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1 23
International Urology andNephrology ISSN 0301-1623 Int Urol NephrolDOI 10.1007/s11255-015-1059-0
A systematic review of recent clinicalpractice guidelines and best practicestatements for the evaluation of the infertilemale
Sandro C. Esteves & Peter Chan
1 23
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Int Urol NephrolDOI 10.1007/s11255-015-1059-0
UROLOGY - REVIEW
A systematic review of recent clinical practice guidelines and best practice statements for the evaluation of the infertile male
Sandro C. Esteves1 · Peter Chan2
Received: 12 June 2015 / Accepted: 8 July 2015 © Springer Science+Business Media Dordrecht 2015
Conclusions While the various panels of experts who con-tributed to the development of the CPG and BPS reviewed should be commended on their tremendous efforts aiming to establish a clinical standard in both the evaluation and man-agement of male infertility, we recognized inconsistencies in the methodology of their synthesis and in the contents of their final recommendations. These discrepancies pose a barrier in the general implementation of these guidelines and may limit their utility in standardizing clinical practice or improving health-related outcomes. Continuous efforts are needed to generate high-quality evidence to allow fur-ther development of these important guidelines for the eval-uation and management of males suffering from infertility.
Keywords Clinical practice guidelines · Diagnosis · Male infertility · Standards · Systematic review
Introduction
Globally, the prevalence of infertility among couples at reproductive age has been reported to be approximately 15 % [1]. The origins of the problem appear to be equally distributed between the male and female partners [1]. Tak-ing into account the world population of 7 billion people in which approximately 40 % is at reproductive age, it is estimated that over 50 million men face infertility [2, 3]. However, only about 8 % of them seek medical assistance for fertility-related problems [4].
Infertility is customarily defined as the inability of a sex-ually active couple with no contraception to achieve natu-ral pregnancy within 1 year [1]. According to the Ameri-can Society for Reproductive Medicine (ASRM), infertility meets the definition of a disease which is defined as ‘any deviation from or interruption of the normal structure or
Abstract Purpose We systematically identified and reviewed the methods and consistency of recommendations of recently developed clinical practice guidelines (CPG) and best prac-tice statements (BPS) on the evaluation of the infertile male.Methods MEDLINE and related engines as well as guide-lines’ Web sites were searched for CPG and BPS written in English on the general evaluation of male infertility pub-lished between January 2008 and April 2015.Results Four guidelines were identified, all of which reported to have been recently updated. Systematic review was not consistently used in the BPS despite being reported in the CPG. Only one of them reported having a patient representative in its development team. The CPG issued by the European Association of Urology (EAU) graded some recommendations and related that to levels (but not qual-ity) of evidence. Overall, the BPS issued respectively by the American Urological Association and American Soci-ety for Reproductive Medicine concurred with each other, but both differed from the EAU guidelines with regard to methods of collection, extraction and interpretation of data. None of the guidelines incorporated health economics. Important specific limitations of conventional semen analy-sis results were ignored by all guidelines. Besides variation in the methodological quality, implementation strategies were not reported in two out of four guidelines.
* Sandro C. Esteves [email protected]
Peter Chan [email protected]
1 ANDROFERT, Andrology and Human Reproduction Clinic, Campinas, SP 13075-460, Brazil
2 McGill University Health Center, Montreal, Canada
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function of any part, organ or system of the body as mani-fested by characteristic symptoms and signs; the etiology, pathology and prognosis may be known or unknown’ [5, 6].
Male infertility can result from congenital or acquired urogenital abnormalities, urogenital tract infections, increased scrotal temperature (as a consequence of varico-cele), endocrine disturbances, genetic abnormalities, immu-nological factors, lifestyle habits (e.g., obesity, smoking and use of gonadotoxins), systemic diseases, erectile dysfunc-tion and incorrect coital habitus [7]. Nevertheless, owing to the limitations in our understanding of all the events that take place during natural conception, and the limited capac-ity of diagnostic tests currently available to identify abnor-malities, the cause of infertility is not determined in nearly half of the cases [8]. Thus, despite our best management efforts with various interventions available, approximately 5 % of couples remain unwillingly childless [9].
Despite the difficulty in estimating the direct and indi-rect cost of its diagnosis and management, infertility rep-resents a significant economic burden to the society and a financial stressor to couples, particularly since infertil-ity services are unsubsidized in most societies. With the continuous growth of medical knowledge and the need to improve efficiency in the diagnosis and treatment of med-ical-related conditions, the role for and utility of clinical practice guidelines (CPG) have received increasing atten-tion. Various guidelines have been developed worldwide for male infertility. Such documents can be useful instru-ments aiming to help clinicians such as urologists and other healthcare professionals to enhance the quality of health-care deliverable to patients and simultaneously discourage potentially harmful or ineffective interventions during the evaluation and management of men with fertility problems.
The aim of this systematic review was to identify and review the methodology and consistency of recommenda-tions of recently developed clinical practice guidelines (CPG) and best practice statements (BPS) on the evaluation of the infertile male.
Methods
This systematic review was conducted based on the Pre-ferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) [10]. The study was exempted from institutional review board approval because there was no direct intervention with patients or related specimens.
Eligibility criteria
Clinical practice guidelines and best practice state-ments endorsed by a national governmental or provider
organization related to the general evaluation of male infer-tility were included. All subgroups of the population were examined to ensure that CPG and BPS focused exclusively on special subtypes of male factor infertility (e.g., azoo-spermia, varicocele, genetic conditions and vasectomy) or specific settings (e.g., assisted reproductive technol-ogy, posthumous sperm utilization and viral transmission) were excluded. To ensure that the most up-to-date CPG and BPS were included, inclusion was limited to January 2008 onward. Only documents written in English were included.
Search strategy and information sources
Medical Subject Headings, namely ‘male infertility’ and ‘standards,’ and text words, namely ‘guidelines,’ ‘best practice statements’ and ‘committee opinion,’ were used to search MEDLINE, Science Citation Index, ScienceDi-rect, Academic OneFile, Scielo and CINAHL Plus using the SEARCHER interface of the University of Edinburgh Library from January 2008 to April 2015. The electronic database search was supplemented by searching guide-lines Web sites. Specifically, the following Web sites were searched: Guidelines International Network (G–I–N; www.g-i-n.net), National Guidelines Clearinghouse (www.guideline.gov) and National Institute for Health and Clini-cal Excellence (NICE; www.nice.org.uk). The term ‘male infertility’ was entered into the guidelines Web sites search utility, and the results were reviewed.
Study selection
One reviewer independently screened the search results for inclusion using the aforementioned relevance criteria. All potentially relevant documents were examined, and these were subsequently screened by a second reviewer. Discrep-ancies at any stages of study selection were resolved by discussion.
Data collection process and data items
One reviewer independently extracted all relevant data. The extracted data included guideline characteristics (e.g., year of dissemination, country/region, development team, fund-ing organization and implementation strategy), methods of development and recommendations related to the evalua-tion and management of men with infertility problems.
Synthesis of results
The included CPG and BPS were summarized and analyzed qualitatively according to the scope and methods used to formulate the guidelines. We noted whether the guidelines made specific recommendations, the level of evidence
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Int Urol Nephrol
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(based on the design of supporting studies referenced) and the grade of recommendation (determined when the guide-lines panel critically appraised the supporting studies refer-enced). The following descriptive categories were used to compare the CPG and BPS: (1) evaluation goals, (2) com-ponents of a basic evaluation and (3) components of a full evaluation.
Results
The search strategy retrieved 409 citations, of which 34 were considered for full-text screening and four were included in this review (Fig. 1). The European Associa-tion of Urology (EAU) guidelines on male infertility were a multinational effort [11], while the remaining guidelines, namely The American Urological Association (AUA) Best Practice Statement for the evaluation of the infertile male [12], Diagnostic evaluation of the infertile male: a com-mittee opinion (ASRM) [13] and Fertility: assessment and
treatment for people with fertility problems (NICE) [14], were conducted respectively within the USA and the UK.
Guideline characteristics
Table 1 depicts the scope and methods related to guide-lines’ development. These guidelines have been regularly and systematically updated and are therefore considered evolving projects. All of them have been endorsed and adopted by some of the most important specialty societies in urology/reproductive medicine worldwide and fulfill to some extent the criteria of ‘Clinical Practice Guidelines’ as developed by the Institute of Medicine [15], which stated that clinical practice guidelines should be devel-oped based on a systematic review of evidence, and the final document must include statements and recommenda-tions intended to optimize patient care and assist physicians and/or other healthcare practitioners and patients to make decisions about appropriate health care for specific clinical circumstances.
Fig. 1 Flowchart for the trial identification and selection process using the PRISMA statement for systematic review
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Int Urol Nephrol
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Tabl
e 1
Sco
pe a
nd th
e m
etho
ds u
sed
to f
orm
ulat
e th
e cl
inic
al p
ract
ice
guid
elin
es a
nd b
est p
ract
ice
stat
emen
ts f
or th
e ev
alua
tion
of th
e in
fert
ile m
ale
AU
AA
SRM
NIC
EE
AU
Gui
delin
e tit
leT
he o
ptim
al e
valu
atio
n of
the
infe
rtile
m
ale:
AU
A b
est p
ract
ice
stat
emen
tD
iagn
ostic
eva
luat
ion
of th
e in
fert
ile
mal
e: a
com
mitt
ee o
pini
onFe
rtili
ty: a
sses
smen
t and
trea
tmen
t fo
r pe
ople
with
infe
rtili
ty p
robl
ems
Gui
delin
es o
n m
ale
infe
rtili
ty
Obj
ectiv
eTo
off
er r
ecom
men
datio
ns f
or th
e
optim
al d
iagn
ostic
eva
luat
ion
of th
e m
ale
part
ner
of a
n in
fert
ile c
oupl
e
To p
rovi
de c
linic
ians
with
pri
ncip
les
an
d st
rate
gies
for
the
eval
uatio
n of
co
uple
s w
ith m
ale
infe
rtili
ty
prob
lem
s
To o
ffer
bes
t pra
ctic
e ad
vice
on
as
sist
ing
peop
le o
f re
prod
uctiv
e ag
e w
ho
have
pro
blem
s co
ncei
ving
To a
ssis
t uro
logi
sts
and
heal
thca
re p
ro-
fess
iona
ls f
rom
rel
ated
spe
cial
ties
in
the
trea
tmen
t of
mal
e in
fert
ility
Inte
nded
use
rsPh
ysic
ians
Phys
icia
nsA
dvan
ced
Prac
tice
Nur
ses
Alli
ed H
ealth
Per
sonn
elH
ealth
Car
e Pr
ovid
ers
Nur
ses
Patie
nts
Phys
icia
n A
ssis
tant
sPh
ysic
ians
Publ
ic H
ealth
Dep
artm
ents
Phys
icia
ns
Met
hods
use
d to
col
lect
/sel
ect
the
evid
ence
ME
DL
INE
sea
rch
span
ning
199
9 th
roug
h O
ctob
er 2
007
was
sup
ple-
men
ted
by h
and-
sear
ches
of
publ
ishe
d lit
erat
ure
Not
sta
ted
Sear
ches
of
elec
tron
ic d
atab
ases
Stru
ctur
ed li
tera
ture
sea
rch
usin
g M
ED
LIN
E, E
MB
ASE
and
Coc
hran
e da
taba
ses
limite
d to
RC
T a
nd m
eta-
anal
yses
, cov
erin
g at
leas
t the
pas
t 3
year
s. A
dditi
onal
sou
rces
incl
ude
othe
r hi
gh-l
evel
evi
denc
e an
d av
aila
ble
high
-qua
lity
guid
elin
es p
rodu
ced
by
othe
r ex
pert
gro
ups
or o
rgan
izat
ions
. T
he c
hoic
e of
the
liter
atur
e is
gui
ded
by th
e ex
pert
ise
of th
e G
uide
lines
W
orki
ng G
roup
Met
hods
use
d to
ana
lyze
the
evid
ence
Rev
iew
of
publ
ishe
d m
eta-
anal
yses
an
d sy
stem
atic
rev
iew
sN
ot s
tate
dH
and-
sear
ches
of
publ
ishe
d lit
erat
ure
(p
rim
ary
sour
ces)
Han
d-se
arch
es o
f pu
blis
hed
liter
atur
e
(sec
onda
ry s
ourc
es)
Sear
ches
of
elec
tron
ic d
atab
ases
Rev
iew
of
publ
ishe
d m
eta-
anal
yses
and
sy
stem
atic
rev
iew
s
Met
hods
use
d to
ass
ess
the
qual
ity a
nd s
tren
gth
of th
e ev
iden
ce
Not
sta
ted
Not
sta
ted
Wei
ghtin
g ac
cord
ing
to a
rat
ing
sche
me
(sch
eme
give
n)W
eigh
ting
acco
rdin
g to
a r
atin
g sc
hem
e (s
chem
e gi
ven)
Met
hods
use
d to
for
mul
ate
the
reco
mm
enda
tions
Exp
ert c
onse
nsus
Exp
ert c
onse
nsus
Exp
ert c
onse
nsus
(no
min
al g
roup
tech
niqu
e)
Info
rmal
con
sens
usE
xper
t con
sens
us
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Int Urol Nephrol
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Tabl
e 1
con
tinue
d
AU
AA
SRM
NIC
EE
AU
Des
crip
tion
of m
etho
ds u
sed
to f
orm
ulat
e th
e re
com
men
-da
tions
The
Inf
ertil
ity B
est P
ract
ice
Stat
e-m
ent P
anel
cre
ated
in 2
007
by th
e A
UA
con
duct
ed th
e dr
aftin
g of
the
docu
men
t. T
he P
ract
ice
Gui
delin
es
Com
mitt
ee (
PGC
) of
the
AU
A s
elec
ts
the
Pane
l Cha
ir w
ho in
turn
app
oint
s th
e Pa
nel m
embe
rs w
ith s
peci
fic
expe
rtis
e in
eva
luat
ion
of th
e in
fert
ile
mal
e. T
he m
issi
on o
f th
e Pa
nel i
s to
de
velo
p an
alys
is-
or c
onse
nsus
-bas
ed
reco
mm
enda
tions
, dep
endi
ng o
n th
e ty
pe o
f ev
iden
ce a
vaila
ble
and
Pane
l pr
oces
ses,
to s
uppo
rt o
ptim
al c
linic
al
prac
tices
con
cern
ing
the
infe
rtile
mal
e
A w
orki
ng g
roup
com
pris
ed o
f 16
m
embe
rs d
raft
ed th
e do
cum
ent.
The
do
cum
ent o
ffer
s co
nsen
sus-
base
d (o
r ev
iden
ce-b
ased
whe
n th
ere
is s
uffic
ient
ev
iden
ce a
vaila
ble)
gui
danc
e re
lativ
e to
a g
iven
pra
ctic
e ac
tivity
. Thi
s gu
id-
ance
, in
addi
tion
to s
cien
tific
and
clin
i-ca
l inf
orm
atio
n, m
ay ta
ke in
to a
ccou
nt
issu
es o
f et
hica
l and
fina
ncia
l con
cern
s
Thi
s gu
idan
ce w
as c
omm
issi
oned
by
NIC
E
and
deve
lope
d in
acc
orda
nce
with
the
guid
elin
e de
velo
pmen
t pro
cess
out
lined
in
the
2009
edi
tion
of “
The
Gui
delin
es
Man
ual”
. In
addi
tion,
a c
onsi
dera
ble
amou
nt o
f re
leva
nt g
uida
nce
has
been
pu
blis
hed
sinc
e 20
04, a
nd th
is u
pdat
e cr
oss-
refe
renc
e th
is (
incl
udin
g th
e W
orld
H
ealth
Org
aniz
atio
n re
fere
nce
valu
es f
or
sem
en a
naly
sis
and
the
Hum
an F
ertil
iza-
tion
and
Em
bryo
logy
Aut
hori
ty C
ode
of
Prac
tice)
, whe
re a
ppro
pria
teA
for
mal
con
sens
us a
ppro
ach
invo
lved
a
seri
es o
f ac
tion
stat
emen
ts r
elat
ing
to
man
agem
ent o
r tr
eatm
ent u
nder
rev
iew
be
ing
draf
ted
by th
e N
CC
-WC
H te
chni
cal
team
. The
se w
ere
colla
ted
into
a c
onse
nsus
qu
estio
nnai
re. T
he g
uide
lines
dev
elop
-in
g gr
oup
(GD
G)
mem
bers
wer
e as
ked
to
inde
pend
ently
com
plet
e th
e qu
estio
nnai
re
stat
ing
thei
r le
vel o
f ag
reem
ent (
rang
-in
g fr
om ‘
stro
ngly
agr
ee’ t
o ‘s
tron
gly
disa
gree
’) w
ith e
ach
stat
emen
t and
pro
vide
co
mm
ents
on
whe
re s
tate
men
ts s
houl
d be
am
ende
d. T
he r
esul
ts o
f th
e vo
ting
wer
e co
llate
d by
the
tech
nica
l tea
m. I
f 70
%
or m
ore
of th
e G
DG
mem
bers
agr
eed
or
disa
gree
d w
ith a
sta
tem
ent t
hen
it w
as c
on-
clud
ed th
at c
onse
nsus
had
bee
n re
ache
d.
If th
ere
was
no
cons
ensu
s th
e st
atem
ent
coul
d be
ada
pted
bas
ed o
n co
mm
ents
and
pr
esen
ted
for
a se
cond
rou
nd o
f vo
ting,
ap
plyi
ng th
e sa
me
maj
ority
thre
shol
d.
Stat
emen
ts w
here
con
sens
us w
as r
each
ed
wer
e th
en u
sed
to d
raft
rec
omm
enda
tions
. T
hese
wer
e di
scus
sed
and
ratifi
ed a
t a
subs
eque
nt G
DG
mee
ting
A w
orki
ng g
roup
com
pris
ed o
f se
ven
mem
bers
fro
m s
ever
al c
ount
ries
dr
afte
d th
e do
cum
ent.
Mos
t of
the
wor
king
gro
up m
embe
rs a
re a
cade
mic
ur
olog
ists
with
a s
peci
al in
tere
st in
the
topi
c. S
peci
alis
ts f
rom
oth
er m
edic
al
field
s ar
e in
clud
ed a
s fu
ll m
embe
rs o
f th
e w
orki
ng g
roup
s as
nee
ded
Rec
omm
enda
tions
are
gra
ded
acco
rdin
g to
the
Oxf
ord
Cen
tre
for
Evi
denc
e-ba
sed
Med
icin
e L
evel
s of
Evi
denc
e,
but t
he li
nk b
etw
een
the
leve
l of
evid
ence
and
gra
de o
f re
com
men
da-
tion
is n
ot d
irec
tly li
near
. Ava
ilabi
lity
of R
CT
may
not
nec
essa
rily
tran
slat
e in
to a
gra
de A
rec
omm
enda
tion
whe
re
ther
e ar
e m
etho
dolo
gica
l lim
itatio
ns o
r di
spar
ity in
pub
lishe
d re
sults
.A
bsen
ce o
f hi
gh le
vel o
f ev
iden
ce d
oes
not n
eces
sari
ly p
recl
ude
a gr
ade
A r
ec-
omm
enda
tion,
if th
ere
is o
verw
helm
ing
clin
ical
exp
erie
nce
and
cons
ensu
s
Rat
ing
sche
me
for
the
stre
ngth
of
the
evid
ence
and
re
com
men
datio
n
Not
sta
ted
Not
sta
ted
Rat
ing
sche
me
base
d on
ove
rall
qual
ity o
f ou
tcom
e ev
iden
ce in
GR
AD
E (
Gra
ding
of
reco
mm
enda
tions
ass
essm
ent,
deve
lop-
men
t and
eva
luat
ion)
Rat
ing
sche
me
base
d on
leve
ls o
f ev
iden
ce
Met
hod
of g
uide
line
valid
a-tio
nE
xter
nal a
nd in
tern
al p
eer
revi
ewPr
opos
ed d
ocum
ents
are
cir
cula
ted
amon
g m
embe
rs o
f th
e so
ciet
y fo
r re
view
bef
ore
final
app
rova
l and
pu
blic
atio
n
Ext
erna
l pee
r re
view
Inte
rnal
pee
r re
view
Ext
erna
l and
inte
rnal
pee
r re
view
Author's personal copy
Int Urol Nephrol
1 3
Tabl
e 1
con
tinue
d
AU
AA
SRM
NIC
EE
AU
Clin
ical
alg
orith
m(s
)N
ot p
rovi
ded
Not
pro
vide
dT
he f
ull v
ersi
on o
f th
e or
igin
al g
uide
line
docu
men
t inc
lude
s a
care
pat
hway
/alg
o-ri
thm
for
ove
rall
care
Not
pro
vide
d
Impl
emen
tatio
n st
rate
gyT
he A
UA
bes
t pra
ctic
e st
atem
ent i
s po
sted
in th
e A
UA
(ht
tps:
//ww
w.
auan
et.o
rg/e
duca
tion/
guid
elin
es/m
ale-
infe
rtili
ty-d
.cfm
) an
d th
e So
ciet
y fo
r th
e St
udy
of M
ale
Rep
rodu
ctio
n (S
SMR
; http
://w
ww
.ssm
r.org
/pro
fes-
sion
als/
mal
e-in
fert
ility
-gui
delin
es.
aspx
) Web
site
s
The
ASR
M p
ract
ice
com
mitt
ee r
epor
t is
pub
lishe
d in
Fer
tility
and
Ste
rilit
y an
d po
sted
on
the
ASR
M W
eb s
ite
(http
://w
ww
.asr
m.o
rg/G
uide
lines
/)
Aud
it cr
iteri
a/in
dica
tors
Clin
ical
alg
orith
mM
obile
dev
ice
reso
urce
sPa
tient
res
ourc
esO
ther
res
ourc
esIn
form
atio
n fo
r th
e pu
blic
: ass
essm
ent
and
trea
tmen
t for
peo
ple
with
fer
tility
pr
oble
ms.
Lon
don
(UK
): N
atio
nal I
nsti-
tute
for
Hea
lth a
nd C
linic
al E
xcel
lenc
e (N
ICE
); 2
013
Febr
uary
(C
linic
al g
uide
-lin
e; n
o. 1
56).
Ele
ctro
nic
copi
es: A
vaila
ble
from
the
Nat
iona
l Ins
titut
e fo
r H
ealth
an
d C
linic
al E
xcel
lenc
e (N
ICE
) Web
site
. A
lso
avai
labl
e fo
r do
wnl
oad
as a
Kin
dle
or
EPU
B e
book
fro
m th
e N
ICE
Web
site
The
EA
U G
uide
lines
ful
l ver
sion
is
repr
inte
d an
nual
ly in
one
boo
k.
Eac
h te
xt is
dat
ed. T
he s
ame
text
is
also
mad
e av
aila
ble
on a
CD
(w
ith
hype
rlin
ks to
Pub
Med
for
mos
t ref
er-
ence
s) a
nd p
oste
d on
the
EA
U W
eb
site
Uro
web
(ht
tp://
ww
w.u
row
eb.o
rg/
guid
elin
es/o
nlin
e-gu
idel
ines
)C
onde
nsed
poc
ket v
ersi
ons,
con
tain
ing
mai
nly
flow
char
ts a
nd s
umm
arie
s, a
re
also
pri
nted
ann
ually
. All
thes
e pu
bli-
catio
ns a
re d
istr
ibut
ed f
ree
of c
harg
e to
all
(mor
e th
an 1
7,00
0) m
embe
rs o
f th
e A
ssoc
iatio
n. A
brid
ged
vers
ions
ar
e pu
blis
hed
in E
urop
ean
Uro
logy
as
orig
inal
pap
ers.
Man
y W
eb s
ites
list
links
to th
e re
leva
nt E
AU
gui
delin
es
sect
ions
on
the
asso
ciat
ion
Web
site
s an
d al
l, or
indi
vidu
al, g
uide
lines
hav
e be
en tr
ansl
ated
to s
ome
25 la
ngua
ges
Cos
t ana
lysi
s re
view
edN
oN
oY
es, b
ut n
ot a
pplic
able
to th
e m
ale
in
fert
ility
eva
luat
ion
Yes
Publ
icat
ion
hist
ory
Firs
t pub
lishe
d in
200
1 in
col
labo
ratio
n w
ith th
e Pr
actic
e C
omm
ittee
of
the
Am
eric
an S
ocie
ty f
or R
epro
duct
ive
Med
icin
e, th
is g
uide
line
was
rev
ised
in
201
0, a
nd v
alid
ity c
onfir
med
in
2011
The
firs
t edi
tion
(200
1) w
as p
repa
red
in
colla
bora
tion
with
the
Mal
e In
fert
ility
B
est P
ract
ice
Polic
y C
omm
ittee
of
the
AU
A. T
his
was
fol
low
ed b
y up
date
s co
nduc
ted
by th
e A
SRM
Pra
ctic
e C
omm
ittee
in 2
006
and
2012
Firs
t edi
tion
publ
ishe
d in
200
4,
follo
wed
by
an u
pdat
e in
201
3Fi
rst p
ublis
hed
in 2
001,
fol
low
ed b
y fu
ll-te
xt u
pdat
es in
200
4, 2
007,
201
0 an
d 20
13
Whe
re g
uide
lines
can
be
foun
dT
he te
xt c
an b
e vi
ewed
and
do
wnl
oade
d fo
r pe
rson
al u
se a
t the
A
UA
soc
iety
Web
site
: http
s://w
ww
.au
anet
.org
/com
mon
/edu
catio
n/cl
inic
al-g
uida
nce/
Mal
e-In
fert
ility
-d.
The
ASR
M p
ract
ice
com
mitt
ee
repo
rt c
an b
e vi
ewed
and
do
wnl
oade
d by
ASR
M m
embe
rs (
view
op
tion
only
for
non
-mem
bers
) at
the
ASR
M W
eb s
ite (
http
://w
ww
.asr
m.o
rg/
Gui
delin
es/)
The
text
can
be
view
ed a
nd
dow
nloa
ded
at th
e N
ICE
Web
site
: ht
tp://
ww
w.n
ice.
org.
uk/g
uida
nce/
CG
156
The
text
can
be
view
ed a
nd d
ownl
oade
d fo
r pe
rson
al u
se a
t the
EA
U s
ocie
ty
Web
site
: http
://w
ww
.uro
web
.org
/gu
idel
ines
/onl
ine-
guid
elin
es/
Dat
e re
leas
ed20
01 A
pril
(rev
ised
201
0; r
evie
wed
an
d va
lidity
con
firm
ed 2
011)
2012
(re
vise
d 20
15)
2004
Feb
ruar
y (r
evis
ed 2
013
Febr
uary
)20
10 A
pril
(rev
ised
201
3 M
arch
)
Author's personal copy
Int Urol Nephrol
1 3
All guidelines were funded by professional organiza-tions and provided some or detailed description concern-ing the affiliation and/or specialties of the developing team members. A list of members with declaration of interest was also available. The size of the guidelines development teams varied from 7 to 16 members. Except for the NICE guidelines, a patient representative was not included in the development team. In one out of four included guidelines, the panel experts were exclusively urologists and/or androl-ogists (AUA). Only two guidelines (EAU and NICE) linked their grade of recommendation to the level of evidence, but they did not elaborate on the quality of studies contribut-ing to the recommendations (Table 2). Of note, the EAU guidelines include a note stating that the link between the level of evidence (LE) and grade of recommendation (GR) was not directly linear since the availability of randomized controlled trials (RCTs) may not necessarily translate into a grade A recommendation due to methodological limita-tions or disparity in the published results. Similarly, the EAU panel stated that the absence of high level of evidence does not necessarily preclude a grade A recommendation if there exists overwhelming clinical experience and general consensus. Only the NICE and EAU guidelines provided a description of implementation strategy.
Clinical practice guideline recommendation
Evaluation goals
Most CPG considered that both partners of couples experi-encing problems in conceiving should be evaluated simul-taneously as they both can be affected by the decisions surrounding investigation and treatment. The timing for the initial screening evaluation was considered to be 1 year after trying to conceive with unprotected intercourse, but earlier evaluation was warranted in special conditions, as clearly stated in two CPG (AUA and ASRM). None of the included guidelines specifically stated what healthcare professionals should conduct the initial male investigation (Table 2).
Basic evaluation
Most guidelines consider that the basic evaluation should include a reproductive history and semen analysis, but dif-fer regarding the minimum number of semen analyses to be evaluated (Table 2). While the AUA guidelines state that a minimum of two properly performed semen analy-sis should be undertaken, the ASRM considers that at least one specimen is required. No specific recommendations on the number of semen analysis are made by the EAU and NICE guidelines. Apart from the NICE guidelines
recommending that an additional semen analysis should be offered in the presence of a first abnormal result and that the interval between semen analyses should ideally be 3 months apart, the remaining guidelines made no specific recommendations in this regard. Of note, the NICE guide-line states that in the presence of a gross sperm deficiency (e.g., azoospermia or severe oligozoospermia) the repeat test should be done as soon as possible. With regard to issues on laboratory proficiency, all guidelines stress the importance of a quality control program or the incorpora-tion of the World Health Organization methods in labora-tories performing semen evaluation. Of note, three out of four guidelines (EAU, ASRM and NICE) have incorpo-rated the reference values of the latest fifth edition of the World Health Organization (WHO) manual for the exami-nation and processing of human semen [16], as given in Table 3.
Full evaluation
A full evaluation is warranted when the initial screening reveals an abnormal male reproduction history or demon-strates abnormal semen parameters, as recommended by the AUA and ASRM guidelines. Both guidelines state that an urologist or other specialist in male reproduction should conduct this evaluation. In contrast, the EAU guidelines recommend that andrological investigations be undertaken only if semen analysis is abnormal in at least two tests (Table 2). Tables 4 and 5 display the recommendations from the CPG about the full evaluation of male infertility. Of note, the EAU guidelines provide recommendations for 13 different male infertility topics, including epidemiology and etiology, investigations, testicular deficiency, genetic disorders, obstructive azoospermia, varicocele, germ cell malignancy and testicular microcalcification, disorders of ejaculation and semen cryopreservation (Table 5). The NICE guidelines do not provide recommendations about the full male infertility evaluation.
Discussion
While all the CPG and BPS evaluated in this review clearly presented their recommendations, they differ in the quality with regard to scientific rigor, stakeholder representation (e.g., inclusion of patient representatives) and implementa-tion applicability.
In general, the recommendations of the CPG on the evaluation goals and basic evaluation were consistent. However, important gaps existed across these guide-lines that could have been addressed, including clarify-ing who should conduct the basic investigation and the
Author's personal copy
Int Urol Nephrol
1 3
Tabl
e 2
Rec
omm
enda
tions
fro
m g
uide
lines
abo
ut e
valu
atio
n go
als,
initi
al e
valu
atio
n an
d w
hen
to d
o a
full
eval
uatio
n
AU
AN
ICE
EA
UA
SRM
Eva
luat
ion
Goa
lsA
cou
ple
atte
mpt
ing
to c
once
ive
shou
ld h
ave
an e
valu
atio
n fo
r in
fert
ility
if p
regn
ancy
fa
ils to
occ
ur w
ithin
1 y
ear
of r
egul
ar u
npro
-te
cted
inte
rcou
rse.
An
eval
uatio
n sh
ould
be
done
bef
ore
1 ye
ar if
(1)
mal
e in
fert
ility
ris
k fa
ctor
s su
ch a
s a
hist
ory
of b
ilate
ral c
rypt
or-
chid
ism
are
kno
wn
to b
e pr
esen
t; (2
) fe
mal
e in
fert
ility
ris
k fa
ctor
s, in
clud
ing
adva
nced
fe
mal
e ag
e (o
ver
35 y
ears
), a
re s
uspe
cted
; or
(3)
the
coup
le q
uest
ions
the
mal
e pa
rt-
ner’
s fe
rtili
ty p
oten
tial.
In a
dditi
on, m
en
who
que
stio
n th
eir
fert
ility
sta
tus
desp
ite th
e ab
senc
e of
a c
urre
nt p
artn
er s
houl
d ha
ve a
n ev
alua
tion
of th
eir
fert
ility
pot
entia
l
Cou
ples
who
exp
erie
nce
pr
oble
ms
in c
once
ivin
g sh
ould
be
see
n to
geth
er b
ecau
se b
oth
part
ners
are
aff
ecte
d by
de
cisi
ons
surr
ound
ing
in
vest
igat
ion
and
trea
tmen
t
To c
ateg
oriz
e in
fert
ility
, bot
h
part
ners
sho
uld
be in
vest
igat
ed
sim
ulta
neou
sly.
In
the
diag
nosi
s
and
man
agem
ent o
f m
ale
subf
ertil
-ity
, the
fer
tility
sta
tus
of th
e fe
mal
e pa
rtne
r m
ust a
lso
be c
onsi
dere
d,
beca
use
this
mig
ht d
eter
min
e th
e fin
al o
utco
me.
The
uro
logi
st/
andr
olog
ist s
houl
d ex
amin
e an
y m
an
with
fer
tility
pro
blem
s fo
r ur
ogen
ital
abno
rmal
ities
. Thi
s ap
plie
s to
all
men
dia
gnos
ed w
ith r
educ
ed s
emen
qu
ality
. A d
iagn
osis
is m
anda
tory
to
sta
rt a
ppro
pria
te th
erap
y (d
rugs
, su
rger
y, o
r as
sist
ed r
epro
duct
ion)
Iden
tifica
tion
and
trea
tmen
t of
corr
ect-
able
con
ditio
ns th
at m
ay im
prov
e th
e m
ale
part
ner’
s fe
rtili
ty a
nd a
llow
co
ncep
tion
to b
e ac
hiev
ed n
atur
ally
, an
d un
derl
ying
med
ical
con
di-
tions
that
may
pre
sent
as
infe
rtili
ty.
Eva
luat
ion
for
infe
rtili
ty is
indi
cate
d fo
r co
uple
s w
ho f
ail t
o ac
hiev
e a
succ
essf
ul p
regn
ancy
aft
er 1
2 m
onth
s or
mor
e of
unp
rote
cted
inte
rcou
rse.
E
arlie
r ev
alua
tion
and
trea
tmen
t m
ay b
e ju
stifi
ed, b
ased
on
med
ical
hi
stor
y an
d ph
ysic
al fi
ndin
gs a
nd is
w
arra
nted
aft
er 6
mon
ths
for
coup
les
in w
hich
the
fem
ale
part
ner
is o
ver
age
35 y
ears
. Men
hav
ing
conc
erns
ab
out t
heir
fut
ure
fert
ility
als
o m
erit
eval
uatio
n
Com
pone
nts
of th
e in
itial
ev
alua
tion
The
initi
al e
valu
atio
n sh
ould
incl
ude
a
repr
oduc
tive
hist
ory
and
two
prop
erly
pe
rfor
med
sem
en a
naly
ses.
If
poss
ible
, th
e tw
o se
men
ana
lyse
s sh
ould
be
sepa
rate
d by
a ti
me
peri
od o
f at
leas
t 1 m
onth
. The
re
prod
uctiv
e hi
stor
y sh
ould
incl
ude
(1)
coita
l fre
quen
cy a
nd ti
min
g; (
2) d
urat
ion
of
infe
rtili
ty a
nd p
rior
fer
tility
; (3)
chi
ld-
hood
illn
esse
s an
d de
velo
pmen
tal h
isto
ry;
(4)
syst
emic
med
ical
illn
esse
s (e
.g.,
diab
etes
m
ellit
us a
nd u
pper
res
pira
tory
dis
ease
s) a
nd
prio
r su
rger
ies;
(5)
sex
ual h
isto
ry in
clud
-in
g se
xual
ly tr
ansm
itted
infe
ctio
ns; a
nd (
6)
gona
dal t
oxin
exp
osur
e in
clud
ing
heat
The
res
ults
of
sem
en a
naly
sis
cond
ucte
d as
par
t of
an in
itial
as
sess
men
t sho
uld
be c
ompa
red
with
the
Wor
ld H
ealth
Org
ani-
zatio
n (W
HO
) re
fere
nce
valu
es
(WH
O 2
010)
. If
the
resu
lt of
the
first
sem
en a
naly
sis
is
abno
rmal
, a r
epea
t con
firm
a-to
ry te
st s
houl
d be
off
ered
Rep
eat c
onfir
mat
ory
test
s sh
ould
id
eally
be
unde
rtak
en 3
mon
ths
afte
r th
e in
itial
ana
lysi
s to
al
low
tim
e fo
r th
e cy
cle
of
sper
mat
ozoa
for
mat
ion
to
be c
ompl
eted
. How
ever
, if
a gr
oss
sper
mat
ozoo
n de
ficie
ncy
(azo
ospe
rmia
or
seve
re o
ligo-
zoos
perm
ia)
has
been
det
ecte
d,
the
repe
at te
st s
houl
d be
und
er-
take
n as
soo
n as
pos
sibl
e
A m
edic
al h
isto
ry a
nd p
hysi
cal
exam
inat
ion
are
stan
dard
as
sess
men
ts in
all
men
, inc
ludi
ng
sem
en a
naly
sis.
If
the
resu
lts o
f se
men
ana
lysi
s ar
e no
rmal
acc
ord-
ing
to W
HO
cri
teri
a, o
ne te
st is
su
ffici
ent
At a
min
imum
, the
initi
al s
cree
ning
ev
alua
tion
shou
ld in
clud
e a
repr
oduc
-tiv
e hi
stor
y an
d at
leas
t one
sem
en
sam
ple
Author's personal copy
Int Urol Nephrol
1 3
standardization on number, interval and proficiency of lab-oratories performing semen analyses.
Across the CPG, the major differences were related to the full male infertility evaluation. The AUA and ASRM guidelines clearly define the components of a full evalua-tion on male infertility and provide a detailed description of the required components for every patient, including additional procedures and tests that could be used to elu-cidate problems discovered by the full evaluation, such as endocrine evaluation, post-ejaculatory urianalysis, transrec-tal and scrotal ultrasonography, specialized sperm function tests and genetic testing. The similarities between the AUA and ASRM guidelines in part relate to the fact that the first editions (2001) of these two documents were prepared by the Male Infertility Best Practice Policy Committee of the AUA in collaboration with the Practice Committee of the ASRM [17]. Both guidelines state that a full evaluation is to be performed by an urologist or other specialist in male reproduction if the initial screening demonstrates an abnor-mal male reproductive history or an abnormal semen analy-sis. This recommendation is based on the assumption that if a male infertility factor is present, it almost always mani-fests with a significant abnormality on the semen analysis and/or in medical history.
In contrast, the EAU guidelines recommend that assess-ment of andrological status must consider the suggestions made by WHO manual for the standardized investigation, diagnosis and management of the infertile couple. This aforementioned WHO manual, developed by consensus opinion of ten experts, was first published in 1993 and then updated only once in 2000 [1]. In brief, the manual provides detailed information on history-taking, physical examination and laboratory investigations. But since its last review 14 years ago there have been significant devel-opments in our ability to understand and manage male factor infertility. The EAU guidelines presented the indi-cations for genetic testing, albeit differing from the AUA and ASRM guidelines on the semen analysis thresholds for recommending genetic evaluation (see Tables 4, 5). In addi-tion, the EAU guidelines recommend that a comprehensive andrological examination should be undertaken only if at least two semen analyses are abnormal in accordance with the latest version of the WHO manual for the examination of human semen. This recommendation implies that men with a so-called normal semen analyses (i.e., with param-eters above the lower WHO reference limits) rarely have sperm that do not function in a manner necessary for fertil-ity, which is nevertheless arguable given the existence of men with unexplained infertility in whom routine semen analysis results are normal and no identified causes are found in the medical history and physical examination [8].
One possible explanation of these discrepancies between the different CPG is the limited evidence available to Ta
ble
2 c
ontin
ued
AU
AN
ICE
EA
UA
SRM
Whe
n to
do
a fu
ll ev
alua
tion
A f
ull e
valu
atio
n by
a u
rolo
gist
or
othe
r sp
ecia
list i
n m
ale
repr
oduc
tion
shou
ld b
e do
ne if
the
initi
al s
cree
ning
eva
luat
ion
dem
onst
rate
s an
abn
orm
al m
ale
repr
oduc
-tiv
e hi
stor
y or
an
abno
rmal
sem
en a
naly
sis.
Fu
rthe
r ev
alua
tion
of th
e m
ale
part
ner
shou
ld a
lso
be c
onsi
dere
d in
cou
ples
with
un
expl
aine
d in
fert
ility
and
in c
oupl
es in
w
hom
ther
e is
a tr
eate
d fe
mal
e fa
ctor
and
pe
rsis
tent
infe
rtili
ty
Not
sta
ted
A c
ompr
ehen
sive
and
rolo
gica
l ex
amin
atio
n is
indi
cate
d if
sem
en
anal
ysis
sho
ws
abno
rmal
ities
co
mpa
red
with
ref
eren
ce v
alue
s (T
able
3)
in a
t lea
st tw
o te
sts.
Im
port
ant t
reat
men
t dec
isio
ns a
re
base
d on
the
resu
lts o
f se
men
an
alys
is; t
here
fore
, it i
s es
sent
ial t
hat
the
com
plet
e la
bora
tory
wor
k-up
is
sta
ndar
dize
d. E
jacu
late
ana
lysi
s ha
s be
en s
tand
ardi
zed
by th
e W
HO
an
d di
ssem
inat
ed b
y pu
blic
atio
n of
th
e W
HO
Lab
orat
ory
Man
ual f
or
the
Exa
min
atio
n an
d Pr
oces
sing
of
Hum
an S
emen
(fif
th e
dn.)
If th
e in
itial
eva
luat
ion
is a
bnor
mal
, th
en r
efer
ral t
o so
meo
ne e
xper
ienc
ed
in m
ale
repr
oduc
tion
Author's personal copy
Int Urol Nephrol
1 3
synthesize recommendations. Alternatively, the authors of the different guidelines may have adopted different meth-ods and criteria to collect, extract and interpret data. Inter-estingly, eight out of 17 recommendations made by the EAU guidelines were graded B and C, thus indicating that the ‘best’ available evidence was derived from non-rand-omized clinical trials and retrospective studies. Further-more, since historically many aspects of the evaluation of male infertility are not subject to literature review, the roles for expert opinion and clinical experience are of impor-tance in a significant portion of the recommendations. The AUA Practice Guidelines Committee, which found insuf-ficient outcome data to support a formal evidence-based guideline, highlighted that evidence used to provide rec-ommendations was generally of a low quality level, being derived overwhelmingly from non-randomized studies [9]. These findings indicate that there are significant opportu-nities for research and improvement in the quality of care deliverable to infertile male.
For example, while the EAU, NICE and ASRM guide-lines consider the latest published (fifth edition) WHO reference values [16] to discriminate patients with semen analysis results within and outside the reference range, the AUA guidelines still refer to the previous version dated of 1999 [18]. The aforementioned WHO reference val-ues, however, differ substantially because reference values of the 2010 manual are markedly lower than those of the 1999 version. These differences pose a problem because the classification of patients with ‘normal’ and ‘abnormal’ semen analysis will depend on the version of the WHO manual [19, 20]. In a recent study, up to 15 % of men with at least one parameter below the 1999 WHO reference val-ues were reclassified as ‘normal’ because all parameters were at or above the 2010 WHO thresholds [21]. We have also contemplated our own data involving 982 men seeking evaluation for infertility that had subnormal semen analy-sis results based on the 1999 WHO criteria. We found that
approximately 39 % of these men would be reclassified as ‘normal’ by the new 2010 criteria [20]. The adoption of the most recent WHO reference values will likely result in more men classified as having a ‘normal’ semen analysis. Therefore, some patients deemed eligible for undertaking a full evaluation based on the 1999 WHO reference values could be hampered in their attempt to elucidate the under-lying cause of infertility if the guidelines recommendations are strictly followed. It is yet to be determined whether the application of the new WHO reference values will lead to a more cost-effective evaluation of the infertile male, thus making this topic an open area for research.
More important it is to question the validity of semen analysis results, as routinely performed, as valid surro-gate measurements of the male fertility status [19, 20]. Semen characteristics that discriminate between infertile and fertile men are not well defined, and results fall within the accepted reference ranges in up to 40 % of those suf-fering from infertility [22–24]. In addition to the various confounders, including the duration of ejaculatory absti-nence, activity of the accessory sex glands and analytical errors that can influence semen analysis results, the inher-ent biological variability within an individual should not be ignored [25–29]. In one study, the intra-individual variabil-ity of 20 healthy subjects assessed over a 10-week follow-up ranged from 10.3 to 26.8 % [27]. Sperm concentration showed the highest intra-individual variation (26.8 %), fol-lowed by the percentages of morphology (19.6 %) and pro-gressive motility (15.2 %), whereas vitality had the lowest variation (10.3 %).
The utility of population-based reference values depends on the individual variability of parameter in question. Ref-erence values of parameters subjected to high intra-indi-vidual variability, such as those assessed in the semen, are generally of limited utility [30, 31]. For instance, regression toward the mean has been demonstrated in semen analyses when screening potential semen donors for artificial insem-ination. For each characteristic, when men with subnormal semen parameters in the first test were reevaluated, a sub-stantial portion of them had results that were significantly higher in the second test [30]. Given the high variability in semen parameters within a single individual, multiple sam-pling would reduce variance and increase accuracy of esti-mation [31].
Thus, though semen analysis represents an essential part of the initial evaluation of infertile couples, it seems unsound to assume that a single ‘normal’ ejaculate could be used as a biomarker for a man’s ability to father a child, as proposed by some of the CPG. Lastly, it should be emphasized that routine semen analysis does not account for sperm dysfunctions such as immature chromatin or DNA damage. It has been reported that about 30 % of men diagnosed with unexplained male infertility harbor sperm
Table 3 Lower reference limits (5th centiles and their 95 % confi-dence interval) for semen characteristics according to the fifth edition World Health Organization (WHO) Laboratory Manual for the Exam-ination and Processing of Human Semen
PR progressive, NP non-progressive
Parameter 5th centile (95 % CI)
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)
Author's personal copy
Int Urol Nephrol
1 3
Tabl
e 4
Com
pone
nts
of a
ful
l mal
e in
fert
ility
eva
luat
ion
acco
rdin
g to
the
reco
mm
enda
tions
fro
m th
e A
UA
and
ASR
M g
uide
lines
AU
AA
SRM
Med
ical
his
tory
It s
houl
d in
clud
e al
l fac
tors
list
ed f
or a
rep
rodu
ctiv
e hi
stor
y (s
ee in
itial
eva
luat
ion)
pl
us: (
1) a
com
plet
e m
edic
al a
nd s
urgi
cal h
isto
ry; (
2) a
rev
iew
of
med
icat
ions
(p
resc
ript
ion
and
non-
pre
scri
ptio
n) a
nd a
llerg
ies;
(3)
a r
evie
w o
f lif
esty
le e
xpos
ures
an
d a
revi
ew o
f sy
stem
s; (
4) f
amily
rep
rodu
ctiv
e hi
stor
y; a
nd (
5) a
sur
vey
of p
ast
infe
ctio
ns s
uch
as s
exua
lly tr
ansm
itted
dis
ease
s an
d re
spir
ator
y in
fect
ions
It s
houl
d in
clud
e a
com
plet
e re
view
of
syst
ems,
fam
ily r
epro
duct
ive
hist
ory
and
a de
taile
d so
cial
his
tory
, inc
ludi
ng a
ny p
ast o
r cu
rren
t use
of
anab
olic
st
eroi
ds, r
ecre
atio
nal d
rugs
and
alc
ohol
Phys
ical
exa
min
atio
nIn
add
ition
to th
e ge
nera
l phy
sica
l exa
min
atio
n, p
artic
ular
foc
us s
houl
d be
giv
en to
th
e ge
nita
lia in
clud
ing:
(1)
exa
min
atio
n of
the
peni
s; in
clud
ing
the
loca
tion
of th
e ur
ethr
al m
eatu
s; (
2) p
alpa
tion
of th
e te
stes
and
mea
sure
men
t of
thei
r si
ze; (
3) p
res-
ence
and
con
sist
ency
of
both
the
vasa
and
epi
didy
mid
es; (
4) p
rese
nce
of a
var
ico-
cele
; (5)
sec
onda
ry s
ex c
hara
cter
istic
s in
clud
ing
body
hab
itus,
hai
r di
stri
butio
n an
d br
east
dev
elop
men
t; an
d (6
) di
gita
l rec
tal e
xam
It s
houl
d in
clud
e: (
1) e
xam
inat
ion
of th
e pe
nis,
not
ing
the
loca
tion
of th
e ur
ethr
al m
eatu
s; (
2) p
alpa
tion
and
mea
sure
men
t of
the
test
es; (
3) th
e pr
esen
ce a
nd c
onsi
sten
cy o
f bo
th v
asa
and
epid
idym
ides
; (4)
the
pres
ence
or
abs
ence
of
a va
rico
cele
; (5)
sec
onda
ry s
ex c
hara
cter
istic
s, in
clud
ing
body
hab
itus,
hai
r di
stri
butio
n an
d br
east
dev
elop
men
t; (6
) di
gita
l rec
tal
exam
inat
ion
whe
re in
dica
ted
End
ocri
ne e
valu
atio
nA
n in
itial
end
ocri
ne e
valu
atio
n sh
ould
incl
ude
at le
ast a
ser
um te
stos
tero
ne a
nd
folli
cle-
stim
ulat
ing
horm
one
(FSH
). I
t sho
uld
be p
erfo
rmed
if th
ere
is: (
1) a
n
abno
rmal
ly lo
w s
perm
con
cent
ratio
n, e
spec
ially
if <
10 m
illio
n/m
L, (
2) im
pair
ed
sexu
al f
unct
ion
or (
3) o
ther
clin
ical
find
ings
sug
gest
ive
of a
spe
cific
end
ocri
nopa
thy
Indi
cate
d fo
r m
en h
avin
g: (
1) a
bnor
mal
sem
en p
aram
eter
s, p
artic
ular
ly
whe
n sp
erm
con
cent
ratio
n is
bel
ow 1
0 m
illio
n/m
L, (
2) im
pair
ed li
bido
an
d se
xual
fun
ctio
n or
(3)
oth
er c
linic
al fi
ndin
gs th
at s
ugge
st a
spe
cific
en
docr
inop
athy
. At a
min
imum
, it s
houl
d in
clud
e m
easu
rem
ent o
f se
rum
te
stos
tero
ne a
nd F
SH c
once
ntra
tions
Post
-eja
cula
tory
uri
naly
sis
Shou
ld b
e pe
rfor
med
in p
atie
nts
with
eja
cula
te v
olum
es o
f <
1 m
L, e
xcep
t in
patie
nts
with
bila
tera
l vas
al a
gene
sis
or c
linic
al s
igns
of
hypo
gona
dism
Indi
cate
d fo
r m
en h
avin
g an
eja
cula
te v
olum
e <
1 m
L, e
xcep
t in
thos
e di
ag-
nose
d w
ith h
ypog
onad
ism
or
CB
AV
D
Tra
nsre
ctal
ultr
ason
og-
raph
yIn
dica
ted
in a
zoos
perm
ic p
atie
nts
with
pal
pabl
e va
sa a
nd lo
w e
jacu
late
vol
umes
to
dete
rmin
e if
eja
cula
tory
duc
t obs
truc
tion
exis
ts. S
ome
expe
rts
reco
mm
end
tran
srec
-ta
l ultr
ason
ogra
phy
for
olig
ospe
rmic
pat
ient
s w
ith lo
w v
olum
e ej
acul
ates
, pal
pabl
e va
sa a
nd n
orm
al te
stic
ular
siz
e to
det
erm
ine
if p
artia
l eja
cula
tory
duc
t obs
truc
tion
is
pres
ent
TR
US
for
diag
nosi
s of
eja
cula
tory
duc
t obs
truc
tion
may
be
indi
cate
d fo
r m
en w
ith a
zoos
perm
ia, p
alpa
ble
vasa
and
low
eja
cula
te v
olum
es.
TR
US
may
als
o be
indi
cate
d fo
r m
en w
ith o
ligoz
oosp
erm
ia, l
ow v
olum
e ej
acul
ates
, pal
pabl
e va
sa a
nd n
orm
al te
stic
ular
siz
e, a
lthou
gh th
ere
is n
o co
nsen
sus
Scro
tal u
ltras
onog
raph
yIn
dica
ted
in th
ose
patie
nts
in w
hom
phy
sica
l exa
min
atio
n of
the
scro
tum
is d
iffic
ult o
r in
adeq
uate
or
in w
hom
a te
stic
ular
mas
s is
sus
pect
edIn
dica
ted
for
men
who
se p
hysi
cal e
xam
inat
ion
is d
iffic
ult o
r in
adeq
uate
or
whe
n in
test
icul
ar m
ass
is s
uspe
cted
. It c
an b
e pe
rfor
med
in m
en h
avin
g te
stes
loca
ted
in th
e up
per
scro
tum
, a s
mal
l scr
otal
sac
or
othe
r an
atom
y th
at h
inde
rs p
hysi
cal e
xam
inat
ion.
It s
houl
d be
als
o co
nsid
ered
for
men
w
ith in
fert
ility
and
ris
k fa
ctor
s fo
r te
stic
ular
can
cer,
such
as
cryp
torc
hid-
ism
or
a pr
evio
us te
stic
ular
neo
plas
m, b
ut n
ot a
s a
rout
ine
scre
enin
g pr
oced
ure
Deo
xyri
bonu
clei
c ac
id
(DN
A)
inte
grity
Cur
rent
ly th
ere
is in
suffi
cien
t evi
denc
e in
the
liter
atur
e to
sup
port
the
rout
ine
use
of
DN
A in
tegr
ity te
stin
g in
the
eval
uatio
n an
d m
anag
emen
t of
the
mal
e pa
rtne
r of
an
infe
rtile
cou
ple.
Pre
sent
ly, t
here
are
no
prov
en th
erap
ies
to c
orre
ct a
n ab
norm
al
DN
A in
tegr
ity te
st r
esul
t
Bec
ause
the
prog
nost
ic c
linic
al v
alue
of
sper
m D
NA
inte
grity
test
ing
may
no
t aff
ect t
he tr
eatm
ent o
f co
uple
s, th
e ro
utin
e us
e of
DN
A in
tegr
ity
test
ing
in th
e cl
inic
al e
valu
atio
n of
mal
e fa
ctor
infe
rtili
ty is
con
trov
ersi
al.
How
ever
, the
eff
ect o
f ab
norm
al s
perm
DN
A f
ragm
enta
tion
on th
e va
lue
of in
trau
teri
ne in
sem
inat
ion
or I
VF
and
ICSI
res
ults
may
be
info
rmat
ive
Rea
ctiv
e ox
ygen
spe
cies
(R
OS)
RO
S te
stin
g ha
s no
t bee
n sh
own
to b
e pr
edic
tive
of p
regn
ancy
inde
pend
ent o
f ro
utin
e se
men
par
amet
ers
nor
are
ther
e an
y pr
oven
ther
apie
s to
cor
rect
an
abno
rmal
test
re
sult.
The
re is
insu
ffici
ent d
ata
to s
uppo
rt th
e ro
utin
e us
e of
RO
S te
stin
g in
the
man
agem
ent o
f th
e m
ale
part
ner
of a
n in
fert
ile c
oupl
e
A n
umbe
r of
bio
chem
ical
test
s of
spe
rm f
unct
ion
have
bee
n st
udie
d,
incl
udin
g m
easu
rem
ents
of
crea
tine
kina
se a
nd r
eact
ive
oxyg
en s
peci
es.
How
ever
, the
se te
sts
have
a v
ery
limite
d ro
le in
the
eval
uatio
n of
mal
e in
fert
ility
bec
ause
they
hav
e lim
ited
clin
ical
util
ity a
nd ty
pica
lly d
o no
t af
fect
trea
tmen
t
Author's personal copy
Int Urol Nephrol
1 3
Tabl
e 4
con
tinue
d
AU
AA
SRM
Les
s co
mm
on s
peci
aliz
ed
test
sSu
ch te
sts
are
not r
equi
red
for
diag
nosi
s of
mal
e in
fert
ility
. The
y m
ay b
e us
eful
in a
sm
all n
umbe
r of
pat
ient
s fo
r id
entif
ying
a m
ale
fact
or c
ontr
ibut
ing
to u
nexp
lain
ed
infe
rtili
ty, o
r fo
r se
lect
ing
ther
apy,
suc
h as
ass
iste
d re
prod
uctiv
e te
chno
logy
Stri
ct s
perm
mor
phol
ogy
Sper
m m
orph
olog
y by
rig
id (
stri
ct)
crite
ria
has
not b
een
show
n to
be
cons
iste
ntly
pr
edic
tive
of f
ecun
dity
and
sho
uld
not b
e us
ed in
isol
atio
n to
mak
e pr
ogno
stic
or
ther
apeu
tic d
ecis
ions
The
re is
no
spec
ific
reco
mm
enda
tion
Gen
etic
scr
eeni
ng a
nd
test
ing
Men
with
con
geni
tal b
ilate
ral a
bsen
ce o
f th
e va
sa d
efer
entia
sho
uld
be o
ffer
ed g
enet
ic
coun
selin
g an
d te
stin
g fo
r cy
stic
fibr
osis
tran
smem
bran
e co
nduc
tanc
e re
gula
tor
mut
atio
ns (
CFT
R).
The
fem
ale
part
ner
shou
ld a
lso
be o
ffer
ed c
ystic
fibr
osis
tran
s-m
embr
ane
cond
ucta
nce
regu
lato
r m
utat
ions
test
ing
befo
re p
roce
edin
g w
ith tr
eat-
men
ts th
at u
tiliz
e th
e sp
erm
of
a m
an w
ith C
BA
VD
. Im
agin
g fo
r re
nal a
bnor
mal
i-tie
s sh
ould
be
offe
red
to m
en w
ith u
nila
tera
l vas
al a
gene
sis
or c
onge
nita
l bila
tera
l ab
senc
e of
the
vasa
def
eren
tia a
nd n
o ev
iden
ce o
f cy
stic
fibr
osis
tran
smem
bran
e co
nduc
tanc
e re
gula
tor
abno
rmal
ities
. Tes
ting
for
CFT
R a
bnor
mal
ities
sho
uld
incl
ude
at m
inim
um a
pan
el o
f co
mm
on p
oint
mut
atio
ns a
nd th
e 5T
alle
le. T
here
cur
rent
ly is
no
con
sens
us o
n th
e m
inim
um n
umbe
r of
mut
atio
ns th
at s
houl
d be
test
edG
ene
sequ
enci
ng m
ay b
e co
nsid
ered
in c
oupl
es w
here
the
wif
e is
a c
arri
er a
nd th
e hu
sban
d w
ith C
BA
VD
test
s ne
gativ
e on
a r
outin
e pa
nel o
f C
FTR
mut
atio
nsK
aryo
typi
ng a
nd g
enet
ic c
ouns
elin
g sh
ould
be
offe
red
to a
ll pa
tient
s w
ith n
on-
obst
ruct
ive
azoo
sper
mia
and
sev
ere
olig
ospe
rmia
(<
5 m
illio
n sp
erm
/mL
)T
here
are
insu
ffici
ent d
ata
to r
ecom
men
d a
min
imal
num
ber
of s
eque
nce
tagg
ed s
ites
to te
st f
or in
pat
ient
s un
derg
oing
Y-c
hrom
osom
e m
icro
dele
tion
anal
ysis
. Alth
ough
th
e pr
ogno
sis
for
sper
m r
etri
eval
is p
oor
in p
atie
nts
havi
ng la
rge
dele
tions
invo
lv-
ing
azoo
sper
mia
fac
tor
(AZ
F) r
egio
n a
or b
, the
res
ults
of Y
-chr
omos
ome
dele
tion
anal
ysis
can
not a
bsol
utel
y pr
edic
t the
abs
ence
of
sper
m
Gen
etic
test
ing
for
CFT
R m
utat
ions
(to
rul
e ou
t the
pos
sibi
lity
of o
ffsp
ring
af
fect
ed w
ith c
ystic
fibr
osis
) sh
ould
be
offe
red
to th
e fe
mal
e pa
rtne
r of
m
en w
ith C
BA
VD
bef
ore
proc
eedi
ng w
ith tr
eatm
ents
that
use
spe
rm f
rom
af
fect
ed m
anM
en w
ith n
on-o
bstr
uctiv
e az
oosp
erm
ia o
r se
vere
olig
ozoo
sper
mia
(<
5 m
illio
n sp
erm
/mL
) ar
e at
incr
ease
d ri
sk f
or h
avin
g a
defin
able
gen
etic
ab
norm
ality
and
sho
uld
be e
valu
ated
with
a h
igh
reso
lutio
n ka
ryot
ype
befo
re u
sing
thei
r sp
erm
to p
erfo
rm I
CSI
Y-c
hrom
osom
e m
icro
dele
tion
anal
ysis
sho
uld
be o
ffer
ed to
men
with
non
-ob
stru
ctiv
e az
oosp
erm
ia o
r se
vere
olig
ozoo
sper
mia
bef
ore
perf
orm
ing
ICSI
usi
ng th
eir
sper
mSp
erm
DN
A a
neup
loid
y ca
n be
ass
esse
d by
fluo
resc
ent i
n si
tu h
ybri
diza
-tio
n te
chno
logy
. Pat
ient
s w
ith r
ecur
rent
pre
gnan
cy lo
ss a
nd r
ecur
rent
in
vitr
o fe
rtili
zatio
n fa
ilure
may
ben
efit f
rom
spe
rm a
neup
loid
y te
stin
gG
enet
ic c
ouns
elin
g m
ay b
e of
fere
d w
hen
a ge
netic
abn
orm
ality
is
susp
ecte
d in
eith
er th
e m
ale
or f
emal
e pa
rtne
r an
d sh
ould
be
prov
ided
w
hene
ver
a ge
netic
abn
orm
ality
is d
etec
ted
The
AU
A g
uide
lines
als
o in
clud
e se
men
ana
lysi
s in
the
full
eval
uatio
n, r
ecom
men
ding
that
a m
inim
um o
f 2
anal
yses
be
perf
orm
ed. F
or th
is, p
hysi
cian
s sh
ould
pro
vide
pat
ient
s w
ith in
stru
ctio
ns
for
sem
en c
olle
ctio
n, i
nclu
ding
a d
efine
d pe
riod
of
abst
inen
ce o
f tw
o to
thr
ee d
ays.
Sem
en c
an b
e co
llect
ed b
y m
astu
rbat
ion
or b
y in
terc
ours
e us
ing
spec
ial
sem
en c
olle
ctio
n co
ndom
s th
at d
o no
t con
tain
sub
stan
ces
detr
imen
tal t
o sp
erm
. The
spe
cim
en m
ay b
e co
llect
ed a
t hom
e or
at t
he la
bora
tory
. The
spe
cim
en s
houl
d be
kep
t at r
oom
or
body
tem
pera
ture
dur
ing
tran
spor
t and
exa
m-
ined
with
in o
ne h
our
of c
olle
ctio
n, in
a la
bora
tory
with
a q
ualit
y co
ntro
l pro
gram
. With
reg
ard
to a
n az
oosp
erm
ic e
jacu
late
, the
AU
A g
uide
lines
sta
tes
that
the
spec
imen
sho
uld
be c
entr
ifug
ed a
t m
axim
um s
peed
(pr
efer
ably
300
0g)
for
15 m
in, a
nd th
e pe
llet e
xam
ined
bef
ore
the
diag
nosi
s of
azo
ospe
rmia
is c
onfir
med
CL
IA C
linic
al l
abor
ator
y im
prov
emen
t am
endm
ents
, CB
AVD
con
geni
tal
bila
tera
l ag
enes
is o
f th
e va
s de
fere
ns, T
RU
S tr
ansr
ecta
l ul
tras
ound
, IC
SI i
ntra
cyto
plas
mic
spe
rm i
njec
tion,
IV
F i
n vi
tro
fert
iliza
tion
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Int Urol Nephrol
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Table 5 Recommendations from the EAU guidelines about male infertility evaluation
1 Rating scheme for the grade of recommendations
Grade A: Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one rand-omized trial
Grade B: Based on well-conducted clinical studies, but without randomized clinical trials
Grade C: Made despite the absence of directly applicable clinical studies of good quality2 World Health Organization. WHO Manual for the Standardised Investigation and Diagnosis of the Infertile Couple. Cambridge, Cambridge University Press, 2000
Area Recommendation Grade of recommendation1
Epidemiology and etiology To categorize infertility, both partners should be investigated simultaneously C
In the diagnosis and management of male subfertility, the fertility status of the female partner must also be considered, because this might determine the final outcome
B
The urologist/andrologist should examine any man with fertility problems for urogenital abnormalities. This applies to all men diagnosed with reduced semen quality. A diagno-sis is mandatory to start appropriate therapy (drugs, surgery or assisted reproduction)
C
Investigations According to World Health Organization (WHO) criteria, andrological investigations are indicated if semen analysis is abnormal in at least two tests
A
Assessment of andrological status must consider the suggestions made by WHO2 for the standardized investigation, diagnosis and management of the infertile couple; this will result in implementation of evidence-based medicine in this interdisciplinary field of reproductive medicine
C
Semen analysis must follow the guidelines of the WHO Laboratory Manual for the Examination and Processing (fifth edn.)
A; upgraded following panel consensus
Testicular deficiency Men with testicular deficiency (primary spermatogenic failure) who are candidates for sperm retrieval must receive appropriate genetic counseling
A
Testicular biopsy is the best procedure to define the histological diagnosis and possibility of finding sperm. Spermatozoa should be cryopreserved for use in intracyto-plasmic sperm injection (ICSI)
A
Obstructive azoospermia Testing for microdeletions is not necessary in men with obstructive azoospermia (OA) (with normal FSH) when ICSI is used because spermatogenesis should be normal
A
Genetic disorders Men with severely damaged spermatogenesis (spermatozoa <5 million/mL) should be advised to undergo Yq microdeletion testing for both diagnostic and prognostic purposes. Yq microdeletion also has important implications for genetic counseling
A
Standard karyotype analysis should be offered to all men with damaged spermatogenesis (spermatozoa <10 million/mL) who are seeking fertility treatment by in vitro fertilization (IVF)
B
Genetic counseling is mandatory in couples with a genetic abnormality found in clinical or genetic investigation and in patients who carry an (potential) inheritable disease
A
For men with severely damaged spermatogenesis (spermatozoa <5 million/mL), testing for Yq microdeletions is strongly advised
A
When a man has structural abnormalities of the vas deferens (unilateral or bilateral absence), he and his partner should be tested for cystic fibrosis (CF) gene mutations
A
Male accessory gland infec-tion
Patients with epididymitis that is known or suspected to be caused by Neisseria gonorrhea or Chlamydia trachomatis must be instructed to refer their sexual partners for evaluation and treatment
B
Germ cell malignancy and testicular microcalcifica-tion
Testicular biopsy should be offered to men with testicular microlithiasis (TM), who belong to one of the following high-risk groups: infertility and bilateral TM, atrophic testes, undescended testes, a history of testicular germ cell tumor or contralateral TM
B
Testicular biopsy, follow-up scrotal ultrasound, routine use of biochemical tumor markers or abdominal or pelvic computed tomography (CT) is not justified for men with isolated TM without associated risk factors (e.g., infertility, cryptorchidism, testicular cancer, atrophic testis)
B
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deficiencies that can be solely identified using sperm func-tional tests, including DNA/chromatin integrity, oxidative stress and antisperm antibodies testing [32, 33]. Notwith-standing, both the AUA and ASRM guidelines acknowl-edge the limitations of the semen analysis results to guide further evaluation by stating ‘further evaluation of the male partner should also be considered in couples with unex-plained infertility and in couples in whom there is a treated female factor and persistent infertility.’
It is worth mentioning that all discussed guidelines highlight the importance of a properly performed semen analysis. These guidelines recommend that laboratories should comply with high-quality standards as defined by either the WHO [16] or the Clinical Laboratory Improve-ment Amendments (CLIA) [34]. This is an important aspect since data from surveys of laboratory practice in the USA and the UK revealed that semen analysis techniques are still poorly standardized, indicating that there is a need of global standardization among the laboratories and the providers of external quality control [35–38]. Clinicians generally rely on the values provided by the laboratory to direct further work-up, diagnose, counsel and manage infertile males. Therefore, both accuracy—the degree to which the measurement reflects the true value—and preci-sion—the reproducibility of the results—need to be assured [39]. Notably, the NICE guidelines were the document to provide specific recommendations about when a semen analysis should be repeated, including the interval of repeat confirmatory testing that takes into account the duration of human spermatogenic cycle.
As guideline panels do not usually undertake independ-ent cost-effectiveness and risk–benefit analyses, it must be emphasized that the developed guidelines should not be regarded as a rigid standard by which physicians must adhere to in their clinical practice. Notwithstanding, guide-line-based treatment strategies may allow the establish-ment of new clinical standards and to guide future research efforts. The creation of measurable standardized variables may facilitate comparisons among studies despite the het-erogeneity in patient populations [40]. Similarly, a stand-ardized approach to the initial evaluation of the infertile male could allow for an improved epidemiological report-ing and comparison of outcomes.
Despite the potential advantages of a guideline-based practice, its widespread adoption continues to face multi-ple barriers. One concern is that policy-makers could uti-lize the current guidelines to reduce the costs of healthcare delivery. However, because guidelines such as those issued by the EAU are formulated on evidence-based outcomes [41–43], the primary objective was to maximize the qual-ity of the treatment without specific consideration to cost [40]. Another factor that limits their dissemination could
be inadequate awareness. Effort to establish a clear imple-mentation plan, as seen in the EAU and the NICE guide-lines offices, may facilitate healthcare professional to adopt these guidelines into daily clinical practice through increase in awareness. Evidently, differences in physi-cians’ clinical practices could also significantly impact on guideline implementation. As an example, current guide-lines recommendations will require multiple office visits, which may not be always feasible in countries with limited resources and medical care accessibility. Lastly, office vis-its and tests/procedures reimbursement could also pose a significant barrier to guideline implementation.
Limitations of this review
Only guidelines written in English were included. As such, it is possible that relevant and well-conducted guidelines written in other languages were missed. Moreover, a sys-tematic approach for grading the quality of the included guidelines was not performed.
Future steps
Although CPG attempt to translate best evidence into prac-tice, there are substantial limitations in the methods of some guidelines’ development, data collection and analysis, which influence both the quality and strength of the state-ments made and the recommendations provided.
Since generalization is an inherent characteristic of any clinical guidelines, clinicians should be aware to constantly use their professional judgment prudently. Ultimately, healthcare professionals must make clinical decisions on a case-by-case basis, using their clinical judgment, knowl-edge and expertise to thoroughly counsel their patients.
Future guideline developments and updates will no doubt continue to incorporate new discoveries for a better management of male infertility. Numerous investigations are ongoing to establish predictive associations between semen findings and overall sperm quality beyond the cur-rently accepted WHO semen characteristics. Among the future potential additions to the current infertility guide-lines, integrating patient counseling and the importance of lifestyle modifications and preventive measures, such as controlling obesity, diabetes and discontinuing smoking/alcohol intake could result in an improvement in the quality of infertility care. Furthermore, given that most recommen-dations were derived from non-randomized clinical trials, as well as retrospective studies and expert opinion, there is an ample opportunity for research and future incorporation of higher-quality standards in male infertility care.
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Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of interest.
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