Elevation of serum testosterone and free testosterone after embolization of the internal spermatic vein for the treatment of varicocele in infertile men

Yigal Gat1, Michael Gornish2, Alexander Belenky2 and Gil N. Bachar2,3

1 Andrology Unit, Department of Obstetrics & Gynecology and 2 Department of Radiology and the Interventional and Vascular Unit, Rabin Medical Center, Beilinson Campus, Petah Tiqva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

3 To whom correspondence should be addressed at: Department of Radiology Rabin Medical Center, Beilinson Campus, Petah Tiqva 49100, Israel. Email: drbachar{at}netvision.net.il


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: To evaluate the effect of internal spermatic vein (ISV) embolization on levels of serum testosterone and free testosterone and on spermatogenesis. METHODS: The files of 83 infertile men treated for varicocele were reviewed for changes in serum testosterone, free testosterone and spermatogenesis after ISV embolization. RESULTS: Mean serum testosterone concentration rose after embolization by 43%, from 12.07 ± 6.07 nmol/l to 17.22 ± 8.43 nmol/l (P<0.001). Mean serum free testosterone concentration rose by 72%, from 5.93 ± 2.44 nmol/l to 10.21 ± 7.69 nmol/l (P<0.001). Mean sperm concentration increased from 7.49 ± 1.73 x 106/ml to 18.14 ± 2.36 x 106/ml (P<0.001); mean sperm motility increased from 21.74 ± 2.47 to 34.47 ± 2.27% (P<0.001); and mean sperm morphology increased from 6.63 ± 1.07 to 13.08 ± 1.44% (P<0.001). CONCLUSIONS: ISV embolization apparently induces an increase in both serum testosterone and free testosterone concentrations and in sperm parameters in infertile patient with varicocele, regardless of the size of the varicocele.

Key words: embolization/infertility/testis/testosterone/varicocele


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Varicocele is considered a major cause of male infertility, with an overall prevalence rate of 40% in men being treated for primary infertility and of 80% in men with secondary infertility (Saypol , 1986Go; Skoog et al., 1997Go; Gat et al., 2003Go, 2004Go). The pathophysiology of varicocele remains controversial, with various studies suggesting the involvement of hyperthermia, hypoxia, adrenal and perirenal reflux, and hormonal dysfunction (Skoog et al., 1997Go). The role of testosterone was investigated in an animal model by Zirkin et al. (1989)Go who found that a high intratesticular testosterone concentration is required to maintain spermatogenesis in rats. Recent studies indicate Leyding cell dysfunction results in testicular androgen deficiency (Rodriguez-Rigau et al., 1978Go; Andreas et al., 1981Go; Chakraborty et al., 1985Go). Sirvent et al. (1990)Go demonstrated a decreased number of Leydig cells in biopsies of men with varicocele.

This finding was associated with a low testicular level of serum testosterone biosynthesis in the presence of varicocele. Accordingly, Comhaire and Vermeulen (1975)Go noted a decrease in plasma testosterone concentration in 10 patients with varicocele compared to controls, and Weiss et al. (1978)Go demonstrated a suppression of testosterone synthesis in infertile men with varicocele compared to controls. Varicolectomy apparently improves serum testosterone level and spermatogenesis, although this finding was statistically significant in some studies and nonsignificant in others (Segenreich et al., 1986Go; Su et al., 1995Go; Cayan et al., 1999Go). Evers and Collins (2003)Go in a systematic review article, stated that, ‘Varicocele repair does not seem to be an effective treatment for male subfertility’. The aim of the present study was to assess the effect of internal spermatic vein (ISV) embolization for the treatment of varicocele on serum testosterone and free testosterone levels and on spermatogenesis. To the best of our knowledge, this is the largest such study to date in the English literature.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
We reviewed the records of 83 consecutive male partners of couples with infertility of at least 12 months' duration who were evaluated for varicocele in a tertiary referral center from January 2000 to December 2002. Patient ages ranged from 20 to 52 years (mean 35.1 ± 6.68). All participants underwent a complete history, physical examination, hormone profile and genetic testing. Patients with cryptorchidism or testicular trauma, and patients after surgery of the urogenital tract, were excluded.

Patients were examined in a warm room after standing for 5 min. The volume, position and consistency of the testes and epididymis were checked, and each spermatic cord was palpated in the standing position and during the Valsalva maneuver. Findings were graded according to the system of Dubin and Amelar as follows: grade I, varicocele palpable only during Valsalva maneuver; grade II, varicocele palpable in standing position; grade III, varicocele detectable by visual scrutiny alone (Dubin and Amelar, 1971Go). All patients underwent contact thermography using a flexible liquid crystal thermostrip (Amsaten, De Pinte, Belgium) (Gat et al., 2003Go). Sclerotherapy of the internal spermatic vein (ISV) was performed after venography (Gat et al., 2004Go). Of the 83 patients, 75 (90.3%) had bilateral varicocele, 3 (3.6%) right-sided varicocele, and 5 (6.0%) left-sided varicocele. Grade I varicocele was noted in 22 patients (26.5%), grade II in 39 (47%) and grade III in 22 (26.5%). Fourteen patients (17%) had secondary infertility.

Semen analysis was performed before embolization and again 4–6 months after. Patients were instructed to abstain from sexual intercourse for 3 days before semen collection. The samples were assessed within 1 h of collection for sperm concentration, motility and morphology according to the World Health Organization criteria (WHO, 1999Go). The pre- and post-procedural semen values were averaged separately.

Endocrinological evaluation was performed before embolization and again 6 weeks or more after. It included assays of serum follicle stimulating hormone (FSH) and luteinizing hormone (LH) (IMMULITE 2000, DPC, Los Angeles, CA) and a commercial kit for testosterone and free testosterone (Roche Diagnostics, Indianapolis, IN). Serum samples were collected in all cases between 8 and 10 a.m. The normal ranges at our laboratory are as follows: FSH, 1–8 IU/l; LH, 4.9–25 IU/l; testosterone 8.5–38.8 nmol/l; free testosterone, 4.3–14.9 nmol/l.

The 2-sample paired Student's t-test was used for statistical analyses. Values are expressed as mean ± standard deviation. P<0.05 was considered significant.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Mean serum testosterone concentration rose after embolization from 12.07 ± 6.07 nmol/l (range 2–27 nmol/l) to 17.22 ± 8.43 nmol/l (range 3–37 nmol/l) (P<0.001). Mean serum free testosterone concentration increased from 5.93 ± 2.44 nmol/l (range 1–12 nmol/l) to 10.21 ± 7.69 nmol/l (range 4–23 nmol/l) (P<0.001) (Table I). No significant differences were noted in mean serum LH (7.3 ± 1.1 IU/l before ISV embolization versus 7.1 ± 1.3 IU/l post embolization) and serum FSH (8.95 ± 1.4 IU/l before ISV embolization versus 8.07 ± 1.5 IU/l post embolization).


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Table I. Sperm quality and testosterone and free testosterone levels in infertile patients (n=83) treated for varicocele

 
Sperm concentration, sperm motility and sperm morphology improved after varicocele treatment (Figure 1). Mean sperm concentration increased from 7.49 ± 1.73 x 106/ml to 18.14 ± 2.36 x 106/ml (P<0.001); mean sperm motility from 21.74 ± 2.47 to 34.47 ± 2.27% (P<0.001); and mean sperm morphology from 6.63 ± 1.07 to 13.08 ± 1.44% (P<0.001).



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Figure 1. Changes in semen parameters after embolization in 83 infertile men with varicocele.

 
Before embolization, testosterone concentration was in the normal range in 52 patients (62%). After embolization, testosterone increased in 79 patients (95%), decreased in three patients (3.6%) and was unchanged in one (1%).

In all cases, oligoasthenoteratospermia (sperm count <20 x 106/ml, sperm motility <40%, and <40% normal forms) was found on two semen analyses prior to embolization. Sperm parameters improved significantly after embolization in 76 patients (91.5%) (Table I). These included 73 of the 79 patients in whom testosterone levels rose significantly after the procedure (Table I). Of the four patients in whom the procedure induced no change or a decrease in testosterone levels, two showed no change or a decrease in sperm counts and sperm motility as well, and in two, these parameters improved. On follow-up, physical examination and thermography revealed recurrence of varicocele in five patients (6%) 4 months after embolization.

Division of the group by grade of varicocele yielded no significant difference in the change in testosterone level between the groups: grade I, 11.82 ± 6.42 nmol/l before embolization to 17.07 ± 7.17 nmol/l after; grade II, 12.23 ± 4.06 nmol/l to 20.63 ± 9.61 nmol/l; grade III 11.96 ± 6.70 nmol/l to 18.10 ± 7.65 nmol/l (P>0.05). This was also true for free testosterone, and for sperm parameters.

In addition, FSH, LH levels and age before treatment was not correlated to testosterone levels or spermatogenesis (after treatment).


    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The pathophysiologic effect of ISV dilatation on spermatogenesis is attributed by some researchers to an increase in intratesticular temperature (Goldstein and Eid, 1989Go; Nagler et al., 1997Go) leading to abnormal morphology and motility of the sperm (Fujjsawa et al., 1989). Ando et al. (1983)Go proposed that the high testicular temperature might affect the function of the enzyme 17{alpha}-hydroxyprogesterone aldolase, which plays a role in the conversion of 17-hydroxyprogesterone to testosterone. Others suggested that the venous reflux into the ISV exposes the testes to adrenal or renal metabolites that affect spermatogenesis (Fujjsawa et al., 1994). Varicocele may also be associated with venous stasis, which causes oxygen depletion and hypoxia in the testis (Andreas et al., 1981Go; Chakraborty et al., 1985Go; Skoog et al., 1997Go). The hormonal theory claims that varicocele is associated with suppression in testosterone synthesis to levels too low to maintain spermatogenesis (Comhaire and Vermeulen, 1975Go; Rodriguez-Rigau et al., 1978Go; Weiss et al., 1978Go). This assumption was supported by Sirvent et al. (1990)Go who demonstrated a decreased number of Leydig cells in biopsies of men with varicocele.

Comhaire and Vermeulen (1975)Go were the first to note that plasma testosterone concentration returned to normal after varicocele repair. By contrast, Hudson et al. (1985)Go and Segenreich et al. (1986)Go noted no siginificant change in serum testosterone levels after varicocelectomy. However, they investigated only small groups (14 and 24 patients, respectively), and their techniques resulted in a higher percentage of varicocele recurrence than the technique used in our patients.

In later studies, using microsurgical varicocelectomy techniques, Su et al. (1995)Go demonstrated a significant (28%) improvement in serum testosterone concentrations (from 319 ± 12 to 409 ± 23 ng/dl) in 53 infertile men with varicocele. Cayan et al. (1999)Go demonstrated a 48% increase in serum testosterone (5.63 ng/ml to 8.37 ng/ml) and 42% increase in free testosterone (23.1 pg/ml to 32.8 pg/ml) in 78 infertile patients, and Younes (2003)Go reported a similar significant increase in serum testosterone levels in 48 patients with impotence and infertility. These findings agree with the significant rates of improvement in the present study of 43% for serum testosterone and 72% in free testosterone in 83 infertile men after embolization. The measured increases in both serum and free testosterone after the procedure support the concept that ISV embolization can improve Leydig cell function in men with varicocele. In one contrasting study, Fujisawa et al. (1994)Go performed high ligation in 25 adolescents with varicocele and noted an improvement in sperm quality in 17 patients but no significant differences in serum testosterone levels.

Our patients also showed highly significant improvements in sperm count, motility and morphology of 142%, 58% and 97%, respectively. These findings are consistent with the study of Su et al. (1995)Go mentioned above, wherein sperm count increased from a preoperative level of 34 ± 6 to 45 ± 7 x 106/ml postoperatively, and sperm motility increased from 34 ± 2 to 39 ± 2%. Cayan et al. (1999)Go however, found no improvement in sperm count, although there was a significant increase in sperm motility, from 29.2% to 38.5%. Su et al. (1995)Go noted that patients with grade I varicocele achieved the greatest mean increase in serum testosterone after varicocelectomy and those with grade III varicocele had the smallest increase. Steckel et al. (1993)Go demonstrated greater improvements in sperm count and motility after the repair of larger varicoceles. By contrast, in the present study, there was no difference in the increment in serum testosterone or free testosterone by size of the varicocele.

A few recent studies have demonstrated that varicocele is associated with venous stasis resulting in oxygen depletion and hypoxia, which causes damage and depletion of the Leydig cells and suppression in testosterone synthesis (Andres et al., 1981Go; Cameron and Snydle, 1982Go; Chakraborty et al., 1985Go; Jones et al., 1988Go; Skoog et al., 1997Go). These factors may play a role in the altered spermatogenesis in varicocele patients. This is consistent with the impaired Leydig cell ultrastructure observed in testis biopsy samples in patients with varicocele (Hintz et al., 1980; Skoog et al., 1997Go) and Leydig cell function in rats with experimental varicocele (Rajfer et al., 1987Go). Biopsy studies of testes in men with varicocele report histopathologic findings of tubular fibrosis, hyalinization and Leydig cell hyperplasia with interstitial and small vessel fibrosis (Andres et al., 1981Go; Cameron and Snydle, 1982Go; Jones et al., 1988Go), representing degenerative ischemic changes known to be associated with abnormalities in both spermatogenesis and testosterone production (Macleod, 1965Go; Aggar and Johnsen, 1978Go). These studies suggest that suboptimal concentrations of intratesticular testosterone caused by altered blood flow, a dilutional effect due to increased venous volume, or compromized Leydig cell function could lower intratesticular testosterone to a level that will not support normal spermatogenesis in some patients with varicocele. Embolization of the ISV prevents stasis and the hypoxic state. The consequent improvement in hormonal function and elevation of serum testosterone and improvement of the anoxic environment of the germ cells may improve spermatogenesis. However, germ cells are more sensitive than Leydig cells to anoxic stimuli. Therefore, the hormonal response to ISV embolization may not occur simultaneously with the changes in spermatogenesis in all patients. Moreover, if the hypoxia is severe and long-standing, it will have caused fibrosis and irreversible damage to the germ cells and vessels. This may explain why not all patients respond to treatment (Evers and Collins, 2003Go). In our series, 73 of the 79 patients with higher testosterone levels after the procedure also had a significantly higher sperm count and sperm motility and improved sperm morphology (Table I). Although a significant increase in mean sperm concentration was observed following ISV embolization, the majority of men still remained oligospermic. Moreover, there remained 10 patients (12%) in whom semen parameters did not improve after embolization.

In summary, ISV embolization has positive effects on Leydig cell function, testosterone production and sperm parameters. Our study demonstrated that the large majority (91.5%) responded favorably to ISV embolization in terms of serum testosterone, free testosterone concentrations and spermatogenesis. Varicocele grade, FSH and LH levels before treatment, and patient age had no effect on this parameter.


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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on February 23, 2004; resubmitted on April 29, 2004; accepted on July 9, 2004.