| BackgroundROS can damage sperm mitochondrial functionality, and reduce ATP generation, resulting sperm motility decrease, the mechanism of ROS injury is:Firstly, ROS cause mitochondrial membrane lipid peroxidation damage, break mitochondrial respiratory chain, leading to the decrease of mitochondrial enzyme-specific activities. Secondly, ROS induce mtNDA mutations, which would undermine its encoded protein synthesis, required for mitochondrial oxidative phosphorylation. Thirdly, ROS induce mitochondrial Ca2+ release, reduced mitochondrial membrane potential and increased intimal permeability, leading to membrane damage. Forthly, Motility of spermatozoa depends on the integrity of the mitochondrial functionality, phospholipids of mitochondrial sheath are a important component, If fatty acids in phospholipids are oxidized by free oxygen radicals, sperm motility will be impaired. In conclusion, oxidative stress can do damage to mitochondrial functionality, leading MMP decrease and obstacle the production of ATP that power sperm motility.Antioxidant therapy is a commonly empirical treatment method of idiopathic male infertility. All drugs are usually administered for at least 3 months to demonstrate any effects on spermatogenesis, as the spermatogenic cycle lasts approximately 75 days. Though some scholars suggested that antioxidants such as vitamin C, vitamin E, carnitine, and glutathione, have been ineffective or are still under evaluation. Ross et al. analyzed 17 trials, including 1,655 men, the target population was infertile men and the therapeutic intervention was oral antioxidants, 82% trials showed an improvement in sperm quality, mainly motility (63%) but also sperm concentration (33%) and/or morphology (17%).Beacause whether TAM could improve sperm motility is not determinant in medicine, this study is also established to explore clinical effect of TAM’s treatment on improving sperm motility.Mitochondria contain a double membrane. The outer membrane allows large molecules to flow into the mitochondrial intermembrane space, and the highly invaginated inner membrane, which has a large surface area, is responsible for oxidative phosphorylation. During the process of oxidative phosphorylation, the protons are pumped from inside the mitochondria to the outside, creating an electrochemical gradient called the inner mitochondiral membrane potential (MMP). MMP is an important indicator of functional integrity of the spermatozoa, and normal MMP is essential for the adenosine triphosphate (ATP) production of the mitochondrial. An increased proportion of spermatozoa with depolarized mitochondria has been reported in asthenozoospermic men. Artificially induced oxidative stress by incubation with H2O2 has been shown to inhibit sperm motility, decrease ATP levels, and dissipate the MMP, indicating that excessive oxidative stress is detrimental to MMP. Espinoza suggested that the MMP was positively correlated with sperm motility. Bilgeri et al. demonstrated that the higher sperm ATP content, the greater potential for fertilization. Other scholars found that the ATP content of sperm is positively correlated with sperm motility. Alessandra Ferramosca et al demonstrated that high levels of reactive oxygen species could decrease sperm mitochondrial respiration by an uncoupling between electron transport and adenosine triphosphate synthesis, which might be one of the reasons responsible for the decrease in sperm motility.Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM), as a commonly drug used in treatment of idiopathic male infertility. The therapeutic mechanism known is:Firstly, TAM block estrogen activity at the level of hypothalamus and anterior pituitary thereby abolishing the negative feedback exerted by estrogen. This results in increased gonadotropin secretion which could theoretically increase testosterone synthesis and enhance spermatogenesis. Secondly, TAM can improve the sensitivity of Leydig cells to luteinizing hormone (LH), promote the ability of Leydig cells to produce testosterone, affecting spermatogenesis. Thirdly, another specific potential indication for TAM is direct interference with xenoestrogens which were found to be higher in semen of infertile men. There is literature shown that the administration of TAM could led to a twofold increase in spermatozoa concentration. However, it has not been shown to induce any marked changes in motility and morphology. However, A meta-analysis showed that TAM can also increase the percentage of progressive motile sperm. Whether TAM can increase the percentage of progressive motile sperm is not determinant. Literatures shown that TAM has antioxidant effects, but there is no research on wether TAM can play antioxidant effects in therapy of idiopathic oligoasthenospermia. It is uncertain whether there is also an additional direct effect for TAM on mitochondrial functionality. This research is to explore the new mechanism of tamoxifen in therapy of idiopathic oligoasthenospermia——antioxidation.Barkay et al. demonstrated that nonsteroidal anti-inflammatory drugs can increase follicle-stimulating hormone (FSH), LH levels and cAMP concentration in seminal plasma, thereby contributing to the development of testicular seminiferous epithelium, elevating sperm density and sperm motility. In 1995, S.AYDIN et al have shown that indomechacin (75mg/bid) can significantly improve sperm motility, which may be due to that indomechacin acts by preventing the deleterious effect of prostaglandins on spermatogenesis and also bring about an increasing in seminal fluid cAMP, which in turn increases sperm motility and fertilizing capacity. Given that indomechacin does not have antioxidant effects and on the basis of its usual prescription in some cases of male infertility, indomechacin was used in clinical control group in this study. Because of ethical reasons and the obligation to provide the best available treatment, we did not use the placebo control.Object1. To explore the effect of TAM in therapy of idiopathic oligoasthenospermia on semen parameters, especially on sperm motility.2. To explore the effect of TAM in therapy of idiopathic oligoasthenospermia on serum and semen oxidative stress indexes.3. To explore the effect of TAM in therapy of idiopathic oligoasthenospermia on mitochondrial functionality.MethodThe subjects are 120 infertile men attending reproduction medicine center outpatient clinic at our hospital from April 2014 to January 2015. This study use a prospective, randomized, controlled clinical trial research,120 cases of oligoasthenospermia are randomizedly devided into experimented group administrating TAM orally for 3 months (10mg/bid), and clinical control group administrating indomethacin orally for 3 months (25mg/bid). Observe the clinical effectiveness of TAM’s treatment on idiopathic oligoasthenospermia. Malondialdehyde (MDA) contents and total antioxidant capacity (TAC) level in serum and seminal plasma were measeured by thiobarbituric acid (TBA) method and ferric reducing ability of plasma method with slightly modifications method respectively to reflect oxidative stress. Succinate dehydrogenase (SDH) was measured by a colorimetric method. Sperm ATP content was measured by the bioluminescence method. Sperm intracellular ROS and mitochondiral membrane potential (MMP) were measured using flow cytometry. The procedure was done before and after the completion of treatment.Result1. General conditionDuring the treatment,14 patients out of 120 dropped out for for various reasons. 5 patients wished to have in vitro fertilization (IVF),5 lost to follow-up. All of the remainder 96 patients completed 3-month follow-up and therefore were eligible for analysis.41 received Indomethacin and 55 received TAM. In indomechacin group, their age is (28.41±4.62 years [mean±SD]), duration of infertility is (4.79±1.95 years [mean±SD]); In TAM group, their age is (27.88±3.38 years [mean±SD]), duration of infertility is (4.65±2.10 years [mean±SD]). The general information of two groups is not statistically significant when compared to each other.2. Changes of semen parameters before and after the completion of treatment.The seminal values for basal evaluation were similar in two groups (P> 0.05). After three months treatment, the clinical control group had significant increase in sperm forward progressive motility and total sperm motility [(21.53±5.20)% vs. (24.78±5.86)%, P<0.05; (31.48±8.31)% vs. (36.78±10.47)%, P<0.05]; experimented group had significant increase in total sperm count [(29.68±9.13)×106 spz vs. (41.27±8.33)×106 spz, P<0.001] and sperm concentration [(10.34±2.13)×106 spz/ml vs. (14.67±3.92)×106 spz/ml, P<0.001], sperm forward progressive[(19.17±7.17)% vs. (24.73±6.53)%, P<0.001], total sperm motility [(30.67±7.53)% vs. (35.72±10.20)%, P<0.05]. In comparison between the two groups, experimented group had significant difference in total sperm count and sperm concentration from clinical control group [(41.27±8.33)×106 spz vs. (32.90±8.48)×106 spz, P<0.001; (14.67±3.92)×106 spz/ml vs. (10.76±3.07)×106 spz/ml, P<0.001].3. Changes of oxidative stress indexes of serum and seminal plasma before and after the completion of treatment. Serum MDA concentration and TAC level,and seminal plasma MDA concentration and TAC level and sperm intracellular ROS for basal evaluation were similar in two groups (P>0.05). After treatment, clinical control group had no significant change in all baseline data; experimented group had significant increase in serum and seminal plasma TAC [(8.14±3.01)×U/ml vs. (12.31±2.89)xU/ml, P<0.001; (11.74±3.57)xU/ml vs. (15.47±3.88)xU/ml, P<0.001], and decrease in sperm intracellular ROS[(3.27±1.08)% vs. (2.27±0.95)%, P<0.001]. In comparison between the two groups, after treatment, experimented group had higher serum and seminal plasma TAC than clinical control group [(12.31±2.89)xU/ml vs. (8.75±2.63)×U/ml, P<0.001; (15.47±3.88)×U/ml vs. (12.62±4.66)×U/ml, P< 0.05] and lower sperm intracellular ROS [(2.27±0.95)% vs. (2.85±0.96)%, P< 0.05].4. Changes of activity of SDH before and after the completion of treatment.The activity of SDH of sperm for basal evaluation were similar in two groups (P >0.05). After treatment, clinical control group had no significant change in SDH activity (P>0.05); experimented group had significant increase in SDH activity [(5.92±1.51)×U/106 spz vs. (6.66±1.61)×U/106 spz, P<0.05]; In comparison between the two groups, after treatment, experimented group had higher activity of SDH[(6.66±1.61)×U/106 spz vs. (5.70±1.49)×U/106 spz,P<0.05].5. Changes of sperm ATP content before and after the completion of treatment.Sperm ATP content for basal evaluation were similar in two groups(P> 0.05). After treatment, clinical control group had significant increase in sperm ATP content [(68.37±12.02)×pmol/106 spz vs. (77.81±14.08)×pmol/106 spz, P<0.001]; experimented group had significant increase in sperm ATP content [(69.37±14.78)×pmol/106 spz vs. (81.44±11.77)×pmol/106 spz, P<0.001]. In comparison between the two groups, after treatment, there is no significant difference in sperm ATP content (P>0.05)6. Changes of sperm MMP level before and after the completion of treatment.Flow cytometry technique show that sperm MMP level for basal evaluation were similar in two groups (P>0.05). After treatment, clinical control group had significant increase in sperm MMP level [(34.84±5.60)% vs. (40.88±8.34)%, P< 0.05]; experiment group had significant increase in sperm MMP level [(36.00±6.17)% vs. (42.53±5.99)%, P<0.001]. In comparison between the two groups, after treatment, there is no significant difference in sperm MMP level (P>0.05)ConclusionNot only TAM supplementation can improve sperm concentration via the endocrine related mechanism, but also is associated with alleviating oxidative stress and improving sperm mitochondrial functionality, and subsequently increasing the sperm motility. |
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