Does the Type of Infertility Affect Varicocelectomy Efficacy?

doi:10.21203/rs.3.rs-5287241/v1

Background:

The aim of the study was to compare varicocelectomy efficacy in men with primary (PI) and secondary infertility (SI).

Materials and methods:

Men suffering from PI (n=22) and SI (n=28) and having varicocelectomy in the period of from January 2021 to December 2022 at Republican Specialized Scientific-Practical Medical Center of Urology were included in the study. Semen parameters before and after varicocelectomy were analyzed according to WHO 2010 Manual.

Results:

Analysis revealed that the mean age of patients of the group I was significantly lower (p <0.001) and duration of infertility was accurately shorter (p <0.01) than those of group II. Main semen parameters increased significantly in group I (e.g., sperm concentration increased by 50%, from 62,2±8,7 to 93,5±10,0 M/ml and total motile sperm count increased by 113%, from 76,7±17,1 to 163,4±27,8 M p<0.05), while in group II only % of progressive motile sperm increased significantly (by 107%, from 13,5±2,6 to 28,0±5,2% p<0.05). We identified significant difference in varicocelectomy efficacy between group I and group II in change of total motile sperm count (by 113% vs. 74% respectively, p<0.01). We also revealed discrepancy between groups in correlation ratio (r) between initial and post-surgical % of progressive motile sperm.

Conclusions:

The mean age and duration of infertility of patients with SI was greater and longer respectively than those of in patients with PI. Varicocelectomy resulted in significant improvement of main semen parameters in patients with PI. In patients with SI varicocelectomy resulted in significant improvement of only % of progressive motile sperm. Advanced paternal age and long infertility duration may affect negatively varicocelectomy efficacy.

varicocele

varicocelectomy

semen analysis

primary male infertility

secondary male infertility

Currently researches are conducted actively on possible causes of male infertility. Varicocele is the most common cause of primary and secondary infertility in men. In this regard, varicocele repair remains the most frequently performed surgery to correct male factor infertility [1]. Analysis of literature demonstrated that among men with primary infertility, the proportion of patients with varicocele is 33–40%, and among those who suffer from secondary infertility - up to 81% [2].

According to data of many authors in varicocele testis suffer from venous overflow and it is supplied with blood poor in oxygen and nutrients, thus it leads to atrophy of its tissue [1, 6]. Another pathogenetic factor is the increase of testicular temperature to + 37^оC due to the overflow of venous blood. Most of men with varicocele are fertile, but the prevalence of infertility in this group is increased compared with the general population. However, more than 40% of patients with varicocele have reduced sperm quality [1]. The relationship between varicocele and semen parameters may be different. Microcirculation disorders evolving with varicocele leads to increase in the testis cells concentration of reactive oxygen species and oxidative stress. The latter is nowadays considered a leading pathophysiological mechanism of pathozoospermia with varicocele [6].

Recent randomized controlled trials (RCTs) have demonstrated that varicocele repair (varicocelectomy) in patients with clinical varicocele and pathologies of semen analysis leads to significant increase in pregnancy rates [3] and improving of semen quality in relation to observation group (control) [4]. Other authors in RCTs revealed low efficiency of varicocelectomy in cases of subclinical varicocele and normal semen parameters [5].

Ricardo Miyaoka et al. referring to the large number of studies indicated that microsurgical (inguinal and subinguinal) ligation of spermatic cord veins is the most appropriate surgery for treatment of clinical varicocele with infertility [6, 7].

Teruo Fukuda et al. conducted study of 71 infertile men who underwent microsurgical varicocelectomy. The subjects had their semen analysis taken 3 times (before and after intervention, in 3 and 12 months.). The results showed that the quality of semen analysis in 3 months after surgery was significantly better than that before surgery. No statistically significant differences were detected between semen parameters taken in 3 and 12 months after surgery [8]. Walsh et al. in their study came to conclusion that men with primary and secondary infertility with varicocele may have different clinical characteristics including semen parameters, i.e. males with secondary infertility had significantly better parameters of the semen (sperm concentration) [9].

In this regard, we aimed to assess initial semen parameters and varicocelectomy efficacy in men with primary and secondary infertility dividing them into two separate groups.

Ethics approval and informed consent statements

The Institutional Review Board of the Republican Specialized Scientific-Practical Medical Center of Urology approved the collection and analysis of those data (№ 8/21 from January 25, 2021), which was conducted following the Declaration of Helsinki and the Good Clinical Practice guidelines. A total of 50 patients who provided written informed consent were included in the final analysis.

Study design

During this single-center prospective study we evaluated the main semen parameters: semen volume (ml), sperm concentration (million/ml) and total sperm count (million), % of sperm with progressive motility, total sperm motility (%) and total motile sperm count (TMC) according to WHO standards by 2010 [10].

Presence of varicocele was determined by visual and palpation methods, as well as using Doppler ultrasound of testis according to 2000 WHO classification of varicocele (subclinical varicocele, I, II, III) [11].

Patients

We used following inclusion and exclusion criteria for recruiting appropriate patients for our study. Inclusion criteria:

- patients had their semen analysis taken before and after varicocelectomy (in 3 – 6 months);

- patients with pathological deviation of at least one of the studied parameters of semen analysis;

- patients with clinical varicocele (grade I-III);

- patients with complaints of pregnancy absence in their partners during 12 months and longer period.

Exclusion criteria:

- patients with azoospermia and normozoospermia;

- patients with other infertility causes.

According to those criteria men suffering from primary infertility (PI) (n=22) and secondary infertility (SI) (n=28) and having varicocelectomy in the period of from January 2021 to December 2022 at Republican Specialized Scientific-Practical Medical Center of Urology were included in the study. Patients were divided into 2 groups: 22 men with PI (aged from 21 to 33 years) were included into group I and 28 ones with SI (aged from 24 to 46 years) into group II.

Intervention (procedure)

All patients underwent microsurgical subinguinal/inguinal varicocelectomy. The interventions were performed by experienced surgeons using the techniques described below. A 2-4 cm incision is made below the external inguinal ring with the subinguinal method and above the inguinal canal with the inguinal method. The spermatic cord was isolated, the veins were separated from the arteries, lymphatic vessels, and vas deferens and ligated under special surgical loupes or a microscope.

Statistics

Statistical data analysis was carried out using statistical package MS Office Excel 2019. Significance of interpretation between calculations using Student's t tests for mean scores; differences were considered significant at p<0.05. For correlation Pearson correlation (r) coefficient was used.

Analysis revealed that the mean age of patients in group I was significantly lower
(p <0.001) and the mean duration of infertility was accurately shorter (p<0.01) than those of in patients of group II (Table №1). Most patients had left-sided varicocele alone (43 patients, 86%) (see Table №1).

Table № 1.

KEY FEATURES OF GROUP OF PATIENTS

Groups	Age M±m	Anthropometric data			Varicocele in abs. (and in %)*						Duration of infertility (in months) M±m
		Height	Weight	BMI**	Side			Grade
		Height	Weight	BMI**	Left	Right	Bilateral	I	II	III
First	27,4±0,6	1,7	81,2	26,8	20 (91)	-	2 (9)	8 (29)	19 (68)	1 (3)	28,7±4,6
Second	31,0±0,6	1,7	79,9	26,5	23 (82)	1	4 (5)	5 (23)	15 (68)	2 (9)	51,8± 5,6
Р	<0,001	-	-	-	-	-	-	-	-	-	<0,01
TOTAL	-	-	-	-	43 (86)	1 (2)	6 (12)	8 (20)	34 (68)	3 (6)	-

* -data are given in absolute numbers and in % (in brackets) in relation to the group.

**-body mass index.

BMI of 18 (36%) patients was slightly higher than normal (25,0-30,0), which was evaluated as pre-obese, 9 (18%) patients’ BMI was significantly higher than normal (> 30.0), which was assessed as obesity, and in 23 (46%) patients BMI was within normal range (18,5-25,0) [12]. Consequently, 27 (54%) patients were obese.

Following table shows the main semen parameters of patients of both groups before surgery for statistical comparison.

Table № 2.

MAIN PARAMETERS OF SEMEN ANALYSIS IN BOTH GROUPS IN PREOPERATIVE PERIOD FOR THEIR COMPARATIVE ESTIMATION

Groups	Semen volume, ml *M±m*	Sperm concentration (M/ml) M±m	Total sperm count (M) M±m	Sperm with progressive motility (%) M±m	Total sperm motility (%) M±m	Total motile sperm count (M) M±m
First	3,4±0,3	62,2±8,7	213,6±35,9	11,4±2,3	30,8±3,6	76,7±17,1
Second	3,7±0,3	47,2±8,6	171,9±33,5	13,5±2,6	35,1±4,6	76,3±19,2
p	>0,05	>0,05	>0,05	>0,05	>0,05	>0,05

As it is seen from Table № 2, no statistically significant differences on the initial semen parameters were revealed between groups.

Preoperative and postoperative semen parameters of patients of both groups are given in Table № 3 for comparison of varicocelectomy efficacy before and after repair, as well as between groups.

Table № 3.

COMPARATIVE ASSESSMENT OF MAIN SEMEN PARAMETERS OF BOTH GROUPS IN PRE- AND POSTSURGICAL PERIOD

Groups	Semen volume, ml *M±m*		Sperm concentration (M/ml) M±m	Total sperm count (M) M±m	Sperm with progressive motility (%) M±m	Total sperm motility (%) M±m		Total motile sperm count (M) M±m
First ¹		3,4±0,3	62,2±8,7	213,6±35,9	11,4±2,3		30,8±3,6	76,7±17,1
First ²		3,4±0,2	93,5±10,0	341,8±46,6	20,0±3,1		46,1±4,5	163,4±27,8
p³		>0,05	*<0,05*	*<0,05*	*<0,05*		*<0,05*	*<0,05*
Second		3,7±0,3	47,2±8,6	171,9±33,5	13,5±2,6		35,1±4,6	76,3±19,2
Second		3,9±0,3	65,7±10,2	246,9±40,8	28,0±5,2		46,0±6,0	132,7±31,3
p		>0,05	>0,05	>0,05	*<0,05*		>0,05	>0,05
p⁴		>0,05	>0,05	>0,05	*<0,01*		>0,05	*<0,01*

1 – preoperative period. 2 – postoperative period. 3 – statistically significant changes. 4 - statistically significant differences between groups.

In postoperative period the following changes were observed in average counts of studied parameters of semen in both groups:

- semen volume in both groups almost remained unchanged (p>0.05);

- sperm concentration increased significantly in group I (by 50% p<0.05), while in group II it increased not significantly (by 39% p>0.05);

- total sperm count increased by 60% (p<0.05) in group I, whereas in the second one this parameter increased by 44% (p>0.05);

- % of sperm with progressive motility increased more accurately in group II (by 107% p<0.05) than that in group I (by 75% p<0.05) and the difference between groups was significant (p<0.01);

- total sperm motility also increased significantly (by 50% p<0.05) in group I, while in group II this parameter also increased, but not accurately (by 31% p>0.05);

- total motile sperm count in group I increased more significantly (p<0.01) than that in group II (113% p<0.05 vs. 74% p>0.05 respectively).

As it was shown above, statistically significant differences were revealed between groups in changes of some postoperative semen parameters. In patients of group I varicocelectomy resulted in significant improvements in all semen parameters. In contrast to group I in the second one statistically accurate improvement occurred to only % of sperm with progressive motility, which increased more significantly than that in group I.

We also revealed significant discrepancy between groups in correlation ratio (r) between the initial and post-operative % of sperm with progressive motility. In patients of group I there was no correlation (r = -0,02), whereas in patients of group II correlation was direct and strong (r = 0,71). In general, differences between groups in mean correlation ratios between initial and postsurgical semen parameters were not significant (r=0.4 for group I and r=0.5 for group II).

Currently, a varicocele is the most common surgically curable cause of male infertility. Although the vast majority of research is supported by the opinion of the beneficial effect of surgical treatment of varicocele on sperm parameters [3, 4, 13], the question of true effect of surgery on testicular function remains unresolved [1]. Although the exact relationship between improvements in indicators of semen analysis and surgical treatment of varicocele has not been finally determined, a meta-analysis of RCTs conducted by Agarwal et al. showed significant improvement in semen parameters after varicocelectomy [13], which corresponds to results of our research. However, interesting is the fact that greater significant changes occurred to patients with primary infertility and varicocele than those to patients with secondary infertility and varicocele, although in patients with secondary infertility positive effect of intervention was also determined.

There are a number of reports on associations between initial semen parameters and the efficacy of the varicocele repair. These studies assumed that men with higher preoperative semen parameters are more likely to see an improvement in their semen parameters after varicocelectomy [14]. Our study confirmed this statement partially, because association between initial and postsurgical semen parameters was moderate.

It is also worth noting that according to some authors the average age of men with secondary infertility is older, which corresponds to our data. However, they also state that there is no significant difference in duration of infertility, whereas our study revealed a significant difference in this parameter between two groups [9, 15]. In addition, above-mentioned authors claim the presence of differences in initial semen parameters of patients with secondary infertility, although to our knowledge no statistically significant differences were revealed in baseline semen parameters of men with primary and secondary infertility.

According to Bozhedomov et al., varicocele is more common in men with SI than in men with SI, but the difference is not so big (+ 3,5%, p < 0,05), and patients with PI and SI were almost at the same age which statement does not agree with our data [16–20].

The main limitation of our study was the difference between groups in mean age of patients and infertility duration.

Patients’ age suffered from secondary infertility and varicocele was greater, and duration of infertility was longer than those of in patients with primary infertility and varicocele. Varicocelectomy resulted in significant improvement of main semen parameters in patients with primary infertility. Patients with secondary infertility varicocelectomy also led to positive effect, but only significant increase occurred to % of sperm with progressive motility, without significant influence on other semen parameters. It was also revealed direct dependence of varicocelectomy efficacy on initial semen parameters, especially in patients with primary and secondary infertility (but in patients with primary infertility connection between initial and post-surgical % of sperm with progressive motility did not reveal), i.e. the higher were preliminary semen parameters the more effective were surgical treatment of varicocele. Revealed above differences in varicocelectomy efficacy between patients with primary and secondary infertility indicate that the male age and infertility duration may affect varicocelectomy efficacy. Further large-scale clinical trials are needed to approve this statement.

Ethics approval and consent to participate

The study was approved by the Republican Specialized Scientific and Practical Medical Center of Urology ethics committee (№ 8/21 from January 25, 2021).

Consent for publication

Not applicable.

Funding

This research did not receive any specific funding.

Author Contribution

SA created conception and design of the study, KS obtained the material, KhU and AS drafted the manuscript. SA wrote the final manuscript. All authors have read and approved the manuscript.

Acknowledgement

The authors would like to express gratitude towards all the patients who tookpart in this study.

Data Availability

All data used in this study are available when asked from the correspondingauthor after approval from our institute.

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No competing interests reported.

Does the Type of Infertility Affect Varicocelectomy Efficacy?

Status:

Version 1

Abstract

INTRODUCTION

MATERIALS AND METHODS

RESULTS

DISCUSSION

CONCLUSIONS

Declarations