Varicocele Treatment and Serum Testosterone

Abstract

Varicoceles are an abnormal dilation of the pampiniform plexus within the spermatic cord that can impair spermatogenesis and testosterone production in the testes through a variety of theorized mechanisms. Nearly 15% of the male population is affected by varicocele, though most men are entirely asymptomatic. Among men presenting with infertility, the incidence of varicocele has been observed to be as high as 35–40%. Varicoceles are the most commonly identified abnormalities in men presenting with infertility, and, when associated with abnormal semen parameters, present the urologist with an opportunity for intervention. Serum testosterone levels have been demonstrated to be lower on average among patients with varicoceles and data have suggested that varicocelectomy improves mean serum testosterone levels postrepair. Nonetheless, there are no current guideline indications for varicocelectomy for men with symptomatic hypogonadism, and it is not yet known whether the reported improvement in serum testosterone with surgical intervention is clinically meaningful. In this review, we discuss the most up-to-date literature on the mechanisms by which varicoceles are purported to impair both spermatogenesis and testosterone production as well as the effect of varicocelectomy on serum testosterone levels.

Introduction

Male factor infertility contributes to ∼50% of cases for couples struggling to conceive with 20–30% of cases being a result of male factor infertility alone. ¹ Among sexually active men in the United States, research has demonstrated that ∼8.7% have used infertility services with an additional 4.8% of this population representing unevaluated infertile men. ² Given that 15% of couples worldwide struggle with infertility, there is great demand for continued research, technological and surgical advancements to bolster fertility rates among couples desiring children. ³

Numerous etiologies for male factor infertility have been identified, including congenital, hormonal, anatomical, acquired disorders of spermatogenesis, and other idiopathic etiologies. Varicoceles are the most commonly identified abnormalities in infertile men, and, when discovered in association with impaired fertility, present the urologist with an opportunity for intervention. ⁴

Varicoceles are an abnormal dilation of the pampiniform plexus within the spermatic cord. Various suspected etiologies exist for varicocele development and progression, although the exact mechanism remains to be elucidated. Purported theories for varicocele development include impaired venous drainage secondary to high pressure, turbulent flow, and refluxing or absent venous valves. Left-sided varicoceles are more common than right, hypothesized to be the result of increased left-sided gonadal vein length and the 90° angle at which it empties into the left renal vein resulting in increased hydrostatic pressure, relative to direct drainage of the right gonadal vein into the inferior vena cava. ⁴

Isolated right-sided varicoceles are relatively uncommon, although current American Urological Association guidelines no longer recommend abdominal imaging for the sole indication of isolated small or moderate sized right varicoceles. Cases of bilateral varicoceles are considered more likely to result from impaired antireflux venous valve mechanisms leading to increased backflow, elevated venous pressures, and abnormal dilation. ¹ Varicoceles may also result from complete lack of antireflux valves rather than valve incompetence. Another proposed mechanism for varicocele development is termed the “nutcracker effect,” describing compression of the renal vein between the aortic and the superior mesenteric artery, resulting in increased hydrostatic pressure. ⁵

Varicoceles are graded clinically based on physical examination by the Dubin and Amelar grading system. ⁶ Grade 0 is assigned to subclinical varicoceles, or those discovered incidentally on imaging that are not palpable on physical exam even with valsalva. Grade 1 is assigned to varicoceles palpable only with Valsalva. Grade 2 is assigned to varicoceles palpated without Valsalva. Grade 3, the highest grade, is assigned to varicoceles that are visible at rest, without Valsalva. ⁷

Varicoceles have been shown to have an incidence near 15% in the general population of men, although most men are asymptomatic and entirely unaffected. Among men presenting with infertility, the rates of varicocele are as high as 35–40% on formal evaluation by fertility specialists. ⁸ Upon evaluation of men with secondary infertility, or those having previously conceived but newly experiencing fertility issues, prevalence of varicocele has been observed to be as high as 70–80%. Increased age has also been associated with increased incidence of varicocele, with a reported rise in incidence of ∼10% per decade reaching ∼75% among men 80 years or older. ⁹

Pathophysiology: Normal Testicular Function and Impact of Varicocele

Two types of cells contribute to the normal endocrine function of the testes: Sertoli cells and Leydig cells. The function of the Sertoli cells, mediated by follicle-stimulating hormone in a healthy male, is to promote spermatogenesis. Sertoli cells augment the presence of intratesticular testosterone through increased production of sex-hormone binding protein and secrete various growth factors necessary for healthy sperm development.

An intratesticular testosterone-to-serum testosterone ratio of 25–100 is mediated by the Sertoli cells providing the optimal environment for high-quality spermatogenesis to occur. Sertoli cells also contribute to the immunologically privileged nature of the testes through a network of tight intercellular junctions. Leydig cells, under the influence of luteinizing hormone, are responsible for testosterone production. Testosterone is uniformly required for spermatogenesis. ¹⁰ Disruption in any part of the sperm development and maturation process can impact subsequent sperm quality and count.

The main three mechanisms by which varicoceles are thought to impair spermatogenesis are through hyperthermia in the scrotal/testicular microenvironment, direct hypoxic damage to testicular tissues, and disruption of the architecture of the blood–testis barrier. Scrotal hyperthermia in patients with clinically significant varicocele results from decreased venous blood flow away from the testis, resulting in dysregulated intratesticular temperature homeostasis and subsequent apoptosis of cells involved in spermatogenesis through a variety of complex mechanisms and pathways outside the scope of this review article.^11–13 Impaired venous drainage and increased venous outflow pressure can also result in testicular ischemia and hypoxic damage to spermatogenic tissues.

Refluxing of adrenal metabolites, mainly catecholamines, can also induce local vasospasm further exacerbating testicular ischemia in varicocele patients. ¹⁴ Ischemia notably prevents vital oxygen from reaching spermatogenic tissues but also decreases necessary flow and supply of nutrients and growth factors vital to sperm production. ¹⁵ With regard to the blood–testis barrier, E-cadherins are essential proteins in the tight-junction makeup, and have been demonstrated to have lower expression in varicocele patients. ¹⁶ A disrupted blood–testis barrier is associated with a higher incidence of antisperm antibodies, however, the link between this and infertility is controversial and remains an active area of study. ¹

Relationship Between Varicoceles and Testosterone

The mechanisms by which varicoceles are theorized to impair spermatogenesis are similarly suspected to affect the rest of the testicular parenchyma, impairing the normal functioning of other intratesticular cells and processes. Most notably, and clinically relevant to the urological patient population, is testosterone production mediated by the testes. Serum testosterone concentrations have been demonstrated to be lower among patient with varicoceles. ¹⁷

Patients with varicoceles may thus present simultaneously or independently with symptoms of testosterone deficiency, including decreased libido, erectile dysfunction, fatigue, depressed or changes in mood, decreased bone mineral density, weight fluctuations, and insulin resistance. ¹⁸ Surgical intervention for palpable varicoceles has been associated with a clinically significant increase in testosterone levels postrepair, although symptomatic testosterone deficiency alone is not currently endorsed as an indication for varicocele repair. ¹ Nonetheless, testosterone production is typically only impaired in higher stage varicoceles that represent the minority of varicoceles discovered in practice.

Histological analyses of testicular tissue in patients with unilateral varicocele have shown that bilateral Leydig cell populations are affected, typically with concomitant reactive bilateral Leydig cell hyperplasia as well as Leydig cell vacuolization and atrophy. ¹⁹ In men with left-sided varicocele, Leydig cell density was increased in patients with oligozoospermia versus those with normal sperm concentrations, and similarly these findings were found bilaterally, suggesting a compensatory hyperplasia in response to varicocele-mediated insult to testicular parenchyma. ²⁰

Several human and animal model studies have demonstrated impaired testosterone synthetic capabilities of Leydig cells harvested from subjects with varicoceles, specifically highlighting the following enzymes with demonstrably impaired functioning: 17, 20-desmolase, 17 α-hydroxylase, and C17, 20-lyase.^21,22 A 2014 study of a novel improved rat varicocele model induced by microsurgical ligation of testicular vein collaterals alongside the classically performed partial renal vein occlusion method demonstrated larger spermatic cord diameter, lower cauda epididymal sperm concentration, lower sperm motility, and worse testicular histology than prior animal models, supporting mechanisms of spermatogenesis impairment with clinically significant varicocele. ²³

Low serum and intratesticular testosterone levels secondary to Leydig cell dysfunction may further worsen the underlying spermatogenic dysfunction that patients with varicocele experience, providing further support for intervention in patients desiring fertility, with the possibility of being able to simultaneously improve symptoms of testosterone deficiency if present. ²⁴

Varicocele Treatment and Impact on Testosterone

Current indications for varicocele treatment include palpable varicocele in patients with semen abnormalities, children with unilateral testicular atrophy alongside varicocele with >20% decrease in relative size, cosmesis, and symptomatic varicocele (pain or discomfort). ¹ Some authors advocate for symptomatic testosterone deficiency as a newer indication for treatment, although this has not yet been formally implemented into society guidelines. ²⁵ Low serum testosterone levels were found to be the second strongest predictor of varicocele repair, second to abnormal semen analysis, on a nationwide commercial database study in 2018. ²⁴

Options for intervention include observation, embolization by interventional radiology, or surgical repair based on symptoms and patient goals, specifically fertility planning, and quality of life. Patients without impaired fertility or not interested in fertility planning, those without discomfort, and those without symptoms of testosterone deficiency or poor testicular growth might elect for observation. Highly comorbid patients desiring intervention may opt for embolization with good outcomes. Several surgical interventions exist for varicoceles, including open microsurgical and minimally invasive approaches. Regardless of surgical approach, key common principles involve ligation of internal and external spermatic veins as well as cremasteric veins using clips or surgical ties. ¹

Tanrikut et al. compared 325 men with palpable varicoceles to 510 control men with vasectomy reversals, finding that mean serum testosterone before repair in the treatment group was 416 ng/dL compared with 469 ng/dL in the control group (p < 0.001) and that this difference persisted when analyzed by age. In the same study, microsurgical varicocelectomy resulted in improvement in serum testosterone levels in 70% of patients, with a notable mean increase of 178 ng/dL. Of the men with low total serum testosterone levels preoperatively, 79% had normal total serum testosterone level after varicocelectomy. ¹⁸

Su et al. found that in a small cohort of 53 infertile men with varicocele, varicocelectomy was associated with a mean serum testosterone increase of 90 ng/dL (p < 0.0004) and that interestingly there was an inverse relationship between preoperative serum testosterone levels and net change in testosterone after repair. The findings of this study suggest that patients with varicocele with more severe preoperative testosterone deficiency might experience the greatest benefit from surgical repair. ²⁶

Among 59 hypogonadal men (serum testosterone <400 ng/dL), Hsiao et al. found that 83% experienced increased serum testosterone after microsurgical varicocelectomy with a mean increase of 109.1 ng/dL, entirely independent of clinical grade. ²⁷ Similarly, a large meta-analysis by Li et al. of nine studies including a total of 814 patients with varicocele demonstrated a mean increase in serum testosterone level of 97.5 ng/dL after varicocelectomy, highlighting globally improved Leydig cell function as a result of surgical intervention. ²⁸

Zohdy et al. examined 141 infertile men with varicocele and found that postvaricocelectomy serum testosterone increased by a mean of 71 ng/dL, and that mean International Index of Erectile Function (IIEF)-5 (as a measure of erectile function) increased from 17.1 to 19.7, highlighting the potential clinical value of improving testosterone parameters in this often hypogonadal patient population. ²⁹

Despite a large body of literature demonstrating the relationship between varicoceles and objective measures of low serum testosterone, as well as the impact of surgical intervention on postoperative testosterone levels, there is a great paucity of literature evaluating objective measures of sexual function in hypogonadal men after varicocelectomy other than through measuring testosterone levels. Nonetheless, varicocelectomy has been shown in two recent studies to improve objective measurements in sexual function in parallel with improvements in serum testosterone levels.

Najari et al. retrospectively reviewed 34 patients with varicoceles presenting either with infertility or with symptomatic hypogonadism and evaluated serum testosterone levels as well as scores on the clinically validated Male Sexual Health Questionnaire (MSHQ). After microsurgical varicocelectomy, mean total MSHQ scores improved by 3.9 points with a notable 1.2 and 1.4 increase in mean erectile function and ejaculatory function scores, respectively. ³⁰ Forty-four percent of men saw improvement in their erectile function and 53% saw improvement in their ejaculatory function. Mean serum testosterone in this retrospective cohort increased by 136 ng/dL after repair. ³⁰

Saylam et al. similarly examined a cohort of patients with clinically significant varicoceles and found that improvements in serum testosterone levels after microsurgical varicocelectomy paralleled improvements in IIEF-5 scores as measures of erectile function, offering that varicocelectomy should be offered to symptomatic hypogonadal men with varicocele. ³¹ However, it is unclear whether the mild improvements in sexual function and serum testosterone after varicocelectomy are clinically meaningful improvements. Continued research is needed to understand true symptomatic testosterone deficiency in varicocele patients and the role for surgical intervention for symptomatic improvement alone.

Although most studies demonstrate a notable improvement in serum testosterone after varicocelectomy, several small studies report either no or minimal postoperative changes. Lima et al. evaluated 30 infertile men who underwent microsurgical varicocelectomy and found improvements in semen volume, sperm concentration, and total motile sperm count after surgery but no change in serum testosterone levels.

The same group evaluated intratesticular testosterone levels pre- and postoperatively as well and similarly found no difference after surgical intervention. ³² Jangkhah et al. prospectively evaluated 115 men with grades II and III varicoceles and observed that mean serum testosterone levels only minimally improved after varicocelectomy. In this same study, preoperative testosterone levels were similar to those of a control group, unlike the majority of data in the literature. ³³

Conclusion

Although the exact mechanisms by which varicoceles impair both spermatogenesis and testosterone production remain to be fully elucidated, their detrimental effect on normal testicular function is clear. Many men presenting with varicoceles are found to be deficient in serum testosterone, reflecting a theorized global Leydig cell dysfunction. Many of these men demonstrate significant improvement in serum testosterone levels after surgical repair across a multitude of studies.

Some men do not experience any or as robust of an improvement in testosterone postrepair relative to others, and, therefore, preoperative predictors of which men may benefit the most from surgical intervention will be paramount to future research endeavors. Continued research on the mechanisms of varicocele-mediated impairments in testicular function may provide both novel therapies and protocols for optimally timed surgical intervention for men presenting with varicocele.