Abstract
Azoospermia is diagnosed in approximately 1 percent of the general population and in up to 15 percent of infertile men. Of these men, 15–20 percent can be further categorized as having obstructive azoospermia [1]. Men with obstructive azoospermia have preserved spermatogenesis, allowing for either surgical repair of their obstruction or sperm retrieval to be used in conjunction with in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI). The obstruction can occur anywhere along the passage of sperm from the efferent ducts within the testis, along the epididymis, through the vas deferens, the ejaculatory ducts, or the distal penile urethra. Causes of obstructive azoospermia can be congenital, acquired, or idiopathic (Table 5.1) [2]. Vasectomy and iatrogenic obstruction to the vas deferens at the time of inguinal hernia repair are the most common causes of acquired obstructive azoospermia. Congenital bilateral absence of the vas deferens (CBAVD) is the most common congenital cause [3,4]. In men with obstruction of the epididymis or vas deferens, microsurgical reanastomosis at the site of obstruction can be done with good fertility-related outcomes. Those who do not wish to undergo surgical repair of their obstruction, have failed surgical repair, have CBAVD, or have an unclear/multifactorial cause of their obstruction can be treated with sperm retrieval and ICSI [5]. Percutaneous epididymal sperm aspiration (PESA), microsurgical epididymal sperm aspiration (MESA), and the recently described minimally invasive epididymal sperm aspiration (MIESA), are all techniques that allow successful retrieval of sperm from the epididymis in men with obstructive azoospermia (Table 5.2).
5.1 Introduction
Azoospermia is diagnosed in approximately 1 percent of the general population and in up to 15 percent of infertile men. Of these men, 15–20 percent can be further categorized as having obstructive azoospermia [1]. Men with obstructive azoospermia have preserved spermatogenesis, allowing for either surgical repair of their obstruction or sperm retrieval to be used in conjunction with in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI). The obstruction can occur anywhere along the passage of sperm from the efferent ducts within the testis, along the epididymis, through the vas deferens, the ejaculatory ducts, or the distal penile urethra. Causes of obstructive azoospermia can be congenital, acquired, or idiopathic (Table 5.1) [2]. Vasectomy and iatrogenic obstruction to the vas deferens at the time of inguinal hernia repair are the most common causes of acquired obstructive azoospermia. Congenital bilateral absence of the vas deferens (CBAVD) is the most common congenital cause [3,4]. In men with obstruction of the epididymis or vas deferens, microsurgical reanastomosis at the site of obstruction can be done with good fertility-related outcomes. Those who do not wish to undergo surgical repair of their obstruction, have failed surgical repair, have CBAVD, or have an unclear/multifactorial cause of their obstruction can be treated with sperm retrieval and ICSI [5]. Percutaneous epididymal sperm aspiration (PESA), microsurgical epididymal sperm aspiration (MESA), and the recently described minimally invasive epididymal sperm aspiration (MIESA), are all techniques that allow successful retrieval of sperm from the epididymis in men with obstructive azoospermia (Table 5.2).
Table 5.1 Common causes of obstructive azoospermia
| Acquired | Infectious
|
Iatrogenic
| |
| Trauma | |
| Young syndrome | |
| Ejaculatory duct obstruction | |
| Congenital | Congenital unilateral and bilateral absence of vas deferens |
| Absence (partial or complete) of the epididymis | |
| Ejaculatory duct cysts | |
| Idiopathic |
Table 5.2 Advantages and disadvantages of approaches to epididymal sperm aspiration
| Advantages | Disadvantages | |
|---|---|---|
| PESA | No microsurgical skills required Local anesthesia Noninvasive Short operative time Lowest cost | Sperm retrieved in lower quantity and quality compared to MESA Risk of vascular injury due to blind nature of procedure Failure rate of up to 20% |
| MESA | Microsurgical approach allows higher-quality sperm to be identified Near 100% sperm retrieval rate Sperm can be cryopreserved Higher quantity and more motility compared to PESA sperm Minimal contamination of specimens | General anesthesia Longer operative times compared to PESA Operative microscope and microsurgical skills required Obliterative MESA: obliteration of epididymal retrieval site precludes future reversal or retrieval in that area Longer convalescence compared to PESA |
| MIESA | Shares the advantages of the MESA approach No microsurgical skills required Local anesthesia with oral sedation Lower cost than conventional MESA | Longer operative times compared to PESA Obliteration of epididymal retrieval site precludes future reversal or retrieval in that area Special training required Often requires monitored anesthesia care |
PESA: Percutaneous epididymal sperm aspiration
MESA: microsurgical epididymal sperm aspiration
MIESA: minimally invasive epididymal sperm aspiration
5.2 Anatomy of the Epididymis
5.2.1 Structure
Convergence of a series of tubules within the testes, known as the efferent ducts, gives rise to the epididymis [6]. It is located along the posterolateral surface of the testicle and is contained within the visceral tunica vaginalis [7]. The gross appearance of the epididymis is that of a tightly coiled tube that can be divided into the caput, corpus, and cauda. Altogether, it measures 3–4 m in length. Moving from the caput to the cauda, there is a progressive increase in the diameter of the epididymal lumen and thickness of surrounding smooth muscle [7]. This surrounding smooth muscle contracts rhythmically to propel contents forward. Each region of the epididymis is further subdivided by connective-tissue septa that create unique microenvironments and provide structural support [6,8]. As sperm pass through these segments, they experience gains in function and motility [9]. Protection of germ cells from host immunity extends from the testicle to the epididymis in the form of the blood–epididymis barrier. A complex interaction of structural, physiological, and immunological factors separates the epididymal lumen from the surrounding vasculature [10].
5.2.2 Arterial Supply of the Epididymis
An understanding of blood supply to the testis and epididymis is required to limit complications during scrotal surgery. While there is some variability in the exact vascular pattern supplying the epididymis, a number of consistencies exist at each segment. In a series of 27 adult specimens, Macmillan characterized the arterial pattern of the human epididymis [11]. The report describes a single epididymal arterial branch at both the caput and corpus of the epididymis. These vessels, termed the superior and inferior epididymal branches, arise from the testicular artery. Their origin may be off of the main trunk of the testicular artery or from one of its main divisions high in the inguinal canal. In the region of the caput, it gives off one or more small capital arteries before descending to the cauda.
There are a variable number of branches to the corpus of the epididymis. This results in an arterial network of convoluted and anastomosing arteries. Along the course of the epididymis, branches from the arterial arcade penetrate within the connective-tissue septae with an extensive amount of coiling. These coiled segments ultimately terminate in a microvascular bed within the epididymis [12]. At the cauda, an anastomotic loop is often observed between the epididymal artery and the vasal artery. The exact distribution and origin of arteries in this region is more variable. Blood supply in the region of the cauda is characterized by communications and anastomoses between the epididymal, vasal, cremasteric, and testicular arteries [11].
5.2.3 Venous Drainage
Veins at the caput of the epididymis drain directly into the pampiniform plexus within the scrotum. A portion of these veins may communicate with the venous drainage of the corpus and cauda of the epididymis. Veins from the remaining portions of the epididymis converge to form the vena marginalis epididymis of Haberer [11].
5.2.4 Lymphatic Drainage
The lymphatic drainage of the epididymis involves a small number of channels arising primarily from the caput. There is a gradual decrease in the number of lymphatics toward the cauda [13]. Channels from the proximal epididymis will merge with those draining the vas deferens and ultimately enter the external iliac nodes. Lymphatics draining the caput and corpus epididymis empty into the pre-aortic nodes [7].
5.3 Indications, Patient Selection, and Uses of Epididymal Sperm
An appropriately selected patient for epididymal sperm aspiration must have either documented or strong clinical suspicion for obstructive azoospermia. Specifically to target epididymal sperm, the patient should have obstruction somewhere between the scrotal vas deferens and the testis (e.g., patients with CBAVD, epididymal obstruction, or vasectomy). Patients with inguinal obstruction and ejaculatory duct obstruction may not have adequate epididymal obstruction and induration to allow for sufficient retrieval from the epididymis and are thus not good candidates for epididymal sperm extraction. The site of obstruction is determined through a thorough male reproductive history, physical examination, and baseline laboratory studies. Determining the most likely site of obstruction also helps determine the etiology, and this crucial information guides the discussion of options. Men with CBAVD may be managed differently from those with a history of vasectomy, for example. In the case of CBAVD, a more thorough exploration with potential conversion to testicular sperm extraction may be required to find adequate sperm, while a man with a prior vasectomy may opt for vasovasostomy.
An azoospermic patient with normal testicular volume, palpable vasa, and a normal follicle-stimulating hormone (FSH) level should have retrograde ejaculation ruled out if semen volume is low or borderline low. In the absence of retrograde ejaculation, transrectal ultrasound should be performed to evaluate for an ejaculatory duct obstruction. If idiopathic or bilateral epididymal obstruction is suspected, even in the absence of a vasal anomaly, mutations of the cystic fibrosis transmembrane conductance regulator gene should be assessed.
Of those men who go on to have some form of epididymal sperm retrieval, there are a few clinical predictors of success. Multivariate analysis of a large sample of men with obstructive azoospermia undergoing PESA found younger age and larger testicular volume to be predictive of motile sperm in the aspirate [14]. While the presence of epididymal cysts in post-vasectomy patients may predict a poor outcome, time since vasectomy and a history of failed vasovasostomy were not associated with worse epididymal aspirates [15]. The cause of obstructive azoospermia has not been shown to be a reliable predictor of a successful epididymal sperm retrieval [14,15].
5.3.1 Epididymal versus Testicular Sperm for IVF/ICSI
In men with obstructive azoospermia, there is no consensus with respect to the superiority of sperm retrieved from the epididymis or testis for use in IVF/ICSI. Despite promising results of early studies of epididymal sperm, systematic reviews and meta-analyses have failed to find sufficient evidence to recommend one sperm retrieval technique over another [16,17]. Some more recent studies have again suggested a benefit to epididymal-derived sperm. This includes higher live birth rates, pregnancy rates, and implantation rates [18,19]. Epididymal sperm has also been shown to produce more clinically stable blastocysts compared to testicular sperm [19].
There is a growing body of evidence suggesting that levels of DNA fragmentation may be lower in testicular sperm. Among men with high levels of DNA fragmentation in ejaculated samples, testicular sperm may produce better outcomes with ICSI [20]. A small series of men with obstructive azoospermia found similar results. The study noted that DNA fragmentation rates were nearly twice as high in epididymal spermatozoa independent of the cause of obstructive azoospermia [21]. The impact this finding on ICSI outcomes is unclear.
5.3.2 Laboratory Handling of Epididymal Sperm
Sperm retrieved from the epididymis or testis is at high risk of compromise compared to ejaculated samples. Proper handling and sperm processing techniques are required by an experienced lab to maximize the fertility potential of the specimen. Epididymal sperm can be used as either a fresh or frozen–thawed specimen for IVF/ICSI [22]. Processing of epididymal sperm should aim to select the best spermatozoa while optimizing their ability to fertilize. To achieve this, the surgeon must first retrieve a high-quality specimen with minimal contaminants such as red blood cells and microorganisms. The laboratory then needs to apply technical skills to optimize the sperm’s environment, including ultraviolet exposure, temperature, laboratory air quality conditions, reagents, culture media, and washing steps [23].
Once obtained, epididymal aspirates are diluted with sperm wash media. This process avoids agglutination of the epididymal spermatozoa and will allow for examination of motile sperm under the microscope. Aspirates should be identified and labeled, including the site of aspiration and the presence or absence of motile sperm. Epididymal sperm may be used for a fresh transfer with ICSI or cryopreserved using similar protocols to those used for ejaculated specimens [22–27]. The cryopreserved epididymal sperm is then resuspended in a small aliquot of medium to allow for identification of motile or twitching sperm. These will then be isolated for use in the ICSI procedure [23,26].
5.3.3 Fresh versus Frozen–Thawed Epididymal Sperm
Use of cryopreserved epididymal sperm to achieve pregnancy was first reported in 1995 as part of a small series comparing frozen and fresh samples [28]. Over the course of the following decades, the use of cryopreserved epididymal sperm has increased significantly. Epididymal sperm retrieved from men with obstructive azoospermia often provide abundant sperm that can then be cryopreserved for future ICSI cycles. Cryopreservation of sperm avoids logistical constraints that can be a barrier to coordination of sperm retrieval with IVF cycles. It also results in a reduction in the number of surgical sperm retrievals per patient [29–31]. This led investigators to test whether cryopreserved epididymal sperm could provide similar outcomes to fresh samples. Rates of fertilization and clinical pregnancy were noted to be similar when compared to fresh samples [27,32–34]. Embryo quality has also been shown to be maintained with cryopreserved epididymal sperm [31,35].
There is, however, a documented effect of cryopreservation on some sperm characteristics, including a reduction in concentration and a decrease in motile counts [35]. Rarely, viable sperm will not be found at the time of thawing, necessitating a fresh retrieval. It is therefore recommended to include a test thaw of cryopreserved epididymal sperm [27]. Fertilization failure using previously cryopreserved epididymal sperm is associated with samples demonstrating poor postthaw motility [36].
5.4 Methods of Epididymal Sperm Aspiration
5.4.1 Percutaneous Epididymal Sperm Aspiration
5.4.1.1 Historical Development and Current Indications
The first use of aspirated epididymal sperm was reported in a 1985 paper by Temple-Smith et al. In it, they describe the case of a 42-year-old man with a history of vasectomy and two subsequent failed reversals with vasoepididymostomy. The patient was ultimately taken back to the operating room a third time for planned fresh transfer in an IVF cycle. Following 90 min of massage at the site of the right ductus epididymis, a total of 0.2 ml was aspirated and found to contain 76 percent motile sperm. Successful fertilization and clinical pregnancy was achieved through IVF [37]. Nearly 10 years later, Craft and Shrivastav described their approach, now known as PESA, in a letter to the editor of the Lancet. At the time, few centers had access to the microsurgical equipment required for MESA. The approach obviated the need for surgical microscope, but was still performed with intravenous or general anesthesia [38]. PESA is now commonly performed in the outpatient setting with local anesthesia.
5.4.1.2 Success Rates and Evidence in Support
The success of PESA is highly dependent on the surgeon’s ability to correctly identify and diagnose obstructive azoospermia in addition to his or her surgical skill and experience. This includes a history, physical examination, and endocrine profile, as previously outlined. Rates of successful sperm retrieval in men with obstructive azoospermia range from 78 to 100 percent with PESA, irrespective of the cause of their obstruction [39]. Those without a successful PESA will need a second procedure such as a testicular sperm aspiration or extraction. In one of the only comparative studies with PESA as an intervention, Collins et al. performed MESA and PESA on both testes in men with previously proven fertility seeking vasectomy reversal. There was no difference in the rate of successful sperm retrieval between MESA and PESA. Due to its less invasive nature, the authors recommended PESA when possible in this carefully selected group of men with obstructive azoospermia secondary to vasectomy [40].
5.4.1.3 Anesthetic Selection
PESA is performed with local anesthesia, with or without oral sedation. Oral sedation may consist of a combination of an anxiolytic and narcotic medication. With this combination of sedation and anesthesia, it is critical that surgeons and their support staff acquire training in office-based sedation safety. Appropriate monitoring and reversal agents should be readily available.
In keeping with current best practices as outlined in the American Urological Association’s guideline “Urologic Procedures and Antimicrobial Prophylaxis,” a single dose of cephalosporin is administered to patients. Ampicillin/sulbactam may be considered in those who are unable to tolerate a first-generation cephalosporin.
5.4.1.4 Procedure
Anesthetic Agents
Local anesthesia at the time of surgery is achieved through a combination of a spermatic cord block, superficial pudendal block, and peri-incisional infiltration of anesthetic. The anesthetic itself is often chosen by surgeon preference. Lidocaine and bupivacaine are commonly used anesthetics in scrotal surgery due to their favorable pharmacodynamics and pharmacokinetics. A combination of lidocaine and bupivacaine (1 percent lidocaine in a 1:1 ratio with 0.25 percent bupivacaine, both without epinephrine) provides excellent anesthesia for office-based sperm aspiration. This provides a local anesthetic with an onset of less than 30 s and a duration of approximately 7 h. Maximum doses are 4 mg/kg of lidocaine without epinephrine and 2 mg/kg of bupivacaine without epinephrine. The typical epididymal sperm retrieval procedure requires approximately 10–20 ml of this anesthetic combination.
Spermatic Cord Block, Superficial Pudendal Block
The procedure begins with a well-performed spermatic cord block. This technique was described by Wakefield and Elewa [41]. With the non-dominant hand, the vas deferens is isolated between the thumb and index finger while elevating the entire cord. The vas deferens is maintained posteriorly while the spermatic cord is held tightly against the scrotal skin in an anterior fashion. Local anesthetic is infiltrated with a 25-gauge, 1.5-inch needle attached to a 10 ml syringe, which has been pre-filled with a 1:1 mixture of 1 percent lidocaine and 0.25 percent bupivacaine (both without epinephrine). The needle is inserted at a point 1 cm below and medial to the pubic tubercle in the direction of the high spermatic cord. As the needle is advanced toward and then into the cord, the anesthetic is continuously and slowly injected. In doing so, the anesthetic creates a hydro-dissecting effect that clears vessels along its course. Approximately three passes of the needle are made into the cord in a fan-like distribution. Superficial branches of the pudendal nerve are then blocked using the remaining local anesthetic. This is done by subcutaneous infiltration lateral to the cord along the scrotal–inguinal plane. The combination of a spermatic cord block and superficial pudendal block typically requires 10 ml of the anesthetic mixture. Finally, a peri-incisional block along the planned skin incision is done using the same syringe, needle, and solution.
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