Infertility Sensitivity and Specificity of Ultrasonography in Predicting Etiology of Azoospermia

Infertility Sensitivity and Specificity of Ultrasonography in Predicting Etiology of Saad R. Abdulwahed, Essam-Eldeen M. Mohamed, Emad A. Taha, Medhat A. Saleh, Yaser M. Abdelsalam, and Ehab O. ElGanainy OBJECTIVE MATERIALS AND METHODS RESULTS CONCLUSION To determine the sensitivity and specificity of different ultrasound (US) modalities in predicting an obstructive vs a nonobstructive etiology of azoospermia. A total of 268 azoospermic men with available histopathologic slides were separated into obstructive (n ¼ 104) and nonobstructive (n ¼ 164) groups. Scrotal US studies, including color Doppler and transrectal US examinations, were performed in all patients and compared with the testicular biopsy results as the reference standard. We found that a decreased testicular volume and intra- and extratesticular varicocele were the most common abnormalities detected using scrotal US in those with nonobstructive azoospermia. In contrast, epididymitis, spermatocele, and duct ectasia were the most common findings in those with obstructive azoospermia. The sensitivity and specificity of scrotal US in detecting nonobstructive azoospermia was 75% and 72%, respectively, and for detecting obstructive azoospermia was 29.8% and 87%, respectively. Prostatic midline cysts, ejaculatory duct calcification, dilated seminal vesicle, and/or vassal ampullae were the most common abnormalities detected using transrectal US for obstructive azoospermia. The sensitivity and specificity of transrectal US in detecting obstructive etiology was 45% and 83%, respectively, and for functional etiology was 39% and 88%, respectively. Scrotal US was more sensitive in detecting functional azoospermia and more specific in detecting obstructive azoospermia. However, transrectal US was more sensitive in detecting obstructive azoospermia and more specific in detecting functional azoospermia. Both tests had greater specificity than sensitivity for obstructive azoospermia, indicating that US has the ability to exclude more than to diagnose cases of obstructive azoospermia. However, US is unlikely to completely replace testicular biopsy. UROLOGY 81: 967e971, 2013. Ó 2013 Elsevier Inc. Infertility is defined as the inability of a sexually active couple to attain pregnancy after 1 year of unprotected sexual intercourse. In 40%-60% of cases of infertility, a contributing male factor is present. 1,2 is defined as the absence of spermatozoa in the semen. 3 is identified in semen analyses in 5%-10% of infertile men. 4 This condition represents the final result of different testicular alterations, ranging from normal spermatogenesis with seminal tract obstruction or the absence of the vas deferens (obstructive azoospermia) to different abnormalities of the spermatogenic process, including hypospermatogenesis, maturation arrest, and a complete absence of germ cells, such as in Financial Disclosure: The authors declare that they have no relevant financial interests. From the Department of Radiology, Faculty of Medicine, Al-Azhar University, Assiut, Egypt; Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Al-Azhar University, Assiut, Egypt; Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Assiut University, Assiut, Egypt; Department of Public Health and Community Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt; and Department of Urology, Faculty of Medicine, Assiut University, Assiut, Egypt Reprint requests: Ehab O. ElGanainy, M.D., Department of Urology, Assiut University Hospital, Faculty of Medicine, Assiut University, Assiut 71111, Egypt. E-mail: ehabelganainy@yahoo.com Submitted: September 15, 2012, accepted (with revisions): January 1, 2013 Sertoli cell-only syndrome (nonobstructive or functional azoospermia). 5,6 The distinction between obstructive and nonobstructive azoospermia is important because men with obstructive azoospermia might have cost-effective treatement options such as microsurgical reconstruction of the reproductive tract. However, for those with functional azoospermia, it might be reasonable to proceed directly to an advanced assisted reproductive technique such as intracytoplasmic sperm injection. 7 Also, a real risk of failure to retrieve spermatozoa exists in men with nonobstructive azoospermia, and couples must be apprised of this risk before attempting assisted reproduction. 8 For the definite diagnosis of obstruction, a testicular biopsy is required, with the finding of a good number of mature spermatid and spermatozoa in the seminiferous tubules. 9 Because of the invasive nature of this procedure, the limited results of surgical treatment of obstructions of the seminal path, and alternative options such as assisted reproductive treatments, testicular biopsies are not routinely performed. 10 Transrectal ultrasonography (TRUS) has conventionally been used as a first-line diagnostic modality to evaluate the prostate and document obstruction in the ª 2013 Elsevier Inc. 0090-4295/13/$36.00 967 All Rights Reserved http://dx.doi.org/10.1016/j.urology.2013.01.001

ejaculatory duct. 11,12 Little has been published about the comparative sensitivity and specificity of ultrasonography (US) in detecting azoospermia vs the more definitive, but invasive, diagnostic testicular biopsy. 13 Although scrotal color Doppler US is routinely performed to check for nonpalpable varicocele, it might also be helpful in distinguishing testicular failure from obstruction in patients with azoospermia, because it can directly demonstrate abnormalities in the proximal mediastinum testis, epididymis, and intrascrotal portion of the vas. 14 The objective of the present study was to determine the sensitivity and specificity of scrotal US (including color Doppler US) and TRUS in the prediction of an obstructive or a nonobstructive etiology in infertile men with azoospermia compared with testicular biopsy as the reference standard. MATERIAL AND METHODS The present study was a prospective, cross-sectional study. It was conducted from March 2010 to May 2012 at our institutes. It included 268 azoospermic men (diagnosed after 2 semen analyses 1 month apart) who had undergone a previous diagnostic testicular biopsy with histopathologic slides available. Those patients having clinically evident small testes and those with clinically evident hypogonadism were excluded to avoid any bias during the US evaluation. The patients were divided into 2 groups according to the testicular histopathologic findings using modified Johnsen scoring 9 : a functional azoospermia group (n ¼ 164) and an obstructive azoospermia group (n ¼ 104). All patients included in the present study underwent complete history taking and general and genital examinations. Patients with clinically evident testicular atrophy or cryptorchidism were excluded. Those patients with retrograde ejaculation revealed by examination of postorgasmic urine were also excluded. Scrotal US, including color Doppler US, was performed using a 7.5-MHz, high-resolution, linear array transducer (Sonoline Versa Plus, Seimens Medical System, Erlangen, Germany) with pulsed and color Doppler capabilities. The patient was placed first in the supine position. The scrotum was elevated with a towel draped over the thighs and the penis placed on the patient s abdomen and covered with a towel. Acoustic gel was used. The testes were examined using scrotal US for their size, volume, echogenicity, and perfusion. The testicular volumes were calculated using the US formula, length width height 0.71, and expressed in milliliters. 15 The total testicular volume was calculated by summing the volumes of the 2 testes and was considered subnormal if <20 ml. 16 The presence of any paratesticular anechoic, tortuous tubular structures (ie, widened spermatic veins) was noted. Next, the patient was examined in the standing position. The color mode was used to evaluate the testicular veins. The veins were examined before, during, and after the Valsalva maneuver for their size and the occurrence of reflux. Spectral analysis was used to detect venous reflux and to determine its duration. Varicocele was diagnosed by US demonstration of 1 veins with a maximal diameter of >3 mm and reflux >1 second. 17 TRUS was done using an AU5 ultrasound machine (Esaote Medical Systems, Genoa, Italy). A self-administered enema was routinely used before the examination. Patients were placed in the left lateral decubitus position. A digital rectal examination was performed for each patient to ensure the absence of rectal abnormalities that could interfere with the scan. After adequate lubrication, the probe was gently inserted into the rectum up to the bladder. The seminal vesicles were examined for their size and echogenicity. The prostate was examined in the transverse and sagittal planes, searching for the ejaculatory ducts. Both vasa differentia were evaluated for their presence or absence, the echogenicity of their lumens, and their calibers. 18 The local ethics committee at our institutes approved the present study, all patients provided written informed consent before enrollment in the study. Statistical Analysis The data was recoded and entered in the Excel 2007 software program, then cleaned, and transformed to the Statistical Package for Social Sciences software, version 16 (SPSS, Chicago, IL). Descriptive statistics are presented as frequencies and the mean standard deviation. The chi-square test was used to compare the valid percentages of findings between groups. The data were considered significant when P.05. RESULTS The study included 268 infertile male patients divided into 2 groups according to the testicular histopathology report: nonobstructive (group 1, n ¼ 164) and obstructive (group 2, n ¼ 104). Demographic data analysis revealed no significant difference between the 2 groups in the age distribution (mean 37.35 7.19 years for group 1 and 36.51 7.72 years for group 2; P >.05) or body mass index (mean 25.24 2.56 kg/m 2 for group 1 and 26.67 1.95 kg/m 2 for group 2; P >.05). Scrotal US yielded significantly more common diagnoses suggesting a functional etiology in the functional azoospermia group, including a subnormal total testicular volume and intra- and extratesticular varicocele. In contrast, it yielded significantly greater findings suggesting obstructive etiology in the obstructive azoospermia group, including epididymitis, efferent duct ectasia, and spermatocele (Table 1). TRUS yielded significantly more common diagnoses suggesting an obstructive etiology (with distal obstruction in the male genital duct) in the obstructive azoospermia group, including prostatitis, midline prostatic cysts, a dilated seminal vesicle and/or ampulla of vas, and ejaculatory duct calcification (Table 2). The diagnostic power of scrotal Doppler and TRUS in detecting azoospermia vs testicular biopsy is presented in Table 3. Using scrotal Doppler US in the functional azoospermia group yielded positive data suggesting a functional etiology in 123 of the 164 patients, for a sensitivity of 75% and specificity of 72%. In the second group with obstructive azoospermia, we found scrotal US data in accordance with obstructive etiology in 31 of 104 patients, for a sensitivity of 29.8% and specificity of 87%. TRUS yielded positive data suggesting an obstructive etiology in 47 of 104 patients (45%) with obstructive etiology, for a sensitivity of 45% and specificity of 83% in obstructive azoospermia, while in functional azoospermia the sensitivity and specificity of TRUS were 39% and 88% respectively. Scrotal Doppler US was more sensitive in detecting 968 UROLOGY 81 (5), 2013

Table 1. Comparison between scrotal and color Doppler ultrasound findings Variable Nonobstructive (n ¼ 164), N (%) Obstructive (n ¼ 104), N (%) P Value* Testis Subnormal total testicular volume 113 (68.9) 6 (5.7).00001 Intratesticular varicocele 30 (18.2) 3 (2.8).027 Testicular microcalcification 15 (9.1) 4 (3.8).227 Epididymis Epididymitis 16 (9.7) 31 (29.8).005 Spermatocele 5 (3.0) 16 (15.3).035 Efferent duct ectasia 3 (1.8) 22 (21.1).001 Pampiniform plexus Varicocele 44 (26.8) 8 (7.6).003 Vas deferens Bilateral absent vas 6 (3) 9 (8.7).237 No pathologic finding 25 (13.9) 9 (7.6).349 * Chi-square test. Table 2. Comparison between transrectal ultrasound findings Variable Nonobstructive (n ¼ 164), N (%) Obstructive (n ¼ 104), N (%) P Value* Prostate Prostatitis 16 (9.7) 18 (17.5).267 Midline cysts 3 (1.8) 13 (12.5).025 Ejaculatory duct calcification 3 (1.8) 8 (7.7).145 Small size prostate 8 (4.8) 5 (4.8) 1.000 Seminal vesicle Dilated seminal vesicles 3 (1.8) 13 (12.5).025 Seminal vesiculitis 8 (4.8) 12 (11.5).337 Small size seminal vesicles 7 (4.2) 5 (4.8) 1.000 Vas deferens Dilated ampulla 3 (1.8) 21 (20.2).001 Bilateral absent vas 5 (3.0) 8 (7.7).237 No pathologic finding 112 (65.0) 3 (2.8).0001 * Chi-square test. functional azoospermia and more specific in detecting obstructive azoospermia; however, TRUS was more sensitive in detecting obstructive and more specific in detecting functional azoospermia. Both tests had greater specificity than sensitivity in detecting obstructive azoospermia. COMMENT US is a widely used and well-tolerated imaging modality for the evaluation of pathologic conditions in male factor infertility. Recent technical advances in US applications have enabled new aspects in the structural and functional analysis of testicular tissue, varicocele, and the seminal tract. The main purpose of the US evaluation in male infertility is to identify and treat correctable causes of infertility. 19 The first-line imaging test is scrotal US, which uses a high-frequency duplex echo transducer and color flow to assess the spermatic vein. 20 Scrotal US can be helpful in determining whether azoospermia is nonobstructive or obstructive. 19 Scrotal US can directly demonstrate abnormalities in the proximal portion of the seminal duct and can also detect secondary changes of the proximal seminal duct caused by obstruction in the distal part of the seminal duct. Evaluation of the proximal genital duct and measurement of the testicular volume with scrotal US are helpful in distinguishing obstructive from nonobstructive azoospermia in infertile men. 14 Scrotal US in our study revealed that a subnormal total testicular size was significantly greater in the functional azoospermia group. Similar results have been reported in other studies using scrotal US. 16 Also, the presence of varicocele, whether intratesticular or extratesticular, was the second most common finding using scrotal US in the present study, in accordance with it being the most common cause of infertility in men. 21 Scrotal Doppler US was shown to be a good diagnostic tool for the diagnosis of varicocele, with a sensitivity 97% and specificity of 94% reported by Trum et al 22 in 1996. However, scrotal US showed a significant increase in epididymitis, spermatocele, and duct ectasia in the patients UROLOGY 81 (5), 2013 969

Table 3. Value of scrotal ultrasonography and transrectal ultrasonography as screening tests vs biopsy as valid diagnostic test for azoospermia Scrotal US vs Biopsy TRUS vs Biopsy Functional Obstructive Functional Obstructive Sensitivity (%) 75 29.8 39 45 Specificity (%) 72 87 88 83 Positive predictive value (%) 85 75 96 90 Negative predictive value (%) 56 70 53 69 TRUS, transrectal ultrasonography; US, ultrasonography. with obstructive azoospermia. Scrotal US were more sensitive in detecting functional azoospermia and more specific in detecting obstructive azoospermia. In our study, the sensitivity and specificity of scrotal US in the diagnosis of functional azoospermia was 75% and 72%, respectively. However, for obstructive azoospermia, the corresponding values were 29.8% and 87%. Thus, scrotal US was more sensitive in the diagnosis of functional azoospermia and more specific in the diagnosis of obstructive azoospermia. In the study by Moon et al, 14 in 2006, of 20 infertile men with azoospermia, 14 were proved to have obstructive azoospermia and 6 nonobstructive azoospermia. According to the US findings, epididymal abnormalities in the head, body, and tail were significantly associated with obstructive azoospermia, and abnormalities of the mediastinum testis were not significant in either group. In the study by Foresta et al, 23 the number of intratesticular vessels detected by color and power Doppler scrotal US was used to predict the etiology of azoospermia. They found that 67% of subjects with functional azoospermia had <3 intratesticular vessels. TRUS has been used in the evaluation of patients with azoospermia to exclude distal obstruction in the male genital ducts and to determine the absence of hypoplasia of the seminal vesicles and prostate, because it can clearly visualize the distal genital tract as vasal ampullae, seminal vesicles, and ejaculatory ducts. 20 TRUS is the most commonly performed study if the diagnosis of distal seminal tract obstruction is being considered, especially if the azoospermia is associated with seminal abnormalities, such as in the case of a low semen volume. 24,25 The role of TRUS has been firmly established in the diagnosing post-testicular causes of infertility. 19 In the present study, prostatitis, midline prostatic cysts, a dilated seminal vesicle and/or vasal ampulla, and ejaculatory duct calcification were the most common abnormalities in those with obstructive azoospermia detected by TRUS. Despite having a low sensitivity of 45%, TRUS had a high specificity of 83% and a positive predictive value of 90% for obstructive azoospermia. Du et al, 13 in 2010, reported a sensitivity, specificity, and accuracy of 95.3%, 97.2%, and 96%, respectively, using a combined assessment of scrotal US and TRUS in discriminating between obstructive and functional cases in patients with of azoospermia. We believe the clear difference between the present results and those from their study could be attributed to differences in the inclusion and exclusion criteria and differences in the methods used. For instance, they calculated the sensitivity, specificity, and accuracy of the combined scrotal US and TRUS in detecting azoospermia but not the sensitivity and specificity of each modality separately, such as was done in the present study. Additional studies to evaluate the diagnostic yield of combining the clinical evaluation, laboratory test, and US findings are recommended. In the present study, the sensitivity of scrotal Doppler US in detecting obstructive azoospermia was rather low. This might have been because of the presence of cases in which the obstruction was distal in the male genital ducts (eg, in the ejaculatory duct), which cannot be revealed using scrotal Doppler US. Also, proximal epididymal obstruction (the most common site of obstruction in our locality) might not be associated with suggestive radiologic findings (eg, spermatocele or changed epididymal echogenicity) in many cases, which would increase the false-negative findings. Again, the visible low sensitivity of TRUS in detecting obstructive azoospermia could be attributed to inclusion of obstructive azoospermia cases in which the obstruction was proximal in the male genital ducts because epididymal obstruction could not be found using TRUS. Similarly, in cases of nonobstructive azoospermia, suggestive radiologic signs, such as subnormal testicular size and varicocele could not be evaluated using TRUS, which might reveal no radiologic findings in such cases, increasing the false-negative findings. CONCLUSION US is an effective noninvasive imaging modality in the diagnosis of nonobstructive azoospermia. For obstructive azoospermia, US has the ability to exclude, more than to diagnose, the cause of azoospermia. We recommend using different US modalities, such as scrotal US, including color Doppler US, and TRUS, in the evaluation of obstructive azoospermia to raise the diagnostic yield before shifting to a more invasive test such as testicular biopsy. However, US is unlikely to completely replace the testicular biopsy, given the sensitivities and specificities reported. Acknowledgment. To the teams of our departments who contributed to the evolution of the present work and to our patients who agreed to participate in this study. 970 UROLOGY 81 (5), 2013

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