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Ultrastructural changes of penile tunica albuginea in diabetic rats Ying-Li Lu1, Zhou-Jun Shen2, Hua Wang2, Shan-Wen Chen2, Xie-Lai Zhou2, Zhao-Dian Chen2 1Department of Endocrinology, Sir Run Run Shaw Hospital, 2Department of Urology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China Asian J Androl 2004 Dec; 6: 365-368 Keywords: tunica albuginea; penis; diabetes mellitus; scanning electron microscopyAbstractAim: To clarify the ultrastructural changes of penile tunica albuginea (TA) in streptozotocin (STZ)-induced diabetic rats. Methods: Intraperitoneal injection of STZ was used to induce diabetes mellitus (DM) in 12 Sprague Dawley rats. Ten rats (age and weight-matched) were used as control. Blood samples from the tail snips of the rats were used for the determination of serum glucose levels with SureStep Plus Blood Meter. At week 4 and 10 after the injection, half of the rats in each group were sacrificed and penile samples were obtained from the middle third of the penile shaft for the examination of TA under scanning electron microscopy. Results: In the diabetic group, the serum glucose levels were higher (P<0.01 at both time points) and the TA were thinner (P<0.05) than those of the controls. In the control group, the fibers of TA were rich and arranged regularly and undulated, while in the diabetic group, the fibers were diminished, lost the undulations and were arranged irregularly. Conclusion: In rats, DM appeared to impair the penile TA ultrastructures and this impairment could contribute to diabetic erectile dysfunction in part by impairing the veno-occlusive function. 1 Introduction Erectile dysfunction (ED) is very common among diabetic patients. Men with diabetes are afflicted with ED at a much higher incidence and an earlier age than the normal men [1]. Extensive previous studies demonstrated that diabetic mellitus (DM) not only destroy the erectile structures, but also interfere in the balance of erectile neurotransmitters [2-6]. ED associated with diabetes seems to result from combinations of impairments from nearly every step in the production of a penile erection. The tunica albuginea (TA) is a fibroelastic sheath surrounding the trabecular smooth muscle of the corpus cavernosum and is composed mainly of thick collagen bundles and elastic fibers. The collagen and elastic fibers are the key structures of the penile compliant tissue that permits the increase in girth and length of penis during tumescence, while providing adequate resilience for returning rapidly to the flaccid state during detumescence [7-8]. There are few reports on the morphological alterations of TA in diabetes and the TA involvement in DM-induced ED remains unclear. Salama et al [4] evaluated the ultra-structural changes of penile TA in Zucker Diabetic Fatty rats (Type 2 diabetes) under scanning electron microscopy and found that, as the disease progressed to 40-week duration, an increase in both the thickness and loss of undulation of collagen bundles in penile TA were found. The present study selects Type 1 diabetic model induced by streptozotocin (STZ) to investigate the ultrastructural changes of penile TA in the early phase of diabetes. 2 Materials and methods 2.1 Animals and treatments Thirty male Sprague-Dawley rats, 10-week old with body weight of 363 ?35 g, were purchased from the Animal Experimental Center, School of Medicine, Zhejiang University. The rats were randomly divided into two groups, the diabetic group (n=20) and the control group (n=10). The diabetic group were treated with a single dose of STZ (60 mg/kg, diluted in 0.1 mol/L sodium citrate buffer, pH 4.5) in intraperitoneal injection. The control group was treated similarly with a sodium citrate buffer. Rats were maintained in a 12 h light/12 h dark animal room with free access to food and tap water. Blood samples were obtained from the tail snips of the rats for the measurement of serum glucose levels and according to the levels, DM was diagnosed and 12 successfully-induced diabetic rats were used. At week 4 and 10 after the injection, the serum glucose levels were determined and then half of the rats in each group were sacrificed by intraperitoneal injection of ketamine. Samples were obtained from the middle third of the penile shaft for the examination of TA. 2.2 Determination of serum glucose levels The serum glucose levels were determined with SureStep Plus Blood Meter (Lifescan Company, USA). The procedure was provided by the producer. 2.3 Scanning electron microscopy The samples were washed with physiological saline, fixed in 2.5 % glutaraldehyde (pH 7.2 - 7.4) and post-fixed in 1 % osmium tetroxide for two hours, dehydrated in graded ethanol solutions and dried by the critical point drying method. The dried samples were then mounted on suitable carriers, coated with gold and examined under a scanning electron microscope (Leica-Stereoscan 260, Germany). While examining, firstly determined the two-dimensional location of the penile cross-section, and the thicknesses of the left-lateral, right-lateral, ventral and dorsal TA were determined and then averaged the 4 thickness values as the thickness of TA of the examined sample. The ultrastructural changes in collagen fibers was also examined by visual observation. 2.4 Data processing The data of serum glucose level and tunica albuginea thickness were expressed in mean±SD and processed with statistical package of SPSS 10.0. Analysis of difference within groups was performed with independent-samples t-test. 3 Results 3.1 Serum glucose levels The serum glucose levels of the two groups were shown in Table 1. The levels in the diabetic group were much higher than those in the controls at week 4 (P<0.01) and week 10 (P<0.01). Table 1. Serum glucose level and thickness of tunica albugina.bP<0.05, cP<0.01, compared with the controls; eP<0.05, week 4 vs week 10 in diabetic groups.
3.2 Ultrastructures of TA The thicknesses of TA of the two groups were listed in Table 1. The TA of the diabetic group was thinner than that of controls at week 4 (P<0.05) and week 10 (P<0.05) . Within the diabetic group, the TA was thicker at week 10 than that at week 4 (P<0.05). In the control group, the fibers (including elastic and collagenous fibers) in TA were rich and arranged regularly and undulated (Figure 1), while in the diabetic groups, they were diminished, lost the undulations and were arranged irregularly (Figure 2). Figure 1. Ultrastructures of tunica albuginea after 10 weeks in controls. Fibers are rich, regularly arranged and undulated (×300). Figure 2. Ultrastructures of tunica albuginea after 10 weeks of STZ treatment in diabetic group. Tunica albuginea was thinner than that in controls and fibers are sparse, irregularly arrange and lose undulations (×300). 4 Discussion The results of the present study results showed that the fibers (including elastic and collagenous fibers) of TA were significantly decreased, irregularly arranged and lost undulations in the diabetic rats when compared with those of age-matched control. The diabetic model used was analogous to Type 1 diabetes. In the study of Salama[4], the Zucker Diabetic Fatty rats were selected as diabetic model. The model was analogous to Type 2 diabetes, and the results showed an increase in the thickness and the loss of undulation of collagen bundles in penile TA. From these studies it can be concluded that the diabetes, either Type 1 or Type 2, may impair the penile TA ultrastructures. Hyperglycemia-accelerated formation of advanced nonenzymatic glycosylation end-products (AGEs) on tissue macromolecules is one potential biochemical basis for most of the irreversible diabetic pathologic processes. AGEs participating in the critical process of glucose-derived cross-link formation alter the structure and function of the vascular wall. Formation of AGEs inside the cells can directly alter intracellular protein and perhaps DNA function in the target tissues. Similarly, the cumulation of the AGEs can impair collagen and elastic fibers [9]. Nishigaki et al [10] reported that at week 4 after STZ administration, increased collagen fibrils were observed in the pericellular spaces of media in aorta of Mongolian gerbils; after one year, increased collagen fibrils and thickened elastic fibers were found around the vascular smooth muscle cells with vacuolization and increased cytoplasmic organelle. The above mechanism may be one potential pathway through which the DM impairs the ultrastructures of penile TA. On the other hand, the decrease of TA thickness in our diabetic group was in contradiction with the increase of TA thickness in Salama抯 study [4]. The contradiction may result from the strain and age differences of the rats used and the different diabetic types used in the two studies. In the early stage of diabetes, the main pathological change of TA may be degeneration and degradation and the tissue degradation could cause the TA to become thinner. Along with the progress of diabetes, the fibrous hyperplasia begins to be advantage to the degra-dation, thus the hyperplastic TA becomes thicker. The thickened TA may be mainly composed of irregularly-arranged hyperplastic collagenous fibers and cannot exercise its normal function. The above deduction can also explain the thicker of TA at week 10 after STZ treatment than that at week 4 in our study. What will occur when the TA structure is impaired? It has been reported that fewer elastic fibers in the TA decreased compliance; a change in both the thickness and the loss of undulation of collagen bundles also damaged the rigidity of the penis and under these circum-stances, the intracavernosal pressure increase must be greater than normal to compensate to obtain an erection[11]. These ultrastructural changes of TA would impair its compressive function and then may lead to failure of the tunical veno-occlusive mechanism. It is well understood that sildenafil, a PDE5 inhibitor, improves the non-diabetic ED much efficiently than the diabetic ED [12]. A possible reason for this situation could be the diffuse venous leakage structural changes in the corpus cavernosum that correlated with failure of the veno-occlusive mechanism. In short, the progress of DM could impair the penile TA structures and consequently influence its function, but as to the role it takes in the mechanism of diabetic ED is still unconfirmed. References [1] Vickers
MA, Wright EA. Erectile dysfunction in the patient with diabetes mellitus.
Am J Manag Care 2004; 10 (1 Suppl 1): S3-11. Correspondence
to: Prof. Zhou-Jun Shen,
Ph.D., M.D., Department of Urology, First Affiliated Hospital, School of
Medicine, Zhejiang University, Hangzhou 310003, China.
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