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Citation: Marinaro, J.; Goldstein, M.
Microsurgical Management of Male
Infertility: Compelling Evidence That
Collaboration with Qualified Male
Reproductive Urologists Enhances
Assisted Reproductive Technology
(ART) Outcomes. J. Clin. Med. 2022,
11, 4593. https://doi.org/10.3390/
jcm11154593
Academic Editor: Luca Boeri
Received: 6 July 2022
Accepted: 4 August 2022
Published: 6 August 2022
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4.0/).
Journal of
Clinical Medicine
Review
Microsurgical Management of Male Infertility: Compelling
Evidence That Collaboration with Qualified Male Reproductive
Urologists Enhances Assisted Reproductive
Technology (ART) Outcomes
Jessica Marinaro 1and Marc Goldstein 2, *
1Department of Urology, Weill Cornell Medicine, New York, NY 10065, USA
2Center for Male Reproductive Medicine and Microsurgery, Weill Cornell Medicine, 525 East 68th St.,
Starr Pavilion, 9th Floor (Starr 900), New York, NY 10065, USA
*Correspondence: mgoldst@med.cornell.edu
Abstract:
A male factor plays a significant role in a couple’s reproductive success. Today, advances
in reproductive technology, such as intracytoplasmic sperm injection (ICSI), have allowed it to
be possible for just a single sperm to fertilize an egg, thus, overcoming many of the traditional
barriers to male fertility, such as a low sperm count, impaired motility, and abnormal morphology.
Given these advances in reproductive technology, it has been questioned whether a reproductive
urologist is needed for the evaluation and treatment of infertile and subfertile men. In this review,
we aim to provide compelling evidence that collaboration between reproductive endocrinologists
and reproductive urologists is essential for optimizing a couple’s fertility outcomes, as well as for
improving the health of infertile men and providing cost-effective care.
Keywords: assisted reproductive technology; infertility; microsurgery; urology
1. Introduction
Infertility is defined as the inability to conceive after 12 months of regular, unprotected
intercourse [
1
]. It is estimated that approximately 15% of all couples are affected by
infertility [
2
]. A male factor is solely responsible in approximately 20% of couples, and
contributory in another 30–40% [
2
]. While a male factor plays a significant role in a couple’s
reproductive success, recent evidence suggests that many men with infertility are never
referred to a reproductive urologist (RU) for evaluation [3,4].
While the reasons for this are likely multifactorial and have not been fully elucidated,
one contributing factor may be a lack of referrals from reproductive endocrinologists (REs).
A recent study by Samplaski et al. demonstrated that reproductive endocrinologists serve
as the “gatekeepers” for male infertility referrals, with approximately 60% of the men
seen by reproductive urologists being referred by an RE or women’s fertility specialist [3].
Among these REs, there is significant variation in the rates of referrals to reproductive
urologists, ranging from 3.7% to 35.8% [4].
This variation in referrals from REs to RUs may be because assisted reproductive
technologies (ARTs) are able to overcome many of the traditional barriers to fertilization
associated with male infertility. Specifically, with the advent of intracytoplasmic sperm
injection (ICSI), only one sperm is required to fertilize an oocyte, thus, overcoming the
fertilization difficulties traditionally caused by low numbers of sperm, impaired motility,
and abnormal morphology [
5
]. With these new ART techniques and high ART success
rates, many men are never referred to a reproductive urologist for a complete evaluation.
In this article, we summarize the current literature available regarding the importance
of evaluating infertile men, as well as the various surgical treatments that reproductive
urologists can offer infertile couples. Our main aim and objective is to prove that a male
J. Clin. Med. 2022,11, 4593. https://doi.org/10.3390/jcm11154593 https://www.mdpi.com/journal/jcm
J. Clin. Med. 2022,11, 4593 2 of 22
evaluation is meaningful and important, not only for the couple’s reproductive success,
but also for the overall health of the male partner.
2. Why Evaluate the Male?
2.1. Optimizing Birth Outcomes Involves More Than Just Performing ICSI
ICSI was initially developed to overcome the most severe forms of male factor infer-
tility; however, in recent years, it has become the most common method of fertilization
used for ART [
6
]. While the percentage of diagnoses of infertility due to a male factor
has remained stable, ICSI use has steadily increased [
6
]. In the United States specifically,
the use of ICSI for all indications increased from 36.4% in 1996 to 76.2% in 2012, with the
largest relative increase seen among cycles without male factor infertility (15.4% to 66.9%,
p< 0.001).
Given the widespread use of ICSI and its invasive nature, researchers have questioned
whether this reproductive technique has adverse health consequences on offspring [
7
].
While several large meta-analyses have found an increased risk of congenital malforma-
tions among ART offspring compared to those conceived naturally [
8
–
11
], few studies
have compared the risk of malformations among ICSI offspring versus those conceived
with conventional
in vitro
fertilization (IVF). While there is limited research on this topic,
there is some evidence to suggest that ICSI may be more hazardous to offspring than
other reproductive techniques. For example, in one large observational study of over
300,000 births in Australia, only ICSI was associated with a higher risk of birth defects
after a multivariate adjustment (OR 1.57, 95% CI 1.30–1.90); conventional IVF was not
associated with any increased risk of birth defects after the same analysis (OR 1.07, 95%
CI 0.90–1.26) [
12
]. Similarly, in a multicenter European cohort study of over 1500 chil-
dren, Bonduelle et al. found that only those conceived through ICSI had a higher rate
of major congenital malformations (OR 2.77, 95% CI 1.41–5.46); those conceived through
conventional IVF did not have a higher rate of major malformations (OR 1.80, 95% CI
0.85–3.81) [
13
]. After adjusting for various sociodemographic and environmental factors,
this higher risk of major malformations persisted for the ICSI children (OR 2.54, 95% CI
1.13–5.71) [13].
There is debate about whether this increase in birth defects is secondary to the ICSI
technique itself or the underlying male infertility factors that necessitate its use. However,
in the previously mentioned study by Bonduelle et al., oligospermia (defined as a sperm
concentration < 20 million/mL) did not influence the presence of major or minor congen-
ital malformations, lending support to the hypothesis that the ICSI technique itself may
contribute to these birth defects [
13
]. Similarly, other studies of children conceived using
ICSI performed for nonmale factor infertility indications found that ICSI in this setting was
associated with a lower birthweight [
14
] and increased risk of autism (adjusted HR 1.57,
95% CI 1.18–2.09) [
15
] versus conventional IVF, again suggesting that the ICSI technique
itself may play a role in the overall health of offspring.
Ultimately, the American Society for Reproductive Medicine (ASRM) concluded in a
recent practice committee opinion that while ICSI has been associated with a small increased
risk of adverse outcomes in offspring, this has generally been attributed to underlying male
factor infertility [
16
]. However, they conceded that it is “unknown how these risks may be
related to ICSI for non-male factor infertility patients” [
16
] and, additionally, high-quality
research is needed to fully understand the role that ICSI itself may play in the overall health
of offspring.
Until these risks are fully elucidated, there is an opportunity for reproductive urolo-
gists to collaborate with female infertility providers to optimize male fertility to achieve the
best birth outcomes for the couple. Specifically, by treating male factor infertility, it may be
possible to use less invasive reproductive techniques, which may lead to the delivery of
healthier children.
J. Clin. Med. 2022,11, 4593 3 of 22
2.2. Male Fertility Is Increasingly Associated with Overall Health
In recent decades, it has been increasingly recognized that male reproductive health
and overall health are related [
17
]. Specifically, many of the conditions known to cause
male infertility have also been associated with broader health consequences. One example
is Klinefelter syndrome (KS, 47XXY). KS is the most common chromosomal abnormality as-
sociated with male infertility, affecting approximately 1 in every 650 newborn males [
18
,
19
].
In addition to the progressive testicular failure and hypergonadotropic hypogonadism
associated with infertility, these men have been found to have significantly higher rates of
comorbidities and an elevated mortality risk [
19
]. Specifically, KS men have been found
to have higher rates of metabolic syndrome, cardiovascular morbidity, venous throm-
boembolism, breast cancer, extragonadal germ cell tumors, and reduced bone mineral
density [
19
]. Referring men with infertility to a reproductive urologist creates the oppor-
tunity to both diagnose these genetic conditions and counsel these men on the associated
health consequences. By identifying these men and referring them to a reproductive
urologist, female fertility experts can directly contribute to better disease surveillance,
preventative care, and clinical outcomes for these men.
Even in those men without a known cause of infertility, studies have demonstrated
an association between reproductive health and overall health. In one European study
of 344 men with male factor infertility and 293 age-matched controls, infertile men had a
significantly higher rate of comorbidities [
20
]. After adjusting for age, BMI, and educational
status, infertile men still had significantly lower general health versus fertile controls [
20
].
This finding has been replicated in other larger studies, including a 2015 study by Eisenberg
et al., which included over 9300 men evaluated for infertility at an academic center in the
United States [
21
]. They found that the Charlson comorbidity index (CCI) was inversely
related to a variety of semen parameters, including semen volume, sperm concentration,
total sperm count, and sperm motility (p
trend
< 0.01 for all parameters) [
21
]. An Italian
study also investigated this relationship between semen quality and the CCI, and similarly
found that the CCI was inversely associated with sperm concentration (p= 0.028) and
sperm motility (p= 0.06) [
22
]. Additionally, this group found that increasing the CCI was
associated with alterations in reproductive hormones, including higher FSH (p= 0.001) and
lower total testosterone (p= 0.04) [22].
In addition to having lower general health, men with infertility have also been found
to be at higher risk for developing certain malignancies and chronic medical conditions.
The strongest and most studied relationship between male infertility and malignancy
is the correlation between infertility and testis cancer [
23
]. Several large, retrospective
cohort studies performed in the United States have estimated the rate of testicular cancer
to be approximately 2 to 3 times higher for men with infertility versus controls, though
in smaller series, the risk of testis cancer has been reported to be up to 20 times greater
for infertile men with abnormal semen parameters versus controls [
24
–
26
]. There has
also been evidence linking male infertility to prostate cancer [
25
,
27
], though this has been
challenged in other series [
28
,
29
]. Finally, analyses of a large, national insurance database
have demonstrated that men with infertility are at higher risk for developing diabetes,
ischemic heart disease, and certain autoimmune disorders (including rheumatoid arthritis,
multiple sclerosis, psoriasis, thyroiditis, and Grave’s disease) versus controls [30,31].
Given these higher rates of comorbidities, malignancies, and chronic medical condi-
tions, it is no surprise that male infertility has also been associated with increased mortality.
In a study of nearly 12,000 men evaluated at two infertility centers in the United States,
men with
≥
2 abnormal semen parameters were found to have an increased risk of death
in both unadjusted (HR 2.96, 95% CI 1.67–5.25) and adjusted (HR 2.29, 95% CI 1.12–4.65)
analyses [32]. This risk of mortality seems particularly notable for men with azoospermia.
In a 2019 Danish study comparing men who underwent ART versus age-matched controls
who conceived naturally, men with azoospermia had an increased risk of death compared
to both men who conceived naturally (HR 3.32, 95% CI 2.02–5.40) and the rest of the group
that used ART (HR 2.30, 95% CI 1.54–3.41) [33].
J. Clin. Med. 2022,11, 4593 4 of 22
While we do not yet know the precise etiology of these associations between infertility,
chronic health conditions, and mortality, referral to a reproductive urologist presents
an opportunity to identify these pathologies and comorbidities. Ultimately, this initial
evaluation by a RU may be essential for optimizing the medical management and overall
health of these patients.
2.3. Reproductive Urologists Have the Surgical Skills Necessary to Treat Many Causes of Male
Infertility and Subfertility
In addition to identifying the pathologies and comorbidities associated with male
infertility, a reproductive urologist also possesses the unique surgical skills required to treat
male infertility. These skills include various methods for overcoming ejaculatory dysfunc-
tion, surgical sperm retrieval techniques, microsurgical varicocelectomy, and microsurgical
vasal reconstruction procedures. By collaborating with reproductive endocrinologists,
reproductive urologists can use this unique surgical skillset to help couples achieve their
family-building goals.
3. Surgical Management of Male Infertility
With the recent advances in ART, only a small number of sperm are required for
successful oocyte fertilization. Despite these advances, reproductive urologists remain
essential for treating couples in which the male partner does not have sperm readily
available in their ejaculate, either due to azoospermia or anejaculation. Reproductive
urologists can also optimize fertility in nonazoospermic men, thus, allowing couples to
use less invasive ART techniques and/or enhancing ART outcomes. Regardless of the
underlying pathology, collaboration between male and female reproductive experts is
essential for identifying infertile and subfertile men that may benefit from treatment, as
well as ensuring that the correct treatment strategy is chosen based on the couple’s unique
goals and priorities.
3.1. Treatment of Anejaculation and Ejaculatory Duct Obstruction
3.1.1. Electroejaculation
Electroejaculation (EEJ) is a technique that can be used to treat men with anejaculation
secondary to a variety of factors, including spinal cord injuries (SCIs), diabetes mellitus,
retroperitoneal lymph node dissection, radical pelvic surgery, multiple sclerosis, and
psychogenic anejaculation [
34
,
35
]. All of these disease processes involve a neurological
disruption of the ejaculatory reflex, which arises from the spinal levels T10 to L2 and,
subsequently, travels through the sympathetic chain ganglia, hypogastric plexus, and
pelvis to the prostate, vas deferens, and seminal vesicles [
36
]. With this technique, an
electrical current is used to induce a neurological response, leading to muscular contraction
and the activation of the ejaculatory reflex [37,38].
While a full description of the EEJ technique is beyond the scope of this review, in
brief, the procedure begins by catheterizing and fully emptying the bladder [
39
]. Since
retrograde ejaculation is common, a buffering medium and/or human tubal fluid may be
instilled into the bladder to preserve any sperm that are deposited there [
34
,
39
]. A digital
rectal exam and anoscopy are performed to ensure that there are no pre-existing rectal
lesions or abnormalities. While men with a complete SCI may undergo the procedure
without anesthesia, those with an incomplete SCI or other pathologies typically require
general anesthesia (without the use of muscle relaxants) [
40
]. Blood pressure monitoring
is performed throughout the procedure, and those men at risk for autonomic dysreflexia
are pretreated with nifedipine [
34
]. An electrical probe is then inserted into the rectum
and positioned with the electrodes in contact with the anterior rectal wall near the prostate
and seminal vesicles [
34
]. Electrical stimulation is administered in progressively increasing
increments until ejaculation occurs [
34
]. The urethra is milked to capture as much antegrade
semen as possible, and the bladder is catheterized to capture any retrograde ejaculate. An
J. Clin. Med. 2022,11, 4593 5 of 22
anoscopy is repeated at the end of the case to ensure that the rectal mucosa has not been
injured [34].
By using this technique, sperm can be retrieved up to 90% of the time [
41
]. This sperm
can then be used for intrauterine insemination (IUI) or
in vitro
fertilization (IVF), with
pregnancy rates similar to those of other healthy couples using these ART techniques [
34
].
In a recent series of over 950 EEJ procedures, the pregnancy rate was 50.0% and live birth
rate was 43.8% for couples using sperm obtained with EEJ in combination with
in vitro
fertilization or an intracytoplasmic sperm injection [
40
]. No complications due to EEJ were
reported [40].
3.1.2. Transurethral Resection of Ejaculatory Ducts (TURED)
Ejaculatory duct obstruction (EDO) is a type of obstructive azoospermia that is present
in 1% to 5% of infertile men [
42
]. For men with EDO, spermatogenesis is typically pre-
served [
42
]. Given that sperm production is normal, the current American Urological
Association (AUA) and American Society of Reproductive Medicine (ASRM) guidelines
state that either a transurethral resection of ejaculatory ducts (TURED) or surgical sperm
extraction may be offered as a treatment strategy [
43
]. Unlike a surgical sperm retrieval
procedure, however, a TURED offers couples the chance to conceive naturally, making
it an attractive option for those who prefer to avoid invasive and potentially costly ART
treatments.
In brief, a TURED procedure is typically performed under general or regional anesthe-
sia, with a surgical setup similar to that used for a transurethral resection of the prostate
(TURP) [
44
]. Specifically, a resectoscope is inserted into the urethra and advanced to the
level of the ejaculatory ducts, near the verumontanum [
42
]. Resection is performed near
the verumontanum with an electrocautery loop on a pure cutting current setting to mini-
mize any additional cautery of the ejaculatory ducts, which may result in restenosis [
44
].
Resection is typically guided with synchronous transrectal ultrasound (TRUS) to confirm
the location of the obstruction and avoid iatrogenic rectal injury [
44
,
45
]. The resolution of
an obstruction is confirmed intraoperatively by the drainage of cloudy, milky fluid from
the opened ducts, or by the drainage of methylene blue if transrectal chromotubation of the
seminal vesicles was performed [
45
,
46
]. While TURED is generally a well-tolerated proce-
dure, complications have been noted in 10% to 20% of patients [
47
]. These complications
primarily include urinary tract infections, epididymitis, hematuria, hematospermia, and
watery ejaculate (due to the reflux of urine through widely patent ejaculatory ducts into
the seminal vesicles and/or unroofed cysts) [
47
,
48
]. There is also a chance of incontinence
or rectal perforation given the nature of the procedure, though the risk is low [47].
After a TURED procedure, approximately 60% to 75% of men with EDO demonstrate
improvements in semen parameters [
46
,
48
,
49
]. Specifically, the mean ejaculate volume,
mean sperm concentration, and mean percent motility have all been found to significantly
increase after TURED (p< 0.001) [49]. These improvements are both statistically and clini-
cally significant. In one study by Kadioglu et al., nearly three-quarters of the cohort (74%)
who underwent TURED demonstrated a >50% increase in postoperative sperm concen-
tration or motility [
49
]. Additionally, 40% of patients who were previously candidates
for IVF or ICSI before surgery (defined as a total motile sperm count
≤
5 million) were
able to achieve a sufficient postoperative total motile sperm count (>5 million) to allow for
referral for IUI [
49
]. In addition to permitting couples to use less invasive ART techniques,
spontaneous pregnancy rates after TURED have been found to range between 13% and
30% [46–49].
Overall, TURED presents another option for some infertile couples affected by EDO
to conceive, either naturally or with less invasive ART procedures. By collaborating
with reproductive endocrinologists, reproductive urologists are able to play a key role in
identifying, diagnosing, and treating these male partners with EDO. Regardless of whether
the couple decides to pursue TURED or a surgical sperm retrieval, involving a reproductive
J. Clin. Med. 2022,11, 4593 6 of 22
urologist in the treatment discussion would ensure that the couple is well-informed about
their options and able to determine an educated decision.
3.2. Sperm Retrieval Techniques
For those men with normal ejaculatory function and azoospermia, surgical sperm
retrieval combined with ICSI offers an opportunity to conceive a biological child. With the
advent of ICSI, surgically retrieved sperm from the testis and/or epididymis are able to
effectively fertilize oocytes [
5
]. While the techniques and success rates for treating these
men with azoospermia vary significantly depending on the etiology (either obstructive or
nonobstructive), a reproductive urologist is a critical part of the reproductive team required
to help these couples achieve a pregnancy.
3.2.1. Sperm Retrieval Techniques for Obstructive Azoospermia (OA)
For men with obstructive azoospermia (OA), spermatogenesis within the testis is
typically normal. Consequently, sperm retrieval with IVF/ICSI offers a high probability of
reproductive success, with sperm retrieval rates reported to be as high as 100% and clinical
pregnancy rates of up to 65% [50,51].
For men with an OA secondary congenital bilateral absence of the vas deferens
(CBAVD) or other causes not amenable to microsurgical reconstruction, a variety of percu-
taneous, open, and microsurgical techniques for retrieving sperm from the testis and/or
epididymis are available [
45
]. These techniques include open testicular biopsy (TESE), per-
cutaneous testicular sperm aspiration (TESA), percutaneous testicular biopsy (PercBiopsy),
percutaneous epididymal sperm aspiration (PESA), and microsurgical epididymal sperm
aspiration (MESA) [
45
]. While the advantages and disadvantages of each sperm retrieval
technique are beyond the scope of this review, it is important to note that MESA has been as-
sociated with the best clinical pregnancy rates and large numbers of sperm being retrieved,
though microsurgical expertise is required [
45
]. Regardless of the technique utilized, re-
productive urologists play a key role in helping these men with OA conceive biological
children—something that would not be possible without the advent of ICSI and continued
collaboration between reproductive endocrinologists and reproductive urologists.
3.2.2. Sperm Retrieval Techniques for Nonobstructive Azoospermia (NOA)
In contrast to men with OA, men with nonobstructive azoospermia (NOA) are more dif-
ficult to treat due to varying degrees of spermatogenic failure present within the testis [
52
].
For men with NOA undergoing a surgical sperm retrieval procedure, microdissection
testicular sperm extraction (microTESE) is the preferred technique [43].
This procedure involves carefully examining the seminiferous tubules of the testis
under an operating microscope at 20–25
×
magnification to find the focal areas of di-
lated tubules that are most likely to contain active spermatogenesis [
53
,
54
]. By using this
technique to identify and selectively remove only dilated tubules, sperm retrieval rates
have increased from 16.7–45% (as initially reported with conventional TESE) to as high
as 70.8% [
55
–
57
]. MicroTESE has also been associated with greater numbers of sperm
retrieved (160,000 vs. 64,000) and 70-fold less testicular tissue being removed (9.4 mg
versus 720 mg) compared to conventional TESE [
53
,
55
]. In addition to the benefits to the
patient associated with removing only a minimal amount of testicular tissue, this technique
also eases the burden on embryology lab personnel. By selecting only the tubules that are
most likely to contain sperm, this obviates the need for an extended search through a large
volume of tissue and allows laboratory personnel to focus their time and efforts on only
the most promising tubules [54].
In addition to higher sperm retrieval rates, microTESE results in lower complication
rates, with fewer hematomas, less testicular fibrosis, and less frequent testicular atrophy
than TESE [
53
]. If sperm are retrieved during microTESE and used for ICSI, the aver-
age pooled clinical pregnancy rate is 39% [
56
]; however, clinical pregnancy rates using
microTESE sperm have been reported to be as high as 72.4% in some series [57].
J. Clin. Med. 2022,11, 4593 7 of 22
While available data from our center and others strongly support the use of mi-
croTESE for the treatment of men with NOA, it is important to consider that this is a
technically challenging, microsurgical procedure that requires a skilled and experienced
surgeon for optimal outcomes [
58
]. In fact, studies have shown that sperm retrieval rates
(SRR) are strongly related to the surgeon’s case volume, with significant improvements in
SRR seen after 50 cases and more subtle, continued improvements seen after more than
500 cases [59,60]
. This steep learning curve may perhaps be one of the reasons why a recent
meta-analysis of 117 studies did not demonstrate any difference in sperm retrieval rates
between microTESE and conventional TESE [
61
]. Ultimately, sufficiently powered and well-
designed randomized controlled trials are needed to confirm the superiority of microTESE
over conventional TESE. However, given our experience at our center, we believe that by
collaborating with reproductive urologists who have advanced microsurgical training and
experience performing microTESE procedures, reproductive endocrinologists are able to
provide NOA couples with the best chances of conceiving a biological child.
3.2.3. Sperm Retrieval as a Method for Reducing DNA Fragmentation and Enhancing
ART Outcomes
While surgical sperm retrieval is an effective method for helping couples with azoosper-
mia conceive, there is also evidence that using testicular and/or epididymal sperm for
ICSI may enhance outcomes for couples in which the male partner has an abnormal ejac-
ulated sperm DNA fragmentation (SDF) [
62
–
67
]. An elevated SDF has been associated
with many adverse reproductive outcomes, including lower natural pregnancy rates, lower
ART pregnancy rates (including IUI, IVF, and ICSI), abnormal embryo development, and
a greater likelihood of recurrent pregnancy loss [
68
–
70
]. Though many conditions have
been associated with an elevated SDF—including environmental factors (i.e., cigarette
smoking, radiation, chemotherapy, heat exposure, and medications), pathologic conditions
(i.e., varicocele, malignancy, infections, obesity, chronic illness), and even iatrogenic causes
(i.e., sperm cryopreservation)—these conditions may lead to DNA damage through sim-
ilar molecular mechanisms [
70
,
71
]. Specifically, these conditions are thought to promote
DNA breaks through sperm chromatin packaging defects, apoptosis, and/or oxidative
stress [
70
,
71
]. While the oocyte may be able to repair some types of sperm DNA damage,
this capacity is limited and may vary depending on the individual oocyte [
72
]. If the dam-
age is not adequately repaired, the embryo cannot develop normally, leading to adverse
reproductive outcomes [70,72].
The management of men with elevated SDF presents another opportunity for collabo-
ration between reproductive endocrinologists and reproductive urologists. By identifying
couples that have suffered recurrent pregnancy loss or other unexplained infertility, re-
productive endocrinologists may be able to identify male partners that are candidates
for SDF testing. If abnormal, these men can then be referred to a reproductive urologist
for a complete evaluation, including an assessment of risk factors for abnormal SDF (i.e.,
varicocele, genital tract infections, cigarette smoking, etc.) [68].
For some of these men with elevated SDF, counseling and lifestyle modifications may
be beneficial [
73
]. While AUA/ASRM guidelines concede that there is limited data on the
specific lifestyle factors that affect male fertility [
17
], some studies have demonstrated a
positive effect of antioxidant therapy on SDF [
74
–
80
], though this has not been reproduced
in all studies [
81
,
82
]. Similarly, a short ejaculatory abstinence interval has also been shown
to have a positive impact on SDF [
83
,
84
]. Finally, given that cigarette smoking [
85
–
88
], air
pollution [
89
–
91
], pesticides [
92
,
93
], cancer treatments (including chemotherapy and/or
radiation) [
94
,
95
], and occupational radiation exposure [
96
] have all been associated with
elevated SDF, it is reasonable to assume that the avoidance of these factors would have a
positive impact on SDF, though high-quality data are lacking [73].
Certain men with elevated SDF may also benefit from surgical treatments, such as
varicocelectomy or surgical sperm retrieval [
73
]. While varicocelectomy is discussed in
greater detail in the next section, in brief, it has been established that varicocele repair
J. Clin. Med. 2022,11, 4593 8 of 22
reduces oxidative stress, thus, reducing SDF and contributing to enhanced reproductive
outcomes [
97
]. Similarly, it has been established that sperm retrieved from the testis and/or
epididymis has lower levels of SDF [
64
,
65
,
98
]. This is likely because sperm are exposed
to oxidative stress during their transit through the male genital tract [
99
]; by retrieving
sperm directly from the testis and/or epididymis, this oxidative stress is avoided, leading
to lower SDF levels and better reproductive outcomes using this sperm versus ejaculated
sperm [62,68].
Given the invasive nature of a sperm retrieval procedure and current low level of
evidence (i.e., no randomized trials) to support using testicular and/or epididymal sperm
from nonazoospermic men with elevated SDF, the routine application of this practice
remains controversial. The current European Association of Urology (EAU) guidelines
recommend approaching this practice with caution, given the risks to the patient associated
with invasive procedures [
100
]. These guidelines clearly state that this technique should
only be used when other possible causes of SDF have been excluded, and patients should
be counseled on the low-quality evidence available to support this approach [
100
]. Sim-
ilarly, AUA/ASRM guidelines note the controversial nature of this practice and limited
evidence available to support it; however, they acknowledge that “in a patient with high
sperm DNA fragmentation, a clinician may consider using surgically obtained sperm in
addition to ICSI” [
17
]. The most recent European Academy of Andrology (EAA) guidelines
may provide the most concrete guidance to clinicians on this topic. The EAA formally
recommends that in cases of
≥
2 ICSI failures using ejaculated sperm with uncorrectable,
elevated SDF, couples should be offered the option of using testicular sperm for ICSI, along
with counseling that this approach is based on low-quality evidence [101].
Given the controversial nature of this practice, collaboration between reproductive
endocrinologists and reproductive urologists likely presents the best opportunity to identify
the couples who would benefit from this procedure. Without clear guidelines or high-level
evidence, combining both male and female reproductive expertise is the best way to ensure
that couples are receiving the most optimal, evidence-based care for their unique infertility
challenges.
3.3. Varicocelectomy
Varicoceles are considered to be the most common correctable cause of male infertil-
ity [
102
]. Defined as an abnormal dilation of the pampiniform plexus of the spermatic cord,
varicoceles are present in approximately 15% of adult men in the general population, but
up to 40% of men with primary infertility and up to 80% of men with secondary infertil-
ity [
102
,
103
]. A growing body of evidence has identified that varicoceles are associated
with negative effects on semen quality, sperm function, reproductive hormone levels, and
pregnancy outcomes [
102
]. While the precise mechanisms by which varicoceles negatively
impact male fertility are likely multifactorial and remain under investigation, it is strongly
suspected that increased oxidative stress plays a key role [102].
This correlation between varicoceles and oxidative stress is well-established. In
2006, a meta-analysis comparing 118 infertile men with 76 healthy controls found sig-
nificantly higher reactive oxygen species (ROS) levels (weighted mean difference 0.73;
95%
CI 0.40–1.06;
p< 0.0001) and a lower total antioxidant capacity (TAC) (p< 0.00001)
in the varicocele group [
104
]. These elevated ROS levels are likely secondary to multiple
factors, including high pressure on venous walls [
105
], heat stress from scrotal hyperther-
mia [106,107], hypoxia [106,107], and/or the reflux of renal and adrenal metabolites [102].
Regardless of the etiology, varicoceles have been shown to negatively impact both
Sertoli and Leydig cells [
108
]. On a microscopic level, the seminiferous tubules of men with
varicoceles have a thick germinal epithelium, increased apoptosis, and Sertoli cells with
extensive cytoplasmic vacuolization [
109
]. This Sertoli cell dysfunction is observed clini-
cally as a decreased responsiveness to the follicle-stimulating hormone (FSH), decreased
androgen-binding protein (ABP), and decreased transferrin levels, all of which contribute
to a disruption in spermatogenesis [
110
]. Similarly, men with varicocele(s) have fewer
J. Clin. Med. 2022,11, 4593 9 of 22
Leydig cells, and those that are present demonstrate increased cytoplasmic vacuolization
and atrophy [
111
]. Clinically, this is likely responsible for the lower serum testosterone
levels observed among men with varicoceles in some studies [112–114].
In addition to this negative effect on testicular cell function and spermatogenesis, the
hostile biochemical environment created by varicocele(s) may also directly damage sperm.
This primary testicular damage may have multiple effects on sperm structure and function,
including oocyte-activating factors (such as phospholipase C-zeta), sperm centrosomal
components, and sperm DNA integrity. Previous studies have suggested that alterations
in these sperm structural and functional components may adversely affect the paternal
contribution to final fertilization events and early postfertilization events (i.e., embryonic
implantation and development) [
115
]. While a full description of these postfertilization
effects is beyond the scope of this review, there is early evidence to suggest that the primary
testicular damage caused by varicoceles may inhibit such embryonic development.
For example, phospholipase C zeta (PLC-z) is a sperm-specific protein that is respon-
sible for oocyte activation after fertilization [
116
]. After gamete fusion, PLC-z is released
into the ooplasm, where it interacts with the oocyte factor(s) to release intracellular calcium
ions (Ca
2+
) [
117
]. These ions regulate a series of molecular events (referred to as ‘oocyte
activation’) which are required to initiate embryo development [
117
]. One study published
in 2016 compared 35 men with infertility and varicocele(s) to 20 fertile controls without
varicoceles. The authors found that the mean relative expression of PLC-z was significantly
lower in men with varicoceles at both the transcriptional and translational levels [
118
].
While these authors did not provide any additional information on the fertility outcomes
of these patients, it has previously been shown that the reduced expression of and/or
mutations in PLC-z are associated with low or failed fertilization in infertile men following
ICSI [
119
,
120
]; thus, it follows that a decrease in PLC-z may be related to the poor IVF/ICSI
outcomes seen among men with varicoceles.
Additionally, primary testicular damage to sperm may impact the sperm centrosome,
which is required for the nucleation of microtubules and formation of the mitotic spin-
dle [
121
]. In one study by Hinduja et al., lower centrosome protein expression was found
in men with oligoasthenozoospermia compared to normozoospermic men [
121
]. While
these authors did not assess for varicocele, given that varicoceles are known to impair
semen parameters, it is possible that such primary testicular damage may affect the sperm
centrosome and, subsequently, impair embryo development.
Finally, varicoceles have been found to negatively impact sperm DNA integrity. In
one meta-analysis by Wang et al., 240 men with clinical varicoceles had significantly
higher levels of sperm DNA damage compared to 176 healthy, fertile controls (mean
difference 9.84%; 95% CI 9.19–10.49; p< 0.00001) [
122
]. While the significance of sperm DNA
fragmentation (SDF) is still debated, prior studies have found elevated SDF to be associated
with lower pregnancy rates, abnormal embryo development, and a greater likelihood
of recurrent pregnancy loss [
68
–
70
]. Fortunately, varicocele repair has been associated
with significant improvement in sperm DNA integrity. A meta-analysis published in 2021
analyzed 19 studies and found a significantly lower sperm DNA fragmentation (weighted
mean difference
−
7.23%; 95% CI
−
8.86 to
−
5.59; I
2
= 91%) among men with clinical
varicoceles after surgical repair [123].
Ultimately, given the convincing clinical evidence that varicoceles are detrimental
to male fertility, recent AUA/ASRM guidelines recommend treating varicoceles in men
attempting to conceive who have palpable varicocele(s), infertility, and abnormal semen
parameters [43].
3.3.1. Surgical Technique
While a full description of the surgical technique is beyond the scope of this review, it
is important to note that a microsurgical approach is considered to be the gold standard,
since it has been associated with the highest pregnancy rates, greatest improvements in
semen parameters, lowest recurrence rates, and lowest complication rates (versus other
J. Clin. Med. 2022,11, 4593 10 of 22
nonmicrosurgical techniques) [
124
,
125
]. This success is likely due to the enhanced visu-
alization afforded by the operating microscope. By using an operating microscope, the
surgeon can see the spermatic cord at up to 25
×
magnification, which allows for more
precise movements, easier identification, the preservation of the testicular arteries and
lymphatics, and avoidance of any iatrogenic injuries [
125
]. Given that this technique re-
quires microsurgical training and expertise, it is important that female infertility specialists
collaborate with reproductive urologists to not only identify which patients may benefit
the most from this procedure, but also to ensure that they are treated by a provider that is
comfortable with a microsurgical technique.
3.3.2. Upgrading Fertility
By treating clinical varicoceles in infertile men, semen parameters may improve signif-
icantly enough to allow couples to utilize less invasive forms of ART [
103
] (Figure 1). This
concept of “upgrading” semen quality has been well-described by Samplaski et al. [
103
].
In this study, the authors evaluated the total motile sperm count (TMSC) of 373 men
with varicoceles before and after repair [
103
]. Overall, TMSC significantly increased from
18.22 ±38.32 million
to 46.72
±
210.92 million (p= 0.007). The authors then defined a
TMSC > 9 million as being suitable for natural pregnancy (NP), TMSC 5 million to 9 million
as suitable for IUI, and TMSC < 5 million as suitable for IVF. Using this criteria, 58.8% of
men initially considered “IVF-only” candidates were upgraded to IUI or NP candidates
after varicocelectomy, and 64.9% of men initially considered IUI candidates were upgraded
to NP candidates after varicocelectomy [
103
]. While the authors acknowledge that these
TMSC cutoffs are not perfect predictors of conception success, these findings emphasize
that varicocele repair may provide couples with the opportunity to use less invasive forms
of ART.
J. Clin. Med. 2022, 11, 4593 11 of 23
Figure 1. Most couples prefer to conceive naturally. Any treatments that can “upgrade” the fertil-
ity status of the couple are beneficial.
3.3.3. Enhancing IVF Outcomes
Even in those couples that still require IVF/ICSI, varicocelectomy may improve re-
productive outcomes. In one recent systematic review and meta-analysis of nonazoosper-
mic infertile men with clinical varicoceles, there was a significant improvement in clinical
pregnancy rates (OR = 1.59, 95% CI: 1.19–2.2, I2 = 25%) and live birth rates (OR = 2.17, 95%
CI: 1.55–3.06, I2 = 0%) among men who underwent varicocelectomy prior to ICSI com-
pared to men who proceeded directly to ICSI [127]. Given these enhanced IVF outcomes,
varicocelectomy prior to IVF has also been found to be a more cost-effective treatment
strategy than proceeding directly to IVF [128]. While the mechanism(s) for this improve-
ment in IVF/ICSI outcomes remains under investigation, it is likely related to the reduc-
tion in oxidative stress in seminal plasma and decreased sperm DNA fragmentation asso-
ciated with varicocelectomy [122,129,130].
Additionally, there is some evidence that varicocelectomy may also be beneficial to
men with nonobstructive azoospermia (NOA). While current AUA/ASRM guidelines
acknowledge that there is no definitive evidence supporting varicocele repair prior to
ART in NOA men, a recent systematic review found an improvement in sperm retrieval
rates (SRRs) for men who underwent varicocelectomy prior to sperm retrieval (SRR 48.9%
in the treated cohort) versus those who did not (SRR 32.1% in the untreated cohort) [131].
These results are similar to those of a previous systematic review and meta-analysis con-
ducted by Esteves et al., who found a significant increase in SRRs for NOA men with a
clinical varicocele who underwent a repair versus those who did not (OR: 2.65, 95% CI
1.69–4.14, p < 0.001) [132]. While additional prospective, randomized controlled trials are
needed to further evaluate this practice, identifying these patients and referring them to a
reproductive urologist for management presents another opportunity for reproductive
urologists and reproductive endocrinologists to collaborate. Specifically, it is a chance for
a reproductive urologist to optimize the male partner’s fertility and enhance reproductive
outcomes: whether that is by increasing the odds that a NOA man may have sperm re-
trieved for ICSI, or by improving the quality of the ejaculated sperm that is used for
IVF/ICSI. In either case, a reproductive urologist is pivotal to the couple’s reproductive
success.
Figure 1.
Most couples prefer to conceive naturally. Any treatments that can “upgrade” the fertility
status of the couple are beneficial.
In addition to minimizing the burden to the female partner, using less invasive forms
of ART is associated with significant cost savings. Given the reported success rates and
cost estimates of both varicocelectomy and ICSI, the average cost per live delivery after
varicocelectomy is USD 26,268 (95% CI: USD 19,138–USD 44,656) compared to USD 89,091
J. Clin. Med. 2022,11, 4593 11 of 22
(95% CI: USD 78,720–USD 99,462) for ICSI [
126
]. For those couples who pay out-of-pocket
for fertility care, this is a significant difference that should be considered by providers.
Ultimately, varicocelectomy presents an opportunity for reproductive urologists and
reproductive endocrinologists to collaborate and maximize a couple’s fertility success. This
may be of particular importance for those couples who wish to avoid or cannot afford the
high costs associated with more invasive forms of ART.
3.3.3. Enhancing IVF Outcomes
Even in those couples that still require IVF/ICSI, varicocelectomy may improve repro-
ductive outcomes. In one recent systematic review and meta-analysis of nonazoospermic
infertile men with clinical varicoceles, there was a significant improvement in clinical
pregnancy rates (OR = 1.59, 95% CI: 1.19–2.2, I
2
= 25%) and live birth rates (OR = 2.17, 95%
CI: 1.55–3.06, I
2
= 0%) among men who underwent varicocelectomy prior to ICSI compared
to men who proceeded directly to ICSI [
127
]. Given these enhanced IVF outcomes, varicoc-
electomy prior to IVF has also been found to be a more cost-effective treatment strategy
than proceeding directly to IVF [
128
]. While the mechanism(s) for this improvement in
IVF/ICSI outcomes remains under investigation, it is likely related to the reduction in
oxidative stress in seminal plasma and decreased sperm DNA fragmentation associated
with varicocelectomy [122,129,130].
Additionally, there is some evidence that varicocelectomy may also be beneficial to
men with nonobstructive azoospermia (NOA). While current AUA/ASRM guidelines
acknowledge that there is no definitive evidence supporting varicocele repair prior to ART
in NOA men, a recent systematic review found an improvement in sperm retrieval rates
(SRRs) for men who underwent varicocelectomy prior to sperm retrieval (SRR 48.9% in the
treated cohort) versus those who did not (SRR 32.1% in the untreated cohort) [
131
]. These
results are similar to those of a previous systematic review and meta-analysis conducted
by Esteves et al., who found a significant increase in SRRs for NOA men with a clinical
varicocele who underwent a repair versus those who did not (OR: 2.65, 95% CI 1.69–4.14,
p< 0.001
) [
132
]. While additional prospective, randomized controlled trials are needed to
further evaluate this practice, identifying these patients and referring them to a reproductive
urologist for management presents another opportunity for reproductive urologists and
reproductive endocrinologists to collaborate. Specifically, it is a chance for a reproductive
urologist to optimize the male partner’s fertility and enhance reproductive outcomes:
whether that is by increasing the odds that a NOA man may have sperm retrieved for ICSI,
or by improving the quality of the ejaculated sperm that is used for IVF/ICSI. In either
case, a reproductive urologist is pivotal to the couple’s reproductive success.
3.3.4. Enhancing Testosterone
Finally, in addition to improving reproductive outcomes, treating varicoceles has
also been shown to improve testosterone levels. In one meta-analysis of nine studies
and 814 men with clinical varicoceles who underwent surgical repair, mean serum testos-
terone levels improved by 97.48 ng/dL (95% CI 43.73–151.22 ng/dL, p= 0.0004) after
treatment [
133
]. To further understand the efficacy of varicocelectomy in treating hypogo-
nadism, a more recent meta-analysis published in 2017 analyzed eight studies (712 men)
with subfertility who underwent surgical varicocelectomy [
134
]. The authors stratified
these patients by their preoperative serum testosterone levels, defining “hypogonadal” as
a preoperative total testosterone level of <300 ng/dL, and “eugonadal” as a preoperative
testosterone level of
≥
300 ng/dL. After evaluating all men, the authors found a modest
but statistically significant improvement in the mean postoperative total testosterone level
of 34.3 ng/dL (95% CI: 22.57–46.04 ng/dL, p< 0.0001, I
2
= 0.0%) [
134
]. On the subanalysis,
however, mean postoperative testosterone levels were significantly greater for hypogonadal
men (improved 123 ng/dL, 95% CI: 114.61–131.35 ng/dL, p< 0.0001, I
2
= 37%) compared
to eugonadal men and untreated controls [134].
J. Clin. Med. 2022,11, 4593 12 of 22
While the precise molecular mechanism(s) behind the negative impact of varicoceles
on testosterone production remains to be elucidated [
102
,
135
,
136
], current evidence strongly
suggests that varicocele is a risk factors for androgen deficiency [
136
]. Additionally, given
that subfertile men with hypogonadism are more likely to benefit from varicocelectomy,
we believe that this cohort should be counseled on and offered surgical repair [
134
,
136
].
Since it has long been established that adequate testosterone levels are important for a
variety of functions—including libido, erectile function, muscle mass, bone density, and
cardiovascular health [
137
–
139
]—this presents an important opportunity for female fertility
specialists to collaborate with reproductive urologists. By identifying men with subfertility,
female fertility specialists can help these men receive the appropriate evaluation, testing,
and, ultimately, surgical care that they need, which would have a long-lasting, positive
impact on their overall health.
3.4. Microsurgical Reconstruction
In addition to retrieving sperm for use in IVF/ICSI and helping couples enhance their
fertility through varicocele repairs, reproductive urologists also possess the unique technical
skills required to treat some patients with obstructive azoospermia through microsurgical
reconstruction techniques, including vasovasostomy (VV) and vasoepididymostomy (VE).
Vasovasostomy (VV) involves removing a site of obstruction within the vas deferens
and anastomosing the unobstructed abdominal and testicular ends together to restore
patency. It is appropriate for patients with vasal obstruction due to a prior vasectomy, iatro-
genic vasal injury (i.e., prior inguinal or scrotal surgery), infection, or
trauma [45,51]
. While
a full description of this technique is beyond the scope of this review and more completely
described elsewhere [
51
,
140
,
141
], it is important to emphasize that a vasovasostomy is only
indicated after an intraoperative vasogram and assessment of vasal fluid, confirming the
patency of both the abdominal and testicular ends of the vas deferens [
140
]. If an abdominal
obstruction is noted, there may be a need for additional, advanced surgical maneuvers
(such as an inguinal VV or crossed VV) depending on the clinical scenario and patency of
the contralateral vas deferens and epididymis [
142
]. Similarly, if an epididymal obstruction
is noted intraoperatively, the surgeon needs to proceed with a VE instead.
A vasoepididymostomy (VE) involves an anastomosis between the vas deferens and
an epididymal tubule. Given the size and fragility of the epididymal tubules, experts
consider a VE procedure to be considerably more challenging than a VV procedure [
140
].
As mentioned, this technique is appropriate for patients with an epididymal obstruction,
which may be due to longstanding vasal obstruction, trauma, or iatrogenic injury [
45
,
51
].
While a full description of the technique is beyond the scope of this review and more
completely described elsewhere [
140
,
143
,
144
], it is important to note that the same surgical
principles are required for either a successful VV or VE. Namely, both require a high-quality,
water-tight, tension-free anastomosis, with close mucosa-to-mucosa approximation and an
adequate blood supply [51,140].
While both VV and VE can be successful options for treating infertility in the hands
of an experienced microsurgeon, prior studies have consistently demonstrated that VV
has a higher success rate than VE. In recent meta-analyses, the pooled mean patency and
pregnancy rates for VV were reported to be 89.4% and 73.0% (respectively), versus only
64.1% and 31.1% for VE [
145
,
146
]. In certain series, however, patency rates have been
reported to be as high as 99.5% for VV [141] and 93% for VE [147].
Achieving these high patency and pregnancy rates requires extensive microsurgical
training and expertise. Specifically, hands-on experience is required to master the delicate
tissue handling, precise 10-0 suture placement, and intraoperative decision making required
for a successful reconstructive procedure [
140
]. It is unclear exactly how many microsurgical
cases a surgeon must perform to overcome this learning curve, though research suggests
that providers with a higher surgical volume (
≥
15 vasectomy reversal cases per year) have
better outcomes than those who operate less frequently (<6 cases per year) [148].
J. Clin. Med. 2022,11, 4593 13 of 22
For some surgeons, overcoming this learning curve may be a challenge due to their
limited exposure to microsurgical cases during residency training. In a recent survey of
the Accreditation Council of Graduate Medical Education (ACGME) urology residency
programs, 22.4% of programs did not have a fellowship-trained microsurgeon on the
faculty [
149
]. While this survey was unable to assess the microsurgical case volume of
these trainees, this finding suggests that approximately one in five United States urology
residents may not have exposure to microsurgical training during their residency.
For these residents in particular, microsurgical laboratory training may be essential to
compensate for a lack of clinical exposure. In one study by Nagler et al., VV patency rates
were 89% for those who practiced in a laboratory versus 53% for those who did not [
150
].
Another study from Canada similarly found that residents who participated in hands-on
VV laboratory training had higher patency rates than those who only received didactic
training (54% versus 0%, p= 0.01) [
151
]. Additionally, these authors found that residents
who underwent hands-on training retained these skills when tested again 4 months later.
Specifically, at this 4-month retention test, the patency rate was 69% for the hands-on group,
versus only 20% for the didactic-only group (p= 0.05) [151].
These findings emphasize the importance of ensuring that those men who desire a
microsurgical reconstructive procedure are referred to an appropriately trained provider.
As the number of male infertility fellowships continues to grow, it is likely that the field
continues to subspecialize and centers of excellence are likely to emerge [
140
]. This presents
an opportunity for female fertility specialists to identify male partners that desire or may
benefit from a reconstructive procedure and refer them to reproductive urologists with the
requisite microsurgical training to deliver optimal surgical outcomes. However, there is
often debate about the utility of such a reconstructive procedure in the IVF era. This debate
is commonly centered around couples in which the male partner has previously undergone
a vasectomy.
The Role of Vasectomy Reversal (VR) in the IVF Era
While it is considered to be a permanent sterilization procedure, approximately 6% of
men undergoing a vasectomy ultimately desire a reversal [
152
]. For these post-vasectomy
patients, both a vasectomy reversal (VR) and sperm retrieval with IVF/ICSI have been
found to have similar live birth rates; however, a vasectomy reversal has been shown to
be more cost-effective, with the cost per live delivery being less than half that of sperm
retrieval with IVF/ICSI [
153
]. Specifically, Lee et al. reported a cost per live delivery of
USD 20,903 for a vasectomy reversal, versus USD 54,797 for a percutaneous testicular
sperm extraction (TESE) with IVF/ICSI, and USD 56,861 from microsurgical epididymal
sperm aspiration (MESA) with IVF/ICSI [
153
]. Earlier studies have similarly demonstrated
the cost effectiveness of VR compared to sperm retrieval with IVF/ICSI [
154
,
155
]—even
among some couples with a female partner older than 37 years [156].
Despite this cost-effectiveness, it is important to consider all aspects of the couple prior
to recommending a vasal reconstruction procedure versus sperm retrieval with IVF/ICSI.
Specifically, female factor infertility, female partner age, obstructed interval, cost of care,
and insurance coverage should all be considered when determining which option is the
best for a particular couple [157].
For couples affected by female factor infertility, natural conception may be challenging
even if the male partner’s vasectomy reversal is successful. While a vasectomy reversal may
still be discussed as a potential option, the couple, reproductive urologist, and reproductive
endocrinologist should all participate in shared decision making to create a plan that best
aligns with the couple’s overall goals [
157
]. For those couples with such significant female
factor infertility that both partners would require reconstructive surgery, the choice to
proceed with IVF is clear; in other, less severe pathologies, the discussion may be more
nuanced [45].
Similarly, for those couples with an older female partner, the discussion about which
treatment strategy to pursue should involve both male and female reproductive experts. At
J. Clin. Med. 2022,11, 4593 14 of 22
this point, it is well-established that female age is an independent predictor of success after
a vasectomy reversal [
45
]. Specifically, postreversal pregnancy and live birth rates have
been found to decrease significantly after ages of 35 to 40 [
158
–
160
]. However, live birth
rates with IVF/ICSI have also been found to drop significantly with maternal age [
161
–
163
].
Given that female age has a negative impact on both natural conception and IVF/ICSI
outcomes, there is no definitive age at which one treatment modality must be pursued
over the other [
157
]. Additional testing (such as ovarian reverse testing) may be helpful in
selecting a treatment option when the female partner is at the critical age of 34 to 40 and on
the cusp of a precipitous decline in fertility [
164
]. Additionally, at the time of counseling,
it is important to consider not only the female partner’s current age, but the age that she
would be once the male has undergone the vasectomy reversal procedure and sperm has
returned to the ejaculate. On average, the time to pregnancy after a successful vasectomy
reversal is 12 months [
165
]; this may be considered too long for those women with a smaller
window of opportunity to conceive [
45
]. Clearly, this nuanced conversation is best had
in collaboration with both male and female fertility experts, who can guide the couple
towards the treatment strategy that is most likely to result in a successful outcome.
While an obstructive interval (OI) has historically been considered an important prog-
nostic factor in VR success [
165
], more recent studies have demonstrated excellent patency,
and at least comparable pregnancy rates can be achieved with prolonged (
>10–20 year
)
obstructive intervals [
157
,
166
–
168
]. However, a longer OI has been found to strongly
correlate with an increased likelihood of epididymal obstruction and the need for a VE
procedure rather than VV [
167
,
168
]. Given that VE has a lower likelihood of success than
VV, this should be discussed when patients are being counseled on different management
strategies.
Finally, the cost of care and insurance coverage should also be considered when
counseling a couple on their treatment options. While vasectomy reversal has traditionally
been more cost-effective than IVF/ICSI [
153
–
155
], this may not be the case for couples with
insurance coverage for IVF. While 19 states have passed laws that require insurers to either
cover or offer coverage for fertility diagnoses and treatment, the qualifications and extent of
coverage vary significantly [
169
]. Providers should consider the laws where they practice
and their patient’s insurance coverage options as part of their shared decision-making
discussion.
Ultimately, given the many complex male and female fertility factors that contribute
to a couple’s decision-making process, the discussion about whether to proceed with a VR
or sperm retrieval with IVF/ICSI is another opportunity for reproductive urologists and
reproductive endocrinologists to collaborate. By sharing their respective expertise, male
and female fertility specialists would be able to provide couples with more comprehensive
counseling and enhance their reproductive outcomes.
4. Conclusions
Reproductive medicine is a unique field that requires providers to consider the health,
goals, and finances of two different individuals to achieve a successful outcome. While
recent advances in reproductive technology (particularly ICSI) have allowed for it to be
possible to overcome many of the traditional barriers caused by male infertility, it is only
through collaboration between both male and female fertility specialists that couples can
achieve the optimal reproductive outcomes that are within their unique preferences and
possibilities (Table 1). Additionally, through collaboration, providers can provide cost-
effective care and have a longstanding positive impact on the health and well-being of
infertile men, who we know are at risk for certain comorbidities and chronic conditions.
J. Clin. Med. 2022,11, 4593 15 of 22
Table 1. Key points.
•Given that modern assisted reproductive technologies (ARTs) can overcome some of the
most severe forms of male factor infertility, many men are not referred to a reproductive
urologist for a full evaluation.
•Evaluating the male partner is crucial for optimizing an infertile man’s overall health and
providing couples with the least invasive and most cost-effective care.
•For couples affected by nonobstructive azoospermia (NOA), reproductive urologists are
essential for retrieving sperm through advanced microdissection testicular sperm extraction
(microTESE) techniques.
•
For couples affected by obstructive azoospermia (OA), reproductive urologists are required
to either retrieve sperm or perform a microsurgical vasal reconstruction procedure
(vasovasostomy or vasoepididymostomy), which may offer couples the chance to conceive
naturally or with less invasive ART techniques.
•
Reproductive urologists can also use their surgical skills to help nonazoospermic couples use
less invasive ART techniques and/or optimize ART outcomes through microsurgical
varicocelectomy.
•
Using less invasive ART techniques is both cost-effective and may result in improved health
outcomes for the offspring, though additional high-quality evidence is needed to fully
understand this potential risk.
•Through collaboration, male and female fertility specialists can combine their relative
expertise to help couples successfully navigate the complex, rapidly evolving world of
reproductive medicine and contribute to better reproductive outcomes.
As our appreciation for and understanding of the complexities of reproductive medicine
continue to grow, we are hopeful that male and female reproductive specialists can continue
to work together to innovate and treat those impacted by infertility. As we have seen,
collaboration is truly more powerful than competition. This is an axiom that we should
continue to support in our clinical and research efforts, as well as instill in our trainees.
Author Contributions:
Conceptualization, M.G.; writing—original draft preparation, J.M.;
writing—review and editing, J.M. and M.G.; supervision, M.G. All authors have read and agreed to
the published version of the manuscript.
Funding:
The author J.M. was supported in part by the Frederick J. and Theresa Dow Wallace Fund
of the New York Community Trust.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
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