Varicocele is an irregular dilation of the pampiniform plexus determining reflux of venous blood flow. It affects around 15% of male population but it is more frequently identified in patients searching medical care for infertility (1, 2). It has been considered for a long time as one of the most frequent diseases affecting fertility potential, and the most common surgically curable cause of male sterility. However, a recent multicenter worldwide study encouraged by the European Academy of Andrology (3, 4) reported in men without any health or fertility problems a high incidence of varicocele (~37%) similar to men with primary infertility (5–7). These records propose that it could have lower effect on semen alteration, and its treatment have to be limited to selected populations. In accordance, ongoing EAU Guidelines on Male Infertility support specific indications for varicocele surgical correction both in adults and adolescents. In particular treating infertile men with clinical varicocele, abnormal semen parameters, or otherwise unexplained infertility in a couple in which the female partner has a good ovarian reserve, to improve the fertility rate, is considered a strong recommendation. On the contrary, there is a weak recommendation to treat men with raised sperm DNA fragmentation or who have suffered from failed assisted reproductive techniques (8).

Ultrasound (US) is the instrumental test of choice for diagnosing varicocele (8–10). Varicoceles are initially identified during physical examination. Color Doppler ultrasound can confirm the diagnosis and provide additional information on the presence of venous reflux and venous diameter (8–10).

There is a correlation among male sterility, ipsilateral testicular atrophy, and clinically detectable, rather than non-detectable, varicocele (11). In agreement with the criteria introduced in 1970 by Dubin and Amelar, varicocele is diagnosed and scored clinically in three grades (12). Grade 1 varicocele is palpable only while standing during Valsalva maneuver; Grade 2 is palpable also at rest while standing; Grade 3 is visible through the skin of scrotus. Among men evaluated for infertility varicocele is still the most frequent finding, identified in 35% of men with primary sterility and 70–80% of men with secondary sterility (13).

The impact of varicocele on semen production and fertility is known, but the relationship between clinical varicocele and impaired hormonal production is not clear; it has been hypothesized that the degree of varicocele may be inversely correlated with testosterone production (13, 14). The aim of the present review was to elucidate the hormonal features of patients with varicocele.

A systematic Pubmed engine search was carried by using a set of keywords as follows: “varicocele” and “hormone,” “testosterone,” “gonadotropins,” “estradiol,” “androgens;” original papers and metanalyses reporting results on hormonal impairment in terms of testosterone, gonadotrophins and other hormones in patients with varicocele were selected and the contents critically evaluated.

The unfavorable impact of varicocele on semen production has been the primary endpoint of many studies and it has long been recognized. A meta-analysis of Agarwal et al. showed that varicocele was the primary reason for alteration of spermiogram in adult infertile men (47). A more recent trial about varicocele and fertility concluded that varicocele has a growing impact on spermatogenesis: the longer the time since its onset, the greater its effects (48).

On the contrary, the relationship between clinically detectable varicocele and hormonal pattern alterations is still unclear. In some studies hormone alterations are mentioned but the information about their role in clinical practice remains scarce.

From literature, the most investigated hormonal impairment was that of testosterone. We know that varicocele can cause Leydig cells dysfunction in various ways, and it becomes gradually more impaired with the duration of the varicocele. As the result of elevated scrotal temperature, ROS production and hypoxia, inhibition of enzymes involved in sexual steroid biosynthesis lead to decreased intratesticular testosterone production and conversion (49). In this regard, many studies concluded that varicocelectomy significantly improves Leydig cells activity and testosterone production as a result of reversible pathological mechanism.

For example, a trial by Tanrikut et al. showed a statistically significant reduction of testosterone levels in patients with varicocele respect to healthy controls persisting even when analyzed by age, but significantly recovering after surgical correction (32). Although numerous studies have shown testosterone reduction in infertile men with varicocele, there are also studies suggesting that it does not cause any changes. In some cases the adrenal androgen secretion might compensate in the first weeks for the impaired Leydig cells function due to varicocele (50). Moreover, findings in experimental models suggest that short duration varicocele affects intratesticular testosterone firstly and subsequently plasmatic concentrations (50). Since testosterone levels might be impaired, it could be necessary to perform a hormonal test at the first diagnosis of varicocele; in this way, the presence and extent of deficit can be ascertained and corrected if necessary. Little is known about LH and FSH, pituitary hormones which regulate testicular function. Varicocele and subsequently testicular warming can cause decrease of testosterone synthesis by Leydig cells and impairment of germinal and Sertoli cells. A meta-analysis by Tian et al. showed higher FSH and LH levels in varicocele-bearing patients that significantly lowered after surgery (34). Although biochemical screening is suggested as part of the clinical management, data on serum FSH as a surrogate marker for spermatogenesis are conflicting. FSH levels seem to depend on the different steps of spermatogenesis at which the impairment occurs. In fact, they increase only when the azoospermia is related to impaired spermatogonia number and function, whereas they persist in the normal range when the azoospermia is related to maturation arrest at spermatocyte or spermatide stage (8, 51). Evaluation of FSH and LH levels may be necessary at the first diagnosis of varicocele especially if the patient is seeking medical attention for infertility. In fact, although in published literature the correlation between varicocele and infertility is no longer so close, gonadotropins impairment could at least in part explain the alteration of spermatogenesis. About the role of other hormones in patients with varicocele, a significantly lower concentrations of AMH was found in subfertile men, as a result of Sertoli cells damage, without differences related to the grades of subfertility. On the contrary, a progressive serum Inh-B levels reduction was observed from less severe to more severe testicular damage (39). These hormones may be useful indicators in case of increased FSH levels, because they could indicate the existence (AMH, Inh-B) and seriousness (Inh-B) of injure of seminiferous epithelium (39). Decreasing levels of Inh-B could, at least in part, explain the rise in FSH levels in patients with varicocele. The damage of the seminiferous epithelium and germ cells with impaired spermatogenesis causes a decline in Inh-B levels with consequent lack of negative feedback on pituitary FSH secretion. AMH, Inh-B and FSH levels are expression of germinal cells damage; their involvement correlate with more severe testicular damage. Therefore, a recovery of normal values of these hormones after varicocele surgical correction may favor a resumption of normal spermatogenesis which has to be verified by a semen analyses.

Under normal scrotal conditions, a counter-current heat-exchange mechanism between the outflow of the pampiniform plexus and testicular arterial inflow supports the cooler scrotal temperature; in varicocele this physiological mechanism is altered, elevating scrotal temperature. The higher than normal temperature impairs Leydig cells function causing reduced testosterone production. Heat inhibits C-17,20-lyase, the enzyme that converts 17-OH-progesterone to androstenedione and then testosterone, contributing to lowering androgen levels and rising 17-OH-progesterone levels (42). Lower testosterone levels inhibit the (androgen dependent) epididymal 5-α-reductase activity with a consequential reduced conversion to DHT (45). On the other hand the lack of conversion to DHT can causes a rise of aromatization in estradiol. In this regard, some authors suggest the use of aromatase inhibitors for male infertility associated with low testosterone levels and impaired T:E ratio (52), others confirm lower testosterone and T:E ratio in men with varicocele but affirm that these parameters may significantly improve after varicocelectomy (44).

Maintaining normal estrogen concentrations is very important since they play a negative role in the testis by inhibiting Leydig cells 17β-hydroxysteroid dehydrogenase (17β-HSD), and thus inhibiting the conversion of androstenedione to testosterone, lowering testosterone production. Castro-Magana et al. observed an increased androstenedione/testosterone (A/T) ratio after hCG administration before, and its normalization 3 months after varicocelectomy, suggesting an impaired 17β-HSD activity in males with varicocele (46). On the basis of these data, at diagnosis, it could be useful to evaluate also estradiol levels to assess T:E ratio. Its impairment may underlie infertility, which if timely treated, could restore physiological wellbeing and improve the fertility rate.

Finally, as suggested in many studies, SHBG levels in varicocele patients are higher than normal; the cause is unknown, but it may contribute to reduction of free androgen levels.

Although recent findings have shown a high prevalence of varicocele in men even without impaired fertility, there is no doubt that varicocele could led to hormonal alterations. Different behaviors in affected patients may likely be influenced by individual and/or environmental factors. This review suggests that the impaired free sexual steroid levels are the result of a slight, deep-rooted defect in the testes of a certain amount of men with varicocele, and as usual in endocrinology, the alteration of one hormone leads to a cascade of hormonal alterations owing to inactivating feedback pathways, enzyme inhibition or overactivity and other biochemical mechanisms. The pathological process may be reversible, as demonstrated by surgical correction. Hormonal assessment together with semen analysis should be recommended in all patients with varicocele.

To date, other multicentre, randomized controlled studies remain mandatory to ascertain the hormonal features of patients with varicocele and to assess the utility of hormonal evaluation for establishing the duration of varicocele and for better identifying those patients who need surgical correction.

All authors contributed to research data from published papers on this issue for the review, to discuss critically the content, to write the manuscript, and edit the draft before submission. Thus, obviously all of them have read and agree to the final version of the manuscript.

Open Access funding provided by Università degli Studi della Campania Luigi Vanvitelli.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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