Benign prostatic hyperplasia is one of the prevalent diseases among middle-aged and elderly men, and the exact pathogenesis remains unclear. At present, TURP is the gold standard for the surgical treatment of BPH, with less painful, less invasive, and faster recovery. However, intraoperative bleeding is still a common complication that can be life-threatening for patients. Deering et al. found that the prostate tissue of BPH patients may contain an "angiogenic switch" that can lead to an increase in MVD, and that this angiogenic effect may begin in the early stages of BPH. MVD is currently recognized as the standard for the evaluation of angiogenesis. Immunohistochemical staining is performed using specific vascular endothelial monoclonal antibody against specific vascular endothelial components (cell adhesion molecule CD-34 or factor VIII antigen) to display microvascular components of tissues and calculate MVD values. Therefore, both CD-34 and factor VIII can be used to assess MVD, with the successful application reported by Bettencourt et al. and Gettman et al..
Finasteride, as a non-competitive 5α-reductase inhibitor, inhibits the conversion of testosterone to DHT, and reduces the concentration of DHT in vivos. After preoperative administration of finasteride, a reduction in DHT concentration was found to be associated with a significant reduction in perioperative bleeding of TURP[16,17]. This may be related to the reduction in DHT concentration, atrophy of the prostate gland, MVD, and lower blood flow after finasteride treatment[18-20]. In addition, it has been suggested that androgens can regulate the vascular distribution in the prostate by regulating different growth factors, such as basic fibroblast growth factor, vascular endothelial growth factor, and epidermal growth factor and so on[18,21-23]. Therefore, changes in androgen levels are essential for the regulation of prostate MVD. In this study, rats were induced by castration combined with different concentrations of estrogen/ androgen, and the results showed that the prostatic MVD in the castration group was significantly lower than that in the control group due to androgen source blocking. Some studies have demonstrated that testosterone acts as a stimulator of vascular endothelial growth factor, while androgen deprivation could lead to reduced blood flow to the prostate[24-26]. Furthermore, androgenic effects are mediated by vasoactive substances produced by dihydrotestosterone-regulated stroma and epithelial cells, which contain androgen receptors. In this study, when exogenous estrogen concentration was constant, the prostate MVD of rats in each group increased with the increase of exogenous DHT concentration except for the E0.05+DHT0.015 mg/kg group. Furthermore, we confirmed that in vitro experiments that androgens play an important role in regulating prostate MVD. The decrease of DHT concentration can cause the decrease of prostatic MVD. Conversely, prostatic MVD can be increased with the increase of DHT concentration. Therefore, for patients with a large prostate volume scheduled for TURP,preoperative non-competitive 5α-reductase inhibitor to reduce DHT concentration in vivo can help reduce the risk of perioperative bleeding.
In our clinical experience, we have found that BPH rarely occurrs in young patients with relatively high androgen levels and low estrogen levels, and more often in middle-aged and elderly patients with relatively low androgen levels and high estrogen levels. Devlin et al. found that, in the aging male, serum androgen levels are decreased and estrogen levels are relatively increased, which can be the possibily vital reasons for the development of BPH. Therefore, it is important to clarify the effect of changes in estrogen levels on the MVD of prostate tissue uring TURP treatment in patients with enlarged prostate. Estrogen plays an important role in angiogenesis in a variety of tissues by increasing coronary blood flow and decreasing coronary resistance and peripheral vascular tension. In this sense, estrogen could induce endothelial cells proliferation and migration, and increase the expression of vascular endothelial growth factor. In addition, Zhang et al. studied on changes in bone microvascular structure and vascular density after exogenous estrogen supplementation in rats, and found that the changes in estrogen levels could affect the bone changes in MVD, and that the formation of blood vessels in bone increases with increased dose of estrogen. Diedrich et al. reported the effect of vulvovaginal atrophy and local estrogen therapy on vaginal microcirculation structure. Using in vivo non-invasive techniques, estrogen therapy was found to have a significant effect on vaginal microcirculation structure, and local estrogen therapy can restore vaginal blood vessels.
At present, there is still a lack of relevant researches on the effect of changes in estrogen levels on MVD of prostate tissue.This is the first systematic study in vitro of the effect of estrogen/androgen changes on prostate MVD. We not only confirmed that androgens play an important role in the regulation of MVD in the prostate of SD rats. In addition, when SD rats were castrated, a certain concentration of exogenous DHT was supplemented to increase estrogen concentration. We first confirmed that the prostatic MVD can be increased with the increase of estrogen concentration. However, it is worth noting that the angiogenic effects of estrogen are caused by several mechanisms. On the one hand, estrogen replacement therapy can increase the expression of vascular endothelial growth factor and its receptor, which regulates endothelial cell proliferation and permeability[33,34]. On the other hand, at weeks 3 and 4 of estrogen therapy, estrogen can increase endothelial progenitor cells, directly stimulate their mitosis and migration activity, and inhibit apoptosis of endothelial progenitor cells[35,36]. Furthermore, the angiogenic effects of estrogen depend on the form, dose, and duration of administration, as well as on the cellular environment. It is suggested that long-term estrogen replacement therapy may increase the expression of vascular endothelial growth factor and endothelial progenitor cells, thereby increasing the synthesis, migration, and lumen formation of prostate microvascular endothelial cells. Without doubt, it is of necessity to be confirmed by more comprehensive and systematic experiments in vivo and in vitro.
In addition, in this study, we also found that the incidence of factor VIII positivity was different from that of positive CD-34. These two endothelial cell antigens, namely factor VIII and CD-34, mark blood vessels of various maturity. Anti-CD34, an antibody that is very sensitive to endothelial cell differentiation, stains tumor endothelial cells more strongly than normal endothelial cells[38,39]. Da Silva et al. found that the MVD detected by anti-CD34 was significantly higher than that of anti-factor VIII in breast cancer tissues. However, there exists a lack of systematic studies on whether there is a difference between CD-34 and factor VIII in detecting MVD in non-tumour tissues, especially in the prostate, which provides a new direction for our research in the next stage.