolos S, Stewart J, Evbuomwan I, McEleny K, Aird I. Assessment of the infertile male. The Obstetrician & Gynaecologist 2013;15:1–9.
dependent upon numerous factors, such as coital
Introduction
frequency, and do not necessarily reflect biological fertility.
It is estimated that one in seven couples in the UK experience Studies in the early 1990s suggested a possible decline in
some difficulty conceiving at some point in their semen quality,6 however, subsequent reports suggest that this
reproductive life.1 Sixteen percent of couples will fail to finding is not universal.7 Demographic data on UK fertility
conceive after 1 year of trying.1 A male factor alone is rates provide evidence to suggest that male infertility is
thought to contribute in up to 30% of these cases, with a increasing.8 This, however, may be the result of increasing
combination of male and female factors affecting up to 40% publicity of available treatments and thus reflect an
of all infertile couples undergoing assisted reproduction.2–4 increasing willingness of couples to seek advice and
‘Normal’ reference values for semen quality were first treatment. Long-term data from the Human Fertilisation
published by McLeod5 in 1951. For several decades male and Embryology Authority (HFEA)9 analysing male factors
infertility was considered an idiopathic and incurable as a cause for referral to fertility centres, has shown that the
condition, however, with advances in assisted reproductive percentage of infertility attributable to male factors appears
technologies, effective treatments have now been developed to have increased from 27.6% in 2000 to 32.5% in 2006, but
and research into factors affecting sperm quality is increasing. since then it averages at approximately 30%.4 The evidence
that sperm counts may be declining has been linked to the
theory of testicular dysgenesis syndrome (TDS), which
Epidemiology of male infertility
comprises a developmental disorder with increased rates of
It is difficult to estimate the prevalence of male infertility in testicular cancer, undescended testes and congenital
the general population, as reported fertility rates are malformations.10 This may be due to environmental
ª 2013 Royal College of Obstetricians and Gynaecologists 1
, Assessment of the infertile male
factors. However, the validity of this theory has recently reduction divisions (meiosis I and II) to form spermatids. By
been questioned.11 the process of spermiogenesis, spermatids transform into
mature cytoplasm-free sperm with condensed DNA in the
head, an apical acrosome and a tail. Normal spermatogenesis
Box 1. Main causes of male factor infertility
is under the influence of follicular stimulating hormone
Pretesticular: (FSH) and testosterone. FSH binds to Sertoli cells
Hypothalamic disease
and increases spermatogonial number and maturation to
‐ Gonadotrophin deficiency (Kallman syndrome) spermatocytes, but it is unable to complete spermatogenesis
Pituitary disease alone. Luteinising hormone (LH) is necessary for testosterone
production by the Leydig cells, and plays an essential role in
‐ Pituitary insufficiency (tumours, radiation, surgery)
‐ Hyperprolactinaemia spermatid maturation. The entire spermatogenic process,
‐ Exogenous hormones (anabolic steroids, glucocorticoid excess, including transit in the ductal testicular system takes
hyper- or hypothyroidism) approximately 3 months.12 This is important to bear in
Testicular: mind when advising individuals on the potential effect of
Congenital lifestyle changes on semen quality improvement.
Genetic
‐ Chromosomal (Kleinfelter syndrome 47, XXY) Causes of male infertility
‐ Y chromosome microdeletions
‐ Noonan syndrome (male Turner syndrome 45, XO) Causes of male factor infertility can be classified into
pretesticular, testicular and post-testicular (Box 1).
Other
Conditions that act at the pretesticular level tend to be
‐ Cryptorchidism hormonal in nature and most of these can be treated with
Acquired hormone manipulation. Causes at the testicular level are
‐ Injury (orchitis, torsion, trauma)
largely irreversible, but can be treated with assisted
‐ Varicocele reproductive technology (ART), if sperm is retrievable.
‐ Systemic disease (renal failure, liver failure) Post-testicular causes can be treated with microsurgery or
‐ Chemotherapy, radiotherapy with ART. It is estimated that in about 50% of men with poor
‐ Testicular tumours
‐ Idiopathic semen quality, no cause for this will be identified.13
Post-testicular (obstruction):
Male age
Congenital
Male age has been shown to have an impact on fertility and
‐ Cystic fibrosis, congenital absence of the vas deferens (CAVD) offspring health.14 A UK study15 has shown that paternal age
‐ Young’s syndrome
of >35 years halves the chance of achieving a pregnancy
Acquired compared with a paternal age of <25 years. The effect of age
‐ Vasectomy on male fertility is more noticeable after the age of 50,16 with
‐ Infection (chlamydia, gonorrhoea) studies showing a concomitant increase in adverse outcome
‐ Iatrogenic vasal injury in the offspring.17,18 For this reason, the age of semen donors
Disorders of sperm function or motility is limited to 40 or 45 years in some countries.19
‐ Immotile cilia syndrome
‐ Maturation defects Environmental, occupational and lifestyle factors
‐ Immunological infertility There is increasing evidence from epidemiological studies
‐ Globozoospermia
that occupational exposures to certain chemicals can affect
Sexual dysfunction semen quality.20,21 More than 104 000 such chemicals and
‐ Timing and frequency physical agents have been identified.1 These include heat,
‐ Erectile/ ejaculatory dysfunction X-rays, heavy metals (lead, mercury), glycol ethers (highly
‐ Diabetes mellitus, multiple sclerosis, spinal cord/pelvic injuries volatile compounds used as solvents)22 and pesticides; a
well documented example being dibromochloropropane
(DBCP),21 a nematocide used in certain crops. The exact
mechanism by which these occupational substances affect
Regulation of spermatogenesis
male fertility remains unclear.
Sperm are formed in the seminiferous tubules, from germinal Despite earlier reports, the level of environmental
cells called spermatogonia. Spermatogonia divide by mitosis estrogens would not appear to be a threat to male
into primary spermatocytes, which in turn undergo two reproductive health.23 Recent observational studies support
2 ª 2013 Royal College of Obstetricians and Gynaecologists
