Role of antioxidants in female infertility Dr. Jyoti Agarwal Lifecare IVF Center New Delhi.
-
Upload
candace-rose -
Category
Documents
-
view
219 -
download
1
Transcript of Role of antioxidants in female infertility Dr. Jyoti Agarwal Lifecare IVF Center New Delhi.
Oxygen toxicity is an inherent challenge to aerobic life
• Oxygen is essential for life.
• Excess oxygen can have harmful effects.
• When oxygen is metabolised in the body , it produces substances called FREE RADICALS which damage our cells.
Oxidative process occur in all cells and tissues throughout human body.
Oxidation reactions can produce free radicals
Free radicals are like robbers which are themselves deficient in energy.
They attack and snatch energy from other cells to satisfy themselves.
Free radical with unpaired electron
Free radicals cause damage by oxidation
Free radicals are highly reactive and can cause damage to molecules in the cell.
ROS PARADOX (delicate balance)
ROS are key signal molecules in many physiological process to maintain cell homeostasis
Whenever there is an excess they precipitate pathologies
ROS act as double edged sword
Prooxidants >>> antioxidants = oxidative stress
Asthma
Arthrits
CVD
ParkinsonsDiabetes
Cancer
Infertility
Oxidative Stress
Counteracting free radical damage
The only defence in this war against free
radicals is by antioxidants.
Antioxidants in action
Oxidation occurs when the apple is left exposed to air
The apple is protected when dipped in orange juice containing the antioxidant vitamin C
Antioxidants prevents
• Lipid peroxidation
• Oxidative damage to protein
• Oxidative damage to DNA
• ANTIOXIDANTS have low redox potential and will sacrifice themselves to prevent oxidative damage
Antioxidants are of two types
• Primary / Enzymatic / natural
• superoxide dismutase
• catalase
• glutathione peroxidase
• glutathion reductase
• Secondary / Non enzymatic / synthetic / dietary supplements• vitamin C
• vitamin E
• selenium
• zinc
• taurine , hypotaurine
• glutathion
• beta carotene , carotene
Antioxidants and infertility
• Etiologies of unexplained infertility and recurrent pregnancy loss remains unclear and present a scientific challenge.
• Oxidative stress is a piece in this puzzle.
Oxidative stress is associated with
• Age related decline in fertility
• Decline in ovarian function
• Decrease steroidogenesis
• ROS negatively affects oocyte maturation
• Decreased oocyte penetration of sperm
• ↓ fertilization and blastocyst development
• Decreased implantation
• Increased loss of implanted embryo
OS affects multiple physiological processes ….. oocyte maturation to fertilization & embryo
development
Reactive oxygen species and the endometrium
• There is a cyclical variation in the expression of superoxide dismutase(SOD) in the endometrium.
• In the late secretory phase SOD activity decreases and levels of ROS increases.
• It is important for endometrial shedding and the onset of menstruation.
Reactive oxygen species and the ovary
• Various biomarkers of OS has been demonstrated in normal cycling human ovaries.
• A delicate balance exists between ROS and antioxidant enzymes in the ovarian tissue.
• These antioxidants enzymes neutralise ROS production and protect the oocycte.
Role of ROS in Endometriosis
• An increased generation of ROS by pelvic macrophages and increased lipid oxidation in patients with endometriosis. (Halme et al)
• Antioxidant levels of superoxide dismutase (SOD) were noted to be significantly lower in peritoneal fluid in patients of endometriosis
• Increased ROS levels in the tubal and the peritoneal environment negatively alter fertilization and embryonic development .
(fertil steril 2003 )
Role of ROS in PCODElevated insulin resistance and hyper homocysteinemia has been
proposed to be caused by OS in patients with PCOD.(j clin endocrino metab 2006) .
Antioxidant supplementation has been shown to improve insulin sensitivity.
The decreased antioxidants status and the increased OS levels may contribute to the increased cardiovascular morbidity in these patients.(fertil steril 2003)
Impact of OS on assisted reproductionThere are multiple sources of ROS generation in patient undergoing ART…
• Oocytes (4 – 5 /dish)
• Cumulus cell mass
• Sperms
• Prolongation of sperm – occyte co incubation time of more than 20 hrs
• ROS levels in day 1 culture media
Impact of ROS on assisted reproduction
Causes a perturbed redox state and affects the development of the embryo by….
• Altering the gene expression
• Impaired adenosine triphosphate production
• Two cell arrest of embyro
• Embyropathies
ROS levels can be utilised to counsel patients before IVF. (agarwal et al ferti steri 2005 )
Oxidative stress influences the entire reproductive span of a women’s life and even
thereafter , i.e. menopause
Assessing levels of ROS and OS
• Electron spin resonance… it identifies the molecules containing unpaired electrons.
• Stable peroxidation product concentrations.. malondialdehyde , lipid peroxidase , and conjugated dienes.
No standard reference valuesNo defined Sensitivity & Specificity
Strategies to overcome oxidative stress in infertility and ART
When OS is diagnosed treatment must focus on identifying and eliminating the source of ROS.
Smoking
Alcohol
Obesity
Stress
Poor diet
Only after the treatment of primary etiology should patients be advised to take antioxidant
supplementation
Antioxidants
Iron• Important mineral for
general well-being and energy
• a subtle deficiency of iron
Female subfertility
Magnesium• Helpful in unexplained
infertility since most have micronutrient deficiency with ROS
• In vitro study shows oocyte activation on exposure to magnesium
http://conditionsinfo.mitamins.com/sexual-Health-STDs/Female-Infertility-Vitamins.html
Zinc essential cofactor for several metabolic reactions
Zinc deficiency
Impairs
Synthesis & Secretion
of FSH
Abnormal
Ovarian development
Impairs
Synthesis & Secretion of LH
Female Infertility
Irregular OvulationImpairment of oocyte maturation
Experientia.1994 Jul 15;50(7):626-40
Zinc .. Supplementation helps to:
• Regulate ovarian development
• Improves oocyte maturation & ovulation
Exerts beneficial effect in female infertility
Vitamin C
• most important antioxidants in extra cellular fluids
• Vitamin C is a chain breaking antioxidant.
• protects tissues against oxidative damage
• It also helps recycle oxidized vitamin E and glutathion.
Vitamin E… strongest antioxidant present‘a free radical scavenger’
Protects the DNA in the cells from damage
Beta-Carotene-provitamin
• Carotenoids are a group of red, orange and yellow pigments found in plant foods, particularly fruits and vegetables.
N-acetyl cysteine : Powerful antioxidant:
NAC
↑ reduced glutathione at cellular level
Acts directly on reactive oxidant radicals
Exerts protective effects to cells
Antioxidant effect
Not found in diet, available as a nutritional supplement
N-acetylcysteine. Altern Med Rev. 2000 Oct;5(5):467-71Rizk et al. Fertil Steril. 2005 Feb;83(2):367-70
Additional benefits of NAC
Improve insulin sensitivityPreserve vascular integrity by vasodilator effectsAntiandrogenic effect: ↓ testosterone levels &
also ↓ free androgen index (FAI)
As an antioxidant and mucolytic agent it detoxify harmful substances in body and promote sperm motility & survival in female genital tract
Badawy et al. Acta Obstetricia et Gynecologica. 2007; 86: 218-222 Detti et al. Diabetes. 2003; 52: 499-505Millea PJ. Am Fam Physician. 2009 Aug 1; 80(3):265-9 Pieper et al. J Cardiovasc Pharmacol 1998; 32:101–5Fulghesu et al. Fertil Steril 2002; 77:1128 –35
L-Arginine • An semi-essential amino acid
• Well known as a precursor to nitric oxide (NO)
• Lower levels of L Arginine causes delayed conception, decline in oocyte fertilization and implantation rates
Acta Obstet Gynecol Scand 2005; 84: 1029-1034
Acta Obstet Gynecol Scand 2005; 84: 883-886
(p < 0.01)(p < 0.05)
Nitric oxide→ increases cervical secretion → improve chances of conception
Measure of cervical secretion: by weight & volume
L-arginine supplementation was reviewed in patients with thin endometrium and high radial artery resistance index
9 patients were given L-arginine and 10 control patients were not given any medication
L-arginine improved RA-RI in eight (89%) out of nine pts & endometrial thickness (ET) in six (67%) patients which was seen in only 1 patient in control group
Improves RA-RI and ET → ↑ uterine blood flow & endometrial receptivity
Takasaki A et al. 2010; 93(6): 1851-8
Sources of L-arginine:
Animal sources:– Dairy products (e.g. milk, yogurt, cottage cheese etc.)– Beef, poultry food, seafood (e.g. lobster, shrimp, snails
etc.)
Vegetable sources:– Wheat, oatmeal, peanuts– Nuts (coconut, walnuts, almonds etc.), soybeans
Grape Seed Extract
Bagchi D. et al. Res Commun Mol Pathol Pharmacol, 1997; 95(2): 179-89Bagchi D. et al. Gen Pharmacol, 1998; 30(5): 771-6
In vitro study: (superoxide anion and hydroxyl radical)
Antioxidants Inhibition of free radicals
GSPE 78-81 %
Vitamin C 12-19 %
Vitamin E succinate 36-44 %(Concentration: 100mg/l)
In animal study: Protective effects of GS-Proanthocyanidins & other antioxidants in mice
Antioxidants ↓ production of ROS
GSPE (20-100mg/kg) 70 %
Vitamin C (100mg/kg) 18 %
Vitamin E succinate (100mg/kg) 47 %
Beta-carotene (50mg/kg) 16 %
Powerful antioxidant: proanthocyanidins
• Green tea, Vit B6, B12,
• Reduces free radical damage
• Improves overall reproductive health
Green tea catechins are 100 times more potent than vitamin C
Hot cocoa tops red wine and tea in antioxidants
2-3 times stronger than green tea, and 4-5 times stronger than black tea
Deficiency of
Vitamin B12
&
Vitamin B6
Increase in Oxidative Stress
Vitamin B12 & Vitamin B6
Failure in Ovulation
Defective Implantation
FemaleInfertility
Asia Pac J Clin Nutr.2005;14(3):250-5 Int J Fertil.1991Jan-Feb;36(1):36-8J Reprod Med.2001 Mar;46(3):209-12 Schweiz Med Wochenschr.1984 Feb 4;114(5):178-9
Human Reproduction Update 2007; 13(3): 225–238
Vitamin B12 &Vitamin B6Supplementation helps to :
Reduce oxidative stress
Improve ovulation
Thus improve reproductive health
J of Reproductive Medicine April 2004
Folate (Folic Acid)Deficiency of folate
Homocysteine & Oxidative stress
Reducedfolliculogenesis
Production of inflammatory
cytokine
Altered Nitric oxidemetabolism
Apoptosis
Female InfertilityAll leads to
Human Reproduction Update 2007; 13(3): 225–238
Folate
Improve
X
Antioxidants in combination
Antioxidants are believed to work better in combination than supplementing alone.
• Together they protect oxidation of each other
• Together they preclude the need for large doses of single nutrient
Clin Exp Obstet Gynecol. 2006;33(4):205-8
There is lack of consenus on the type and dosage of antioxidants to be used.
Validation by large randomised double blind case control trials is needed as evidence
Take Home Message…..
• Oxidative stress has a significant impact on female infertility.
• The role of oxidative stress in female reproduction cannot be underestimated.
• The best way to add antioxidants to the diet is to eat generous servings of fruits and vegetables daily.
J of Reproductive Medicine April 2004
Antioxidants optimize the environment and offers complementary role to correct and support female factor fertility and conception