Abstract
Introduction
Varicocele is estimated to affect about 15% of the general male population. It usually occurs only on the left side, and is often asymptomatic. There is little evidence that varicocele reduces male fertility, although it is found in 12% of male partners of couples presenting with infertility and in 25% of men with abnormal semen analysis.
Methods and outcomes
We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of treatments in adult males with varicocele? We searched: Medline, Embase, The Cochrane Library, and other important databases up to November 2013 (BMJ Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview).
Results
Searching of electronic databases retrieved 203 studies. After deduplication and removal of conference abstracts, 91 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 53 studies and the further review of 38 full publications. Of the 38 full articles evaluated, one existing systematic review was updated and two systematic reviews and five RCTs were added at this update. We performed a GRADE evaluation of nine PICO combinations.
Conclusions
In this systematic overview we categorised the efficacy for four interventions, based on information relating to the effectiveness of embolisation, expectant management, sclerotherapy, and surgical ligation.
Key Points
The prevalence of varicocele varies considerably between the general population and infertile men. It usually occurs only on the left side, and is often asymptomatic. If symptoms do occur, they may include testicular ache or distress about cosmetic appearance.
There is little evidence that varicocele reduces male fertility, although it is found in 15% of the general male population and in 35% (19%-42%) of men with primary infertility.
Varicocele is caused by dysfunction of the valves in the spermatic vein.
We searched for evidence of effectiveness from RCTs and systematic reviews of RCTs.
We reported on clinical outcomes such as spontaneous pregnancy rate, spontaneous live birth rates, pain or discomfort, quality of life, and adverse effects. We excluded non-clinical outcomes such as sperm count, testicular temperature, and blood flow.
Overall, we found insufficient evidence from RCTs to support the concept that successful varicocele treatment will increase the chance of spontaneous pregnancy.
We do not know whether surgical ligation or embolisation of the spermatic vein increase pregnancy rates or reduce symptoms of varicocele.
Sclerotherapy may be no more effective than no treatment at improving pregnancy rates. We don't know whether it reduces symptoms of varicocele.
We don't know how expectant management and embolisation compare, as we found no evidence from RCTs.
Clinical context
General background
Varicocele is a common asymptomatic condition. Although the majority of men with varicoceles are fertile, it remains the most common diagnosis seen in infertile men.
Focus of the review
Despite the absence of definitive studies on fertility outcomes after varicocele treatment, repair is commonly offered as it is considered as a correctable cause for male infertility. The effectiveness of varicocele treatment has continued to stimulate intense debate for a long time. Therefore, the focus of this overview is varicocele treatment versus conservative treatment in men with varicocele, with the main outcome being spontaneous pregnancy rate (our focus being on patient outcomes rather than non-clinical ones such as sperm count).
Comments on evidence
There are insufficient data to support a beneficial effect of varicocele repair on spontaneous pregnancy rates in routine practice. However, there is some limited evidence (low-quality) from recent studies that treatment may be beneficial in men with clinical varicocele and abnormal semen parameters from couples with unexplained infertility.
Search and appraisal summary
The literature search was carried out from the date of the last search, May 2008, to November 2013. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the overview, please see the Methods section. Searching of electronic databases retrieved 203 studies. After deduplication and removal of conference abstracts, 91 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 53 studies and the further review of 38 full publications. Of the 38 full articles evaluated, one existing systematic review was updated and two systematic reviews and five RCTs were added at this update.
About this condition
Definition
Varicocele is a dilation of the pampiniform plexus of the spermatic cord. Severity is commonly graded as follows: grade 0 (subclinical) only demonstrable by imaging investigation; grade 1 palpable or visible only on Valsalva manoeuvre (straining); grade 2 palpable but not visible when standing upright at room temperature; and grade 3 visible when standing upright at room temperature. Varicocele is unilateral and left-sided in at least 85% of cases. In most of the remaining cases, the condition is bilateral. Unilateral right-sided varicocele is rare. Many men who have a varicocele have no symptoms. Symptoms may include testicular ache or discomfort, and distress about cosmetic appearance. This overview deals with varicocele in adult males only.
Incidence/ Prevalence
We found few data on the prevalence of varicocele. Prevalence of varicocele varies considerably between the general population and infertile men. One study suggests states that varicocele is found in 15% of the male general population and in 35% (19%–41%) of men with primary infertility. One multicentre study found that, in couples with subfertility, the prevalence of varicocele in male partners was about 12%. In men with abnormal semen analysis, the prevalence of varicocele was about 25%.
Aetiology/ Risk factors
We found few reliable data on epidemiological risk factors for varicocele, such as a family history or environmental exposures. An increased incidence has been reported in first-degree relatives. A small study showed a higher prevalence in tall and heavy men. Anatomically, varicoceles are caused by dysfunction of the valves in the spermatic vein, which allows pooling of blood in the pampiniform plexus. This is more likely to occur in the left spermatic vein than in the right because of normal anatomical asymmetry. Varicocele is present in one quarter of men with abnormal semen analyses. However, the precise association between male subfertility and varicocele is unclear.
Prognosis
Varicocele is believed to be associated with male subfertility, although reliable evidence is sparse. The natural history of varicocele is unclear.
Aims of intervention
To improve the rate of pregnancy in couples in which the male partner has varicocele and the woman has no identified fertility problems; to reduce pain and discomfort associated with varicocele, with minimal adverse effects.
Outcomes
Spontaneous pregnancy rate; spontaneous live birth rate (i.e., without assisted reproductive techniques such as in vitro fertilisation); pain or discomfort (we found no scales that have been specifically validated for this condition); quality of life, including time to return to normal activities after intervention; and adverse effects. Non-clinical outcomes such as testicular temperature, blood flow, or sperm count were excluded.
Methods
Search strategy BMJ Clinical Evidence search and appraisal November 2013. Databases used to identify studies for this systematic review include, Medline 1966 to November 2013, Embase 1980 to November 2013, The Cochrane Database of Systematic Reviews 2013, issue 10 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and the Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria for inclusion in this overview were systematic reviews and RCTs published in English, at least single blinded, and containing more than 20 individuals; there was no maximum loss to follow-up. There was a minimum follow-up of 1 year. We excluded all studies described as 'open', 'open label', or not blinded, unless blinding was impossible. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the review. In addition, information that did not meet our predefined criteria for inclusion in the benefits and harms section, may have been reported in the 'Further information on studies' or 'Comment' section. Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Data and quality To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue which may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Varicocele.
| Important outcomes | Pain or discomfort, Quality of life, Spontaneous live birth rate, Spontaneous pregnancy rate | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of treatments in adult males with varicocele? | |||||||||
| 3 (293) | Spontaneous pregnancy rate | Embolisation versus surgical ligation | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for incomplete reporting of results; consistency point deducted for conflicting results |
| at least 7 (at least 610) | Spontaneous pregnancy rate | Expectant management versus surgical ligation | 4 | –1 | –1 | –1 | 0 | Very low | Quality point deducted for weak methods; consistency point deducted for statistical heterogeneity; directness point deducted for result depending on specific analysis performed |
| 1 (65) | Spontaneous pregnancy rate | Expectant management versus sclerotherapy | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and poor follow-up |
| 1 (155) | Spontaneous pregnancy rate | Sclerotherapy versus surgical ligation | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (155) | Spontaneous live birth rate | Sclerotherapy versus surgical ligation | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 64 (1) | Quality of life | Antegrade versus open (inguinal) sclerotherapy | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, imprecise reporting of absolute results, and lack of statistical analysis |
| 9 (at least 1140) | Spontaneous pregnancy rate | Different ligation techniques versus each other | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 2 (79) | Pain or discomfort | Different ligation techniques versus each other | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and weak methods |
| at least 4 (at least 284) | Quality of life | Different ligation techniques versus each other | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for incomplete reporting and weak methods |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- Antegrade sclerotherapy
A small incision is made at the root of the penis. The selected vein is ligated and a small catheter is placed beyond the ligature, to infuse sclerosing agent.
- Bernardi technique of ligation
The spermatic vein(s) are ligated close to the internal (deep) inguinal ring. Surgery is usually performed as a day case under general anaesthesia. Occasionally, the surgery is performed with a local anaesthetic.
- Embolisation
The left spermatic vein is catheterised through the left renal vein. Selective spermatic venography is then performed to demonstrate the venous anatomy. The vein is embolised by various liquids and materials, including coils (Gianturco or microcoils), detachable balloons, sclerosant agents (such as alcohol, sodium tetradecyl, or glue), or a combination. Transcatheter embolisation is performed as a day case procedure under intravenous sedation and analgesia.
- Ivanissevich technique of ligation
The spermatic vein(s) are ligated high, close to the iliac crest. Surgery is usually performed as a day case under general anaesthesia. Occasionally, the surgery is performed with a local anaesthetic.
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Microsurgery
Surgery involving optical magnification to allow the use of much finer instruments and suture material in addition to a non-touch technique, with the aim of minimising tissue handling and damage.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Palomo technique of ligation
The retroperitoneal internal spermatic vein(s) are ligated at the level of the anterior superior iliac spine. Surgery is usually performed as a day case under general anaesthesia. Occasionally, the surgery is performed with a local anaesthetic.
- Sclerotherapy
A sclerosing substance is injected into the spermatic vein to produce endothelial destruction, resulting in occlusion owing to fibrosis. Sclerotherapy can be performed with a local anaesthetic.
- Subinguinal varicocele ligation
The spermatic vein(s) are ligated just below the external inguinal ring, and this technique may be useful in men with a history of inguinal surgery. A subinguinal approach is more difficult than a high inguinal ligation and is performed under local anaesthetic.
- Tauber's technique
Antegrade scrotal sclerotherapy.
- Very low-quality evidence
Any estimate of effect is very uncertain.
- Visual Analogue Scale (VAS)
A commonly used scale in pain assessment. It is a 10-cm horizontal or vertical line with word anchors at each end, such as 'no pain' and 'pain as bad as it could be'. The person is asked to make a mark on the line to represent pain intensity. This mark is converted to distance in either centimetres or millimetres from the 'no pain' anchor to give a pain score that can range from 0–10 cm or 0–100 mm.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Rebecca Macleod, Pinderfields General Hospital, Wakefield, UK.
Chandra Shekhar Biyani, St James's University Hospital, Leeds, UK.
Jon Cartledge, St James's University Hospital, Leeds, UK.
Ian Eardley, St James’s University Hospital, Leeds, UK.
References
- 1.Cozzolino DJ, Lipshultz LI. Varicocele as a progressive lesion: positive effect of varicocele repair. Hum Reprod Update 2001;7:55–58. [DOI] [PubMed] [Google Scholar]
- 2.World Health Organization. The influence of varicocele on parameters of fertility in a large group of men presenting to infertility clinics. Fertil Steril 1992;57:1289–1293. [PubMed] [Google Scholar]
- 3.Mohammadali Beigi F, Mehrabi S, Javaherforooshzadeh A. Varicocele in brothers of patients with varicocele. Urol J 2007;4:33–35. [PubMed] [Google Scholar]
- 4.Mokhtari G, Pourreza F, Falahatkar S, et al. Comparison of prevalence of varicocele in first-degree relatives of patients with varicocele and male kidney donors. Urology 2008;71:666–668. [DOI] [PubMed] [Google Scholar]
- 5.Hassanzadeh K, Yavari-Kia P, Soleymanpour H,et al. Effect of body mass index on severity and prevalence of varicocele. Pak J Biol Sci 2011;14:869–875. [DOI] [PubMed] [Google Scholar]
- 6.Kroese AC, de Lange NM, Collins J, et al. Surgery or embolization for varicoceles in subfertile men. In: The Cochrane Library, Issue 10, 2013. Chichester, UK: John Wiley & Sons, Ltd. Search date 2012. [DOI] [PubMed] [Google Scholar]
- 7.Yavetz H, Levy R, Papo L, et al. Efficacy of varicocele embolization versus ligation of the left internal spermatic vein for improvement of sperm quality. Int J Androl 1992;15:338–344. [DOI] [PubMed] [Google Scholar]
- 8.Sayfan J, Soffer Y, Orda R. Varicocele treatment: prospective randomized trial of 3 methods. J Urol 1992;148:1447–1449. [DOI] [PubMed] [Google Scholar]
- 9.Nieschlag E, Behre HM, Schlingheider A, et al. Surgical ligation vs angiographic embolization of the vena spermatica: a prospective randomized study for the treatment of varicocele-related infertility. Andrologia 1993;25:233–237. [DOI] [PubMed] [Google Scholar]
- 10.Kim KH, Lee JY, Kang DH, et al. Impact of surgical varicocele repair on pregnancy rate in subfertile men with clinical varicocele and impaired semen quality: a meta-analysis of randomized clinical trials. Korean J Urol 2013;54:703–709. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Krause W, Müller HH, Schäfer H, et al. Does treatment of varicocele improve male fertility? Results of the 'Deutsche Varikozelenstudie', a multicentre study of 14 collaborating centres. Andrologia 2002;34:164–171. [DOI] [PubMed] [Google Scholar]
- 12.Fayez A, El Shantaly KM, Abbas M, et al. Comparison of inguinal approach, scrotal sclerotherapy and subinguinal antegrade sclerotherapy in varicocele treatment: a randomized prospective study. Urol Int 2010;85:200–203. [DOI] [PubMed] [Google Scholar]
- 13.Zucchi A, Mearini L, Mearini E, et al. Treatment of varicocele: randomized prospective study on open surgery versus Tauber antegrade sclerotherapy. J Androl 2005;26:328–332. [DOI] [PubMed] [Google Scholar]
- 14.Ding H, Tian J, Du W, et al. Open non-microsurgical, laparoscopic or open microsurgical varicocelectomy for male infertility: a meta-analysis of randomized controlled trials. BJU Int 2012;110:1536–1542. [DOI] [PubMed] [Google Scholar]
- 15.Gontero P, Pretti G, Fontana F, et al. Inguinal versus subinguinal varicocele vein ligation using magnifying loupe under local anaesthesia: which technique is preferable in clinical practice? Urology 2005;66:1075–1079. [DOI] [PubMed] [Google Scholar]
- 16.Abd Ellatif ME, El Nakeeb A, Shoma AM, et al. Dye assisted lymphatic sparing subinguinal varicocelectomy. A prospective randomized study. Int J Surg 2011;9:626–631. [DOI] [PubMed] [Google Scholar]
- 17.Almaramhy HH, Aly M. Magnified and non magnified subinguinal varicocelectomy in infertile and/or symptomatic men: a comparative study of the outcome. Afr J Urol 2012;18:161–166. [Google Scholar]
- 18.Sun HB, Liu Y, Yan MB, et al. Comparing three different surgical techniques used in adult bilateral varicocele. Asian J Endosc Surg 2012;5:12–16. [DOI] [PubMed] [Google Scholar]
- 19.Pan F, Pan L, Zhang A, et al. Comparison of two approaches in microsurgical varicocelectomy in Chinese infertile males. Urol Int 2013;90:443–448. [DOI] [PubMed] [Google Scholar]
- 20.Kang DH, Lee JY, Chung JH, et al. Laparoendoscopic single site varicocele ligation: comparison of testicular artery and lymphatic preservation versus complete testicular vessel ligation. J Urol 2013;189:243–249. [DOI] [PubMed] [Google Scholar]