Guidelines On Male Infertility
Guidelines On Male Infertility
Guidelines On Male Infertility
Male
Infertility
A. Jungwirth (chair), T. Diemer, G.R. Dohle, A. Giwercman,
Z. Kopa, C. Krausz, H. Tournaye
2. INVESTIGATIONS 9
2.1 Semen analysis 9
2.1.1 Frequency of semen analysis 10
2.2 Recommendations for investigations in male infertility 10
2.3 References 10
6. VARICOCELE 30
6.1 Introduction 30
6.2 Classification 30
6.3 Diagnosis 30
6.4 Basic considerations 30
6.4.1 Varicocele and fertility 30
6.4.2 Varicocelectomy 30
6.5 Treatment 31
6.6 Conclusions and recommendations for varicocele 31
6.7 References 32
7. HYPOGONADISM 33
7.1 Introduction 33
7.2 Hypogonadotrophic hypogonadism: aetiology, diagnosis and therapeutic management 34
7.3 Hypergonadotrophic hypogonadism: aetiology, diagnosis and therapeutic management 35
7.4 Conclusion and recommendation for hypogonadism 35
7.5 References 36
8. CRYPTORCHIDISM 36
8.1 Introduction 36
8.2 Incidence of cryptorchidism 37
8.3 Testicular descent and maldescent 37
8.4 Hormonal control of testicular descent 37
8.5 Pathophysiological effects in maldescended testes 37
8.5.1 Degeneration of germ cells 37
8.5.2 Relationship with fertility 37
8.5.3 Germ cell tumours 37
8.6 Treatment of undescended testes 38
8.6.1 Hormonal treatment 38
8.6.2 Surgical treatment 38
8.7 Conclusions and recommendations for cryptorchidism 38
8.8 References 38
It should be noted that when recommendations are graded, the link between the level of evidence (LE) and
grade of recommendation (GR) is not directly linear. Availability of randomised controlled trials (RCTs) may not
necessarily translate into a grade A recommendation where there are methodological limitations or disparity in
published results.
Alternatively, absence of high level of evidence does not necessarily preclude a grade A
recommendation, if there is overwhelming clinical experience and consensus. There may be exceptional
situations where corroborating studies cannot be performed, perhaps for ethical or other reasons and in this
case unequivocal recommendations are considered helpful. Whenever this occurs, it is indicated in the text
as “upgraded based on panel consensus”. The quality of the underlying scientific evidence - although a very
important factor - has to be balanced against benefits and burdens, values and preferences, and costs when a
grade is assigned (2-4).
The EAU Guidelines Office does not perform structured cost assessments, nor can they address
local/national preferences in a systematic fashion. But whenever these data are available, the expert panel will
include the information.
1.6 Definition
“Infertility is the inability of a sexually active, non-contracepting couple to achieve spontaneous pregnancy in
one year”, World Health Organization (WHO) (8).
In 30-40% of cases, no male-infertility-associated factor is found (idiopathic male infertility). These men
present with no previous history of diseases affecting fertility and have normal findings on physical examination
and endocrine laboratory testing. However, semen analysis reveals a decreased number of spermatozoa
(oligozoospermia), decreased sperm motility (asthenozoospermia), and many abnormal forms of sperm
(teratozoospermia). These sperm abnormalities usually occur together and are called oligo-astheno-
teratozoospermia (OAT) syndrome.
Table 3 summarises the main male-infertility-associated factors. Idiopathic male infertility is assumed
to be caused by several factors, including endocrine disruption as a result of environmental pollution, reactive
oxygen species, or genetic and epigenetic abnormalities.
The cumulative pregnancy rate is 27% in infertile couples with 2 years of follow-up and oligozoospermia as
the primary cause of infertility (11). Female age is the most important single variable influencing outcome in
assisted reproduction (12). Compared to a woman aged 25 years, the fertility potential of a woman aged 35
years is reduced to 50%, to 25% at 38 years, and less than 5% at over 40 years. In many Western countries,
women postpone their first pregnancy until after their education and starting a career.
Recommendations GR
To categorise infertility, both partners should be investigated simultaneously. C
In the diagnosis and management of male subfertility, the fertility status of the female partner must B
also be considered, because this might determine the final outcome (9).
The urologist/andrologist should examine any man with fertility problems for urogenital abnormalities. C
This applies to all men diagnosed with reduced semen quality. A diagnosis is mandatory to start
appropriate therapy (drugs, surgery, or assisted reproduction).
2. INVESTIGATIONS
2.1 Semen analysis
A medical history and physical examination are standard assessments in all men, including semen analysis.
A comprehensive andrological examination is indicated if semen analysis shows abnormalities compared with
reference values (Table 4). Important treatment decisions are based on the results of semen analysis, therefore,
it is essential that the complete laboratory work-up is standardised. Ejaculate analysis has been standardised
by the WHO and disseminated by publication of the WHO Laboratory Manual for the Examination and
Processing of Human Semen (5th edn.) (1). It is the consensus that modern spermatology must follow these
guidelines.
Often, all three anomalies occur simultaneously, which is defined as OAT syndrome. As in azoospermia, in
extreme cases of oligozoospermia (spermatozoa < 1 million/mL), there is an increased incidence of obstruction
of the male genital tract and genetic abnormalities.
Recommendations GR
According to WHO criteria, andrological investigations are indicated if semen analysis is abnormal in A
at least two tests.
Assessment of andrological status must consider the suggestions made by WHO for the standardised C
investigation, diagnosis, and management of the infertile couple; this will result in implementation of
evidence-based medicine in this interdisciplinary field of reproductive medicine (2).
Semen analysis must follow the guidelines of the WHO Laboratory Manual for the Examination and A*
Processing of Human Semen (5th edn.) (1).
*Upgraded following panel consensus
2.3 References
1. World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human
Semen. 5th edn. WHO, 2010.
http://www.who.int/reproductivehealth/publications/infertility/9789241547789/en/index.html
2. World Health Organization. WHO Manual for the Standardised Investigation and Diagnosis of the
Infertile Male. Cambridge: Cambridge University Press, 2000.
http://www.who.int/reproductivehealth/publications/infertility/0521774748/en/
3.2 Aetiology
The causes of testicular deficiency are summarised in Table 5.
Factors Causes
Congenital Anorchia
Testicular dysgenesis/cryptorchidism
Genetic abnormalities (karyotype, Y-chromosome deletions)
Acquired Trauma
Testicular torsion
Post-inflammatory forms, particularly mumps orchitis
Exogenous factors (medications, cytotoxic or anabolic drugs, irradiation, heat)
Systemic diseases (liver cirrhosis, renal failure)
Testicular tumour
Varicocele
Surgery that may compromise vascularisation of the testes and lead to testicular atrophy
Idiopathic Unknown aetiology
Unknown pathogenesis
3.4 Investigations
Routine investigations include semen analysis and hormonal determinations. Other investigations may be
required depending on the individual situation.
The results of ICSI are worse when using sperm retrieved from men with NOA compared to sperm from
ejaculated semen and from men with obstructive azoospermia (OA) (20-24). Birth rates are lower in NOA versus
OA (19% vs 28%) (25).
• ICSI results in significantly lower fertilisation and implantation rates (26).
• Miscarriage rates are higher in NOA versus OA (11.5% vs 2.5%) (27).
• Neonatal health in terms of birth parameters, major anomalies and chromosomal aberrations in a large
cohort of children born after use of non-ejaculated sperm are comparable to the outcome of children
born after use of ejaculated sperm (28).
In OA, there were no significant differences in ICSI results between testicular and epididymal sperm (23). Also,
no significant differences have been reported in ICSI results between the use of fresh and frozen-thawed sperm
(23,25,26).
Conclusions LE
Impaired spermatogenesis is often associated with elevated FSH concentration. 3
Spermatozoa are found in about 50% of patients with NOA. 2a
Pregnancies and live births are eventually obtained in 30-50% of couples with NOA, when 3
spermatozoa have been found in the testicular biopsy.
Recommendations GR
Men who are candidates for sperm retrieval must receive appropriate genetic counselling. A
Testicular biopsy is the best procedure to define the histological diagnosis and possibility of finding A
sperm. Spermatozoa should be cryopreserved for use in ICSI.
For patients with NOA who have spermatozoa in their testicular biopsy, ICSI with fresh or A
cryopreserved spermatozoa is the only therapeutic option.
Men with NOA can be offered TESE with cryopreservation of the spermatozoa to be used for ICSI (28). A
To increase the chances of positive sperm retrieval in men with NOA, TESE (microsurgical or multiple) A
should be used.
3.6 References
1. World Health Organization. WHO Manual for the Standardized Investigation, Diagnosis and
Management of the Infertile Male. Cambridge: Cambridge University Press, 2000.
http://www.who.int/reproductivehealth/publications/infertility/0521774748/en/
4.2.1 ex chromosome abnormalities (Klinefelter’s syndrome and variants [47,XXY; 46,XY/47, XXY
S
mosaicism])
Klinefelter’s syndrome is the most common sex chromosome abnormality (3,8). Adult men with Klinefelter’s
syndrome have small firm testicles, devoid of germ cells. The phenotype varies from a normally virilised man to
one with the stigmata of androgen deficiency, including female hair distribution, scant body hair, and long arms
and legs due to late epiphyseal closure. Leydig cell function is commonly impaired in men with Klinefelter’s
syndrome (9). Testosterone levels may be normal or low, oestradiol levels normal or elevated, and FSH levels
increased. Libido is often normal despite low testosterone levels, but androgen replacement may be needed as
the patient ages.
Germ cell presence and sperm production are variable in men with Klinefelter’s mosaicism,
46,XY/47,XXY. There is one case report of declining spermatogenesis in a man with Klinefelter’s syndrome, with
the recommendation that early sperm retrieval should be considered (10). Based on sperm fluorescence in situ
hybridisation (FISH) studies showing an increased frequency of sex chromosomal abnormalities and increased
incidence of autosomal aneuploidy (disomy for chromosomes 13, 18 and 21), concerns have been raised about
the chromosomal normality of the embryos generated through ICSI (11).
The production of 24,XY sperm has been reported in 0.9% and 7.0% of men with Klinefelter’s
mosaicism (12,13) and in 1.36-25% of men with somatic karyotype 47,XXY (14-17). In patients with
azoospermia, TESE or (micro-TESE) can be proposed as a therapeutic option since spermatozoa can
be recovered in about 30% of cases. To date, 49 healthy children have been born using ICSI without
preimplantation genetic diagnosis (PGD) and the conception of one 47,XXY foetus has been reported (8).
However, a study of ICSI combined with PGD in 113 embryos reported a significant fall in the rate of normal
embryos for couples with Klinefelter’s syndrome with respect to controls (54% vs 77.2%) (15). Due to the
significant increase of sex chromosomal and autosomal abnormalities in the embryos of Klinefelter’s patients,
PGD or amniocentesis analysis should be considered.
Follow-up (possibly every year) of men with Klinefelter’s syndrome is required and androgen
replacement therapy should be started when testosterone level is in the range of hypoandrogenism.
Conclusions LE
gr/gr deletion has been confirmed as a significant risk factor for impaired sperm production, whereas 2b
further evidence of the prognostic significance of gr/gr and development of a testicular germ cell
tumour is needed.
A son who inherits a complete AZF deletion will have abnormal spermatogenesis because these 2a
deletions have not been reported in normozoospermic men.
Recommendations GR
Testing for microdeletions is not necessary in men with OA (with normal FSH) when ICSI is used A
because spermatogenesis should be normal.
Men with severely damaged spermatogenesis (spermatozoa < 5 million/mL) should be advised to A
undergo Yq microdeletion testing for both diagnostic and prognostic purposes. Yq microdeletion also
has important implications for genetic counselling (see below).
If complete AZFa or AZFb microdeletions are detected, micro-TESE is not necessary because it is A
extremely unlikely that any sperm will be found.
If a man with Yq microdeletion and his partner wish to proceed with ICSI, they should be advised that A
microdeletions will be passed to sons, but not to daughters.
Table 6: Less common inherited disorders associated with infertility and other alterations to phenotype
Conclusions LE
New insights into the genetic basis of infertility and the advent of ICSI require a good understanding of 3
genetics by clinicians and the general public.
Diagnostic advances will allow us to identify the genetic basis of more disorders and diagnose known 2a
disorders at a lower cost. For some of these disorders, gene therapy might be practical in the future.
Recommendations GR
Standard karyotype analysis should be offered to all men with damaged spermatogenesis B
(spermatozoa < 10 million/mL) who are seeking fertility treatment by IVF.
Genetic counselling is mandatory in couples with a genetic abnormality found in clinical or genetic A
investigation and in patients who carry a (potential) inheritable disease.
All men with Klinefelter’s syndrome need long-term endocrine follow-up and may require androgen A
replacement therapy.
For men with severely damaged spermatogenesis (spermatozoa < 5 million/mL), testing for Yq A
microdeletions is strongly advised.
When a man has structural abnormalities of the vas deferens (unilateral or bilateral absence), he and A
his partner should be tested for CF gene mutations.
4.11 References
1. Griffin DK, Finch KA. The genetic and cytogenetic basis of male infertility. Human Fertil Mar 2005
Mar;8(1);19-26.
http://www.ncbi.nlm.nih.gov/pubmed/15823847
2. Carrell DT. The clinical implementation of sperm chromosome aneuploidy testing: pitfalls and
promises. J Androl 2008 Mar-Apr;29(2):124-33.
http://www.ncbi.nlm.nih.gov/pubmed/17881765
3. Johnson MD. Genetic risks of intracytoplasmic sperm injection in the treatment of male infertility:
recommendations for genetic counseling and screening. Fertil Steril 1998 Sep;70(3):397-411.
http://www.ncbi.nlm.nih.gov/pubmed/9757865
4. Clementini E, Palka C, Iezzi I, et al. Prevalence of chromosomal abnormalities in 2078 infertile couples
referred for assisted reproduction techniques. Hum Reprod 2005 Feb;20(2):437-42.
http://www.ncbi.nlm.nih.gov/pubmed/15567875
5. Vincent MC, Daudin M, De MP, et al. Cytogenetic investigations of infertile men with low sperm
counts: a 25-year experience. J Androl 2002 Jan-Feb;23(1):18-22.
http://www.ncbi.nlm.nih.gov/pubmed/11780918
6. Foresta C, Ferlin A, Gianaroli L, et al. Guidelines for the appropriate use of genetic tests in infertile
couples. Eur J Hum Genet 2002 May;10(5):303-12.
http://www.ncbi.nlm.nih.gov/pubmed/12082505
7. Dul EC, Groen H, van Ravenswaaij-Arts CM, et al. The prevalence of chromosomal abnormalities in
subgroups of infertile men. Hum Reprod 2012 Jan;27(1):36-43.
http://www.ncbi.nlm.nih.gov/pubmed/22740498
8. Lanfranco F, Kamischke A, Zitzmann M, et al. Klinefelter’s syndrome. Lancet 2004 Jul 17-23;
364(9430):273-83.
http://www.ncbi.nlm.nih.gov/pubmed/15262106
9. Wang C, Baker HW, Burger HG, et al. Hormonal studies in men with Klinefelter’s syndrome. Clin
Endocrinol (Oxf) 1975 Jul;4(4):399-411.
http://www.ncbi.nlm.nih.gov/pubmed/1157343
10. Ichioka K, Utsunomiya N, Kohei N, et al. Adult onset of declining spermatogenesis in a man with
nonmosaic Klinefelter’s syndrome. Fertil Steril 2006 May;85(5):1511.e1-2.
http://www.ncbi.nlm.nih.gov/pubmed/16616747
11. Staessen C, Tournaye H, Van Assche E, et al. PGD in 47,XXY Klinefelter’s syndrome patients. Hum
Reprod Update 2003 Jul-Aug;9(4):319-30.
http://www.ncbi.nlm.nih.gov/pubmed/12926526
12. Chevret E, Rousseaux S, Monteil M, et al. Increased incidence of hyperhaploid 24 XY spermatozoa
detected by three-colour FISH in a 46,XY/47,XXY male. Hum Genet 1996 Feb;97(2):171-5.
http://www.ncbi.nlm.nih.gov/pubmed/8566948
5. OBSTRUCTIVE AZOOSPERMIA
5.1 Definition
Obstructive azoospermia OA is the absence of spermatozoa and spermatogenetic cells in semen and post-
ejaculate urine due to bilateral obstruction of the seminal ducts. OA is less common than NOA and occurs in
15-20% of men with azoospermia. Common causes of OA are summarised in Table 7.
Men with OA present with normal FSH, normal size testes, and epididymal enlargement. Sometimes,
the vas deferens is absent due to congenital factors or previous inguinal or scrotal surgery. Obstruction in
primary infertile men is often present at the epididymal level; other sites of obstruction are the ejaculatory
ducts and the vas deferens. In 25% of men with a suspected obstruction, no spermatozoa are found in the
epididymis during scrotal exploration, indicating an intratesticular obstruction or non-obstructive cause.
Table 7: Classification of OA, on the basis of ductal obstruction due to congenital and acquired causes
5.3 Diagnosis
5.3.1 Clinical history
Clinical history taking should follow the suggestions for investigation of infertile men (see Chapter 2).
5.3.5 Ultrasonography
Scrotal ultrasound is 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 microcalcifications) and associated CIS of the testis. For patients with
a low seminal volume and in whom distal obstruction is suspected, transrectal ultrasound (TRUS) is essential. If
possible, TRUS should be performed at high resolution and with high-frequency (> 7 MHz) biplane transducers.
Seminal vesicle enlargement (anterior-posterior diameter 15 mm) (21) and round, anechoic areas in the seminal
vesicle (24) are TRUS anomalies more often associated with ejaculatory duct obstruction; especially when
semen volume is < 1.5 mL. Mullerian duct or urogenital sinus/ejaculatory duct cysts (20) and ejaculatory duct
calcifications (25) are other known anomalies in OA. TRUS may also be used to aspirate seminal vesicle fluid
(26).
Invasive diagnosis, including testicular biopsy, scrotal exploration, and distal seminal duct evaluation,
are indicated in patients with OA in whom an acquired obstruction of the seminal ducts is suspected.
Explorative and recanalisation surgery should be carried out simultaneously.
5.4 Treatment
5.4.1 Intratesticular obstruction
Intratesticularly, seminal duct recanalisation is impossible. TESE allows sperm retrieval in nearly all OA patients
Conclusions LE
Obstructive lesions of the seminal tract should be suspected in azoospermic or severely 3
oligozoospermic patients with normal-sized testes and normal endocrine parameters.
Recommendation GR
In azoospermia caused by epididymal obstruction, standard procedures include vasovasostomy and B
tubulovastomy.
Sperm retrieval techniques, such as MESA, TESE, and PESA, can be used additionally. These B
methods should be used only when cryostorage of the material obtained is available
In azoospermia caused by epididymal obstruction, scrotal exploration with microsurgical epididymal B
sperm aspiration and cryopreservation of spermatozoa should be performed. Microsurgical
reconstruction should be performed, if applicable. Results of reconstructive microsurgery depend on
the cause and location of the obstruction, and the surgeon’s expertise.
5.6 References
1. Hendry WF. Azoospermia and surgery for testicular obstruction. In: Hargreave TB (ed). Male Infertility.
Berlin: Springer-Verlag, 1997, pp. 319-36.
2. Hendry WF, Parslow JM, Stedronska J. Exploratory scrototomy in 168 azoospermic males. Br J Urol
1983 Dec;55(6):785-91.
http://www.ncbi.nlm.nih.gov/pubmed/6652453
3. Jequier AM. Obstructive azoospermia: a study of 102 patients. Clin Reprod Fertil 1985 Mar;3(1):21-36.
http://www.ncbi.nlm.nih.gov/pubmed/3978535
4. Pierik FH, Vreeburg JT, Stijnen T, et al. Serum inhibin B as a marker of spermatogenesis. J Clin
Endocrinol Metab 1998 Sep;83(9):3110-4.
http://www.ncbi.nlm.nih.gov/pubmed/9745412
5. Oates RD, Amos JA. The genetic basis of congenital bilateral absence of the vas deferens and cystic
fibrosis. J Androl 1994 Jan-Feb;15(1):1-8.
http://www.ncbi.nlm.nih.gov/pubmed/8188533
6. Handelsman DJ, Conway AJ, Boylan LM, et al. Young’s syndrome: obstructive azoospermia and
chronic sinopulmonary infections. New Engl J Med 1984 Jan;310(1):3-9.
http://www.ncbi.nlm.nih.gov/pubmed/6689737
7. Silber SJ, Grotjan HE. Microscopic vasectomy reversal 30 years later: a summary of 4010 cases by the
same surgeon. J Androl 2004 Nov-Dec;25(6):845-59.
http://www.ncbi.nlm.nih.gov/pubmed/15477352
8. Schoysman R. Vaso-epididymostomy - a survey of techniques and results with considerations of delay
of appearance of spermatozoa after surgery. Acta Eur Fertil 1990 Sep-Oct;21(5):239-45.
http://www.ncbi.nlm.nih.gov/pubmed/2132475
9. Matthews GJ, Schlegel PN, Goldstein M. Patency following microsurgical vasoepididymostomy and
vasovasostomy: temporal considerations. J Urol 1995 Dec; 154(6):2070-3.
http://www.ncbi.nlm.nih.gov/pubmed/7500460
10. Jarvi K, Zini A, Buckspan MB, et al. Adverse effects on vasoepididymostomy outcomes for men with
concomitant abnormalities in the prostate and seminal vesicle. J Urol 1998 Oct;160(4):1410-2.
http://www.ncbi.nlm.nih.gov/pubmed/9751365
11. Raleigh D, O’Donnell L, Southwick GJ, et al. Stereological analysis of the human testis after
vasectomy indicates impairment of spermatogenic efficiency with increasing obstructive interval. Fertil
Steril 2004 Jun;81(6):1595-603.
http://www.ncbi.nlm.nih.gov/pubmed/15193483
12. McVicar CM, O’Neill DA, McClure N, et al. Effects of vasectomy on spermatogenesis and fertility
outcome after testicular sperm extraction combined with ICSI. Hum Reprod 2005 Oct;20(10):
2795-800.
http://www.ncbi.nlm.nih.gov/pubmed/15958397
13. Sheynkin YR, Hendin BN, Schlegel PN, et al. Microsurgical repair of iatrogenic injury to the vas
deferens. J Urol 1998 Jan;159(1):139-41.
http://www.ncbi.nlm.nih.gov/pubmed/9400456
14. Shin D, Lipshultz LI, Goldstein M, et al. Herniorrhaphy with polypropylene mesh causing inguinal
vassal obstruction: a preventable cause of obstructive azoospermia. Ann Surg 2005 Apr;241(4):553-8.
http://www.ncbi.nlm.nih.gov/pubmed/15798455
6. VARICOCELE
6.1 Introduction
Varicocele is a common abnormality (see Chapter 2) with the following andrological implications:
• failure of ipsilateral testicular growth and development;
• symptoms of pain and discomfort;
• male infertility.
6.2 Classification
The following classification of varicocele (1,2) is useful in clinical practice:
• subclinical: not palpable or visible at rest or during Valsava manoeuvre, but can be shown by special
tests (Doppler ultrasound studies) (3);
• grade 1: palpable during Valsava manoeuvre, but not otherwise;
• grade 2: palpable at rest, but not visible;
• grade 3: visible and palpable at rest.
6.3 Diagnosis
The diagnosis of varicocele is made by clinical examination and should be confirmed by colour Doppler
analysis (2). In centres where treatment is carried out by antegrade or retrograde sclerotherapy or embolisation,
diagnosis is additionally confirmed by X-ray.
6.4.2 Varicocelectomy
Varicocele repair has been a subject of debate for several decades: controversy exists as to whether varicocele
repair results in more spontaneous pregnancies as compared to observation. The 2009 Cochrane Database
review concluded that there is no evidence that treatment of varicocele improves a couples’ chance of
conception (7). This meta-analysis was criticised for including several heterogeneous studies, men with normal
semen analysis, and men with a subclinical varicocele (8). In three RCTs repair of a subclinical varicocele was
found to be ineffective (9-11). Also, studies of men with a varicocele and normal semen analysis have shown no
clear benefit of treatment over observation (12,13).
The duration of infertility also seems to be important. In a recent study it was shown that couples with
infertility of > 2 years duration had a significantly higher pregnancy rate after varicocelectomy compared to
6.5 Treatment
Several treatments are available for varicocele (Table 9). The type of intervention chosen depends mainly on
the experience of the therapist. Although laparoscopic varicocelectomy is feasible, it must be justified in terms
of cost-effectiveness. Current evidence indicates that microsurgical varicocelectomy is the most effective and
least morbid method among the varicocelectomy techniques (17).
Table 9: Recurrence and complication rates associated with treatments for varicocele
Conclusions LE
Current information supports the hypothesis that the presence of varicocele in some men is 2a
associated with progressive testicular damage from adolescence onwards and a consequent
reduction in fertility.
Although the treatment of varicocele in adolescents may be effective, there is a significant risk of 3
overtreatment.
Varicocele repair may be effective in men with subnormal semen analysis, a clinical varicocele and 1a
otherwise unexplained infertility.
6.7 References
1. Hudson RW, Perez Marrero RA, Crawford VA, et al. Hormonal parameters in incidental varicoceles and
those causing infertility. Fertil Steril 1986 May;45(5):692-700.
http://www.ncbi.nlm.nih.gov/pubmed/3084304
2. World Health Organization. WHO Manual for the Standardized Investigation, Diagnosis and
Management of the Infertile Male. Cambridge: Cambridge University Press, 2000.
http://www.who.int/reproductivehealth/publications/infertility/0521774748/en/
3. Dhabuwala CB, Hamid S, Moghissi KS. Clinical versus subclinical varicocele: improvement in fertility
after varicocelectomy. Fertil Steril 1992 Apr;57(4):854-7.
http://www.ncbi.nlm.nih.gov/pubmed/1555699
4. No authors listed. The influence of varicocele on parameters of fertility in a large group of men
presenting to infertility clinics. World Health Organisation. Fertil Steril 1992; 57(6):1289-93.
http://www.ncbi.nlm.nih.gov/pubmed/1601152
5. Argawal A, Deepinder F, Cocuzza M, et al. Efficacy of varicocelectomy in improving semen
parqameters: new meta-analytical approach. Urology 2007 Sep;70(3):532-8.
http://www.ncbi.nlm.nih.gov/pubmed/17905111
6. Zini A, Dohle G. Are varicoceles associated with increased deoxyribonucleic acid fragmentation? Fertil
Steril 2011 Dec;96(6):1283-7.
http://www.ncbi.nlm.nih.gov/pubmed/22035729
7. Evers JH, Collins J, Clarke J. Surgery or embolisation for varicoceles in subfertile men. Cochrane
Database Syst Rev 2009 Jan 21;(1):CD000479.
http://www.ncbi.nlm.nih.gov/pubmed/19160180
8. Ficarra V, Cerruto MA, Iguori G, et al. Treatment of varicocele in subfertile men: The Cochrane review -
a contrary opinion. Eur Urol 2006 Feb;49(2):258-63.
http://www.ncbi.nlm.nih.gov/pubmed/16426727
9. Grasso M, Lania C, Castelli M, et al. Low-grade left varicocoele in patients over 30 years old: the
effect of spermatic vein ligation on fertility. BJU Int 2000 Feb;85(3):305-7.
http://www.ncbi.nlm.nih.gov/pubmed/10671887
10. Yamamoto M, Hibi H, Hirata Y, et al. Effect of varicocoelectomy on sperm parameters and pregnancy
rates in patients with subclinical varicocele: a randomized prospective controlled study. J Urol 1996
May;155(5):1636-8.
http://www.ncbi.nlm.nih.gov/pubmed/8627841
11. Unal D, Yeni E, Verit A, et al. Clomiphene citrate versus varicocoelectomy in treatment of subclinical
varicocoele: a prospective randomized study. Int J Urol 2001 May;8(5):227-30.
http://www.ncbi.nlm.nih.gov/pubmed/11328423
12. Nilsson S, Edvinsson A, Nilsson B. Improvement of semen and pregnancy rate after ligation and
division of the internal spermatic vein: fact or fiction? Br J Urol 1979 Dec;51(6):591-6.
http://www.ncbi.nlm.nih.gov/pubmed/534846
13. Breznik R, Vlaisavljevic V, Borko E. Treatment of varicocoele and male fertility. Arch Androl 1993 May-
June;30(3):157-60.
http://www.ncbi.nlm.nih.gov/pubmed/8498867
14. Giagulli VA, Carbone MD. Varicocele correction for infertility: which patients to treat? Int J Androl 2011
Jun;34(3):236-41.
http://www.ncbi.nlm.nih.gov/pubmed/20579135
15. Baazeem A, Belzile E, Ciampi A, et al. Varicocele and male factor infertility treatment: a new
metaanalysis and review of the role of varicocele repair. Eur Urol 2011 Oct;60(4):796-808.
http://www.ncbi.nlm.nih.gov/pubmed/21733620
16. Abdel-Meguid, TA, Al-Sayyad A, Tayib A, et al. Does varicocele repair improve male infertility? An
evidence-based perspective from a randomized, controlled trial. Eur Urol 2011 Mar;59(3):455-61.
http://www.ncbi.nlm.nih.gov/pubmed/21196073
7. HYPOGONADISM
7.1 Introduction
Hypogonadism is characterised by impaired testicular function, which may affect spermatogenesis and/
or testosterone synthesis. The symptoms of hypogonadism depend on the degree of androgen deficiency
and if the condition develops before or after pubertal development of the secondary sex characteristics. The
symptoms and signs of hypoandrogenism presenting before and after completion of puberty are provided in
Table 10.
Table 10: Symptoms and signs of hypogonadism appearing before and after completion of puberty*
The aetiological and pathogenetic mechanisms of male hypogonadism can be divided into three main
categories:
1. Primary (hypergonadotrophic) hypogonadism due to testicular failure.
2. Secondary (hypogonadotrophic) hypogonadism caused by insufficient gonadotropin-releasing
hormone (GnRH) and/or gonadotropin (FSH, LH) secretion.
3. Androgen insensitivity (end-organ resistance).
The most common conditions within these three categories are given in Table 11 (see also Chapter 4).
Conclusion LE
It is generally agreed that patients with primary or secondary hypogonadism associated with 1b
hypoandrogenism should receive testosterone substitution therapy.
Recommendation GR
Effective drug therapy is available to achieve fertility in men with hypogonadotrophic hypogonadism A*
(4).
Testosterone replacement is strictly contraindicated for the treatment of male infertility (13). A*
*Upgraded following panel consensus
8. CRYPTORCHIDISM
8.1 Introduction
Cryptorchidism is the most common congenital abnormality of the male genitalia and is found in 2-5% of
newborn boys, depending on gestational age (cryptorchidism occurs more often in premature boys) and age
after birth. At the age of 3 months, the incidence of cryptorchidism falls spontaneously to 1-2%. Approximately
20% of undescended testes are non-palpable and may be located within the abdominal cavity.
The aetiology of cryptorchidism is multifactorial, involving disrupted endocrine regulation and several
gene defects. The normal descent of the testes requires a normal hypothalamic-pituitary-gonadal axis.
Endocrine disruption in early pregnancy can potentially affect gonadal development and normal descent of the
testes; however, most boys with maldescended testes show no endocrine abnormalities after birth. 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 includes hypospadias, reduced fertility, increased risk of malignancy, and Leydig
cell dysfunction (1).
Conclusions LE
Cryptorchidism is multifactorial in origin and can be caused by genetic factors and endocrine 3
disruption early in pregnancy.
Cryptorchidism is often associated with testicular dysgenesis and is a risk factor for infertility and GCT. 2b
Whether early surgical intervention can prevent germ cell loss is still debatable, but in a randomised
study it improved testicular growth in boys treated at the age of 9 months compared to those aged 3
years at the time of orchidopexy.
Paternity in men with unilateral cryptorchidism is almost equal to that in men without cryptorchidism. 3
Bilateral cryptorchidism significantly reduces the likelihood of paternity. 3
Recommendations GR
Hormonal treatment of cryptorchidism in adults is not recommended. A
Early orchidopexy (6-12 months of age) might be beneficial for testicular development in adulthood. B
If undescended testes are corrected in adulthood, testicular biopsy for detection of ITGCNU (formerly B
CIS) is recommended at the time of orchidopexy.
8.8 References
1. Skakkebaek NS, Rajpert-De Meyts E, Main KM. Testicular dysgenesis syndrome: an ncreasingly
common developmental disorder with environmental aspects. Hum Reprod 2001 May;16(5):972-8.
http://www.ncbi.nlm.nih.gov/pubmed/11331648
2. Boisen KA, Kaleva M, Main KM, et al. Difference in prevalence of congenital cryptorchidism in infants
between two Nordic countries. Lancet 2004 Apr;363(9417):1264-9.
http://www.ncbi.nlm.nih.gov/pubmed/15094270
3. Heyns CF, Hutson JM. Historical review of theories on testicular descent. J Urol 1995 Mar;153
(3 Pt 1):754-67. [No abstract available]
http://www.ncbi.nlm.nih.gov/pubmed/7861531
4. Scorer CG. The descent of the testis. Arch Dis Child 1964 Dec;39:605-9.
http://www.ncbi.nlm.nih.gov/pubmed/14230757
Recommendation GR
Medical treatment of male infertility is recommended only for cases of hypogonadotrophic A
hypogonadism.
9.3 References
1. Pierik FH, Van Ginneken AM, Dohle GR, et al. The advantages of standardized evaluation of male
infertility. Int J Androl 2000 Dec;23(6):340-6.
http://www.ncbi.nlm.nih.gov/pubmed/11114979
2. Foresta C, Bettella A, Spolaore D, et al. Suppression of the high endogenous levels of plasma FSH
in infertile men are associated with improved Sertoli cell function as reflected by elevated levels of
plasma inhibin B. Hum Reprod 2004 Jun;19(6):1431-7.
http://www.ncbi.nlm.nih.gov/pubmed/15117900
3. Chua ME, Escusa KG, Luna S, et al. Revisiting oestrogen antagonists (clomiphene or tamoxifen) as
medical empiric therapy for idiopathic male infertility: a meta-analysis. Andrology 2013 Sep;1(5):
749-57.
http://www.ncbi.nlm.nih.gov/pubmed/23970453
4. Paradisi R, Busacchi P, Seracchioli R, et al. Effects of high doses of recombinant human follicle
stimulating hormone in the treatment of male factor infertility: results of a pilot study. Fertil Steril 2006
Sep;86(3):728-31.
http://www.ncbi.nlm.nih.gov/pubmed/16782097
5. Showell MG, Brown J, Yazdani A, et al. Antioxidants for male subfertility. Cochrane Database Syst Rev
2011 Jan;(1):CD007411.
http://www.ncbi.nlm.nih.gov/pubmed/21249690
These approaches remain experimental. The method nearest to being generally available clinically is hormonal
male contraception, which is based on the suppression of gonadotropins and testosterone substitution
to maintain male sexual function and bone mineralization, and to prevent muscle wasting (6). Various
contraceptive regimens have been developed and tested, including testosterone monotherapy, androgen/
progestin combinations, testosterone with GnRH analogues, and selective androgen- and progestin-receptor
modulators. There are racial differences in the response to androgens alone. However, a combination of
testosterone with progestin results in complete suppression of spermatogenesis in all races, and provides
contraceptive efficacy equivalent to female hormonal methods (7). Phase III clinical trials of depot preparations
of androgen/progestin combinations are in progress.
10.2 Vasectomy
Vasectomy is an effective method of permanent male surgical sterilisation (8). Extensive guidelines on
vasectomy were published by the EAU in 2012 (9). Before vasectomy, the couple should be fully informed
about the benefits and risks, especially as an Australian telephone survey found that 9.2% of respondents
regretted having a vasectomy (10).
10.2.2 Complications
Vasectomy does not significantly alter spermatogenesis and Leydig cell function. The volume of ejaculate
remains unchanged. Potential systemic effects of vasectomy, including atherosclerosis, have not been proven,
and there is no evidence of a significant increase in any systemic disease after vasectomy. An increased rate
of prostate cancer in men who underwent vasectomy has not been detected (16,17). Acute local complications
associated with vasectomy include haematoma, wound infection, and epididymitis in up to 5% of cases (17).
The potential long-term complications (e.g., chronic testicular pain) (18) must be discussed with the patient
before the procedure. Epididymal tubal damage is common, and is associated with consequent development
of sperm granuloma and time-dependent secondary epididymal obstruction, which limits vasectomy reversal.
10.2.4 Counselling
Counselling with regard to vasectomy must address the following aspects:
• Vasectomy should be considered irreversible.
• Vasectomy is associated with a low complication rate; however, because it is an elective operation,
even small risks must be explained, because men (and their partners) might wish to consider these
before giving consent.
• Vasectomy can fail, although the failure rate is low.
• Couples should be advised to continue with other effective contraception until clearance is confirmed.
• All available data indicate that vasectomy is not associated with any serious, long-term, side effects
(15).
• Vasectomy involving cauterisation and fascial interposition appears to be the most effective technique
(12-14).
10.3.2 Tubulovasostomy
The chance of secondary epididymal obstruction after vasectomy increases with time. After an interval of
10 years, 25% of men appear to have epididymal blockage. If secondary epididymal obstruction occurs,
tubulovasostomy is needed to reverse the vasectomy (see Chapter 5) (23).
10.3.3 Microsurgical vasectomy reversal versus epididymal or testicular sperm retrieval and ICSI
According to the calculations of cost per delivery for vasectomy reversal versus sperm retrieval/ICSI, under a
wide variety of initial assumptions, it is clear that vasectomy reversal is associated with a considerably lower
cost per delivery and higher delivery rates (24,-27). Sperm retrieval and ICSI must yield an 81% pregnancy rate
per cycle to achieve equal costs to vasectomy reversal.
Conclusions LE
Vasectomy is considered the gold standard for the male contribution to contraception. 1
All available data indicate that vasectomy is not associated with any serious, long term side effects. 1b
Pregnancy is still achievable after successful vasectomy reversal. 2a
Methods of male contraception other than vasectomy are associated with high failure rates or are still 3
experimental (e.g., hormonal approach).
Recommendations GR
Vasectomy meets best the criteria for the male contribution to contraception, with regard to efficacy, A
safety and side effects. Cauterisation and fascial interposition are the most effective techniques.
Patients seeking consultation about vasectomy must be informed about the surgical method, risk A*
of failure, irreversibility, the need for post-procedure contraception until clearance, and the risk of
complications.
Microsurgical vasectomy reversal is a low-risk and (cost-) effective method of restoring fertility. B
MESA/TESE/PESA and ICSI should be reserved for failed vasectomy reversal surgery. A
For couples wanting to achieve pregnancy, sperm aspiration together with ICSI is a second-line option B
for selected cases and in those with failed vasovasostomy.
*Upgraded following panel consensus
10.5 References
1. Reproductive Health Strategy. Reproductive Health Research World Health Organisation, Geneva.
Adopted at the 57th World Health Assembly, 2004.
http://www.who.int/reproductive-health/publications/strategy.pdf
2. Handelsman D, Waites G. Tradional methods. In: Schill W, Comhaire F, Hargreave T (eds). Andrology
for the Clinician. Berlin: Springer Verlag, 2006, pp. 122-4.
3. Griffin D, Ringheim K. Male hormonal contraception. What prospects exist and how acceptable are
they? Plan Parent Chall 1996;(2):20-4.
http://www.ncbi.nlm.nih.gov/pubmed/12291936
4. Gallo MF, Grimes DA, Lopez LM, et al. Non-latex versus latex male condoms for contraception.
Cochrane Database Syst Rev 2006 Jan;(1):CD003550.
http://www.ncbi.nlm.nih.gov/pubmed/16437459
5. Naz RK. Antisperm immunity for contraception. J Androl 2006 Mar-Apr;27(2):153-9.
http://www.ncbi.nlm.nih.gov/pubmed/16474022
11.2.9 Therapy
Treatment of chronic prostatitis is usually targeted at relieving symptoms (31,32). Andrologically, the aims of
therapy for altered semen composition in male adnexitis (acute and chronic infections of the male urogenital
tract) are:
• reduction or eradication of microorganisms in prostatic secretions and semen;
• normalisation of inflammatory (e.g., leukocytes) and secretory parameters;
• improvement of sperm parameters to counteract fertility impairment (33).
Treatment includes antibiotics, anti-inflammatory drugs, surgical procedures, normalisation of urine flow,
physical therapy, and alterations in general and sexual behaviour.
Only antibiotic therapy of chronic bacterial prostatitis (NIH II) has provided symptomatic relief,
eradication of microorganisms, and a decrease in cellular and humoral inflammatory parameters in urogenital
secretions. The use of α-blockers for symptom relief is controversial. Although antibiotics might improve sperm
quality (33), there is no evidence that treatment of chronic prostatitis increases the probability of conception
(1,34).
11.3 Epididymitis
11.3.1 Introduction
Inflammation of the epididymis causes unilateral pain and swelling, usually with acute onset. Among sexually
active men < 35 years of age, epididymitis is most often caused by C. trachomatis or Neisseria gonorrhoea
(35,36). Sexually transmitted epididymitis is usually accompanied by urethritis. Non-sexually transmitted
epididymitis is associated with urinary tract infection and occurs more often in men aged > 35 years, those who
have recently undergone urinary tract instrumentation or surgery, and those who have anatomical abnormalities
(37).
11.3.3 Treatment
Antibiotic therapy is indicated before culture results are available (Table 13). Treatment of epididymitis results in:
• microbiological cure of infection;
• improvement of clinical signs and symptoms;
• prevention of potential testicular damage;
• prevention of transmission;
• decrease of potential complications (e.g., infertility or chronic pain).
Patients with epididymitis known or suspected to be caused by N. gonorrhoeae or C. trachomatis must be told
to refer their sexual partners for evaluation and treatment (47).
Conclusions LE
Urethritis and prostatitis are not associated clearly with male infertility. 3
Antibiotic treatment often only eradicates microorganisms; it has no positive effect on inflammatory 2a
alterations, and cannot reverse functional deficits and anatomical dysfunction.
Although antibiotic treatment for MAGI might provide improvement in sperm quality, it does not 2a
necessarily enhance the probability of conception.
Recommendations GR
Patients with epididymitis that is known or suspected to be caused by N. gonorrhoeae or B
C. trachomatis must be instructed to refer their sexual partners for evaluation and treatment.
11.5 References
1. Weidner W, Krause W, Ludwig M. Relevance of male accessory gland infection for subsequent fertility
with special focus on prostatitis. Hum Reprod Update 1999 Sep-Oct;5(5):421-32.
http://www.ncbi.nlm.nih.gov/pubmed/10582781
2. World Health Organization. WHO Manual for the Standardized Investigation, Diagnosis and
Management of the Infertile Male. Cambridge: Cambridge University Press, 2000.
http://www.who.int/reproductivehealth/publications/infertility/0521774748/en/
3. Purvis K, Christiansen E. Infection in the male reproductive tract. Impact, diagnosis and treatment in
relation to male infertility. Int J Androl 1993 Feb;16(1):1-13.
http://www.ncbi.nlm.nih.gov/pubmed/8468091
4. Engeler D, Baranowski AP, Dinis Oliveira P, et al. Members of the EAU Guidelines Office. EAU
Guidelines on Chronic Pelvic Pain. In: EAU Guidelines, edition presented at the 27th EAU Annual
Congress, Paris 2012. ISBN 978-90-79754-83-0.
5. Grabe M, Bjerklund Johansen TE, Botto H, et al. Members of the EAU Guidelines Office. EAU
Guidelines on Urological Infections. In: EAU Guidelines, edition presented at the 27th EAU Annual
Congress, Paris 2012. ISBN 978-90-79754-83-0.
6. Liversedge NH, Jenkins JM, Keay SD, et al. Antibiotic treatment based on seminal cultures from
asymptomatic male partners in in-vitro fertilization is unnecessary and may be detrimental. Hum
Reprod 1996 Jun;11(6):1227-31.
http://www.ncbi.nlm.nih.gov/pubmed/8671429
Recommendations GR
As for all men, patients with TM and without special risk factors (see below) should be encouraged to B
perform self-examination because this might result in early detection of TGCT.
Testicular biopsy should be offered to men with TM, who belong to one of the following high-risk B
groups: infertility and bilateral TM, atrophic testes, undescended testes, a history of TGCT, or
contralateral TM.
If there are suspicious findings on physical examination or ultrasound in patients with TM and B
associated lesions, surgical exploration with testicular biopsy or orchidectomy should be considered.
Testicular biopsy, follow-up scrotal ultrasound, routine use of biochemical tumour markers, or B
abdominal or pelvic CT is not justified in men with isolated TM without associated risk factors (e.g.,
infertility, cryptorchidism, testicular cancer, and atrophic testis).
Men with TGCT are at increased risk of developing hypogonadism and sexual dysfunction and should B
therefore be followed up.
12.5 References
1. Skakkebaek NE. Carcinoma in situ of the testis: frequency and relationship to invasive germ cell
tumours in infertile men. Histopathology 1978 May;2(3):157-70.
http://www.ncbi.nlm.nih.gov/pubmed/27442
2. von der Maase H, Rorth M, Walbom-Jorgensen S, et al. Carcinoma in situ of contralateral testis
in patients with testicular germ cell cancer: study of 27 cases in 500 patients. Br Med J 1986
Nov;293(6559):1398-401.
http://www.ncbi.nlm.nih.gov/pubmed/3026550
3. Jacobsen R, Bostofte E, Engholm G, et al. Risk of testicular cancer in men with abnormal semen
characteristics: cohort study. BMJ 2000 Sep;321(7264):789-92.
http://www.ncbi.nlm.nih.gov/pubmed/11009515
4. Huyghe E, Matsuda T, Thonneau P. Increasing incidence of testicular cancer worldwide: a review.
J Urol 2003 Jul;170(1):5-11.
http://www.ncbi.nlm.nih.gov/pubmed/12796635
5. Giwercman A, Muller J, Skakkebaek NE. Carcinoma in situ of the undescended testis. Semin Urol
1988 May;6(2):110-9. [No abstract available]
http://www.ncbi.nlm.nih.gov/pubmed/2903524
6. Petersen PM, Skakkebaek NE, Vistisen K, et al. Semen quality and reproductive hormones before
orchiectomy in men with testicular cancer. J Clin Oncol 1999 Mar;17(3):941-7.
http://www.ncbi.nlm.nih.gov/pubmed/10071288
7. Eberhard J, Stahl O, Giwercman Y, et al. Impact of therapy and androgen receptor polymorphism on
sperm concentration in men treated for testicular germ cell cancer: a longitudinal study. Hum Reprod
2004 Jun;19(6):1418-25.
http://www.ncbi.nlm.nih.gov/pubmed/15105386
8. Willemse PH, Sleijfer DT, Sluiter WJ, et al. Altered Leydig cell function in patients with testicular
cancer: evidence for bilateral testicular defect. Acta Endocrinol (Copenh) 1983 Apr;102(4):616-24.
http://www.ncbi.nlm.nih.gov/pubmed/6133401
9. Nord C, Bjoro T, Ellingsen D, et al. Gonadal hormones in long-term survivors 10 years after treatment
for unilateral testicular cancer. Eur Urol 2003 Sep;44(3):322-8.
http://www.ncbi.nlm.nih.gov/pubmed/12932930
10. Eberhard J, Stahl O, Cwikiel M, et al. Risk factors for post-treatment hypogonadism in yesticular
cancer patients. Eur J Endocrinol 2008 Apr;158(4):561-70.
http://www.ncbi.nlm.nih.gov/pubmed/18362304
13.2.2 Anorgasmia
Anorgasmia is the inability to reach orgasm and can give rise to anejaculation. Anorgasmia is often a primary
condition and its cause is usually psychological. Some patients report sporadic events of nocturnal emission or
of ejaculation during great emotional excitement unrelated to sexual activity (3).
Neurogenic Pharmacological
Spinal cord injury Antihypertensives
Cauda equina lesions α1-adrenoceptor antagonists
Multiple sclerosis Antipsychotics and antidepressants
Autonomic neuropathy (diabetes mellitus) Alcohol
Retroperitoneal lymphadenectomy Bladder neck incompetence
Sympathectomy or aortoiliac surgery Congenital defects/dysfunction of hemitrigone
Colorectal and anal surgery Bladder extrophy
Parkinson´s disease Bladder neck resection (transurethral resection of the
prostate)
Urethral Prostatectomy
Ectopic ureterocele
Urethral stricture
Urethral valves or verumontaneum hyperplasia
Congenital dopamine β-hydroxylase deficiency
13.3 Diagnosis
Diagnostic management includes the following recommended procedures.
13.4 Treatment
Infertility caused by disorders of ejaculation is seldom treated on the basis of aetiology. Treatment usually
involves retrieval of spermatozoa for use in ARTs. 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.
Sperm collection from post-orgasmic urine for use in ART is recommended if:
• drug treatment is ineffective or intolerable as a result of side effects;
• the patient has a spinal cord injury;
• drug therapy inducing retrograde ejaculation cannot be interrupted.
Sperm retrieval is timed to coincide with the partner’s ovulation. Urine must be alkalinised (pH 7.2-7.8)
and osmolarity must be 200-300 mOsmol/kg. Alternatively, a catheter can be inserted into the bladder to
allow instillation of 10-50 mL Tyrode’s or Ham’s F-10 medium. The patient must ejaculate, and a second
catheterisation is carried out immediately to retrieve spermatozoa. The latter treatment minimises contact
between spermatozoa and urine (17,18).
If the biological sperm preparation is not of sufficient quality for intrauterine insemination, the couple
must undergo in vitro reproductive procedures (e.g., ICSI) with fresh or cryopreserved spermatozoa. In the case
of insufficient drug therapy, testicular (TESE or PESA) or epididymal (MESA) sperm retrieval techniques can be
used for assisted reproduction.
13.6.3 Anejaculation
Drug treatment for anejaculation caused by lymphadenectomy and neuropathy, or psychosexual therapy for
anorgasmia is not very effective. In all these cases, and in men who have a spinal cord injury, vibrostimulation
(i.e., application of a vibrator to the penis) is first-line therapy.
In anejaculation, vibrostimulation evokes the ejaculation reflex (19), which requires an intact
lumbosacral spinal cord segment. Complete spinal injuries and injuries above T10 show a better response to
vibrostimulation. Once the safety and efficacy of this procedure has been assessed, patients can manage the
process in their own home. Intravaginal insemination using a 10-mL syringe during ovulation can be carried
out. If the quality of semen is poor, or ejaculation is retrograde, the couple may enter an IVF programme.
If vibrostimulation has failed, electroejaculation is the therapy of choice (20). Electroejaculation
involves electrical stimulation of the periprostatic nerves via a probe inserted into the rectum, which seems
unaffected by reflex arc integrity. Anaesthesia is required except in cases of complete spinal cord injury. In 90%
of patients, electrostimulation induces ejaculation, which is retrograde in one-third of cases. Semen quality is
often poor and most couples will need to enter an IVF programme (21).
When electroejaculation fails or cannot be carried out, sperm can be retrieved from the seminal ducts
by aspiration from the vas deferens (22) (see Chapter 5) or seminal tract washout (23).
When sperm cannot be retrieved, epididymal obstruction or testicular failure must be suspected). If
only immotile sperm can be retrieved, DNA damage is very likely and will yield poor IVF results. TESE can then
be used (8,24). Anejaculation following either surgery for testicular cancer or total mesorectal excision can be
prevented using monolateral lymphadenectomy or autonomic nerve preservation (24), respectively.
Conclusion LE
Ejaculation disorders can be treated using a wide range of drugs and physical stimulation, with a high 3
level of efficacy.
Recommendations GR
Aetiological treatments for ejaculatory disorders should be offered before sperm collection and ART is B
performed.
Premature ejaculation can be treated successfully with either topical anaesthetic creams or SSRIs. A
In men with spinal cord injury, vibrostimulation and electroejaculation are effective methods of sperm B
retrieval.
14.2 Introduction
Cryopreservation was first developed in the 1940s by veterinarians and adapted for human sperm in the 1950s.
The first pregnancy that used cryopreservation took place in 1954 (1). In fertility practice, clinical indications for
cryopreservation include storage of sperm and testicular tissue.
Cryopreservation can be used for sperm collected through TESE, avoiding repeated sperm retrieval procedures
and unnecessary hyperstimulation of the female partner.
• In any situation in which sperm have been obtained by a sperm retrieval procedure (e.g., after failed
vasectomy reversal, or in some cases of epididymal obstruction not amenable to surgery).
• For storage of donor sperm, because cryopreservation reduces the risk of transmission of infection
from sperm donors. According to the European directives 2004/23 EC and 2006/17 EC fresh sperm
are no longer to be used for non-partner donations.
Conclusions LE
The purpose of sperm cryopreservation is to enable future assisted reproduction techniques 1b
procedures.
Cryopreservation techniques are not optimal, and future efforts are needed to improve the outcome of 3
sperm banking.
Recommendations GR
Cryopreservation of semen should be offered to all men who are candidates for chemotherapy, A
radiation or surgical interventions that might interfere with spermatogenesis or cause ejaculatory
disorders.
If testicular biopsies are indicated, sperm cryopreservation is strongly advised. A
If cryopreservation is not available locally, patients should be advised about the possibility of visiting, C
or transferring to, the nearest cryopreservation unit before therapy starts.
Consent for cryopreservation should include a record of the man’s wishes for his samples if he dies or C
is otherwise untraceable.
Precautions should be taken to prevent transmission of viral, sexually transmitted or any other C
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. Samples from men who are positive for hepatitis virus or HIV
should not be stored in the same container as samples from men who have been tested and are free
from infection.
14.8 References
1. Bunge RG, Keettel WC, Sherman JK. Clinical use of frozen semen; report of four cases. Fertil Steril
1954 Nov-Dec;5(6):520-9. [No abstract available]
http://www.ncbi.nlm.nih.gov/pubmed/13210484
2. Saito K, Suzuki K, Iwasaki A, et al. Sperm cryopreservation before cancer chemotherapy helps in the
emotional battle against cancer. Cancer 2005 Aug;104(3):521-4.
http://www.ncbi.nlm.nih.gov/pubmed/15968690
3. Desrosiers P, Legare C, Leclerc P, et al. Membranous and structural damage that occur during
cryopreservation of human sperm may be time-related events. Fertil Steril 2006 Jun;85(6):1744-52.
http://www.ncbi.nlm.nih.gov/pubmed/16643911
4. Donnelly ET, McClure N, Lewis SE. Cryopreservation of human semen and prepared sperm: effects on
motility parameters and DNA integrity. Fertil Steril 2001 Nov;76(5):892-900.
http://www.ncbi.nlm.nih.gov/pubmed/11704107
5. Chohan KR, Griffin JT, Carrell DT. Evaluation of chromatin integrity in human sperm using acridine
orange staining with different fixatives and after cryopreservation. Andrologia 2004 Oct;36(5):321-6.
http://www.ncbi.nlm.nih.gov/pubmed/15458552
6. Askari HA, Check JH, Peymer N, et al. Effect of natural antioxidants tocopherol and ascorbic acids in
maintenance of sperm activity during freeze-thaw process. Arch Androl 1994 Jul-Aug;33(1):11-5.
http://www.ncbi.nlm.nih.gov/pubmed/7979804
7. Smith KD, Steinberger E. Survival of spermatozoa in a human sperm bank. Effects of long-term
storage in liquid nitrogen. J Am Med Assoc 1973 Feb;223(7):774-7.
http://www.ncbi.nlm.nih.gov/pubmed/4739258
8. Agarwal A, Said TM. Oxidative stress, DNA damage and apoptosis in male infertility: a clinical
approach. BJU Int 2005 Mar;95(4):503-7.
http://www.ncbi.nlm.nih.gov/pubmed/15705068
Conflict of interest
All members of the Male Infertility Guidelines working group have provided disclosure statements of all
relationships that they have that might be perceived as a potential source of a conflict of interest. This
information is publicly accessible through the European Association of Urology website. This guidelines
document was developed with the financial support of the European Association of Urology. No external
sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited
to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have
been provided.