Document Type : Original Article
1 Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2 Urology Department, Imam Sajjad Hospital, Iran University of Medical Sciences, Shahriar, Iran
3 4Faculty of Medicine, Hamedan University of Medical Sciences, Hamedan, Iran
4 Men's Health and Reproductive Health Research Center (MHRHRC), Reconstructive Urology Department, Shohada-e-Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Approximately 6-8% of married couples (Fig about 42-60 million
men), experience vasectomy as contraception (
A meta-analysis on 32 studies about vasovasostomy with
6633 patients revealed that mean post-procedure patency
and pregnancy rates were 89.4 and 73.0%, respectively, with
the mean obstruction interval of 7.2 years. No statistically
significant difference in vasovasostomy outcomes was seen
in the comparison of single versus multilayer anastomosis.
Obstructive interval less than 10 years was a predictor of
higher patency and pregnancy rates (
The most common early complication of vasovasostomy
is hematoma. The hematomas are perivasal and very small,
thus they usually require no surgical drainage. Wound infection
is another possible early complication. Late complications
include sperm granuloma at the anastomotic site (5%).
Late stricture and obstruction are relatively common (12-
18% in 12 months). With microsurgical techniques, patency
can reach to 70-90% (
Several surgeons have used mitomycin-C (MMC) as
an antifibrotic adjunct to ab-externo trabeculectomy and
Dacryocystorhinostomy (DCR). It seems that intra-operative
local MMC with a controlled concentration is a safe
agent for reducing fibrosis (
Evidence for MMC-induced carcinogenicity is considered
sufficient for animals, but inadequate for humans. As
such, MMC is classified by International Agency for Research
on Cancer (IARC) as possibly carcinogenic agent
to humans (group 2B). A meta-analysis studied the effect
of varying concentrations of MMC and treatment durations
on cellular proliferation and viability of the fibroblasts.
They found MMC at 0.4 mg/ml beyond the 5 minutes,
and 0.5 mg/ml concentration at all time-points were
lethal and caused extensive cell deaths, compared to controls.
The minimum effective concentration appeared to
be 0.2 mg/ml for 3 minutes (
The important point is that all of the previous studies have examined MMC as an anti-fibrotic agent for ophthalmologic surgeries and internal urethrotomies. But intra-operative local MMC has not been studied in vasovasostomy yet. Therefore, our study is performed to determine the overall safety and efficacy of intra-operative local MMC as the anti-fibrotic agent in vasovasostomy.
In this randomized clinical trial, 58 patients, visited for vasectomy reversal in Shohada-e-Tajrish Hospital (Tehran, Iran) between January and October 2016, were enrolled.
The main priority of these patients was to have the opportunity of becoming a father. It was indicated to the patients that this method may not improve the outcome of vasovasostomy procedure and they preferred to participate in this trial. All patients were fully informed about the method of trial and subsequently they were blindly sub-grouped. All recruited and conducted participants were informed about the trial results by email after data analysis.
In this randomized controlled trial (RCT) the burden of the intervention such as pain and surgical site infection, or hematoma were assessed by patients and also residents of urology in the outpatient clinic and they were then recorded in our database.
Inclusion criterion was ‘males who underwent vasectomy and wanted reversal of vasectomy. Exclusion criteria were testicular atrophy, history of urethral or bladder neck surgery, history of previous vasovasostomy, history of scrotal region radiotherapy, history of chemotherapy, age of partner out of fertility range and any situation suggesting the need for vasoepididymostomy.
Six patients had testicular atrophy, history of previous vasovasostomy and age of their partners was out of fertility range. Eight patients were candidates for vasoepididymostomy, because of previous scrotal surgery or manipulation like percutaneous sperm aspiration (PESA). Hence, all of them were excluded from the allocation.
Finally, 44 consecutive patients were allocated randomly into two groups: the case group (n=22) was candidate for vasovasostomy in addition to intra-operative local MMC. The control group (n=22) was allocated for standard vasovasostomy. Randomization was performed by a random number table and opaque envelopes were used for allocation.
The primary endpoints included presence of sperm in semen, sperm count more than 20 million/ml, sperm motility rate and normal morphology rate in sperms. The secondary endpoints include hematoma, inflammatory reaction, tissue necrosis and any sign of surgical site infection. As mentioned before, all patients were informed about the disease, method of study and treatment possibilities. They had been informed about the possible complications and other applicable managements. Then, an informed consent was taken from each patient.
The proposal of this study was approved by Shahid Beheshti Medical University (SBMU) Ethical Committee (IR.SBMU.MSP.REC.1395.100) and research board of Infertility and Reproductive Health Research Center (IRHRC). Ethical issues were respected based on Declaration of Helsinki. The RCT was approved and documented by IRCT (IRCT2015092324166N1).
Initial pre-operative evaluations included detailed medical history, complete physical examination and sperm analysis. In MMC group, pre-operation evaluation included laboratory tests and cardiovascular consultation. In the operating room, under spinal anesthesia, the procedure was carried out using bilateral high vertical incision of scrotum. After finding each vas deferens and preparing the site of anastomosis, two ends of vas deferens were floated in 0.2 mg/ml MMC solution for 5 minutes, and they were then washed by normal saline. Finally, anastomosis was performed microscopically (CARL ZEISS F170 T surgical microscope binoculars 10×/22B; Zeiss, Germany) using modified two-layered vasovasostomy. Two 5-0 poly-propylene sutures were placed at 5 and 7 o’clock positions in the sero-muscular layer to approximate two ends of the vas. Next, four 8-0 poly-propylene sutures were sequentially placed inside out in the mucosa of the vasal ends, at 3, 6, 9, and 12 o’clock positions and tied up. Two additional sero- muscular sutures were placed at 1 and 11 o’clock positions to complete the anastomosis. In the control group, vasovasostomy procedure was carried out as the MMC group, except for floatation in MMC solution. All surgeries were performed by the same surgical team.
Upon finishing the procedure, patients in both groups were in complete bed rest the day after operation. The second day after surgery, they were discharged providing the tests and general condition were normal. Patients were advised to have relative rest at home for two weeks, avoiding intercourse for one month and to have scrotal support for at least one week. The patients were informed about possible early and late complications, in addition to the time of next necessary following up visits. The patients were followed up at 1, 3, and 6 months after surgery by a complete history and a physical examination to monitor the complications (hematoma, inflammatory reaction, tissue necrosis and any sign of operation failure). Sperm analysis was also performed 1 and 6 months after surgery for measuring patency (presence of sperm in semen), sperm count, sperm morphology and motility.
These data were gathered and documented via checklists consisting demographical data which include the interval between vasectomy and vasovasostomy, intra- operative local MMC application, sperm analysis results and any complication related to the procedure. In MMC group, during the procedure, two patients were not compatible with the inclusion criteria, since they were candidate for vasoepididymostomy. So, they were omitted from the study and 20 patients received allocated intervention. In this group one patient lost the follow up. Finally, the data of 19 patients were analyzed. In the control group, all of the 22 patients received allocated intervention. During follow up, one patient immigrated to another city and he was out of reach. Therefore, the data of 21 patients were analyzed. Figure 1 shows the CONSORT flow-diagram of the data in this study. The data analysis method was per- protocol and performed by SPSS (version 23.0) software (SPSS, Chicago, USA). Fisher exact test, Independent t test, chi-square test and likelihood ratio chi square test were used to compare and analyze the data. P value significance level was defined as 0.05.
CONSORT 2010 flow-diagram.
Primary data analysis
|Group||Mean age (Y)||Normalmorphology (%)||Motile sperms (%)||Sperm count||Mean sperm count (m/ml)||Patency|
|<20 M/ml||>20 M/ml||Azoospermia||Sperm present|
|MMC||39.95 ± 5.553||20.05 ± 14.69||27.05 ± 16.98||9 (47)||10 (53)||(23.6 ± 2.3)×106||4 (21)||15 (79)|
|Control||40.95 ± 6.659||17.05 ± 17||18.71 ± 15.96||18 (86)||3 (14)||(9.4 ± 1.4)×106||9 (43)||12 (57)|
Data are presented as mean ± SD or n (%). MMC; Mitomycin-C.
Data analysis based on post-vasectomy interval
|Sperm present||Azoospermia||>20 M/ml*||<20 M/ml|
|Interval<5 Y (n=7)|
|MMC||2 (50)||2 (50)||0||4 (100)|
|Control||3 (100)||0||1 (33)||2 (67)|
|5 Y<interval<10 Y (n=18)|
|MMC||10 (100)||0||8 (80)||2 (20)|
|Control||4 (50)||4 (50)||0||8 (100)|
|Interval>10 Y (n=15)|
|MMC||3 (60)||2 (40)||2 (40)||3 (60)|
|Control||5 (50)||5 (50)||2 (20)||8 (80)|
Data are presented as n (%). *; Likelihood ratio chi square test, MMC; Mitomycin C, and Y; Year.
Mean age in MMC group and control group was 39.95
(± 5.55) and 40.95 (± 6.65) years, respectively (P=0.609,
Then, we analyzed data in three subgroups based on the
interval between vasectomy and reversal (less than 5,
Intra-operative MMC application is described for DCR, trabeculectomy, and some urological surgeries. All of these reports emphasized that MMC, as a local antifibrotic agent, is effective and safe. This trial, for the first time, demonstrates the effects of local intra-operative MMC in vasovasostomy. We cannot use previous trial estimate the best sample size. So we conducted a pilot study to find if any benefit exist using intra-operative MMC in vasectomy reversal. It seems that the increase of sperm count is the main effect of local intra-operative MMC in vasovasostomy, but it has no effect on sperm motility and morphology. This effect is more prominent in both patency and sperm count more than 20 million/ ml; especially, in a subgroup with 5-10 years of interval between vasectomy and reversal. If the interval is less than 5 years or more than 10 years, MMC application has no benefit in the reversal outcomes. It is important that MMC application has lower cost in comparison with intracytoplasmic sperm injection (ICSI) or other new techniques described for vasovasostomy, and it has no side effects if the concentration is controlled. It needs no special training and the time of surgery is relatively the same as standard vasovasostomy.
The main limitations of our study are small sample size, the use of very low concentration of MMC, relatively short follow up term and not enough follow up to study the pregnancy rate.
Intra-operative local MMC in vasovasostomy can be regarded as a safe and efficient technique which has several advantages including lower cost. Increase of sperm count is the main effect of local MMC application that is more prominent when the interval between vasectomy and reversal is 5-10 years. However, further studies should be conducted with larger sample sizes and different MMC dosage, longer durations, and multi-center sampling to attain more definite results.