Abstract
Varicocele surgical repair can improve the function of the testis for patients with varicocele. We carried out a systematic review and meta-analysis to assess the effects of varicocele surgical repair on serum hormones and inhibin B levels in patients with varicocele. A literature search was performed in August 2022, and no language or geographic region restrictions were applied. The search included the following databases: PubMed, Embase, and Medline. A literature review was performed to identify all published clinical trials assessing serum hormone and inhibin B levels before and after varicocele surgical repair. The reference lists of retrieved studies were also investigated. A systematic review and meta-analysis were conducted. Eight articles were selected from 162 articles, including 452 patients. The combined analysis showed that after surgical treatment, mean serum testosterone, inhibin B, and sperm concentration levels increased compared with preoperative levels (p < .05). After surgical treatment, mean serum follicle-stimulating hormon (FSH), and Luteinizing hormone (LH) levels decreased compared with preoperative levels (p < .05). This meta-analysis demonstrates that varicocele surgical repair can improve testicular function, increase serum testosterone, and inhibin B levels and decrease serum FSH and LH levels in patients with varicocele. This might be related to the improvement of infertility. A large-scale multicenter randomized controlled study is needed for further confirmation.
Background
In young adult males, approximately 15% suffer from varicocele (Rottenstreich et al., 2017). In contrast, varicocele is reported in up to 35% of infertile male patients (Alsaikhan et al., 2016). Many studies have illustrated data about the etiology and pathophysiology of varicocele and its impact on spermatogenesis and the reproductive hormonal axis (Cüce et al., 2016). It has a negative effect on testicular function in various ways. An increasing number of studies have reported that varicocele surgical repair may contribute to a higher probability of pregnancy in patients with varicocele, but the reasons are not conclusive (Chiba & Fujisawa, 2016; Tiseo et al., 2016). One of the viewpoints was that varicocele surgical repair could improve the function of Leydig cells and the level of serum testosterone. For example, there was a meta-analysis that reported that mean serum testosterone levels increased after varicocelectomy (Li et al., 2012). However, more evidence has been reported that varicocele surgical repair also changes the levels of other serum hormones and inhibin B. An increasing number of people have begun to believe that the improvement in fertility potential may also be connected to changes in serum hormone and inhibin B levels. The effects of varicocele surgical repair on serum hormone and inhibin B levels in patients with varicocele are controversial, so we performed a meta-analysis to explore this issue.
The aim of our meta-analysis was to assess the effects of varicocele surgical repair on testicular function and changes in serum hormone and inhibin B levels.
Materials and Methods
Search Strategy
We conducted a literature search in August 2022 using the PubMed, EMBASE, and MEDLINE databases. We scrutinized the reference lists of the included studies to further choose the more relevant articles and abstracts. We used the following search terms: varicocele, follicle-stimulating hormone (FSH), Luteinizing hormone (LH), testosterone, inhibin B, and varicocele surgical repair.
Inclusion Criteria
Clinical trials that met the following criteria were included: (1) a study design in which patients with varicocele underwent varicocele surgical repair; (2) the study provided accurate data that could be analyzed and included at least one or more objects of study (serum testosterone, FSH, LH, inhibin B, and sperm concentration levels) before and after surgery, respectively; (3) the outcome reported as the mean and standard deviation; and (4) the full text of the study could be accessed. If these inclusion criteria were not met, then the study was excluded from the analysis.
Trial Selection
If the same group of subjects was studied in multiple experiments, each study was included. Although we included as many studies as possible, we clarified that we did not apply the same data to their findings multiple times. If the same study was published in different articles, the most frequently cited article was included. We discussed each of the studies that were included or excluded. A flow diagram of the study selection process is presented in Figure 1.
The Flow Diagram of the Study Selection
Quality Assessment
Two independent reviewers assessed the quality of the included studies according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Not only randomized controlled trials included in our meta-analysis, but there are many observational studies, such as comparative studies and controlled clinical trials, in which risk factors in research generally cannot be randomized because they relate to inherent human characteristics or practices, and exposing subjects to harmful risk factors is unethical (Stroup et al., 2000). There are many risk factors in research that cannot be randomized. Based on the quality assessment criteria, the quality of each study was broadly classified as one of the following two categories: A, all quality criteria were met (adequate), and the study was deemed to have a low risk of bias; B, one or more of the quality criteria were only partially met (unclear), and the study was deemed to have a moderate risk of bias. Differences were resolved by discussion among the reviewers.
Data Extraction
The data were extracted and cross-checked by two independent reviewers using a predesigned form, which included the first author’s name, publication year, number of patients, age, country, grade of varicocele, follow time, and surgical approach. Disagreements were discussed by the third person. The primary outcome was the changes in serum hormone and inhibin B levels preoperation and postoperation. The secondary outcome was mean sperm concentration levels preoperation and postoperation.
Statistical Analysis
Statistical analysis was performed by Review Manager 5.1.0. (Higgins & Greeen, 2011). Outcomes were expressed as continuous outcomes, including the mean difference (MD) with 95% confidence interval (CI) and the p value and odds ratios (OR) for dichotomous outcomes. We used the I2 heterogeneity test to quantify the effect of result heterogeneity. If I2 was no more than 50%, we chose a fixed effects model. If I2 was more than 50%, we chose a random effects model. We used a funnel plot to evaluate the presence of publication bias. A funnel plot of the studies represented in this meta-analysis is presented in Figure 2.
Funnel Plot of the Studies Represented in this Meta-Analysis.
Results
Characteristics of Individual Studies
The database search found 162 articles that could potentially have been included in our meta-analysis. Based on the inclusion and exclusion criteria, 101 articles were excluded after a simple reading of the titles and abstracts of the articles. Forty-nine articles were excluded because they were not preoperation and postoperation clinical trials. Four articles were excluded due to a lack of useful data. All eight articles (Di Bisceglie et al., 2007; Fujisawa et al., 2001; Ghanem et al., 2011; Ozden et al., 2008; Pierik et al., 2001; Prasivoravong et al., 2014; Reşorlu et al., 2010; Zohdy et al., 2011) involving 450 patients were included in the analysis: pre- and postoperation. The clinical trials in these articles were conducted in Japan, Egypt, Turkey, The Netherlands, Italy, and France. The number of patients included in each study of the eight articles was relatively small, varying between 30 and 103 patients. Follow-up for all studies was 6 months. The baseline characteristics of the studies included in our meta-analysis are listed in Table 1.
The Main Characteristic and Quality Assessment of Eligible Studies
Note. NA = not available.
A: If all quality criteria were adequately met, the study was deemed to have a low risk of bias; B: if one or more of the quality criteria was only partially met or was unclear, the study was deemed to have a moderate risk of bias.
Changes in Serum Hormone Levels Preoperation and Postoperation
Ten studies included data on the changes in serum FSH levels representing 391 participants (391 preoperation and 391 postoperation). According to the heterogeneity test, there was no heterogeneity among the trials, so we chose a fixed effects model. The pooled estimate of MD was −0.78, and the 95% CI was −1.08 to −0.48, p < .05. This result shows that the level of mean serum FSH was decreased by 0.78 mIU/ml postoperation compared with preoperation (Figure 3A).
Forest Plots Showing the Changes of Serum Hormone Levels Post-Operation and Pre-Operation. (a) FSH Post-Operation vs Pre-Operation. (b) LH Post-Operation vs Pre-Operation and (c) Testosterone Post-Operation vs Pre-Operation.
Seven studies included data on the changes in serum LH levels, representing 276 participants (276 preoperation and 276 postoperation). According to the heterogeneity test, there was no heterogeneity among the trials, so we chose a fixed effects model. The pooled estimate of MD was −0.48, and the 95% CI was −0.81 to −0.15, p < .05. This result shows that the level of mean serum LH was decreased by 0.48 mIU/ml postoperation compared with preoperation (Figure 3B).
Eleven studies included data on the changes in serum testosterone levels, representing 450 participants (450 preoperation and 450 postoperation). According to the heterogeneity test, there was heterogeneity among the trials, so we chose a random effects model. The pooled estimate of MD was 35.19, and the 95% CI was 8.61 to 61.77, p < .05. This result shows that the level of mean serum testosterone was increased by 35.19 ng/dl postoperation compared with preoperation (Figure 3C).
Changes in Serum Inhibin B Levels Preoperation and Postoperation
Six studies included data on the changes in serum inhibin B levels, representing 251 participants (251 preoperation and 251 postoperation). According to the heterogeneity test, there was heterogeneity among the trials, so we chose a random effects model. The pooled estimate of MD was 25.19, and the 95% CI was 15.77 to 34.61, p < .05. This result shows that the level of mean serum inhibin B was increased by 25.19 pg/ml postoperation compared with preoperation (Figure 4).
Forest Plots Showing the Changes of Serum Inhibin B Level Post-Operation and Pre-Operation.
Changes in Sperm Concentration Level Preoperation and Postoperation
Seven studies included data on the changes in sperm concentration levels representing 307 participants (307 preoperation and 307 postoperation). According to the heterogeneity test, there was heterogeneity among the trials, so we chose a random effects model. The pooled estimate of MD was 11.74, and the 95% CI was 4.85 to 18.63, p < .05. This result shows that the mean serum sperm concentration was increased by 11.174 × 106/ml postoperation compared with preoperation (Figure 5).
Forest Plots Showing the Changes of Sperm Count Level Post-Operation and Pre-Operation.
Discussion
There are three main types of testicular cells: mesenchymal cells, Sertoli cells, and spermatogenic cells (Kang et al., 2022). Although the functions of the three testicular cells are different, they have close connections with each other. The main function of spermatogenic cells is to produce sperm, but the process of spermatogenesis is regulated by testosterone, LH, FSH, and inhibin B (Pastuszak & Wang, 2015). Testosterone is secreted by Leydig cells and is an essential hormone for spermatogenesis. The secretion of testosterone is regulated by LH. The function of Sertoli cells is regulated by FSH and has an important influence on spermatogenesis. Sertoli cells can secrete inhibin B to promote spermatogenesis. The level of serum testosterone can reflect the function of Leydig cells, and the level of serum inhibin B can infer the function of Sertoli cells (Pastuszak & Wang, 2015). According to the negative feedback mechanism of the hypothalamus-pituitary-gonad axis, the secretion of testosterone is regulated by serum LH, and the secretion of inhibin B is regulated by serum FSH (Hayden & Tanrikut, 2016). Despite the sperm concentration, the changes in the levels of serum hormones and inhibin B can also reflect the improvement in testicular function.
We found that patients with varicocele have a higher probability of infertility. (Jensen et al., 2017). One of the most likely reasons is that varicocele can decrease testicular function. The exact mechanism of the effect of varicocele on infertility is poorly understood thus far. Several hypotheses have been suggested to explain the deleterious effect of varicocele on testis function. The most accepted hypothesis is related to alterations in the testicular thermal environment (Jin & Yang, 2014). The spermatic veins leaving the testicles form a communicating meshwork of veins that produces a countercurrent heat-exchange mechanism to cool the arterial blood (Goldstein & Eid, 1989). This mechanism is eliminated in patients with varicocele, causing elevated scrotal temperatures. Spermatic enzyme activity, such as enzyme 5α-reductase (SRD5A), affects the conversion of testosterone into 5α-dihydrotestosterone and is decreased in patients with varicocele, which may be an important additional mechanism involved in the harmful effect of varicocele on male fertility (Aquila et al., 2015). This can be reversed after surgery, improving the testicular cell environment for enzyme activity, thus leading to a postoperative increase in the levels of serum testosterone and inhibin B. As negative feedback, the levels of serum LH and FSH will be decreased after surgery.
The changes in the levels of serum hormones and inhibin B after surgery are controversial. Chen and Chen (2011) suggested that the significant predictive factor of successful varicocelectomy in infertile patients was a low serum concentration of FSH. Li et al. (2012) carried out a meta-analysis that reported that the mean serum testosterone level increased after varicocelectomy. Kumanov et al. (2006) suggested that serum inhibin B measurement was a better marker of fertility. However, a study noted that the levels of serum FSH, LH, T hormones, and pregnancy rate (23.3% versus 22.9%) within the first year of treatment showed no meaningful difference (Salem & Mostafa, 2009). We conducted a meta-analysis to further explore this issue.
In the results of our analysis, we found that the levels of serum testosterone and inhibin B and sperm count levels were increased (p < .05, respectively), and the levels of serum FSH and LH were decreased (p < .05, respectively) after varicocele surgical repair. The results were meaningful and corresponded with the mechanism of negative feedback of the hypothalamus–pituitary–gonadal axis. The results suggest that the function of Leydig cells and Sertoli cells was improved after surgical repair. In addition, we further evaluated the sperm concentration after surgery and found that the sperm concentration increased postoperation (p < .05). It would also suggest the improvement of testicular function and infertility after varicocle surgical repair.
In summary, varicocele surgical repair can improve testicular function, increase serum testosterone and inhibin B levels, and decrease serum FSH and LH levels in patients with varicocele. This might be related to the improvement of infertility.
Limitations
This meta-analysis included 8 articles and 450 patients. The sample sizes were not large. In addition, unpublished studies were not included in the analysis. These factors may have resulted in bias. The major bias was that some studies were observational studies, such as comparative studies and controlled clinical trials. It made a self-comparison of the patients with varicocele preoperation and postoperation. Second, the outcomes of these studies may have been measured by different methods. Third, the researchers in the trials were different. Finally, potential selection biases could have influenced the homogeneity of the groups, and relatively small sample sizes limited the statistical power for identifying true associations. After the heterogeneity among individual studies is taken into account, this meta-analysis remains crucial for assessing varicocele surgical repair on testicular function and changes in serum hormone and inhibin B levels. Further high-quality trials with larger samples are proposed to learn about varicocele surgical repair on testicular function and changes in serum hormone and inhibin B levels.
Conclusion
This meta-analysis demonstrates that varicocele surgical repair can improve testicular function, increase serum testosterone and inhibin B levels and decrease serum FSH and LH levels in patients with varicocele. This might be related to the improvement of infertility. A large-scale multicenter randomized controlled study is needed for further confirmation.
Footnotes
Acknowledgements
All authors have no acknowledgments to disclose.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval and Consent to Participate
The authors have no ethical conflicts to disclose.
