l' .2

.A Blackwell Asian JAndro12006; 8 (2): 143-15} AJ A
.b Publishing DOl: 10,111l/j,1745-7262,2005.00123.x
.2

]diopathic ol!goasthenoterato~,oospermia
2 Definition 3.2 Non-inflammatory functional alterations in postte~.ticular
organs
Infertility means that a couple has failed to achieve Low seminal concentration of prostate-specific
,
a pregnancy within one year of regular (at least three antigen, zinc, frUctose [9] and prostatic acid phosphatimes
per month) unprotected intercourse. One ob- tase [10], and low seminal activity of neutral alpha.glujection
to the general use of the term "infertility" is cosidase are linked to isolated asthenospermia as well as
that the condition which is actually meant may in- to increased viscoelasticity [11] and osmolarity of semistead
be that of subfertility, as the ability to father or nal plasma [12].
to conceive may exist with a different partner. Three spermatogenesis-specific genes were found
However, here too it is difficult to delineate clearly to be unmethylated in adult spermatogenetic cells in the
between definitions. Infertility pertains to approxi- testis, but were then found to be remethylated in mature
mately 15% of sexually acti ve couples [3] .A male spermatozoa in the vas deferens. A role of post-testicu-
.factor is present in approximately 40% of infertility lar organs (epididymis?) on DNA male gamete methylacases.
It is considered a male factor when an alter- tion might be suspected U3]. DNA methylation is ination
in sperm concentration and/or motility and/or volved in imprinted gene expression in animal cells [14].
morphology could be found in at least one sample of The methylation occurs at cytosine-guanine (CpG) ditwo
sperm analyses which comply with World Health
nucleotides at which methyl groups become covalently
Organization (WHO) 1999 guidelines collected be- bound to cytosine residues [15]. Methylation mediates
tween 1-4 weeks apart. "Idiopathic" means that no transcriptional repression by recruiting histone deacetylase
etiological factor could be found with the common [16]. Most tissue-specific genes are fully methylated in
clinical, instrumental or laboratory methods. Approxi- sperm and in almost all somatic cells of the adult
mately 30% of OAT infertile men are diagnos.ed as organism. In tissue expression the same genes undergo
"idiopathic". iOAT is classified as: isolated asthe- a striking demethylation that is necessary for gene
no :t: teratospermia (no alteration in sperm con-cen- transcription. Specific genes that are expressed in sotration);
moderate (sperm concentration < 20 x 106/mL matic cell types have distinctive patterns ofDNA methyand
> 5 x 106/mL); or severe (sperm concentration lation that have been correlated to the expression profile
< 5 x 106/mL) [4]. [17], even though more recent studies suggest that methylation
is not necessary for transcription repression in
3 Etiology many organs [18]. Even some germ cell-specific genes
are regulated by (de)methylation [19] at CpG dinu-
Descriptions of reputed etiologies of iOAT have at cleotides. Changes in CpG methylation are involved in
least two biases: I) two patterns have been described senescence (even at the epydidymallevel [20]) and
whose alterations are linked to male infertility with nor- tumoringenesis [21].
mal sperm parameters [5, 6]; 2) the sum of the percentages
of patients with different etiologies of iOAT gave a 3.3 Infective agents
result much higher than 100%. This means that etiolo- Longitudinal observational studies to determine the
role, if any, of Chlamydia trachomatis (CT) asymptom-
atic infection in the aetiology of iOAT look extremely
difficult. The alternative is to contrast and compare between
fertile and infertile patients with regards to the
gies overlap and/or that the primary cause (if any) of
iOAT is still unknown and/or that more than one cause is
needed to affect sperm patterns.
Nevertheless, the following factors are accepted eti-
ologies of iOAT, therefore the concept that iOAT is com-
detection and occurrence of CT, CT products, and/or of
posed of an assortment of infertilities is confIrmed [7]. an immune response towards the CT products.
Some researchers estimate the prevalence of asymp-
3.1 Age tomatic CT infection at approximately 20% in men with
Semen volume and sperm motility, but not sperm iOAT. As this percentage is higher than in the control
concentration, continuously decrease between the ages population, asymptomatic CT infection has been regarded
of 22 years and 80 years, with no evidence of a thre- by some as a cause of iOAT [22, 23]. On the contrary,
shold [8].
other researchers have maintained that CT prevalence in
.144.

Asian JAndrol 2006; 8 (2): 143-157
..
iOAT and in fertile subjects is similar (approximately 5%) fertile men with meiotic arrest completely lack the
[24]. Different detection techniques have been regarded BOULE gene and its target (cdc 25 phosphatase) exas
an explanation for this difference [25]. Furthermore, pression [39}. Furthermore, several patients with a de-
CT antibodies were not significantly related to the out- fective expression of B6ULEprotein and of cdc 25 phoscome
of seminal analyses, including an anti-sperm anti- phatase could be correctly classified as iOAT because
bodies analysis an.d an analysis of several parameters of their testicle displayed a histological picture of mixed
sperm function [26t Therefore, proof of the role as- atrophy, their sperm analyses displayed OAT and their
ymptomatic .CT infection has in infertility is considered serum displayed normal levels of testosterone, FSH and
inconclusive. LH [39].
Herpes virus and adeno-associated viruses have been pyridoxal-kinase mRNA splice variant (PKH-7) gene
linked to OAT without significant leukospermia [27,28]. is expressed in the adult testes and in spermatozoa, but
it has no expression in the testis of men with Sertoli cell-
3.4 Gamete genome only syndrome. PKH-T was found to be expressed in
y chromosome microdeletion [29-31], androgen re- three ourof four patients with spermatogenetic arrest,
ceptor gene defects, and/or somatic karyotype aberra- and in one out of two patients with spermatid arrest. It
tion [30] are rarely found in iOAT patients (I %-3% ). was unexpressed in a minority of OAT patients with nor-
Of the 11 955 rat loci investigated, 1 268 were iden- mal serum levels of testosterone, FSH and LH [40] .
tified as having been specifically transcribed in germ cells
during the course of gametogenesis; 200 of these genes 3.5 Mitochondrial alterations
are important for the male germ cell development [32]. In asthenospermia, both mitochondrial membrane
Approximately 4% of the mouse genome is dedicated to potential [41] and DNA mitochondrial [42] content
the expression of post-meiotic male germ cells. Targeted are impaired. Mitochondrial DNA oxidative damage
disruption of 19 of these genes has displayed their criti- has been observed in asthenospermic infertile men [43]
cal roles in fertility [33]. In order to be considered a key and has been confirmed in experimental models [44].
for iOAT, a gene must display three characteristics: 1) it These alterations are very similar to the peculiar mishould
be specifically expressed in the germ cell line; 2) tochondrial modifications found in apoptotic sperm
it should have an essential role in spermatogenesis; and cells [ 45-49].
3) its altered expression should be associated with iOAT [34].
For example, cyclic adenosine monophosphate-responsive
element modulator (CREM) is a transcription
factor which is highly expressed in testicular post-meiotic
germ cells and which regulates the expression of
sperm qua!lity is a matter of discussion.
The hypothesis that environmental hormonally-acseveral
germ cell-specific genes by controlling the imbalance
between apoptosis and development. Its activa-
tion depends on follicle-stimulating hormone (FSH) and 1992 [50].
luteinizing hormone (LH) [35]. In histological patterns
of the testicle, CREM expression was found significantly
reduced in severe OAT patients who had round spermatid
maturation arrest or mixed atrophy in combination with
3.6 Environmental pollutants
The possible effect of environmental pollutants on
tive compounds of industrial origin (endocrine disrup-
ters) may affect semen quality was first synthesized in
Several laboratories published a decline in sperm
concentration, motility, and morphology using archival
data [51-56], yet there was no detectable deterioration
in sperm analyses in areas that are similar in terms of
norma1bloodlevelsoftestosterone,FSHandLH(i.e.,iOAT human pollutant exposure [57-62]. Therefore, on one
patients) [36,37]. However, azoospermic patients lack- hand, it has been maintained that the current data are
ing spermatid elongation but who had spermatid matura- insufficieQt to support a causal relationship between hution
arrest were not found to necessarily have defective man exposure to endocrine disruptors and the decline of
CREM expression [38].
sperm count and sperm quality [63], on the other hand,
The BOULE gene (a member of the deleted in endocrine disruptors are regarded as developmental and
azoospermia [DAZ] gene family) encodes a key factor reproductive toxicants which can increase seminal reac-
(a cdc 25 phosphatase protein) which promotes progres- tive oxygen species (ROS) concentration [6,4]. In
sion through meiosis. A major group of azoospermic in- addition, an association among urinary phthalate
.145.

idiopathic oligoasJhenoteralozoospermia
concentration, increased FSH and lowered inhibin B concentration
has been found [65].
from cellular physiological metabolism of 02 in aerobic
conditions. Seminal cells include mature and immature
gametes, leukocytes, epithelial cells, and red blood cells.
3.7 "Subtle" hormonal abnormalities ROS are mainiy produced by leukocytes and immature
A decreased LH pulse frequency has been found to gametes, therefore an increase in one or both cell types
occur in iOAT men whose amplitude parallels the sever- increases ROS and reduces TAC [72]. Leukocytes and/
ity of the disorder [771
or immature gametes can be found in several types of
The Gly102Ser variant of LH might be implicated in
iOAT [781
iOAT displays a shift toward lower testosterone (T)
serum levels, lower calculated free T index, and lower
T/LH ratio, and a shift toward higher serum LH levels,
OAT (hormonal alterations [73], inflammation [74], and
varicocele [75]), therefore increased ROS and reduced
TAC are not characteristic of iOAT. Physiological ROS
concentration has positive effects. ROS are metabolic
intermediates in metabolism ofprostanoid, in the regula-
'higher estradiol (E2) levels, and higher E2rr levels [79] .tion of vasotonous, in gene regulation, and in facilitating
Also, significantly lower inhibin (1) levels and significantly sperm capacitation and acrosome reaction, but at a higher
higher FSH levels have been found in i(O)ATs when com- concentration they exert negative effects [74]. WHO [4]
pared to the levels in fertile men [82].
defines a 106leukocytes/mL threshold above which leu-
All of these etiologies can be correctly classified as kocytes and/or their product(s)/ROS illpair(s) fertility.
etiologies ofiOAT. The causal link between these patholo- This threshold is commonly accepted today [4] but is
gies and iOAT is not always evident, nevertheless, the com- still under discussion [76-79]. Therefore it may be asmon
final result is the impairment of spermatogenesis.
summmed that the main source of ROS in iOAT is imm~ture
Despite this range of possible etiologies, male infer- gametes.
tility also appears to have a familial occurrence espe- ROS are short-lived chemical intermediates which
cially among brothers and maternal uncles, who often contain one or more electrons with unpaired spin. In orhave
normal blood levels of FSH and LH [56]. Observations
were also consistent with an autosomal recessive
der to overcome this state of unpaired electrons, they
are highly and unspecifically reactive molecules able to
mode of inheritance in over half of the cases [57]. These interact with lipids, amino acids and nucleic acids [74];
published reports fit with a genetic etiology of iOAT which Seminal plasma is the human fluid with the highest conof
late has received great consensus. Such a consensus centration of anti-oxidants to protect gametes from ROS.
is lacking, however, in the case of pollution and infection. Seminal plasma TAC is the sum of the potential anti-
On one hand, genetic etiology is consistent with iOAT ROS activities: 1) of enzymes (superoxide dismutase,
being composed of an assortment of infertilities; on the catalase, glutathione peroxidase); 2) of low molecular
other hand, it provides a holistic approach to the disease.
Therefore, even though in the future genetic etiology will
The above etiologies are regarded to affect spermato-
genetic process. Impaired spermatogenesis leads to in-
cing fragmentation, aberrant recombination, and/or decreased
ROS concentration and to unbalanced germ cell
apoptosis. The result of these processes is an affected
sperm concentration,. motility and morphology.
weight substances ( a-tocopherols, ~-carotene, ascorbate,
urate); and 3) of the transition metal chelators (transnot
prove to be the most probable cause of iOAT, it is ferring, lactoferrin, ceruloplasmin) [80].
currently the most convenient to accept.
ROS exert their activity on all cellular structures during
the course of tubular spermatogenesis and sperm
4 Pathogenesis maturation during the migration through the seminiferous
tubules and epididymis [74].
ROS attack nuclear and mitochondrial DNA, indu-
fective packaging [81]. 2-Deoxyguanosine, a normal DNA
base, is oxidized to 8-0H-deoxyguanosine. Whereas the
former nucleotide binds to cytosine, the latter will form
a base pair with thymine during DNA replication. Thym-
4.1 Increased ROS ine will bind to adenosine so that a point mutation is in-
Increased ROS concentration and reduced total anti-
troduced in the DNA [82]. The extept of DNA damage
oxidant capacity (TAC) were found in the tubula and the depends on the degree of oxidative stress [83].
seminal plasma of the majority of iOAT. ROS originate~ ROS irreversibly damages cell membranes. Mam-
.146.

AsianJ Androl 2006;8 (2): 143-~57
malianspenu cell membranes have a highly specific lipid with spermatogenetic failures [96]. PCD is an active
composition: a high content of polyunsaturated fattyaci'ds process; it involves specific gene expression and requires
(PUPA), plasmalogens and sphingomyelins. The unusual mRNA and protein sypthesis.
"
Apoptosis of type A2, A3
structure of their membrane is responsible for th,e flexi- and A4 spennatogonia reduces the number of genu cells
bility and the functional ability of spenuatozoa. ROS- produced to approximately 25% of that expected if all Al
dependent peroxidation of PUFA is an autocatalytic self- spenuatogonial progeny were to survive. It has been propropagating
reaction. The first step (initiation) is the posed that individual spermatogenesis is the result of a
extraction of a hydrogen atom from an unsaturated fatty framework involving the imbalance between pro-apoptotic
acid. The second step (propagation) is the fonuation of and pro-survival factors [45]. In fact, the BCL-2 protein
a lipid-alkyl radical followed by its rapid reaction with family can either support cell survival (BCL-2, BCL-XL,
oxygen to form a lipid-peroxyl radical. The peroxyl radical BCL- W, MCL-l , Al/BFL-l ) or promote cell death (BAX,
can extract a hydrogen atom from a PUFA wit~ the BAK, BCL-XS, BAD, BID, BIK, BOK, DIVA, HRK).
concomitant fonuation of a lipid radical and lipid hydro- BCL-2 family members interact competitively, thereby
peroxide. As the peroxyl and alkyl radicals are regenerated, regulating activation of the proteases ( cysteinyl asparthe
cycle of propagation could continue indefinitely or tate-specific proteinases [caspases]) which dismantle the
until one of the substrates is consumed or terminated in germ cell [97]. Furthermore, the C-kit stem cell factor
the radical-radical reaction [84-86]. system, bone morphogenetic protein 8B [45], lactate [98],
An increase in ROS changes the tertiary structure and sphingosine-l-phosphate [99] inhibit male genu cell
and expression of proteins, protein membrane receptors, apoptosis, whereas the fibroblast-associated death recepand
membrane transport proteins, which in turn results tor (Fas)/Fas-ligand (Fas-L) system is regarded as a proin
disturbances in the ionic balance. The function of en- apoptotic factor [ 45] .
zymes with thiolic (SH) groups may also be altered by Interestingly, toxicants and increased concentration
ROS [87].
of ROS from activated leukocytes or from immature
Sperm epididymal maturation involves extensive spenuatozoa trigger PCD [45-47]. These substances may
protamination and chromatin condensation [88,89]. In- [100] or may not [101] interact with the Fas/Fas-L syscreased
ROS concentration has been linked to DNA de- tem to activate caspase [48, 101], which leads to cellular
naturation in infertile men [90]. DNA denaturation is morphological and biochemical alterations and finally to
negatively correlated with semen parameters [91] but is death [45-49].
positively correlated with cytoplasmic residues [92], that The evidence of ethnic differences in the susceptiis,
with the morphological markers of immature gametes. bility of genu cells to PCD [102] may indicate that alter-
Death of gametes (necrosis and/or apoptosis, i.e., oligo-
/terato-spermia), reduction in the percentage of sperm typical
fonus, and impainuent of spenu motility (i.e., asthenospermia)
are resulting patterns. Asthenospermiais caused
by axonemal damage mostly as a result of adenosine triph-
ations of PCD may occur in the absence of an exogenous
triggering. The degree of decreased expression of
survivin (a PCD inhibitor) parallels the severity of iOAT
[102], just as the overexpression of the Pas gene has
been associated with altered meiotic and post-meiotic
osphate depletion [93,94]. spenu cell maturation [103].
Despite the progress in our knowledge ofROS activity, Ejaculated spenuatozoa from infertile men display a
the causal link between these alterations and iOAT is not number of apoptosis markers: various degrees of plasma
always evident. membrane translocation of phosphatidylserine; DNA
fragmentation; and active capsase-3 (the main executor
4.2 Modified apoptosis of apoptosis) with an apparent exclusive cellular location
in the mid-piece [104]. The apoptotic process is proba-
bly set in motion before ejaculation [105] because healthy
Apoptosis or programmed cell death (PCD) is critical
for mammalian tissue morphogenesis because it eliminates
unwanted or defective cells through an orderly process of human ejaculated spenuatozoa cannot initiate apoptosis,
cellular disintegration without inflammation, thus ensuring at least not under in vitro conditions [ 106] .
the production of intact functional spermatozoa [95}. Apoptosis has been inversely linked with spenu mo-
Therefore, as a general rule, PCD is involved in the re- tility [107], morphology, vitality and concentration [108].
moval of arrested genu cells from the testicles of patients
Increased apoptosis was found in a variety of infer-
.147.

idiopathic oligoasthenoteratPzoospe rmia
tilities, such as hormonal infertilities [109], anti-sperm 5 Diagnosis
auto-antibodies (ASA)-associated infertility, varicocele,
testicle torsion [110] and inflammation [111]. Therefore, iOAT is co!llmonly diagnosed by exclusion; the difincreased
PCD is not atypical ofiOAT. ferential diagnosis is presented in Table 1.
In conclusion, the pathogenetic mechanisms of iOAT Impaired spermatogenesis of iOAT was assayed with
are not peculiar to this kind of disease and can be found testicular arteries duplex examination and inhibin B sein
several types of OAT.
rum levels.
Table 1. Differential diagnosis Q of male infertility .-:[112].
Reproductive failure mechanism
-~
Methods of diagnosis
Chromosomal [ 113-116] X chromosome disorders Objective examination, y microdeletion detection, karyotype,
y chromosome disorders
screening of cystic fibrosis, hormonal profiles, androgen recep
.Autosomal disorders tor detection, semen analysis.
Ductal obstruction
Didymal-epidydimal interruption
(vasography; fructose, L-camitine and alpha-glycosidase semi
nal plasma determination), semen analysis.
Ectopic testicle
Retarded descent
(Floating testicle)
Testicular tumors
Bilateral atrophy
Testicular torsion
semen analysis.
-Trauma
Genital tract inflarnrnation[117] Urethritis Clinical history, objective examination, scrotal echography,
Prostatitis
seminal leukocyte concentration/mL, urethral swab, urine
Epididymitis
analyses, sperm and urine cultural analysis.
Varicocele
Orchitis
Objective examination, scrotal bilateral
echo-color Doppler examination,
semen analysis.
Endocrine [118, 119] Pituitary disorders Hormonal profiles, semen analysis.
Iatrogenic
Hypothalamic disorders
Testicle disorders
Thyroid disorders
Adrenalgland(s) Surgery -~ , , disorders
Clinical history, objective examination, semen analysis.
Drug or radiation administration --,
Sexual related aetiologies Erectile deficiency Clinical history, semen analysis.
Disturbed eiaculation
General diseases Renal diseases Specific tests, clinical history, semen analysis.
Sperm auto-antibodies
Idiopathic oligo-astheno-terato-
Liver diseases
Neurological diseases
Gastrointestinal diseases
Haematologic diseases
Autoimmune diseases
Infectious diseases (AIDS)
Psoriasis, sarcoidosis
Diabetes
Agglutination, microagglutination, immun~fluorescence
[120], se~enanalysis.
Semen analysis, exclusion criteriaspermia
.
.148.

Asian J Andro12006; 8 (2); 143-!57
iOAT displayed peak systolic velocity (PSV) levels Indirect proof (i.e., animal models) is difficult to obtain.
significantly lower than those of riormospermic fertile Spermatozoa are not amenable to conventional molecumen,
inflammatory OAT patients, and varicocele OAT lar biology techniques, because of the lack of much funcpatients
[121]. An echo-colour Doppler semi-quantita- tional mRNA and the lack of many post-translational
tive score has been used to distinguish obstructive modifications of gern:l cells during maturation [132, 133].
azoospermic pati.ents from non-obstructive azoospermic ,Circumstantial evidence (i.e., the favourable response to
patients affected by primary testicular pathology [122]. immuno-suppression) was not demonstrated because it
The intratesticular arterial blood flow and maximum blood
is impossible to treat infertile patients with cytotoxic
flow velocity were significantly lower in patients with drugs [132].
germ cell hypoplasia or maturation arrest [123]. The ASA are made of numerous antibodies interacting
pulsatility index of the testicular transmediastinal artery with multiple sperm components [134]. These findings
was significantly higher in patients with obstructive support the hypothesis there might be a relatively nonazoospermia
than in those with non-obstructive azoosper- specific binding of antibodies to the surface of spermamia
[124]. Arterial impedence of undescended testes in tozoa [135] probably through crystalizable fragment (FC)
adults may have a predictive value and provide more ac- or disulphide bonds [131].
curate information about histology than testicular vol- On the other hand, ASA are reputed to affect the
ume [125]. These data link blood arterial supply to sper- following: cervical mucus penetration [135], acrosome
matogenesis [121]. Currently there is no direct explana- reaction [132], zona binding [136], zona penetration [137],
tion for this phenomenon, Testicular arteries are target oolemma binding [138] and pronucleus formation [139].
organs for androgens [126] and in infertile men testicu- The effects of ASA on motility [140, 141] and on in vitro
lar arteries have a narrow lumen caused by enlarged en- fertilization [139, 142, 143] are questionable. The WHO
dothelial cells, a thickened subendothelial layer, and an recommends direct testing for ASA on the surface of
abundant adventitia rich in connective fib!es and ground spermatozoa [4], nevertheless only some trials on iOAT
substance [127].
therapy look for sperm autoimmunity [144-146], there-
The clinical usefulness ofa blood level measurement
of inhibin B is considered rather low [128]; inhibin B
serum. levels are regarded as markers of Sertoli cell
function, but the prediction of the quality of spermatogenesis
is not higher than FSH [129]. iOAT men who
had been exposed to phthalate displayed increased levels
fore underestimating the role of ASA in infertility. Our
opinion is that ASA detection may be a prudent technique
for interpreting results in infertility management.
Seminal leukocyte concentration greater than 106/mL
is considered the lowest threshold of inflammation.
Controversial results have been published about the efof
inhibin B, lowered levels of FSH, and phthalate uri- ficacy of antimicrobial therapy on sperm quality and
nary excretion [65].
There are two pathologies that may confound the
pregnancy rate in MAGI, even though seminalleukocyte
concentration was found to fall below 106/mL after
practitioner: sperm auto-immunity and male accessory therapy [147, 148].
gland inflammation (MAGI).
Some reasons for discrepancy may be: poor pa-
Disruption of the epithelial (i.e., Sertoli cell) blood tient selection [147], inadequate drug administration
barrier elicits ASA. Some reputed causes of ASA are [148], persistence of leukocytes [149] and/or of their
vasectomy, vas obstruction, testicular trauma, torsion,
products (ROS) [150], elastase [151], interleukin (IL)-8
malignancy and infection of the urogenital tract [130]. and IL-6 [151].
ASA are found in 26%-55% of infertile couples, in up to Regardless, the vast majority of trials for idiopathic
19% of fertile men, and in 43% of fertile women, which oligoasthenoteratozoospermiaconsiderlQ6/mLleukocytes
means that not all ASA cause infertility [131].
to be the threshold for the diagnosis of MAGI.
In order to be defined as an "autoimmune disease",
three criteria must be met: direct proof, indirect evidence 6 Indications for therapy
and circumstantial evidence [132]. The direct proof is
easy to obtain because ASA can be transferred to the If sperm concentration exceeds 20 x 106/mL, the
sperm of healthy persons and an impairment of func- probability of spontaneous conception depends only to a
tions can be demonstrated in the receiving cells [132}.
minor extent on sperm motility, viability, and morphology.
.149.

Idiopathic oligoasthenoteraLozoospermia
tion wi» have a stronger effect on the probability of con-
ception when the initial sperm count is low, rather than
The lack of prognostic significance contrasts with the
fact that these characteristics discriminate well between
the semen of fertile andsubfertile men. Men whose sperm
when the initial sperm count is high [158]. The TC data
f
concentration is over 20 x 106/mL but who have abnor- were principalry reviewed by Vanderkerckove et at. [159]
mal motility or morphology of idiopathic origin have a and Comhaire [158]. Vanderkerckove maintained that
40% high.er probability of achieving spontaneous con- there is not enough evidence to use TC to increase the
ception than men in whom the sperm alterations are re- fertility of iOATs [159] .Comhaire showed that, because
lated to a demonstrable cause [130]. Therefore it is dif- a lower sperm concentration is related with a lower
ficult to justify the therapy of an iOAT patient with a fecundability, the pregnancy rate with TC treatment is
sperm concentration of 40 x 106/mL spermatozoa arid a
class A WHO motility of 24%,
stronger in trials containing lower treatment-independent
pregnancy rates [158]. In addition, Comhaire [158] also
found an increased sperm concentration in trials that were
7 Therapy discharged by Vanderkerckove [159].
The effects on s~al parameters ofTC (10 mg x 2/d)
Evidence-based medicine indicates that studies with- combined with testosterone undecanoate (TU) (40 mg x 3/d)
out a placebo-treated group should not be taken into were studied in men with iOAT. The results were that
TC + TU improved total sperm count, motility and func-
tional sperm fraction after 3 and 6 months [160]. A fur-
consideration. "Placebo treatment" differs from "no treatment"
because a placebo can improve sperm parameters
due to a psychological mechanism [144, 145]. It is man- ther report showed a 33.9% (pregnancy rate per couple
datory to establish whether an improvement in sperm per month [prcm] = 3.8%) rate of incidence of spontacount
and quality is statistically or clinically significant, neous pregnancy in the TC + TU treatment group at 9
because the latter involves the former, but not vice versa. months, and a 10.3% (prcm= 1.1%) rate ofspontane-
Spontaneous pregnancy rate when the partner is free from ous pregnancy in the placebo group at 9 months [161].
any detectable factor of infertility is an accepted method, TC was introduced as an empirical treatment for iOAT
even though 11 %-17% of infertile couples do not dis- [162] because of its stimulatory action on gonadotropin
play any cause of infertility as detected by the common secretion [163], its direct effect on Leydig cell function
[126], and because of its production of 5a-dihydrotes-
tosterone in tubules and epididymis [164]. To overcome
the putative inferior androgenic environment in the re-
techniques [130]. Therefore to define a drug as active, it
should improve sperm patterns and pregnancy rates in at
least one blind, prospective, placebo-controlled trial; more
of these trials from independent groups are necessary in
order to define a drug as unquestionably active [2].
productive tract of men with iOAT, androgen-depen-
dent epididymal and accessory gland function [165] were
Despite these instruments, difficult-to-interpret boosted by androgen administration [160].
data still materialize. Two typical examples are recom- The effects of folic acid and zinc sulfate treatment
binant FSH (rFSH) and tamoxifen citrate (TC). rFSH on seme!l variables in fertile and subfertile men were
was reputed effective when compared to a "no treatment"
group [152, 153], or ineffective when compared
studied. One hundred and eight fertile and 103 subfertile
men were randomly assigned to receive one of four treatto
a "placebo-treated"group [154]. A recent meta-analy-
sis showed that rFSH given to nien with iOAT increases
the clinical pregnancy rate, the fertilization rate, and the
rate of doubling sperm count significantly [155].
OAT decreases the monthly chance of conception in a
ments for 26 weeks: folic acid and placebo; zinc sulfate
and placebo; zinc sulfate and folic acid; and two placebos.
Folic acid was given at a daily dose of 5 mg, and zinc
sulfate was given at a daily dose of 66 mg. Subfertile
men demonstrated a significant 74% increase in total
dose-dependent manner, adding its effect to the duration normal sperm count and a minor increase of 4% in abof
infertility [156]; an increased sperm concentration in normal spermatozoa. A similar trend was observed in
OAT infertile males has been associated with dispropor- fertile men. The beneficial effect on fertility, if any, retionately
higher fecundability [157]. Further pregnancies
can be expected on the basis of hyperbolic regression be-
mains to be established. Despite a putative role of zinc
on post-testicular organs, a direct anti-oxidant effect of
tween sperm concentration and fecundability [157]. both drugs on tubules was sustained [166].
Therefore, treatments which double sperm concentra-
Although there is no clear pathophysiological hypoth-
.150.

Asian J Androl 2006; 8 (2):143-1.;;7
esisfor the use of a-blockingagents in the treatment of zyme A concentration through the higher availability of
iOAT, studies have been performed using these sub- acetyl groups, which in turn results in an increase in
stances [167]. Two placebo-controlled studies claimed mitochondrial respirat~n and monoamine-oxidase activan
improvement in spenn concentration but not of ejacu- ity and thus increasing the metabolism of histamine; carlated
volume, morphology, motility or pregnancy rate nitines stabilize cell membrane fluidity by regulating phoswhen
compared t,o placebo [168, 169].
pholipid levels and reducing ceramide production and
In bioptic testicle specimens, mast cell counts were insulin-like growth factor 1. Carnitines prevent cellular
higher in idiopathic infertile men than in nonnospennic death and apoptosis. Most of their activities take place in
men [170]. Tranilast (a mast cell blocker) was first used the tubular microenvironment rather than in epididymal
in an uncontrolled study and demonstrated a clinical functions [144-146]. No biochemical study was perbenefit
on semen parameters and conception rates fonned regarding the role of C suppositories in increas-
(prcm = 9.5%) [171]. A further double-blind controlled ing the efficacy of carnitines. The effect of oral and
trial showed that tranilast significantly increased sperm injected NSAIDs on sperm analyses was lower than that
concentration, but not motility, morphology or pregnancy
rate when compared to placebo [172]. It has been con-
of suppositories. A more direct effect of suppositories
on seminal plasma may be presumed because of the reccluded
that tranilast demonstrates a certain clinical benefit
in tenns of improvement in semen parameters in-
1al-prostatic lymphatic pathways. Hydrophilic NSAIDs
were less active than C, whose lipophilia facilitate abvolving
severe iOAT, but it does not appear to afford
clinical benefit in the long tenn [173]. A second mast cell
blocker (fexofenadine) was found ineffective [174].
sorption [176]. An animal model showed that chronic
treatment with NSAIDs at low doses improved sperm
quality and fertility [178]. Carnitine administration was
Acetyl-L-camitine (ALC) 500 x 2 g/d + L-camitine (LC) found to increase E2 prostaglandin concentration [ 179],
1 x 2 g/d have been shown to increase spenn count, spenn which affects spenn count [180, 181]. Finally, polyzooquality
and pregnancy rate in patients with an ultrasound spennia has been associated with lowered prostaglandin
picture of genital inflammation and leukocyte spenn con- content of tubuloseminal plasma and OAT has been ascentration
< 106/mL [175]. LC alone 2 g/d was shown to sociated with increased prostaglandin content of
increase spenn concentration and motility [144] in iOATs, tubuloseminal plasma [180, 181]. NSAIDsstabilize lyalthough
a higher activity on iOAT was found using LC sosomal membranes, thereby partially preventing
2 g/d + ALC 1 g/d [136]. Another therapy studied was in- apoptosis [176].
termittent administration of a non-steroidal anti-inflamma- The efficacy of conventional anti-ROS drugs (vitamin
tory drug (NSAID). Cinnoxicam (C) (one 30 mg supposi- E, vitamin C and essential fatty acids) is controversial.
tory every 4 days) was found to increase spenn concen- An uncontrolled study found that N-acetyl-cysteine or
tration and quality in low grade varicoceles [176]. There- the combination of vitamins A + E with essential fatty
fore one 30 mg C suppository every 4 days was used in acids improved spennconcentration, and that acrosome
combination with LC 2 g/d + ALC 1 g/d. This three-drug reaction reduced ROS and sperm oxidized DNA [182],
association significantly increased spenn concentration, but no significant difference was found in tenns of spenn
motility, morphology, or round cells. A double-blind pla-
cebo-controlled
, c~
study maintained that vitamin E + selenium
was effective because they combination improved spenn
motility and lipid peroxidation markers. The number of
patients who dropped out (n = 34) is much higher than
motility, morphology, and pregnancy rates when compared
to placebo and to the two carnitines alone [146]. Although
more effective than placebo, a recent analysis of literature
indicates that the spontaneous prcm following carnitine
therapy is 2.3% both in placebo-controlled and open stud-
ies [177]. The use ofLC + ALC + C gave a prcm of 8.5%
in iOAT patients (51% at 6 months) [146].
Carnitines have several activities which might be use-
the actual group studied (n = 20 patients), therefore its
conclusions might be reputed as unreliable [183]. Vita-
min E + C was ineffective in a prospective double-blind
ful for the male gamete: free-radical production is re- controlled trial [184].
duced by depleting fatty acid peroxidation; carnitines re- Finally, T + TC and (C+)ALC + LCmay be regarded
store the phospholipid composition of mitochondrial as active drugs, whereas TC and FSH are considered to
membranes; carnitines enhance cellular energetics in most likely be active drugs. As yet, no drug can be demitochondria
which increases cytoplasmic acetyl-coen- fined as unquestionably effective. Actually C + ALC
.151.

Idiopathic oligoasthenoterqtozoospermia
proved significantly more active than placebo in two blind men. Hum Reprod 2003; 18: 447-54.
prospective controlled trials [145 146] therefore it is 9 Elzanaty S, Richthoff I, Malm I, Giwerkman A. The impact
k 1 h h d .' b ' d d of epididymal and accessory gland sex function on sperm
l .
I e ~ t at t ese ~gs are goillg to e regar e as un- motility. Hum Reprod 2002; 17: 2904-11.
questionably effective. 10 Carpino A, Sisci D, Aquila S, Salemo R, Siciliano L, Sessa M,
et al. Adnexal gland secretion markers in unexplained
8 Conclusion asthenozoospermia. Arch Androl1994; 32: 37-43.
11 Elzanaty S, MaIm I, Giwerkrnan A. Visco-elasticity of semi-
The seasonal [ 185] regional [ 186] and racial [ 187] nal fluid in relation to the epididymal and accessory sex gland
..' .' ...function and its impact on sperm motility. Int I AndroI2004;
dIfferences ill sperm count and qualtty make It dIfficult 27: 94-100.
to consider iOAT data as absolutely valid, therefore fur- 12 Rossato M, Balercia G, Lucarelli Q, Foresta C, Mantero F.
ther multicentric studies should be performed in this field. Role of seminal plasma osmolarity in the reduction of human
sperm motility. Int I Androl 2002; 25: 230-5.
Acknowledgment
13 Ariel M, Cedar H, McCarrey I. Developmental c1:1anges in
methylation of s~rmatogenesis-specific genes include repro-
'
...gramrning in the epididymis. Nat Gen 1994; 7: 59-63.
I would ltke to thank Mr Luca Glanarolt, M.D. 14 Reik W, Walter I. Genomic imprinting: parental influence on
(Societa ltaliana di Medicina della Riproduzione [SISMER] the genome. Nat Rev Genet 2001; 2: 21-32.
Scientific Director), Mrs Anna Pia Ferraretti, M.D. 15 Zhang LP, Stroud IC, WalterCA, Adrian OS, McCarrey )R. A
(SISMER Clinical Director), and Mrs Maria Cristina gene specific promoter in transgenic mice directs testis-spe-
Magli, B.D. (SISMER Laboratory Director) for their ac- cific demethylation prior to transcriptional activation in viva.
.BioI Reprod 1998: 59: 284-92.
tive encouragement of my research over the years. A 16 Nan X, Campoy FI, Bird A. MeCP2 is a transcriptional respecial
acknowledgement to Ms Tracy Hammerstrom pressor with abundant binding sites in genomic chromatin.
for her technical and editing contribution. Ce!11997; 88: 471-8.
17 Ariel M, McCarrey I, Cedar H. Methylation patterns of testis
specific genes. Proc Natl Acad Sci 1991; 88: 2317-21.
18 MlillerC, ReadheadC, Diederichs S, Idos O, Yang I, Tidow N,
References
et al. Methylation of the cyclin AI promoter correlates with
gene silencing in somatic celllines, while tissue specific ex-
Bonanomi N, Lucente G, Silvestrini B. Male fertility: core pression of cyclin Al is m~thylation independent. Mol Cell
chemical structure in pharmacological research. Contraception BioI 2000; 20: 3316-29.
2002; 65: 317-20. 19 Xie W, Han S.Y, KhanM, DeJong G. Regulation of ALF gene
2 Altman DG, Schultz KF, Moher D, Egger M, Davidoff F, expression in somatic and male germ line tissues involves par-
Elbourne D, et al. The revised consort statement for reporting tial specific and site specific patterns of methylation. I BioI
randomized trials: explanation and elaboration. Ann Intern Med Chem 2002; 277: 17765-74.
2001; 134: 663-94 20 Hafez ESE, Hafez B, Hafez SD. An Atlas of reproductive
3 Nieschlag E, Behre HM, eds. Andrology. Male reproductive physiology in men. Boca Raton (USA): Parthenon Publishing;
health and dysfunction. Berlin: Springer; 1996. p4-18
2004. p25-46.
4 World Health Organization. WHO laboratory manual for the 21 Cameron EE, Bachman KE, Myohanen I, Herman IG, Baylin
examination of human semen and semen-cervical mucus SB. Synergy of demethylation and histone deacetylase inhibiinteraction,
4th ed. Cambridge: Cambridge University Press; tion in the re-expression of genes in silenced cancer. Nat Genet
1999. pl-86. 1999; 21: 103-7.
5 Saleh RA, Agarwal A, Nelson DR, Nada EA, EI- Tonsi MH, 22 Penna Videau S, Cermeno Vivas I, Salazar N. IgA antibodies to
Alvarez IG, et al. Increased sperm nuclear DNA damage in Chlamydia trachamatis and seminal parameters in asympnormozoospermic
infertile men: a prospective study. Fertil tomatic infertile males. Arch Androl 2001; 46: 189-95.
SteriI2002; 78: 313-8. 23 Veznik Z, Pospisil L, Svecova D, Zajicova A, Unzeitig V.
6 Iensen M, Leffers H, Petersen IH, Nyboe Andersen A, Chlamydiae in the ejaculate: their influence on the quality and
Iorgensen N, Carlsen E, et al. Frequent polymorphism of the morphology of sperm. Acta Obstet Scand 2004; 83: 656-60.
mitochondrial DNA polymerase gamma gene (POLG) in pa- 24 Bollman R, Engel S, Petzoldt R, oobel UB. Chlamydia
tients with normal spermiograrns and unexplained subfertility.
trachomatis in andrologic patients. Direct and indirect detection.
Hum Reprod 2004; 19: 65-70. Infection 2001; 29: 113-8.
7 Silber SI. Evaluation and treatment of male infertility. Clin 25 Krause M, Bohring C. Male infertility and genital chlamydial
Obstet Gynecol 2000; 43: 854-88. infection: victim or perpetrator? Andrologia 2003; 35: 209-
8 EskenaziB, WyrobeckA.I,SloterE,KiddSA,MooreL, Young 16.
S, et al. The association of age and semen quality in healthy 26 Eggert-Kruse W, Rohr G, Demirakca T, Rusu R, Naher H,
.152.

Asian JAndro[ 2006; 8 (2): 143-157
...
Petzoldt D, et at. Chlamydial serology in 1303 asymptomatic T, in human testis. Asian J Androl 2004; 6: 83-91 :
subfertile couples. Hum Reprod 1997; 12: 1464-75. 41 KasaiT, OgawaK,MizunoK, Nagai S, Uccida Y, OhtaS, et at.
27 ErIes K, Rohde V, Thaele M, Roth S, Edler L, Schlehofer JR. Relationship between sperm mitochondrial membrane
DNA of adeno associated virus (AA V) in testicular tij!sue and potential, sperm motility and fertility potential. Asian J Androl
in abnormal semen samples. Hum Reprod 2001; 16: 2333-7. 2002; 4: 97-103.
28 Kapranos N, Petrakou E, Anastasiadou C, Kotronias D.De- 42 Kao SH, Chao HT, Liu HW, Liao TL, Wei YH. Sperm mitotection
of he~es simplex virus, cytomegalovirus, and Epstein- chondrial DNA depletion in men with asthenospe~a. Ferti!t
Barr virus in the semen of men attending an infertility clinic. Steri12004; 82: 66-73.
Fertil SteriI2003; 71: 1556-70.
43 Sharma RK, Said T, Agarwal A. Sperm DNA damage and its
29 El Awady MK, El Shater FF, Ragaa E, Atek K, Shaheen IM, clinical relevance in assessing reproductive outcome. Asian J
Megiud NA. Molecular study on Y chromosome microdeletions Andro12004; 6: 139-48.
in Egyptian males with idiopathic infertility. Asian J Androl 44 Paisley D, Banks S, Selfridge J, McLennan NF, Ritchie AM,
2004; 6: 53-7. McEwan C, et at. Male infertility and DNA damage in Doppel
30 Dada R, Gupta NP, Kucheria K. AZF microdeletions associ- knockout and prion protein/Doppel double-knockout mice.
ated with idiopathic and non-idiopathic case with cryptorchi- Am I Patho12004; 164: 2279-88.
dism and varicocele. Asian J Androl 2002; 4: 259-63.
45 Boekelheide K, Fleming SL, Johnson JK, Patel SR, Schoenfeld
31 Shimizu A, Ichikawa T, Suzuki N, Yamazaki T, Imamoto T, HA. Role of Sertoli cells 1n injury-associated testicular germ
Kojima S, et at. Microdeletions in the Y chromosome of pa- cell apoptosis. Proc Soc Exp BioI Med2000; 225: 105-15.
tients with idiopathic azoospermia. Asian J Androl 2002; 4: 46 Villegas I, Schultz M, Soto L, Iglesias T, Miska W, Sanchez R.
111-5. Influence of reactive oxygen species produced by activat~d leu-
32 Schlecht U, Demougin P, Koch R, Hermida L, Wiederker C, kocytes at the level of apoptosis in mature human spermatozoa.
Descombes P, et at. Expression profiling of mammalian cell Fertil SteriI2005; 83: 635-42.
meiosis and gametogenesis identifies novel candidate genes for 47 Henkel R, Kierspel E, Stalf T, Mehnert C, Menkveld R,
roles in the regulation of fertility. Mol BioI Ce112004; 15: Tinneberg HR, et at. Effect of reactive oxygen species pro-
1031-43. duced by spermatozoa and leukocytes on sperm functionsln
33 Schultz N, Harnra KF, Garbers DL. A magnitude of genes non-leukocytospermic patients. Fertil Steril 2005; 83: 635-
expressed solely in meiotic or postmeioticspermatogeneic 42.
cells offers a myriad of contraceptive targets. Proc Natl Acad 48 Said TM, Paasch U, Glander HJ, Agarwal A. Role of caspase
Sci USA 2003; 100: 12201-6. in male infertility. Hum Reprod Update 2004; 10: 39-51.
34 Makela S, EklundR, Lahdetie J, MikolaA, Hovatta 0, Kere J. 49 Erkkila K, Pentikainen V, Wikstrom M, Parvinen M, Dunkel
Mutational analysis of the human SLC26A8 gene: exclusion L. Partial oxygen press~re and mitochondrial permeability tranas
a candidate for male infertility due to primary spermatoge- sition affect germ cell apoptosis in the human testis. J Clin
nic failure. Mol Hum Reprod 2005; 11: 129-32. Endocrinol Metab 1999; 84: 4253-9.
35 Sassone-Corsi P. CREM: a master switch regulating the bal- 50 Colborn T, Clement C, eds. Chemical induced alterations is
ance between differentiation and apoptosis in male germ cells.
Mol Reprod Dev 2000; 56: 228-9.
sexual and functional development and functional development:
the wildlife/human connection. Princeton: Princeton Scientific
36 Wienbauer OF, Behr R, Bergaman M, Nieschlag E. Testicular Publishing; 1992. pl-386.
cAMP responsive element modulator (CREM) protein is ex- 51 Adamopoulos D, Pappa A, Nicopoulou S, Andreou E,
pressed in round spermatids but is absent or reduced in men Karamertzanis M, Michopoulos J, et at. Seminal volume and
with round spermatid maturation arrest. Mol Hum Reprod total sperm number trends in men attending subfertility clinics J
1998; 4: 9-15. in the greater Athens area during the period 1977-1993. Hum
37 Peri A, Krausz C, Cioppi F, Granchi S, Forti G, Francavilla S, Reprod 1996; 11: 1936-41.
et at. Cyclic adenosine 3',5'-monophosphate-responsive ele- 52 Auger J, Kunstmann IN, Czyglic F, Jouannet P. Decline in
ment modulator gene expression in germ cells of normo- and semen quality among fertile men in Paris during the past 20
oligoazoospermic men. I Clin Endocrinol Metab 1998; 83: years. N Engl J Med 1995; 332: 281-5.
3722-6. 53 Irvine S, Cawood E, Richardson D, Macdonald E, Aitken J.
38 Palermo I, Arcidiacono G, Barone N, Italia F, Arizzi M, Spera Evidence of deteriorating semen quality in the United Kingdom:
G, et at. Normal expression of isoforms activating cyclic ad- birth cohort study in 577 men in Scotland over 11 years. BMJ
enosine monophosphate responsive element modulator in pa- 1996; 312: 467-71.
tients with spermatid maturation arrest. Fertil Steri12004; 82: 54 Menchini-Fabris S, Rossi P, Palego P, Simi S, Turchi P.
1072-6. Declinining sperm counts in Italy during the past 20 years.
39 Luetjens CM, Xu EY, Rejo Pera MA, Kamischke A, Nieschlag Andrologia 1996; 28: 304.
E, Gromoll J. Association of meiotic arrest with lackofBOULE 55 Van Waeleghem K, De Clercq N, Vermeulen L, Shoonians F,
expression in infertile men. J Clin Endocrinol Metab 2004; 89: Comhaire F. Deterioration of seprm quality in young healthy
1926-33. Belgian men. Hum Reprod 1996; 11: 325-9.
40 Fang X,Zhou ZM, Lu L, Yin LL, Li JM, Zhen J, et at. Expres- 56 Younglai E, Collins JA, Foster WG. Canadian semen quality:
sionofa novel pyridoxal kinase niRNA splice variant, PKH- an analysis of sperm density among eleven academic fertility
.153.

Idiopathic oligoasthenoteratozoospermia
centers. Fertil Steri11998; 70: 76-80.
73 McLachlan RI, Wreford NO, O'Donnel L, De Krester DM,
57 Bujan L, Mansat A, Pontonnier F, Mieusset R. Time series Robertson DM. The endocrine regulation of spennatogenesis:
analysis of spenn concentration in fertile men in Toulouse independent roles for testosterone and FSH. J Endocrinol1996;
(France) between 1977 and 1992. BMJ 1996; 312: 471-2. 148: 1-9. I?'
58 Fisch H, OoluboffET, Olson JH, Feldshuh J, Broder SJ, Barad 74 OchendorfFR. Infections in the male genital tract and reactive
DH. Semen analyses in 1,283 men from the United States over oxygen species. Hum Reprod Update 1999; 5: 399-420.
a 25-year period: no decline in quality. Fertil Steri11996; 65: 75 Aitken RJ, Krausz C. Oxidative stress, DNA damage and the
1009-14. Y chromosome. Reproduction 2001; 122: 497-506.
59 Itoh N, Kayama F, Tatsuki J, Tsukamoto T. Have sperm 76 Depuydt C, Zalata A, Christophe A, Mahmoud A, Cornhaire
counts deteriorated over the past 20 years in healthy young F. Mechanisms of spenn deficiency in male accessory gland
Japanese men? Results from the Sapporo area. J AndroI2001; infection. Andrologia 1998; 30: 29-33.
22: 40-4. 77 Sharma RK, Pasqualotto AE, Nelson DR, Thomas AJ, Agarwal
60 Paulsen CA, Bennan NO, Wang C. Data from men in greater A. Relationship between seminal white blood cell count and
Seattle area reveals no downward trend in semen quality: fur- oxidative stress in men treated at an infertility clinic. J Androl
ther evidence that detrioration of semen quality is not geo-. 2001; 22: 575-83.
graphically unifonn. Fertil Steri11996; 65: i015-20.
78 Kaleli S, Ocer F, Ir~z T, Budak K, Aksu MF. Does leukocyto-
61 Rasmussen PE, Erb K, Westergaard LO, Laursen SB. No spennia associate with poor sperm parameters and spenn
evidence for decreasing semen quality in four birth cohorts of functions in male infertility? The role of different seminal
1,055 Danish men born between 1950 and 1970. Fertil Steril leukocyte concentrations. Eur J Oynecol Reprod Bio12000;
1997; 68: 1059-64. 89: 185-91.
62 Vierula M, Niemi M, Keiski A, Saarinen M, Saarikoski S, 79 Yanushpolsky EH, Politch JA, Hill JA, Anderson DJ. Is
Suominen J. High and unchanged spenn counts of Finnish leukocytospennia clinically relevant? .Fertil Steril1996; 66:
men. IntJAndrol1996; 19: 11-7. 822-5.
63 Nilsson R. Endocrine modulators in the food chain and 80 Sanocka D, Kurpisz M. Reactive oxygen species and spenn
environment. Toxicol PathoI2000; 28: 420-31. cells. Reprod Biol EndocrinoI2004; 2: 12-9.
64 Cornhaire FH, Mahmoud A. The role of food supplements in 81 Hughes CM, Lewis SE, McKelvey-Martin VJ, Thompson W.
the treatment of the infertile man. Reprod Biomed Online A comparison and baseline induced DNA damage in human
2003; 7: 385-91. spennatozoa from fertile and infertile men, using a modified
65 Duty SM, Calafat AM, Silva MJ, Ryan L, Hauser R. Phtha- comet assay. Mol Hum Reprod 1996; 2: 613-9.
late exposure and reproductive honnones in adult men. Hum 82 Cheng KH, Cahil1 DS, Kasai H, Nishimura S, Loeb LA. 8-
Reprod 2005; 20: 604-10.
Hydroxyguanine, an abundant fonn of oxidative damage, causes
66 Odabas 0, Atilla MK, Yilmaz Y, Sekeroglu MR, Sengul E, O- T and A-C substitutions. J Bioi Chem 1992; 267: 166-72.
Aydin S. Luteinizing honnone pulse frequency and amplitude 83 Fraga CO, Motchnik PA, Shigenaga K, Helbock H, Jacob RA,
in azoospennic, oligozoospennic and nonnal fertile men in Ames BN. Ascorbic acid protects against endogenous oxida-
Turkey. Asian J AndroI2002; 4: 156-8.
tive DNA damage in human spenn. Proc Natl Acad Sci USA
67 Ramanujan LN, Liao WX, Roy AC, Ng SC. Association of 1991; 88: 11003-6.
molecular variant of luteinizing honnone with male infertility. 84 Oil-Ouzman E, Ollero M, Lopez MC, Sharrna RK, Alvarez
Hum Reprod 2000; 15: 925-8.
JO, Thomas AJ Jr, et al. Differential production of reactive
68 Andersson AM, Jorgensen N, Frydelund-Larsen L, Rajpert- oxygen species by subsets of human spennatozoa at different
De Meyts E, Skakkebaek NE. Impaired Leydig cell function in stages of maturation. Hum Reprod 2001; 16: 1922-30.
infertile men: a study of 357 idiopathic infertile men and 318 85 Kumagai A, Kodama I, Kumagai J, Fukuda J, Kawamura K,
proven controls. J Clin Endocrinol Metab 2004; 89: 3158-60. Tanikawa H, et al. Xantine oxidase inhibitors suppress tes-
69 Andersson AM, Petersen JH, Jorgensen M, Jensen TK, ticular germ cell apoptosis induced by experimental
Skakkebaek NE. Serum inhibin B and follicle-stimulating hor- cryptorchidism. Mol Hum Reprod 2002; 8: 118-23.
mone levels as tools in the evaluation of infertile men: signifi- 86 Buttke TM, Sandstrom PA. Oxidative stress as a mediator of
cance of adequate reference values from proven fertile men. J apoptosis. Immunol Today 1994; 15: 7-10.
Endocrinol Clin Metab 2004; 89: 2873-9.
87 Comhaire FH, Mahmoud AM, Depuydt CE, Zalata AA,
70 van Oolde RJ, van der Avoort lA, Tuerlings JH, Kiemeney Christophe AB. Mechanisms and effects of male genital tract
LA, Meuleman EJ, Braat DD, et al. Phenotypic characteris- infection on sperm quality and fertilizing potential: the
tics of male subfertility and its familial occurrence. J Androl andrologist's viewpoint. Hum Reprod Update 1999; 5: 393-
2004; 25: 819-23. 8.
71 Lilford R, Jones AM, Bishop DT, Thornton J, Mueller R. 88 Sharma RK, Pasqualotto F, Nelson DR, Thomas AJ, Agarwal
Case-control study of whether subfertility in men is familial. A. The reactive oxygen species-total antioxidant capacity score
BMJ 1994; 309: 570-3.
is a new measure of oxidative stress to predict male infertility.
72 Agarwal A, Saleh RA, Bedaiwy MA. Role of reactive oxygen Hum Reprod 1999; 14: 2801-7.
species in the pathophysiology of human reproduction. Fertil 89 Said TM, Agarwal A, Sharma RK, Thomas AJ, Sikka SC.
SteriI2003; 79: 829-43.
Impact of spenn morphology on DNA damage caused by
.154.

Asian JAndro12006; 8 (2): 143-L57
oxidative stress induced by beta-nicotinamide adenine dinucle spern1atozoa. J BioI Regul Homeost Agents 2004; 18: 115-9.
otide phosphate. Fertil SteriI2005; 83: 95-103.
106 Lachaud C, Tesarik J, Canadas M, Mendoza C. Apoptosis
90 Zini A, Fischer MA, Sharir S, Shayegan B, Phang B, Jarvi K. and necrosis in human ejaculated spern1atozoa. Hum Reprod
Prevalence of abnorn1al spern1DNA denaturation in fertile and 2004; 19:.607-10. 1:
infertile men. Urology 2002; 60: 1069-72.
107 Barroso G, Morshedi M, Oehninger S. Analysis of DNA
91 Fischer MA, Willis J, Zini A. Human spern1 DNA integrity: fragmentation, plasma membrane translocation of
correlation with spern1 cytoplasmic droplets. Urology 2003; phosphatidylserine and oxidative stress in human spern1atozoa.
61: 207-11. .Hum Reprod 2000; 15: 1338~4.
92 Agarwal A, Prabakaran SA, Said TM. Prevention of oxidative 108 Shen HM, Dai J! Chia SE, Ong CN. Detection of apoptoic
stress injury to spern1. J Androl. 2005; 26:654-60.
alterations in sperm in subfertile patients and their correla-
93 de Lamirande E, Gagnon C. Reactive oxygen species and hu- tions with sperm quality. Hum Reprod 2002; 17: 1266-73.
man spern1atozoa. I. Effects on the motility of intact spern1a- 109 Sinha Hikim AP, Swerdloff RS. Horn1onal and genetic control
tozoa and on sperm axonemes. J Andro11992; 13: 368-78. of gern1 cells apoptosis in the testis. Rev Reprod 1999; 4: 38-
94 de Larnirande E, Gagnon C. Reactive oxygen species and hu- 47.
man spermatozoa. II. Depletion of adenosine triphosphate 110 Said TM, Paasch U, Glander HJ, Agarwal A. Role of capases
plays an important role in the inhibition of spern1 motility. J in male infertility. Hum Re;prod Update 2004; 10: 39-51.
Andro11992; 13: 379-86.
111 Shang XJ, Huang YF, Xiong CL, Xu JP, Yin L, Wang CC.
95 Kwon J, Mochida K, Wang YL, Sekiguchi S, Sankai T, Aoki S, Uraplasma urealyticum infection and apoptosis of spern1atoet
al. Ubiquitin C-terminal hydrolase L-l is essential for the genetic cells. Asian J Andro11999; 1: 121-9.
early apoptotic wave of germinal cells and for sperm quality 112 Rowe PJ, Comhaire FH, Hargreave TB, Mahmoud AMA.
control during spern1atogenesis. BioI Reprod 2005; 73: 29-35. WHO manual for the standardized investigation, diagnosis
96 Tesarik J, Greco E, Cohen-Bacrie P, Mendoza C. Gern1 cell and management of the infertile male. Cambridge: Cambridge
apoptosis in men with complete and incomplete spern1atoge- University Press, 2000.
nesis failure. Mol Hum Reprod 1998; 8: 757-62.
113 Diemer T, Desjardins C. Developmental and genetic disorders
97 Yan W, Huang JX, Lax AS, Pelliniemi L, Salminen E, Poutanen in spern1atogenesis. Hum Reprod Update 1999; 5: 120-40.
M, et al. Overexpression of Bcl-w in the testis disrupts 114 Huynh T, Mollard R, Trouson A. Selected genetic factors
spern1atogenesis: revelation of a role of BCL- Win male germ associated with male infertility. Hum Reprod Update 2002; 8:
cells cycle control. Mol Endocrinol2003; 17: 1868'-79. 183-92
98 Erkkila K, Aito H, Aalto K, Pentikainen V, Dunkel L. Lactate 115 Forti G, Krausz C. Clinical review lOO: Evaluation and treatinhibits
germ cell apoptosis in the human testis. Mol Hum ment of the infertile couple. J ,Clin Endocrinol Metab 1998;
Reprod 2002; 8: 109-17. 83: 4177-88. ,
99 Suomalainen L, Hakala JK, Pentikainen V, Otala M, Erkkila 116 Layman LC. Genetic causes of human infertility. Endocrinol
K, Pentikainen MO, et al. Sphingosine-l-phosphate in inhibi- Metab Clin North Am 2003; 32: 549-72.
tion of male gern1 cell apoptosis in the human testis. J Clin 117 Weidner W, Krause W, Ludwig M. Relevance of male acces-
Endocrinol Metab 2003; 88: 5572-9.
sory gland infection for subsequent fertility with special focus
100 Koji T, Hishikawa Y, Ando H, Nakanishi Y, Kobayashi N. on prostatitis. Hum Reprod Update 1999; 5: 421-32.
Expression of FAS and FAS ligand in normal and ischemia 118 Jarow JP. Endocrine causes of male infertility .Urol Clin North
reperfusion testes: involvement of the Fas system in the in- Am 2003; 30: 83-90,
duction of the germ cell apoptosis. Biol Reprod 2001; 64: 119 Islam N, Trainer PJ. The ho~onal assessment of the infertile
946-54. male. BJU Int 1999; 82: 69-75: Tanriverdi F, Silveira LGF,
101 Grunenwald S, Paasch U, Said TM, Sharma RK, Glader HJ, MacColl GS, Bouloux PMG. The hypothalamic-pituitary-
Agarwal A. Caspase activation in human spematozoa in re- gonadal axis: immune function and autoirnmunity. J Endocrinol
sponse to physiological and pathological stimuli. Fertil Steril 2003; 176: 293~304.
2005; 83: 1106-12. 120 Hafez ESE, Hafez B, Hafez SD. An atlas of reproductive
102 Hikim AP, Wang C, Lue Y, Johnson L, Wang XH, Swerdloff physiology in men. Boca Raton: Parthenon Publishing, 2004,
RS. Spontaneous germ cell apoptosis in humans: evidence for p97 -111.
ethnic differences in the susceptibility of germ cells to pro- 121 Biagiotti G, Cavallini G, Modenini F, Vitali G, Gianaroli L.
grammed cell death. J Clin Endocrinol Metab 1998; 83: 152-6. Spermatogenesis and spectral echo-colour Doppler traces from
103 Francavilla S, D' Abrizio P, Cordeschi G, Pelliccione F, the main testicular artery. BJU Int 2002; 90: 903-8.
Necozione S, Ulisse S, et al. Fas expression correlates with 122 Foresta C, Garolla A, Bettella A, Ferlin A, Rossato A, Candiani
human germ cell degeneration in meiotic and post-meiotic ar- F. Doppler ultrasound of the testis in azoospermic subjects as
rest of spern1atogenesis. Mol Hum Reprod 2002; 8: 213-20. a parameter of testicular function.. Hum Reprod 1998; 13:
104 Oheninger S, Morshedi M, Weng SL, Taylor S, Duran H, Beebe 3090-3.
S. Frequence and significance of somatic cell apoptosis in hu- 123 Battagl.ia C, Giulini S, Regnani G. Seminal plasma nitrite/niman
ejaculated spermatozoa. Reprod Biomed Online 2003; 7: trate and intratesticular Doppler flow in fertile and infertile
469-79. subjects. Hum Reprod 2000; 15: 2554-8.
105 Oosterhuis GJ, Vermes I. Apoptosis in human ejaculated 124 Battaglia C, Giulini S, Regnani G, Magdar I, Facchinetti F,
.155.

Id io pathi colig oas the noter.gtozoos pe rmia
Volpe A. Intratesticulal. Dopplerflow, seminal plasma nitrites/ 142 Ford WC, Williams KM,McLaughin EA, Harrison S, Ray B,
nitrates and nonobstructivesper~ extraction from patients Hull MG. The indirect immunobead test for seminal antisperm
with obstructive and nonobstructive azoospermia. Fertil Steril antibodies and fertilization rates at in vitro fertilization. Hum
2001;75: 1088-94" Reprod 1996; 11: 1418-22.
125 Atilla MK, Sargin H, Yilmaz Y, Odabas 0, Keskin A, Aydin S. 143 Patrizio P, Silber SI, Ord T, Moretti Rojas I, Asch RH. Rela-
Undescended testes in adults: clinical significance of resistive tionship of epididymal sperm antibodies to their in vitro ferindex.
values of the testicular artery measured by Doppler tilization capacity in men with congenital absence of the vas
ultrasound as a predictor of testicular histology. I Uro11997; deferens. FertilSteril1992; 58: 1006-10.
158: 841-3. )44 Lenzi A, Lombardo F, Sgrb P, Salacone P, Caponnecchia L,
126 Hsu TH, Huang IK, Ho DM, Liu RS, Chen MT; Chang LS. Dondero F. Use of carnitine therapy in selected cases of male
Role of the spermatic artery in spermatogenesis and sex hor- factor infertility: a double blind cross over trial. Fertil Steril
mone synthesis. Arch Andro11993; 31: 191-7. 2003; 79: 292-300.
127 Iezek D, Schulze W, Rogatsch H, Hittmair A. Structure of 145 Lenzi A, Sgrb P, Salacone P, Paoli D, Gilio B, Lombardo F,
small blood vessels in the testes of infertile men. Int I Androl et al. A placebo-controlled double-blind randomized trial of
1996; 19: 299-306. the use of combined l-carnitine and l-acetyl-carnitine treat-
128 Meachem SI, Nieschlag E, Simoni M. Inhibin B in male ment in men wi~ asthenozoospermia. Fertil SteriI2004; 81:
reproduction: pathophysiology and clinical relevance. Eur I 1578-84.
EndocrinoI2001; 145; 561-71. 146 Cavallini G, Ferraretti AP, Gianaroli L, Biagiotti G, Vitali G.
129 Bohring C, Krause W. Serum levels of inhibin B in men with Cinnoxicam and L-carnitine/acetyl-L-carnitine treatment for
different causes of spermatogenic failure. Andrologia 1999; idiopathic and varicocele-associated oligoasthenospermia. I
31: 137-41. AndroI2004; 25: 761-70.
130 Comhaire FH, ed. Male Infertility: Clinical investigation, cause 147 Weidner W, Frause W, Ludwig M. Relevance of male of accesevaluation
and treatment, 2nd ed. London: Chapman & Hall sory gland infection for subsequent fertility with special focus
Medical, 1997, pp.123-31. on prostatitis. Hum Reprod Update 1999; 5: 421-32.
131 Chiu WW, Chamley LW. Use of antisperm antibodies in dif- 148 Keck C, Gerber-Schafer C, Clad A, Wilhelm C, Breckwoldt
ferential display Western blotting to identify sperm proteins M. Seminal tract infections: impact on male fertility and treatimportant
in fertility. Hum Reprod 2002; 17: 984-9. ment options. Hum Reprod Update 1998; 4: 891-903.
132 Bohring C, Krause W. Immune infertility: towards a better 149 Vicari E. Effectiveness and limits of antimicrobial treatment on
understanding of sperm (auto)-immunity. The value of seminal leukocyte concentration and related reactive oxygen
proteomic analysis. Hum Reprod 2003; 18: 915-24.
species production in patients with male accessory gland
133 Clayton R, Moore H. Experimental models to investigate the infection. Hum Reprod 2000; 15: 2536-44.
pathology of antisperm antibodies: approach and problems. 150 Zorn B, Virant-Klun I, Meden-Vrtovec H. Semen granulocyte
Hum Reprod Update 2001; 7: 457-9.
elastase: its relevance for the diagnosis and prognosis of silent
134 KoideSS, Wang L, Kamada M. Antisperm antibodies associ- genital tract inflammation. Hum Reprod 2000; 15: 1978-84.
ated with infertility: properties and encoding genes of target 151 Eggelt-Kruse W, Boit R, Rohr G, Aufenanger J, Hund M,
antigens. Proc Soc Exp BioI Med 2000; 224: 123-32.
Strowitzki T. Relationship of seminal plasma interleukin (IL)-
135 lager S, Kremer I, KuikenJ, Mulder I. The significance of the 8 and IL-6 with semen quality. Hum Reprod 2001; 16: 517-8.
Fc part of antispermatozoal antibodies for the shaking phe- 152 Foresta C, Bettella A, Merico M, Garolla A, Ferlin A, Rossato
nomenon in the sperm-cervical mucus contact test. Fertil Steril M. Use of recombinant human follicle-stimulating hormone in
1981; 36: 792-7. the treatment of male infertility. Fertil SteriI2002; 77: 238-
136 Zouari R, De Almeida M. Effect of sperm associated antibod- 44.
ies on human sperm ability to bind to zona pellucida and to 153 Baccetti P, Piomboni P, Bruni E, Capitani S, Gambera L,
penetrate zona-free hamster oocytes. J Reprod ImmunoI1993; Moretti E, etal. Effect offollicle-stimulatinghormone on sperm
24: 175-86. quality and pregnancy rate. Asian J AndroI2004; 6: 133-7,
137 Clarke GN. Induction of the shaking phenomenon by IgA 154 Kamische A, Behre HM, Bergman M, Simoni M, Schafer T,
class antispermatozoal antibodies from serum. Am J Reprod Nieschlag E. Recombinant human follicle stimulating hormone
Immuno11985; 9: 12-4. for treatment of male idiopathic infertility: a randomized,
138 Liu DY, Clarke GN, Baker HW. Inhibition of human sperm- double-blind, placebo-controlled, clinical trial. Hum Reprod
zona pellucida and sperm-oolemma binding by antisperm 1998; 13: 596-603.
antibodies. Fertil Steril1991 ; 55: 440-2.
155 Sallam H, EI-Garem Y, Agameya AF. FSH therapy for
139 Naz RK. Effects of antisperm antibodies on early cleavage of oligoasthenospermia- a meta-analysis of randomized trial.
fertilized ova. BioI Reprod 1992; 46: 130-9.
Hum Reprod 2004; 19 (Suppll) i23. Proecedings of the 20th
140 Munuce MJ, Berta CL, Pauluzzi F, Caille AM. Relationship Annual Meeting ofthedEuropean Society of Human Reprobetween
antisperm antibodies, sperm movement, and semen duction and Embriology. Berlin, Germany, 27th-30th June
quality. Urol Int 2000; 65: 200-3. 2004.
141 Blasco L. Clinical tests of sperm fertilization ability. Fertil 156 Jansen RP. Relative infertility: modeling clinical paradoxes.
'
Steri11984; 41: 177-92. Fertil Steri11993; 59: 1041-5.
.156.

Asian JAndrol 2006; 8 (2): 143-157
..
157 Adamopou1os DA, Pappa A, Billa E, Nicopou1ou S, Koukkou 173 Hibi H, Kato K, Mitsui K, Taki T, Yamada Y, Ronda N, et al.
E, Michopoulos J. Effectiveness ofcombined tamoxifen cit- Treatment of oligoasthenozoospermia with tranilast, a mast
rate and testosterone UIldecanoate treatment in men with idio- cell blocker, after long-term administration. Arch Andro12002;
pathicQligozoospetmia. Fertil Steri12003; 80: 914-20. 48: 451-9. ;1
158 Coltlhaire F. Clinical andrology: from evidence-ba$e to ethics. 174 Cayan S, Apa PD, Akbay E. Effect offexofenadine, a mast cell
The E-quintet in clinical andrology. Hum Reprod 2000; 15: blocker, in infertile men with significantly increased testicular
2067-71, mast cells. Asian J Andro12002; 4: 291-4.
159 Vandekerckove P, Lilford R) Vail A, Hughes E.. Clomiphene or 175 Vicari E, Calogero AE. Effects of treatment with carnitines in
tarnoxifen for idiopathic oligo/asthenospermia. Cochrane Da- infertile patients with prostato-vesiculo-epididymitis. Hum
tabase Syst Rev 2000; (2): CDOO0151. Reprod 2001; 16:2338-42.
160 Adamopoulos DA. Medical treatment of idiopathic oligozo- 176 Cavallini G, Biagiotti G, Ferraretti AP, Gianaroli L, Vitali G.
ospermia and male factor subfertility. Asian J Andro12000; 2: Medical therapy of oligoasthenospermia associated to left
25-32. varicocele: an option. Bm Int 2003; 91: 513-8.
161 Adamopoulos DA, Nicopoulou S, Kapolla N, Karamertzanis 177 Comhaire FR, Mahmoud AM. [Editorial commentary on:
M, Andreou E. The combination of testosterone undecanoate Cav!illini G, Ferraretti AP, Gianaroli L, Biagiotti G, Vitali G.
'with tamoxifen citrate enhances the effects of each agent given Cinnoxicam and L-carnitine/acetyl-L-carnitine treatment for
independently on seminal parameters in men with idiopathic idiopathic and varicocel~-associated oligoasthenospermia. J
oligozoospermia. Fertil Steril1997; 67: 756-62. Andro12004; 25: 761-70]. JAndro12004;25: 771-2.
162 Vermeulen A, Coltlhaire F. Hormonal effects of anantiestrogen, 178 Loescher W, Littengau H, Schlegel W. Pharmacokinetics of
tarnoxifen, in normal and oligospermic men. Fertil Steril. 1978; non steroidal anti-inflammatory drugs in male rabbits after
29: 320-7. acute and chronic administration and effect of chronic treat-
163 Willis KJ, London DR, Bevis MA, Butt WR, Lynch SS, Holder ment on seminal plasma. J Reprod Fertil1988;82: 353-64.
G. Hormonal effects of tamoxifen in oligospermic men. J 179 Cipol1a MJ, Nnicoloff A, Rebello T, Amato A, Porter JM.
Endocrinoll977; 73: 171-8. Propionyl-L-carnitine dilates human subcutaneous arteries
164 Vermeulen A, Coltlhaire F. Hormonal effects of an antiestrogen, through an endothelium-dependent mechanism. J Vasc Surg
tamoxifen, in normal and oligospermic men. Fertil Steril1978; 1999; 29: 1097-103.
29: 320-7, 180 Fuse H, MinagawaR, Ito H, Shimazaki J. The effects of
165 Smals AG, Pieters GF, Drayer JI, Boers GR, Benraad TJ, prostaglandin synthetase inhibitor on male infertility.
Kloppenborg PW. Tamoxifen suppresses gonadotropin-in- Hinyokika Kiyo 1984; 30: 1439-45.
duced 17 alpha-hydroxyprogesterone accumulation in normal 181 Bendvold E, Gottlieb C, Svanborg K, Bygdeman M, Eneroth
men. J Clin Endocrinol Metab 1980; 52: 1026-9.
P. Concentration of prostaglandins in seminal fluid of fertile
166 Wong WY, Merkus HM, Thomas CM, Menkveld R, Zielhuis men. Int J Androl1987; 10: 463-9.
GA, Steegers- Theunissen RP. Effects of folic acid and zinc 182 Comhaire FR, Christophe AB, Zalata AA, Dhooge WS,
sulfate on male factor subfertility: a double-blind, randomized, Mahmoud AM, Depuydt CE. The effects of combined conplacebo-controlled
trial. Fertil Steri12002; 77: 491-8.
ventional treatment, oral antioxidants and essential fatty acids
167 Gulmez I, Tatlisen A, Karacagil M, Kesekci S.. Seminal pa- on sperm biology in subfertile men. Prostaglandins Leukot
rameters of ejaculates collected successively with sixty minute Essent Fatty Acids 2000; 6: 159-65.
interval in infertile men: effect of combination of prazosin and 183 Kesker-Ammar L, Feki Chacroun N, Rebai T, Sahnoun Z,
terbutaline on these parameters. Andrologia 1991; 23: 167-9. Ghozzi H, Hammami S, et al. Sperm oxidative stress and the
168 Yamamoto M, Hibi H, Miyake K. Comparison of the effec- effect of an oral vitamin E and selenium supplement on semen
tiveness of placebo and alpha-blocker therapy for the treat- quality in infertile men. Arch Andro12003; 49: 83-94.
ment of idiopathic oligozoospermia. Fertil Steril 1995; 63: 184 Rolf C, Cooper TG, Yeung CH, Nieschlag E. Antioxidant treat-
396-400. ment of patients with asthenozoospermia or moderate
169 Gregoriou 0, VitoratosN, Papadias C, Gargaropoulos A, oligoasthenozoospermia with high-dose vitamin C and vita-
Konidaris S, Giannopoulos V, et al. Treatment of idiopathic min E: a randomized, placebo-controlled, double-blind study.
oligozoospermia with an alpha-blocker: a placebo-controlled Hum Reprod 1999; 14: 1028-33.
double-blind trial. Int J Fertil Womens Med 1997; 42: 185 Gyllenborg J, Skakkebaek K,Nielsen NC. Secular and sea-
301-5. sonal changes in semen quality among young Danish men: a
170 Apa DD, Cayan S, Polat A, Akaby E. Mast cells and fibrosis statistical analysis of semen samples fI:om 19ndonor candion
testicular biopsies in male infertility. Arch Androl 2002; dates during 1977-1995. Int J Androl1999; 22: 28-36.
48: 337-44. 186 Jorgensen N, Andersen AG, Eustache F, Irvine DS, Suominen
171 YamamotoM, Hibi H, Miyake K. New treatment of idiopathic
severe oligozoospermia with mast cell blocker: results
J, Petersen JR, etal. Regional differences in semen quality in
Europe. Hum Reprod2001; 16: 1012-9. .
of a single-blind study. Fertil Steril1995: 64: 1221-3.
187 von Eckardstein S, Syska A, Gromoll J, Kamischke A, Simoni
172 Hibi H, KatQ K, Mitsui K, TakiT, Yamada Y, Ronda N, et al. M, NieschlagE. Inverse correlation between sperm concentra-
The treatment with tranilast, a mast cell blocker, for idiopathic tionand number ofandrogen receptor CAG repeats innormal
oligozoospermia. Arch Andro12001; 47: 107-11. men. J Endocrinol Clin Metab 2001; 86: 2585-90.
.157.