EAU GUIDELINES ON MALE

INFERTILITY

(Limited text update March 2017)

A. Jungwirth (Chair), T. Diemer (Vice-Chair), Z. Kopa, C. Krausz,

H. Tournaye
Guidelines Associates: B. Kelly, R. Pal

Introduction
‘Infertility is the inability of a sexually active, non-contracept-
ing couple to achieve spontaneous pregnancy in one year.’
(World Health Organization 2000).

Epidemiology and aetiology

About 15% of couples do not achieve pregnancy within one
year and seek medical treatment for infertility.

Male fertility can be reduced as a result of:

• congenital or acquired urogenital abnormalities;
• malignancies;
• urogenital tract infections;
• increased scrotal temperature (e.g. as a consequence of
varicocele);
• endocrine disturbances;
• genetic abnormalities;
• immunological factors.

Prognostic factors
The main factors influencing the prognosis in infertility are:
• duration of infertility;
• primary or secondary infertility;
• results of semen analysis;
• age and fertility status of the female partner.

220 Male Infertility

Diagnostic evaluation
The diagnosis of male fertility should focus on a number of
prevalent disorders (Table 1). Simultaneous assessment of the
female partner is preferable, even if abnormalities are found in
the male, since data show that in 1 out of 4 couples both male
and female partners have pathological findings.

Semen analysis
A comprehensive andrological examination is indicated if
semen analysis shows abnormalities compared with reference
values (Table 1).

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 Table 1: Lower reference limits (5th centiles and their 95%
CIs) for semen characteristics

Parameter Lower reference

limit (range)
Semen volume (mL) 1.5 (1.4-1.7)
Total sperm number (106/ejaculate) 39 (33-46)
Sperm concentration (106/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 leukocytes (106/mL) < 1.0
Optional investigations
MAR test (motile spermatozoa with < 50
bound particles, %)
Immunobead test (motile spermatozoa < 50
with bound beads, %)
Seminal zinc (μmol/ejaculate) ≥ 2.4
Seminal fructose (μmol/ejaculate) ≥ 13
Seminal neutral glucosidase (mU/ejacu- ≤ 20
late)
CIs = confidence intervals; MAR = mixed antiglobulin reaction;
NP = non-progressive; PR = progressive.

It is important to differentiate between the following:

• oligozoospermia: spermatozoa < 15 million/mL;
• asthenozoospermia: < 32% progressive motile
spermatozoa;
• teratozoospermia: < 4% normal forms.

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 Recommendations GR
Perform semen analyses according to the guidelines A*
of the WHO Laboratory Manual for the Examination
and Processing of Human Semen (5th edn).
Perform further andrological assessment when semen A*
analysis is abnormal in at least two tests.
Adhere to the 2010 WHO Manual for the standard- C
ised investigation, diagnosis and management of the
infertile male for diagnosis and evaluation of male
subfertility.
*Upgraded following panel consensus.

Primary Spermatogenic Failure

Diagnostic evaluation
Routine investigations include semen analysis and hormonal
determinations. Other investigations may be required depend-
ing on the individual situation.

Semen analysis
In non-obstructive azoospermia (NOA), semen analysis shows
normal ejaculate volume and azoospermia after centrifuga-
tion. A recommended method is semen centrifugation at
3000 g for 15 minutes and a thorough microscopic examina-
tion by phase contrast optics at x 200 magnification of the
pellet. All samples can be stained and re-examined micro-
scopically.

Hormonal determinations
In men with testicular deficiency, hypergonadotropic hypo-
gonadism is usually present, with elevated levels of follicle
stimulating hormone (FSH) and luteinising hormone (LH), and
sometimes low levels of testosterone. Generally, the levels
of FSH correlate with the number of spermatogonia and are

Male Infertility 223

 elevated when spermatogonia are absent or markedly dimin-
ished. Spermatocytic arrest is typically associated with normal
FSH.

Testicular biopsy
Testicular biopsy and testicular sperm extraction (TESE) can
be part of intracytoplasmic sperm injection (ICSI) treatment in
patients with clinical evidence of NOA.

Recommendations GR
For men who are candidates for sperm retrieval, give A
appropriate genetic counselling even when testing for
genetic abnormalities was negative.
In men with non-obstructive azoospermia (NOA), A
perform simultaneous testicular biopsy with multiple
testicular sperm extraction (TESE) (or micro- TESE)
to define spermatogenesis and diagnose intratubular
germ cell neoplasma of unclassified type (ITGCNU)
and eventually kryopreservation of sperm.

Genetic Disorders in Infertility

Current routine clinical practice is based on the screening
of genomic DNA from peripheral blood samples, however,
screening of chromosomal anomalies in spermatozoa is also
feasible and can be performed in selected cases.

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Recommendations GR
Obtain standard karyotype analysis in all men with B
damaged spermatogenesis (spermatozoa
< 10 million/mL) who are seeking fertility treatment by
in vitro fertilisation (IVF).
Provide genetic counselling in all couples with a A
genetic abnormality found in clinical or genetic
investigation and in patients who carry a (potential)
inheritable disease.
For all men with Klinefelter’s syndrome, provide long- A
term endocrine follow-up and androgen replacement
therapy, if necessary.
Do not test for microdeletions in men with obstructive A
azoospermia (OA) when intracytoplasmic sperm
injection (ICSI) is used because spermatogenesis
should be normal.
Inform men with Yq microdeletion and their partners A
who wish to proceed with intracytoplasmic sperm
injection (ICSI) that microdeletions will be passed to
sons, but not to daughters.
In men with structural abnormalities of the vas A
deferens (unilateral or bilateral absence), test the man
and his partner for cystic fibrosis transmembrane
conductance regulator (CFTR) gene mutations.

Obstructive Azoospermia
Obstructive azoospermia (OA) is the absence of spermatozoa
and spermatogenetic cells in semen and post-ejaculate urine
due to obstruction. Sometimes, the vas deferens is absent as
in Congenital Bilateral Absence of the Vas Deferens (CUAVD)
or Congenital Unilateral Absence of the Vas Deferens
(CUAVD). Obstruction in primary infertile men is frequently
present at the epididymal level.

Male Infertility 225

 Diagnostic evaluation
Clinical examination should follow suggestions for the diag-
nostic evaluation of infertile men. The following findings indi-
cate OA:
• at least one testis with a volume > 15 mL, although a small-
er volume may be found in some patients with OA and con-
comitant partial testicular failure;
• enlarged and hardened epididymis;
• nodules in the epididymis or vas deferens;
• absence or partial atresia of the vas.

Semen analysis
At least two examinations must be carried out at an interval of
one to two months, according to the WHO. When semen
volume is low, a search must be made for spermatozoa in
urine after ejaculation. Absence of spermatozoa and
immature germ cells in semen smears suggest complete semi-
nal duct obstruction.

Hormone levels
Serum FSH and Inhibin B levels may be normal, but do not
exclude a testicular cause of azoospermia (e.g. spermatogenic
arrest).

Ultrasonography
In addition to physical examination, a scrotal ultrasound may
be helpful in finding signs of obstruction (e.g. dilatation of rete
testis, enlarged epididymis with cystic lesions, or absent vas
deferens) and may demonstrate signs of testicular dysgenesis
(e.g., non-homogeneous testicular architecture and microcal-
cifications) and testis tumours.

Testicular biopsy
In selected cases, testicular biopsy is indicated to exclude
spermatogenic failure. Testicular biopsy should be combined

226 Male Infertility

with extraction of testicular spermatozoa (i.e. TESE) for cryo-
preservation.

Recommendations GR
Perform microsurgical vasovasostomy or tubulovasos- B
tomy for azoospermia caused by vasal or epididymal
obstruction.
Use sperm retrieval techniques, such as microsurgical B
epididymal sperm aspiration (MESA), TESE, and per-
cutaneous epididymal sperm aspiration ( PESA) only
when cryostorage of the material obtained is available.

Varicocele
Varicocele is a common abnormality which may be associated
with the following andrological conditions:
• failure of ipsilateral testicular growth and development;
• symptoms of pain and discomfort;
• male subfertility;
• hypogonadism.

Diagnostic evaluation
The diagnosis of varicocele is made by clinical examination
and should be confirmed by colour Duplex analysis. In centres
where treatment is carried out by antegrade or retrograde
sclerotherapy or embolisation, diagnosis is additionally
confirmed by X-ray.

Disease management
Several treatments are available for varicocele. Current
evidence indicates that microsurgical varicocelectomy is the
most effective with the lowest complication rate among the
varicocelectomy techniques.

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 Recommendations GR
Treat varicoceles in adolescents with progressive fail- B
ure of testicular development documented by serial
clinical examination.
Do not treat varicoceles in infertile men who have A
normal semen analysis and in men with a subclinical
varicocele.
Treat varicoceles in men with a clinical varicocele, A
oligospermia and otherwise unexplained infertility in
the couple.

Hypogonadism

Idiopathic hypogonadotropic hypogonadism

Idiopathic hypogonadotropic hypogonadism is characterised
by low levels of gonadotropins and sex steroid in the absence
of anatomical or functional abnormalities of the hypo-
thalamic-pituitary-gonadal axis. Stimulation of sperm produc-
tion requires treatment with human chorionic gonadotropin
(hCG) combined with recombinant FSH or urinary FSH or
human menopausal gonadotropins (HMGs).

Hypergonadotropic hypogonadism
Many conditions in men are associated with hypergonado-
tropic hypogonadism and impaired fertility (e.g. anorchia,
maldescended testes, Klinefelter’s syndrome, trauma, orchitis,
systemic diseases, testicular tumour, varicocele etc).

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 Recommendations GR
Provide testosterone replacement therapy for A
symptomatic patients with primary and secondary
hypogonadism who are not considering parenthood.
In men with hypogonadotropic hypogonadism, induce A*
spermatogenesis by an effective drug therapy (human
chorionic gonadotropin (hCG), human menopausal
gonadotropins (hMG) and recombinant follicle-
stimulating hormone rFSH)).
Do not use testosterone replacement for the treat- A*
ment of male infertility.
*Upgraded following panel consensus.

Cryptorchidism
The aetiology of cryptorchidism is multifactorial, involving
disrupted endocrine regulation and several gene defects. It
has been postulated that cryptorchidism may be a part of the
so-called testicular dysgenesis syndrome (TDS), which
is a developmental disorder of the gonads caused by
­environmental and/or genetic influences early in pregnancy.
Besides cryptorchidism, TDS may include hypospadias,
reduced fertility, increased risk of malignancy, and Leydig cell
dysfunction.

Recommendations GR
Do not use hormonal treatment of cryptorchidism in A
adults.
If undescended testes are corrected in adulthood, per- B
form simultaneous testicular biopsy for detection of
ITGCNU (formerly carcinoma in situ [CIS]).

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 Idiopathic Male Infertility

Recommendations GR
Medically treat male infertility only for cases of A
hypogonadotropic hypogonadism.
No clear recommendation can be made for treatment B
with gonadotropins, anti-oestrogens and antioxidants
even for a subset of patients.

Male Contraception

Recommendations GR
Cauterisation and fascial interposition are the most A
effective techniques for the prevention of early
recanalisation.
Inform patients seeking vasectomy about the A*
surgical method, risk of failure, potential irreversibility,
the need for post-procedure contraception until
clearance, and the risk of complications.
To achieve pregnancy, MESA/PESA/TESE - together B
with ICSI is a second-line option for men who decline
a vasectomy reversal and those with failed vasectomy
reversal surgery.
*Upgraded following panel consensus

Male Accessory Gland Infections and Infertility

Diagnostic evaluation
Ejaculate analysis
Ejaculate analysis clarifies whether the prostate is involved as
part of a generalised male accessory gland infection and
provides information about sperm quality.

230 Male Infertility

Microbiological findings
After exclusion of urethritis and bladder infection, >106 perox-
idase-positive white blood cells (WBCs) per millilitre of ejacu-
late indicate an inflammatory process. In this case, a culture
should be performed for common urinary tract pathogens.

Epididymitis
Inflammation of the epididymis causes unilateral pain and
swelling, usually with acute onset.

Diagnostic evaluation
Ejaculate analysis
Ejaculate analysis according to WHO criteria, might indicate
persistent inflammatory activity.

Disease management
Antibiotic therapy is indicated before culture results are
available.

Recommendation GR
Instruct patients with epididymitis that is known or B
suspected to be caused by N. gonorrhoeae or
C. trachomatis to refer their sexual partners for evalu-
ation and treatment.

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 Germ Cell Malignancy and Testicular Microcalcification
(TM)

Recommendations GR
As for all men, encourage patients with TM and with- B
out special risk factors (see below) to perform self-
examination because this might result in early detec-
tion of testicular germ cell tumour (TGCT).
Do not perform testicular biopsy, follow-up scrotal B
ultrasound, routine use of biochemical tumour mark-
ers, or abdominal or pelvic computed tomography
(CT), in men with isolated TM without associated risk
factors (e.g. infertility, cryptorchidism, testicular can-
cer, and atrophic testis).
Perform testicular biopsy for men with TM, who B
belong to one of the following high-risk groups: infer-
tile and bilateral TM, atrophic testes, undescended
testes, a history of TGCT.
If there are suspicious findings on physical examina- B
tion or ultrasound in patients with TM and associated
lesions, perform surgical exploration with testicular
biopsy or orchidectomy.
Follow men with TGCT because they are at increased B
risk of developing hypogonadism and sexual dysfunc-
tion.

Disorders of Ejaculation
Disorders of ejaculation are uncommon, but important causes
of male infertility.

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Diagnostic evaluation
Diagnostic management includes the following recommended
procedures:
• clinical history;
• physical examination;
• post-ejaculatory urinalysis;
• microbiological examination;
• optional diagnostic work-up

This diagnostic work-up can include:

• neurophysiological tests (bulbocavernosus evoked
response and dorsal nerve somatosensory evoked
potentials);
• tests for autonomic neuropathy;
• psychosexual evaluation;
• videocystometry;
• cystoscopy;
• transrectal ultrasonography;
• uroflowmetry;
• vibratory stimulation of the penis.

Disease management
The following aspects must be considered when selecting
treatment:
• age of patient and his partner;
• psychological problems of the patient and his partner;
• couple’s willingness and acceptance of different fertility
procedures;
• associated pathology;
• psychosexual counselling.

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 Recommendations GR
Offer aetiological treatments for ejaculatory disorders B
before performing sperm collection and assisted
reproduction technique (ART).
To treat disorders of ejaculation, offer pharmacological A
treatment of either dapoxetine on demand (a short-
acting SSRI that is the only approved pharmacological
treatment for premature ejaculation), or other off-label
antidepressants, i.e. daily selective serotonin reuptake
inhibitors (SSRIs) and clomipramine, that are not
amenable to on-demand dosing.
Alternatively offer topical anaesthetics or tramadol. A

234 Male Infertility

Semen cryopreservation

Recommendations GR
Offer cryopreservation of semen to all men who are A
candidates for chemotherapy, radiation or surgical
interventions that might interfere with spermato-
genesis or cause ejaculatory disorders.
Offer simultaneous sperm cryopreservation if A
testicular biopsies will be performed for fertility diag-
nosis.
If cryopreservation is not available locally, inform C
patients about the possibility of visiting, or
transferring to a cryopreservation unit before therapy
starts.
Take precautions to prevent transmission of viral, C
sexually transmitted or any other infection by
cryostored materials from donor to recipient, and
to prevent contamination of stored samples. These
precautions include testing of the patient and the use
of rapid testing and quarantine of samples until test
results are known. Do not store samples from men
who are positive for hepatitis virus or HIV in the same
container as samples from men who have been tested
and are free from infection.

This short booklet text is based on the more comprehensive

EAU Guidelines ISBN 978-90-79754-91-5), available to all members of
the European Association of Urology at their website,
http://www.uroweb.org/guidelines.

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