Received: 17 September 2019 | Revised: 6 November 2019 | Accepted: 14 November 2019

DOI: 10.1111/and.13500

ORIGINAL ARTICLE

Time to improvement of semen parameters after microscopic

varicocelectomy: When it occurs and its effects on fertility

Graham Luke Machen1 | Dane Johnson2 | Melissa A. Nissen1 | Evan Naber1 |

Jay I. Sandlow1

1
Department of Urology, Medical College of
Wisconsin, Milwaukee, WI, USA Abstract
2
Division of Urology, Washington University While ligation of clinical varicoceles has been clearly shown to improve semen pa-
in St Louis, St Louis, MO, USA
rameters in subfertile men, evidence describing when to expect improvement and
Correspondence the potential effects on fertility following surgery are sparse. A chart review was
Graham Luke Machen, Department of
undertaken to identify men who had undergone a microscopic subinguinal varicoce-
Urology, Medical College of Wisconsin, 8701
Watertown Plank Rd, Milwaukee, WI 53226, lectomy from January 1, 2006, to June 30, 2018. Semen analyses were reviewed to
USA.
determine if a significant improvement occurred post-operatively and when the im-
Email: glmachen@gmail.com
provement was seen. Pregnancy data were reviewed to determine if fecundity rates
were affected by semen parameter improvement or the interval at which improve-
ment occurred. A total of 170 men met criteria for inclusion, including pregnancy data
on 140. 69.4% of patients experienced a significant improvement in total progressive
sperm count (TPSC), 78.8% of which occurred after 3 months. The overall pregnancy
rate was 40.7%. When comparing men whose TPSC improved to those who did not,
there was an odds ratio (OR) of 5.89 (2.28–15.28, 0.0003) for achieving pregnancy,
while an OR of 2.05 (0.80–5.28, 0.13) was found when comparing pregnancy rates
between early and late improvement in semen parameters. Pregnancy rates were
not affected by time to improvement, but were higher in men who had a significant
improvement in TPSC after surgery.

KEYWORDS
infertility, male, microscopic varicocelectomy, semen parameters, varicocele

1 | I NTRO D U C TI O N 2014). Other possible mechanisms include testicular hypoxia or re-

flux of renal and adrenal metabolites, which may also result in in-
Varicoceles remain the most common correctable cause of male in- creased oxidative stress (Balci et al., 2008; Comhaire & Vermeulen,
fertility, present in approximately 40% of men with primary infertil- 1974; Lee, Jeng, & Lee, 2006).
ity and up to 80% of men with secondary infertility (Clarke, 1966; Both the American Urological Association and the American
Masson & Brannigan, 2014). While there is some debate as to the Society for Reproductive Medicine have established practice guide-
true pathophysiology of varicoceles, it is generally felt to be the re- lines regarding varicoceles, with the indications for treatment to
sult of venous stasis leading to a disruption in the countercurrent include a palpable varicocele in a male with abnormal semen param-
temperature exchange. This causes increased scrotal temperatures, eters (Practice Committee of the American Society for Reproductive
resulting in Sertoli and Leydig cell dysfunction, possibly through in- Medicine & Society for Male Reproduction and Urology, 2014) While
creased reactive oxygen species and oxidative stress (Cho, Esteves, it has been well established that repair of varicoceles improves
& Agarwal, 2016; Johnson & Sandlow, 2017; Masson & Brannigan, semen parameters in most men (Agarwal et al., 2007; Schauer,

Andrologia. 2019;00:e13500. wileyonlinelibrary.com/journal/and © 2019 Blackwell Verlag GmbH | 1 of 5

https://doi.org/10.1111/and.13500
2 of 5 | MACHEN et al.

Madersbacher, Jost, Hubner, & Imhof, 2012), evidence supporting Semen analyses were completed in a single andrology laboratory
improved spontaneous pregnancy rates with varicocelectomy has at our institution. Patients with at least 50% improvement in total
been more difficult to conclusively demonstrate. To illustrate this, progressively motile spermatozoa (TPMS) on their post-operative
in 2008 a Cochrane Review of eight studies found no benefit to sur- SA were classified as having a significant improvement in semen pa-
gical ligation or embolisation in regard to improving fecundity rates rameters after varicocelectomy. TPMS was calculated using the for-
(Evers, Collins, & Clarke, 2008). This review was updated several mula volume (ml) × concentration (millions/ml) × progressive motility
years later with two additional studies and did find treatment of (%). For purposes of calculation, early improvement was defined as
varicoceles had favourable results for pregnancy rates, although the 3 months, while patients with improvements in TPMS 6 months or
quality of existing evidence was somewhat low (Kroese, de Lange, later were considered to have late improvement.
Collins, & Evers, 2012). Pregnancy outcomes were gathered retrospectively, and suc-
It is common to check a semen analysis in 3-month intervals fol- cessful pregnancy was defined as live birth after intrauterine in-
lowing varix ligation, corresponding to the 64–72 day duration for semination (IUI) or spontaneous pregnancy. Patients who conceived
spermatogenesis (Clermont, 1972; Heller & Clermont, 1963). This with IVF were considered negative. Patients were included in the
is a method corroborated by the practice committee of the ASRM pregnancy analysis if at least 1 year of post-op pregnancy data were
(Practice Committee of the American Society for Reproductive available. Statistical calculations were performed with GraphPad
Medicine & Society for Male Reproduction and Urology, 2014). using chi-square and t tests where appropriate to compare categor-
The time to semen parameter improvement may be of paramount ical and continuous variables, respectively. A p-value of <.05 was
importance, at times dictating treatment courses for infertile cou- considered statistically significant.
ples. However, the current evidence describing the time to semen
parameter improvement and its implications after varicocelectomy is
sparse. Thus, with this report, we set out to evaluate the time frame 3 | R E S U LT S
for changes in semen parameters following varicocelectomy and ex-
amine its impact natural conception. A total of 170 men with subfertility who underwent subinguinal
varicocelectomy from January 1, 2006, to June 30, 2018, and 170
met inclusion criteria for the study. The mean patient age was 32.6
2 | M ATE R I A L S A N D M E TH O DS (SD = 4.31) and range was 23–50, while the mean partner age was
30.5 (SD = 3.35) and range 20–39. Thirty-three patients under-
After IRB approval was obtained, a retrospective chart review was went unilateral varix ligation, while the remaining 137 had bilateral
undertaken. Men were included in the study if they had a palpable varicocelectomies.
varicocele on examination with at least one abnormal semen param- See Table 1 for a summary of laboratory data and testicular size
eter on pre-operative semen analysis (SA). Varicoceles identified for the patient cohort. Of note, there was no statistically significant
solely on ultrasound were not treated. Additionally, patients had difference among laboratories or testicular size between patients
to have post-operative SA data available at both 3 and 6 months. who experienced a significant improvement in semen parameters
Exclusion criteria included men with azoospermia pre-operatively following surgery and those that did not. Additionally, the mean FSH
and clomiphene citrate or anastrozole use during the study period. and testosterone were 5.66 IU/ml (SD = 2.99) and 379.5 ng/dl (SD =
Laboratory values were obtained as part of the evaluation pre-oper- 107.5) for patients who had an early improvement, and there was
atively, and when appropriate, in the post-operative period as well. no significant difference when compared to those who experienced
Testicular size was estimated via physical examination with the aid delayed improvement (FSH = 5.81 IU/ml SD = 3.92, T = 406.8 ng/dl
of an orchidometer. SD = 123.3, p-values .86 and .35, respectively).
All surgeries were performed by a single surgeon (JIS) utilising The mean follow-up of the patient cohort was 16.5 (SD = 14.52)
an operative microscope and a standard subinguinal approach as de- months. Pre-operatively, the average total progressive sperm count
scribed elsewhere (Marmar & Kim, 1994; Mehta & Goldstein, 2013). (TPSC) was 7.95 million (SD = 9.07), and post-operative TPSC was

TA B L E 1 Mean laboratory values and

L testicle size R testicle
testicular size
FSH (IU/ml) T (ng/dl) (cc) size (cc)

Overall 5.85 (SD = 398.06 (SD = 16.8 (SD = 18.7 (SD =

3.55) 125.06) 2.84) 2.5)
Patients with significant SA 5.61 (SD = 389.05 (SD = 16.6 (SD = 18.7 (SD =
improvement 3.05) 113.8) 2.96) 2.36)
Patients without significant 6.40 (SD = 418.7 (SD = 17.2 (SD = 2.6) 18.7 (SD =
SA improvement 4.49) 148.1) 2.89)
p-value .20 .17 .18 .93
MACHEN et al. | 3 of 5

24.6 (SD = 25.5; p-value = .0001). A total of 118 (69.4%) patients 4 | D I S CU S S I O N

experienced a 50% or greater improvement in their TPSC. The mean
patient and partner age for those who improved was 32.6 and 30.4, Our results demonstrate that a significant improvement in
compared to 32.6 and 30.6 for those who did obtain significant semen parameters occurred in close to 70% of men status-post
TPSC improvement (p = .91 and .81, respectively). Average follow-up varicocelectomy, and while the vast majority of responders ex-
also did not statistically differ (17.2 vs. 14.9 months, p = .35). Among perienced improvement by 3 months, 18.7% of responders im-
the men who experienced improvement in TPSC, 93 (78.8%) saw im- proved at 6 months or later. Furthermore, time to improvement
provement at 3 months, 20 (16.9%) at 6 months, and 5 (4.2%) beyond demonstrated a trend towards higher pregnancy rates for early
6 months. There was no difference between patient age (32.7 vs. improvement, although this was not statistically significant.
32.8, p .92), partner age (30.49 vs. 30.16, p = .66) or degree of fol- Understandably, a significant improvement in TPSC was found to
low-up (16.6 vs. 18.4, p = .42) when comparing those individuals who increase the likelihood of spontaneous pregnancy. On sub-anal-
improved early versus later. yses, unilateral repairs were more likely to improve at 3 months,
Pregnancy data were available on 140 patients. The overall preg- while varicocele grade did not have an effect on the time to im-
nancy rate after varicocelectomy was 40.7% (57/140), including 43 provement, although grade 3 varicoceles were more likely to have
natural pregnancies and 14 occurring after IUI. With this data avail- a significant increase in TPSC.
able, we set out to determine if there was a relationship between the As mentioned previously, only a limited number of studies exist
timing of improvement and pregnancy rate. See Table 2 for summary that have examined this topic. In 2011, Tarhan et al set out to deter-
of results. An odds ratio of 5.89 (95% CI 2.28–15.28, p = .0003) was mine the effect of varicocelectomy on testicular blood flow in their
found for those men whose TPSC improved post-operatively relative cohort of 30 patients (Tarhan, Ucer, Sahin, & Gumus, 2011). They
to those who did not. Additionally, an odds ratio (OR) of 2.05 was describe an improvement of mean total motile sperm counts from
found when comparing early to late improvement. However, this did 59.06 million to 80.22 million at 3 months and then to 88.75 million
not reach statistical significance (95% 0.80–5.28, p = .13). Results were at 6 months (Tarhan et al., 2011). The following year, Bakri et al at-
similar if pregnancies achieved through IUI were excluded from analy- tempted to directly examine the time for improvement in semen pa-
sis, including an OR of 3.04 (95% CI 1.12–8.28, p = .026) for pregnan- rameters and found mean total motile sperm counts were increased
cies in men who improved significantly after surgery. Additionally, the by 5.65× and 5.47× at 3 and 6 months, respectively (Al Bakri et al.,
OR of 1.68 (95% CI 0.63–4.52, p = .361) for natural pregnancies when 2012). Of note, they also report that there was no difference in im-
improvement occurred at 3 months as opposed to later. provement when comparing unilateral to bilateral varix ligations.
Sub-analyses were performed to determine if varicocele grade Both studies demonstrate that the largest jump in sperm quality oc-
or the type of operation (unilateral or bilateral) affected the time to curred at 3 months and then remained elevated at 6 months. Our
improvement of semen parameters. See Tables 3 and 4. In regard results expand upon these studies by reporting the proportion of
to varicocele grade, as there were only seven patients who under- patients that improve at each 3-month interval.
went surgery with a grade 1 varix, these were combined with the In our cohort, an overall pregnancy rate of 40.7% was noted, which
grade 2 patients. Ultimately, grade 3 varicoceles were more likely is comparable to existing literature. A meta-analysis from 2007 of men
to obtain a 50% or greater improvement in TPSC (88.2% vs. 64.7%); undergoing varicocelectomy, including randomised controlled trials,
otherwise there was no statistical difference between time to SA found a rate of 33% and an odds ratio of 2.87 (95% CI 1.33–6.20) for
improvements or pregnancy rates. For the comparison of unilateral spontaneous pregnancy following varicocelectomy (Marmar et al.,
to bilateral operations, unilateral patients were more likely to im- 2007). Schauer et al. (2012) found a pregnancy rate of 41.48% follow-
prove at 3 months, but differences in overall improvement rate and ing subinguinal varicocelectomy in their meta-analysis of 14 studies.
pregnancy rate did not reach statistical significance. Additionally, our results found a marked difference in pregnancy rates
between those with significant improvements in TPSC versus men
who did not improve (50% vs. 17%, p = .001). Given these results, along
with our findings that 96% of patients improved by 6 months, it may be
TA B L E 2 Fecundity rates based on improvement and time to prudent to recommend patients seek further treatment if their TPSC is
improvement after varix ligation not improved by 6 months post-varix ligation.
Odds ratio (95% What constitutes a “significant improvement” is not well estab-
Pregnancy rate p-value CI, p-value) lished after varicocelectomy, and as previously mentioned our defini-

Improvement post-op tion was a >50% increase in total progressive motile counts. There are
multiple studies historically that have utilised a 50% improvement in
Yes 51/100 (51.0%) .0001 5.89 (2.28–15.28,
.0003) total motile count to determine success of varicoclectomy (Cayan et
No 6/40 (15.0%)
al., 2002; Cayan, Kadioglu, Tefekli, Kadioglu, & Tellaloglu, 2000; Cayan,
Time to improvement
Lee, Black, Reijo Pera, & Turek, 2001; Smit et al., 2010). Our defini-
3 months 42/76 (55.3%) .16 2.05 (0.80–5.28,
tion is an extrapolation of this, as TPSC are utilised at our institution
≥6 months 9/24 (37.5%) .13)
to guide management in regard to assisted reproductive techniques.
4 of 5 | MACHEN et al.

TA B L E 3 Improvement interval and

Overall improvement
pregnancy rates based on varicocele grade
Varix grade rate 3 months ≥6 months Pregnancy rate

1–2 (n = 124) 88/136 (64.7%) 67 (76.1%) 21 (23.9%) 44/112 (39.3%)

3 (n = 30) 30/34 (88.2%) 26 (86.7%) 4 (13.3%) 13/28 (44.8%)
p-value .0069 .30 .52

Bolded values achieved statistical significance.

TA B L E 4 Improvement interval and

Overall
pregnancy rates based on operation
improvement
performed
Procedure rate (%) 3 months ≥6 months Pregnancy rate

Unilateral (n = 33) 25/33 (75.8%) 24/25 (96%) 1/25 (4%) 15/29 (51.7%)
Bilateral (n = 137) 93/124 (75%) 69/93 (74.2%) 24/93 (25.8%) 42/111 (37.8%)
p-value .19 .025 .21

Bolded values achieved statistical significance.

Given the stark difference in pregnancy rates (50% vs. 17%, p = .001) when bilateral clinical varicoceles are encountered, even if the right-
when comparing men with and without significant improvements, our sided varicocele is small.
results supply evidence that a 50% increase in TPSC may be a reason- The limitations of our study include its retrospective nature.
able designation for meaningful improvement after varix ligation. Although female factor infertility was considered, subtle female fac-
Furthermore, it is interesting to consider the results of our sec- tor may have negatively skewed our fecundity rates.
ondary analyses. We found a higher proportion of men improving
after repair of a grade 3 varicocele when compared to grades 1 and
2 (Table 2, 90% vs. 64.5%, p = .0072). This corroborates existing 5 | CO N C LU S I O N S
data that show that treatment of higher-grade varicoceles is asso-
ciated with greater improvement in semen parameters (Jungwirth This study provides further evidence that improvements in semen
et al., 2001; Steckel, Dicker, & Goldstein, 1993). Additionally, it is parameters following varicocelectomy typically occur by 3 months
unclear why the vast majority of men who underwent unilateral re- post-op and are rare beyond 6 months. Additionally, pregnancy rates
pair would experience early improvement (96% vs. 76.8%). Perhaps were unaffected by the time to semen parameter improvement, and
testicular impairment is more profound in the setting of bilateral higher among individuals who experienced significant improvement
varicoceles, taking longer for the testicles to respond. For example, in TPMS. This information may allow clinicians to better counsel cou-
in a recent study, Agarwal et al found that while there was no dif- ples following varix ligation.
ference in semen parameters between men with unilateral and bi-
lateral varicoceles, reactive oxygen species and DNA fragmentation DATA AVA I L A B I L I T Y S TAT E M E N T
levels were higher in the bilateral patients (Agarwal et al., 2015). All data underlying the results are available as part of the article and
While this hypothesis is intriguing, further studies are necessary to no additional source data are required.
confirm.
It is also important to note that a large proportion of our study ORCID
cohort underwent bilateral varix ligation. More specifically, 80.6% Graham Luke Machen https://orcid.org/0000-0002-0543-3900
of patients included in our analysis and 69.3% of all patients under-
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