1. Optimising fertility with nutrition
IIRRM September 2014

2. Glenville Nutrition Clinics in UK and Ireland
Run by Dr Marilyn Glenville PhD
Evidence-based protocols
Focus on getting pregnant, staying pregnant and having a healthy baby
In common with IIRRM, supporting patients’ reproductive function naturally
Talk will cover
some research on the nutrients shown to be important for fertility
Information about tests we use to determine nutritional status
Dietary advice for patients
Supplement do’s and don’ts
Lifestyle factors

3. The role of nutrition in fertility
‘There is strong evidence that complementary treatment with an appropriate nutraceutical improves the natural conception rate of infertile couples and increases the success rate of assisted reproductive techniques.’
(Comhaire F, 2010, Andrologia, 42, 5, )
Wealth of evidence for both male and female fertility

4. Causes of infertility Ovulatory failure including PCOS Tubal damage
Endometriosis
Male problems
Unexplained
20%
15% 5%
26%
30%
Nutrition can help with all except tubal damage
Mayo Clinic
In about one-third of cases, the cause of infertility involves only the male.
In about one-third of cases, the cause of infertility involves only the female.
In the remaining cases, the cause of infertility involves both the male and female, or no cause can be identified.
Napro Technology Ireland Dr Phil Boyle presentation – many patients come with unexplained infertility, but only a very small percentage remain in that category. Important to also identify nutrition and lifestyle issues that may be contributing to fertility issues and deal with them.

5. Three Month Action Plan
Diet
Lifestyle
Environmental / occupational hazards
Supplements
Medical investigations
Eggs take approx 90 days to mature
Sperm take approx 100 days (74 days to form and then days to mature)

6. Well-balanced diet is a myth
Fewer than 1 in 10 Americans meet their MyPyramid fruit or vegetable recommendations
(Kimmons, Medscape J Med, 2009; 11(1))
Netherlands – health conscious diet associated with lower DNA frag due to higher intake of fruit and veg – excellent sources of antioxidants, Vujkovic et al, 2009
Only 9% of Irish 18 – 64 yr olds are achieving the 400g of fruit and vegetables minimum recommended by the World Health Organisation
Fewer than 1 in 10 Americans meet their MyPyramid fruit or vegetable recommendations. Kimmons Medscape J Med. 2009; 11(1):  The primary contributors to total fruit intake were whole fruits among adults and fruit juices among adolescents. The largest single contributor to overall fruit intake was orange juice. Potatoes dominated vegetable consumption, particularly among adolescents, in whom fried potatoes increased the median vegetable intake from 0.72 cup to 1.21 cups per day. However potatoes should actually be in starch / carbohydrate category
We know from experience and from statistics that many people do not have a healthy or balanced diet
People are stressed. People undergoing fertility issues even more stressed. Impacts how and what they eat
USDA recommend 5 – 9 servings daily

7. Crucial nutrients for fertility for men and women
B vitamins including folic acid
Zinc
Vitamins C and E
Vitamin D
Selenium
Essential fatty acids
CoQ10
Amino acids L Carnitine and L Arginine also helpful for sperm health

8. Effects of zinc and folic acid on male factor subfertility
Subfertile men taking zinc and folic acid demonstrated a significant 74% increase in total sperm count
(Wong WY, 2002, Fertility and Sterility, 77, 3, 491-8)
Zinc: integral element in development of spermatozoa and DNA synthesis, acts as important antioxidant in seminal fluid

9. Zinc reduces oxidative stress
Zinc supplementation results in improved sperm parameters with less oxidative stress, sperm apoptosis and sperm DNA fragmentation index
(Omu AE et al, 2008, Med Princ Pract, 17, 2, )
Asthenozoospermia significantly associated with oxidative stress
Motility issues associated with low zinc levels, can be improved with zinc supplementation.
Food sources of zinc include
Seafood
Spinach
Pumpkin, sesame seeds
Cashew nuts, almonds
Mushrooms
Lentils, chickpeas
Asparagus
Quinoa
Tofu
Green leafy vegetables

10. Many antioxidants possess a beneficial effect on fertility
Their use is recommended as supportive therapy for the treatment of infertility in men.
(Walczak-Jedrzejowska R et al Cent European J Urol. 2013;66(1):60-67)
Non-enzymatic antioxidants include vitamins A, E, C, and B complex, glutathione, pantothenic acid, coenzyme Q10 and carnitine, and micronutrients such as zinc, selenium, and copper. It seems that a deficiency of any of them can cause a decrease in total antioxidant status. In vitro and in vivo studies demonstrate many antioxidants possess a beneficial effect on fertility and, therefore, their use is recommended as supportive therapy for the treatment of infertility in men.

11. Antioxidants support male fertility
Cochrane Review
34 studies, varied antioxidants
All undergoing assisted conception
Antioxidant users 5 times as likely to have a live birth compared to placebo
(Showell MG et al, 2011, Cochrane Database Syst Rev, CD007411)

12. Antioxidants support pregnancy rate
82% of the studies - resulted in an improvement in either sperm quality or pregnancy rate.
19% pregnancy rate with antioxidants compared to 3% in placebo group for natural conception.
(Ross C et al, 2010, Reprod BioMed Online, 20, )

13. Vitamin C Vitamin C can increase sperm counts by up to a third
(Akmal, M. et al, 2006, J Med Food, Fall, 9 (3), )
DNA fragmentation lower in men with higher
dietary intake of vitamin C
(Schmid et al., 2012 Fertil. Steril. 98, 1130–1137.e1)
Protects against DNA damage to sperm.

14. Vitamin E and vitamin C given to men after one failed ICSI treatment
Vitamins E and C
Vitamin E and vitamin C given to men after one failed ICSI treatment
Mean DNA fragmentation reduced from 22.1% to 9.1% in treatment group. No change in placebo group
Significant improvement in pregnancy rate (48.2% versus 6.9%) after just two months of treatment.
(Greco E et al, 2005, Hum Reprod, 20(9):2590-4)
Work synergistically
Vit C regenerates Vit E
In this study mean DNA frag markedly reduced from 22.1% to 9.1% in treatment group, with no change in placebo group
In follow up trial group divided into responders and non-responders. Responders DNA frag reduced from 24% to 8.2%

15. Vitamin C helpful for women
RCT with 150 patients
Vitamin C associated with significantly higher fertility rates and progesterone levels than placebo
(Dennehy CE, 2006, J Midwifery Womens Health, 51, )

16. Vitamins C and E support oocyte production in older women
Supplementation with vitamins C and E may help prevent the maternal age associated decrease in the number of ovulated oocytes after exogenous ovarian stimulation
(Tarin J et al, 1998, Reproduction, Nutrition, Development, 38, 5, )
Study showed that vitamins C and E can help with older women where the number of viable eggs produced in a IVF cycle may be less.

17. Antioxidants – a balance
Antioxidants play a protective role, although a delicate balance of reduction and oxidation is required for essential sperm function including fertilisation.
Thus supplementation should be carried out where risk and necessity has been assessed.
(Wright C, Leeson H, Reproductive BioMedicine Online (2014) 28, 684–703)
However,high doses of vitamin C may be linked with negative effects.
Ascorbate can reduce disulphide bridges of cysteine residues (Giustarini et al., 2008), potentially damaging the chromatin structure. A study of mixed antioxidants,
including just 400 mg of ascorbic acid daily for 3 months, attributed this effect to the induction of chromatin decondensation in spermatozoa (Menezo et al., 2007b)
In order to avoid oversupplementation, blood tests can be used to determine plasma concentrations of vitamin C,
Vitamin C found in most fresh fruit and vegetables. Bell peppers, parsley, kiwi fruits are very good sources. Water soluble, levels start to reduce as soon as fruit or vegetable is picked. Eat local vegetables or fruit. Most frozen vegetables and fruit have relatively high levels of vit C. Do not overcook
Include food sources.
Use in ascorbate form e.g. magnesium ascorbate and no more than 500mg at a time for men.

18. Selenium supports male fertility
Selenium supplementation given to infertile men increased:
sperm count
motility
number of normal sperm
(Safarineiad MR, Safarineiad S, 2009, J Urol, 181(2):741-51)
Support endogenous antioxidant pathways e.g. glutathione peroxidase
Important role in thyroid function
100 – 200ug
Food sources of selenium
Brazil nuts
Tuna, salmon, sardines, cod
Prawns, Scallops, oysters, clams
Turkey
Lamb
Mushrooms nb shitake, crimini
Eggs
Tofu
Brown rice
Sunflower, sesame, flax seeds

19. Selenium as measure of antioxidant capacity
Selenium deficiency may be a prominent determinant of abnormal sperm parameters and idiopathic male infertility.
Measurement of selenium levels may help determine antioxidant capacity in infertile patients.
(Eroglu M et al Biol Trace Elem Res. 2014 Apr 23. [Epub ahead of print]
Measurement of Selenium levels may help determine antioxidant capacity in infertile patients, which may help distinguish those patients who will benefit from supplementation therapy

20. Co-enzyme Q10
Concentrated in the mitochondrial mid-piece of sperm – providing energy for movement
Fat soluble nutrient naturally produced in our bodies and needed by mitochondria in every cell.
Plays important role in cellular energy and is an important antioxidant
Coenzyme Q10 (CoQ10) is the fifth most popular supplement in the United States, taken by about 53 percent of Americans, according to a 2010 survey by ConsumerLab.com.

21. Co-enzyme Q10
300mg in a RCT
Significant increase in sperm count, normal forms and motility
Acrosome reaction increased significantly
(Safarinejad MR, 2009, J Urol, 182, 1, )
CoQ(10) can be quantified in seminal fluid, where its concentration correlates with sperm count and motility. 
A number of studies have shown that the reduced form of Coenzyme Q10 (ubiquinol) may be more effective than the oxidized form (ubiquinone), especially for those over the age of 25. Factors affecting metabolism of ubuiquinone to ubiquinol include oxidative stress, ageing
NB Statins work by reducing an enzyme in the liver, which not only reduces the production of cholesterol, but also reduces the production of coenzyme Q10. Recommend CoQ10 to all patients on statins, minimum 100mg
For supplement make sure it contains at least ubiquinol, ideally both ubuiquone and ubquinol
Found in beef, chicken, mackerel and also broccoli, parsley, oranges

22. Immunology Infertility and Miscarriage

23. Antiphospholipid Antibodies
15% of women with recurrent miscarriage
90% miscarriage rate without treatment
Treatment is heparin and aspirin

24. Omega 3 fish oil
22 women with persistent antiphospholipid syndrome associated with 3 or more miscarriages were treated with fish oil over a period of 3 years. 22 patients had 23 pregnancies, with no miscarriages.
(No baby under 2.5kg)
(Rossi E and Costa M, Lupus, 1993, 2, 5, )
Omega 3: anti-coagulant and anti-inflammatory effects

25. But not Omega 6 fatty acids
Natural Killer Cells
Fish oil, especially EPA, decreases NK cell activity by 48%.
(Thies F et al, 2001, Am J Clin Nutr, 3, 3:539-48).
Inhibition of TNF alpha by as much as 90% after dietary supplementation of fish oil
(James MJ et al, 2000, Am J Clin Nutr, 71, 343S-8S)
But not Omega 6 fatty acids
NK cells make up 50% of all white blood cells
Ongoing research on relevance of periphereal blood NK cells vs uterine endometrial NK cells
Hypothesis: elevated peripheral NK cells = increase in TH1 cytokine-mediated response
Th1 – autoimmune response Th2 – suppressive response
Dominance of Th1 can increase the risk of infertility and miscarriage
Common treatment is anti-TNF alpha drugs, steroids
Cytokine production decreases as cellular EPA increases
NB not cod liver oil – can be teratagenic

26. Omega 3 fatty acids
238 men with oligoasthenoteratospermia randomised to EPA/DHA for 32 weeks
Significant increase in sperm count compared to placebo
Antioxidant activity increased with Omega 3
(Safarinejad MR, 2011, Andrologia, 43, 1, 38-47)

27. Omega 3 – are we getting enough?
Western diets are deficient in Omega 3 fatty acids. Human beings evolved on a diet with a ratio of 1:1 Omega 6 to 3 and now Western diets have a ratio of 10:1 up to 25:1.
(Simopoulos AP, 2011, Mol Neurobiol, Jan)
Sources of omega 6: palm, soya bean, rapeseed (Canola), sunflower oil, poultry, nuts, cereals
Excess omega−6 fatty acids from vegetable oils interfere with the health benefits of omega−3 fats, in part because they compete for the same rate-limiting enzymes. A high proportion of omega−6 to omega−3 fat in the diet shifts the physiological state in the tissues toward the pathogenesis of many diseases: prothrombotic, proinflammatory and proconstrictive
Sources of omega 3:
Best is oily fish: salmon (preferably organic or wild), mackerel, sardines, herring.
Avoid large fish e.g. tuna, marlin, swordfish
Other sources include linseeds (flaxseeds) – grind them to release oils, walnuts, pumpkin seeds. Chia seeds,

28. More than 50% of adults in the UK have insufficient vitamin D levels
(Pearce SH, Cheetham TD, 2010, BMJ, 340, 7738, )
In the USA overall prevalence rate of vitamin D deficiency was 41.6%
(Forest KY et al, Nutr Res. 2011 Jan;31(1):48-54)
Vitamin D not a true vitamin. A compound is called a vitamin when it cannot be synthesized by an organism, and must be obtained from the diet.
Vitamin D3 (cholecalciferol) is produced photochemically in the skin from 7-dehydrocholesterol. The precursor of vitamin D3, 7-Dehydrocholesterol is produced in relatively large quantities, 10,000 to 20,000 IU of vitamin D are produced in 30 minutes of whole-body exposure
1 in 4 Australians now estimated to be vitamin D deficient
In the USA overall prevalence rate of vitamin D deficiency was 41.6%, with the highest rate seen in blacks (82.1%), followed by Hispanics (69.2%)
Vitamin D deficiency was defined as a serum 25-hydroxyvitamin D concentrations ≤20 ng/mL (50 nmol/L), lower than what we would consider optimal vit D threshold

29. Deficiencies of vitamin D connected to autoimmune problems
(Cantorna, M. T., et al, 2004, Exp Biol Med 229(11): )
Vitamin D promotes the suppressor Th2 cells that help the body maintain a pregnancy
(Hayes, C. E. et al, 2003, Cell Mol Biol. 49(2): )
Acts as an immune modulator. Regulates the T helper cells and decreases Th1 response
If vitamin D levels too low (less than 25 nmol/L) increases IgE
If vitamin D levels too high (more than 135 nmol/l) increases IgE
(Hyponnen E et al, 2009, Allergy, 54, 4, )
Among women, vitamin D appears to impact endometriosis, polycystic ovary syndrome (PCOS) as well as boost levels of progesterone and estrogen, which regulate menstrual cycles and improve the likelihood of successful conception
Ideal range between 80 and 135nmol/L for fertility
Liquid D3 best for to supplement. Use 1000 – 2000 iu daily but always test and modify dose, then retest after 3 months.

30. Vitamin D and sperm
In men, vitamin D level significantly associated with sperm motility, progressive motility and morphology
(Blomberg Jensen M et al, 2011, Hum Reprod, 26, 6, )
Vitamin D receptor expressed in sperm
Among women, vitamin D appears to impact endometriosis, polycystic ovary syndrome (PCOS) as well as boost levels of progesterone and estrogen, which regulate menstrual cycles and improve the likelihood of successful conception

31. Useful tests General nutrient & antioxidant status
Homocysteine / MTHFR polymorphism
Essential Fatty Acids
HbA1C
Comprehensive thyroid
Gut function
Male hormones, DNA fragmentation
Individual approach – there is no ‘one size fits all’. Check what your patient needs.
Check vitamins and mineral already mentioned. NB vitamin D. Also basics e.g. iron, folate, ferritin, B12
Defective methylation, MTHFR polymorphism. Hyperhomocystenia can lead to induction of oxidative stress. defective methylation may lead to aberrant gene expression resulting in abnormal fetal development and malignant diseases (Reik and Walter, 2001).
Where MTHFR polymorphism present look for products that contain the Metfolin brand, or list “5-methyltetrahydrofolate” or “5-MTHF” on the label.
Comprehensive thyroid: TSH, FT3, FT4, antibodies, reverse T3, iodine
Gut function: comprehensive stool analysis (Doctor’s Data, Genova Diagnostics), coeliac / Cyrex testing
Beyond standard peak plus 7 levels – SHBG, androgen index for women, testosterone and free testosterone for men

32. Dietary Checklist
Eat 5 portions of vegetables and 2 – 3 portions of fruit daily
Drink plenty of water – ideally 1.5L
Eat regularly – healthy meals and snacks
Eat whole grains instead of simple carbohydrates
Eat essential fats – oily fish, nuts, seeds, avocados
Eat a wide variety of different foods
Avoid soft drinks, juices
Limit sugary foods and treats
Limit processed ready meals and convenience foods
Avoid diet and low fat products with sugar substitutes
Avoid alcohol
Limit caffeine
Eat a whole food, low GI diet. Also supports weight management.
Healthy fats needed for hormone production and absorption of fat soluble vitamins – A, D, E, K
Eating a wide variety ensures you are accessing the widest possible variety of nutrients

33. Core supplements Male / female fertility multivitamin and mineral
Omega 3
Antioxidant support
Vitamin C
Vitamin E
CoQ10
Many other antioxidants. Some research e.g.
Lycopene
Pycnogenol (picknogenol)
ALA
But better to check what patients need first

34. Quality of supplements
Omega 3: 750mg EPA and 450mg DHA
Form of nutrient will significantly impact absorption
D3 87% more effective in raising and maintaining vitamin D levels than D2
(Heaney RP et al, 2011, J Clin Endocrinol Metab, 96, 3, E447-52)
Avoid: Sulphates, carbonates and oxides
Use: Citrates, ascorbates
Calcium carbonate = CHALK
Magnesium – magnesium oxide absorb 6% compared to magnesium citrate, absorb c. 90%

35. Lifestyle Factors

36. Caffeine intake and delayed conception (Bolumar F et al, European Study of Infertility and Subfecundity AJE 1997; 145: 324)
3,000 women
5 countries
High caffeine consumers:
45% increased risk of delayed conception
European study, which collected data retrospectively from women.
High caffeine >500mg/day shows longer waiting time to conception compared to lower intakes. There was a 45% increased risk of subfecundity, >=9.5 months to conception.
Upper limit of moderate daily dose is 300mg caffeine (FDA & AMA)
Coffee 150ml = c. 150mg caffeine
Tea 150ml black tea = c. 80mg caffeine

37. Caffeine and miscarriage
Drinking only 2 cups of coffee (200mg of caffeine) a day associated with a 25% increased risk of miscarriage compared to 12% for women who avoided all caffeine
(Weng X et al, 2008, Am J Obstet Gynecol, Jan 21)

38. Caffeine and male fertility
For men - problems with sperm count, motility and abnormalities are dose related to the number of cups of coffee drank per day
(Parazzini F et al, 1993, Archives of Andrology, 31, 2, )

39. Alcohol
Alcohol intake for women AT ANY LEVEL, significantly reduced fertility by up to 50%.
(Hakim R et al, 1998, Fertility and Sterility, 70, 4, 632-7)
‘Important for the female partner in an infertile couple to limit alcohol intake or to not drink at all.’ 7, 393 women followed over 18 years
(Eggert J et al, 2004, Fertility and Sterility, 81, 2, )
Clarify what a unit of alcohol is for patients e.g bottle of wine = 8.5 units on average

40. Alcohol
Study on unexplained dyspermia in infertile men - alcohol drinkers were at increased risk and the risk increased with number of drinks.
(Parazzini F, 1993, Archives of Andrology, 31, 2, )
Progressive alcohol-induced sperm alterations leading to spermatogenic arrest but reversed within 3 months after withdrawal
(Sermondade N et al, 2010, Reprod Biomed Online, 20, 3, 324-7)

41. Smoking harms male fertility
Smoking more than 20 a day or longer than 10 years has negative effects on semen volume, sperm morphology and DNA integrity
(Niu ZH et al, 2010, Zhonghua Nan Ke Xue, 16, 4, 300-4)
120,000 men between ages in UK are rendered impotent by smoking each year
(BMA report, 2004)

42. Smoking harms female fertility
Women who smoke are 40% less likely to conceive than those who don’t
Smoking linked to 5,000 miscarriages per year
(BMA report, 2004)

43. Stress and male fertility
Reduces count, motility and increases levels of abnormal sperm
(Gollenberg AL et al, 2010, Fertil Steril, 93, 4, )
Can also disturb testosterone levels
Includes lack of sleep.
953 young Danish men from the general population who were recruited in Copenhagen at the time of determination of fitness for military service between January 2008 and June Men with a high level of sleep disturbance (score >50) had a 29% (95% confidence interval: 2, 48) lower adjusted sperm concentration and 1.6 (95% confidence interval: 0.3, 3.0) percentage points’ fewer morphologically normal spermatozoa than men with a sleep score of 11–20. This appears to be the first study to find associations between sleep disturbances and semen quality -

44. Stress and female fertility
Can increase levels of prolactin
Can impair progesterone uptake
Higher levels of anxiety and tension may cause release of ova which are not mature enough to be fertilised
(Berga SL, Loucks TL, 2005, Minerva Ginecol, 57, 1, 45-64)
Elevated cortisol can impair progesterone uptake by cells
GENTLE exercise can be helpful

45. Weight
For men – being overweight reduces the quality and quantity of the sperm
(Sallmen M et al, 2006, Epidemiology, 17, 5, 520-3)
Acrosome reaction is impaired in spermatozoa of obese men
(Samavat J et al, 2014 Fertility & Sterility Sept 2014)
Acrosome reaction is impaired in spermatozoa of obese men: a preliminary study – published online ahead of print

46. Weight
Increased adiposity associated with lower levels of anti-oxidants and fat-soluble vitamins
(Xanthakos S, Pediatr Clin North Am. Oct 2009; 56(5): 1105–1121.)
For women - being overweight can affect the success of assisted fertility treatments
(Linsten A et al, 2005, Human Reproduction, 20, 7, )
Will affect response to drugs
May seem paradoxical in light of excess caloric intake, but several micronutrient deficiencies appear to higher in prevalence in overweight and obese adults NB vitamin D
Underweight also an issue as can negatively impact steroid hormone production
BMI between 20 and 25 is optimal

47. Negative lifestyle
Couples with more than 4 negative lifestyle variables took 7 times longer to get pregnant.
Dose dependent effects occurred with smoking, alcohol and tea/coffee consumption
(Hassan MA and Killick SR, 2004, Fertil Steril, 81, 2, )
Cumulative effect

48. Occupational hazards
Increase in scrotal temperature in drivers. Scrotal temperature increased significantly after two hours of driving ( °C) compared to walking
(Bujan L et al, 2000, Hum Reprod, 15, 6, )
Increase in scrotal temperature in laptop computer users
(Sheynkin Y et al, 2005, Hum Reprod, 20, 2, 452-5)
Also cycling, triathletes
Mobile phone radiation
saunas

49. Support for your patients
Teamwork
Discuss diet and it’s importance
Discuss life style factors
Check nutrient status
Judicious supplementation
Refer for specialist support
Both man and woman should work as a team
Giving some influence back to the patients
Important to discuss diet and lifestyle, even if referring to nutritionist specialising in fertility. Will support their work
Check what supplements or herbs your patients are taking. They may not be aware of side effects or interactions

50. Thank You