1. Introduction
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.
2. Treatment of Anejaculation and Ejaculatory Duct Obstruction
2.1. 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
[1][2]. 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
[3]. With this technique, an electrical current is used to induce a neurological response, leading to muscular contraction and the activation of the ejaculatory reflex
[4][5].
While a full description of the EEJ technique is beyond the scope of this research, in brief, the procedure begins by catheterizing and fully emptying the bladder
[6]. 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
[1][6]. 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)
[7]. Blood pressure monitoring is performed throughout the procedure, and those men at risk for autonomic dysreflexia are pretreated with nifedipine
[1]. 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
[1]. Electrical stimulation is administered in progressively increasing increments until ejaculation occurs
[1]. The urethra is milked to capture as much antegrade semen as possible, and the bladder is catheterized to capture any retrograde ejaculate. An anoscopy is repeated at the end of the case to ensure that the rectal mucosa has not been injured
[1].
By using this technique, sperm can be retrieved up to 90% of the time
[8]. 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
[1]. 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
[7]. No complications due to EEJ were reported
[7].
2.2. 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
[9]. For men with EDO, spermatogenesis is typically preserved
[9]. 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
[10]. 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 anesthesia, with a surgical setup similar to that used for a transurethral resection of the prostate (TURP)
[11]. Specifically, a resectoscope is inserted into the urethra and advanced to the level of the ejaculatory ducts, near the verumontanum
[9]. Resection is performed near the verumontanum with an electrocautery loop on a pure cutting current setting to minimize any additional cautery of the ejaculatory ducts, which may result in restenosis
[11]. Resection is typically guided with synchronous transrectal ultrasound (TRUS) to confirm the location of the obstruction and avoid iatrogenic rectal injury
[11][12]. 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
[12][13]. While TURED is generally a well-tolerated procedure, complications have been noted in 10% to 20% of patients
[14]. 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)
[14][15]. There is also a chance of incontinence or rectal perforation given the nature of the procedure, though the risk is low
[14].
After a TURED procedure, approximately 60% to 75% of men with EDO demonstrate improvements in semen parameters
[13][15][16]. Specifically, the mean ejaculate volume, mean sperm concentration, and mean percent motility have all been found to significantly increase after TURED (
p < 0.001)
[16]. These improvements are both statistically and clinically 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 concentration or motility
[16]. 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
[16]. 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%
[13][14][15][16].
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 urologist in the treatment discussion would ensure that the couple is well-informed about their options and able to determine an educated decision.
3. 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
[17]. 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.
3.1. 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%
[18][19].
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 percutaneous, open, and microsurgical techniques for retrieving sperm from the testis and/or epididymis are available
[12]. These techniques include open testicular biopsy (TESE), percutaneous testicular sperm aspiration (TESA), percutaneous testicular biopsy (PercBiopsy), percutaneous epididymal sperm aspiration (PESA), and microsurgical epididymal sperm aspiration (MESA)
[12]. While the advantages and disadvantages of each sperm retrieval technique are beyond the scope of this research, it is important to note that MESA has been associated with the best clinical pregnancy rates and large numbers of sperm being retrieved, though microsurgical expertise is required
[12]. Regardless of the technique utilized, reproductive 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. Sperm Retrieval Techniques for Nonobstructive Azoospermia (NOA)
In contrast to men with OA, men with nonobstructive azoospermia (NOA) are more difficult to treat due to varying degrees of spermatogenic failure present within the testis
[20]. For men with NOA undergoing a surgical sperm retrieval procedure, microdissection testicular sperm extraction (microTESE) is the preferred technique
[10].
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 dilated tubules that are most likely to contain active spermatogenesis
[21][22]. 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%
[23][24][25]. 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
[21][23]. 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
[22].
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
[21]. If sperm are retrieved during microTESE and used for ICSI, the average pooled clinical pregnancy rate is 39%
[24]; however, clinical pregnancy rates using microTESE sperm have been reported to be as high as 72.4% in some series
[25].
While available data from the researchers' center and others strongly support the use of microTESE 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
[26]. 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
[27][28]. 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
[29]. Ultimately, sufficiently powered and well-designed randomized controlled trials are needed to confirm the superiority of microTESE over conventional TESE. However, given the experience at the researchers' center, the researchers 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.
3.3. 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 azoospermia 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 ejaculated sperm DNA fragmentation (SDF)
[30][31][32][33][34][35]. 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
[36][37][38]. 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 similar molecular mechanisms
[38][39]. Specifically, these conditions are thought to promote DNA breaks through sperm chromatin packaging defects, apoptosis, and/or oxidative stress
[38][39]. 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
[40]. If the damage is not adequately repaired, the embryo cannot develop normally, leading to adverse reproductive outcomes
[38][40].
The management of men with elevated SDF presents another opportunity for collaboration between reproductive endocrinologists and reproductive urologists. By identifying couples that have suffered recurrent pregnancy loss or other unexplained infertility, reproductive 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.)
[36].
For some of these men with elevated SDF, counseling and lifestyle modifications may be beneficial
[41]. While AUA/ASRM guidelines concede that there is limited data on the specific lifestyle factors that affect male fertility
[42], some studies have demonstrated a positive effect of antioxidant therapy on SDF
[43][44][45][46][47][48][49], though this has not been reproduced in all studies
[50][51]. Similarly, a short ejaculatory abstinence interval has also been shown to have a positive impact on SDF
[52][53]. Finally, given that cigarette smoking
[54][55][56][57], air pollution
[58][59][60], pesticides
[61][62], cancer treatments (including chemotherapy and/or radiation)
[63][64], and occupational radiation exposure
[65] 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
[41].
Certain men with elevated SDF may also benefit from surgical treatments, such as varicocelectomy or surgical sperm retrieval
[41]. While varicocelectomy is discussed in greater detail in the next section, in brief, it has been established that varicocele repair reduces oxidative stress, thus, reducing SDF and contributing to enhanced reproductive outcomes
[66]. Similarly, it has been established that sperm retrieved from the testis and/or epididymis has lower levels of SDF
[32][33][67]. This is likely because sperm are exposed to oxidative stress during their transit through the male genital tract
[68]; 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
[30][36].
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
[69]. 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
[69]. Similarly, 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”
[42]. 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
[70].
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.
4. Varicocelectomy
Varicoceles are considered to be the most common correctable cause of male infertility
[71]. 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 infertility
[71][72]. 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
[71]. 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
[71].
This correlation between varicoceles and oxidative stress is well-established. In 2006, a meta-analysis comparing 118 infertile men with 76 healthy controls found significantly 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
[73]. These elevated ROS levels are likely secondary to multiple factors, including high pressure on venous walls
[74], heat stress from scrotal hyperthermia
[75][76], hypoxia
[75][76], and/or the reflux of renal and adrenal metabolites
[71].
Regardless of the etiology, varicoceles have been shown to negatively impact both Sertoli and Leydig cells
[77]. 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
[78]. This Sertoli cell dysfunction is observed clinically 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
[79]. Similarly, men with varicocele(s) have fewer Leydig cells, and those that are present demonstrate increased cytoplasmic vacuolization and atrophy
[80]. Clinically, this is likely responsible for the lower serum testosterone levels observed among men with varicoceles in some studies
[81][82][83].
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)
[84]. While a full description of these postfertilization effects is beyond the scope of this research, 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 responsible for oocyte activation after fertilization
[85]. 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+)
[86]. These ions regulate a series of molecular events (referred to as ‘oocyte activation’) which are required to initiate embryo development
[86]. 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
[87]. 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
[88][89]; 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 spindle
[90]. In one study by Hinduja et al., lower centrosome protein expression was found in men with oligoasthenozoospermia compared to normozoospermic men
[90]. 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)
[91]. 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
[36][37][38]. 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
[92].
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
[10].
5. 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, iatrogenic vasal injury (i.e., prior inguinal or scrotal surgery), infection, or trauma
[12][19]. While a full description of this technique is beyond the scope of this research and more completely described elsewhere
[19][93][94], 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
[93]. 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
[95]. 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
[93]. As mentioned, this technique is appropriate for patients with an epididymal obstruction, which may be due to longstanding vasal obstruction, trauma, or iatrogenic injury
[12][19]. While a full description of the technique is beyond the scope of this research and more completely described elsewhere
[93][96][97], 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
[19][93].
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
[98][99]. In certain series, however, patency rates have been reported to be as high as 99.5% for VV
[94] and 93% for VE
[100].
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
[93]. 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)
[101].
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
[102]. 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
[103]. 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)
[104]. 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)
[104].
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
[93]. This presents an opportunity for reproductive endocrinologists 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.