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Keywords:

  • azoospermia;
  • epididymis;
  • infertility;
  • ultrasonography

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contribution
  9. References

The relationship between epididymis ultrasonography (US) and infertility is poorly defined probably owing to lack of objective and reproducible criteria of US evaluation. Here, we evaluated US size of testes, caput and of corpus epididymis in infertile men: 165 with total sperm count ≥39 × 106, 187 with total sperm count <39 × 106 and 75 azoospermic men. Blood levels of follicle stimulating hormone (FSH) and of total testosterone were also evaluated. US measures obtained using a high-frequency (12 MHz) linear array transducer, included the mean value of bilateral testicular volumes (mL) (Testes-M), of bilateral longitudinal diameter of caput epididymis (mm) (Caput-M) and of the bilateral antero-posterior diameter of the corpus measured on a longitudinal scan (mm) (Corpus-M). Testicular histology of azoospermic men was obtained and the percentage of seminiferous tubules with elongated spermatids (%T) was used to classify cases with normal spermatogenesis (obstructive azoospermia) (= 17; %T ≥ 80), or with deranged spermatogenesis (= 58; %T ≤ 33). Caput-M was correlated with Testes-M (= 0.0003; = 0.17) and with FSH serum levels (= 0.024; = −0.14) but not with semen parameters. Caput-M but not Corpus-M values resulted greater in obstructive azoospermia compared with other groups, but difference was not significant. Cut-off values of Testes-M, Caput-M and of FSH correctly classified cases of obstructive azoospermia (AUC > 0.5). A patient with FSH < 7.8 IU/mL had a 63.6% chance (CI 40.1–83.2%) of being affected by obstructive azoospermia. US Caput-M ≥10.85 mm, which represented the cut-off value with the highest combination of sensitivity (58.8%, CI 32.9–81.6%) and specificity (91.4%, CI 81.0–97.1%) applied in cases with FSH < 7.8 IU/mL increased the probability for obstructive azoospermia from 63.6% up to 92.3% (CI 76.5–98.8%). US evaluation of the caput epididymis diameter helped in predicting the obstructive origin of azoospermia when FSH was not increased, whereas it was not relevant in non-azoospermic men.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contribution
  9. References

Scrotal ultrasonography (US) represents a non-invasive diagnostic procedure extensively proposed in the evaluation of infertile men (Behre et al., 1995; Oyen, 2002; Dogra et al., 2003; Moon et al., 2006; Du et al., 2010). In particular, ultrasonographic measure of testicular volumes is a reproducible correlate of spermatogenic function and is positively correlated with ejaculated sperm number, and negatively correlated with serum level of FSH (Lenz et al., 1993, 1994; Sakamoto et al., 2008). Reduced testicular volume is therefore a useful predictor of deranged spermatogenesis, and prospective variation in testicular volume represents a valuable indicator for spermatogenesis improvement during pharmacological treatment of hypogonadotropic hypogonadism (Kliesch et al., 1994). On the contrary, in spite of the physiological contribution of the epididymis in human spermatozoa maturation (Hinrichsen & Blaquier, 1980; Moore et al., 1983; Dacheux et al., 1987; Yeung et al., 1993), the relevance of epididymis in infertility (de Kretser et al., 1998; Pelliccione et al., 2004, 2009, 2011) and the role of epididymis US in the work-up of male infertility still remains elusive. Descriptive changes in both caput and corpus epididymis were reported in cases of obstructive azoospermia (Moon et al., 2006; Du et al., 2010). An enlarged diameter of caput and of corpus epididymis would occur in 14% of undefined andrological patients, after considering a normal caput epididymis diameter as being under 10 mm and a normal corpus being under 3 mm (Behre et al., 1995). A caput epididymis diameter ranging between 10 and 12 mm was considered normal along with a corpus of 2–5 mm (Rifkin et al., 1984; Oyen, 2002; Dogra et al., 2003), although no information was provided regarding the source of data. More recently, a comparative analysis of 112 undefined infertile men and a reference group with undefined fertility status failed to show differences in the mean value of diameter of caput and of corpus epididymis (Puttemans et al., 2006).

Taken together such data suggest that the relevance of epididymis US in the evaluation of infertile men needs to be determined by introducing objective and reproducible criteria of ultrasound evaluation coupled with well-defined patient selection criteria. Here, we evaluated US size of the caput and of the corpus epididymis in azoospermic and in non-azoospermic infertile men. Epididymis diameters were compared with US testicular volume, serum level of FSH and semen parameters to define the clinical value of epididymis ultrasonography in subfertile men.

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contribution
  9. References

Four hundred and twenty-seven men (aged 36 ± 5 years) who had sought medical care because of couple infertility of least 18 months were included in a retrospective study, which evaluated semen parameters, hormones levels and scrotal US. Patients with scrotal pain and/or scrotal enlargement indicative for orchiepididymitis were excluded from the study. The local institutional human research committee approved the study. FSH blood levels and total testosterone were measured by a chemiluminescent microparticle immunoassay (ARCHITECT System; Abbott, Longford, Ireland); according to the manufacturer, the analytical sensitivity was <0.05 IU/L for FSH and <0.08 ng/mL for total T. Semen analysis was performed according to World Health Organization (2010) criteria, and ejaculates were collected through masturbation at the Andrology Clinic of University of L'Aquila, after 3–5 days of sexual abstinence.

Scrotal ultrasonography

Scrotal examination was performed by two experienced examiners (AB and AP), using a Logiq7 (General Electric, Healthcare, WI, USA) equipped with a high-frequency (12 MHz) linear array transducer. Grey-scale sonograms of the testes were obtained in the transverse and longitudinal planes to evaluate the testicular volume for each side and to measure diameters of the caput and of the corpus epididymis. Bilateral testicular volumes (in millilitres) were calculated by using the formula: length × breadth × depth × π/6 (Fuse et al., 1990), assuming that the testis is an ellipsoid. The mean value of the two testicular volumes (Testes-M) in each case was used for statistical analysis. The anatomic position of the epididymis was determined using standard longitudinal and transverse scanning of the testis as reference planes. Caput epididymis size (mm) was measured on a longitudinal scan, when the caput appears as a pyramidal structure above the upper pole of the testis, and the maximal diameter was measured from the top to the base of the pyramid (Puttemans et al., 2006) (Fig.1a). The maximal antero-posterior diameter (mm) of the corpus was measured at its middle portion on a longitudinal scan when it was clearly differentiated from the testis (Fig. 1b). The mean value of the two caput (Caput-M) and corpus (Corpus-M) was used for statistical analysis. Cauda epididymis and ductus deferens were not included in this study as a preliminary evaluation failed to define an objective and reproducible size of these segments of the excretory duct.

image

Figure 1. (a) Longitudinal ultrasonographic image of caput epididymis appearing as a pyramidal structure above the upper pole of the testis. The maximal diameter is measured from the top to the base of the pyramid (dotted line). (b) The maximal antero-posterior diameter of the corpus is measured at its middle portion on a longitudinal scan (dotted line). (c) Longitudinal image of caput epididymis containing two microcysts (arrow).

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Testicular histology

Testicular histology was available from 75 azoospermic men submitted to testicular biopsy for testicular sperm extraction (Francavilla et al., 2001). Specimens were fixed in Bouin's solution, dehydrated in alcohol and embedded in paraffin wax. Non-serial 3–5 μm sections from each case were submitted to Schiff stain and analysed under a Leica DM LB microscope (Leica Microsystem, Wetzler, Germany). Twenty to 30 cross-sections of seminiferous tubules in each case were scored with a 100× oil immersion lens to identify and to count elongated spermatids, according to the presence of a condensed chromatin in a pear shaped nucleus. The percentage of seminiferous tubules with elongated spermatids (%T) and the mean number of elongated spermatids/seminiferous tubule (Sds/T) were determined in each biopsy. Two different readers (SF and AM) blindly scored all specimens showing 95% concordance for %T and for number Sds/T.

Statistical analysis

Data are presented as means ± SD and median (5th–95th centiles). Kruskall–Wallis one-way analysis of variance (anova) by ranks, followed by the Wilcoxon rank-sum test with a downward adjustment of the α level to compensate for multiple comparisons, to maintain the overall probability at a level of 0.05, were used to evaluate differences among groups. Spearman's rho non-parametric correlation was applied to evaluate correlations between variables. Receiver operating characteristics (ROC) analysis was applied, using the trapezoidal method of Hanley & McNeil (1983), to estimate the global accuracy of cut-off values of Caput-M, Testes-M and FSH, to correctly classify obstructive azoospermic men. The area under the ROC curve (AUC) was used as an indicator of the overall correct classification rate. Statistical analysis was performed using the SAS statistical software (version 9.1, 2003; SAS Institute, Inc., Cary, NC).

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contribution
  9. References

Correlation of US measures with semen parameters, hormones levels and spermatogenesis

Caput-M was correlated with testes volume assessed as mean of the two sides (= 0.0003; = 0.17) and with FSH serum levels (= 0.024; = −0.14) (Fig. 2) but not with semen parameters or with serum level of testosterone, whereas no correlation was found between Corpus-M and all parameters. Epididymal US parameters were than compared in 4 categories of patients according to semen analysis (World Health Organization, 2010) (Table 1): a group with a total sperm count ≥39 × 106 (= 165), a group with a total sperm count <39 × 106 (= 187), 75 azoospermic men divided into two groups on the basis of histological parameters. Spermatogenesis was analysed by counting the percentage of seminiferous tubules with elongating spermatids (%T) and the mean number of elongating spermatids per tubule (Sd/T). The two parameters were strictly correlated (< 0.0001; = 0.989), therefore %T was used for subsequent statistical analysis. Specimens showing %T ≥ 80 were included in the group of azoospermia and normal spermatogenesis (= 17) (Pühse et al., 2011). These were compared with 58 specimens showing %T ≤ 33 that formed the group of azoospermia and deranged spermatogenesis. The former group certainly included all cases of obstructive azoospermia as it was assumed that spermatogenesis progressing to completion in at least 80% of tubules should result in ejaculation of spermatozoa (Holstein & Schirren, 1983). The latter group included cases of true secretory azoospermia, along with cases with deranged spermatogenesis associated with a complete or incomplete obstruction. As the patency of the whole excretory duct is not objectively assayable, the latter group was defined as azoospermia and deranged spermatogenesis instead of secretory azoospermia. A similar value of Testes-M was observed in men with a total sperm count ≥39 × 106 (13.7 ± 3.3 mL) and in case of obstructive azoospermia (13.7 ± 4.0 mL). A significant and progressive decrease in Testes-M was recorded in men with a total sperm count <39 × 106 (10.9 ± 3.7 mL) and in azoospermia with a deranged spermatogenesis (8.1 ± 4.2 mL) (< 0.0083) (Table 1). Caput-M resulted higher in obstructive azoospermia (10.7 ± 2.6 mm) compared with all other groups, although the difference was significant only compared with cases with a total sperm count <39 × 106 (9.5 ± 3.9 mm) (< 0.0083). Corpus-M and serum testosterone levels did not show differences among groups. Serum FSH was significantly higher in azoospermia and deranged spermatogenesis (18.8 ± 11.1 mIU/mL) compared with all other groups (< 0.0083), and it was lower in cases with a total sperm count ≥39 × 106 (4.8 ± 2.9 mIU/mL) compared with cases with a total sperm count <39 × 106 (7.9 ± 5.5) and in cases with azoospermia and deranged spermatogenesis (< 0.0083) (Table 1).

image

Figure 2. Correlation between the caput epididymis longitudinal diameter assessed as mean of the two sides (Caput-M) and (a) testes volume assessed as mean of the two sides (Testes-M), or (b) the serum level of follicle stimulating hormone (FSH).

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Table 1. Laboratory characteristics of the studied groups
Laboratory parametersTotal sperm count ≥39 × 106, N = 165Total sperm count <39 × 106, = 187Azoospermia with deranged spermatogenesis, N = 58Obstructive azoospermia, N = 17 p
  1. Values indicate mean ± SD (5th–95th centile). FSH: follicle stimulating hormone; US: ultrasonography.

  2. a

    Kruskall–Wallis test.

  3. b

    Wilcoxon rank-sum test.

  4. c

    < 0.0083 vs. all.

  5. d

    < 0.0083 vs. obstructive azoospermia.

  6. e

    < 0.0083 vs. total sperm count <39 × 106 and azoospermia with deranged spermatogenesis at post hoc analysis with Wilcoxon rank-sum test after adjusting for multiple comparisons (p < 0.0083).

Semen volume (mL)3.1 ± 1.5 (1.0–6.0)3.0 ± 1.5 (1.0–5.5)3.3 ± 2.0 (0.6–8.1)1.7 ± 1.2 c (0.2–4.0)0.0011a
Semen pH7.7 ± 0.2 (7.4–8.0)7.7 ± 0.2 (7.4–8.0)7.6 ± 0.3 (7.2–8.0)7.4 ± 0.6c (6.4–8.5)0.0005a
Sperm concentration (N × 106/mL)53.3 ± 39.8 (12.0–132.0)4.6 ± 5.7 (0.2–16.0)00<0.0001b
Total sperm count (N × 106) 150 ± 128 (45–404)11 ± 10 (06–31)00<0.0001b
Sperm motility (%)49.4 ± 12.6 (25.0–73.0)29.1 ± 18.2 (0.0–49.0)00<0.0001b
Sperm normal forms (%)13.5 ± 7.3 (3.0–32.0)6.6 ± 7.2 (0–18.0)00<0.0001b
Leucocytes (no. ×106/mL)0.3 ± 1.2 (0–1.2)0.4 ± 1.8 (0–1.6)00NS
Serum FSH (mIU/mL)4.8 ± 2.9e (1.5–10.5)7.9 ± 5.5 (2.1–20.3)18.8 ± 11.1c (4.4–42.5)4.5 ± 2.5 (1.1–7.8)<0.0001a
Serum testosterone (ng/dL)4.9 ± 1.9 (2.2–8.4)5.0 ± 2.1 (2.5–8.9)4.8 ± 2.4 (1.9–9.1)4.4 ± 0.7 (3.0–5.4)NS
US mean testes volume (mL)13.7 ± 3.3 (9.0–20.0)10.9 ± 3.7c (5.8–18.0)8.1 ± 4.2c (2.0–16.5)13.7 ± 4.0 (7.5–25.0)<0.0001a
US mean caput diameter (mm)9.6 ± 2.4 (6.5–13.6)9.5 ± 3.9d (6.7–11.8)9.1 ± 1.6 (6.5–12.0)10.7 ± 2.6 (6.0–16.0)NS
US mean corpus diameter (mm)2.6 ± 0.5 (1.9–3.3)2.7 ± 0.7 (1.8–3.9)2.7 ± 0.8 (1.5–4.5)2.8 ± 1.7 (0–6.0)NS

Predictive value of US and of serum FSH to discriminate azoospermia with normal or deranged spermatogenesis

Table 2 and Fig. 3 show that cut-off values of Testes-M, Caput-M and FSH correctly classified cases of obstructive azoospermia (AUC > 0.5). The pairwise comparison of ROC curves of the three parameters showed an insignificant difference between AUC of FSH and of Testes-M (= 0.089), whereas AUC of Caput-M was significantly different from that of both FSH (= 0.003) and Testes-M (= 0.044). Cut-off values with the best combination of sensitivity and specificity of the three measures were then applied sequentially, starting from FSH serum levels, to predict cases of obstructive azoospermia, which, in our population of 75 azoospermic men, had a 22.66% probability. A patient with FSH ≥ 7.8 IU/mL, which represented the cut-off value with the highest combination of sensitivity [100%, confidence intervals (CI) 76.8–100%] and specificity (84.9%, CI 72.4–93.3%) had no probability of being affected by obstructive azoospermia, whereas a patient with FSH < 7.8 IU/mL only had 63.6% (CI 40.1–83.2%) probability of being affected by obstructive azoospermia. When US Testes-M was applied in cases with FSH < 7.8 IU/mL, a mean testicular volume >10 mL, which represented the cut-off value with the highest combination of sensitivity (88.2%, CI 63.3–98.5%) and specificity (74.1%, CI 61.0–84.7%), increased the probability of obstructive azoospermia up to 85.6% (CI 72.7–94.0%). When US Caput-M was applied in cases with FSH < 7.8 IU/mL and with Testes-M >10 mL, a mean caput epididymis diameter ≥10.85 mm, which represented the cut-off value with the highest combination of sensitivity (58.8%, CI 32.9–81.6%) and specificity (91.4%, CI 81.0–97.1%), further increased the probability of obstructive azoospermia up to 97.6% (CI 86.5–100%). The relevance for Caput-M evaluation was further underlined by the observation that a value >10.85 mm in cases with FSH <7.8 IU/mL increased the probability of obstructive azoospermia from 63.6% to 92.3% (CI 76.5–98.8%).

image

Figure 3. Receiver operating characteristics (ROC) analysis to estimate the global accuracy of cut-off values of Caput-M (∆), Testes-M (▲) and FSH (○), to correctly classify azoospermic men with normal spermatogenesis. The area under the ROC curve (AUC), an indicator of the overall correct classification rate, was higher than 0.5 for the three different parameters.

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Table 2. Accuracy of cut-off values of US mean testes volume, of US mean caput diameter and of serum FSH selected by ROC analysis in discriminating cases of obstructive azoospermia (AUC > 0.5)
 AUCSE95% CI
  1. US: ultrasonography; FSH: follicle stimulating hormone; AUC: area under the curve at receiver operating characteristics (ROC) analysis; SE: standard error; CI: coefficient interval; US: ultrasonography.

  2. a

    = 0.0031 compared with FSH and = 0.044 compared with US mean testes volume at pairwise comparison of ROC curves.

Serum FSH (mIU/mL)0.9330.02960.844–0.979
US mean testes volume (mL)0.8440.04500.742–0.917
US mean caput diameter (mm)a0.6990.08970.582–0.799

Mycrocysts were often observed in the caput epididymis with US analysis (Fig.1c). However, the frequency of mycrocysts was not significantly different in men exhibiting obstructive azoospermia subdivided into two groups according to caput epididymis diameter: Caput-M <10.85 mm [12.5% (1/8)], or Caput-M ≥10.85 mm [22% (2/9)], respectively (p=0.08; Fisher exact test). This suggests that caput epididymis diameter in our population of obstructive azoospermia was not related to the presence of mycrocysts.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contribution
  9. References

The clinical relevance of epididymidis US in the work-up of the infertile man is undefined. Information is largely restricted to descriptive changes of caput and of corpus epididymis described in cases of obstructive azoospermia (Moon et al., 2006; Du et al., 2010), the relevance of which in the diagnosis of azoospermia is at the best limited. Objective parameters such as epididymis diameters were proposed in the evaluation of andrologic patients (Rifkin et al., 1984; Behre et al., 1995; Oyen, 2002; Dogra et al., 2003; Puttemans et al., 2006), but their relevance is undefined because of the limited knowledge of values in the normal epididymis. Indeed a normal epididymis has been determined in a population of men evaluated because of unknown scrotal symptoms (Rifkin et al., 1984), in men undergoing scrotal sonography for various undefined indications except infertility (Puttemans et al., 2006) or in men attending an infertility clinic, classified as “normal” based on palpation of left and right epididymis (Nashan et al., 1990). Epididymis abnormalities consisting in subjective evidence of duct ectasia, partial absence or inflammatory mass like were significantly more frequent in obstructive compared with non-obstructive azoospermia (Moon et al., 2006; Du et al., 2010).

Here, we first analysed epididymis caput and corpus diameters in subfertile men with a total number of ejaculated spermatozoa in a range of fertile men according to World Health Organization (2010) (≥39 × 106), and found no difference compared with men with a low total number of ejaculated spermatozoa (<39 × 106), and no relationship with sperm parameters. Therefore, US objective evaluation of caput and of corpus epididymis size had no clinical relevance in the clinical work-up of non-azoospermic men. On the contrary, a larger caput but not corpus diameter was observed in obstructive azoospermia compared with azoospermia with a deranged spermatogenesis. We showed that the US diameter of caput epididymis had a diagnostic relevance in the azoospermic men with normal level of FSH to correctly identify obstructive azoospermia.

Determination of blood level of FSH is the endocrine parameter routinely used as an index of the spermatogenesis status. To this respect, an increased level of FSH is associated with a reduced number of ejaculated spermatozoa (Sina et al., 1975; Jensen et al., 1997; Mahmoud et al., 1998; Uhler et al., 2003; Meeker et al., 2007), and an elevated level of FSH is an accurate indicator of a deranged spermatogenesis in case of azoospermia (de Kretser et al., 1972; Bergmann et al., 1994; von Eckardstein et al., 1999). The diagnostic accuracy of FSH is, however, limited by its reported normal level in some cases of a deranged spermatogenesis (Franchimont et al., 1972; de Kretser et al., 1972). Although FSH is particularly elevated in case of complete Sertoli cell only (SCO) syndrome and in seminiferous tubule hyalinization (de Kretser et al., 1972), and a positive correlation was found between FSH and the frequency of tubules containing Sertoli cells only (Bergmann et al., 1994; von Eckardstein et al., 1999), levels are variably increased in germ cell arrest of spermatogenesis and in hypospermatogenesis (Franchimont et al., 1972; de Kretser et al., 1972; Bergmann et al., 1994), as well as in cases of focal SCO (Bergmann et al., 1994). In keeping with these observations, here we showed that azoospermic men with a normal level of FSH had a 63.6% probability (CI 40.1–83.2%) to be affected by true obstructive azoospermia. We demonstrated the novel finding that US evaluation of caput epididymis diameter strongly helped in predicting the obstructive origin of azoospermia when FSH was within the normal range. Indeed a value of Caput-M >10.85 mm in cases with FSH<7.8 IU/mL increased the probability of obstructive azoospermia from 63.6% to 92.3% (CI 76.5–98.8%). Worth mentioning is the finding that the sequential application to diagnosis of azoospermia of FSH, US Testes-M and Caput-M reached the probability for excretory azoospermia of 97.6% (CI 86.5–100%). Open testicular biopsy associated with cryopreservation of testicular spermatozoa represents the most common procedure to reach the diagnosis of obstructive azoospermia in azoospermic men with normal serum FSH concentration (Practice Committee of the American Society for Reproductive Medicine in collaboration with the Society for Male Reproduction & Urology, 2008a). The invasiveness of this procedure can be reduced but not abrogated by diagnostic percutaneous methods of testicular sperm aspiration (TESA) (Practice Committee of the American Society for Reproductive Medicine in collaboration with the Society for Male Reproduction & Urology, 2008b; Van Peperstraten et al., 2008). The combined determination of US testes volume and caput epididymis diameter in case of azoospermia associated with normal values of serum FSH gives a valuable alternative to a diagnostic TESA, and should allow to plan an oocyte intracytoplasmic sperm injection with fresh testicular or epididymal percutaneous spermatozoa aspiration in case of obstructive azoospermia. (Nicopoullos et al., 2004; Practice Committee of the American Society for Reproductive Medicine in collaboration with the Society for Male Reproduction & Urology, 2008b; Van Peperstraten et al., 2008).

The study has some limitations. It has been shown that a low level of seminal α-glucosidase in azoospermic men with normal level of FSH and a normal testis volume increases the probability for spermatogenesis present in the testis (Tüttelmann et al., 2011). Seminal plasma biochemical determinations were not included in this study. However, aim of this investigation was to explore the diagnostic potential in the evaluation of subfertile men of scrotal sonography: a first level diagnostic tool extensively available in fertility clinics. A second limitation is the lack of information on possible aetiologies for azoospermia. Indeed the study aimed to compare an objective and reproducible sonographic evaluation of the most proximal segment of the male excretory duct in men with a normal or a deranged spermatogenesis assessed by a semi-quantitative histological analysis. Further studies might analyse whether caput epididymis sonographic size gives differential information on congenital or acquired genital tract obstruction or in different histological phenotypes of primary testicular failure.

In conclusion, the US caput epididymis diameter determination represents a new valuable step in the evaluation of the infertile man, mostly in case of azoospermia and normal level of serum FSH. On the contrary, it has not provided any relevant information in non-azoospermic men.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contribution
  9. References

The authors declare no potential conflicts of interest. This work was supported by a grant from the Ministero dell'Università e Ricerca (I), PRIN 2009 (attributed to SF).

Author contribution

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contribution
  9. References

A. Pezzella was involved in acquisition of data and drafting the article. A. Barbonetti, A. Micillo and S D'Andrea were involved in acquisition, analysis and interpretation of data. S. Necozione was involved in statistical analysis and interpretation of data. L. Gandini and A. Lenzi critically revised the manuscript for important intellectual content. F. Francavilla performed the analysis and interpretation of data, and drafted the article. S. Francavilla was involved in conception and design, analysis and interpretation of data, critical revision for important intellectual content, final approval of the version to be published.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contribution
  9. References
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