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Review of Clinical Trials on Effects of Oral Antioxidants on Basic Semen and Other Parameters in Idiopathic Oligoasthenoteratozoospermia
Infertility affects 50 to 80 million people worldwide. Male factor is a cause of infertility in almost half of cases, mainly due to oligoasthenoteratozoospermia (OAT). With common diagnostic methods no cause can be found in approximately 30% of cases of male infertility due to OAT and these are considered idiopathic. Reactive oxygen species (ROS) play an important role in male infertility and are proved to be higher in infertile men; antioxidants could oppose their effect. The aim of this paper was to review the literature on clinical trials in the period from year 2000 to year 2013 studying the effects of various types of antioxidant supplements on basic and other sperm parameters and pregnancy rates in subfertile males with idiopathic OAT. The majority of studies were randomized and placebo controlled and confirmed beneficial effect of antioxidants on at least one of the semen parameters; the biggest effect was determined on sperm motility. In many of these trials combinations of more antioxidants were assessed. The optimal dosages of one or more antioxidants were not defined. We concluded that antioxidants play an important role in protecting semen from ROS and can improve basic sperm parameters in case of idiopathic OAT.
Almost 15% of all couples trying to conceive are affected by infertility, and in almost half of these cases male infertility is the sole or a contributing factor . While conditions such as varicocele, cryptorchidism, and hypogonadism are definable causes for infertility, no cause may be determined for an abnormal semen analysis in over 25% of cases . Such idiopathic infertility and oligoasthenoteratospermia (iOATs) is a condition in which sperm concentration, the proportion of motile sperms, and the proportion of morphologically normal sperms are below the World Health Organization (WHO) reference values .
Elevated reactive oxygen species (ROS) levels in the semen may be an etiologic factor for male infertility . It is estimated that 25% of infertile men possess high levels of semen ROS, whereas fertile men do not have high levels of semen ROS [5, 6]. ROS are needed for capacitation, the acrosome reaction, and ultimately fertilization . However, their uncontrolled production is detrimental to cell function as they damage a variety of biomolecules such as lipids, amino acids, carbohydrates, protein, and DNA and adversely affect sperm function  due to DNA damage [9, 10], reduced motility , and defective membrane integrity [12, 13]. Spermatozoa are particularly susceptible to oxidative injury due to the abundance of plasma membrane polyunsaturated fatty acids. These unsaturated fatty acids provide fluidity that is necessary for membrane fusion events (e.g., the acrosome reaction and sperm-egg interaction) and for sperm motility . The human ejaculate contains a number of potential sources of ROS. These include leukocytes, germ cells, or abnormal sperms . At the same time, a number of cellular molecules called antioxidants, which protect the cell from excessive ROS-induced lipid peroxidation, are also present within the ejaculate . Studies have shown that seminal antioxidant capacity is suppressed in infertile men with high ROS levels compared to men with normal levels of ROS [17, 18].
2. Materials and Methods
We searched PubMed with keywords, including combinations of search terms such as “male infertility” and “antioxidants.” We searched for reviews, controlled and randomized controlled clinical studies. From the numerous search results for the period between 1st January 2000 and 31st December 2013, 32 primary studies on idiopathic oligoasthenoteratozoospermia (OAT) were chosen and their data were gathered in order to provide a complete overview of the literature. Given the different antioxidants used (both alone and in combination), the different dosages, different duration of treatment, and various number of participants (from very small groups to large researches), we looked up for statistical significance of changes in basic sperm parameters and pregnancy rates.
3. Results and Discussion
The review of the studies on antioxidants in clinical studies is illustrated in Table 1.
|Legend: Addyzoa: Gokshura (Tribulus terrestris) 200 mg, Ashtavarga 200 mg, Guduchi (Tinospora cordifolia) 150 mg, Ashwagandha (Withania Somnifera) 150 mg, Amalaki (Emblica officinalis) 75 mg, Balamool (Sida cordifolia) 75 mg, Vridhadharu (Argyreia speciosa) 75 mg, Shatavari (Asparagus racemosus) 75 mg, Shwet musli (Chlorophytum arundinaceum) 150 mg, Shuddha kapikachchhu (Purified Mucuna pruriens) 150 mg, Varahikand (Tacca aspera) 30 mg, Chopchin (Smilax china) 30 mg, Vidarikand (Ipomoea digitata) 30 mg, Munjatak (Eulophia campestris) 15 mg, Purnachandrodaya rasa 45 mg, Suvarnavang 30 mg, Muktashukti bhasma 30 mg, Suvarnamakshik bhasma 30 mg, Shilajit shuddha 30 mg, Abhrak bhasma 15 mg, Makardhwaj rasa 15 mg, Rasa sindur 5 mg; AR: acrosome reaction; CG: control group; DDS: DNA degraded sperm; DFI: DNA fragmentation index; Fertilovit Mplus: L-citrulline (20.2 %), L-carnitine-L-tartrate, D-alpha-tocopheryl acetate, hydroxypropyl methylcellulose (capsule coating), acidifier tartaric acid, L-ascorbic acid (6.7%), parting compound silicon dioxide, calcium carbonate, lycopene, N-acetyl-L-cysteine, glutathione (reduced), corn starch, zinc oxide, coenzyme Q10, vegetable oil, shellac coating, pteroyl-L-glutamate, sodium selenite, coloring agent titanium dioxide (capsule), coloring agent orange yellow S (capsule); CoQ10: coencyme Q10, FISH: fluorescent in situ hybridization; FSH: follicle-stimulating hormone; ICSI: intracytoplasmic sperm injection; iOAT: idiopathic OAT; IVF: in vitro fertilization; LH: luteinizing hormone; MDA: malondialdehyde; MSOME: motile sperm organelle morphology examination; OAT: oligoasthenoteratozoospermia; PG: placebo group; ROS: reactive oxygen species; Sairei-to: a Chinese herbal drug; SCSA: sperm chromatin structure assay; Se: selenium; SG: study group; T: testosterone; TAC: total antioxidant capacity; TUNEL: TdT (terminal deoxyribonucleotidyl transferase)—mediated dUTP nick-end labeling; Xuanju: Formica fusca, Herba epimedii, Fructus cnidii, and Fructus lycii; Zn: zinc.|
3.1. Sperm Concentration
Low sperm concentration or oligozoospermia is defined as concentration less than spermatozoa/mL according to WHO reference value from 2010  and less than spermatozoa/mL according to WHO reference values from 1999 , which were considered in most of researches in this review. Many researches showed significant improvements in sperm concentration after oral intake of different antioxidants [19–31]. Most of these researches investigated combination of different antioxidants, like L-carnitine, coenzyme Q10 (CoQ10), vitamin C, vitamin E, zinc (Zn), selenium (Se), and so forth. But there are also some studies that investigated only one type of antioxidant. Safarinejad et al. showed that intake of 200 mg CoQ10 daily for 26 weeks improved sperm concentration in study group ( spermatozoa/mL) versus placebo group ( spermatozoa/mL) () . After 6 months of intake of combination of 25 mg clomiphene citrate and 400 mg vitamin E per day sperm concentration improved from spermatozoa/mL to spermatozoa/mL () . There was also significant improvement in sperm concentration from spermatozoa/mL to spermatozoa/mL () after consumption of 1 g of vitamin C twice daily taken for 2 months as proved by Akmal et al. .
3.2. Sperm Motility
Asthenozoospermia is defined as less than 40% of motile spermatozoa  and according to WHO reference value from 1999 less than 50% of motile spermatozoa . 20 out of 32 studies in our review proved significant improvement in sperm motility after the use of antioxidants [19, 20, 22–39]. Improvement in sperm motility has been shown mostly in researches considering mixture of more antioxidants such as selenium and vitamin E [38, 39]. Most of studies with just one type of antioxidant were about CoQ10 but in different dosages and in different duration of consuming [22–24, 37]. Kumar et al. showed that consumption of herbal-mineral supplement Addyzoa for 3 months improved total and progressive sperm motility in study group. Total motility improved from % before the treatment to % after the treatment (). Progressive motility improved from % before treatment to % after treatment with Addyzoa () . Wang et al. showed that L-carnitine in combination with vitamin E taken for 3 months significantly improved forward sperm motility from to (), compared with just vitamin E . After treatment with 200 mg CoQ10 twice daily for 6 months sperm motility improved from before the therapy to after the therapy () .
3.3. Sperm Morphology
WHO reference values from 1999  defined teratozoospermia as less than 14% of normal shape and form spermatozoa according to strict Krüger criteria. Although WHO reference values from 2010 define teratozoospermia as less than 4% of normal shape and form spermatozoa  strict Krüger criteria are still used as reference value for assessing sperm morphology. L-carnitine in combination with CoQ10, vitamins E and C, zinc, selenium [20, 40], CoQ10 alone [23, 24], pentoxifylline , N-acetyl-cysteine with Se , vitamin C alone , combination of papaya, beta-glucan, lactoferrin, vitamins C and E , Se, and vitamin E , and pycnogenol  significantly improved sperm morphology. Therapy with 200 mg CoQ10 daily for 26 weeks improved sperm morphology in 114 participants in study group to versus in 114 participants in placebo group () . Safarinejad also showed that intake of 400 mg of pentoxifylline twice daily for 24 weeks of treatment phase significantly improved percentage of sperm with normal morphology to in study group versus in placebo group () . Combination of 20 mg beta-glucan, 50 mg fermented papaya, 97 mg lactoferrin, 30 mg vitamin C, and 5 mg vitamin E, twice per day for 3 months, improved percentage of morphologically normal sperm in 36 participants from to () .
3.4. Sperm DNA Fragmentation and Chromatin Integrity
ROS can cause sperm DNA damage and integrity of sperm DNA can be measured with DNA fragmentation. The levels of sperm-derived ROS (measured in sperm preparations having minimal leukocyte contamination) have been associated with sperm DNA damage . High level of denatured DNA in spermatozoa with large nuclear vacuole could arise from precocious decondensation and disaggregation of sperm chromatin fibers . Dietary antioxidants may be beneficial in reducing sperm DNA damage, particularly, in men with high levels of DNA fragmentation . Five out of 32 studies confirmed that the usage of different antioxidants had important influence on DNA fragmentation and chromatin integrity [20, 42–46]. Song et al. showed that combination of Chinese medicine Compound Xuanju Capsule with vitamin E taken for 3 months decreased degree of DNA fragmentation index (DFI) after therapy to compared just to vitamin E with degree of DFI of () . Greco et al. [44, 45] had proved that 1 g of vitamin C and 1 g of vitamin E together taken for 2 months significantly decreased the degree of DNA fragmentation from to () . Raigani et al. showed that zinc sulphate significantly improved sperm chromatin integrity .
3.5. Pregnancy Rate
CoQ10 , clomiphene citrate with vitamin E , lycopene , L-carnitine with vitamin E [34, 35], and selenium with vitamin E  significantly improved spontaneous pregnancy rates during duration of treatment, while L-carnitine with cinnoxicam  and vitamins C and E together  significantly improved pregnancy rates per cycle after assisted reproductive technology with intracytoplasmic sperm injection (ICSI). Ghanem et al. proved higher spontaneous pregnancy rate in 30 participants after the intake of combination of 25 mg clomiphene citrate and 400 mg vitamin E per day for 6 months (36.7%) than in placebo group (13.3%) with . L-Carnitine, 2 g, with vitamin E taken for 3 months improved spontaneous pregnancy rate to 31.1% compared to vitamin E group with pregnancy rate of 3.8% () . Another example in study by Greco et al. confirmed higher pregnancy rate after 2 months therapy with 1 g of vitamin C and 1 g of vitamin E daily. After ICSI clinical pregnancy rate was 48.2% after therapy versus 6.9% before therapy () .
3.6. Negative or No Effect on Sperm Parameters
In this review we find out also rare negative effects of antioxidants on sperm parameters or no effect. Pycnogenol caused nonsignificant fall in baseline sperm count by 10% . Similarly, treatment with vitamins C and E, -carotene, zinc, and selenium significantly increased sperm decondensation . Large research on saffron showed no statistically significant improvements in any of the studied semen parameters .
3.7. Other Parameters
We looked at the basic sperm parameters but there were also many other positive influences; for example, CoQ10 and pentoxifylline caused improvements in total antioxidant capacity and acrosome reaction [22, 25, 49, 50]; FSH value [22, 23] decreased after CoQ10 treatment, semen leucocyte concentration decreased , and level of ROS  decreased after antioxidant mixtures. Antioxidants protect unsaturated fatty acids and so provide fluidity that is necessary for membrane fusion events like the acrosome reaction. Although hormonal abnormalities are not always evident, iOAT is sometimes associated with lower serum testosterone and inhibin levels and higher serum estradiol, LH, and FSH levels [55, 56]. The increased serum FSH level in men with azoospermia or severe oligozoospermia indicates damaged seminiferous tubule  and is inversely associated with sperm concentration, motility, and morphology . ROS has been found in the seminiferous tubules and seminal plasma of most patients with iOAT . Decreased levels of ROS due to antioxidant consumption can cause fall in serum FSH level. Leukocytes are potential source of ROS and due to protective influence of antioxidants their concentration may decrease . In addition, studies have found an increase in inhibin B value  and in superoxide-dismutase- (SOD-) like and catalase activity [21, 25], which among others represent the total antioxidant capacity of seminal plasma . Inhibin B in positively correlated with sperm concentration and is, like FSH, thought to be a marker of spermatogenesis and Sertoli cell function [61, 62].
Most of the published studies were randomized and placebo controlled. The majority of studies confirmed beneficial effect of different antioxidants on at least one of the semen parameters and the biggest effect was determined on sperm motility. In many of these trials combinations of more antioxidants were assessed. The optimal dosages of one or more antioxidants were not defined.
Most commonly antioxidants studied were vitamin E, vitamin C, selenium, CoQ10, N-acetyl-cysteine, L-carnitine, and zinc and their favorable effect was confirmed. According to this review favorable effects on iOAT have been determined with CoQ10, vitamin E, selenium, and also vitamin C and N-acetyl-cysteine treatments. In case of oligozoospermia vitamin E and CoQ10 were most often proved to be effective. Favorable effects on asthenozoospermia have most often been determined with vitamin E, CoQ10, and selenium treatments. In teratozoospermia selenium and CoQ10 treatments were most often proved to be effective. In addition, combination of vitamin C and E showed the biggest favorable effect on DNA fragmentation; similar effects were determined with zinc and selenium treatments.
In conclusion, antioxidants play an important role in protecting semen from ROS and can improve basic sperm parameters in case of idiopathic oligoasthenoteratozoospermia.
Conflict of Interests
The authors declare that they have no conflict of interests regarding the publication of this paper.
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