Review Article
Conservative Nonhormonal Options for the
Treatment of Male Infertility: Antibiotics, Anti-Inflammatory
Drugs, and Antioxidants
Aldo E. Calogero,
1
Rosita A. Condorelli,
1
Giorgio Ivan Russo,
2
and Sandro La Vignera
1
1
Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
2
Department of Surgery , U r ology Section, U n iversity of Catania, Catania, Italy
Correspondence should be addressed to Sandro La Vignera; sandrolavignera@unict.it
Received 2 November 2016; Revised 4 December 2016; Accepted 5 December 2016; Published 9 January 2017
Ac
ademic Editor: Yujiang Fang
Copyright © Aldo E. Calogero et al. is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribut ion, and reproduction in any medium, provided the original work is properly
cited.
e nonhormonal medical treatment can be divided into empirical, when the cause has not been identied, and nonempirical, if
the pathogenic mechanism causing male infertility can be solved or ameliorated. e empirical nonhormonal medical treatment
has been proposed for patients with idiopathic or noncurable oligoasthenoteratozoospermia and for normozoospermic infertile
patients. Anti-inammatory, brinolytic, and antioxidant compounds, oligo elements, and vitamin supplementation may be
prescribed. Infection, inammation, and/or increased oxidative stress oen require a specic treatment with antibiotics, anti-
inammatory drugs, and/or antioxidants. Combined therapies can contr ibute to improve sperm quality.
1. Introduction
e nonhormonal medical treatment has a relevant role in
male infertility since it may solve the cause of infertility,
whereas in some other times it may ameliorate sperm param-
eters by improving the environment where spermatozoa are
produced and mature. e nonhormonal treatment may be
classied into empirical and nonempirical.
2. Empirical Treatment
e empirical nonhormonal medical treatment has been
prescribed to patients with idiopathic oligoasthenoterato-
zoospermia (OAT), pat ients with OAT due to a noncurable
disease, and normozoospermic infertile patients without
identiable risk factors for infertility. Sometimes, a slight
improvement of the sperm leads to the achievement of
pregnancy.
e scientic evidence of the eectiveness of such a treat-
ment has been scanty. Anti-inammatory, brinolytic, and
antioxidant compounds and vitamin supplementation are
used. Antioxidant treatment for subfertile couples has been
also prescribed to the male partner of couples undergoing
assisted reproduction techniques (ART). Further studies are
required to clarify the role of these drugs [].
3. Nonempirical Treatment
A nonempirical treatment has been prescribed when the
cause of infertility has been identied and it has been curable.
Such a treatment has been based on drugs t hat can specically
eradicate the etiopathogenic noxa. Aside from endocrine
causes, three oen coexisting conditions interfering with the
reproductive function may require nonempirical treatment:
infections, inammation, and/or increased oxidative stress.
A nonempirical treatment for infertility due to urogen-
ital tract infections has been based on the use of specic
antibiotics, following identication of the microorganisms
by appropriate microbiological investigation and the relative
antibiogram. We can distinguish the presence of microorgan-
isms, therefore, as microbial or inammatory forms.
Microb ial forms show the growth of more than
3
pathogenic bacteria or more than
4
nonpathogenic bac-
teria per ml, in culture of diluted seminal plasma. Some
Hindawi
BioMed Research International
Volume 2017, Article ID 4650182, 17 pages
https://doi.org/10.1155/2017/4650182
BioMed Research In ternational
Gram-negative bacteria (Enterobacteriaceae such as Escher-
ichia coli, Klebsiella species, Proteus, Serratia,andPseu-
domonas species) and etiological agents of sexually trans-
mitted diseases (Chlamydia trachomatis, Ureaplasma ure-
alyticum, Treponema pallidum, Neisseria gonorrhoeae,etc.)
are recognized as “certain pathogens” of the prostate (cate-
gory II according to the National Institutes of Health clas-
sication). On the other hand, some microorganisms of the
prostate, which are occasionally detectable i n the urogenital
tract, are considered by some authors to be “nonpathogenic,”
“likely pathogens,” “occasional pathogens” (Gram-positive
germs, such as En terococcus spp., Staphylococcus aureus,
and obligate anaerobes), or “possible pathogens” (coagulase-
negative germs, such as Staphylococcus haemolyticus, Staphy-
lococcus epidermidis, and mycoplasmas) [].
Recently, an elevated frequency of HPV infection in
patients with infertility [], as a viral for m, cannot rely on
antibiotic treatment. e most frequently used families of
antimicrobial drugs for the treatment of the microbial forms
are uoroquinolones, macrolides, and tetracyclines [, ].
e inammatory forms are characterized by leukocy-
tospermia (seminal uid leukocyte concentration >
6
/mL)
and/or overproduction of reactive oxygen species (ROS).
An increased number of leukocytes in the seminal uid
may persist even aer antibiotic treatment for a microbial
form in some patients with complicated infection of the
male accessory glands, such as prostatovesiculoepididymitis
(PVE). In addition to leukocytospermia [], these patients
have oen abnormal conventional sperm parameters (con-
centration, motility, and morphology) [] and other signs of
inammation. Seminal leukocytes are predominantly poly-
morphonuclear leukocytes (neutrophils), but histochemistry,
the technique used for their identication (based on the
presence of peroxidase in granulocytes), does not detect
other types of leukocytes. Other markers of inammation are
represented by some cytokines (IL-, IL-, IL-, IL-, IL-,
𝛼TNF, and 𝛾INF) []. In these patients an anti-inammatory
treatment may be done using nonsteroidal anti-inammatory
drugs (NSAIDs) [] that can be administered simultaneously
before or aer the antibiotic therapy [] or nutraceutical
com pounds with anti-inammatory and brinolytic proper-
ties.
eoxidativestressisanotherimportantmechanism
that damages spermatozoa. I t arises from an elevated pro-
duction of ROS, byproducts of aerobic life, which exceeds
the natural scavenger ability of spermatozoa and of the
seminal uid. In fertile men, ROS production and the
total antioxidant capacity remain in balance []. However,
infections, autoimmune disorders, chronic disease, advanced
age, alcohol consumption, cigarette smoking, stress, and
obesity alter this balance and increase the oxidative stress
[]. In small amount, ROS play a physiological, useful role
in sperm function. Spermatozoa produce a small amount
of ROS in their earliest stages of development []. In this
phase, ROS are in volved both in the process of sperm
chromatin condensation and in the induction of apoptosis or
proliferation of spermatogonia, in order to regulate the nal
number of germ cells []. Instead, in mature spermatozoa,
ROS are necessary to boost the capacitation process and the
acrosome reaction and they are involved in mitochondrial
sheath stability and sperm motility. I t has been found that
spermatozoa with abnormal morphology, mainly those with
cytoplasmic residues which indicate their immaturity and
reducedfertilepotential,producehigheramountofROSthan
normally shaped spermatozoa [, ].
e seminal plasma contains natural antioxidant, such as
vitamins C and E, superoxide dismutase (SOD), glutathione,
uric acid, and the polyamine spermine that acts as a free
radical scavenger []. However, the high concentration of
unsaturated lipids in the plasma membrane and the relative
paucit y of oxyradical scavenger enzyme (due to the virtual
absence of cytoplasma) make mature spermatozoa particu-
larly susceptible to oxidat ive stress. Superoxide anion radical
(O
2
−
)isthemainROSproducedbyspermatozoa,whichgen-
erates hydrogen peroxide spontaneously or following SOD
activity. e pathways that contribute to ROS production are
the NADPH oxidase system at level of cell plasma membrane
and the NADH oxidoreductase at themitochondria level [].
Infections and/or inammation of the urogenital tract
may increase the number of seminal uid leukocytes, and
their activation results in a ROS overproduction. In fac t,
leukocytes, under physiological conditions, produce up to
times more ROS than spermatozoa. is production
plays an important role in the cellular defense mechanism
against infections and inammation but at the same time may
damage spermatozoa. An increased number of leukocytes in
theseminalplasmacanalsobepresentinvaricocele,long
sexual abstinence, or exposure to environmental factors [–
].
e polyunsaturated fatty acids of sperm plasma mem-
brane are a target of ROS action leading to lipid peroxida-
tion, measurable as malondialdehyde (MDA) in the seminal
plasma, and loss of sperm motility []. ROS can also
alter biof unctional sperm parameters, resulting in a greater
number of spermatozoa with fragmented DNA that seems
to be inversely correlated with sperm count, morphology,
motility, and fertilization rate [, ]. ROS overproduction
causes also a greater frequency of single- and double-strand
DN A breaks and increased DN A protein cross-linking [].
Furthermor e, ROS hav e the ability to damage mitochondrial
DN A [].
ese ndings support the administration of molecules
with antioxidant activity in patients with oxidative stress-
induced sp erm damage. Antioxidants are widely available
and relatively inexpensive when compared to other molecules
used for fertility treatment. In addition, there is no evidence
of adverse events and they seem to be eective in improving
sperm parameters and in increasing a couple’s chance of
having a live birth [].
4. Antibiotic Treatment
e choice of the antibiotic should be based on the nature of
the microorganism identied and the results of the relative
antibiogram, since a targeted therapy is recommended. Sev-
eral classes of antibiotics may be used [, ]. We would also
point out that most of these microorganisms may be sexually
BioMed Research In ternational
transmitted and it is necessary to stop sexual contacts for the
time of treatment and also treat female partner to eradicate
the infection when necessary.
4.1. Quinolones. Quinolones (ciprooxacin, levooxacin,
ooxacin, noroxacin, peoxacin, enoxacin, eroxacin,
lomeoxacin, and other new ones) have a favorable phar-
macokinetic prole, with excellent oral bioavailability (great-
er than %) for most. However, dierences in pea k serum
concentrations and 𝛽-half-lives of elimination exist. As sug-
gested by high apparent volumes of distribution and low
binding to serum proteins, penetration into many body
tissues and uids is advantageous.
Oral bioavailability of quinolones has been shown to be in
general good in sick as well as healthy subjects but is reduced
by coadministration with magnesium- and aluminum-
cont aining acids, sucralfate (which contains aluminum), or
ferrous sulfate []. Quinolones have an excellent ability to
penetrate into the prostate and good activity against typical
and atypical pathogens. ey are associated with phototoxic-
ity, CNS adverse events (variable among the dierent agents),
and tendonitis.
Quinolones are considered a rst-line therapy. Among
the dierent quinolones, the most used in clinical practice
are ciprooxacin and levooxacin. Ciprooxacin is absorbed
primarily on the duodenum and jejunum. Studies also sug-
gest this drug is cleared by transepithelial elimination into
the bowel lumen as well as by the renal route. Levooxacin
seems to oer advantages over ciprooxacin for bacterial
eradication rates and clinical improvement in patients with
chronic prostatitis [], whereas another study of similar size
and design showed no signicant dierences between these
two agents [].
Doseanddurationshouldbesucienttoeradicate
the infection, for example, ciprooxacin mg (once or
twice/day) and levooxacin mg (once/daily) for –
days. e treatment may be split into two cycles of – days,
separated by an interval of one-two weeks.
4.2. Trimethoprim. Trimethoprim is rapidly absorbed from
the gastrointestinal tract, widely distributed into body tissues
and uids, including seminal uid and prostatic tissue. It is
eliminated by glomerular ltration and tubular secretion in
urine; only small amounts are excreted in feces by biliary
elimination. Trimethoprim is active against many relevant
pathogens but has no activity against Pseudomonas,some
enterococci, and some Enterobacteriaceae. Monitoring is
unnecessary. It is a second-line therapy.
Doseanddurationshouldbesucienttoeradicatethe
infection, for example, mg once or twice/day for days.
e treatment may be split into two cycles of – days,
separated by an interval of one-two weeks.
4.3. Tetracyclines. Tetracyclines are readily absorbed and
bound with plasma proteins, concentrated by the liver in
thebile,andexcretedintheurineandfecesathighcon-
centrations in a biologically ac tive form. ese drugs are
contraindicated in renal and liver failure. ey have good
activity against Chlamydia trachomatis and Mycoplasma
and lower ecacy against coagulase-negative staphylococci,
Escherichia coli, other Enterobacteriaceae, and enterococci.
ere is no activity against Pseudomonas aeruginosa.eyare
associated with risk of skin sensitization. Tetracyclines are a
second-line therapy. Dose and duration should be sucient
to eradicate the infection.
e Ureaplasma sp. isolates are susceptible to doxycycline
and j osamycin. Most studies report lower resistance rates for
tetracyclines (<%).
Doxycycline is administered at the dose of mg once
or twice/ day for days. e treatment may be split into
two cycles of – days, separated by an interval of one-two
weeks.
4.4. Macrolides. Macrolides have good penetration into the
prostate and are active against Chlamydia trachomatis and
Gram-positive bacteria but have an unreliable activity against
Gram-negative bacteria. Macrolides are used for special indi-
cations, based on the microbiologica l ndings. Minor side
eects of macrolide administration include nausea, vomiting,
diarrhea,andringingorbuzzingintheears(tinnitus).Serious
side eects, including allergic reaction and cholestatic hepati-
tis (inammation and congestion of bile ducts in the liver),
are generally associated only with the use of erythromycin.
Doseanddurationshouldbesucienttoeradicatethe
infection. Azithromycin is prescribed at the dose of g
once/dayfor–days.
Anumberofstudieshavecomparedthemicrobiological
eradication rate between the dierent antibiotics.
Higher eradication rates (>%) have been reported with
azithromycin and levooxacin either alone, in combination,
or sequentially, depending upon the infection site (urethral,
prostatic, or both) in patients with chronic bacterial prostat i-
tis by Chlamydia trachomatis infection [].
4.5. 𝛽-Lactam Antibiotics. 𝛽-lactam antibiotics (penicillin
derivatives, cephalosporins, monobactams, and carbapen-
ems)havealimiteduseinmaleinfertility.Someofthemcan
be used if a particular quinolone-resistant male urogenital
infection is present, such as acute prostatitis caused by
extended-spectrum 𝛽-lactamase-producing bacteria, w hich
seems to be sensible to imipenem, cefoxitin, and amoxi-
cillin/clavulanic acid [].
Other uses include management of Neisseria gonor-
rhoeae infections whose prevalence has grown over the past
decades. It is the second most commonly reported sexually
transmitted bacterial infection in the U nited States, aer
Chlamydia trachomatis. e Centers for Disease Control
and Prevention guidelines recommend dual therapy with
intramuscular ceriaxone and oral azithromycin as rst-line
treatment, although comp onents of this type of treatment are
met with a high level of resistance [].
e recommended dose for uncomplicated gonococca l
urethral infections is a single dose of ceriaxone, mg
intramuscularly, and either azithrom ycin ( g orally) or doxy-
cycline ( mg orally twice/day) for seven days.
4.6. Antibiotics and Sperm Toxicity. Although the antibiotic
treatment has been essential to preserve or restore normal
BioMed Research In ternational
sperm parameters in urogenital infections, some of them
havespermotoxiceects.issideeecthasnotyetbeen
directly shown in humans by randomized clinical trials, but
there are data concerning testicular and/or sperm toxicity for
some antibiotics in rats or mice. ese include ciprooxacin
and peoxacin [ ], ooxacin [], lomeoxacin [], tetra-
cyclines [], cefonicid and other cephalosporins [], and
noroxacin in quails [].
5. Anti-Inflammatory Treatment
5.1. Nonsteroidal An ti-I nam ma tory Drugs (NSAIDs)
5.1.1. Salicylates. Salicylates include salicylates, diunisal,
and salsalate. ere are no available data on the last two
categories. e negative eect of mesalazine on fertility has
been shown in patients with irritable bowel disease that
at a certain point requires treatment cessation to achieve
fertility. Indeed, the mean sperm concentration, sperm motil-
ity, percentage of spermatozoa with normal form, seminal
uid volume, and total motile sperm count increase aer
mesalazine discontinuation []. Another study showed a
decrease of sper m count and motility in mice treated with
sulfasalazine []. e administration of salicylate ( mg
four times a day) signicantly decreased sperm motility aer
days of treatment in four patients. e negative eect on
sperm motility was not due to necrozoospermia [].
5.1.2. Fenamic Acids. No data on fenamic acids are available
on male fertility.
5.1.3. Profens. Few data are available on profens. A study
showed that ibuprofen may cause a signicant alteration
of sperm parameters and chromatin/DNA integrity in
mice. ese deleterious eects are dose-dependent and are
observed in early and late stages of drug administration [].
On the other hand, another study showed that reproductive
damage induced by continuous or intermittent hypoxia was
partially ameliorated by the simultaneous treatment with
ibuprofen [].
5.1.4. Cox-2 Inhibitors (Coxibs). e data are contrasting for
this class of NSAIDs. Studies on mice and turkeys showed
a negative eect of coxibs on sperm parameters [, ]. In
cont rast, sperm parameters (but not morphology) improved
in patients with chronic pelvic pain syndrome treated with a
combination of 𝛼-blockers and coxibs []. Similarly, sperm
motility and morphology improved and seminal uid leuko-
cyte concentration decreased in pat ients with amicrobial
leukocytospermia undergoing assisted reproductive tech-
nique treated with rofecoxib []. Similar data were reported
in another study whose p atients were given valdecoxib [].
ese ndings suggest that coxibs may be prescribed in
infertile p atients with leukocytospermia. However, more data
are needed to assess this indication.
e dose used in the clinical trials was of mg for
rofecoxib, for a period of days or mg once/day for
valdecoxib for two weeks. is indication has been currently
o-label for leukocytospermia in Italy.
5.1.5. Arylacetics. No recent data are available on the eects
of arylacetics for male fertility.
5.1.6. Sulfonanilides. Sulfonanilides include the relatively
COX- selective nimesulide. A study was conducted with
nimesulide, in cases of abacterial prostatovesiculitis and no
specied infertility issue, showing that its oral administration
at t he dose of mg twice/day for three cycles of days each
reduceddysuricsymptomsandimprovedinammatorysigns
at transrectal prostate ultrasound evaluation. However , no
statistically signicant changes on sperm count and motility
were obs erved, while a signicant reduction in the number
of abnormal forms occurred []. Another study showed that
nimesulide does not seem to be spermatoxic in prepubertal
rats at normal therapeutic doses [].
5.1.7. Oxicams. No data are available on the eects of oxicams
on male fertility.
Overall, NSAIDs should be considered for the treatment
of the acute forms of male accessory gland inammation for
symptoms relief and they should be avoided for chronic usage
(if possible) in patients with infertility. Additional studies are
needed to explore the possibility of positive eects of coxibs
on patients with “idiopathic” leukocytospermia.
5.2. Steroidal Anti-Inammatory Drugs. Glucocorticoids are
employed for the treatment of infertility when antisperm
antibodies (ASA) are demonstrated. Recent studies have
investigated the eec ts of ASA and the correlation between
ASA and sperm parameter abnormalities, but inconsistent
results have been reported. A recent meta-analysis shows a
signicantnegativeeectofASAonspermconcentrationand
total sperm motility (progressive + nonprogressive) which
are lower in ASA positive patients than in ASA negative and
sperm liquefaction which has been longer in ASA positive
patients []. In addition, an immune-suppressive treatment
has been found poorly eective and many other treatments
have been proposed such as ART (intrauterine insemination
and in vitro fertilization) and laboratory techniques (sperm
washing, immunomagnetic sperm separation, proteolytic
enzyme treatment, and use of immunobeads) [].
6. Fibrinolytic Treatment
In this section, we discuss three of the main brinolytic agents
evaluated in literature and widely used clinical practice:
serratiopeptidase, bromelain, and escin.
6.1. Serratiopeptidase. Serratiopeptidase is a proteolytic en-
zyme of ,–, kD molecular weight and particularly
ametalloproteasecontainingazincatomwhichplaysa
pivotal role for its proteolytic activity []. It derives from
nonpathogenic enterobacteria belonging to Serratia species
E-. is microor ganism was originally isolated during late
s from the intestines of silkworm Bombyx mori,its
naturalhabitat.eenzymefacilitatestheemergingmoth
to dissolve its cocoon. Serratiopeptidase is produced by
purication from culture of Serratia E- bacteria [].
BioMed Research In ternational
In rats, orally administered serratiopeptidase is absorbed
from the intestinal tract and reaches the circulation in an
enzymatically active form [, ]. However, pharmacoki-
netic data including its oral bioavailability and the minimal
concentration required for its therapeutic ac tion are not
reported in humans.
Serratiopeptidase seems to ac t as analgesic, anti-inam-
matory, and brinolytic/caseinolytic [–]. As for the anti-
inammatory property, this enzyme reduces swelling by
decreasing the amount of uid i n the tissues, thinning the
uid, and facilitating uid drainage. In addition, its enzyme
activity dissolves dead tissue surrounding the injured area
so that healing is accelerated. It acts also by modifying cell-
surfaceadhesionmoleculesthatguideinammatorycells
to site of inammation. Its brinolytic/caseinolytic activity
relates on the breaking down of brin and other dead or
damaged tissues without harming the healthy tissue. is
couldenablethedissolutionofbloodclots,atherosclerotic
plaques, and facilitating antibiotic penetration. Two animal
and eight clinical studies support its use as anti-inammatory
agent but larger, better-designed, placebo-controlled trials
are needed to clearly prove its ecacy. In addition, data
on tolerability and long-term safety of this enzyme lack
[].
A clinical study showed a small signicant increase in
sperm count compared to pretreatment value, aer treat-
ment with levooxacin plus serratiopeptidase, in patients
with > years infertility and male accessory gland infec-
tion/inammation, while sperm motility and morphology
didnotchange[].Itispossiblethattheenzymecould
enhance the penetration of antibiotics in the infected tissue
and increase the activity of quinolones against the develop-
ment of bacterial biolms [].
erearenotmanypublishedarticlesontheadversedrug
reactions (ADRs) to s erratiopeptidase. e only information
maybeobtainedfromdrugcompanymonographs.eADRs
include allergic skin reaction that ranges from dermatitis
to extreme cases of Stevens-J ohnson syndrome or erythema
multiforme, m uscle aches and joint pains, gastric distur-
bances like anorexia, nausea, and abdominal upset, cough
rarely pneumonitis [], and coagulation abnormalities. It
has to be taken on an empty stomach or at least two hours
aer eating, and no food should be consumed for about
minutes aer the ingestion of serratiopeptidase.
e recommended dose of serratiopeptidase for specic
indications, in particular, has been not mentioned anywhere;
however, serratiopeptidase-based drugs commonly range
from to UI/day.
6.2. Bromelain. Bromelain has been studied since and
it is used as a phytomedical compound []. Bromelain
is a mixture of dierent thiol endopeptidases and other
components like phosphatases, glucosidase, peroxidases, cel-
lulases, glycoproteins, carbohydrates, and several protease
inhibitors []. Bromelain seems to exert a wide range of
therapeutic benets; it is known to enhance absorption of
drugs, particularly antibiotics [, ]. Bromelain acts on
brinogen giving products that are similar, at least in its
eect, to those formed by plasmin []. Experiment in mice
showed that antacids such as sodium bicarbonate preserve
the proteolytic ac tivity of bromelain in the gastrointestinal
tract []. Bromelain is absorbed by the human intestine
without degradation and loss of its biological activity [, ].
e body can absorb signicant amount of bromelain; about
g/day of bromelain can be consumed without any major
side eects.
Clinical studies have shown that bromelain may be
useful for the treatment of several disorders (cardiovascular
diseases, osteoarthritis, immunogenicity, blo od coagulation,
brinolysis, diarrhea, eects on cancer cells, and debridement
burns)[].Nodataarehoweveravailableontheroleof
bromelain given alone on male fertility. However, many stud-
ies suggest an eect of bromelain on antibiotic potentiation;
combined bromelain and antibiotic therapy has been shown
more eective than antibiotic alone in eradication of various
infections, including urinary tract infection [].
Bromelain has been used in therapeutic schemes ranging
from mg per day to – mg/day. e best results
occurred when it was administered four times a day and
the eectiveness was dose-dependent []. Bromelain has
very low toxicity []. In human clinical tests, side eects
were generally not observed; however, a report indicated that
individuals with preexisting hypertension might experience
tachycardia following high doses of bromelain []. More-
over, bromelain can cause IgE-mediated respiratory allergies
of both the immedia te type and the late phase of immediate
type [].
6.3. Escin. Escin is a natural mixture of triterpene saponins
extracted from the seeds of Aesculus chinensis Bgem or
Aesculus wilsonii Rehd,whichmainlyconsistofA,B,CandD
escin. Experimental evidence suggests that escin exerts anti-
inammatory and antiedematous eects. At present, escin
injection has been widely used clinically to prevent inam-
matory edema aer trauma such as fracture and surgery in
China[,].Fewstudieshaveanalyzedapossibleroleof
escin in male fertility. A Chinese study, evaluating the role of
escin in varicocele-associated infertility, showed that a daily
oral dose of mg ( mg every h) for months improved
sperm concentration and caused changes in the diameter of
the spermatic vein []. is dose is higher than the dose
used for the venous insuciency of other districts (orally:
mg daily; or intravenously: – mg daily). Treatment
duration is not well established, although medium- and
long-term administration do not inuence general toler-
ance.
Escin causes mild adverse eects with very low frequen-
cies, most of which can be reduced or avoided without
the need to administer sym ptomatic drug aer advising
the patients to take escin aer meal. e most important
adverse eects occur when es cin is administered parentally.
e most common reactions are phlebitis and allergic reac-
tions; phlebitis occurring at the rst day aer intravenous
medication accounts for % and can cause physical and
psychological pain, which directly aects its clinical use.
Escin has little eect on vital signs, blood counts, liver, or
kidney function.