Oral Antioxidant Therapy

Pregnancy Miracle

The Pregnancy Miracle by Lisa Olson

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As outlined in Chap. 23, many studies have been conducted examining the effect of a wide variety of different antioxidant combinations on sperm function and pregnancy outcome. Table 16.2 summarises the outcomes of the various antioxidant treatment regimes tested in a placebo controlled setting. In January 2011, the Cochrane collaboration, widely perceived as the definitive authority on evidence-based medicine, published a review on the effect of oral antioxidant therapy on sperm quality and pregnancy outcomes [178]. This review identified 34 randomised placebo controlled studies examining the effect of antioxidants on sperm quality and pregnancy outcomes in couples seeking fertility assistance. While 15 trials examined the effect of antioxidants on pregnancy rates, unfortunately only 3 studies examined live birth rate, the most meaningful clinical outcome. Further compounding the effective performance of a meta-analysis was the fact that dozens of different antioxidant combinations for various periods of time were used in these studies. Despite these drawbacks, the Cochrane review concluded that there is good evidence suggesting

Table 16.2 Placebo controlled studies examining the effect of antioxidant therapy on male reproductive heath

Duration Oxidative stress

Table 16.2 Placebo controlled studies examining the effect of antioxidant therapy on male reproductive heath

Duration Oxidative stress

Study

of therapy

as an inclusion

Positive changes

Positive changes in

Positive changes in

reference

Therapy used per day

(months)

criteria

in semen quality

sperm OS end points

reproductive outcomes

[183]

Vitamin E 300 mg

6

No

t Motility

4 MDA

Pregnancy 17% active group vs. 0% placebo

[184]

Vitamin E 300 mg

3

No

Nil

Nil

Improved sperm zona binding

[185]

Vitamin C 200 or 1,000 mg

1

No

t Motility, morph and viability

Not tested

Not reported

[186]

Vitamin E 800 mg, vitamin C 1,000 mg

2

No

Nil

Not tested

None

[187]

Vitamin E and C 1,000 mg each

2

No

Nil

J. Sperm DNA damage

Not reported

[188]

Vitamin E 10 mg, vitamin C 5 mg, zinc 200 mg

3

No

Nil

Trend for J, MDA

Not reported

[189]

Coenzyme Q10 300 mg

6

No

f Cone and motility

Not tested

No difference in pregnancy rates

[190]

Sn 100 mg, vitamin A 1 mg, vitamin C 10 mg. vitamin E 15 mg

3

No

t Motility

Not tested

No difference in pregnancy rates (11% vs. 0% placebo)

[191]

Sn 200 mg. NAC 600 mg

6

No

] Cone, motility and morph

Not tested

Not reported

[192]

Glutathione 600 mg

2

No

] Motility and morph

Not tested

Not reported

[193]

l-Carnitine 2 g

2

No

Nil (raw data analysis)

No change in MDA

No difference

[194]

NAC 600 mg

3

No

f Sperm concentration

Not tested

Not reported

[195]

NAC 600 mg

3

No

t Motility

Not tested

Not reported

[196]

Astaxanthin 16 mg

3

No

t Motility

I Semen ROS

f Natural + IUI conceptions

[197]

Vitamin E 400 mg, Sn 225 mg

3

No

t Motility

| MDA

Not reported

[198]

Vitamin C 30 mg, vitamin E 5 mg, beta-glucan 20 mg, papaya 50 mg, lactoferrin 97 mg

3

No

f Motility and morph

No change in DNA quality

Not reported

[199]

Menevit (vitamin C, vitamin E, Sn, lycopne, folate, zinc and garlic oil)

3

No

Not reported

Not tested

t IVF-ICSI conceptions on active antioxidant

(38.5% vs. 16%' placebo)

MDA malondialdehyde; ROS reactive oxygen species; Sn selenium; NAC N-acetyl cysteine; IUI intra-uterine insemination

MDA malondialdehyde; ROS reactive oxygen species; Sn selenium; NAC N-acetyl cysteine; IUI intra-uterine insemination that oral antioxidant therapy can boost both natural and IVF assisted pregnancy and live birth rates. As antioxidant therapy is relatively inexpensive compared to other fertility treatments, and there is no definitive evidence that antioxidants will cause harm to patients, this positive Cochrane review should result in a more widespread uptake of oral antioxidant therapy for male infertility in the future.

To date there have been no trials clearly showing one antioxidant formulation to be superior to another. Therefore, when faced with the dilemma of imperfect information the treating clinician must make his/her own decision on what is the ideal antioxidant combination.

Vitamin E is an essential fat soluble vitamin, with alpha-tocopherol being the most common form of vitamin E available in food. Vitamin E is major chain breaking antioxidant that directly neutralises superoxide anions, hydrogen peroxide and the hydroxyl radical. As sperm membranes contain abundant phospholipids which are prone to oxidative damage, it is believed that vitamin E plays a critical role in protecting cellular structures from damage caused by free radicals and reactive products of lipid peroxidation. Second, vitamin E exhibits some anti-inflammatory activity and therefore may reduce leukocyte initiated sperm oxidative stress. The Recommended Dietary Allowance (RDA) for vitamin E is suggested to be 15 mg (equivalent to 22.4 IU) of alpha-tocopherol per day for adult men, with the tolerable upper intake being suggested as 1,000 mg (1,500 IU) by the US National Institute of Health [179]. However, a meta-analysis of 19 clinical trials using long-term vitamin E supplementation in patients with chronic disease has reported that at dosages of 400 IU or greater per day, vitamin E may actually increase overall mortality compared to placebo [ 180] . Studies using dosages of 200-300 mg vitamin E (300450 IU) have been shown to produce a significant fall in sperm lipid peroxidation (Table 16.2) so it would appear that 400 IU of vitamin E per day is a safe and effective therapy for sperm oxidative stress. However, as vitamin E is known to inhibit platelet aggregation and has been linked with an increased risk of haemorrhagic stroke, its use in infertile men on anticoagulants or at risk of serious haemorrhagic illness is probably contraindicated [180].

Vitamin C (ascorbic acid) is an important water soluble antioxidant that competitively protects lipoproteins from peroxyl radical attack while also enhancing the antioxidant activity of vitamin E by assisting in its recycling. Seminal plasma vitamin C levels are tenfold higher than serum [181], suggesting a very important protective role for vitamin C in the male reproductive tract. The RDA for vitamin C in the adult male is 75 mg, with the tolerable upper intake limit being suggested as 2,000 mg/day [179] . While some trials have used vitamin C supplementation at doses as high as 1,000 mg/day, lower-dose supplementation such as 100 mg/day is probably more preferable, since vitamin C can act as a pro-oxidant at high concentrations in the presence of iron [182]. Furthermore, high-dose vitamin C may also lead to the development of kidney stones and cause side effects such as nausea, abdominal cramps and diarrhoea.

Phytochemicals with known powerful antioxidant and anti-inflammatory action include lycopene, garlic and astaxanthin, with all being shown to various degrees to reduce oxidative attack on sperm and improve male reproductive performance

Table 16.3 Recommended Dietary Allowance (RDA) and Tolerable Upper Intake Levels (UL) of common dietary antioxidants*

Antioxidant nutrient

Vitamin C Vitamin E Selenium Zinc

90 15 55 11

2,000 1,000 400

RDA = The average daily dietary nutrient intake sufficient to meet the nutritional requirements of the majority of healthy individuals UL = The highest daily intake level that is likely to pose no risk of adverse heath effects to the majority of individuals in the general population

*US National Academy of Sciences, Washington, USA, 2005

(Table 16.2). Finally, minerals such as zinc and selenium both have antioxidant properties and play an important role in protamination packaging of sperm DNA, helping protect the sperm DNA from ROS mediated damage (Table 16.2). It would therefore appear logical that an ideal fertility promoting antioxidant formulation would contain these two minerals.

The current recommendations for the Recommended Dietary Allowances (RDA) for various antioxidant compounds issued by the National Academy of Sciences (USA) [179] are presented in Table 16.3 as they will hopefully guide the clinicians in deciding the safe and effective dose of an antioxidant to prescribe to their own infertile patients.

The various studies examining the effect of oral antioxidants on sperm function have used antioxidant therapy for between 4 and 26 weeks duration, with the majority of studies being of 2-3 months duration (Table 16.2). Since sperm production takes on average 70 days, it would appear logical that at least 3 months of antioxi-dant therapy is most likely to have a beneficial effect on sperm function. It is our own clinical practice to start men on antioxidant therapy several months before the female partner commences her fertility treatment.

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