The term “Retrograde Ejaculation” (RE) refers to a condition in which failure of bladder neck closure results in the retrograde flow of semen into the bladder. This is an uncommon cause of infertility, accounting for only 1% of male-factor cases. retrograde ejaculation can result from a variety of causes. The purpose of this post will be to review the anatomy and physiology of ejaculation, examine the different etiologies of retrograde ejaculation, and discuss current treatment options in light of the recent advances in assisted reproductive technologies (assisted reproductive technology (ART).

Anatomy and Physiology

There are two phases of ejaculation. During the initial phase coined “emission,” semen is deposited into the posterior urethra. Emission is under the control of the sympathetic nervous system: afferent stimuli from the genitalia travel via the pudendal nerve to the cerebral cortex. Efferent impulses travel by way of the anterolateral columns to the sympathetic nerves, T12 to L3. Through the hypogastric nerve, impulses cause the contraction of the vas deferens, seminal vesicles, and prostate gland, as well as bladder neck closure. These two simultaneous events governed by the sympathetic nervous system result in emission of the ejaculate into the posterior urethra.

During the second phase, propulsion, semen is propelled out of the posterior urethra. Normal propulsion occurs in an antegrade direction and results from (i) bladder neck closure and (ii) a strong contraction of the bulbospongiosus and perineal muscles. The latter is under the control of the parasympathetic nervous system: impulses travel via the parasympathetic outflow of S2 to S4 to the internal pudendal nerve. Stimulation of the internal pudendal nerve results in contraction of the bulbocavernosus and the deep and superficial perineal muscles, resulting in expulsion of the ejaculate. If there is failure of the sympathetic nerves to effect bladder neck closure, the contraction of perineal and bulbospongiosus muscles will result in retrograde flow of the ejaculate into the urinary bladder, thereby causing retrograde ejaculation.

Etiology of Retrograde Ejaculation

A careful history will often reveal the etiology of retrograde ejaculation and will help guide the treatment plan. Table 1 summarizes the different conditions that can result in retrograde ejaculation. This discussion will be limited to the five most common causes of retrograde ejaculation.

Transurethral prostatectomy (TURP) remains the most common surgical cause of retrograde ejaculation. In this procedure, the hyperplasric tissue in the center of the prostate gland is removed by endoscopic resection. This results in a large opening at the bladder neck, which may temporarily or permanently alter effective coaptarion. It has been reported that between 40% and 95% of patients who undergo transurethral prostatectomy will have retrograde ejaculation. For this reason, in young men with bladder outlet obstruction due to an enlarged prostate gland, transurethral incision of the prostate (TUIP) is the recommended procedure-of-choice. In TUIP, two incisions are made in the bladder neck extending from the ureteral orifices toward the verumontanum (posterior urethra). Because there is no removal of prostatic tissue, the procedure is associated with retrograde ejaculation in less than 5% of men.

In the past, rerroperitoneal lymph node dissection (RPLND) for testis cancer was a common reason for retrograde ejaculation and other ejaculatory disturbances, as rerroperitoneal lymph node dissection involves the dissection of lymphatic tissue along the sympathetic chains bilaterally. Since most men undergoing lymphadenectomy for testis cancer are in the reproductive age group, ejaculatory dysfunction presented a major problem. Modifications to rerroperitoneal lymph node dissection were first proposed in the early 1980s by Narayan et al. By preserving the sympathetic chain on one side below the level of the inferior mesenteric artery, ejaculation continued to be antegrade in approximately half of the patients. Richie reported 94% antegrade ejaculation postoperarively in a prospective study of 85 men with clinical stage I nonseminomatous germ cell rumors who had undergone the modified RPLND.

Lumbar sympathectomy is performed in patients who are symptomatic from excessive sympathetic output. The consequences of sympathectomy may range from retrograde ejaculation in less-extensive cases to total ejaculatory failure when bilateral sympathetic chains are destroyed from T8 to L3.

Presacral nerve damage caused by aortoiliac surgery or abdominoperineal resection can also result in retrograde ejaculation. When care is taken to preserve the presacral nerves in aneurysmectomy, antegrade ejaculation is retained in 90% of patients.

Diabetes mellitus has been associated with retrograde ejaculation, probably due to a peripheral neuropathy involving the bladder neck. Diabetic neuropathy may also be associated with erectile dysfunction and ejaculatory failure.

Pharmacological agents may also lead to retrograde ejaculation. Any medication that disturbs α-adrenergic receptors at the bladder neck may be a culprit. The most common of these is the class of antihypertensive medications known as α-blockers, which are currently prescribed for the treatment of obstructive urinary symptoms due to benign prostaric hyperplasia. Certain anripsychoric agents have also been associated with retrograde ejaculation. A partial list of medications associated with retrograde ejaculation is provided in Table Etiologies of Retrograde Ejaculation.

Table Etiologies of Retrograde Ejaculation

Anatomical
Congenital:
Posterior urethral valves
Utricularcyst
Extrophy or hemitrigone
Acquired:
Transurethral resection of the prostate
Retropubic prostatectomy
Y-V plasty
Pelvic trauma
Neurogenic
Spinal cord lesions:
Surgical injury:
Lumbar sympathectomy
Retroperitoneal lymphadenectomy
Aortoiliac surgery
Abdominoperineal resection
Neuropathies:
Diabetes mellitus
Multiple sclerosis
Pharmacological
α-adrenergic blockade:
Phenoxybenzamine
Prazosin
Terazosin
Peripheral sympatholytics:
Guanethidine
Ganglion blockers:
Hexamethonium
Antipsychotics:
Chlorpromazine
Haloperidol
Mechanical obstruction
Urethral stricture
Meatal stenosis
Urethral valves
Urethrocele
Idiopathic

Diagnosis of Retrograde Ejaculation

RE should be suspected in men with low-volume ejaculates and any of the aforementioned underlying conditions. It should be noted, however, that the most common reason for a low-volume ejaculate in the absence of the medical conditions listed above is a sampling error. Men who consistently make a low-volume specimen through masturbation should be encouraged to collect via condom during sexual intercourse.

Because the seminal vesicles contribute most of the ejaculate volume, ejaculatory duct obstruction and absent or arreric seminal vesicles are also common explanations for low-volume ejaculate. To differentiate these conditions from retrograde ejaculation, a postejaculate urine sample is obtained. The patient is asked to empty his bladder into a container immediately after intercourse or masturbation. The urine is cenrrifuged at 300 g for 10 minutes and the pellet is examined under 40x power magnification. If the patient has absent sperm in his antegrade ejaculate, the presence of 6 to 10 sperm per high power field confirms the diagnosis of retrograde ejaculation. If the patient has a low-volume ejaculate and low sperm concentration, the presence of a higher concentration of sperm in the postejaculatory urine than the ejaculated specimen confirms a significant component of retrograde ejaculation. If the patient has low-volume azoospermia and no sperm are recovered from the urine, a transrectal ultrasound should be performed to evaluate for ejaculatory duct obstruction. A low-volume ejaculate with oligospermia and no sperm in the postejaculatory urine suggests absent or atretic seminal vesicles, and, again, a transrectal ultrasound is indicated.

Treatment of Retrograde Ejaculation

Several different treatment options have been proposed for retrograde ejaculation. These are summarized in Table Methods for Restoring Antegrade Ejaculation. The primary treatment is sympathomimerics to restore bladder neck closure. Several α-adrenergic medications have been used. Until recently, the most common was phenylpropanolamine hydrochloride (Omade), 25 mg twice daily. Reports of hemorrhagic stroke associated with the first-time use of phenylpropanolamine hydrochloride may make this a less-attractive alternative, however. Oxedrine (Synephrine, Boehringer Ingleheim, Ridgefield, Connecticut) has been effective in a single dose of 15 to 60 mg.

Table Methods for Restoring Antegrade Ejaculation

Medications
α-adrenergics:
Imipramine 25 mg by mouth 2-4 times daily
Phenylpropanolamine HCI by mouth twice daily
Ephedrine 25 mg by mouth 4 times daily
Pseudoephedrine 60 mg by mouth 4 times daily
Pseudoephedrine (sustained release) 120 mg dailyx4 days
Anticholinergics:
Brompheniramine maleate
Other:
Imipramine
Surgical treatment
Abrahams vesical neck reconstruction
Young-Dees procedure

Anticholinergics have also been used successfully, the most common being brompheniramine maleate (Dimetane), 8 mg twice daily.

Imipramine (chlorpropamide hydrochloride) 25 to 50 mg daily has also been used successfully. Although the precise mechanism by which imipramine works is unknown, it appears to have both anticholinergic and α-adrenergic properties.

When retrograde ejaculation is the result of bladder neck surgery, bladder neck reconstruction has been suggested. Two procedures have been proposed to correct bladder neck dysfunction. The first is the Young-Dees procedure, which involves fashioning a 1.5 cm strip of posterior urethral mucosa over a catheter to create a new bladder neck. The prostaric mucosal remnant is stripped and the denuded prostaric and posterior urethral muscles are imbricated over the urethral reconstruction.

A second procedure, proposed by Abrahams et al., involves a transvesical approach to the bladder neck. A U-shaped incision is made at the bladder neck through the mucosa beginning at 8 o’clock and ending at 4 o’clock. The mucosa is elevated for 1 cm into the prostatic urethra and incised. The scar tissue is removed and four zero-chromic catgut sutures are used to close the defect. The vesical sphincter is reconstructed to the diameter of a 16-Foley catheter. In their small series, Abrahams et al. reported that antegrade ejaculation was restored in two patients who had previously undergone Y-V plasty of the bladder neck.

Improved sperm recovery techniques combined with the success of assisted reproductive technology today have rendered surgical treatment for retrograde ejaculation of historic significance only.

Sperm Recovery and Use in Assisted Reproduction

When antegrade ejaculation cannot be restored medically, it may be necessary to use spermatozoa from the bladder. The obvious limitation is the deleterious effect of acidic urine on sperm quality. Due to the contribution of an alkaline secretion from the seminal vesicles, the fresh ejaculate maintains a pH ranging from 7.2 to 8.2, and an osmolarity ranging from 300 mOsm / kg to 380 mOsm / kg. Acidification causes immobilization of spermatozoa, while exposure to hypertonic urine can lead to disruption of the cell membrane. These effects are duration dependent. Makler et al. observed that neutralization of the pH is therefore not sufficient to restore motility and should be accompanied by adjustments in osmolarity as well. The pH of the medium can be adjusted with NaOH to be alkaline, while serum albumin may be used to buffer pH fluctuations.

Different protocols have been proposed to obtain the optimal sample from the patient with retrograde ejaculation. One of the earliest, proposed by Hotchkiss in 1955, involves passing a catheter into the patient’s bladder after he has urinated to wash the bladder with a buffer solution. Two milliliters of buffer are left in the bladder and the patient masturbates. The bladder is catheter-ized again to retrieve the specimen, which is prepared as above.

To avoid catheterization, Urry et al. suggested giving patients two tablets of sodium bicarbonate in a glass of water every two hours, beginning 8 to 12 hours before sperm recovery. Thirty minutes to one hour before insemination, the husband is asked to empty his bladder, ejaculate via masturbation or intercourse, and then urinate. The latter urine sample is collected and diluted with modified Ham’s F-10 medium (Gibco, Grand Island, New York, U.S.) at a ratio of one to two parts medium per one part urine. Samples are gently mixed and centrifuged at 250 g for 10 minutes. Extra care is taken since spermatozoa from retrograde ejaculates are more fragile. The supernatant is removed, and the pellet is resuspended in 0.5 to 1 mL of Ham’s F-10 medium. Urry et al. reported pregnancies in six of seven patients treated with this technique.

Brassesco et al. used a different protocol that involved adjusting the pH and osmolarity of the urine the day of insemination only. They instructed the patient to drink a solution containing sodium bicarbonate 4 gm in 250 mL of water on the day of insemination. The patient would void every 15 minutes thereafter, and the urine pH and osmolarity were determined. When a pH between 6.5 and 8.0 and an osmolarity between 300 and 500 mOsm / kg were reached, the patient was instructed to masturbate and then urinate. This protocol has the advantage of no catheterization for sperm recovery, and no preparation prior to the insemination day. With this technique and using three intracervical inseminations per cycle, the authors reported pregnancies in seven couples.

An even more simplified approach is suggested by a case report, in which a couple achieved a pregnancy through self-inseminations with semen collected through urination. In this case, the husband had retrograde ejaculation secondary to bladder neck surgery as a child. Just prior to insemination, the patient was asked to masturbate and then urinate. In the urine-semen mixture, the unliquefied semen was identifiable as a gelatinous mass measuring 2 mL in volume. This mass was easily aspirated into a syringe, and the couple used the specimen for intravaginal insemination at home. Of note, because the semen was retrieved from the urine immediately, no adjustments in bladder pH or osmolarity were necessary. Using this technique, the couple achieved a pregnancy after their fifth cycle of inseminations.

Based on reports such as these, the authors no longer require alkalinization in retrograde ejaculation patients prior to sperm procurement, provided the exposure to urine is limited. In patients for whom bladder catheterization is necessary, alkalinization is not advised. Similarly, in patients who “urinate” their ejaculate, alkalinization is not advised provided the specimen can be processed within 30 minutes of production. Only in rare instances, when a specimen is expected to remain exposed to urine for greater than 30 minutes, is alkalinization recommended with one of the regimens described above. This approach has simplified considerably the management of patients with retrograde ejaculation.

Results

Few centers report separate pregnancy success rates in couples with retrograde ejaculation. One of the few reports in the literature is by Okada et al. and describes seven men with retrograde ejaculation treated with a variety of methods. In their small series, three men achieved antegrade ejaculation with imipramine, while three additional patients required retrieval of sperm from the bladder after alkalinization. Further, two patients achieved pregnancies with intercourse after imipramine, one patient achieved a pregnancy with artificial insemination, and two required in vitro fertilization (in vitro fertilization (IVF) to achieve a pregnancy. Of the remaining two patients, one was unmarried and the other failed in vitro fertilization with intracytoplasmic sperm injection ( intracytoplasmic sperm injection (ICSI). Since the wife of this latter patient was 42 years of age, additional treatment was not pursued. Although this series is small, it illustrates the importance of making available a variety of assisted reproductive techniques depending on the quality of the sperm retrieved.

A Rational Approach To Achieve Pregnancies In Re

Patients with retrograde ejaculation have presented a challenge to fertility specialists for years. Procuring optimal quality semen with the least inconvenience to the patient requires a thorough understanding of the physiology of ejaculation and the available armamentarium for treatment. A rational approach combines effective sperm retrieval with the appropriate assisted reproductive technique.

Intracytoplasmic sperm injection (ICSI) has not changed the basic approach to sperm procurement in men with retrograde ejaculation. The specimen can be retrieved from voided urine or through catheterization. The development of intracytoplasmic sperm injection as a highly successful reproductive technique has allowed for the use of extremely poor-quality semen specimens for fertilization in vitro.

Table Rational Approach to Treating the Infertile Couple with Retrograde Ejaculation

Restore antegrade ejaculation pharmacologically when possible.
Obtain voided postejaculate urine when antegrade ejaculation cannot be restored.
Catheterize bladder after alkalinizing, if voided specimen unsatisfactory.
If 5 million or greater total motile sperm, proceed to intrauterine insemination.
Less than 5 million total motile sperm, consider in vitro fertilization / intracytoplasmic sperm injection.

A rational approach to the patient with retrograde ejaculation is summarized in Table Rational Approach to Treating the Infertile Couple with Retrograde Ejaculation. One should start with efforts to restore antegrade ejaculation by pharmacological means. When such measures fail, or if drugs cannot be tolerated (such as the patient with hypertension in whom α-adrenergic medications are conrraindicated), retrieval of sperm from postejaculatory urine is the next step. Depending on the quality of the sperm obtained, that specimen can be used for artificial insemination or in vitro fertilization. Most practitioners feel that 5 million total motile sperm are adequate for intrauterine insemination. A lower number constitutes a relative indication for in vitro fertilization in most centers. Other factors relating to the female partner should be elucidated prior to such decisions. This is one of several conditions where a team approach, consisting of a reproductive urologist, a reproductive endocrinologist, and a quality andrology laboratory, allows for optimal management. Patients with retrograde ejaculation should be counseled that in the absence of additional major infertility factors, the prognosis for a pregnancy is excellent.

 

Selections from the book: “Male Reproductive Dysfunction. Pathophysiology and Treatment”, Edited by Fouad R. Kandeel, 2007.

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