Effect of Varicocelectomy on Oxidative Stress

Varicocelectomy is the most common urological procedure for male factor infertility. In most of the published studies, varicocele repair has been associated with an improvement in semen parameters and spontaneous pregnancy rates, although the data remain controversial [81, 82] . Varicocele repair may improve pregnancy outcomes after assisted reproduction technologies (ARTs) [83, 84]. There is now evidence to show that varicocelectomy may reduce seminal oxidative stress and this provides another mechanism for the improved male fertility potential following varicocelectomy, as seminal OS has been associated with poor sperm function and reduced fertility potential [85] .

As discussed earlier, seminal ROS levels are higher in semen samples from infertile men with varicocele [53, 86, 87] (including men with normozoospermia [86, 88]) than in controls and there are now several reports showing that varicocelectomy is generally associated with a reduction in seminal OS. However, the effect of varico-celectomy on seminal antioxidant capacity and seminal antioxidant enzyme activity (e.g., SOD) is mixed—with some studies reporting lower and others higher antioxidant activity after varicocelectomy [58, 60, 89-93] (Table 18.3). Nevertheless, the true effect of varicocelectomy on seminal OS is not proven as most of the studies are retrospective and none are randomized, controlled trials.

Table 18.3 Summary of studies that measured seminal OS and antioxidant (AOX) capacity before and after varicocelectomy

Study

OS marker and/or AOX capacity

n

Before varicocelectomy

After varicocelectomy

P-value

Conclusion

Zini [89], 1999

% Sperm with residual

43

28.5%

18.1%

0.0003

Reduced OS

cytoplasm

Mostafa [90], 2001

MDA (nm/mL)

68

MDA = 23.2±2.7

At 3-6 months

P< 0.0001 except

Reduced OS and

MDA =15.3 ±4.6

albumin and

increased AOX

H20, (jim/mL)

H,0, = 45.2±10.2

H202 = 39.4±7.9

vitamin E

capacity

NO (nm/L)

NO = 5.8± 1.0

NO = 5.5 ±0.9

SOD (U/mL)

SOD = 6.6± 1.7

SOD = 10.7±2.6

CAT (fim/mL)

CAT=6.1 ± 1.1

CAT=9.4±2.5

GPx (U/mL)

GPx=1.3±0.6

GPx = 2.7± 1.2

Vitamin C and E ((.ig/mL)

Vitamin C = 2.7 ±0.6

Vitamin C = 3.1 ±0.7

Vitamin E = 0.36 ±0.06

Vitamin E = 0.25 ±0.08

Albumin (mg/mL)

Albumin = 0.28 ±0.04

Albumin = 0.29 ±0.03

Mancini

TAC

25

Lag time = 107±8.8 s

At 10-24 months

NS

No change in TAC

[91], 2004

Lag time = 106 ±8.6 s

Hurtado de Catalfo

GSH and GSSG ((.imol/L)

36

GSH = 1.5±0.21

At 8 months

<0.05 only for

Reduced OS and

et al. [58], 2007

GST=2.2 ±0.22

GSH, Zn, Se

reduced AOX

GSSG = 0.19±0.01

GSSG = 0.1 ±0.06

capacity

Zn (mg/dL)

Zn = 45 ± 16

Zn = 233±ll

Se ((.ig/L)

Se = 41.5±4.4

Se = 58.3 ±6.5

SOD

SOD = 1,703 ±134

SOD = 1,380 ±135

CAT (U/g Hb)

CAT= 157±21

CAT= 124 ± 17

Chen [92], 2008

8-OHdG (/10A5 dG)

30

8-OHdG = 10.27 ±2.24

At 6 months

P<0.001

Reduced OS and

8-OHdG = 5.95 ±1.46

increased AOX

Protein thiols (nmol/mL)

Thiols = 0.77 ±0.75

Thiols = 3± 1.17

capacity

Ascorbic acid (AA) (mg/dL)

AA= 1.87±0.40

AA = 3.12±0.94

(continued)

Table 18.3 (continued)

Study

OS marker and/or AOX capacity

n

Before varicocelectomy

After varicocelectomy

P-value

Conclusion

Sakamoto et al.

NO ((.imol/L)

30

NO = 17.1(9.1)

At 6 months

P<0.001

Reduced OS sperm

[60], 2008

NO = 7.5(4.5)

DNA damage

8-OHdG ((.imol/L)

8-OHdG = 10.3(4.7)

8-OHdG = 6.2(2.5)

and increased

SOD (%)

SOD = 85.8(5.8)

SOD = 78.1(8.1)

AOX capacity

HEL ((.imol/L)

HEL= 137.3(67.9)

HEL = 90.9(28.5)

Dada [93], 2010

ROS levels in washed (W)

11

W = 3.121.725.65

At 3-6 months

P<0.001

Reduced OS

and neat (N) semen

W = 98,971.081

N= 142.897.704

N = 6.456.249

(RLU/20 million sperm/min)

8-OHdG 8-Hydroxy-2'-deoxyguanosine; CAT catalase; GPx glutathione peroxidase; GSH reduced glutathione; GSSG oxidized glutathione; HEL hexanoyl-lysine; MDA malondialdehyde; NO nitric oxide; ROS reactive oxygen species; Se selenium; SOD superoxide dismutase; TAC total antioxidant capacity; TBARS thiobarbituric acid reactive substances; Zn zinc

Shiraishi and Naito examined the effect of varicocelectomy on the levels of testicular 4-hydroxy-2-nonenal (4-HNE)-modified proteins, an OS marker. They found higher levels of testicular 4-HNE-modified proteins in those men who responded to varicocelectomy suggesting that varicocelectomy reduces OS in those infertile men who exhibit a high level of baseline testicular OS and that varicocelctomy is not as effective in men without OS [64] . Mostafa et al. [90] reported a significant reduction in seminal plasma oxidants (NO, H2O2, MDA) and a significant increase in seminal plasma antioxidant levels (SOD, catalase, glutathione peroxidase, and vitamin C) at 3 and 6 months after varicocele repair. Hurtado de Catalfo et al. [58] demonstrated a shift in the seminal glutathione status (with increased reduced glutathione, GSH and decreased oxidized glutathione, GSSG), an increase in the levels of nonenzymatic antioxidants (Zn, Se), and a paradoxical decrease in the antioxidant enzyme levels (to levels comparable to that of fertile controls) as early as 1 month after varicocele repair. Chen et al. evaluated the effect of varicocelectomy on sperm mitochondrial DNA deletions (by polymerase chain reaction), DNA oxidation (8-OHdG), and seminal plasma protein thiols and ascorbic acid levels. They reported lower sperm mito-chondrial DNA deletions and DNA oxidation levels and higher seminal plasma protein thiols and ascorbic acid levels at 6 months after varicocelectomy compared to preoperatively [92]. Dada et al. [93] evaluated the effect of varicocelectomy on seminal ROS levels and sperm DNA damage and reported lower semen ROS levels as early as 1 month after surgery with a delayed improvement in sperm DNA integrity (at 3 and 6 months after surgery). Sakamoto et al. [60] evaluated the effect of varico-celectomy on markers of seminal OS (nitric oxide, 8-OHdG, hexanoyl-lysine) and seminal SOD activity and reported lower levels of semen OS markers levels and lower seminal SOD activity after surgery. In contrast to otherwise largely positive studies, Mancini et al. [91] evaluated the effect of varicocelectomy on seminal plasma TAC and reported no significant reduction in seminal TAC after varicocele repair.

One report evaluated the effect of varicocelectomy on peripheral blood plasma oxidative stress markers (C-reactive protein, TBARS, and plasma lipid peroxidation susceptibility) in 11 adolescents with left-side varicocele and ipsilateral testicular hypotrophy [94]. They reported higher levels of TBARS and a higher mean plasma peroxidation susceptibility in adolescents with varicocele compared to controls. They also observed a significant reduction in plasma TBARS levels and in the plasma peroxidation susceptibility 1 year after varicocelectomy [94].

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