Fig. 7.1
Neural pathways involved in ejaculation
While retrograde ejaculation is classically attributed to failure of bladder neck coaptation, there has been evidence that this is not the causative process in many cases. A study comparing transrectal color Doppler ultrasonography findings during ejaculation in a healthy man and a spinal cord-injured man demonstrated that in both patients, the bladder neck closed appropriately during ejaculation. However, the external urethral sphincter did not relax sufficiently to allow antegrade flow of semen in the spinal cord-injured man. Once the expulsion phase concluded, the semen in the prostatic urethra slowly flowed retrograde into the bladder [5]. As discussed in further detail in this chapter, α(alpha)-antagonist mediated ejaculatory dysfunction has been shown to be an anejaculation caused by blockade of α(alpha)1A receptors in the vas deferens, prostate, and seminal vesicles.
In vitro studies have demonstrated that once exposed to the high osmolarity and acidic environment of the urine, spermatozoa lose motility and die quickly [6–8]. These findings underpin the importance of sperm preparation in the sperm retrieval techniques discussed in this chapter.
Diagnosis and Workup
A thorough history and physical examination are crucial to the diagnosis of retrograde ejaculation. Symptoms include decreased ejaculate volume or absent ejaculate as well as cloudy urine. In line with the common causes of retrograde ejaculation, affected men may have comorbidities that can result in neurogenic retrograde ejaculation such as diabetes mellitus or multiple sclerosis or may have had prior surgery that can affect the ability of the bladder neck to coapt. It is important to note that men with isolated retrograde ejaculation still retain the ability to orgasm. As discussed elsewhere in this text, orgasm and ejaculation are separate processes and inability to orgasm does not necessarily cause anejaculation or retrograde ejaculation or vice versa. However, the two may coexist.
Apart from neurologic examination findings associated with comorbidities such as diabetes mellitus or multiple sclerosis, men with isolated retrograde ejaculation tend to have otherwise normal genitourinary examination findings. In some men, the urine may appear cloudy due to the presence of semen. In addition, semen analysis may reveal a low-volume or absent ejaculate with or without oligospermia or azoospermia. In men with these semen analysis findings, obstructive azoospermia remains part of the differential diagnosis. Physical examination therefore represents an important opportunity for the clinician to distinguish between these disease entities. In a man with isolated retrograde ejaculation, both vasa deferentia should be palpable and the digital rectal examination should not reveal any palpable dilated midline structures, which are suggestive of ejaculatory duct obstruction.
The American Society for Reproductive Medicine (ASRM) recommends post-ejaculatory urinalysis for men with ejaculate volume <1.0 mL unless the patient is diagnosed with hypogonadism or congenital bilateral absence of the vas deferens [9]. However, there have been no strict criteria established defining a “normal” versus an “abnormal” post-ejaculatory urinalysis that is suspicious for retrograde ejaculation. Prior investigators have demonstrated the absence of sperm in the pre-ejaculatory urinalysis and the presence of sperm in the urine in post-ejaculatory urinalysis of fertile men. This supports the hypothesis that even in men without retrograde ejaculation, post-ejaculatory urinalyses may contain residual sperm that were washed out from the urethra during micturition [10]. Subsequent efforts have been made to refine the interpretation of post-ejaculatory urinalysis findings. A prospective study comparing 77 men being evaluated for infertility and 71 control male subjects by Mehta et al. showed that although the presence of sperm in the post-ejaculatory urinalysis was more common in the group being evaluated for infertility, it was still very common even in the control group (98.7% vs. 88.7%, respectively). Subjects who were being evaluated for infertility were more likely to have greater than 50% of their total sperm count in the post-ejaculatory urinalysis and had a higher percentage of their post-ejaculatory urinary sperm count in the initial fraction of voided urine than were control subjects [11]. A similar study of 15 fertile men and 66 non-azoospermic men being evaluated for infertility found that 73% and 65% of the fertile and infertile men, respectively, had sperm in their post-ejaculatory urinalysis. This study did not find a statistically significant difference in proportion of sperm in urine between the two groups [12].
As previous studies demonstrate, there are no physical examination or diagnostic test findings that are pathognomonic for retrograde ejaculation. Findings can overlap considerably between fertile and infertile men. It is important to distinguish retrograde ejaculation from obstructive azoospermia and anejaculation, all three of which may present in a similar manner as azoospermia. Thus, diagnosis relies upon clinical suspicion combined with supportive findings on workup.
Etiologies of Retrograde Ejaculation
Neuropathic Changes
Genitourinary neuropathic diseases such as diabetes mellitus [13] and multiple sclerosis [14] have the potential to cause retrograde ejaculation (Table 7.1). Of these, diabetes mellitus is the most common cause of retrograde ejaculation, with various series reporting prevalence rates of 6–34.6% among diabetic men [15–18]. Of note, these figures may represent an underestimation of the true rate, as retrograde ejaculation among diabetics is felt by some investigators to be under-diagnosed and underreported [19]. Cases of retrograde ejaculation in this patient population are thought to be caused by an autonomic neuropathy resulting in failure of bladder neck coaptation during ejaculation [20]. As with other sequelae of diabetes mellitus, the presence of ejaculatory dysfunction is correlated with the degree of the particular patient’s glycemic control and the duration of diabetes. Theoretically speaking, retrograde ejaculation in patients with multiple sclerosis may be caused by the same mechanism as in diabetic patients, though the authors are not aware of any studies specifically demonstrating this mechanism. Prevalence estimates for retrograde ejaculation specifically are difficult to find in the literature. However, it has been reported that 31–50% of multiple sclerosis patients experience some sort of ejaculatory or orgasmic disturbance [21, 22].
Table 7.1
Etiologies of retrograde ejaculation
Neuropathic | Diabetes mellitus Multiple sclerosis Spinal cord injury |
Postsurgical | Transurethral resection of prostate Photovaporization of prostate Transurethral microwave therapy of prostate Transurethral incision of prostate Retroperitoneal lymph node dissection Pelvic/spinal surgery |
Medication-induceda | Antipsychotics? |
Postsurgical
Postsurgical causes of retrograde ejaculation remain a common cause seen in urologic clinical practice (Table 7.1). Classically, surgical treatment for benign prostatic hypertrophy (BPH) has been long associated with retrograde ejaculation. The other prominent urologic cause of postsurgical retrograde ejaculation is patients undergoing retroperitoneal lymph node dissection (RPLND) for testicular cancer.
Transurethral resection of prostate (TURP) remains the gold standard for the surgical treatment of BPH. A thorough resection leads to a wide-mouthed TUR defect, causing failure of bladder neck coaptation. Patients should be counseled extensively preoperatively that retrograde ejaculation is very common after TURP. A recent review by Marra et al. noted that the overall rate of retrograde ejaculation was 66.1% [23].
Other treatment modalities for BPH have been examined with the goal of achieving comparable clinical efficacy compared to TURP while minimizing the side effects. Photovaporization of the prostate (PVP) was associated with a postoperative rate of retrograde ejaculation of 41.9% in 1 meta-analysis, compared to 61.4% in the TURP group. Less invasive techniques have lower reported rates of retrograde ejaculation. Examples include transurethral needle ablation (TUNA—0%), transurethral microwave therapy (TUMT—21.2%), and transurethral incision of the prostate (TUIP—21.1%) [23]. However, it must be noted that these techniques must be used on appropriately selected patients with smaller prostates.
The prostatic urethral lift procedure (UroLift®, Neotract, Pleasanton, CA) is a promising tissue-sparing technique where intraprostatic implants are delivered to separate the lateral lobes of the prostate without impacting the bladder neck. This offers relief of urinary obstruction without vaporization, ablation, or resection of prostatic tissue. Prospective studies have shown this technique preserves sexual function with no differences in preoperative and postoperative rates of sexual bother or ejaculatory dysfunction. Again, patient selection is important as the UroLift® technique has best results in patients with no median lobe, lack of an elevated bladder neck, and a post void residual of <350 ml [23, 24].
Retroperitoneal lymph node dissection disrupts the pre-aortic postganglionic sympathetic fibers, which can interfere with ejaculation (but not erection) [25]. Classically, reported rates of retrograde ejaculation after bilateral RPLND varied widely, with some series reporting rates of up to 90% [26]. However, recent advances in the understanding of the anatomy and physiology of erection, the adoption of modified unilateral templates of resection (sparing the contralateral sympathetic nerves, and use of nerve-sparing in bilateral templates) have decreased the risk of retrograde ejaculation after RPLND. A more recent series by Beck et al. showed preservation of normal ejaculation in 97% of patients undergoing primary RPLND [27]. Even patients undergoing post-chemotherapy RPLND had antegrade ejaculation rates of up to 85% [28].
Medication Side Effects
α(Alpha)-Antagonists
Alpha-antagonist medications such as tamsulosin, which are widely used for the treatment of lower urinary tract symptoms secondary to benign prostatic enlargement, are well known for their side effect of ejaculatory dysfunction (Table 7.2). Traditional teaching holds that the use of α(alpha)-antagonists causes loss of bladder neck coaptation, resulting in retrograde ejaculation. Over the last decade, multiple studies have demonstrated that this is, in fact, not the cause of α(alpha)-antagonist mediated ejaculatory dysfunction and that this process is actually mediated by antagonism of the α(alpha)1A adrenoreceptor.
Table 7.2
Medications associated with ejaculatory dysfunction
Medication class | Examples |
|---|---|
α(alpha)-blockers | Tamsulosin, sildosin, doxazosin, prazosin, terazosin, alfuzosin |
Antipsychotics | Levemepromazine, iloperidone, clozapine, risperidone |
Activation of this receptor is required for contraction of the vas deferens [29]. A study involving the use of real-time polymerase chain reaction on radical prostatectomy and cystoprostatectomy specimens showed that α(alpha)1A was also the predominant adrenoreceptor subtype in the seminal vesicles [30], another structure whose function is crucial to the process of ejaculation. The same study also assigned 17 healthy men to treatment with tamsulosin (predominantly α(alpha)1A vs. α(alpha)1D antagonism) and naftopidil (predominantly α(alpha)1D vs. α(alpha)1A antagonism) in a crossover manner. Results demonstrated lack of retrograde ejaculation and lack of sperm in post-ejaculatory urinalysis on transrectal color Doppler ultrasound after administration of either medication [30]. A randomized crossover study of tamsulosin, alfuzosin, and placebo in healthy adult males showed that the use of tamsulosin was associated with a >20% decrease in ejaculate volume in 90% of subjects and anejaculation in 35% of subjects in comparison with alfuzosin and placebo. In this study, there were no statistically significant differences in post-ejaculatory urine sperm concentrations between the three groups [31]. A randomized double-blind crossover study of 15 healthy male urologists demonstrated anejaculation in all subjects after 3 days of silodosin administration, with return of semen volume and sperm count to baseline 3 days after cessation of silodosin [32]. Interestingly, there has been speculation that the presence of ejaculatory dysfunction may serve as a sign of effective treatment of lower urinary tract symptoms in patients taking α(alpha)-antagonists for benign prostatic hyperplasia. In one literature review, an odds ratio of 1.68 was calculated for improvement in International Prostate Symptom Score by 3 points and maximal urinary flow rate by 3 mL per second [33].
Antipsychotic Medications
Antipsychotic medications used for the treatment of psychiatric disorders such as schizophrenia have been associated with rare reports of retrograde ejaculation (Table 7.2). Case reports have implicated several typical and atypical antipsychotics including levomepromazine [34], iloperidone [35], clozapine [36], and risperidone [37–39]—all of which have α(alpha)1-antagonistic effects. The authors are not aware of any studies in which post-ejaculatory urinalyses were collected in patients taking these medications. It is therefore possible, as is the case with reports involving α(alpha)1-antagonists, that these antipsychotics may be causing anejaculation instead of retrograde ejaculation. Alternatively, some investigators have suggested that ejaculatory dysfunction, retrograde or otherwise, may be the indirect result of other endocrine imbalances such as hyperprolactinemia which can be caused by these antipsychotics [40].
Spinal Cord Injury
Retrograde ejaculation has been diagnosed in men with spinal cord injury through the use of penile vibratory stimulation and rectal probe electroejaculation followed by catheterized post-ejaculatory urinalyses [41–43]. Certainly, there are known ejaculatory derangements that other investigators have proposed to be the cause of retrograde ejaculation in men with spinal cord injury. These include the tendency for sacral cord injuries to result in loss of the expulsion phase of ejaculation as well as detrusor-sphincter and detrusor-bladder neck dyssynergia [44–46]. However, as noted previously, post-ejaculatory urinalyses containing sperm are found even in neurologically intact men. Studies clearly demonstrating a mechanism of retrograde ejaculation in spinal cord-injured men remain relatively rare, with a notable exception being a study of nine men undergoing penile vibratory stimulation or electroejaculation with simultaneous urodynamic catheter monitoring of internal and external urethral sphincter pressures. This study demonstrated that in each of the nine men, forceful contraction of the external followed by the internal urethral sphincter preceded ejaculation, but that in the men undergoing electroejaculation, the external sphincter pressure exceeded that of the internal sphincter shortly after ejaculation, providing a possible mechanism for electroejaculation-induced retrograde ejaculation [47]. As mentioned earlier, transrectal color Doppler ultrasonography studies have shown that the bladder neck or internal sphincter closes appropriately during ejaculation in some patients with spinal cord injury. Rather, it is a failure of external urethral sphincter relaxation, or a form of detrusor-sphincter dyssynergia, that causes retrograde ejaculation in these patients [5]. While rare, spinal cord conditions such as perineural cysts or tethered cord syndrome can cause retrograde ejaculation as well [48, 49].
Treatment of Retrograde Ejaculation
Noninvasive Techniques
The method of treatment of retrograde ejaculation can vary widely depending on severity and etiology (Table 7.3). In general, less invasive treatment options are preferred for initial management. In some cases simple substitution, discontinuation, or dose reduction of the offending medication can restore normal ejaculation. In cases of retrograde ejaculation caused by antipsychotic medication, referral to a psychiatrist for dosage adjustment or substitution with a different medication may be indicated. Dose reduction has been reported to be successful in restoring normal ejaculation in patients taking risperidone, for example [38]. Prior authors have reported on circumvention of retrograde ejaculation by instructing men to ejaculate with a full bladder. According to one published case report, two patients with retrograde ejaculation were able to convert to antegrade ejaculation with the use of this technique [7]. In a separate report, ejaculate retrieved in this manner from one patient was used for intrauterine insemination and resulted in a successful pregnancy [50]. Other noninvasive techniques include the combination of urinary alkalinization followed by voiding of urine directly into the vagina after intercourse or intravaginal insemination of the postcoital urine–semen mixture using a syringe [51–53].
Table 7.3
Treatment of retrograde ejaculation
Noninvasive | Discontinuation, dose reduction of medications | Ejaculation with full bladder | |
|---|---|---|---|
Medical | α(alpha)-agonists (midodrine, pseudophedrine, ephedrine) | Anticholinergics, antihistamines, tricyclic antidepressants | |
Sperm retrieval | Modified Hotchkiss technique | Retrograde instillation of sperm media and extraction | Epididymal or testicular sperm extraction |
Surgical | Young-Dees technique (bladder neck reconstruction) | Y-V plasty of bladder neck | Transurethral collagen injection of bladder neck |
Medical Therapy
Medical therapy has been described in the literature, mostly in the form of α(alpha)-agonists, tricyclic antidepressants, and antihistamines aimed at increasing sympathetic tone and/or decreasing the parasympathetic tone of the bladder neck. Commonly used α(alpha)-agonists include midodrine (known as milodrin in several older studies), pseudoephedrine, and ephedrine. The use of these medications has been described in the past [54, 55]. A few notable recent studies involving patients diagnosed with retrograde ejaculation have been published. A study of 33 patients with diabetes mellitus and retrograde ejaculation found that imipramine, pseudoephedrine, and a combination of both were able to produce antegrade ejaculation in 38.5, 47.8, and 61.5% of cases, respectively [56]. Hsiao et al. were able to restore antegrade ejaculation using pseudoephedrine in two of four patients with retrograde ejaculation after chemotherapy and retroperitoneal lymph node dissection for testicular cancer [57]. Tomasi et al. reported on the use of intramuscular self-injection of methoxamine 30 min prior to sexual intercourse or masturbation in two patients. Antegrade ejaculation was restored in both patients with one of the two patients able to achieve pregnancy after 3 months of methoxamine treatment [58].
Tricyclic antidepressants also have been used for the medical treatment of retrograde ejaculation. In one series, 11 of 11 patients with retrograde ejaculation after retroperitoneal surgery were treated with daily imipramine for 7 days prior to the female partner’s planned ovulation. Using this regimen, antegrade ejaculation was produced in all 11 patients with only minor side effects such as dizziness, weakness, nausea, or sweating. Two spontaneous pregnancies were reported and two successful fertilizations without successful pregnancy were induced with the help of intracytoplasmic sperm injection (ICSI) [59]. In another study, antegrade ejaculation was achieved in three of seven patients using imipramine. Of these three patients, two went on to conceive naturally. All three of these patients initially had partial retrograde ejaculation [2]. The use of various other medications has been described in some older studies including the antihistamines bromphenoramine [60] and chlorpheniramine—the latter in combination with phenylpropanalamine [55].
A meta-analysis reported that of retrograde ejaculation patients treated with medical therapy, antegrade ejaculation was achieved in 50% and spontaneous pregnancy was achieved in 34%. The authors found that imipramine was the most widely used medication but did note that there were no randomized controlled trials comparing the various medical treatments of retrograde ejaculation on a head-to-head basis [55]. Indeed, some clinicians prefer the use of alpha-agonists such as pseudoephedrine due to the potentially more dangerous adverse effects associated with imipramine [57].
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