eNOS gene T786C,G894T and 4a4b polymorphisms and male infertility susceptibility: a meta‐analysis

The association between polymorphism of eNOS and male infertility in several studies was controversial. To explore a more precise estimation of the association, a meta‐analysis of eight case–control studies, including 1,968 cases and 1,539 controls, were selected. The meta‐analysis was conducted by calculating the pooled odds ratio (OR) with a 95% confidence interval (95% CI). Overall, the association between T786C and risk of male infertility was obvious (TC vs. TT: OR, 1.20; 95% CI, 1.01–1.42; CC vs. TT: OR, 3.37; 95% CI, 1.65–6.87; TC/CC vs. TT: OR, 1.47; 95% CI, 1.25–1.73; CC vs. TT/TC: OR, 3.18; 95% CI, 1.54–6.56; TC vs. TT: OR, 1.65; 95% CI, 1.27–2.03). However, no overall association was observed between the other two polymorphisms of eNOS (G894T and 4a4b) and male infertility. Stratified analysis showed that significantly strong association between T786C polymorphism and semen quality was present in all three types of male infertility (azoospermia, oligozoospermia and asthenozoospermia). In the subgroup analysis based on ethnicity, both T786C and 4a4b could influence the risk of male infertility in Asian and Caucasian. Further studies of polymorphisms of eNOS with their biological functions are needed to understand the role in the development of male infertility.     

Systematic review and meta‐analysis of the genetic association between protamine polymorphism and male infertility

While several previous studies have proposed an association between male infertility and protamine polymorphism, the reported findings have shown some inconsistency. To evaluate the potential association between the two most common single nucleotide polymorphisms (rs2301365 and rs1646022) in protamine and male infertility, we performed a meta‐analysis involving 2713 cases and 2086 controls from 15 published case‐controlled studies. Overall, our analysis showed significant associations between the specific protamine single‐nucleotide polymorphism (rs2301365) and male infertility, and this association was indicated by all of the models we tested. Subgroup analysis revealed significant associations with a Caucasian background, PCR sequence, population‐based, case size of > 150 and case size of < 150 subgroups. Similarly, significant associations were found between rs1646022 and male infertility in the hospital population and case size of < 200 subgroups. However, trial sequential analysis showed that the number of patients in the study did not reach optimal information size. Further studies with larger sample sizes are now warranted to clarify the potential roles of the two protamine polymorphisms in the pathogenesis of male infertility. This may help us to understand the precise molecular mechanisms underlying the effect of protamines upon male infertility.     

Open non‐microsurgical,laparoscopic or open microsurgical varicocelectomy for male infertility: a meta‐analysis of randomized controlled trials

Study Type – Therapy (systematic review) Level of Evidence 1a What's known on the subject? and What does the study add? There are several surgical techniques for the treatment of varicocele in infertile men, including open non‐microsurgical, laparoscopic and microsurgical varicocelectomy. It is currently unclear, however, which is the most beneficial method for patients. The present meta‐analysis found that microsurgical varicocelectomy is the most effective and least morbid method among the three varicocelectomy techniques for treating varicocele in infertile men.

OBJECTIVE

• ? To compare various techniques of open non‐microsurgical, laparoscopic or microsurgical varicocelectomy procedures to describe the best method for treating varicocele in infertile men.

PATIENTS AND METHODS

• ? We searched PubMed, Embase, the Cochrane Library, the Institute for Scientific Information (ISI) – Science Citation Index and the Chinese Biomedicine Literature Database up to June 2011. Only randomized controlled trials (RCTs) were included in the present study.
• ? The outcome measures assessed were pregnancy rate (primary), the incidence of recurrent varicocele, time to return to work, the incidence of postoperative hydrocele and operation duration (secondary).
• ? Two authors independently assessed the study quality and extracted data. All data were analysed using Review Manager (version 5.0).

RESULTS

• ? The present study included four randomized controlled trials comprising 1,015 patients in total.
• ? At the follow‐up endpoints, patients who had undergone microsurgery showed a significant advantage over those who had undergone open varicocelectomy in terms of pregnancy rate (odds ratio [OR]= 1.63, 95% confidence interval [CI]: 1.19–2.23].
• ? There was no significant difference between laparoscopic and open varicocelectomy (OR = 1.11, 95% CI: 0.65–1.88) or between microsurgery and laparoscopic varicocelectomy (OR = 1.37, 95% CI: 0.84–2.24).
• ? The incidences of recurrent varicocele and postoperative hydrocele were significantly lower after microsurgery than after laparoscopic or open varicocelectomy.
• ? The time to return to work after microsurgery and laparoscopic varicocelectomy was significantly shorter than that after open varicocelectomy.
• ? The operation duration of microsurgical varicocelectomy was longer than that of laparoscopic or open varicocelectomy.

CONCLUSIONS

• ? Current evidence indicates that microsurgical varicocelectomy is the most effective and least morbid method among the three varicocelectomy techniques for treating varicocele in infertile men.
• ? More high‐quality, multicentre, long‐term RCTs are required to verify the findings.

     

Meta‐analysis of the association of oestrogen receptor‐beta gene RsaI (G/A) and AluI (A/G) polymorphisms with male infertility

A more precise assessment of association of oestrogen receptor‐beta genes RsaI(G/A) and AluI(A/G) polymorphisms with male infertility from current contradictory results is the aim of this meta‐analysis including five RsaI and six AluI studies respectively. No association was observed between infertility and RsaI or AluI. In the stratified analysis by ethnicity, increased risk was found among Caucasians with GA versus GG (OR = 2.263, 95% CI = 1.073–4.776, I² = 57.1%) and dominant model (OR = 2.117, 95% CI = 1.018–4.403, I² = 49.0%) of RsaI. It was not observed for AluI. In the stratified analysis by infertility subtypes, a reduced risk in GA of AluI was observed among azoospermia or severe oligospermia (GA versus AA: OR = 0.686, 95% CI = 0.498–0.945, I² = 21.2%; recessive model: OR = 1.403, 95% CI = 1.056–1.864, I² = 31.7%), and reduced risk was in recessive model (OR = 0.650, 95% CI = 0.446–0.948, I² = 0.0%) of subtypes, except for azoospermia or severe oligospermia. However, this finding was not observed in RsaI. The meta‐analysis showed GA and GG of AluI are possibly resistant factors for spermatogenesis dysfunction and deteriorated sperm quality.     

CAG repeat length in the androgen receptor gene affects the risk of male infertility

During recent years several studies have suggested that a slight increase in the number of CAG repeat sequences in exon 1 of the androgen receptor gene causes idiopathic oligozoospermia. We tested whether CAG repeats are more numerous in men with idiopathic infertility compared to those with known causes of oligozoospermia. CAG repeats were analysed in a consecutive sample of 217 infertile men covering a wide range of diagnoses and sperm counts. Data were compared with those of a control group of 131 normozoospermic men including 62 fathers. CAG repeats (x +/- SD) did not differ between idiopathically (21.4 +/- 2.9) and non-idiopathically infertile men (21.6 +/- 2.8) or normozoospermic men of unproven fertility (20.6 +/- 3.0). Only fathers had significantly fewer repeats (19.4 +/- 3.1; p < 0.001). Different from controls, no correlation between CAG repeats and any semen parameter existed in patients. Comparison of our and published studies showed that odds ratios for infertility in men with CAG repeat length in the upper quartile of the normal range increased when the controls were selected by proven fertility. We conclude that more numerous CAG repeats do not directly cause oligozoospermia and propose that men with longer CAG repeats might be more prone to develop infertility in response to any pathogen/epigenetic factors.     

Association between seminal plasma zinc level and asthenozoospermia: a meta‐analysis study

Zinc is proposed to have an important role in the morphology, viability and motility of spermatozoa. There are inconsistent reports on the association between seminal plasma zinc concentration and male infertility. For this purpose, papers reporting the level of seminal zinc among asthenozoospermic groups were selected and used for further analysis. This meta‐analysis of previous published studies was performed to obtain more precise information on the association between seminal plasma zinc and asthenozoospermia. Relevant studies for inclusion were identified after preliminary investigation of research papers published on electronic databases up to February 2015. Eight reports and 475 subjects were finally included in the meta‐analysis. In the overall analysis, a statistically significant reduction in seminal plasma zinc concentrations was observed in asthenozoospermic infertile men. Random‐effects method was used to evaluate the summary effect size due to the presence of significant heterogeneity. The effect of zinc on asthenozoospermia was significant (Hedge's G effect size = ?0.506, 95% confidence interval (95% CI): ?0.998 to ?0.014, P = 0.044). Taken together, despite of significant statistical heterogeneity between studies, our findings were indicative of significant association between zinc concentration and asthenozoospermia. In conclusion, the meta‐analysis suggests that seminal plasma zinc concentration is negatively associated with male infertility.     

Association of androgen receptor gene CAG and GGN repeat polymorphism with cryptorchidism: A meta‐analysis

Researches on association between variations in the androgen receptor (AR) gene repeat polymorphisms and cryptorchidism (CO) had conflicting results. The aim of this meta‐analysis was to analyse the potential effects of AR CAG and/or GGN repeat polymorphism on CO. Studies were independently appraised by two investigators on PubMed, Web of Science, EBSCO databases and Foreign Medical Retrieval System. Case–control studies with measurement of CAG and/or GGN repeat length were included. Weighted mean difference (WMD) and 95% confidence intervals (CIs) for the CAG or GGN repeat polymorphism and CO were calculated. Five reports were included in this analysis. Overall, no difference was identified between patients and fertile men in CAG repeat length. However, when the CO was divided into unilateral and bilateral, longer CAG repeat region was significantly associated with CO in bilateral group (WMD = 0.74; 95% CI, 0.01–1.47; p < .05). In addition, GGN lengths were significantly higher in patients compared with those in controls (WMD = 1.17; 95% CI, 0.28–2.06; p < .05). No obvious effect was found in the GGN length when compared unilateral or bilateral group with control respectively. The results in this meta‐analysis indicated that AR CAG and GGN repeat polymorphisms may be an important pathogenesis of CO.     

The CAG repeat polymorphism of mitochondrial polymerase gamma (POLG) is associated with male infertility in Tunisia

Male fertility largely depends on sperm quality, which may be affected by environmental and genetic factors. Recent data emphasised the implication of the polymorphism of mitochondrial DNA polymerase gamma (POLG) CAG repeats in male infertility. In this report, we explored a possible role of the (POLG) gene polymorphism in male infertility in Tunisian men. The polymorphic CAG repeat in the nuclear POLG gene was studied in 339 male subjects (216 patients with infertility (69 azoospermic, 115 oligoasthenoteratospermic and 32 normospermic) and 123 fertile) after DNA amplification by PCR, followed by genotyping using an automatic sequencer. The heterozygous and the homozygous mutant genotypes (10/ ≠ 10 and ≠ 10/ ≠ 10) were significantly more frequent among infertile patients than among fertile controls (11.2% versus 1.6%, P = 1.3 × 10(-3) and 4.6% versus 0.8%, P = 4.2 × 10(-7) respectively). We also found a significant difference between the frequencies of 10/ ≠ 10 genotype in azoospermic (4.4%) and in oligoasthenoteratospermic (15.6%) infertile patients (P = 2.6 × 10(-2) ). However, the homozygous mutant genotype (≠ 10/ ≠ 10) was seen at similar frequencies in azoospermic, normospermic and oligoasthenospermic men (4.4%, 3.1% and 5.2% respectively). Under our conditions, the findings showed an association between POLG CAG repeat polymorphism and male infertility in Tunisian population.     

α‐Blockers to assist stone clearance after extracorporeal shock wave lithotripsy: a meta‐analysis

Study Type – Therapy (meta‐analysis)
Level of Evidence 1a

OBJECTIVE

To review the evidence for the use of α‐blockers after extracorporeal shock wave lithotripsy (ESWL) in enhancing the effectiveness of renal and ureteric stone clearance.

METHODS

We searched MEDLINE, Embase and the Cochrane Library up to January 2009. All randomized controlled trials in which α‐blockers were evaluated after ESWL were eligible for the analysis. Outcome measures assessed were clearance rate (primary) and expulsion time (secondary). Two authors independently assessed study quality and extracted data. All data were analysed using RevMan 5.

RESULTS

Of the 29 identified papers, seven trials with a total of 484 patients met the predefined criteria. These studies evaluated the effectiveness of the α‐blocker tamsulosin, and studied clearance rate as the primary outcome. There was large heterogeneity between trials, but their methodological quality was adequate. The pooled absolute risk difference of clearance rate was 16% (95% confidence interval 5–27%) in favour of the tamsulosin group, i.e. an average of six patients have to be treated with tamsulosin after ESWL to achieve clearance in one. Subgroup analysis for the six studies that used a dose of 0.4 mg tamsulosin showed a pooled risk difference of 19 (10–29)%. The expulsion time was analysed in three studies and the pooled mean difference was 8 (?3–20) days in favour of the tamsulosin group. Pain and analgesic usage was reported to be lower with tamsulosin. Adverse effects of tamsulosin, mainly dizziness, were reported in eight patients (3%).

CONCLUSIONS

Treatment with tamsulosin after ESWL appears to be effective in assisting stone clearance in patients with renal and ureteric calculi. To make a definite clinical recommendation to use tamsulosin after ESWL for renal and ureteric calculi, a high quality confirmatory trial is warranted.     

CAG repeat length in androgen receptor gene and male infertility in Egyptian patients

The CAG repeat and its association with infertility has been debatable. Therefore, this study was planned to assess the distribution of CAG repeat expansion in Egyptian patients and to investigate its association with male infertility. Forty-five infertile men were eligible for the study in addition to 20 aged-matched fertile males as control. Semen analysis, scrotal sonography, assay of serum testosterone, follicle-stimulating hormone (FSH) and luteinising hormone (LH), and determination of the CAG repeat number within exon 1 of the androgen receptor (AR) gene were carried out. Statistically significant difference was found between infertile and control groups regarding sperm count, sperm motility, serum FSH level and CAG repeats (P < 0.05); statistically insignificant difference for the CAG repeats (P = 1.0) was found between oligozoospermic and asthenospermic groups; negative correlation was found between CAG repeat length and sperm count, and a positive correlation was found between CAG repeat length and serum FSH (P < 0.05). Our results validate the concept that long stretches of CAG repeat may be associated with lower AR function with derangement of sperm production, and this may contribute to male infertility in Egyptian men.     

Association of polymorphisms of A260G and A386G in DAZL gene with male infertility: a meta-analysis and systemic review

To investigate the association of single nucleotide polymorphism 260 and 386 (SNP260 and SNP386) gene with male infertility, an electronic search was performed to identify case-control studies evaluating the relationship of SNP260 or SNP386 of deleted in azoospermia-like (DAZL) and male infertility. Review Manager 5 was used to process the meta-analysis and other statistical analysis. A total of 139 records were retrieved, of which 13 case-control studies with total 2715 patients and 1835 normozoospermic men were included. SNP260 was found not to play a functional role in male oligo/azoospermia either for Caucasians or for Asians. But for SNP386, models of allele (A/G), dominant (AA/AG + GG), co-dominant (AA/AG) and super-dominant (AA + GG/AG) had a strong correlation to spermatogenic failure with related odds ratio being 0.15 (95% confidence interval [95% CI] 0.07 to 0.34, P < 0.00001), 0.16 (95% CI 0.07 to 0.35, P < 0.00001), 0.15 (95% CI 0.06 to 0.33, P < 0.00001) and 0.15 (95% CI 0.06 to 0.33, P < 0.00001), respectively. Moreover, this correlation was only found in the Chinese Han population (decreasing around 85% risk of oligo/azoospermia infertility) and not found in India, Japan, and Caucasian countries. Our analysis demonstrated that SNP260 of DAZL did not contribute to oligo/azoospermia while SNP386 was correlated to male infertility. However, this correlation was only found in China with a country-specific and ethnicity-specific manner.     

Clinical significance of subclinical varicocelectomy in male infertility: systematic review and meta‐analysis

Recent meta‐analysis by the Cochrane collaboration concluded that treatment of varicocele may improve an infertile couple's chance of pregnancy. However, there has been no consensus on the management of subclinical varicocele. Therefore, we determine the impact of varicocele treatment on semen parameters and pregnancy rate in men with subclinical varicocele. The randomised controlled trials that assessed the presence and/or treatment of subclinical varicocele were included for systematic review and meta‐analysis. Random effect model was used to calculate the weighted mean difference of semen parameters and odds ratio of pregnancy rates. Seven trials with 548 participants, 276 in subclinical varicocelectomy and 272 in no‐treatment or clomiphene citrate subjects, were included. Although there was also no statistically significant difference in pregnancy rate (OR 1.29, 95% CI 0.99–1.67), surgical treatment resulted in statistically significant improvements on forward progressive sperm motility (MD 3.94, 95% CI 1.24–6.65). However, the evidence is not enough to allow final conclusions because the quality of included studies is very low and further research is needed.     

Joint effect of glutathione S‐transferase genotypes and cigarette smoking on idiopathic male infertility

Inconsistent results of association studies investigated the role of glutathione S–transferase genes in idiopathic male infertility may be explained by ethnical differences in gene–gene and gene–environment interactions. In this study, we investigated a joint contribution of GSTM1, GSTT1 and GSTP1 gene polymorphisms and cigarette smoking to the risk of idiopathic infertility in Russian men. DNA samples from 203 infertile and 227 fertile men were genotyped by a multiplex polymerase chain reaction (GSTM1 and GSTT1 deletions) and PCR‐restriction fragment length polymorphism (GSTP1 I105V) methods. The GSTP1 genotype 105IV was associated with increased risk of male infertility (OR = 1.50 95% CI 1.02–2.20 P = 0.04). Genotype combinations GSTP1 105II/GSTT1 del (G1), GSTM1 del/GSTT1 del (G2) and GSTM1 + /GSTT1 del (G3) were associated with decreased risk of male infertility (P ≤ 0.003), whereas a genotype combination GSTP1 105IV/GSTT1 + (G4) was associated with increased disease risk (P = 0.001). The genotype combinations G3 and G4 showed a significant association with infertility in smokers; however, nonsmokers carriers did show the disease risk. In conclusion, GSTM1, GSTT1 and GSTP1 genes are collectively involved in the development of idiopathic male infertility and their phenotypic effects on the disease risk are potentiated by cigarette smoking.     

Determination of seminal oxidation–reduction potential (ORP) as an easy and cost‐effective clinical marker of male infertility

Oxidative stress (OS) is an important contributing factor to male infertility. While previous methods to measure seminal OS are time‐consuming and limited to the use of freshly produced semen, oxidation reduction potential (ORP) is easier and quicker to perform and can also be used in frozen semen. Therefore, this study evaluated the clinical utility of ORP as a potential marker of male infertility. ORP was measured in semen samples from 293 patients and 15 fertile controls and categorised according to WHO criteria as normozoospermic, oligozoospermic, asthenozoospermic, teratozoospermic and oligoasthenoteratozoospermic. Receiver operating characteristic (ROC) curves were generated to differentiate these categories. Semen parameters were significantly different when subjects were grouped as control and patients or between the patient and normozoospermic group for concentration and morphology. ORP levels were significantly different between the control and normozoospermic group. When subjects were grouped based on concentration, motility, morphology or a combination of these, the area under the ROC curve, sensitivity, specificity, positive predictive value and cut‐off values were significantly different. These differences were significant when combined with ORP and grouped with any two sperm abnormalities. In conclusion, ORP is a quick, easy, cost‐effective and reliable marker of semen quality as well as oxidative stress for use in a clinical setting.     

Association between interleukin‐4R and TGF‐β1 gene polymorphisms and the risk of colorectal cancer in a Korean population

Aim Colorectal cancer is associated with inflammatory bowel disease. The mechanisms of how different genetic make‐ups of cytokines might influence the individual susceptibility to develop particular types of tumours are still unknown. The authors analysed the association between genetic polymorphisms in cytokine/cytokine receptor genes and the risk of colorectal cancer in a Korean population. Method The authors assessed polymorphisms of the interleukin: IL‐1, IL‐1R, IL‐2, IL‐4, IL‐4R, IL‐10, transforming growth factor (TGF)‐β1, IFN‐γ genes in Korean patients with colorectal cancer (n = 170) and in a normal healthy control group (n = 130) to investigate the association between theses cytokine gene polymorphisms and the risk of colorectal cancer. Results The IL‐4R 1902*T allele was found to be associated with an increased risk of colon cancer (P < 0.01, OR = 2.0) and rectal cancer (P < 0.05, OR = 1.8). The IL‐4R 1902*C allele was associated with a decreased risk of both colon cancer (P < 0.01, OR = 0.51) and rectal cancer (P < 0.05, OR = 0.5). The TFG‐β1 10*T allele was found to be associated with an increased risk of colon cancer (P < 0.00, OR = 2.3) and the TFG‐β1 10*C allele with a decreased risk of colon cancer (P < 0.00, OR = 0.43). Conclusion These results suggest that the genetic polymorphisms of IL‐4R and TGF‐β1 are associated with the risk of colorectal cancer in a Korean population.     

Association of oestrogen receptor alpha polymorphisms and androgen receptor CAG trinucleotide repeats with male infertility: a study in 109 Greek infertile men

This study was performed to examine the contribution of genetic polymorphism of oestrogen and androgen receptor (AR) genes in male infertility. We have studied in total 173 Greek men, 109 infertile patients and 64 controls (group A). Patients were divided in to three subgroups: group B (n=29) with idiopathic moderate oligospermia, group C (n=42) with azoospermia or idiopathic severe oligospermia and group D (n=38) with azoospermia or oligospermia of various known aetiologies. All patients and controls were genotyped for two polymorphisms of the oestrogen receptor alpha (ERalpha) gene and also for the (CAG)n repeat length polymorphism of the X-linked androgen receptor (AR)gene. The control group had statistically significant difference from group C regarding the XbaI polymorphism of ERalpha gene. Despite the fact that we did not observe any statistically significant differences in the mean and range of the CAG repeat number, the frequency of the higher repeats of the nucleotide repeat sequence (CAG)n of the AR gene was 2-4 times higher in groups B and C compared with the control group A. Our results indicate that both ERalpha and AR gene play significant role in male fertility. It is possible that a synergy may exist between unfavourable genotypes of these two genes in male infertility.     

Associations between folate metabolism enzyme polymorphisms and breast cancer: A meta‐analysis

We performed this meta‐analysis to explore associations between folate metabolism enzyme polymorphisms and breast cancer (BC) in a larger pooled population. Systematic literature research was performed to identify eligible studies for pooled analyses. Totally 92 genetic association studies were included for analyses. The pooled analyses revealed significant findings for MTRR rs1801394 polymorphism in South Asians, for MTR rs1805087 polymorphism in Caucasians and East Asians, and for MTHFR rs1801133 polymorphism in East Asians. In conclusion, the present meta‐analysis indicated that MTRR rs1801394, MTR rs1805087, and MTHFR rs1801133 polymorphisms could be used to identify individuals at high risk of developing BC.     

Effects of epidural volume extension by saline injection on the efficacy and safety of intrathecal local anaesthetics: systematic review with meta‐analysis,meta‐regression and trial sequential analysis

Epidural volume extension, a modification of combined spinal–epidural anaesthesia, involves the epidural injection of saline in order to increase the spread of drugs given intrathecally. Results from individual studies have so far been contradictory and we aimed to gather the available evidence for this technique. We performed a systematic literature search for randomised, controlled trials comparing epidural volume extension after spinal injection with a control group without epidural injection in patients undergoing surgery. Conventional meta‐analyses, trial sequential analyses and meta‐regression were performed, with the Grading of Recommendations on Assessment, Development and Evaluation (GRADE) approach used to express reliability of outcome estimates. We included 15 studies with 1177 participants. Meta‐analyses for the primary outcomes, such as maximum sensory height (6 studies, 274 participants, mean difference (MD) (95%CI) ?0.59 (?1.24 to 0.07) dermatomes, low‐quality evidence) and hypotension (10 studies, 683 participants, risk ratio (95%CI) 0.84 (0.66–1.07), low‐quality evidence), did not differ significantly between the two treatment arms, but trial sequential analysis suggested insufficient evidence to be certain of these findings. Meta‐regression suggested a volume‐dependent effect, with higher volumes causing a higher spread of intrathecal drugs and a higher incidence of hypotension. A sub‐group analysis indicated a pronounced effect on motor block recovery time when a lower anaesthetic dose plus epidural volume extension was compared with a higher anaesthetic dose without epidural volume extension, the MD (95%CI) being ?66.75 (?76.0 to ?57.5) min, with trial sequential analysis suggesting the evidence was sufficient to draw this conclusion. In trials using the same anaesthetic mixture in the epidural volume extension and the control groups, motor block recovery time did not differ between groups, with a MD (95%CI) of ?1.06 (?5.48 to 3.36) min, although trial sequential analysis suggested insufficient evidence. In summary, there is not enough evidence to draw definite conclusions on the effect of epidural volume extension. The quality of the current evidence is low for both efficacy (maximum sensory height) and safety (hypotension). However, there may be a significantly shorter motor block recovery time when different anaesthetic mixtures are used in epidural volume extension and control groups; this warrants further investigation.