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Treating Idiopathic Male Infertility with a Combination of Tamoxifen Citrate and a Natural Compost with Antioxidant and Androgen-Mimetic Action

Authors:

Abstract

Background: We investigated the efficacy of a combination therapy with tamoxifen citrate and a natural composite containing Tribulus terrestris, alga Ecklonia bicyclis and polymers of d-glucosamine and n-acetyl d-glucosamine in treating male idiopathic infertility. Methods: In this prospective, randomized double blind, placebo-controlled study, we enrolled ninety infertile men at our department of urology at University Federico II of Naples. Mean age was 29.2 ± 7.8 [± SD]. Inclusion criteria consisted of the repeated exhibition of oligoasthenozoospermia (OA) without detectable cause (unexplained OA). Patients were randomly assigned to three treatment groups: Group A (n=30) receiving tamoxifene citrate (20 mg/day) and a natural composite with an antioxidant and androgen-mimetic action (150 mg of alga Ecklonia Bicyclis, 396 mg of Tribulus terrestris and 144 mg of polymers of d-glucosamine and n-acetyl d-glucosamine); Group B (n=30) receiving tamoxifene citrate (20 mg/day) and Group C receiving placebo (n=30). We evaluated the number of spontaneous pregnancies, sperm volume, concentration, sperm total motility, sperm forward progressive motility, normal sperm morphology. Results: After 6 months of therapy the number of spontaneous pregnancies was markedly higher in the Group A (13 pregnancies, 33.3%) then the other two groups: Group B (6 pregnancies, 20%) and Group C (4 pregnancies, 13.3%). Sperm concentration improved in the Group A from a mean 8.49 × 106 cells/ml ± 5.57 at baseline to 22.1 × 106 cells/ml ± 1,63 (p ≤ 0.001). In the Group B there was an improvement from a mean 7.98 × 106 at baseline to 14.43 × 106 cells/ml ± 3,43 (p=0.002). Group C did not see a statistically significant improvement of sperm number, from a concentration of 9.65 × 106 cells/ml ± 6.54 to 10.53 × 106 cells/ml ± 8.5 (p=0.0025). In Group A, sperm total motility improved from 31% ± 11% at baseline to 40% ± 14% (p=0.007) whilst the forward progressive motility slightly improved from 5% ± 3% to 9% ± 4% (p=0.0034). In the group B and C, there were not reported statistically significant changes of motility. Conclusions: The combination therapy with tamoxifen citrate and the natural compound with an andorgen-mimetic and antioxidant action leads to a higher incidence of pregnancy rates and gives a statistically significant improvement of semen parameters comparing with the single use of tamoxifen citrate and with the control group.
Research Article Open Access
Steroids & Hormonal Science
Iacono et al., J Steroids Hormon Sci 2013, S5
http://dx.doi.org/10.4172/2157-7536.S5-002
J Steroids Hormon Sci Hormonal Therapy ISSN: 2157-7536 JSHS, an open access journal
Keywords: Male infertility; Antioxidant; Oligospermia;
Oligoasthenozoospermia (OA); Tamoxifen citrate
Background
Infertility is one of the most important issues among married
couples and it represents a major clinical problem aecting people not
just medically but psychologically too.
It has been demonstrated that 15% of all the couples in the US are
infertile and male factor is responsible for the 25% of the cases [1].
Couples that have not achieved a pregnancy in the last 12-24
months are considered as barren.
e cause of male infertility with abnormal semen parameters
remains unknown in 25% of men [2]. In many Western countries,
women postpone their rst pregnancy until they have nished their
education and have started a career, so also female age is the important
variable inuencing outcome in assisted reproduction. In fact
compared to a woman at 25 years old, the fertility potential is reduced
to 50% at age 35, to 25% by 38 years and <5% at over 40 years [3].
Men with idiopathic infertility are prone to receive a number of
empirical therapies.
Otherwise while 25% of men with sperm density lower than 12.5
million per ml could father a child through spontaneous conception,
10% with a normal female partner cannot contribute to pregnancy even
with a number of more than 25 million per ml [3].
ese ndings suggest that there could be other parameters that
aect pregnancy and study outcomes based only on improvement
in semen parameters are not enough. A more eective outcome
parameter would probably be the pregnancy rate since that is the
ultimate end point of therapy. Commonly used medications include
hormonal medications as follicle stimulating hormone (FSH),
androgens (mesterolone, testosterone undecanoate/enanthate) [3,4]
and antiestrogen (tamoxifen/clomiphen citrate); antioxidant like
glutathione, lycopene, vitamin E; Sperm vitalizer as L-carnitine, coQ10.
*Corresponding author: Ruffo A, Department of Urology, University “Federico
II’’ of Naples Via S. Pansini, 5 80131 Naples , Italy, Tel: +39 3339323372, +39
0817462607; E-mail: antonio.ruffo7@gmail.com
Received January 28, 2013; Accepted March 13, 2013; Published March 31,
2013
Citation: Iacono F, Prezioso D , Ruffo A, Di Lauro G, Illiano E, et al. (2013) Treating
Idiopathic Male Infertility with a Combination of Tamoxifen Citrate and a Natural
Compost with Antioxidant and Androgen-Mimetic Action. J Steroids Hormon Sci
S5: 002. doi:10.4172/2157-7536.S5-002
Copyright: © 2013 Iacono F, et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited.
Treating Idiopathic Male Infertility with a Combination of Tamoxifen
Citrate and a Natural Compost with Antioxidant and Androgen-Mimetic
Action
Iacono F, Prezioso D , Ruffo A*, Di Lauro G, Illiano E, Romeo G and Romis L
Department of Urology, University “Federico II’’ of Naples, Italy
Abstract
Background: We investigated the efcacy of a combination therapy with tamoxifen citrate and a natural composite
containing Tribulus terrestris, alga Ecklonia bicyclis and polymers of d-glucosamine and n-acetyl d-glucosamine in
treating male idiopathic infertility.
Methods: In this prospective, randomized double blind, placebo-controlled study, we enrolled ninety infertile men
at our department of urology at University Federico II of Naples. Mean age was 29.2 ± 7.8 [± SD]. Inclusion criteria
consisted of the repeated exhibition of oligoasthenozoospermia (OA) without detectable cause (unexplained OA).
Patients were randomly assigned to three treatment groups: Group A (n=30) receiving tamoxifene citrate (20 mg/day)
and a natural composite with an antioxidant and androgen-mimetic action (150 mg of alga Ecklonia Bicyclis, 396 mg of
Tribulus terrestris and 144 mg of polymers of d-glucosamine and n-acetyl d-glucosamine); Group B (n=30) receiving
tamoxifene citrate (20 mg/day) and Group C receiving placebo (n=30). We evaluated the number of spontaneous
pregnancies, sperm volume, concentration, sperm total motility, sperm forward progressive motility, normal sperm
morphology.
Results: After 6 months of therapy the number of spontaneous pregnancies was markedly higher in the Group
A (13 pregnancies, 33.3%) then the other two groups: Group B (6 pregnancies, 20%) and Group C (4 pregnancies,
13.3%). Sperm concentration improved in the Group A from a mean 8.49 × 106 cells/ml ± 5.57 at baseline to 22.1 ×
106 cells/ml ± 1,63 (p ≤ 0.001). In the Group B there was an improvement from a mean 7.98 × 106 at baseline to 14.43
× 106 cells/ml ± 3,43 (p=0.002). Group C did not see a statistically signicant improvement of sperm number, from a
concentration of 9.65 × 106 cells/ml ± 6.54 to 10.53 × 106 cells/ml ± 8.5 (p=0.0025). In Group A, sperm total motility
improved from 31% ± 11% at baseline to 40% ± 14% (p=0.007) whilst the forward progressive motility slightly improved
from 5% ± 3% to 9% ± 4% (p=0.0034). In the group B and C, there were not reported statistically signicant changes
of motility.
Conclusions: The combination therapy with tamoxifen citrate and the natural compound with an andorgen-mimetic
and antioxidant action leads to a higher incidence of pregnancy rates and gives a statistically signicant improvement
of semen parameters comparing with the single use of tamoxifen citrate and with the control group.
Citation: Iacono F, Prezioso D , Ruffo A, Di Lauro G, Illiano E, et al. (2013) Treating Idiopathic Male Infertility with a Combination of Tamoxifen Citrate
and a Natural Compost with Antioxidant and Androgen-Mimetic Action. J Steroids Hormon Sci S5: 002. doi:10.4172/2157-7536.S5-002
Page 2 of 6
J Steroids Hormon Sci Hormonal Therapy ISSN: 2157-7536 JSHS, an open access journal
Of the many causes of male infertility, oxidative stress (OS) has
been shown to aect the fertility status and for this reason it has been
widely studied in the past few years.
Spermatozoa, like all other aerobic cells are particularly susceptible
to oxidative stress induced damage because of the large polyunsaturated
fat content in their membranes. Men with high ROS may have a lower
fertility potential compared to those with low ROS [5].
High levels of reactive oxygen species in semen have been correlated
with reduced sperm motility and damage to sperm nuclear DNA [5].
For example, IL-1 α, IL-1 β and tumor necrosis factorα (TNF-α),
stimulate sperm peroxidation by increasing ROS generation [6]; IL-6
has been shown to play a pivotal role in the induction of capacitation
and the acrosomal reaction in sperm [7]. However, high levels of
cytokines in the semen have been correlated with sperm injury, most
notably cell membrane lipid peroxidation in the presence of elevated
IL-6 [6,8]. Further, increased levels of IL-6 have also been noted in the
seminal uid of infertile men [9].
Also, IL-1, IL-6, IL-8 and TNF have all been shown to induce
increased ROS production, leading to increased sperm cell membrane
lipid peroxidation [6,8,10].
Interferon gamma (IFN-γ) and TNFα have been shown to decrease
the motility of spermatozoa.
is condition is common in cases of genitourinary tract infections
and inammation, in which oxidative mechanism produce the
oxidative stress [11].
Antioxidants in seminal plasma are the most important form of
protection available to spermatozoa against ROS [6,12].
at is why it is commonly used to prescribe antioxidant oral
therapy for the idiopathic male oligoastenospermia to decrease
oxidative stress and improve fertility.
Antiestrogens have been one of the oldest and most commonly
prescribed forms of therapy for idiopathic male infertility. ese drugs
inhibit the negative feedback eect of estrogen on the hypothalamus
and pituitary, increasing endogenous gonadotropin secretion.
Antiestrogen therapy was reported to yield pregnancy rates
ranging from 20%–40% following 6-9 months of therapy [13] from the
hypothalamus and FSH and LH secretion directly from the pituitary,
increasing their levels, thereby stimulating spermatogenesis [14].
Pregnancy rates following varicocelectomy were approximately
40% [15].
Methods
is is a prospective, randomized double blind, placebo-controlled
study. We enrolled ninty infertile men attending our department of
urology at University Federico II of Napsssles. Mean age of male partner
was 29.2 ± 7.8 [±SD] while female partner mean age was 27.4 ± 6.8 [±
SD]. We included a minimum of 1 year of regular unprotected sexual
activity without achieving pregnancy. Inclusion criteria consisted of
the repeated exhibition of oligoasthenozoospermia without detectable
cause (unexplained OA). We evaluated the number of spontaneous
pregnancy, sperm volume and concentration, sperm total motility,
forward progressive motility and normal morphology.
Exclusion criteria included cases with known etiology or
leukocytospermia, and alterated testicular volume, varicocele (as
detected by clinical examination and ultrasonography) or an abnormal
FSH level. Couples with combined male and female factors were
excluded. Patients signed a informed consent explaining the nature of
the study, the possibility of treatment failure, and possible side eects.
ey underwent a clinical evaluation including history taking, general
examination, and genital examination for possible causes of infertility.
Investigations for the male partner included semen analysis according
to World Health Organization criteria [16]. Only couples with no
female factor infertility were included in the study.
Patients were blindly randomized into three groups: Group A
(time of infertility 2.4 ± 1.2 years [± SD]) receiving a combination of
an antiestrogen [tamoxifen citrate 20 mg/day] and a natural composite
with an antioxidant and androgen-mimetic action [150 mg of alga
Ecklonia Bicyclis, 396 mg of Tribulus terrestris and 144 mg of polymers
of d-glucosamine and n-acetyl d-glucosamine (Tradamix®); n=30];
Group B (time of infertility 2.2 ± 1.1 years [± SD]) receiving tamoxifen
citrate (n=30) and Group C (time of infertility 1.9 ± 1.0 years [± SD]
receiving placebo (n=30). Treatment was continued for 6 months. All
statistical measurements were performed using ANOVA tests. We
wanted to have a level of signicance with p<0.05.
Results
Aer 6 months of therapy the cumulative number of pregnancy
was markedly higher in the Group A (13 pregnancies, 33.3%) then
the other two groups: Group B (6 pregnancies, 20%) and Group C (4
pregnancies, 13.3%). is dierence is statistically signicant (p=0.023)
(Table 1).
In the tables 1 and 2, are reported the changing in semen parameters
before and aer treatment in the three groups.
Sperm concentration signicantly improved in the Group A from
a mean 8.49 × 106 cells/ml ± 5,57 at baseline to 22.1×106 cells/ml ± 1,63
(p ≤ 0.001) comparing with the tamoxifen recipients (Group B) where
the was an improvement from a mean 7.98 × 106 at baseline to 14.43 ×
106 cells/ml ± 3.43 (p=0.002). Group C had an improvement of sperm
number, from a concentration of 9.65 × 106 cells/ml ± 6.54 to 10.53
×106 cells/ml ± 8.5 (p=0.0025) (Table 2A).
Group Cases Pregnancies
(1-3 mo)
Pregnancies
(3-6 mo)
Total
pregnancies
Tamoxifen+Tradamix®30 6 7 13 (33.3%,
p=0.025)
Tamoxifen 30 3 3 6 (20%,
p=0.032)
Placebo 30 2 2 4 (13.3%,
p=0.038)
Table 1: Pregnancy rates in the 3 Groups.
Table 2A: Semen parameters before treatment in the 3 Groups.
Semen parameters before treatment
Group Volume (ml) Count (× 106) TM (%) FPM (%) ABF (%)
Tamoxifen+Tradamix®2.4 8.49 31 5 37
Tamoxifen 2.2 7.98 30 8 39
Placebo 2.5 9.65 29 6 37
Table 2B: Semen parameters after treatment in the 3 Groups.
Semen parameters after treatment
Group Volume (ml) Count (× 106) TM (%) FPM (%) ABF (%)
Tamoxifen+Tradamix®3.2 22.1 40 7 35
Tamoxifen 2.7 21.6 35 5 38
Placebo 2.9 10.53 30 4 48
Citation: Iacono F, Prezioso D , Ruffo A, Di Lauro G, Illiano E, et al. (2013) Treating Idiopathic Male Infertility with a Combination of Tamoxifen Citrate
and a Natural Compost with Antioxidant and Androgen-Mimetic Action. J Steroids Hormon Sci S5: 002. doi:10.4172/2157-7536.S5-002
Page 3 of 6
J Steroids Hormon Sci Hormonal Therapy ISSN: 2157-7536 JSHS, an open access journal
In Group A sperm total motility improved from 31% ± 11%
at baseline to 40% ± 14% (p=0.007) whilst the forward progressive
motility slightly improved from 5% ± 3% to 9% ± 4% (p=0.0034). For
the other two groups there were not reported statistically signicant
changes of motility (Table 2B).
Seminal volume did not change aer the treatment in the Group A
(2.47 ± 1.4 at baseline, 2.9 ± 1.6 at 6 months) and no dierence from
Group B and placebo recipients (Group C) were observed.
No remarkable dierence in sperm form was reported.
Discussion
In this study, we evaluated the eectiveness of the combination of
tamoxifen citrate and this natural compost in treating idiopathic male
infertility. Combination therapy for male infertility has been evaluated
by other investigators. Comhaire et al. [17] studied 30 men with
infertility and female partners with no demonstrable cause of infertility
who received conventional treatment according to the guidelines of
the World Health Organization [16], and either a strong antioxidant,
astaxanthin (16 mg/day), or a placebo for 3 months. e results revealed
total pregnancy rates of 10.5% among the placebo cases, compared with
54.5 in the active treatment arm (p=0.028).
Our results (Table 1) are similar with the findings of Adamopolous
and Comhaire, and suggest that combination therapies for male
infertility should be further evaluated [18,19].
A recent short review assessing evidence-based treatments for male
infertility show many methodological difficulties with these works [20]
given by the short duration of most of these studies. Although married
couples are allowed 1 year of unprotected intercourse to conceive before
a diagnosis of infertility is made, most studies allow only an average of 3
months of observation, even if seminal parameters improve. Results of
medical treatment in terms of cumulative pregnancy rates may dier if
the observation period is long enough. is has been clearly suggested
by the improved pregnancy rate aer 6 months shown in our work as
well as by Adamopolous et al. [18] and Ghanem et al. [20]. is study
suggests that combination of an antiestrogen with a substance with an
antioxidant and androgen-mimetic action is a valid therapy for men
with oligoasthenozoospermia.
is composite (Tradamix®) contains these three compounds: alga
Ecklonia bicyclis, Tribulus terrestris and polymers of d-glucosamine
and n-acetyl-d-glucosamine.
Alga bicyclis is a macro algae widely distributed along the Pacic
coast of central Japan and Korea where, when conditions are suitable,
forming extensive underwater meadows (kelp forests), oen mixed.
e biological properties attributed to these species are instead traced
to the presence of particular secondary metabolites also known as
the phlorotannins and made the union of various units of the same
monomer, the 1,3,5-triidrossi phenol or phloroglucinol. So far a
dozen such compounds has been identied, the most important
of which are shown in the gures [21-24]. Right now, more than
20,000 new compounds have been isolated from marine organisms;
numbers of these naturally occurring derivatives are developed as
potential candidates for pharmaceutical applications. Phlorotannins
are secondary metabolites distributed in a variety of plants. ey are
phloroglucin derivatives with a variety of biological functions in vitro
and in vivo, such as a strong radical scavenging and antioxidant action
[25,26].
Ecklonia cava radical scavenger activity 10-100 powerful than any
other polifenol terrestris plants, including green tea catechins, which
have only 3-4 fenolic and rings that are commonly considered among
the most eective antioxidant molecules. Common polyphenols are
soluble in water also and have a relatively short half-life introduced
into the body. All phlorotannins had antioxidant properties in vitro,
especially, bieckol, dieckol and phlorofucofuroeckol [26] (Figures 1-3).
Inammatory cells might generate and release a number of
inammatory mediators: for example, proinammatory cytokines and
inammatory cytokines, such as interleukins [27-30], TNF-α [27-30],
p53 [31], cytochrome P-450 [27-32] and NADPH-cytochrome P-450
[27-31] causing abnormal metabolism of the hypoxanthine/xanthine
oxidase system and the xanthine/xanthine oxidase system, producing
many abnormal metabolites [27-33].
ese inammatory cells and reactions might also activate and
release a large amount of COX-2 [27-29] transcription NF-k B [27-29]
iNOS, and an amount of inammatory oxidants and other chemokines
[27,34,35] and without question, they might induce, generate and
release a large number of O2
-
, ·OH, NO and other free radicals, as well
as O2, H2O2, and other ROS [27,28,31,33,34]. Excessive free radicals and
ROS, as strong oxidants, might aects replication and transcription
OH
OH
OH
OH
OH
OH
OH
OH
HO
HO
HO
HO
O
O
O
O
O
O
Figure 1: Bieckol.
OH
OH
OH
OH
OH
OH
OH
OH
HO
HO
HO
O
O
O
O
O
O
O
Figure 2: Dieckol.
Citation: Iacono F, Prezioso D , Ruffo A, Di Lauro G, Illiano E, et al. (2013) Treating Idiopathic Male Infertility with a Combination of Tamoxifen Citrate
and a Natural Compost with Antioxidant and Androgen-Mimetic Action. J Steroids Hormon Sci S5: 002. doi:10.4172/2157-7536.S5-002
Page 4 of 6
J Steroids Hormon Sci Hormonal Therapy ISSN: 2157-7536 JSHS, an open access journal
of mtDNA and results in a decline in mitochondrial function which
in turn leads to enhanced ROS production and further damage to
mtDNA [36].
In the Ecklonia cava there are molecules that are able to reduce the
response inammatory, partially neutralizing the inammatory damage
caused by ROS and in part by slowing the gaming lipoxygenase and
inhibiting the formation of prostaglandin E2, a powerful inammatory
mediator. Jung et al. revealed that dieckol inhibits LPS-induced NO
and PGE2 [37] production in a concentration-dependent manner
and inhibits inducible iNOS and COX-2 in BV2 microglia without
causing [38,39]. Alga ecklonia treatment signicantly reduced NF-kB
translocation and DNA-binding in LPS-stimulated BV2 microglia [39]
and p38 mitogen-activated protein kinases (MAPKs) activation [37].
Phlorotannins suppresses the induction of cytokines by LPS, as well
as iNOS and COX-2 expression, by blocking NF-kappaB and MAPK
activationas well as reactive oxygen species (ROS) production [39].
ese ndings provide mechanistic insights into the anti-inammatory
and neuroprotective actions of EC in BV2 microglia [40]. It also
signicantly reduced the generation of proinammatory cytokines,
such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α.
Kim et al. revealed extracts reduced the concentrations of IL-4 and
IL-5 by 66% and 84%, respectively, and resulted in a 73% reduction in
the secretion of TNF-α [35].
e second compound contained in the composite used in this
therapy is Tribulus terrestris. is plant native of India, but now present
in most of North America has a weed Active ingredients: protodioscin.
e plant contains also avonoids, alkaloids and amides, although its
properties seem to be completely attribuited to protodioscin (Figure 4).
e parts used are the seeds and fruits, and, more generally, the
aerial parts of the plant. e protodioscin is a steroidal saponin, which is
about 45% of the extract obtained from aerial parts of Tribulus terrestris
(Figure 4). e substance is able to increase the endogenous production
of testosterone, dihydrotestosterone, a hormone luteinizing hormone
(LH), dehydroepiandrosterone (DHEA) and dehydroepiandrosterone
sulfate (DHEA-S) [40]. Because of these eects in experimental animals
there is an increase in spermatogenesis and the frequency of matches
[41]. In the rabbit in particular has been shown that the compound
stimulates the release of nitric oxide (NO) by vascular endothelium
of the corpora cavernosa thereby having a pro-erectile eect [41].
e mechanism behind this eect appears to involve the pathway of
steroid hormones [41]. Although humans protodioscin is used for the
treatment of erectile dysfunction [42, 43].
A study conducted on 150 italian patients aected by erectile
dysfunction treated with the same composite containing Tribulus
terrestris, alga Ecklonia bicyclis and polymers of d-glucosamine
and n-acetyl-d-glucosamne showed and improvement of 28% of the
testosterone levels from a baseline mean value of 5.3 ± 1.1 ng/ml to 6.8
± 1.6 (p<0.01) post treatment [44].
Polymers of d-glucosamine and n-acetyl-d-glucosamine acts on as
a nitric oxide synthetase (NOS) stimulator [44] (Figure 5).
Nitric oxide (NO) is a free radical generated from the oxidation
of L-arginine to L-citrulline by reduced nicotinamide adenine
dinucleotide phosphate (NADPH)-dependent nitric oxide synthase
(NOS). Nitric oxide is diusible, multifunctional, and acts as a
transcellular messenger, being implicated in numerous physiologic and
pathologic conditions [45].
Nitric oxide, at physiologic concentrations, is relatively nonreactive,
but most of its actions are mediated by activation of cyclic guanosine
monophosphate production [46]. It is reported that NO modulates
sexual and reproductive functions in mammalian species [47,48]. e
presence of NO in seminal plasma has been conrmed [49]. e source
of NO in seminal plasma may be either male reproductive organs or
macrophages [50,51]. e production of NO in human and animal
sperm has also been reported [50,51].
Nitric oxide is reported to be a novel mediator of sperm function
[52]. It has both positive and negative eects. e positive modulation
reects the role of NO in physiologic processes like sperm capacitation
[52] and acrosome reaction [53].
HO
OH
OH
OH
OHOH
OH
OH
HO
O
O
O
O
O
Figure 3: Phlorofucofuroeckol.
O
O
O
O
OO
HO
HO
OH
OH
OH
HO
HO
HO
OH
OH
OH
O
O
O
H
H
H
H
H
HO
HO
Figure 4: Protodioscin contained in Tribulus terrestris.
CH2OH CH2OH CH2OH
O
O
O
OOOH
OH
OHOH
NH2NH2NH2
OH
n
Figure 5: Polymers of d-glucosamine and n-acetyl-d-glucosamine.
Citation: Iacono F, Prezioso D , Ruffo A, Di Lauro G, Illiano E, et al. (2013) Treating Idiopathic Male Infertility with a Combination of Tamoxifen Citrate
and a Natural Compost with Antioxidant and Androgen-Mimetic Action. J Steroids Hormon Sci S5: 002. doi:10.4172/2157-7536.S5-002
Page 5 of 6
J Steroids Hormon Sci Hormonal Therapy ISSN: 2157-7536 JSHS, an open access journal
Conclusion
In conclusion, in this study we investigated that the association of
an antiestrogen and a natural compound containing antioxidant and
androgen-mimetic substances is a valid, safe and eective therapy for
treating men with idiophatic oligoasthenozoospermia.
In fact we have demonstrated that the use of this combination
signicantly improves the number and the motility of sperms.
Furthermore there is an improvement of the pregnancy rate comparing
with the group taking just tamoxifen citrate and to placebo recipients.
is treatment protocol is inexpensive, safe, and easy to administer.
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Citation: Iacono F, Prezioso D , Ruffo A, Di Lauro G, Illiano E, et al. (2013) Treating Idiopathic Male Infertility with a Combination of Tamoxifen Citrate
and a Natural Compost with Antioxidant and Androgen-Mimetic Action. J Steroids Hormon Sci S5: 002. doi:10.4172/2157-7536.S5-002
Page 6 of 6
J Steroids Hormon Sci Hormonal Therapy ISSN: 2157-7536 JSHS, an open access journal
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efcacy of a new natural compound made of the alga Ecklonia bicyclis, Tribulus
terrestris and BIOVIS® in order to improve male sexual function . Journal of
Men’s Health 8: 282-287.
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This article was originally published in a special issue, Hormonal Therapy
handled by Editors. Dr. Ratna K Vadlamudi, University of Texas San Antonio,
TX, USA; Dr. Baharudin Bin Abdullah, School of Medical Sciences, Health
Campus USM, Malaysia
Citation: Iacono F, Prezioso D , Ruffo A, Di Lauro G, Illiano E, et al. (2013)
Treating Idiopathic Male Infertility with a Combination of Tamoxifen Citrate and
a Natural Compost with Antioxidant and Androgen-Mimetic Action. J Steroids
Hormon Sci S5: 002. doi:10.4172/2157-7536.S5-002
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... Pregnancy rate. Only one study, Iacono and Prezioso [23], reported total pregnancy rates in their study outcomes. These were 6/30 for the tamoxifen group and 4/ 30 for the placebo group. ...
... Tamoxifen's effect on pregnancy rates was reported in only one study [23], which showed a pregnancy rate of 6/30 for the tamoxifen group and 4/30 for the placebo group. A recent review reported higher pregnancy rates in patients treated with SERMs than placebo-treated or non-treated controls (OR 3.42; 95% CI 1.37e8.52; ...
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Objective Selective estrogen receptor modulators (SERMs) have demonstrated efficacy in the treatment of hypogonadism in males and male factor infertility. Two SERMs, clomiphene citrate and tamoxifen, are now prescribed for off-label use to treat both conditions in males. However, existing literature compares mixed protocols with active management. We aimed to conduct a meta-analysis to evaluate the effect of clomiphene and tamoxifen versus placebo on natural pregnancy rates. Methods We conducted a comprehensive systematic review of electronic databases: MEDLINE, PubMed/PMC, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, Google Scholar, and Web of Science. Articles satisfying all selection criteria were analyzed. The primary outcome was the incidence of pregnancy after receiving the treatment. Secondary outcomes included serum follicle-stimulating hormone, luteinizing hormone, and testosterone levels, and sperm count and motility. We calculated the pooled odds ratio, risk ratio, and risk difference to ascertain possible alterations in the direction of the pooled effect size. Results Ten randomized controlled trials were ultimately included and underwent data extraction. Clomiphene citrate and placebo groups had similar pregnancy rates (10.4% and 7.1%, respectively; odds ratio 1.30 [95% confidence interval 0.27–6.17]; p=0.74). No meta-analysis could be calculated for pregnancy rates in tamoxifen versus placebo groups. Heterogeneity among the studies of both SERMs ranged from low to high. Conclusion Although clomiphene citrate and tamoxifen are often used off-label for the treatment of male infertility secondary to hypogonadism, studies of SERMs in the treatment of idiopathic male factor infertility are limited and heterogenous, preventing this meta-analysis from investigating the efficacy of SERMs on male infertility. The effect of clomiphene citrate or tamoxifen on the pregnancy rate remains uncertain.
... Men with high ROS may have a lower fertility potential compared to those with low ROS. High levels of ROS in semen have been correlated with reduced sperm motility and damage to sperm nuclear DNA Iacono et al., 2013). ...
... It has no exact pathogenesis until now. The most accepted theory is that an undetectable cause leads to accummulation of ROS with resulting OS with its negative feedbacks on spermatogenesis (El-Taieb et al., 2009;Iacono et al., 2013). ROS play a fundamental role in the aetiology of male factor infertility; indeed, high ROS concentrations have been detected in 25-40% of infertile male semen sample (Agarwal et al., 2003;Venkatesh et al., 2009). ...
... Tamoxifen citrate, when combined with natural compounds like Tribulus terrestris, Ecklonia bicyclis, and other antioxidants, significantly increased the sperm concentration and motility. This combination led to higher pregnancy rates compared to tamoxifen alone [99]. Astaxanthin and other antioxidants have proven their worth as supplements to conventional treatments to improve both sperm quality and pregnancy rates [100]. ...
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Background/Objectives: Male infertility is a prevalent issue impacting numerous couples worldwide. This review aims to evaluate the effectiveness of empirical therapies for male infertility, focusing on both lifestyle modifications and medical treatments. This study provides a comprehensive overview of interventions aimed at improving male fertility outcomes. Methods: A thorough review of the existing literature was conducted, encompassing studies on lifestyle changes such as dietary changes, smoking cessation, alcohol moderation, and exercise. Additionally, medical treatments including selective estrogen receptor modulators, gonadotropins, aromatase inhibitors, phosphodiesterase-5 inhibitors, antioxidants, dopamine agonists, kallikrein, indomethacin, low-dose corticosteroids, alpha-blockers, and nitric oxide donors were evaluated. The study population included males diagnosed with infertility, focusing on various underlying causes. Results: Lifestyle modifications were found to have a positive impact on sperm quality. Evidence shows that a healthy diet, smoking cessation, moderate alcohol consumption, and regular exercise improve fertility outcomes. Medical treatments demonstrated significant improvements in sperm production and quality. Selective estrogen receptor modulators and gonadotropins enhanced sperm parameters. Aromatase inhibitors and phosphodiesterase-5 inhibitors specifically improved sperm motility and increased pregnancy rates. Antioxidants, such as vitamins E and C and coenzyme Q10, reduced oxidative stress and enhanced sperm counts, motility, and morphology. Dopamine agonists, particularly cabergoline, normalized prolactin levels and improved fertility outcomes. Kallikrein therapy improved sperm parameters and increased pregnancy rates. Indomethacin treatment was associated with increased sperm concentrations and motility. Low-dose corticosteroids and alpha-blockers showed variable results, and nitric oxide donors like L-arginine enhanced sperm counts and motility. Conclusions: Empirical therapies, including lifestyle modifications and medical treatments, significantly enhance sperm quality and reproductive potential. These integrated approaches are essential in improving fertility outcomes in males. However, further extensive randomized trials are necessary to definitively establish the most effective treatments.
... It may be that oxidative stress plays an important role, triggering a variety of abnormalities. In particular, the progressive sperm motility essential for oocyte fertilization may be compromised by oxidative stress that extensively disturbs spermatozoal energy metabolism (Agarwal et al., 2003;El-Taieb et al., 2009;Iacono et al., 2013;Venkatesh et al., 2009;Zhou et al., 2007). We evaluated the utility of oral administration of a supplement containing L-carnitine fumarate, acetyl L-carnitine, vitamin C, coenzyme Q 10 , zinc, folic acid, selenium, and vitamin B 12 (Proxeed Plus) in terms of improving general semen parameters, including ejaculate volume, sperm concentration, total sperm count, sperm motility, and sperm morphology evaluated at the time of diagnosis and at 3 and 6 months later. ...
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The male factor is responsible for infertility in about 35–40% of all cases. Idiopathic oligo- and/or astheno- and/or therato-zoospermia is one of the most common male fertility disorders and remains a significant therapeutic challenge. The primary cause of idiopathic male infertility remains unknown but seems to be associated with oxidative stress. Objective: The use of antioxidative formulation to improve qualitative and quantitative deficiencies in the male gametes. In total, 78 subjects were treated with a combination of 1,725 mg L-carnitine fumarate, 500 mg acetyl-L-carnitine, 90 mg vitamin C, 20 mg coenzyme Q 10 , 10 mg zinc, 200 µg folic acid, 50 µg selenium, and 1.5 µg vitamin B 12 (Proxeed ® Plus, Sigma-Tau, Italy) for 6 months; the preparation was taken twice daily from the time idiopathic infertility was diagnosed. Basic seminal parameters were evaluated by a European Society of Human Reproduction and Embryology (ESHRE) -certified embryologist following the fifth edition of the World Health Organisation (2010) guidelines at three time points: at baseline and 3 and 6 months of treatment. Improvements in semen parameters (differing in terms of dynamics) were evident at 3 months and gradually improved over the 6 months of treatment. Each parameter: sperm concentration, total sperm count, sperm total and progressive motility improved significantly after treatment except for the percentage of sperm of abnormal morphology and ejaculate volume. Proxeed Plus was effective for patients with idiopathic infertility; however, a long treatment period is needed to achieve optimal results.
... The Primary infertility affects approximately 15% of couples, with male factor infertility accounting for 50% of cases[2]. In more than 20 % of the cases, the causes of infertility remain unexplained[3]. Antisperm antibodies (ASA) are the whole mark of humoral immune infertility. These antibodies are directed to various sperm antigens and implicated in sperm dysfunction. ...
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Assessment of male infertility is the first step in resolving this worldwide problem. The aim of the present study is to investigate the predictive value of using ELISA (Enzyme Linked Immuno-Sorbent Assay) test for serum and seminal plasma Antisperm antibodies (ASA) as a complementary tool to assist in diagnosis of infertility. This study was carried out between January 2013 and November 2013 including one hundred (100) selected infertile men who attended to fertility Center in Al-Sadr Medical City. The study also included twenty (20) healthy volunteer fertile as a control. The results showed that the incidence of serum and seminal ASA in infertile men is significantly (p<0.05) higher than that in control fertile men. the incidence of serum and seminal ASA is significantly (p<0.05) higher in normozoospermic patients than that in control fertile men. There was a high significant negative correlation (p<0.01) between the concentration of serum and seminal ASA in infertile men and each of : sperm motility, progressive motility, while a high significant positive correlation (p<0.01) is seen between serum and seminal ASA in infertile men and sperm agglutination, and a significant positive correlation (p<0.05) with seminal WBC count. The study concluded that ELISA ASA assay can be routinely used as a complementary test to diagnose infertility .
... Nearly 15% of couples are infertile, 25% of which are related to male factors. Cause of infertility in 25% of infertile men with abnormal semen is unknown (1). Many environmental and genetic factors affect male infertility (2,3). ...
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Pinpointing causal genes for spermatogenic failure (SpF) on the Y chromosome has been an ever daunting challenge with setbacks during the past decade. Since complex diseases result from the interaction of multiple genes and also display considerable missing heritability, network analysis is more likely to explicate an aetiological molecular basis. We therefore took a network medicine approach by integrating interactome (protein-protein interaction (PPI)) and transcriptome data to reconstruct a Y-centric SpF network. Two sets of seed genes (Y genes and SpF-implicated genes (SIGs)) were used for network reconstruction. Since no PPI was observed among Y genes, we identified their common immediate interactors. Interestingly, 81% (N=175) of these interactors not only interacted directly with SIGs, they were also enriched for differentially expressed genes (89.6%;N=43). The SpF network, formed mainly by the dys-regulated interactors and the two seed gene sets, comprised three modules enriched for ribosomal proteins and nuclear receptors for sex-hormones. Ribosomal proteins generally showed significant dys-regulation with RPL39L, thought to be expressed at the onset of spermatogenesis, strongly down-regulated. This network is the first global PPI network pertaining to severe SpF and if experimentally validated on independent datasets can lead to more accurate diagnosis and potential fertility recovery of patients.
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Aim The aim of the present study is to evaluate the fertility outcomes of intracytoplasmic sperm injection (ICSI) as well as sperm count, motility and morphology in couples with infertile male partners exhibiting idiopathic oligoasthenozoospermia (OA) and treated with tamoxifen citrate and/or L-carnitine. Materials and methods In this randomized controlled trail, couples with female cause of infertility were excluded. Only couples with male cause of infertility with idiopathic OA were admitted to this study and randomly assigned into four different groups of treatments as follow: Group A (n = 45) received an anti-estrogen compound (tamoxifen 20 mg/day), group B (n = 20) received L-carnitine (1000 mg/day), group C (n = 34) received tamoxifen 20 mg/day plus L-carnitine 1000 mg/day, whereas group D (n = 29) received placebo. Treatments were continued for 3 to 6 months. Results Treatment groups of A, B, and C showed an overall improvement in the tested parameters of sperm when compared to the control group that showed an overall reduction in those parameters after termination of the treatment. In this context, sperm count increased from 7.58 ± 2.93 × 10 ⁶ /ml before treatment to 10.81 ± 1.84 × 10 ⁶ /ml after treatment in group A (p = 0.016). Similarly, sperm count increased from 5.32 ± 2.09 × 10 ⁶ /ml to 8.92 ± 2.29 × 10 ⁶ /ml in group C (p = 0.01). Patients from group C did not only have an improved total motility of sperm from 8.03 ± 1.59% to 13.78 ± 3.85% (p = 0.045) but also an improved sperm normal morphology from 0.88 ± 0.45% to 1.99 ± 0.71% (p = 0.026). Patients from group A or C exhibited an improved ICSI outcomes when compared to those in patients from group B or D (48.9 or 48.3 vs 16.6 or 20, respectively, p = 0.46). Conclusion It is concluded that administration of tamoxifen and L-carnitine can improve both sperm parameters of fertility and ICSI outcomes. Combined tamoxifen and L-carnitine treatments result in maximum therapeutic effect in men with idiopathic OA. How to cite this article Haje M, Naoom K. Combined Tamoxifen and L-Carnitine Therapies for the Treatment of Idiopathic Male Infertility Attending Intracytoplasmic Sperm Injection: A Randomized Controlled Trial. Int J Infertil Fetal Med 2015;6(1):20-24.
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Defective sperm function is the most common cause of infertility, and until recently, was difficult to evaluate and treat. Mammalian spermatozoa membranes are rich in poly unsaturated fatty acids and are sensitive to oxygen induced damage mediated by lipid peroxidation. Hence, free radicals and reactive oxygen species [ROS] are associated with oxidative stress and are likely to play a number of significant and diverse roles in reproduction. The excessive generation of reactive oxygen species by abnormal spermatozoa and by contaminating leukocytes [leukocytospermia] has been identified as one of the few defined etiologies for male infertility. Moreover, environmental factors, such as pesticides, exogenous estrogens, and heavy metals may negatively impact spermatogenesis since male sperm counts were declined. In addition, aging is also likely to further induce oxidative stress. Limited endogenous mechanisms exist to reverse these damages. In a normal situation, the seminal plasma contains antioxidant mechanisms which are likely to quench these ROS and protect against any likely damage to spermatozoa. However, during genitourinary infection/inflammation these antioxidant mechanisms may downplay and create a situation called oxidative stress. Assessment of such oxidative stress status [OSS] may help in the medical treatment of male infertility by suitable antioxidants. The cellular damage in the semen is a result of an improper balance between ROS generation and scavenging activities. Therefore, numerous antioxidants such as vitamin C, vitamin E, glutathione, and coenzyme Q10, have proven beneficial effects in treating male infertility. A multi-faceted therapeutic approach to improve male fertility involves identifying harmful environmental and occupational risk factors, while correcting underlying nutritional imbalances to encourage optimal sperm production and function.
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Objective To investigate whether pregnancy-induced hypertension (PIH) may increase oxidative stress in women with PIH, and to explore the mechanisms by which PIH may increase oxidative stress and potential free radical damage. Methods Seventy women with PIH and seventy women with uncomplicated normotensive pregnancy (UNP) whose age, nutritional conditions, levels of hemoglobin and albumin were all matched, were enrolled in a randomized controlled trial. Their plasma concentrations of nitric oxide (NO), vitamin C (VC), vitamin E (VE), and beta-carotene (beta-CAR) as well as their erythrocyte malondialdehyde (MDA), and activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) were determined by spectrophotometry. Results Compared with average values of the above experimental parameters in the women with UNP, the average value of erythrocyte MDA in the women with PIH significantly increased (P < 0.0001), while the average values of plasma NO, VC, VE, and beta-CAR as well as those of erythrocyte SOD, CAT, and GPX in the women with PIH significantly decreased (P < 0.0005-0.0001). The findings from partial correlation analysis (controlling for age) for 70 women with PIH showed that with elevated systolic blood pressure (SBP) and diastolic blood pressure (DBP), MDA value gradually increased (P < 0.001), and NO, VC, VE, beta-CAR, SOD, CAT, and GPX values gradually decreased (P < 0.02-0.001). The findings from reliability analysis for NO, VC, VE, beta-CAR, SOD, CAT, GPX, and MDA values used to reflect increased oxidative stress and potential free radical damage in women with PIH showed that the reliability coefficients (alpha, 8 items) = 0.7062, P < 0.0001, and the standardized item alpha = 0.9116, P < 0.0001. Conclusion The findings in the present research suggest that pregnancy-induced hypertension can increase oxidative stress and potential free radical damage in women with pregnancy-induced hypertension.
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Varicoceles are common. They may be detected in 15% of the male population, 35% of men with primary infertility, and as many as 80% of men with secondary infertility. A substantial body of evidence suggests that varicoceles cause a progressive decline in testicular function over time. The most likely pathophysiologic mechanism is an elevation of testicular temperature owing to impaired scrotal thermoregulation. Refined methods of varicocele repair have improved results and reduced the incidence of complications. Although controversy continues regarding varicocelectomy as a treatment of male factor infertility, abundant data support this form of therapy. Ultimately, a final answer will require a large, prospective, randomized, and controlled study using a microsurgical artery- and lymphatic- sparing technique.
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Feeding-deterrent activities of the methanol extracts from the brown algae of the family Laminariaceae, Ecklonia cava, E. kurome, Laminaria japonica, L. religiosa, L. angustata, and L. angustata var. longissima, were tested on the ezo-abalone Haliotis discus hannai by a bioaasay with the cellulose plate method. Three phlorotannin-rich fractions from the methanol extracts of E. cava and E. kurome, which are perennial algae, showed potent feeding-deterrent activity as in the cases of E. stolonifera and Eisenia bicyclis. On the other hand, none of the fractions from the methanol extracts of four Laminaria species, which are annual algae, showed any significant feeding-deterrent activity as in the cases of Eckloniopsis radicosa. Among four perennial species, the feeding-deterrent activities are, in order of effectiveness, E. stolonifera, E. kurome, E. cava, and Eisenia bicyclis, this being in reciprocal proportion to their size. It was concluded that laminariaceous algae have a chemical defense mechanism against marine herbivores, which adaptively depends on the rate of algal growth and size.
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食用海藻として期待されているアラメ(Eisenia bicyclis)に含まれる抗酸化性物質5種を薄層クロマト法で検出後、単離した。それらの構造をNMR, FAB-MS等を用いて分析し、それぞれ、 phloroglucinol, eckol, phloro fucofuroeckol A, dieckol, 8,8'-bieckol であると同定した。これらフロロタンニン類の抗酸化性を α- リノレン酸メチルを用いて評価した。
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Background We investigated the therapeutic efficacy of a new composite natural drug based on Tribulus terrestris, BIOVIS® and the alga Ecklonia bicyclis in order to improve male sexual function, selecting patients using the International Index of Erectile Function (IIEF), Nocturnal Penile Tumescence and Rigidity Testing (NPTR) using the RigiScan® device and hormonal levels.
Article
The antioxidant properties of cinnamophilin were evaluated by studying its ability to react with relevant reactive oxygen species, and its protective effect on cultured cells and biomacromolecules under oxidative stress. Cinnamophilin concentration-dependently suppressed non-enzymatic iron-induced lipid peroxidation in rat brain homogenates with an IC50 value of 8.0±0.7 μM and iron ion/ADP/ascorbate-initiated rat liver mitochondrial lipid peroxidation with an IC50 value of 17.7±0.2 μM. It also exerted an inhibitory activity on NADPH-dependent microsomal lipid peroxidation with an IC50 value of 3.4±0.1 μM without affecting microsomal electron transport of NADPH-cytochrome P-450 reductase. Both 1,1-diphenyl-2-picrylhydrazyl and 2,2′-azo-bis(2-amidinopropane) dihydrochloride-derived peroxyl radical tests demonstrated that cinnamophilin possessed marked free radical scavenging capacity. Cinnamophilin significantly protected cultured rat aortic smooth muscle cells (A7r5) against alloxan/iron ion/H2O2-induced damage resulting in cytoplasmic membranous disturbance and mitochondrial potential decay. By the way, cinnamophilin inhibited copper-catalyzed oxidation of human low-density lipoprotein, as measured by fluorescence intensity and thiobarbituric acid-reactive substance formation in a concentration-dependent manner. On the other hand, it was reactive toward superoxide anions generated by the xanthine/xanthine oxidase system and the aortic segment from aged spontaneously hypertensive rat. Furthermore, cinnamophilin exerted a divergent effect on the respiratory burst of human neutrophil by different stimulators. Our results show that cinnamophilin acts as a novel antioxidant and cytoprotectant against oxidative damage.