A rare abnormality of ejaculatory duct opening in the bladder trigone in a 33-year-old male associated with primary infertility: Case report and literature review

Genitourinary anomalies constitute a large proportion of congenital malformations. However seminal tract anomalies, particularly ejaculatory duct (ED) anomalies are very rare and little information exists on the topic. We are reporting a very rare case of bilateral ectopic EDs opening in the bladder trigone in a 33-year-old gentleman presenting for evaluation for primary infertility. The patient's semen analysis showed low-ejaculate-volume, fructose negative, acidic pH and azoospermia. His hormonal profile was normal. Cystoscopy revealed an empty posterior urethra, and the verumontanum and the openings of the EDs could not be identified in the posterior urethra. The ED openings were found inside the bladder trigone. Vasography combined with cystoscopy confirmed the opening of the ED in the trigone following Intra-vasal injection of methylene blue. Our patient had a successful intracytoplasmic sperm injection using testicular spermatozoa that resulted in a healthy baby boy. We also did a formal literature review through PUBMED, MEDLINE and Google Scholar with the search term (ectopic ED). Search results were filtered to exclude vas deferens ectopia. Our literature search revealed five studies comprising 24 patients with ectopic EDs. Mean age at diagnosis was 29.88 ± 12.88 years. The most common presenting symptom was hemospermia. The ectopic EDs most commonly opened in a midline cyst (21 cases), bladder trigone (1 case), or bladder neck (1 case). The most common management used for symptomatic patients with ectopic EDs opening in the midline cyst was through transurethral fenestration. In conclusion, ectopic ED openings in the bladder trigone are very rare. Management varies by case depending on the presentation, anatomy of underlying anomaly, associated complication/s and desire for fertility

Embryologically, the ureters develop as out-budding from the caudal end of the mesonephric duct to reach the metanephros and ascend cranially (Tanagho, 1976). While the bladder is developing, the distal ureter separates from the mesonephric duct, which migrates caudally to join the posterior urethra (Tanagho, 1976). Between weeks 8 and 12 of gestation, the epididymis, rete testis, vas deferens, seminal vesicles and EDs start to develop from the mesonephric duct in response to the testosterone produced by the fatal testis. As long as the seminal ducts, the ureter and the bladder trigone all have a mesonephric origin, congenital anomalies that connect all of them are expected.
We report a 33-year-old male with ESTO associated with primary infertility. Unique about this case is that the ectopic openings of the bilateral EDs were in the bladder trigone. We also undertook a review of the literature on similar published cases. Only 24 cases of ectopic openings of EDs have been reported in the literature to date. However, ectopic openings of the bilateral EDs in the bladder trigone have only been reported once in previous publications.

| Presentation of case
A 33-year-old Syrian gentleman presented to our Infertility Clinic at Hamad Medical Corporation (largest tertiary hospital in the state of Qatar) complaining of primary infertility since more than 1 year and low volume ejaculate since puberty. Past medical and surgical history of the patient revealed no chronic medical conditions. The patient did not report any lower urinary tract symptoms, repeated urinary tract infection nor significant testicular pain denoting epididymitis or epididymo-orchitis. The family history showed no history of infertility in the patient's family and no consanguinity. The patient reported good libido and erectile functions but stated that since puberty, semen volume had always been low with both intercourse and masturbation. His wife was a healthy 26-year-old lady with regular menstrual history. Upon examination, the patient showed well-developed secondary sexual characters. Scrotal examination was unremarkable with bilateral normal sized testes, normal epididymis bilaterally, vas deference could be palpated on both sides with no defects or lesions and no varicocele was found on both sides.
Semen analysis showed azoospermia with low volume ejaculate (0.5 ml), and acidic pH, and fructose negative. Post-orgasmic urine was repeated twice and showed no spermatozoa. The hormonal profile (luteinizing hormone, follicular stimulating hormone, testosterone) was within normal ranges. Obstructive azoospermia secondary to ED obstruction was suspected. MRI of the pelvis with contrast showed a small-sized prostate (approximate volume of 3.9 cc) with a small cystic structure superior to the prostate ( Figure 1A-C). Both seminal vesicles were partially distended; however, assessment of vas deferens and EDs was limited due to thick image sections (Figure 2A,B). Accordingly, the patient was diagnosed with ED obstruction and the patient was counselled for a trial of transurethral resection of EDs and deroofing of the prostatic cyst and he agreed to go on with the procedure. On day of surgery, with the patient under full anaesthesia and in the lithotomy position, left testicular percutaneous sperm aspiration was done as the first step. Fresh examination of the sample revealed many motile and immotile spermatozoa. The sample was sent for cryopreservation. Obstructive azoospermia was confirmed, thus, we proceeded with cystoscopy, which revealed an empty posterior urethra, and the verumontanum and both EDs openings could not be found. The urinary bladder trigone showed a small cystic structure lying near the midline with two small openings on its surface 25 spermatozoa per tubule. The results were discussed with the patient, and he was advised that the congenital anomaly he is having cannot be repaired by any intervention, and that for fertility, he could proceed with percutaneous epididymal or testicular sperm aspiration and intracytoplasmic sperm injection (ICSI). The patient underwent ICSI using the sperm frozen from the testicular biopsy. His wife was successfully pregnant from the first ICSI trial.

| DISCUSSION
To the best of our knowledge, this is the second reported case of bilateral ectopic openings of the EDs into the bladder trigone reported in the English literature; and the first case of bilateral ectopic ED openings in the bladder trigone in an adult male presenting with primary infertility. In addition, we provide the findings of our literature review of published cases of ectopic openings of EDs (Table 1). We identified 24 such published cases (Khunovich et al., 2020;Lin et al., 2012;Reisman, 1977;Wang et al., 2009;Wu et al., 2020); of which only one reported case was of bilateral ectopic EDs openings in the bladder trigone observed in a 3-year-old child (Khunovich et al., 2020). Hence, to our knowledge, our case is the second ever reported of bilateral ectopia of EDs openings in the bladder trigone; and the first observed in an adult associated with primary infertility.
In terms of the anomaly, the literature review we undertook (  (Lin et al., 2012;Wu et al., 2020). In a few rare cases, the ectopic ED invades the bladder trigone, bladder neck and urethra (Reisman, 1977;Wang et al., 2009;Wu et al., 2020). One patient had the ED ending in a large cystic dead-end, compressing the bladder and the contralateral ED (Wang et al., 2009). However, bilateral EDs opening into the bladder trigone was only reported once (Khunovich et al., 2020 location in the enlarged prostatic utricle (EPU), and the relationship between the ED or vas opening and the contralateral seminal tract (Wu et al., 2020). Interestingly, all the ESTO classification were restricted to ectopic openings of either VD or ED into the EPU without approaching ureteric or vesical ectopia (Wu et al., 2020).
As for other associated anomalies, our patient displayed no other congenital anomalies, concurring with most of the identified cases of ectopic EDs (Table 1) (Lin et al., 2012;Wang et al., 2009;Wu et al., 2020), with one case from each of the USA and Israel (Khunovich et al., 2020;Reisman, 1977). Hence, urologists need to be more aware of the condition and to report cases of EDs ectopia, worldwide and more specifically in the Middle East region so that a proper prevalence can be computed.
Regarding presentation, our patient presented with primary infertility, in agreement with the literature, where a case series reported infertility among 7 of the 20 adult cases of ectopic EDs (Wu et al., 2020). Interestingly, our patient had no hemospermia, which is quite common among such cases (Lin et al., 2012), being reported among 14 of 20 cases of ectopic EDs (Wu 2019). Other presentations for patients with ectopic ED include perineal pain (Wu et al., 2020), recurrent epididymitis (Khunovich et al., 2020;Reisman, 1977), or incidentally discovered during routine evaluation for other congenital anomalies such as hypospadias (Wu 2019 Management of ectopic ED/s opening in a midline cyst, traditionally, the most common management option for smaller cysts has been transurethral fenestration of the cyst (Table 1) (Lin et al., 2012;Wu et al., 2020). Open and laparoscopic excision has been successfully undertaken for larger and symptomatic cysts (Wang et al., 2009;Wu et al., 2020). Interestingly, in a patient with ectopic ED associated with recurrent epididymitis, submucosal 'Deflux' injection in the dilated ectopic intravesical opening of the ED has been conducted with satisfactory results (Khunovich et al., 2020).
As our patient had no symptoms other than primary infertility, no surgical intervention was directed to the congenital anomaly itself.
However, the medical advice was to proceed with an assisted reproductive technique in order to gain fertility. We assume that the patent ectopic opening of the ED into the trigone in this patient was associated with repeated minor infections that may have resulted in secondary obstruction at the epididymal or testicular level which could explain why no spermatozoa was found in the post-orgasmic urine or vasal aspirate.

| CONCLUSION
We report the first case of bilateral ectopia of EDs openings in the bladder trigone associated with primary infertility. Diagnosis of such cases is not straight forward and is usually established during TURED procedure. Management of such rare anomaly varies in a case-by-case manner depending on the mode of presentation, underlying anomaly, associated complication/s and the desire for fertility. Surgical intervention is not always feasible as in the current case.

ACKNOWLEDGEMENT
Open access funding provided by the Qatar National Library.