Evidence based medicine in management of varicocele 2015

Evidence based medicine in
Management ofVaricocele
By
Ahmad Motawi, Msc., FECSM
Ass. Lecturer of Andrology, Sexual medicine and STDs
Faculty of medicine
Cairo University

Varicocele in brief
Definition
• A varicocele is the abnormal dilation of the internal spermatic veins and
pampiniform plexus that drain the testis (Nguyen, 2007).
HT, N. 2007. Hernia, hydroceles, testicular torsion, and varicocele. In: Docimo SG, Canning DA, Khoury AE, eds. Clinical pediatric
urology. London, UK: Informa Healthcare; .

Varicocele in brief
Epidemiology
• 10% and 15% of men and adolescent boys in the general population have
varicocele (Evers and Collins, 2003).
• The majority (>80%) of adult varicoceles are not associated with infertility (Green
et al., 1984, Sylora and Pryor, 1994).
• 40% of men presenting with infertility have a varicocele and up to 80% of men
with secondary infertility have a varicocele (Gorelick and Goldstein, 1993).
• 90% percent of varicoceles are on the left side, while approximately 10% are
bilateral .
EVERS, J. L. & COLLINS, J. A. 2003. Assessment of efficacy of varicocele repair for male subfertility: a systematic review. Lancet,
361, 1849-52.
GREEN, K. F., TURNER, T. T. & HOWARDS, S. S. 1984. Varicocele: reversal of the testicular blood flow and temperature effects by
varicocele repair. J Urol, 131, 1208-11.
SYLORA, J. A. & PRYOR, J. L. 1994. Varicocele. Curr Ther Endocrinol Metab, 5, 309-14.
GORELICK, J. I. & GOLDSTEIN, M. 1993. Loss of fertility in men with varicocele. Fertil Steril, 59, 613-6.

Varicocele in brief
Aetiology
• Increased hydrostatic pressure in the left renal vein (8 to 10 cm longer).
• Incompetent or congenitally absent valves.
• The right-angle insertion of the left testicular vein into the left renal vein.
• The 'nutcracker' phenomenon is thought to exist as the left renal vein traverses
under the superior mesenteric artery.
PRAVIN, R., SIAM, O., JEFFREY, D., W., D. H. & EDMUND, S. 2014. Varicocele. BMJ Best Practice. [Online]. Available:
http://bestpractice.bmj.com/best-practice/monograph/1103.html. [Accessed 16 November 2014].
It is clear that varicocele formation cannot be explained by a single theory and results from a combination
of the above anatomical factors (Pravin et al., 2014).

Varicocele in brief
Pathophysiology
• Effects: abnormal gonadotrophin levels, impaired spermatogenesis, histological
changes, and infertility.
• The exact cause is not known.
• Suggested theories
- Thermal damage secondary to an impaired countercurrent mechanism.
- Reactive oxygen species.
- Reflux of toxic adrenal and renal metabolites.
- Hypoxia (Bong and Koo, 2004).
BONG, G. W. & KOO, H. P. 2004. The adolescent varicocele: to treat or not to treat. Urol Clin North Am, 31, 509-15, ix.

Varicocele in brief
Classification
Varicoceles may be graded based on their size.
• Grade I (small): varicocele palpable only withValsalva manoeuvre.
• Grade II (moderate): varicocele palpable withoutValsalva manoeuvre.
• Grade III (large): varicocele visible through the scrotal skin.
• Sub-clinical: varicocele detected only by Doppler ultrasound.

Varicocele in brief
Key points in diagnosis
• Semen analyses (on 2 or 3 separate occasions).
• Evaluation of serum FSH and testosterone levels help assess testicular function.
• Abnormal sperm production in the context of an elevated FSH is consistent with
impaired spermatogenesis.
• Of note, FSH levels in the high normal of the reference range are considered
abnormal in men with impaired semen parameters.
• Reduced testosterone levels suggest impaired steroidogenesis.Varicocele has
been increasingly recognised as an uncommon cause of decreased testosterone
production in men for whom fertility is not a concern (Pravin, Siam et al. 2014).
Pravin, R., et al. (2014). "Varicocele. BMJ Best Practice.". Retrieved 16 November, 2014, from http://bestpractice.bmj.com/best-
practice/monograph/1103.html.

Evolving concepts in varicocele evaluation

SMIT, M., DOHLE, G. R., HOP, W. C., WILDHAGEN, M. F., WEBER, R. F. & ROMIJN, J. C. 2007. Clinical correlates of the biological variation of sperm DNA fragmentation in infertile men
attending an andrology outpatient clinic. Int J Androl, 30, 48-55.
DADA, R., VENKATESH, S., KUMAR, K. & SHAMSI, M. B. 2010. Re: Decreased sperm DNA fragmentation after surgical varicocelectomy is associated with increased pregnancy rate: M.
Smit, J. C. Romijn, M. W. Wildhagen, J. L. Veldhoven, R. F. Weber and G. R. Dohle J Urol 2010; 183: 270-274. J Urol, 184, 1577; author reply 1578.
BAKER, K., MCGILL, J., SHARMA, R., AGARWAL, A. & SABANEGH, E., JR. 2013. Pregnancy after varicocelectomy: impact of postoperative motility and DFI. Urology, 81, 760-6.
SMIT, M., ROMIJN, J. C., WILDHAGEN, M. F., VELDHOVEN, J. L., WEBER, R. F. & DOHLE, G. R. 2013. Decreased sperm DNA fragmentation after surgical varicocelectomy is associated
with increased pregnancy rate. J Urol, 189, S146-50.
WANG, Y. J., ZHANG, R. Q., LIN, Y. J., ZHANG, R. G. & ZHANG, W. L. 2012. Relationship between varicocele and sperm DNA damage and the effect of varicocele repair: a meta-
analysis. Reprod Biomed Online, 25, 307-14.
PRAVIN, R., SIAM, O., JEFFREY, D., W., D. H. & EDMUND, S. 2014. Varicocele. BMJ Best Practice. [Online]. Available: http://bestpractice.bmj.com/best-practice/monograph/1103.html.
DNA fragmentation index (DFI):
• DNA fragmentation index (DFI) testing has become common due to its
comparatively low clinical variability (Smit et al., 2007) and its
correlation with pregnancy rates (Dada et al., 2010).
• DFI testing is not yet considered part of the standard evaluation of
men with varicoceles. Moreover, reports suggest that varicocele repair
is associated with improvement in DFI (Baker et al., 2013, Wang et
al., 2012) and pregnancy rates (Smit et al., 2013).
• Thus, abnormal DFI is considered an emerging indication for repair
of a clinical varicocele (Pravin et al., 2014).

Varicocele diagnosis by scrotal colour doppler
KHERA, M. & LIPSHULTZ, L. I. 2008. Evolving approach to the varicocele. Urol Clin North Am, 35, 183-9, viii.
CHIOU, R. K., ANDERSON, J. C., WOBIG, R. K., ROSINSKY, D. E., MATAMOROS, A., JR., CHEN, W. S. & TAYLOR, R. J. 1997. Color
A total score of 4 or more determines the presence of a varicocele by CDU.
• There are currently no standard and clearly deﬁned criteria for diagnosing a varicocele by ultrasound
(Khera and Lipshultz, 2008) but literature search revealed only one 15 years old study that suggested
a scoring system for varicocele diagnosis and correlating it to the clinical findings (Chiou et al., 1997):

Recommendations for the best practice in
varicocele
Based on
• EuropeanAssociation of Urology Guidelines on Male Infertility:The
2015 Update.
• Report on varicocele and infertility published by the American
Urological association and the American Society for Reproductive
Medicine in 2001, last reviewed and validated 2012.
• The British medical Journal best practice guidelines, 2014.

varicocele
• sub-clinical or grade I
varicocele
Adult:
Re-assurance ± observation
• No treatment is necessary.
• If fertility is a concern, semen
analysis may be offered (Pravin et
al., 2014).

varicocele
• Grade II or III varicocele:
American Urological Association; American Society for Reproductive Medicine. Report on varicocele and infertility. April 2001.
http://www.auanet.org (last accessed 25 September 2014).
JAROW, J. P., SHARLIP, I. D., BELKER, A. M., LIPSHULTZ, L. I., SIGMAN, M., THOMAS, A. J., SCHLEGEL, P. N., HOWARDS, S. S.,
NEHRA, A., DAMEWOOD, M. D., OVERSTREET, J. W., SADOVSKY, R. & MALE INFERTILITY BEST PRACTICE POLICY COMMITTEE
OF THE AMERICAN UROLOGICAL ASSOCIATION, I. 2002. Best practice policies for male infertility. J Urol, 167, 2138-44.
Adult:
Observation
• Recommendations are that adult
men with a palpable
asymptomatic varicocele and
normal semen parameters can be
observed with serial semen
analysis every 1 to 2 years (AUA,
2014 Jarow et al., 2002).
asymptomatic or with
normal semen parameters

varicocele
BONG, G. W. & KOO, H. P. 2004. The adolescent varicocele: to treat or not to treat. Urol Clin North Am, 31, 509-15, ix.
American Urological Association; American Society for Reproductive Medicine. Report on varicocele and infertility. April 2001.
http://www.auanet.org (last accessed 25 September 2014).
JAROW, J. P., SHARLIP, I. D., BELKER, A. M., LIPSHULTZ, L. I., SIGMAN, M., THOMAS, A. J., SCHLEGEL, P. N., HOWARDS, S. S.,
NEHRA, A., DAMEWOOD, M. D., OVERSTREET, J. W., SADOVSKY, R. & MALE INFERTILITY BEST PRACTICE POLICY COMMITTEE
OF THE AMERICAN UROLOGICAL ASSOCIATION, I. 2002. Best practice policies for male infertility. J Urol, 167, 2138-44.
Adult: Surgery
• Pain: Although only a small
percentage of patients have
significant pain, correcting the
varicocele may have a high
response rate in relieving the
symptoms (Bong and Koo, 2004).
• Abnormal semen: varicocele
repair should be offered (AUA,
2014 Jarow et al., 2002).
symptomatic or with
abnormal semen
parameters

In summary adult varicocele repair should be
offered when:
1) A varicocele is palpable.
2) The couple has documented infertility.
3) The woman has normal fertility or potentially correctable infertility.
4) The male partner has 2 or more abnormal semen parameters or sperm
function test results.

varicocele
• Open repair (microsurgical subinguinal, inguinal and Palomo).
• Laparoscopic repair.
• Percutaneous embolization.
• Sclerotherapy.
Techniques:

Which technique is the best?
• A meta-analysis has suggested a small but real absolute benefit with
microsurgical varicocele ligation over percutaneous and open non-
microsurgical approaches with regard to recurrence and complications
(Thomas and Elder, 2002).
THOMAS, J. C. & ELDER, J. S. 2002. Testicular growth arrest and adolescent varicocele: does varicocele size make a difference? J
Urol, 168, 1689-91; discussion 1691.

Which technique is the best? Cont..
• While surgical varicocelectomy is controversial, meta-analyses that carefully
excluded men with sub-clinical varicoceles and normal semen parameters
suggest that the procedure improves semen parameters in patients with
palpable varicocele and abnormal semen parameters. Pregnancy rates in
infertile couples where the male has a palpable varicocele were also
improved (Evers and Collins, 2003, Agarwal et al., 2007, Marmar et al.,
2007, Kroese et al., 2012).
AGARWAL, A., DEEPINDER, F., COCUZZA, M., AGARWAL, R., SHORT, R. A., SABANEGH, E. & MARMAR, J. L. 2007. Efficacy of
varicocelectomy in improving semen parameters: new meta-analytical approach. Urology, 70, 532-8.
EVERS, J. L. & COLLINS, J. A. 2003. Assessment of efficacy of varicocele repair for male subfertility: a systematic review. Lancet,
361, 1849-52.
KROESE, A. C., DE LANGE, N. M., COLLINS, J. & EVERS, J. L. 2012. Surgery or embolization for varicoceles in subfertile men.
Cochrane Database Syst Rev, 10, CD000479.
MARMAR, J. L., AGARWAL, A., PRABAKARAN, S., AGARWAL, R., SHORT, R. A., BENOFF, S. & THOMAS, A. J., JR. 2007.
Reassessing the value of varicocelectomy as a treatment for male subfertility with a new meta-analysis. Fertil Steril, 88, 639-48.

Which technique is the best? Cont..
• A recent publication in the Asian journal of andrology performed a multiple-
treatment meta-analysis to assess the effectiveness and safety of 10 methods of
varicocelectomy and embolization/sclerotherapy. It systematically reviewed 35
randomized controlled trials and observational studies, from 1966 to August 5,
2013, which compared any of the following treatments for varococeles:
Laparoscopic.
Retroperitoneal.
Open inguinal and subinguinal varicocelectomy.
Microsurgical subinguinal and inguinal varicocelectomy.
Percutaneous venous embolization.
Antegrade sclerotherapy.
Retrograde sclerotherapy.
Expectant therapy (no treatment).

WANG, J., XIA, S. J., LIU, Z. H., TAO, L., GE, J. F., XU, C. M. & QIU, J. X. 2014. Inguinal and subinguinal micro-varicocelectomy, the
optimal surgical management of varicocele: a meta-analysis. Asian J Androl.
• Inguinal and subinguinal microsurgery, open inguinal and laparoscopic
varicocelectomy showed a signiﬁcant advantage over expectant therapy in terms
of pregnancy rates.
• Compared with retroperitoneal open surgery, inguinal microsurgery showed an
improvement of sperm density and sperm motility.
• Subinguinal and inguinal microsurgery outperformed retroperitoneal open surgery
in terms of recurrence.
• Antegrade sclerotherapy and subinguinal microsurgery were associated with the
lowest risk of hydrocele formation.
• The odds of overall complications, compared with retroperitoneal open
varicocelectomy, were lowest for inguinal microsurgery, followed by subinguinal
microsurgery.
• Inguinal and subinguinal micro-varicocelectomy had the highest pregnancy rates,
signiﬁcant increases in sperm parameters, with low odds of complication. (Wang et
al., 2014).

Complication of varicocelectomy
Recurrence
• Microsurgical subinguinal
approach (2.1%).
• Percutaneous (5%).
• Open (16%; lower
recurrence rate if
microscope used).
• Laparoscopic (15%; lower
recurrence if mass cord
ligation performed).
• Usually occurs as a result of missing veins during primary surgery;
recurrence is higher if an artery-sparing technique is used.
• Can take up to 6 months to see resolution of varicocele depending on
technique chosen.

Recurrence
• Subinguinal approach
(2.1%).
• Open (16%; lower
recurrence rate if
microscope used).
Hydrocele
• Subinguinal approach
(0.8%).
• Open (5%).
• Laparoscopic (7% to 15%).
• Unclear aetiology; may be secondary to lymphatic obstruction.
• Most can be safely observed and regress without treatment; some will respond to simple puncture,
although if further recurrence is symptomatic, open repair may be indicated.
• Usually, hydrocele forms anywhere from 6 months to 3 years after procedure.

Recurrence
• Subinguinal approach (2.1%).
• Open (16%; lower recurrence
rate if microscope used).
Hydrocele
• Subinguinal approach (0.8%).
• Open (5%).
• Laparoscopic (7% to 15%).
Post-operative bleeding/wound
infection
• Can occur with any surgical approach.

Coil
migration/extravasation
of contrast material
Bowel Injury Testicular atrophy
Damage to the testicular
artery may result in
testicular atrophy. Can
occur with any surgical
approach.
Can occur following
percutaneous
embolisation, but
relatively uncommon.
Usually from
transperitoneal
laparoscopic approach.

Varicocele in the adolescent
Examination & diagnosis:
• If a varicocele is suggested, it is critical that a supine exam is also performed
to ensure drainage of the varicocele in the recumbent position. If the
varicocele does not drain, this may suggest a retroperitoneal process such
as a renal mass that would require further evaluation.
• In the supine position, complete genitourinary examination assessing
Tanner stage, testicular size, presence or absence of testicular mass or
fullness of the spermatic cord, consistency of testes, and relative size
comparison should be performed.
• A right-sided varicocele alone is rare and should also raise suspicion of a
retroperitoneal or pelvic compressive mass (Pravin et al., 2014).

adolescent varicocele
Based on
• EuropeanAssociation of Urology Guidelines on paediatric urology
2014.
• The British medical Journal guidelines for best practice , 2014.

Management of adolescent varicocele
• sub-clinical or grade I
varicocele
Adolescent:
Re-assurance
• No treatment is necessary
and patient/parental
reassurance should be
given (Pravin et al., 2014).

Management in adolescent varicocele
NGUYEN, H. T. 2007. Hernia, hydroceles, testicular torsion, and varicocele. In: Docimo SG, Canning DA, Khoury AE, eds. Clinical
pediatric urology. London, UK: Informa Healthcare; .
Adolescent: Observation
• The grade of the varicocele does
not predict the need for surgical
intervention (Nguyen, 2007).
• The adolescent must be
counselled about his chance for
fertility problems later in life
(Pravin et al., 2014)
With <20% size
difference or
symmetrical testes

Management in adolescent varicocele
Adolescent:
Surgery
• Patients can expect a 50% to 80%
chance of ipsilateral 'catch-up'
growth of the affected testis
following surgery; this may take
up to 6 months.(Pravin et al.,
2014)
With asymmetrical (>2
cm or >20% difference
in size).

Different varicocele
presentations

Right subclinical varicocele: how to manage in
infertile patients with clinical left varicocele?
• A prospective study published in fertility and sterility journal in 2009, compared the
results of bilateral varicocelectomy (n=73) and left varicocelectomy (n=72) for
treatment of infertile patients with subclinical right and clinical left varicoceles with
oligoasthenospermia (Inguinal approach using using optical loupes (x2.5) was
used).
• They suggested that,because there was more improvement in semen parameters
and pregnancy rate in patients who underwent the bilateral surgery,
right subclinical varicocele should be surgically treated in conjunction with the left
one (Elbendary and Elbadry, 2009).
ELBENDARY, M. A. & ELBADRY, A. M. 2009. Right subclinical varicocele: how to manage in infertile patients with clinical left
varicocele? Fertil Steril, 92, 2050-3.

Right subclinical varicocele: how to manage in
infertile patients with clinical left varicocele?
Cont..
• Interstingely a comparative study also published in 2009 in the Journal of Urology,
they studied the efficacy of bilateral (n=51) and left varicocelectomy (n=53) in
infertile men with left clinical and right subclinical varicoceles (retroperitoneal
approach was used).
• They found that no significant differences in the postoperative sperm
concentration, sperm motility, normal morphology, bilateral testicular volume,
serum testosterone level, and spontaneous pregnancy rate between the 2 groups
(Zheng et al., 2009).
• However this study is highly critised due to the use of the retroperitoneal approach.
ZHENG, Y. Q., GAO, X., LI, Z. J., YU, Y. L., ZHANG, Z. G. & LI, W. 2009. Efficacy of bilateral and left varicocelectomy in infertile men
with left clinical and right subclinical varicoceles: a comparative study. Urology, 73, 1236-40.

Varicocele and non-obstructive azoospermia
• Kim and colleagues demonstrated that varicocele repair can result in sperm in the
ejaculate of men who have azoospermia when severe hypospermatogenesis or late
maturation arrest is identiﬁed histologically (Kim et al., 1999).
• However, other investigators have found that men with nonobstructed
azoospermia rarely have adequate sperm in their ejaculate after varicocele repair
to avoid testicular sperm extraction (Schlegel and Kaufmann, 2004).
• A recent meta-analysis showed that sperm can return to the ejaculate in 39% of
azoospermic men with a varicocele after surgical repair (Weedin et al., 2010).
KIM, E. D., LEIBMAN, B. B., GRINBLAT, D. M. & LIPSHULTZ, L. I. 1999. Varicocele repair improves semen parameters in
azoospermic men with spermatogenic failure. J Urol, 162, 737-40.
SCHLEGEL, P. N. & KAUFMANN, J. 2004. Role of varicocelectomy in men with nonobstructive azoospermia. Fertil Steril, 81, 1585-8.
WEEDIN, J. W., KHERA, M. & LIPSHULTZ, L. I. 2010. Varicocele repair in patients with nonobstructive azoospermia: a meta-
analysis. J Urol, 183, 2309-15.

Clinical varicoceles and astheno or
teratozoospermia and normal sperm density
to operate or not?
• No significant improvement in semen parameters may be obtained in
patients with clinical varicocele and preoperative normospermia. It is
possible that only patients with preoperative oligospermia may benefit from
varicocelectomy (Okeke et al., 2007).
OKEKE, L., IKUEROWO, O., CHIEKWE, I., ETUKAKPAN, B., SHITTU, O. & OLAPADE-OLAOPA, O. 2007. Is varicocelectomy
indicated in subfertile men with clinical varicoceles who have asthenospermia or teratospermia and normal sperm density? Int J
Urol, 14, 729-32.

Varicocele andTestosterone
• Although testosterone levels often rise after varicocele ligation (Kumar et
al., 2013), varicocele is thought to be an uncommon cause of
hypogonadism.Thus, repair for this indication should be undertaken only
after thoughtful patient counselling (Pravin et al., 2014).
KUMAR, A., GARG, M. & GOEL, A. 2013. Re: Hsiao et al.: varicocelectomy is associated with increases in serum testosterone
independent of clinical grade (Urology 2013;81:1213-1218). Urology, 82, 748-9.

Varicocele and pain
• A recent meta-analysis published in India reviewed studies published from March
2000 to May 2013 evaluating surgical management in painful varicoceles to provide
an evidence based review of effectiveness of varicocelectomy in relieving pain in
patients with symptomatic painful varicoceles.
• They found that the association between varicoceles and pain is not clearly
established.
• Conservative treatment is warranted as the first line of treatment in men with
painful clinical varicoceles.
• In carefully selected men with clinically palpable varicoceles and associated
characteristic chronic dull ache, dragging or throbbing pain who do not respond to
conservative therapy, varicocelectomy is warranted and is associated with
approximately 80% success. However, surgical success does not always translate
into resolution of pain and pain might persist even when no varicoceles are
detected postoperatively (Abrol et al., 2014).
ABROL, N., PANDA, A. & KEKRE, N. S. 2014. Painful varicoceles: Role of varicocelectomy. Indian J Urol, 30, 369-73.

Varicocele and Portal hypertension
• Varicocelectomy in patients with known portal hypertension must be
carefully considered and be based on enlargement of the veins, complaints
related to it and the stage of the portal hypertension.
• Surgical intervention should be avoided in advanced cases with history of
other varices as it might result in unanticipated blood loss or rupture of
another portosystemic shunt (Schulte-Baukloh et al., 2005).
SCHULTE-BAUKLOH, H., KAMMER, J., FELFE, R., STURZEBECHER, B. & KNISPEL, H. H. 2005. Surgery is inadvisable: massive
varicocele due to portal hypertension. Int J Urol, 12, 852-4.

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