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Keywords:

  • Diabetes;
  • infertility

Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References

ABSTRACT: The aim of the study was to evaluate the ultrasound characteristics of the seminal vesicles (SV) of infertile patients with diabetes and neuropathy, and possible changes in relation to duration of diabetes. Sixty infertile patients with type 2 diabetes and symptomatic neuropathy were selected. Patients were divided into 3 groups according to duration of diabetes (group A ≤5 years, group B between 5 and 15 years, and group C ≥15 years). A pathological control group of 20 infertile patients without diabetes and a real control group of 20 healthy fertile men were selected and compared. Patients underwent prostate-vesicular transrectal ultrasonography and sperm analysis. The following ultrasound parameters were recorded: 1) body anteroposterior diameter (APD); 2) fundus APD; 3) parietal thickness of the right and left SVs; 4) number of polycyclic areas within both SVs; 5) fundus-to-body ratio; 6) difference of the parietal thickness between the right and the left SVs; and 7) pre-ejaculatory and postejaculatory APD difference. All patients with diabetes had a significantly (P < .05) higher fundus-to-body ratio compared with controls. Group C had a significantly (P < .05) higher fundus-to-body ratio compared with other diabetes groups. There was no significant difference (P > .05) relative to the number of polycyclic areas in patients with diabetes and controls. All patients with diabetes had a significantly lower (P < .05) preejaculatory and postejaculatory difference in body SV APD compared with controls. Group A and group B had a similar preejaculatory and postejaculatory difference in body SV APD, whereas this difference was significantly (P < .05) lower in group C. In conclusion, infertile patients with diabetes and neuropathy have peculiar SV ultrasound features suggestive of functional atony, and duration of disease is associated with worse changes in ultrasound findings.

Male patients with diabetes may face infertility as a negative impact that diabetes mellitus (DM) exerts on many aspects of reproductive function. These aspects include hypogonadism (Chandel et al, 2008), alteration of conventional and nonconventional sperm parameters (Agbaje et al, 2007), and sexual abnormalities, such as erectile dysfunction and ejaculatory disorders (retrograde ejaculation, anejaculation, and hypoposia; Malavigne et al, 2008). Neuropathy, a frequent complication of DM, not only may cause sexual dysfunction, but also infertility by altering seminal vesicle (SV) function (Ali et al, 1993).

Dysfunction of the SVs is a possible cause of infertility and sexual impairment; for example, the inflammation of the male accessory sex glands has been reported regarding their influence on sperm parameters and other andrologic disorders, such as premature ejaculation and erectile dysfunction (Vicari, 1999; Schultheiss, 2008).

There are no reported histopathologic characteristic features of the SVs in diabetes, only some data in animals describing reduction of the weight of male accessory sex glands, which is reversible after insulin treatment (Jackson and Hutson, 1984). Additional recent evidence indicates that Solanum lycocarpum St. Hill, a native shrub very common in the Brazilian savannah and employed in folk medicine for the management of diabetes, increased relative weights of SVs in male rats (Soares Mota et al, 2010).

In addition, it was reported that there are significant changes in the sympathetic innervation of the SV during the course of streptozotocin (STZ) diabetes, and that alterations in the reuptake, release, and synthesis of the neurotransmitter noradrenaline may contribute to changes in the concentration of the amine in the tissue. It is possible that the changes observed are related to the remodeling and regrowth of sympathetic nerve endings damaged in the early stages of hyperglycemia. These changes may also contribute to disorders of ejaculation in diabetes (Morrison et al, 2006). Another study showed a decrease in the sensitivity of the vasoactive intestinal polypeptide (VIP) receptor/effector system in SV membranes from STZ-treated rats, suggesting a physiopathological role for VIP in the seminal neuropathy observed in diabetes (Rodriguez-Pena et al, 1994).

Prostate-vesicular transrectal ultrasonography (TRUS) is the most suitable method to evaluate SV morphology. Ultrasonographically, SVs appear as claviform-shaped organs with an irregular profile, a slender ultrastructural dyshomogeneity, and an echogenicity slightly lower than that of the prostate gland. SV length varies a lot among individuals (40–60 mm), whereas the width (15–20 mm) and mainly the SV body anteroposterior diameter (APD; 7–14 mm) are more reliable measures. Another important feature is the echo structure, which normally does not show multiple anechoic areas (Sarteschi and Palego, 2003).

TRUS is extensively used for the morphological evaluation of the male accessory glands, including the SVs, in patients with male accessory gland infections. Male accessory gland infections encompass different nosological entities characterized by inflammation of one or more of the posttesticular structures deputed to the transit and maturation of the male gamete. The inflammatory involvement of the SV is defined according to well-standardized ultrasound criteria, which have been divided into conventional and nonconventional. The conventional ultrasound criteria of vesiculitis that we published previously are: 1a) increased monolateral or bilateral APD (>14 mm); 1b) asymmetry (>2.5 mm) between the right and the left SVs, even with normal APD (7–14 mm); 1c) reduced monolateral or bilateral APD (<7 mm); 2) thickened or calcified glandular epithelium; and 3) the presence of polycyclic areas separated by hyperechogenic septa (honeycomb aspect) in one or both SVs. The nonconventional ultrasound criteria of vesiculitis are: 1) fundus-to-body (F/B) ratio lower than 1 or greater than 2.5; and 2) unchanged body APD after ejaculation (Vicari, 1999; La Vignera et al, 2008).

Ultrasonographic examinations are useful for the diagnosis of diabetic neuropathy. In a recent study the cross-sectional area and echo intensity of the peripheral nerve were evaluated at the carpal tunnel and proximal to the wrist of the median nerve and in the tibial nerve at the ankle, showing a significant increase in the cross-sectional area and hypoechoic area of the nerve in patients with diabetes compared with controls (Watanabe et al, 2010). Cholecystomegaly was found in patients with type 2 diabetes, and it was significantly correlated with age, body mass index (BMI), and the severity of autonomic neuropathy. In men with type 2 diabetes, gallbladder volume was significantly correlated with low-density lipoprotein cholesterol levels. In women with type 2 diabetes, gallbladder volume was significantly correlated with waist-to-hip ratio. Gallbladder volume also had significant correlation with proliferative diabetic retinopathy but not with glycemic control, microalbuminuria, hypertension, or the duration of diabetes (Agarwal et al, 2004). In addition, ultrasonographic measurement of gastric emptying time successfully identifies noninvasively abnormal gastric motility in different types of disease (Dorlars et al, 1994). Gastroparesis is a real complication in DM and can be documented using an ultrasonographic method. Poor glucose control and autonomic neuropathy are associated with gastroparesis (Moldovan et al, 2005).

Instead, data on morphological alterations in SVs of patients with diabetes are missing. To accomplish this, prostate-vesicular TRUS was performed in infertile patients with type 2 DM and symptomatic neuropathy without other causes of male infertility; in addition, we examined whether the different duration of disease influenced the characteristics of the ultrasound findings.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References

A total of 60 infertile patients with diabetes and neuropathy were selected for this study and divided into 3 different groups:

  • Twenty patients with diabetes (group A) with duration of disease less than 5 years: they had a mean age of 47 ± 0.5 years (range, 39–48 years);

  • Twenty patients with diabetes (group B) with duration of disease between 5 and 15 years: they had a mean age of 43 ± 0.6 years (range, 37–48 years);

  • Twenty patients with diabetes (group C) with duration of disease more than 15 years: they had a mean age of 45 ± 0.4 years (range, 35–48 years).

Patients with diabetes had a mean BMI of 28 ± 0.8 kg/m2 (range, 25–30 kg/m2) and mean glicated hemoglobin percentage of 7.9% ± 0.6% (range, 7.1%–8.6%). All patients examined showed a symptomatic neuropathy (stage 2 of Dyck classification; Dyck, 1988; Vinik et al, 2003).

Retrospective data analyses of 2 control groups (real and pathological) were compared with patients with diabetes.

Pathological control group data analysis: 20 patients with idiopathic oligoasthenoteratospermia without diabetes had a mean age of 42 ± 0.4 years (range, 34–47 years) and a mean BMI of 27 ± 0.5 kg/m2 (range, 22–30 kg/m2).

Real control group data analysis: 20 healthy fertile men had a mean age of 40 ± 1.2 years (range, 30–50 years) and a mean BMI of 28 ± 1.5 kg/m2 (range, 24–30 kg/m2).

Each patient enrolled underwent an accurate andrologic diagnostic work-up that included physical examination, sperm analysis (WHO, 1999), and ultrasound scans.

Exclusion criteria were: 1) ultrasound signs of proximal (epididymal) and/or distal (ampullo-prostato-vesicular) obstruction; 2) ultrasound and/or microbiological signs of male accessory gland infections; and 3) hormonal disorders (hypogonadism, hyperestrogenism, hyperprolactinemia, hypothyroidism).

All patients underwent prostate-vesicular TRUS after 1 day of sexual abstinence before and 1 hour after ejaculation, using a transrectal 7.5-MHz biplan biconvex transducer (Esaote GPX Megas, Genoa, Italy).

The following SV ultrasound parameters were recorded from each patient, by the same blinded operator (S.L.V.): 1) body APD; 2) fundus APD; 3) parietal thickness of the right and left SVs; and 4) number of polycyclic areas within both SVs (Figure 1). These parameters were used to calculate: 1) F/B ratio; 2) difference of the parietal thickness between the right and the left SVs; and 3) pre-ejaculatory and postejaculatory APD difference. The operator repeated the measurements of these parameters 2 times, which were expressed as mean on the final report.

image

Figure 1. . (A) Seminal vesicle (SV) with normal morphology. (B) Inflammation of SV. (C) Patient with diabetes with duration of disease less than 5 years. (D) Patient with diabetes with duration of disease more than 15 years. APD indicates body anteroposterior diameter.

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The protocol was approved by the Institutional Review Board, and an informed written consent was obtained from each patient.

Results are reported as mean ± SEM throughout the study. The data were analyzed by 1-way analysis of variance (ANOVA) followed by the Duncan's multiple-range test. Statistical analysis was performed using SPSS 9.0 for Windows (SPSS Inc, Chicago, Illinois). A P value lower than 0.05 was accepted as statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References

There was no statistically significant difference within the group of patients with diabetes in relation to age, BMI, and glycemic control (low dispersion, more than 50% of patients are between the first and third quartiles).

All patients with diabetes had a significantly (P < .05) higher body APD, fundus APD, and F/B ratio compared with controls. In particular, among patients with diabetes, group C had a significantly higher SV body and fundus APD (P < .05 vs groups A and B, 1-way ANOVA followed by Duncan's test). In addition, group C had a significantly higher F/B ratio compared with other diabetes groups (P < .05, 1-way ANOVA followed by Duncan's test; Figure 2).

image

Figure 2. . Ultrasonographic means of body anteroposterior diameter (APD), fundus APD, and fundus-to-body (F/B) ratio of seminal vesicles in patients with diabetes and controls (controls A, pathological; controls B, real). Color figure available online at ww.andrologyjournal.org.

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No significant differences were found in the number of polycyclic areas, parietal thickness, and difference of the parietal thickness between the right and the left SVs between patients with diabetes and controls. (1-way ANOVA followed by Duncan's test; Figure 3).

image

Figure 3. . Ultrasonographic means of parietal thickness, parietal difference, and number of polycyclic areas of seminal vesicles in patients with diabetes and controls (controls A, pathological; controls B, real). Color figure available online at www.andrologyjournal.org.

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All patients with diabetes had a significantly lower (P < .05) pre-ejaculatory and postejaculatory difference of the body SV APD compared with controls. Finally, group A (0.48 ± 0.08 mm) and group B (0.48 ± 0.14 mm) had a similar pre-ejaculatory and postejaculatory difference in body SV APD, whereas this difference was significantly lower in group C (0.13 ± 0.06 mm; P < .05 vs other groups, 1-way ANOVA followed by Duncan's test; Figure 4).

image

Figure 4. . Ultrasonographic means of pre-ejaculatory and post-ejaculatory difference of body anteroposterior diameter (APD) of seminal vesicles (SV) in patients with diabetes and controls (controls A, pathological; controls B, real). Color figure available online at www.andrologyjournal.org.

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Semen Analysis

All patients with diabetes showed sperm concentrations of leukocytes significantly higher compared with the pathological and real control groups (P < .05). In particular, group C had a higher concentration of sperm leukocytes compared with other groups of patients with diabetes (P < .05). In addition, among patients with diabetes, group C showed significantly lower levels of all conventional parameters (density, progressive motility, and normal forms) compared with other diabetes groups and the real control group (P < .05; Table).

Table Table. . Sperm analysis of patients with diabetes and controlsa
GroupsSperm Concentration, ×106/mLTotal Sperm Number, ×106/ejaculatedProgressive Motility, % Grades a + b, After 1 hMorphology, % Oval FormsLeukocytes, ×106/mL
  • a

    Values are median, with 10th to 90th percentile given in parentheses

  • b

    P < .05 vs real control group (U test)

  • c

    P < .05 vs pathological and real control group (U test)

  • d

    P < .05 vs patients with diabetes (<5 years; U test)

  • e

    P < .05 vs patients with diabetes (5–15 years; U test)

Patients with diabetes <5 y54.0 (38.0–86.0)134.0 (95.5–190.0)44.8 (38–51)18.0 (10–34)b1.2 (0.6–2.2)c
Patients with diabetes 5–15 y31.5 (20.0–70.0)b,d86.0 (40.0–110.0)b,d34.2 (20–40)b,d12.0 (7–28)b,d1.4 (0.7–2.4)c
Patients with diabetes >15 y18.0 (11.0–40.0)b,d,e48.0 (24.0–66.0)b,d,e20.8 (15–33)b,d,e8.0 (2–20)b,d,e2.2 (0.9–3.6)c,d
Pathological control group7.5 (2.0–13.0)b17.0 (12.0–20)b15.8 (10–24)b4.0 (1–8)b0.8 (0.1–1.9)
Real control group57.5 (40.0–90.0)144.0 (100.0–212.0)48.8 (41–56)38.0 (30–44)0.4 (0.1–1.1)

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References

The results of this study showed that the SVs of patients with diabetes and neuropathy showed the presence of peculiar ultrasound features. First, the SVs of DM patients did not have the characteristic claviform conformation showed by the increased F/B ratio (>2.5) observed in about 75% of them (45 of 60 patients). In addition, patients with DM had an unchanged postejaculatory APD.

Therefore, patients with DM have a completely different SV postejaculation function. In fact, although a large proportion of these patients (about 50%;30of60 patients) had an increased pre-ejaculation APD, DM patient SVs were unable to undergo an adequate postejaculation contraction.

In patients with a longer duration of disease, pathological ultrasonographic findings were accentuated as the F/B ratio and postejaculatory APD. Finally, patients with diabetes showed low sperm quality, and in particular higher sperm concentrations of leukocytes.

In the infertile patients with diabetes and neuropathy, it is likely to find anatomo-pathological aspects similar to those reported during SV inflammation. These include the presence of parietal inflammatory lesions caused by the vesicular fluid stasis, regressive-reparative and destructive lesions of the muscular and fibroelastic fibers, and epithelial cell alterations. Indeed, the main columnar cells lose their cylia or undergo metaplasia favoring the stasis; and the basal cells increase the production of proteins involved in clot formation.

In addition, patients with DM may have vascular and neurologic anatomo-pathological alterations of the muscular wall of the SV due to an altered ratio between elastic and collagen fibers, with a consequent alteration of the ampullo-deferento-vesicular voiding mechanism. Functional alterations of the ampullo-deferento-vesicular neutrotransmission may also contribute to the abnormal SV function.

Patients with DM may have an ineffective neurotransmission because of the altered purinergic (ATP-mediated) transmission or ATP synaptic clearance compared with the efficient clearance of other neuroeffectors, such as acetylcholine and acetyl-cholinesterase. ATP and nitrogen oxide are cotransmitters that interact with the classical neurotransmitters (acetylcholine, norepinephrine, dopamine). ATP and norepinephrine have been described in the postganglion of the vas deferens (Westfall et al, 2002; Burnstock, 2009) and are always coreleased.

The unchanged SV APD after ejaculation for patients with DM is similar to what we found in patients with alcoholic or dysvitaminosis neuropathy. Subsequently, we reported that in this form of SV, functional atony is associated with a greater leukocyte concentration in the seminal fluid. Therefore, it may favor the onset of a chronic inflammatory response of prostate-ampullo-vesicular tract in these young infertile patients (Vicari et al, 2008).

To our knowledge, this is the first study exploring the ultrasound characteristics of the SV of infertile patients with DM and without any other known cause of infertility. This lack is of particular relevance given the increasing interest in the negative impact of DM on sperm parameters, and consequently on male reproductive function (Bener et al, 2009).

Although dysfunction of the SVs are not a primary cause of infertility or ejaculatory dysfunction in patients with diabetes, further studies will assess the functional expressions of these peculiar ultrasonographic features in these patients. Probably, these ultrasound characteristics and leukocytospermia are two elements contributing to oxidative stress in these patients, therefore patients with diabetes could benefit from prevention with antioxidants.

Conclusion

This study showed that infertile patients with DM and neuropathy have SV with morphological abnormalities suggestive of a functional atony. This may play a pathogenetic role in the fertility disturbance experienced by patients with diabetes. In addition, a longer duration of diabetes worsens these ultrasonographic findings.

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References
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