Abstract
Introduction
Varicocele is estimated to affect 10% to 15% of men and adolescent boys. 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 review and aimed to answer the following clinical question: What are the effects of treatments in men with varicocele? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 11 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: embolisation, expectant management, sclerotherapy, and surgical ligation.
Key Points
Varicocele is estimated to affect 10% to 15% of men and adolescent boys, 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 12% of male partners of couples presenting with infertility and in 25% of men with abnormal semen analysis.
Varicocele is caused by dysfunction of the valves in the spermatic vein.
We do not know whether expectant management is effective in men with varicocele compared with surgical treatments, because studies have been of poor quality.
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 do not know whether it reduces symptoms of varicocele.
About this condition
Definition
Varicocele is a dilation of the pampiniform plexus of the spermatic cord. Severity is commonly graded as follows: grade 0: only demonstrable by technical 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 review deals with varicocele in adult males only.
Incidence/ Prevalence
We found few data on the prevalence of varicocele. Anecdotally, it has been estimated that about 10% to 15% of men and adolescent boys in the general population have varicocele. 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 no reliable data on epidemiological risk factors for varicocele, such as a family history or environmental exposures. 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.
Prognosis
Varicocele is believed to be associated with 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
Where available, we have reported on spontaneous live birth rate (i.e. without assisted reproductive techniques such as in vitro fertilisation), spontaneous pregnancy rate, 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 of treatment. Non-clinical outcomes such as testicular temperature, blood flow, or sperm count were excluded. Varicocele is a physical abnormality present in one quarter of men with abnormal semen analyses. However, the precise association between male subfertility and varicocele is unclear. There is also a lack of evidence to support the concept that successful treatment will increase the chance of spontaneous pregnancy. Painful varicoceles are present in 2% to 10% of men with infertility. There is a lack of placebo-controlled trials examining the effects of treatment or no treatment on pain caused by varicocele. It is likely that a well-designed, adequately powered, prospective, randomised trial is needed to answer the question definitively. Until then, given the current evidence, treatment should be used cautiously, as first-line therapy for varicoceles is painful.
Methods
Clinical Evidence search and appraisal May 2008. The following databases were used to identify studies for this review: Medline 1966 to May 2008, Embase 1980 to May 2008, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2008, Issue 2. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. All relevant RCTs that were identified were reviewed. Abstracts of the studies retrieved were assessed independently by two information specialists using predetermined criteria to identify relevant studies. Studies that included adolescent varicocele repair were excluded. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single blinded, and containing more than 20 individuals, of whom more than 80% were followed up. The minimum length of follow-up required for inclusion was 1 year. We excluded all studies described as "open", "open label", or not blinded, unless blinding was impossible. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the review as required. 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 RRs and ORs. 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, Spotaneous live birth rate | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of treatments in men 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 |
| 4 (301) | Spontaneous pregnancy rate | Expectant management versus surgical ligation | 4 | –2 | –1 | 0 | 0 | Very low | Quality points deducted for heterogeneity between RCTs and poor methodology. Consistency point deducted for conflicting results |
| 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 |
| 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 |
| 3 (308) | Spontaneous pregnancy rate | Different ligation techniques versus each other | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (99) | Pain or discomfort | Different ligation techniques versus each other | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and unclear randomisation methods |
| () | 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.
- 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.
- Very low-quality evidence
Any estimate of effect is very uncertain.
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
Chandra Shekhar Biyani, Pinderfields General Hospital Wakefield, UK.
Jon Cartledge, St James's University Hospital, Leeds, UK.
Günter Janetschek, Elisabethinen Linz, Austria.
References
- 1.Evers JL, Collins JA. Surgery or embolisation for varicocele in subfertile men. In: The Cochrane Library, Issue 3, 2006. Chichester, UK: John Wiley & Sons, Ltd. Search date 2003. Primary sources Cochrane Menstrual Disorders and Subfertility Group's specialised register of controlled trials, Medline, hand searches of 22 specialist journals (first issue until 2004), and searches of references of identified studies. [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.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]
- 4.Sayfan J, Soffer Y, Orda R. Varicocele treatment: prospective randomized trial of 3 methods. J Urol 1992;148:1447–1449. [DOI] [PubMed] [Google Scholar]
- 5.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]
- 6.Madgar I, Weissenberg R, Lunenfeld B, et al. Controlled trial of high spermatic vein ligation for varicocele in infertile men. Fertil Steril 1995;63:120–124. [DOI] [PubMed] [Google Scholar]
- 7.Nilsson S, Edvinsson A, Nilsson B. Improvement of semen and pregnancy rate after ligation and division of the internal spermatic vein: fact or fiction? Br J Urol 1979;51:591–596. [DOI] [PubMed] [Google Scholar]
- 8.Yamamoto M, Hibi H, Hirata Y, et al. Effect of varicocelectomy on sperm parameters and pregnancy rate in patients with subclinical varicocele: a randomized prospective controlled study. J Urol 1996;155:1636–1638. [PubMed] [Google Scholar]
- 9.Grasso M, Lania C, Castelli M, et al. Low-grade left varicocele in patients over 30 years old: the effect of spermatic vein ligation on fertility. BJU Int 2000;85:305–307. [DOI] [PubMed] [Google Scholar]
- 10.Krause W, Muller HH, Schafer 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]
- 11.Ficarra V, Cerruto MA, Liguori G, et al. Treatment of varicocele in subfertile men: the Cochrane Review - a contrary opinion. Eur Urol 2006;49:258–263. [DOI] [PubMed] [Google Scholar]
- 12.Dohle GR, Pierik F, Weber RF. Does varicocele repair result in more spontaneous pregnancies? A randomised prospective trial. J Urol 2003;169(suppl):408–409 [abstract 1525]. [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.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]
- 15.Al-Kandari AM, Shabaan H, Ibrahim HM, et al. Comparison of outcomes of different varicocelectomy techniques: open inguinal, laparoscopic, and subinguinal microscopic varicocelectomy: a randomized clinical trial. Urology 2007;69:417–420. [DOI] [PubMed] [Google Scholar]