Serum Total Testosterone Levels Pre- and Post-Subinguinal Microsurgical Varicocelectomy in Men with Clinical Varicoceles

Background: Varicocele is abnormal dilation and tortousity of the scrotal venous pampiniform plexus that drain blood from each testicle. Recently, it has been linked to low serum total testosterone (TT) levels by affecting the optimal functioning of the leydig cell via increasing the scrotal temperature. Varicocele repair has been found post-operatively to increase the serum levels of TT. This study looks at the pre and post-subinguinal microsurgical varicocelectomy serum TT levels in male patients with clinical varicocele. Methods: The study involved 88 male patients with clinical varicoceles who met the inclusion criteria. These patients after good history taking and physical examination had their serum TT levels measured pre varicocelectomy and 6 months postsubinguinal microsurgical varicocelectomy. The varicoceles were diagnosed by physical examination and use of scrotal color Doppler ultrasonography (US). Results: The number of patients with varicocele were 88 males. The mean age of the patients was 33.43 ± 7.82 years. There was isolated left varicocele in 57 (64.8%) patients and bilateral varicocele in 27 (30.7%) patients. Pre varicocelectomy, 61 (69.3%) patients had serum TT of between 100 290 nanogram/deciliter (ng/dl) and a mean value of 241 ± 0.91 ng/dl. Post varicocelectomy 56 (63.6%) patients had serum TT in the range of 300 490 ng/dl with a mean of 482 ± 2.87 ng/dl, showing a robust significant increase in the serum TT post-operatively (P < 0.001). Conclusion: There was statistically significant improvement in the serum TT levels with 55 (79%) patients exhibiting normalization of serum TT levels after subinguinal microsurgical varicocelectomy.


Introduction
Varicocele is abnormal dilatation and tortousity of the scrotal venous pampiniform plexus that drain blood from each testicle [1] [2] [3] [4]. It is the most commonly identifiable correctable cause of male infertility [5]. Incidence of varicocele in healthy men is found to be 4.4% to 22.6% with an average of 15% [1] [4] [6] [7]. The prevalence in adolescent population and childhood mirrors that of the adult population and is 15.7% [7]. Varicocele affects 21% -39% of subfertile men [8]. It is found in 35% -50% of men presenting with primary infertility and 69% -81% of men presenting with secondary infertility [3] [4] [5] [6]. The left spermatic vein drains into the left renal vein in a perpendicular fashion. This drainage fashion coupled with the fact that the left spermatic vein traverses 8 cm -10 cm longer with a greater increase in hydrostatic pressure accounts for a preponderance of varicocele on the left side by about 80% -90% [1] [4] [6] [9] [10]. Where there is a left sided varicocele, there is a 30% -50% probability it is a bilateral condition [1] [4] [10] [11]. Furthermore, an isolated right sided varicocele may be a pointer to associated situs inversus or retroperitoneal tumors necessitating further investigations [11]. For the diagnosis of clinical varicoceles, physical examination remains the gold standard [11] [12]. Varicoceles are graded according to the scale developed by Dubin and Amelar in 1970 [4] [11] [13]. A widely accepted US diagnosis of varicocele is the existence of veins larger than 2 millimeters (mm) in diameter [11]. The pathogenic mechanisms of varicoceles which include oxidative stress, heat stress, toxin accumulation can affect adversely the function of the leydig cells of the testis responsible for 95% testosterone production in adult men [6] [14]. This study looks at serum TT in patients with clinical varicocele and also serum TT 6 months post-subinguinal microsurgical varicocelectomy with a view to finding out if there is improvement in the serum TT.

Material and Method
This is a prospective study involving male patients seen at the urology clinic of a Federal teaching hospital in southeast Nigeria between January 2016 and December 2018. Approval for the study was obtained from the ethical committee of the hospital and informed written consent from the individual patients.
3) Those on treatment for any form of Hypogonadism. A minimal sample size of 102 was calculated for the study. These 102 patients were seen at the urology clinic. 14 of them had one of the exclusion criteria.
Eighty eight patients with inclusion criteria were recruited into the study.
The age, marital status, occupation and drug history of the individual patients were obtained and recorded in a proforma. Presenting complaints were docu-

Statistical Analysis
The data were analyzed using both descriptive and inferential statistics. The descriptive statistics, frequency, percent, mean and standard deviation were used to summarize the data. The inferential statistics, Mann-Whitney test was used to ascertain the effect of varicocelectomy on TT values at 5% level of significance.
Kruskal-Wallis and ANOVA were used to compare different increases in TT in the varicocele grades and ages respectively. The unit of testosterone in this study is ng/dl. Significant effect hence existed if P-value was less than 0.05 (P < 0.05) otherwise no significance. These statistics were done with the aid of the statistical package for social sciences (SPSS v25 and Microsoft. The normal range of serum total testosterone level in the hospital of study is 300 -1000 ng/dl.

Results
A total of 88 men who met the inclusion criteria were enrolled into the study.    The overall range was between 2.5 -6.5 mm with mean and standard deviation of 4.2 ± 0.78 mm (  (Table 3 and Table 4) and ( Figure 6).    Table 3. Testosterone values pre-and post-varicocelectomy (n = 88).   Table 5(a)).
Furthermore, analysis into the impact of age on total testosterone improvement post varicocelectomy shows that mean increase in TT for age groupings, less than 30 years, 31 -40 years and above 40 years were 190 ± 0.33, 169 ± 0.22 and 153 ± 0.28 ng/dl respectively. Using ANOVA to compare these respective mean increases gave a p-value of 0.238. This implies there is no statistical difference between the TT mean increments in the three age groupings. Hence age did not have any impact on TT improvement after varicocelectomy in this study.
There is post varicocelectomy improvement in TT at all ages (See Table 5(b)).

Discussion
It has been shown that men with clinical varicoceles have lower testosterone le-  [17]. The incidence of scrotal pain in this study was 18%. In other studies, 10% of varicoceles will present with scrotal pain [3] [4]. The higher prevalence in this study could be due to late presentation with worsening pathophysiology. Left sided varicocele was noted in 95.5% of the patients in this series. A prevalence of 85% -90% was reported by Leslie et al. [1] and by Gat et al. [18]. Furthermore bilateral varicocele was found in 30.7% of the patients and this was by physical palpation and color Doppler US of the scrotum. Alsaikhan et al. noted that 50% of men had bilateral varicocele [19]. Gat et al. using venography in his series found bilateral varicocele in 80.8% of his patients [18].
In this series the pre-varicocelectomy mean TT was 241 ± 0.91 ng/dl. Several   [20]. Furthermore there is increased exposure of the testis to gonadotoxins from suboptimal drainage due to venous dilatation [21], varicocele induced increase in reactive oxygen species production and testicular hypoperfusion [6] [14] [19] [20]. Leydig cells are the principal androgen producing cells producing up to 95% of TT in men [6] [14]. Patients with clinical varicocele have leydig cell atrophy, leydig cell structural changes and marked decrease in quantity of testosterone positive leydig cells [20]. Testosterone production in leydig cell is a 5-stage enzymatic process that leads to conversion of 17-hydroxyprogesterone to testosterone by the enzyme 17 alpha-hydroxyprogesterone aldolase. The most accepted hypothesis that explains the effect of varicocele on leydig cell function hinges on changes on the testicular thermal environment. The testicular veins leaving the testis form a communicating meshwork of veins that produce a counter-current heat exchange mechanism to cool the arterial blood flowing into the testis [22]. This cooling mechanism is lost in patients with clinical varicocele causing elevated scrotal temperatures by 2.6˚C due to regurgitation of warm abdominal blood through incompetent valves [23] [24] [25]. Thus the scrotal hyperthermia affects adversely this enzyme that produces testosterone [ [32]. Furthermore 60% -80% of men with low serum testosterone will exhibit normalization of testosterone levels after varicocele repair [33]. In this series, 55 (79%) patients exhibited normalization of testosterone le-  [34]. When this high venous pressure exceeds the arteriolar pressure in the testicular microcirculatory system, the hypoxic effect occurs bilaterally [34]. It must be stated that both palpable and non-palpable veins have the same adverse effects on the testis and so varicocelectomy on the left ignoring bypasses is not adequate to correct the problem [34]. Thus bilateral varicocele repair was done in these patients to reverse bilateral testicular dysfunction and improve testosterone production.
In stratifying the TT improvement after subinguinal varicocelectomy based on varicocele grade, it was found that varicocele grade had no impact on Serum TT improvement after varicocele repair. Other studies have noted similar findings [32] [33]. Furthermore, stratification of the patients into various age groupings showed that testosterone improvement occurred across all age groupings. Age did not impact the TT improvement after varicocele repair as TT improvement was noted in older age groups in another study [35].
The limitations of the study are low awareness of varicocele within the population of study and thus decrease flow of patients with clinical varicoceles to the urology clinic. Lack of previous research work on the topic from this part of the world thus paucity of local data to work with. Hormonal assays are expensive and posed economic stress on the researcher.

Conclusion
The results from this study support the observation that subinguinal microsurgical varicocelectomy robustly increases the serum levels of TT. This will reverse the adverse effects of low testosterone in patients. Open Journal of Urology lection.

Permission
The ethical committee of the hospital gave permission for this study to be carried out.

Conflicts of Interest
The author declares no conflicts of interest regarding the publication of this paper.