الفهرس 
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Abstract
This study tried to investigate the effect of ursolic acid on possible fertility disorders induced by metabolic syndrome in experimental male Wistar rats.
It was performed on 84 male Wistar rats allocated into six main groups (each group consists of 14 rats): -
1- group I (Control group, C): Rats in this group were fed regular diet.
2- group II (CL): Rats in this group were fed the same diet as in group I and received ursolic acid in a dose of 5mg/Kg daily by oral gavage for 8 weeks.
3- group III (CH): Rats in this group were fed the same diet as in group I and received ursolic acid in a dose of 16mg/Kg daily by oral gavage for 8 weeks.
4-group IV (Metabolic syndrome-induced group, Met.S): Rats in this group were fed high fat high fructose – enriched diet for 8 weeks for induction of metabolic syndrome.
5- group V (Metabolic syndrome-induced group and received low dose of ursolic acid, Met.S.L): Rats in this group were fed the same diet as in group IV and received ursolic acid in a dose of 5mg/Kg daily by oral gavage for 8 weeks.
6- group VI (Metabolic syndrome-induced group and received high dose of ursolic acid, Met.S.H): Rats in this group were fed the same diet as in group IV and received ursolic acid in a dose of 16mg/Kg daily by oral gavage for 8 weeks.
All rats in all groups were subjected for measurement of the following parameters: -
1- Measurement of initial and final body weight, % change in body weight, waist circumference, BMI calculation, measurement of retroperitoneal fat weight and epididymal weight.
2- Measurement of fasting blood glucose level, serum insulin level and calculation of the insulin resistance HOMA score.
3- Measurement of initial and final systolic blood pressure, diastolic blood pressure and heart rate.
4- Measurement of lipid profile (triglycerides, total cholesterol and high density lipoprotein cholesterol) and calculation of low density lipoprotein cholesterol, HDL/LDL ratio and the atherogenic index.
5- Measurement of blood levels of prolactin, FSH and testosterone hormones.
6- Measurement of testicular tissue malondialdehyde (MDA) level and glutathione peroxidase activity (G-PX).
7- Immediate semen analysis for epididymal sperm count.
8- Microscopic histopathological examination of testicular tissue.
Statistical Analysis:
One way ANOVA test (analysis of variance) for difference between means of different groups was performed on results obtained in our study.
Results of the study could be summarized in the following points:-
1- In comparison to normal control group, ursolic acid administration to groups II and III, in either low and high dose respectively, was able to induce a significant decrease in final body weight (p<0.001 for both doses), % change in body weight (p< 0.01 for both doses), waist circumference (in high dose only, p<0.02), BMI (in high dose only p<0.05), retroperitoneal fat weight (p<0.001 for both doses) and epididymal weight (in high dose only, p< 0.02).
2- Metabolic syndrome induced group (group IV) exhibited a significant increase in final body weight (p<0.01), waist circumference (p<0.02) and retroperitoneal fat weight (p<0.01), while, % change in body weight, BMI and epididymal weight, all were non-significantly changed compared to normal control group. On the contrary, ursolic acid concomitant use with this high fructose high fat- enriched diet has induced a significant decrease in waist circumference (p<0.05) and retroperitoneal fat weight (p<0.01) with high dose only, while the other above mentioned parameters were non-significantly changed compared to metabolic syndrome induced group.
3- Ursolic acid supplementation in groups II and III was not able to produce any significant change in fasting blood glucose, serum insulin levels, and the calculated insulin resistance HOMA score compared to normal control group (group I).
4- In this study, high fructose high fat enriched –diet in group IV produced a significant increase in fasting blood glucose (p<0.01), serum insulin level and HOMA score (p<0.001 for both) compared to normal control group. Ursolic acid administration with this diet regimen in groups V and VI has induced a significant decrease in serum insulin level (by high dose only, p<0.05) and HOMA score by both low dose (p<0.05) and high dose (p<0.01) compared to the metabolic syndrome induced group (group IV).
5- Control groups rats that received ursolic acid in either low and high doses (group II and group III respectively) showed a non-significant change in final systolic blood pressure, diastolic blood pressure and heart rate compared to normal control group. On the other hand, rats of the metabolic syndrome induced group (group IV) exhibited a significant increase in final systolic blood pressure (p<0.001), final diastolic blood pressure (p<0.01) with a non-significant change in final heart rate compared to normal control group (group I), but in metabolic syndrome induced groups that received low and high doses of ursolic acid (group V and group VI respectively), only the high dose of ursolic acid had significantly decreased the final systolic blood pressure compared to group IV and group V (p<0.01 and p<0.05 respectively).
6- Compared to normal control group, ursolic acid administration to rats of group II and III achieved a significant decrease in total cholesterol level (p<0.05 in low dose and p<0.02 in high dose), LDL-c (p<0.02 in low dose and p<0.01 in high dose), the calculated atherogenic index (p<0.02 in low dose and p<0.01 in high dose) and serum triglycerides (by high dose only, p<0.01). On the opposite side, there was a significant increase in HDL/LDL (p<0.05 in low dose and p< 0.02 in high dose) and HDL-c (by high dose only, p<0.02).
7- Metabolic syndrome induced group (group IV) exhibited worsening in all lipid profile parameters compared to normal control group, manifested in a significant increase in serum triglycerides (p<0.01), total cholesterol, LDL-c and the calculated atherogenic index (p<0.001 for all), additionally, there was a significant decrease in HDL-c (p<0.05) and HDL/LDL (p<0.02), while with ursolic acid co-administration in groups V and VI, only the atherogenic index was significantly decreased with the high dose (p<0.05) and all other parameters were non-significantly changed compared to the metabolic syndrome induced group.
8- Control groups that received ursolic acid in low and high doses showed a non-significant change in the measured hormones compared to normal control group, while in metabolic syndrome induced group (group IV), there was a significant increase in serum prolactin level (p<0.01), and a significant decrease in serum testosterone level (p<0.02) compared to normal control group (group I). Meanwhile, ursolic acid administration, in either low or high doses, did not produce any significant change in the level of measured hormones in group V and VI compared to group IV except in serum prolactin level which was significantly increased with both dose regimens (p<0.01 for both).
9- Compared to normal control group, there was a significant increase in testicular tissue G-PX activity with high dose only in group III (p< 0.05), while testicular tissue MDA level was non-significantly changed. On the contrary, in metabolic syndrome induced group (group IV), there was a significant increase in testicular tissue MDA level (p<0.01) and a significant decrease in G-PX activity (p<0.05) compared to normal control group, indicating a state of oxidative stress. Furthermore, upon ursolic acid adding to diet of groups V and VI, there was a significant decrease in testicular tissue MDA level (p<0.05 for both low and high doses), while G-PX activity did not show any significant change compared to the metabolic syndrome induced group.
10- Control groups that received ursolic acid in high dose exhibited a significant decrease in epididymal sperm count (p<0.05) compared to normal control group. On the opposite side, in metabolic syndrome induced group (group IV), there was a significant decrease in epididymal sperm count (p<0.01) compared to normal control group, while, in group V and VI, epididymal sperm count was non-significantly changed in comparison to metabolic syndrome induced group.
Overall conclusion and recommendations: -
1- High fat high fructose – enriched diet in this study resulted in dyslipidemia, hypertension, insulin resistance, increased waist circumference and retroperitoneal fat. In addition, higher serum prolactin and testicular tissue MDA levels were observed together with significantly decreased serum testosterone and epididymal sperm count compared to normal control group rats. Moreover, testicular tissue on histological examination showed decrease in number of primary spermatocytes.
2- Both low and high doses of ursolic acid supplementation in concomitant with the regular diet in group II and group III respectively caused a significant decrease in %change in body weight, retroperitoneal fat weight and better lipid profile which was marked with high dose. Moreover, epididymal weight and epididymal sperm count were significantly decreased by high dose of ursolic acid compared to normal control group.
3- When ursolic was given in concomitant with induction of metabolic syndrome (group V &VI), it improved insulin resistance, systolic blood pressure, distribution of body fat specially with high dose yet it caused higher serum prolactin in comparison to the metabolic syndrome induced group (group IV).
4- Ursolic acid use in the four tested groups showed decrease in number of primary spermatocytes in examined testicular tissues.
5- To conclude, metabolic syndrome has a negative impact on male fertility, which could not be improved by ursolic acid supplementation that aggravated these fertility changes.
6- Finally, we recommend avoid use such drug for males who are seeking children, but the whole thing needs more investigations in the future, especially to be tried on female rats.
7- Ursolic acid use in athletics to increase muscle mass is recommended by many studies, but it is in need for more research.