antioxidants and male infertility dr. abhishek singh parihar m.s.( obs & gynae), fellow...
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ANTIOXIDANTS AND MALE INFERTILITY
DR. ABHISHEK SINGH PARIHAR
M.S.( OBS & GYNAE), FELLOW REPRODUCTIVE MEDICINE.
CONSULTANT : LIFECARE I.V.F
E), FELLOW REPRODUCTIVE MEDICINE
Consultant – Life care IVF
In 40- 60% Of Infertile Couples A Male Related Problem Is A Cause Of Infertility .
Sperm production cycle occurs in a mean 64 ± 8 days (range: 42–76 days)—(by stable isotope and gas spectrometric analysis)
Several reports describe reduction in male fertility over recent decades.
Estimates that sperms counts in U.S males decreasing by 1.5% each year
50%
30%-80% of infertile men have elevated markers of OS Agarwal et al., Urology 2006
Reactive Oxygen Species (ROS)(Log ROS + 1; cpm)
OXIDATIVE STRESS
An emergingexplanationfor several
cases of maleinfertility
2,5
2
1,5
1
0,5
0
REACTIVE OXYGEN SPECIES (ROS)
Chemical species with unpaired electron capable to oxidize lipids, proteins and nucleic acids:
Superoxide anion (•O-2) Hydroxyl radical (•OH) Hydrogen peroxide (H2O2) Peroxyl radical (ROO•) Hypochlorite ion (OCl-) Generated from aerobic metabolism in mitochondria. Sources: Leukocytes (extrinsic) Spermatozoa (intrinsic) Sperm and Seminal Plasma Antioxidants: Enzymatic (SOD, catalase, GPX): inactivate ROS
(conversion into other substances) Non-enzymatic (ascorbic acid, alpha-tocopherol,
carnitine, etc.): neutralize ROS Lampiao et al., Oxidative stress. In: Male Infertility. Parekattil & Agarwal (eds) 2012, pp.225-35
SPERM DNA FRAGMENTATION AND ASSISTED CONCEPTION
Live Birth Rates byIntrauterine Insemination
OR = 0.07 [95% CI: 0.01-0.48]
Normal Elevated
Pregnancy by Method in Casesof Elevated Sperm DNA
Fragmentation
42%
26%
P <0.05
Adapted from Bungum et al., Hum Reprod 2007
ICSI
1.5%
IVF
19%19%
19%
SPERM DNA FRAGMENTATION AND MISCARRIAGEPopulation: Meta-analysis of 16 cohort studies (2,969 couples), 14 prospective.Techniques for DNA integrity:Acridine orange-based assays, TUNEL and COMET. Findings: Significant increase in miscarriage rates in patients undergoing IVF/ICSI with high sperm DNA damage compared with those with low DNA damage. Risk ratio (RR) = 2.16 (1.54, 3.03), P < 0.00001).
Miscarriage rates are positively correlated with sperm DNA damage levels
I Robinnson L et al. Hum Reprod. 2012; 27(10): 2908-17 Rob
SIGNS OF OXIDATIVE STRESS IN SEMEN ANALYSIS Reduction of sperm parameters
( Asthenozoospermia is the best surrogate marker of OS ( Kesks et al. , Ammar et al. )
DNA fragmentation ( Kao et al. 2007)
Hyperviscosity– (ureaplasma infection ? ) Semen leukocytes ( round cells ) count using
peroxidase or seminal elastase test ( Kopa et al. 2003)
Testing Malondialdehyde level in sperm/seminal
plasmaOr
Chemoluminescence assays using luminol/lucigenin are expensive, complicated and highly sensitive.
MANAGEMENT OF OS –RELATED INFERTILITY
In >80% of males medical treatment is ineffective .General measures1 –Lifestyle modification ( smoking , poor diet ,
alcohol ,obesity, stress)
2–Avoid activities heating the scrotum
3–Proper ventilation /use of personal protective equipment to reduce exposure to chemicals /metals linked with OS
4–Treatment of infections / variecocele5–ANTIOXIDANTS ,VITAMINS AND FOOD
SUPPLEMENTATION.
ROLE OF MICRONUTRIENTS IN FERTILITY
Nutrition plays vital role in maintaining
male fertility:
Involved in the successful maturation
of sperm
Provides nutrition for motility of sperm
Improvement in sperm count and
motility
Helps in production of sex hormones
Prevents sperm damage
NUTRITIONAL CONSIDERATIONS
Various micronutrients are
associated with male
fertility.
Deficiency of these
Micronutrients &
ANTIOXIDANTS may result
in infertility.
Nutritional Factors
Free radical scavengers L-Carnitine Lycopene Coenzyme Q10 Vitamin C Zinc Vitamin E Arginine Glutathione Vitamin B12 Selenium
IDEAL NUTRACEUTICAL FOR MALE INFERTILITY
Coenzyme Q10
Improves sperm motility by providing energy through ATP generation in mitochondrion
L-carnitine
Improves sperm motility by providing energy to the sperm cell through fatty acid metabolism
Lycopene
Increases sperm count and improves morphology by reducing oxidative damage to sperm DNA and lipids
Zinc
Promotes sperm production & maturation testosterone synthesis & improves sperm morphology
VITAMINS , MINERALS AND HERBS USED FOR INFERTILITY TREATMENT
Vitamins B complex combat the effect of oxidative stress. B5 –for hormone production Folic acid – Arole in RNA and DNA synthesis during
spermatogenesis and has antioxidative properties.
Vitamin C: Helps carry oxygen to sex organs Necessary for balanced hormone / sperm
production
Selenium is related to significantly a higher concentration of sperm per ejaculate .
Herbs: Red clover / rich in every trace element, vitamins and
proteins . Red raspberry – high in essential minerals . Damiana–potent aphrodisiac
ORAL ANTIOXIDANT THERAPY
Methodological weakness of antioxidants trials make it difficult to determine “who”,“how” and “for how long??
Patient selection and controls
Associated pathology
Single or combination antioxidants
Dosage & formulation
Outcome measures
Varying duration of treatment
Lack of diagnostic markers for oxidative stress
Presence of molecular and genetic differences
Controversies
ORAL ANTIOXIDANTSIN MALE INFERTILITY
BeneficialKodama 1997Dawson, 1992
Kessopoulou, 1995Vezina, 1996
Vicari, 2001; 2002Lenzi, 2003; 2004
Cavallini, 2004Comhaire, 2005
Grecco 2005Menezo 2007
Tremellen 2007Piomboni 2008Gil Villa 2009
No effectGiovenco, 1987Moilanen, 1993Iwanier, 1995
Rolf, 1999Sigman, 2006
Detrimentallong-term use andhigh doses;increased mortality
incancer population-based studies.
No Consensus Yet.
Short-term useappear to be safe.
Caution againstindiscriminate useof high dosages forlong periods.
HOW TO USE ANTIOXIDANT THERAPYTREATMENT STRATEGY
Once OS is diagnosed,focus on identifying and
controlling source of increased ROS
Varicocele Genital Infection
Smoking
Medication
Drug abuse Systemic disease
Pollution Radiation
Differentiate betweensperm and leukocytesource of ROS
Testing forLeukocytes in Semen
Select antioxidantformulation and dosage
Ascorbic acid (Vit. C)
- tocopherol (Vit. E)
Glutathione
N-acetyl-cysteine
Carnitine
Coenzyme Q10
Lycopene
Picnogenol
Pentoxifylline
Selenium
Shao-Fu-Zhu-Yu-Tang
Astaxanthin
Lepidium meyenii
-linolenic acid and lignans
Folic acid
Zinc
ORAL ANTIOXIDANTS IN MALE INFERTILITY
OUR FORMULA MAXOLA -L Co Enzyme Q 10-20mcg Vitamin B12 2.5 mcg
Folic acid 500 mcg Zinc Sulfate 10mg
Selenium 50 mcg Lycopene 2500mcg
Fructose 1g L-Carnitine fumarate -1g
Acetyl-L-Carnitine 0.5g Citric Acid 50mcg
PLAIN MAXOLA does not contain LYCOPENE.
How long: minimum 2 months
From initiation of sperm production to ejaculation
Old concept ~80 days
New concept 60 days
Oral AntioxidantsCochrane Review 2011
Outcome
Live birth
Pregnancy rate
DNA fragmentation
Miscarriage, spermcount, sperm motility
Adverse effects
Nstudies
3
15
1
6-16
6
participants
214
964
64
242-700
426
Effect size(OR; 95% CI)
4.85 [1.92, 12.24]
4.18 [2.65, 6.59]
-13.80 [-17.50, -10.10]
No effect
No effectImprove the outcomes of live birth and pregnancy rate for
subfertile couples undergoing ART cycles
ALTERNATIVE TREATMENT
Testicular (not epididymal) sperm extraction in men with poor sperm DNA quality if conservative treatment ( AO and lifestyle modification) have failed. ( Greco2005, O΄Connell 2002 ).
Reduce centrifugation time prior to IUI /IVF
Use of non–centrifuge separation techniques (swim–up etc…)
Limit the sperm culture time in media away from seminal plasma
ALTERNATIVE TREATMENT
Culturing sperm under low oxygen tension ( 5% O2) reduces seminal leukocyte ROS.
Avoid using frozen sperm (if possible ) since ROS are produced during freezing /thawing ( Watson 2000)
Supplement sperm separation media with a variety of AO ( catalase—Rossi et al 2001,vit.C — Zheng and Zhang, EDTA, glutathione/hypotaurine , albumin, N– acetyl–cysteine.
SUMMARY Oxidative stress impairs sperm function and is a risk factor for male infertility and miscarriage .
current evidence suggest that OA supplementation for subfertile males improve the chances for pregnancy and live birth for couples undergoing ART.
Well-designed studies are needed to determine the best candidate for AO therapy and which formulation and dosages yield better results.
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