ABOUBAKR ELNASHAR

1. ANTIOXIDANTS
for female infertility
Review of systematic
reviews
Prof. Aboubakr
Elnashar
Benha university, Egypt
ABOUBAKR ELNASHAR

2. I. INTRODUCTION
1. IMPORTANCE OF THIS REVIEW
2. OXIDATIVE STRESS
3. ANTIOXIDANTS
1. What?
2. Examples
3. Sources
4. Treatment strategies using antioxidants
5. Antioxidants used in female infertility
6. Mechanism of action
II. AIM OF THE REVIEW
III. METHODS
IV.RESULTS
V. Conclusion
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3. I. INTRODUCTION
1. IMPORTANCE OF THIS REVIEW
Antioxidants
Readily available, mostly unregulated
Significant number of infertile
Taking antioxidants in the expectation that this will
improve their chances of conception
(Stankiewicz 2007).
Many doctors
 Prescribing expensive antioxidants
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4. What is the Evidence:
Whether antioxidants improve fertility?
Limited
Trials show different results
It is important to establish
Whether or not this therapy does improve fertility?
whether it is associated with any harm?
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5. 2. OXIDATIVE STRESS
ROS (Reactive Oxygen Species) & Antioxidants are
contained in balanced levels throughout the body
: maintain homeostasis and prevent oxidative stress.
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6. Impact of oxidative stress on female reproduction
1. Endometriosis
2. Hydrosalpinges
3. PCOS
4. Unexplained infertility
5. Age related infertility
6. Early Menopause
7. ART: poor outcome
{increased ROS in semen and culture media}
(Zhao, 2006; Ruder, 2008)
1. Fetal malformations
2. Miscarriage
3. IUGR
4. PTL
5. PET
6. Hydatiform mole
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7. 3. ANTIOXIDANTS
1. What?
Biological and chemical compounds that
Reduce oxidative damage
Give an electron to free radical molecules convert
them to an harmless configuration
avoiding damaging chain reaction, which can involve
lipids, proteins enzymes carbohydrates, DNA, cell
and nuclear membranes up to the cell death.
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8. 2. Examples
1. Enzymes
Superoxide dismutase(SOD)
Catalase
Glutathione Peroxidase/reductase
2. Non-enzymes:
Vits (E, C, B complex)
Polyphenols (flavonoids)
Carotenoids
Trace minerals
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9. ABOUBAKR ELNASHAR

10. 3. Sources
1. Acquired from dietary sources
2. Endogenously formed
In females antioxidants are found in:
Ovarian follicles
Follicular, tubal and peritoneal fluid
Endometrial epithelium
In males antioxidants are found in:
Testis
Epididymis
Secretions of the male accessory organs
Seminal plasma .
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11. ABOUBAKR ELNASHAR

12. 4. Treatment strategies using antioxidants
1. Alone with no ART
in an attempt to improve fertility.
2. Several months prior to ART:
minimize endogenous sources of ROS
3. Simultaneously with ART
4. In vitro supplementation:
in media during the ART protocol itself:
minimize exogenous sources of ROS
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13. 5. Antioxidants used in treatment of female infertility
I. Single antioxidant
1. N-acetyl-cysteine;
2. Melatonin
3. Vitamins A, C and E
4. Folic acid
5. Myo-inositol
6. Zinc
7. Selenium.
8. Pentoxiphylin
9. L arginine
10.PUFAs
II. Combined antioxidant
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14. 6. Mechanism of action
Antioxidants neutralize pro-oxidants by either
1. Preventing its formation via termination of
propagative oxidative chain reactions
2. Scavenging existing ROS:
maintaining the delicate pro-oxidant/anti-oxidant
balance:
protecting the cell and its microenvironment
from oxidative damage
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15. Vit E
 improvement in epithelial growth in blood vessels
and in the endometrium
(Ledee-Bataille 2002).
Higher vit D levels
increased likelihood of successful pregnancy and
may be of particular benefit to women with PCOS in
lowering hyperandrogenism
(Thomson 2012).
Myo-inositol
helps ovarian function and decreases
hyperandrogenism and insulin resistance
(Nestler 1998)
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16. L-arginine
Improves endometrial blood flow
(Battaglia 1999)
N-acetyl-cysteine
needed for fertile cervical mucus and ovulation
(Badawy 2007)
PUFAs
influence prostaglandin synthesis and
steroidogenesis and also play a role in the
composition of cell membranes of the spermand
oocyte, which is important during fertilisation
(Wathes 2007).
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17. II. AIM OF THE REVIEW
Whether antioxidants improve fertility ?
III. METHODS
Pub med search:
from 2000 to January 2017
Key words:
Systematic Reviews
Antioxidants, infertility, IVF, ICSI
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18. WHAT IS THE BEST EVIDENCE?
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19. RESULTS
3 Cochrane SR
3 Non Chochrane SR
1. Pentoxifylline for endometriosis. Cochrane SR
(Lu et al, 2012)
2. Vitamin D for PCOS. SR
(Thomson, 2012)
3. Effect of myoinositol on PCOS. SR
(Unfer 2012).
4. Antioxidants for female subfertility. Cochrane SR
(Showell et al, 2013)
5. Melatonin supplementation during COS
(Seko et al, 2014)
6. Oral antioxidant supplementation in women seeking
IVF/ICSI. Cochrane SR
(Youssef et al, 2015)
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20. 1. Pentoxifylline for subfertile women with
endometriosis
(Cochrane SR, Lu, 2012)
Dose:
Pentoxifylline 400 mg twice a day for 12 months
Evidence is insufficient
to support use of pentoxifylline in tt of endometriosis
in terms of
subfertility and
relief of pain outcomes.
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21. 2. Vitamin D for PCOS.
(SR, Thomson, 2012)
Evidence is limited
for the beneficial effects of vitamin D supplementation
on menstrual dysfunction
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22. 3. Effect of myoinositol on PCOS
(SR, Unfer, 2012).
Dose:
2 g/d given over 3 months
Beneficial effect
improving insulin sensitivity of target tissues
positive effect on the reproductive axis
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23. 4. Antioxidants for female subfertility
(Cochrane SR, Showell et al, 2013)
Antioxidants;
were not associated with an increased LBR
compared with placebo or no treatment/standard
treatment
(OR1.25, 95% CI 0.19 to 8.26, P = 0.82, 2 RCTs, 97 women, I2 = 75%, very
low-quality evidence).
Antioxidants were not associated with an increased
CPR compared with placebo or no treatment/standard
treatment
(OR 1.30, 95% CI 0.92 to 1.85, P = 0.14, 13 RCTs, 2441 women, I2= 55%, very
low-quality evidence).
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24. Subgroup analysis
1. women undergoing IVF/ICSI:
No evidence
of effects of antioxidants
No benefit or harm from antioxidants for a
particular indication of infertility
No association between antioxidants and
CPR
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25. 2. Combined antioxidants:
An association with CPR
However, only 3 trials were included in this MA
3. Single antioxidant
No association was seen with
N-acetyl-cysteine
Melatonin
vit E
Ascorbic acid
L-arginine or
Myo-inositol.
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26. Pentoxifylline
Was associated with an increased CPR in women
undergoing IVF/ICSI
Dose:
Pentoxifylline: 400 mg
Vit E: 400 mg twice a day for two cycles
before ICSI
However, only 3 trials
2 reported on pentoxifylline
1 reported on pentoxifylline plus vitamin E.
No association between pentoxifylline and CPR in
endometriosis
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27. 4. PCOS:
An association was between antioxidants and CPR
However, heterogeneity was extremely high.
5. Endometriosis
Unexplained infertility
Tubal infertility
No association was seen between antioxidants
and CPR
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28. 5. Melatonin supplementation during COS for ART
(SR, Seko et al, 2014)
Dose:
3mg from D5 till OR day
5 RCT:
pooled risk ratio of 1.21 (95% CI 0.98 - 1.50) in favour
of melatonin for the outcome of CPR.
However
adequacy of the data evaluating is poor
should not yet be recommended for routine use
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29. 6. Oral antioxidant supplementation in women
seeking IVF/ICSI
(Cochrane SR, Youssef et al, 2015)
28 trials, 3548 women
very low quality evidence
Antioxidant intake was neither associated with:
increased CPR
(1 trials, 2441 women) (OR 1.30, 95% CI 0.92-1.85; P = 0.14,I2 = 55%)
nor with LBR
(2 trials, 97 women) (OR 1.25, 95% CI 0.19-8.26; P = 0.82, I2 = 75%).
Data from 3 trials (276 women):
Pentoxifylline was associated with increased CPR (OR
2.03, 95% CI 1.19-3.44, P = 0.009, I2 = 0%) in subfertile women
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30. Combined antioxidants
(multivitamins and minerals (amino acid chelated)
did not improve oocyte quality and CPR in women
with unexplained infertility undergoing IVF/ICSI
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31. CONCLUSION
Combined Antioxidant
No evidence
Of an association between Antioxidants and CPR
in women with
Endometriosis
Unexplained infertility
Tubal infertility
Undergoing IVF/ICSI
Insufficient evidence
Of an association between antioxidants and CPR
in women with PCOS
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32. Single Antioxidant
No evidence
Of association between CPR and
N-acetyl-cysteine
Melatonin
vit E
Ascorbic acid
L-arginine or
Myo-inositol.
Insufficient evidence to support the use of
Pentoxifylline in treatment of endometriosis
Vit D supplementation in PCOS
Myo-inositol in treatment of PCOS
Pentoxifylline and vit E before ICSI
Melatonin before ICSI
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33. ABOUBAKR ELNASHAR
You can get this lecture from:
1.My scientific page on Face book:
Aboubakr Elnashar Lectures.
https://www.facebook.com/groups/2277
44884091351/
2.Slide share web site
3.elnashar53@hotmail.com
4.My clinic: Elthwara St. Mansura

34. Cochrane Database Syst Rev. 2017 Jul 28;7:CD007807. doi: 10.1002/14651858.CD007807.pub3.
Antioxidants for female subfertility. Showell MG , Mackenzie-Proctor R, JordanV, Hart RJ.
Abstract A couple may be considered to have fertility problems if they have been trying to
conceive for over a year with no success.This may affect up to a quarter of all couples
planning a child. It is estimated that for 40% to 50% of couples, subfertility may result from
factors affecting women. Antioxidants are thought to reduce the oxidative stress brought on
by these conditions. Currently, limited evidence suggests that antioxidants improve fertility,
and trials have explored this area with varied results.This review assesses the evidence for the
effectiveness of different antioxidants in female subfertility.To determine whether
supplementary oral antioxidants compared with placebo, no treatment/standard treatment
or another antioxidant improve fertility outcomes for subfertile women.We searched the
following databases (from their inception to September 2016) with no language or date
restriction: Cochrane Gynaecology and FertilityGroup (CGFG) specialised register, the
Cochrane Central Register of Studies (CENTRAL CRSO), MEDLINE, Embase, PsycINFO,
CINAHL and AMED.We checked reference lists of appropriate studies and searched for
ongoing trials in the clinical trials registers.We included randomised controlled trials (RCTs)
that compared any type, dose or combination of oral antioxidant supplement with placebo,
no treatment or treatment with another antioxidant, among women attending a reproductive
clinic.We excluded trials comparing antioxidants with fertility drugs alone and trials that only
included fertile women attending a fertility clinic because of male partner infertility.Two
review authors independently selected eligible studies, extracted the data and assessed the
risk of bias of the included studies.The primary review outcome was live birth; secondary
outcomes included clinical pregnancy rates and adverse events. We pooled studies using a
fixed-effect model, and calculated odds ratios (ORs) with 95% confidence intervals (CIs) for
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