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>j�%�%�%GE�+�+�+�+����$�����������������Type of article: Original Article
Title of the article: Effects of Angiogenesis Inhibition by Spironolactone on Testis Morphology in an Experimental Varicocele Model in Rats
Running title : Effect of Spironolactone in Varicocele 

Contributors 
1. Mustafa G�khan K�SE. Baskent University School of Medicine, Department of Urology, Ankara; TURKEY
2. ^. Remzi ERDEM. Baskent University School of Medicine, Department of Pharmacology, Ankara; TURKEY
3. �etin Levent PE^K0RC0OLU. Baskent University School of Medicine, Department of Urology, Ankara; TURKEY
4. Mehmet �ET0NKAYA. Mula University School of Medicine, Department of Urology, Mula; TURKEY
5. Kadir �NEM. 19 May1s University School of Medicine, Department of Urology, Samsun; TURKEY
6. Berrin �AYLAK. Baskent University School of Medicine, Department of Pathology, Ankara; Turkey 

Corresponding Author: Mustafa Gokhan KOSE, MD
Baskent University School of Medicine, Department of Urology,
Mare_al Fevzi �akmak Cad. 5. sok No: 45
Bah�elievler, �ankaya
Ankara; TURKEY

Tel: 00903122122912

GSM: 00905363524137

e-mail: vensyou@mynet.com  
             vensyou@gmail.com 

Total number of pages: 15
Total number of figures: 4
Total number of tables: 0
Word counts :
for abstract: 115
for the text: 2350

Presentation at a meeting: no

Conflicting Interest: there is no conflicting interest

Financial support: supported by Baskent University Research Fund (Project no: DA 07/12)

Introduction
The incidence of varicocele, one of the most common factors in male infertility, is estimated as 35% in men with primary infertility and 81% in men with secondary infertility [1]. Varicocele is detected on the left in 75-95% of the cases. The etiology of varicocele has been explained by the theories such as anatomical differences between left and right testicular veins, the lack of venous valves and nutcracker phenomenon [2-4]. 

Some theories such as, hyperthermia, alterations in the testicular blood flow, renal and/or adrenal reflux, hormonal disorders, autoimmunity, apoptosis and oxidative stress, are still not sufficient to clarify how varicocele causes infertility [5-10]. 

 Angiogenesis is the formation of new vessels from an existing vasculature. Vascular endothelial growth factor (VEGF) is one of the most potent angiogenic factors [11]. VEGF promotes a tyrosine kinase cascade, stimulates the production of the agents, such as nitric oxide (NO), which leads to a stimulation of vessel permeability, proliferation, migration and new vessel formation [11].  It has been reported that varicocele promotes angiogenesis; however it is not exactly understood how spermatogenesis is affected by angiogenesis [12].  Angiogenesis may enhance the toxic metabolites through the testis by increasing the distribution through new vasculature. If so, the inhibition of angiogenesis may improve spermatogenesis. However, if angiogenesis occurs as a protective process, inhibiting angiogenesis may impair spermatogenesis more.

Recently, antiangiogenic effect of spironolactone (SPL), a competitive antagonist of aldosterone that has been widely used as a potassium sparing diuretic drug, has been described. This inhibition is considered as unrelated to the antimineralocorticoid effect of SPL and can not be prevented by VEGF [13].

The objective of the present study is to investigate the effect of SPL on a rat model of experimental left varicocele (ELV). We hypothetize that SPL improves the detrimental effect of varicocele on spermatogenesis in experimentally induced varicocele in rats by inhibiting the angiogenetic process. 

Material and Methods

After being approved by the Baskent University Local Ethical Comittee (DA 07/12), the study was performed in 24 adult (12 to 14 months) male Wistar albino rats (282,75(20,47 g). The animals were fed by standard rat chow and tap water ad libitum and maintained in the animal facility with constant environmental conditions (room temperature: 20(2 �C, relative humidity: 50(10%, light-dark cycle: 12:12-h). The rats were randomized into 4 groups (n=6, for each); 1. Control, 2. Sham operated, 3. ELV,  4. ELV + Spironolactone (20 mg/kg/d, p.o., 45 days)-treated (V + S).

Each animal was anesthesized by 10% ketamine hydrocloride (60 mg/kg, i.p.) and xylazine (10 mg/kg, i.p.). After an abdominal midline incision; the left renal vein, inferior vena cava and left spermatic vein were identified. A 4/0 silk ligature was loosely placed at the site of the left renal vein and left spermatic vein insertion over a rigid hydrophilic guide wire of 0.64 mm that was placed on the left renal vein. The ligature was loosely tied and the guide wire was removed leading to an immediate dilation of the left renal and left spermatic vein. The incision was sutured with 4/0 silk ligature. All of the surgical procedure in the sham-operated group was identical to that of ELV group, except for the vein ligature step.

Animals in the V+S and ELV were weighed on the first day postoperatively, to adjust the dose of spironolactone or the volume of saline to be given, respectively. The rats in the V+S received spironolactone at the dose of 20 mg/kg/day through an orogastric catheter, for 45 days, beginning with the first day postoperatively. Spironolactone was dissolved in saline (5 mg/ml). The ELV group received only the corresponding volume of saline for 45 days.

All rats were sacrified by ketamin overdose (150 mg/kg, i.p.) on the postoperative 45th day and then underwent bilateral orchidectomy. The testis tissue was fixed in Bouine�s solution and embedded in parafin, then stained with hematoxylin and eosin for histopathological examination. 

The degree of angiogenesis was assessed by counting stained microvessels. Only vessels with a clearly defined lumen or well-defined linear vessel shape were counted as microvessels. Newly forming vessels that consisted of only one layer of endothelial cells were excluded. In each specimen the 3 areas with the highest degree of vascularization were identified by x100 magnification. Then, the number of vessels in the selected field was counted at high power (x400). For each testis the highest of these 3 vessel counts were recorded as microvessel density (MVD). Mean MVD values + SEM in each group were compared.

To determine the biochemical effects of spironolactone, peripheral venous blood samples were achieved preoperatively and postoperatively from each animal. Serum sodium and potassium levels were determined by ion selective electrode method and total testosterone level was determined by radioactive immune assay (Testo-RIA-CT KIP 1709, Biosource, Belgium).

Statistical analysis

The data were taken as the mean and standard error of mean (SEM). For biochemical data, one way ANOVA was used as parametric test and post hoc Bonferroni test was used to determine the difference among groups. For intra-group comparisons (such as basal vs post administration) paired t test was used. For statistical evaluation of the histopathological data, Kruskal-Wallis analysis of variance was used. If any difference was detected between the groups, post hoc Dunn�s test was used to compare the groups. P< 0.05 was accepted as statistically significant.

Results

Histopatological changes in testes were reported as atrophized germ cells in any stage of spermatogenesis, hyperplasia in Leydig cells and decline in Sertoli cell numbers (mixed atrophy). The amount of atrophy was recorded as (+) when it was seen in 1/3 of the specimen, (++) when it was seen in 2/3 and (+++) when it was found in 3/3 of the slides.

Spermatogenesis in the left testes was disturbed in ELV and V+S (P<0.05 and P<0.001, respectively; Figure 1. Such a disturbance was not observed in the right testes. Congestion was more significant in the Sham and ELV in the left (P<0.01 and P<0.001, respectively) and only in the ELV in the right testis (P<0.01); Figure 2. However, no difference was determined in the V+S neither on the left, nor on the right testis. 
MVD was different in the V + S neither on the left nor on the right testes when compared with the control. However, MVD increased in the ELV in comparison with the V+S and Control (P<0.001 and P<0.05, respectively) on the left and in the ELV and sham (P<0.001 and P<0.05, respectively) on the right testes. (Figures 3 and 4). 

Basal and post sacrification serum sodium (Na+) levels were significant neither intra-groups nor inter-group. Basal potassium (K+) levels were higher in ELV and V+S groups when compared with the control group (p< 0.05). Although the last K+ values were not significantly different between the groups, K+  level tended to increase in the control group (p<0.05) and to decrease in the V+S group (p< 0.01). Basal and the last TT values were not different between the groups. 


Discussion

The similarity of the primary and secondary drainage of the testes via internal spermatic vein and internal iliac vein, rare ratio of spontaneous varicocele occurence and the lack of anastomosis between left and right testicular veins in rats, make them the most suitable candidates for ELV model [14]. However, the onset and the formation of varicocele are sudden and iatrogenic. Also it may not fully mimic the adolescent varicocele, since the adolescent varicocele does not have a sudden onset, instead it occurs eventually. Nevertheless, ELV models in animals are still crucial to enlight the pathophysiology of varicocele. For example, the nutcracker phenomenon can be mimicked to form ELV model. Detecting and ligating the collateral veins are of importance in such an ELV model, since collateral formation in varicocele may lead to increases in the pressure and blood flow in the spermatic vein [8, 14].

Turner suggested that mitogenic factors or vasoactive agents might be responsible for the increase in blood flow and total ligation of spermatic vein could return the blood flow to the normal ranges [14]. It may explain the improvement in testicular blood flow and spermatogenesis after varicocele repair in ELV models. 

Varicocele may be inducing angiogenesis, to trigger an inflammatory process in the testes. However, it is not exactly known how angiogenesis affects this process. Angiogenesis may stimulate new collateral formation, and eventually increases in testicular blood flow, pressure and temperature may disrupt spermatogenesis. Early repair of varicocele returns testicular temperature and blood flow to normal, possibly by preventing angiogenesis in the testes, earlier. On the other hand, an ongoing and long lasting angiogenic process in the testes may explain why testicular atrophy occurs or blood flow returns to normal after a late varicocele surgery. In the present study, MVD was more prominent in the ELV compared with the V+S and Control groups suggesting that spironolactone inhibited the varicocele-induced angiogenesis. However, spermatogenesis was disturbed in the ELV and V+S groups being more marked in the latter. More comprehensive study may be performed two more groups, control + spironolactone and sham + spironolactone, to truly test the effects of medication or to reduce the false positive results about medication. We did not determine micro vessel density in sham or control groups. Therefore, we suggest that, if this was not caused by antimineralocorticoid and/or antiandrogenic activity of SPL, angiogenesis may play a protective role in varicocele. 

Isoyama and Sofikitis have suggested that factors inducing vascularization improve the spermatogenic factors by regulating the counter-current heat system and the distribution of the nutrients in varicocelized testes, in line with our findings [15] . This might explain the more marked disruption in spermatogenesis in the V+S than that in ELV, in the present study.  
Hypoxia inducible factor-1 alpha and VEGF expression were documented in some ELV models. Kilinc et al reported that varicocele could lead to tissue hypoxia and related pathophysiological events, such as angiogenesis [12]. Shiraishi and Naito examined the expression and the role of VEGF in human testes with varicocele and showed the increased expression of VEGF which was inversely correlated with total motile sperm count and testicular volume [16]. The authors concluded that excessive VEGF expression impaired spermatogenesis in testes with varicocele. However, Tek et al   investigated the effect of VEGF injection into the testes on spermatogenesis and apoptosis in an ELV model and stated that VEGF might improve testicular damage and play a significant role in decreasing apoptosis [17]. 

Recently, it has been shown that spironolactone inhibits angiogenesis and decreases vascular damage and/or fibrosis independent of its antiandrogenic and antimineralocorticoid effects [18]. The expression of VEGF has been detected in male genital organs such as testis, epididymis, prostate and seminal vesicles, and VEGF receptor-2 (VEGFR-2) expression in the blood vessels supplying the above-mentioned organs [19]. VEGF is one of the main promoters of vascular growth and permeability. Its mitogenic effects are regulated by VEGFR-2. Lissbrant and collegues showed the higher endothelial cell proliferation in testis and epididymis than that in the other tissues including the brain, liver and muscle. Although it has not been defined as a classical angiogenesis, cell proliferation is affected by testosterone treatment or withdrawal [20]. Testosterone treatment promotes cell proliferation. Ge and collegues investigated mineralocorticoid receptor expression in Leydig cells and concluded that Leydig cells express mineralocorticoid receptors and that testosterone production is regulated by aldosterone [21]. Aldosterone was also shown to increase ischemia-induced neovascularization in mice through the activation of angiotensin signaling [22]. Interestingly, Miternique-Grosse et al determined that spironolactone inhibits angiogenesis in human umbilical vein endothelial cells and in fibrin gell chambers implanted to rats. Since, the inhibitory effect of spironolactone could not been prevented by VEGF and aldosterone had no effect, the authors concluded that spironolactone inhibited angiogenesis in vivo and in vitro independent of its antimineralocorticoid activity [13]. 

In the present study, MVD was found to be more in the ELV than that in the V+S and Control groups in the left testes, while, MVD was more in the ELV and Sham groups than that in the Control, in the right testis. This finding, namely the enhanced MVD in the right testes of the sham is confusing and is subject to further research. The basal and final TT values did not differ among the groups. Since, spironolactone administration did not affect testosterone levels in the present study; we suggest that the antiangiogenic effect of spironolactone is independent of its antiandrogenic effect. This finding is in accordance with Miternique-Grosse et al. 13. However, in contrast to Ge et al, who have shown that SPL alters TT values, SPL pre-treatment failed to cause such an effect in the present study
Spermatogenesis in the left testis was found to be worse in V+S than that of the ELV, while it did not cause such a differential effect in the right testes. Thus, we suggest that the antiangiogenic effect of spironolactone is independent of its antiandrogenic activity. Supportingly, MVD was not different between the control and V+S groups. Spironolactone inhibited angiogenesis in both testes, while spermatogenesis was not affected in the right testis. TT values were not different among the groups. We may not exactly know how Leydig functions are affected in 45 days. However, testicular morphology was normal in right testicles for all groups and TT levels did not change.  Therefore, we suggest that spironolactone administration impairs spermatogenesis through a mechanism involving its antiangiogenic but not antiandrogenic effect, yet longer studies are required.  

The diversity in the basal K+ values is difficult to explain, since the rats were randomized at the beginning of the study. The higher serum potassium concentration detected in some of the rats, might have been due to the hemolytic process resulting in the leakage of intracellular K+ to serum.


In conclusion, we showed that, varicocele increased MVD and angiogenesis in both testes, to result in an impairment in testicular morphology. Spironolactone inhibited angiogenesis in the varicocele group, while it significantly impaired spermatogenesis as well. Therefore, we conclude that angiogenesis may play a protective role in the varicocele-related process. The antiangiogenic effect of spironolactone, seemed to be associated neither with its antimineralocorticoid nor antiandrogenic effect. Nevertheless, further studies are required to clarify the relationship between varicocele and angiogenesis. 










References

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(2)    Karazincir S, Balci A, G�r�r S, Sumbas H, Kiper AN (2007). Incidence of the   	retroaortic left  renal vein in patients with varicocele. J Ultrasound Med 26: 601-604.
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	(21) 	Ge RS, Dong Q, Sottas CM, Latif SA, #9���������Ϲ��w_I5$!hP65�B*mHnHphsH	u'hQ�hP65�CJOJQJaJmH	sH	+hQ�hP6CJOJQJaJmHnHsH	u.hQ�hP65�CJOJQJaJmHnHsH	u.hQ�hP6CJOJQJ\�aJmHnHsH	u*hQ�hP65�CJOJQJ\�aJmH	sH	'hyI-hP65�CJOJQJaJmH	sH	+hiThP6CJOJQJaJmHnHsH	uhiThP6B*phhiThP65�B*ph0jhiThP65�B*UmHnHphsH	u#����[	�
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	(22) 	Michel F, Ambroisine ML, Duriez M, Delcayre C, Levy BI, et al (2004) Aldosterone enhances ischemia-induced neovascularization through angiotensin II-dependent pathway. Circulation 109: 1933-1937.








Titles and legends to figures

Figure 1. Normal spermatogenesis (A-B). Mixed atrophy in ELV group (C). Germinal cells are disturbed and calsification in Sertoli cells in V + S group (D) (H&E staining x200 HPF). 
* indicates calsification in Sertoli cells. 
HPF: high powered focus

Figure 2. Congestion in ELV group (H&E staining x200 HPF). 

Figure 3. MVD is obviously seen in ELV group (H&E staining x200 HPF). 

Figure 4. MVD is not dense in V + S group (H&E staining x200 HPF).
















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