If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Reprint requests: Fatemeh Haidari, Ph.D., Associate Professor, Department of Nutrition and Metabolic Research Center, Faculty of Paramedical Sciences, Ahvaz Jundishapur University of Medical Sciences, Golestan Street, Ahvaz, Iran.
Semen analysis, anthropometric, dietary, and physical activity assessments, total antioxidant capacity, and malondialdehyde.
At the end of study, the total sperm count, sperm concentration, and motility in the intervention group were significantly higher than in the control group. In the ALA group, the total sperm count, sperm concentration, and motility levels were also significantly increased at the end of study compared with baseline values. However, there were no significant differences in ejaculate volume, normal morphology percentage, and live sperm between groups. ALA supplementation also resulted in a significant improvement in seminal levels of total antioxidant capacity (TAC) and malondialdehyde compared with the placebo.
According to the results, medical therapy of asthenoteratospermia with ALA supplement could improve quality of semen parameters. However, further investigation is suggested in this regard.
). Although certain cases of male infertility are due to anatomic abnormalities, such as varicocele, ductal obstructions, and ejaculatory disorders, an estimated 40%–90% of cases are due to deficient sperm production of unidentifiable origin (
Reactive oxygen species (ROS) can have beneficial or detrimental effects on sperm function, depending on the nature and the concentration of the ROS as well as the location and length of exposure to ROS (
). During epididymal transit, sperm acquire the ability to move progressively; however, they acquire the ability to fertilize in the female tract through a series of physiologic changes called “capacitation” (
). Studies have indicated that male germ cells at various stages of differentiation have the potential to generate ROS. Excessive generation of ROS in semen by leukocytes as well as by abnormal spermatozoa could be a cause of infertility (
). It has been reported that moderately elevated concentrations of ROS do not affect sperm viability but cause sperm immobilization, mostly via depletion of intracellular adenosine triphosphate (ATP), and decreased phosphorylation of axonemal proteins (
). Exogenous ALA supplementation results in increased unbound ALA levels, which can act as a strong antioxidant and improve oxidative stress status both in vitro and in vivo. Inside cells and tissues, ALA is reduced to dihydrolipoic acid (DHLA), which is even more potent as an antioxidant (
). ALA or its reduced form, DHLA, quenches a number of oxygen-free radical species in both lipid and aqueous phases, chelates transition metals, and prevents membrane lipid peroxidation and protein damage via interactions with glutathione (
Based on the above facts, the present study was conducted to study the effect of daily oral supplementation of ALA on the quality of semen parameters and seminal markers of oxidative stress, including MDA, and total antioxidant capacity (TAC) levels in infertile men. As such, the results of this study may have wide clinical importance in fertility clinics and laboratories.
Material and methods
This randomized, triple-blind, placebo-controlled clinical trial was conducted on 44 infertile men with idiopathic asthenozoospermia in the infertility clinic of Ahvaz Jundishapur University of Medical Sciences, Iran, in 2014. After laboratory investigations, if the mobility of sperm was <50% and rapid mobility in the direct path of sperm was <25%, the diagnosis was idiopathic asthenozoospermia (
). Patients were recruited in the study after fulﬁlling certain criteria, including unwilling childlessness at least 24 months in duration with a female partner, no medical condition that could account for infertility, and a normal fertile female partner according to investigations. All patients were needed to have stopped all medical therapy ≥12 weeks before study initiation. Exclusion criteria included the history of epididymo-orchitis, prostatitis, genital trauma, testicular torsion, inguinal or genital surgery, urinary tract infection, or previous hormonal therapy; another genital disease (cryptorchidism, current genital inflammation or varicocele); severe general or central nervous system disease and endocrinopathy; use of cytotoxic drugs, immunosuppressants, anticonvulsants, androgens, or antiandrogens; and a recent history of sexually transmitted infection. Patients were also excluded from analysis if they had psychologic or physiologic abnormalities that would impair sexual performance or the ability to provide semen samples; drug or alcohol abuse; hepatobiliary disease; significant renal insufficiency; occupational and environmental subjections to possible reproductive toxins (
); a body mass index of ≥30 kg/m2; participation in another investigational study; and unlikely availability for follow-up. The study was approved by Medical Ethical Committee of the Ahvaz Jundishapur University and recorded by the identification code of IRCT2013111010181N3 in the clinical trials registry of Iran. Written consent was obtained from each of the participants. The work was financially supported by a grant from the Vice-Chancellor for Research Affairs of Jundishapur University of Medical Sciences, Ahvaz, Iran.
At the beginning of the study, patients were randomized to group 1, who received 600 mg ALA once daily, and group 2, who received matching placebo for 12 weeks. Each eligible patient received a randomization number which was determined by a computer-generated schedule. Then a randomization table was generated by the method of random permuted blocks. Persons who were operationally independent from the study investigator performed the study randomization. The investigator, clinician prescriber, and patients were blinded to the treatment condition. To maintain and guarantee blinding, ALA and placebo were identical in appearance. Patients' data collected during this trial were kept confidential and locked in a secure area. Randomization codes of the study were opened only after all participants had completed the study protocol.
Demographic data, medical history, lifetime history of tobacco use, intake of multivitamin supplements, and lifestyle information were collected from each patient. Weight was measured with the use of digital scales (Soehne) with patients minimally clothed. Height was measured with the use of a fixed-to-wall nonstretch tape meter with patients in a standing position. The body mass index (BMI) was then calculated in kilograms per meters squared. Participants were interviewed face to face by trained professional nutritionists. After the baseline screening, data, including dietary habits, were collected from 44 asthenozoospermia patients.
Preparation of Semen Samples
Semen samples were obtained after 3 days of sexual abstinence at the urology unit of Imam Infertility Clinic, Ahvaz, Iran. All semen was held at 37°C to liquefy. After liquefaction, the samples were analyzed according to the World Health Organization (WHO) criteria (
). Remnants of liquefied semen samples were immediately centrifuged at 300 rpm for 10 minutes. The seminal plasma was divided into several aliquot parts and kept frozen at −80°C for biochemical analysis.
Assessment of Sperm Motility
Motility assessment of sperm was performed according to WHO criteria (
All data were presented as mean ± SD. The distribution of the data was evaluated by means of the Kolmogorov-Smirnov test. Owing to normal distribution of variables, the independent-sample t test and the paired-sample t test were applied to analyze differences in semen variables between and within groups, respectively. To control confounding variables, analysis of covariance (ANCOVA) test were used to determine the differences between the two groups after intervention, adjusting for baseline measurements and covariates. Statistical computations were calculated with the use of SPSS 16 for Windows software. P<.05 was considered to be statistically significant.
In this study, a total of 48 patients were recruited, but only 44 patients completed the whole study: 23 of 24 in the ALA group and 21 of 24 in the placebo group (Fig. 1). Table 1 lists characteristics of the study participants. There were no significant differences in baseline features of participants between the two groups. The mean age of all participants in the two groups was 33.56 ± 5.07 years. The mean age of subjects did not differ between the ALA and placebo groups (32.98 ± 5.35 vs. 34.12 ± 4.79 years). Also, the baseline weights (88.14 ± 9.51 vs. 89.51 ± 11.08 kg), BMI (28.04 ± 2.88 vs. 28.78 ± 3.39 kg/m2), and physical activity (31.79 ± 9.73 vs. 33.23 ± 10.69 MET-h/wk) did not vary significantly between the ALA and placebo groups (P>.05; Table 1). There were no significant changes in BMI, weight, and physical activity in the subjects after consuming of ALA and placebo (Table 1).
Table 1Demographic and anthropometric characteristics of participants at baseline and end of the study.
ALA (n = 23)
Placebo (n = 21)
32.98 ± 5.35
34.12 ± 4.79
Duration of marriage (y)
4.08 ± 1.40
5.72 ± 2.35
Less than high school
High school diploma
Bachelor degree or higher
88.14 ± 9.51
89.51 ± 11.08
88.58 ± 10.62
90.01 ± 11.84
177.23 ± 7.23
176.35 ± 7.15
Body mass index (kg/m2)
28.04 ± 2.88
28.78 ± 3.39
28.18 ± 3.23
28.94 ± 3.62
Physical activity (MET-h/wk)
31.79 ± 9.73
33.23 ± 10.69
31.83 ± 9.93
32.44 ± 11.51
Note: Data are expressed as mean ± SD or n (%), and were tested by means of independent-sample t test. ALA = alpha-lipoic acid.
Sperm quality parameters of participants at baseline and end of the study are presented in Table 2. There were no significant differences in baseline levels of sperm concentration, sperm count, and sperm total motility between the two groups. However, ALA supplementation, compared with placebo, significantly increased sperm concentration, sperm count, and sperm total motility (P<.001).This effect remained significant even after adjusting for confounders. Within-group analyses indicated that the sperm concentration, sperm count, and sperm total motility significantly increased after intervention in the ALA-treated group (P<.05). Other sperm parameters, such as ejaculate volume and morphology, were not significantly different between the two groups (P>.05).
Table 2Effects of ALA supplementation on sperm quality parameters in infertile men.
The effect of ALA supplementation on seminal oxidative stress biomarkers in infertile men are summarized in Table 3. At baseline, there were no significant differences in seminal MDA and TAC levels between the two groups. However, ALA supplementation, compared with placebo, caused a significant increase in seminal TAC levels (1.13 ± 0.42 vs. 1.78 ± 0.40 μmol/L; P=.001). Seminal MDA levels were also affected by ALA supplementation: MDA levels significantly decreased in the ALA-treated group compared with the control group (P=.002).
Table 3Effects of ALA supplementation on seminal oxidative stress biomarkers in infertile men.
No side effects due to the oral administration of ALA were observed in any participants. ALA resulted in no clinically significant changes in vital signs, urinalyses, serum chemical values, or hematologic values.
During the past decade, understanding the reproductive performance of male in the incidence of infertility has been considered. Now many infertile men have disorders correctable with the use of medication, and if diagnosed and treated properly, natural fertilization can be attained.
In the context of reproduction, a balance normally exists between ROS generation and antioxidant-scavenging activities conferred by seminal plasma, which contains enzymes that scavenge ROS, such as catalase and superoxide dismutase (
). As a result of such balance, only minimal amounts of ROS remain. These metabolites usually enhance sperm function by stimulating DNA compaction and promotion of redox-regulated cyclic adenosine monophosphate–mediated pathways (
). That is central to the induction of sperm capacitation. However, the production of excessive amounts of ROS in semen can overwhelm the antioxidant defense mechanisms of spermatozoa and seminal plasma, stimulating DNA fragmentation and loss of sperm function that is associated with peroxidative damage to the sperm plasma membrane. This can eventually lead to loss of fertility (
). It shows beneficial effects in oxidative stress conditions because of its synergistic action with other antioxidants. ALA, which is a universal antioxidant, functions in both aqueous and membrane phases (
The present study was an attempt to evaluate the efficacy of ALA for improving semen parameters and sperm function in a randomized controlled trial. Controlled studies are mandatory for assessing any clinical intervention for idiopathic oligoasthenoteratospermia. This study demonstrated that daily administration of 600 mg ALA for 12 weeks signiﬁcantly improved semen parameters and sperm function.
In the placebo group, ejaculate volume, sperm count, sperm concentration, and motility did not differ significantly after 12 weeks, whereas a statistically significant improvement in density, count, and motility was achieved in the ALA group.
Statistically significant differences were found between the groups in 12th-week sperm count and motility values (P<.001). However, a significant difference was not found in sperm morphology.
Until now, no studies have been conducted in humans on this topic with ALA. Studies have been conducted mainly with other antioxidants. For example, the administration of selenium to subfertile patients induced a statistically significant increase in sperm motility (
). Antioxidants are essential for sperm function and male fertility. Antioxidant deficiency has been linked to reproductive dysfunctions in rats, mice, chickens, pigs, and cows, and supplementation with antioxidants has been reported to improve reproductive performance in sheep and mice (
Regulation, structural integrity, and providing energy are three main factors that sperm mobility is largely dependent on. Movement is controlled at the midpiece, particularly the flagella and principal area. These locations handle a special function of sperm movement. The flagella midpiece controls the activation of motility, whereas the principal midpiece handles hyperactivation. ALA regulation of metabolism, increased availability of mitochondrial coenzymes, and improvement of protection from free radicals are thought to eventually lead to a reduced incidence of mitochondrial dysfunction, thus ensuring adequate ATP for sperm motility. In the present study, we observed that ALA administration improved sperm motility in the intervention group (
Free radicals attack the unsaturated lipid and saturated protein channels in the midpiece in the sperm. ALA added into the extender media allows the antioxidant to protect these components by creating a shield surrounding the midpiece and within the structure itself. ALA creates a strong shield on the cell membrane, along with the liquid that encompasses the sperm indirectly, enhancing the ability of the sperm to tolerate higher volumes of free radical attack (
). This ability will, in turn, indirectly reduce formation of deep pores and cracks on the sperm surface, thus protecting structural integrity. The rate of sperm motility is mainly dependent on the availability of its provided energy. Thus, normal-function sperm usually have very active functioning mitochondria, which in turn create high levels of free radicals (
To ensure constant yield of ATP, external and internal structural integrity of the organelle must be kept. Because the membrane wall and the various compartments of the organelle are high in lipid content, ALA addition would save these structures from the ever-increasing free radicals which are a by-product of the Krebs cycle (
). Our study has shown that ALA, compared with placebo, increased motility.
In Yeni et al.’s study from 2010, ALA administration effect was found to be significant (P<.05) in some reproductive tract measures—motility, membrane integrity, and abnormal rate of sperm—in adult male rats compared with the placebo group (
). ALA is a thiol-consisting nucleophile, which acts in opposition to endogenous electrophiles, including free radicals and reactive drug metabolites. ALA is also reported to replenish the glutathione pool via reduction of oxidized glutathione. Consumption of ALA helps to overcome oxidative stress by increasing the reduce glutathione status, which results in increased free radical–scavenging activity (
Results of the present study showed that seminal TAC and MDA levels were improved by ALA consumption compared with placebo. Although the effect of ALA on oxidative stress has been assessed among diabetic patients (
) showed no significant negative correlation between seminal plasma level of MDA and sperm count or motility, but they observed that spermatozoal MDA concentration was higher with decreased sperm motility. The results of the present study are compatible with earlier ﬁndings (
) indicated that TAC levels in the seminal plasma of asthenospermic men were significantly lower than in healthy men. In addition, they found a positive correlation between reduced TAC levels and low sperm motility.
Our findings on the motility ratio were similar to other reports (
), in a systematic review, evaluated 17 randomized trials of the effect of antioxidants supplementation, including vitamins C and E, zinc, selenium, and carnitine, on male infertility, considering a total of 1,665 men. Of the 17 trials, 14 (82%) showed an improvement in sperm quality after antioxidant therapy (
The design of the present investigation, repeated assessment of diet and physical activity, exclusion of subjects using tobacco or with acute inflammatory disease, and control for covariates were strengths of our study. This study is the first that has investigated the effect of supplementation with ALA on infertile men, and the results have been statistically reported and discussed. Obviously, to clarify the clinical relevance of the data, more studies with larger sample sizes and longer durations are needed. Furthermore, owing to budget limitations we were not able to include healthy individuals in the study and measure ROS radicals and endogenous antioxidants such as glutathione, selenium, and vitamin E.
In conclusion, ∼3 months of supplementation with ALA can improve sperm quality. After 12 weeks of treatment in oligoasthenoteratozoospermic men, mean count, concentration, and motility increased significantly compared with the placebo group. Based on our findings, medical therapy of asthenoteratospermia with oral antioxidants, such as ALA, can improve quality of semen parameters.
Definition and epidemiology of unexplained infertility.