The hormonal regulation of the prostate - Influence of the natriuretic peptides

Abstract

Benign prostatic hyperplasia (BPH) is the most common disease in men, with 40 % of men aged 40 years suffering from BPH. The incidence continues to rise and 70-80 % of men aged 80 years have BPH. The disease develops in the transition zone of the prostate, and both the epithelial and stromal parts are involved. There is uncontrolled growth and proliferation of cells, whereby the stromal part with it smooth muscle cells (SMCs) is more affected. Due to the anatomical specificity of the prostate with its outer capsule, growth takes place inward and prostate tissue presses on the urethra. This leads to lower urinary tract symptoms (LUTS). Current treatment options with α1-adreneroreceptor antagonists or 5-α-reductase inhibitor aim to reduce the muscle tone and to inhibit cell proliferation. However, these treatments have side effects and a massive impact on patients' lives due to libido loss and ejaculatory disorders. Novel treatment options with phosphodiesterase (PDE)-5 inhibitors influence the cGMP signalling pathway, which leads to the relaxation of SMCs. Here, none of the side effects observed with α1-adreneroreceptor antagonists or 5-α-reductase inhibitors were seen. Thus, the cGMP pathway represents a target for the development of new therapeutic options for BPH. This pathway was further investigated because a high concentration of the natriuretic peptide CNP, which activates the pathway via guanylyl cyclase-B (GC-B), was found in the prostate and seminal plasma. In this study, a more detailed investigation of CNP/GC-B was aimed at revealing new therapeutic applications of the cGMP signalling pathway. The expression of key components of the cGMP signalling pathway was measured in the human prostate, with a significantly higher expression of the CNP receptor GC-B than the other GCs (GC-A and sGC) and local expression of the natriuretic peptide CNP. This indicates that the CNP/GC-B signalling pathway may play a more important role than ANP/GC-A or nitric oxide/soluble GC in the human prostate. In this study, stronger activation of the cGMP signalling pathway in prostatic SMCs (HPrSMCs) via CNP (compared with ANP) was demonstrated using a specific cGMP ELISA. This cGMP signalling pathway could be specifically activated by NPs or their analogues in the prostate to treat BPH. As the cGMP signalling pathway not only led to relaxation in SMCs, but also had an antiproliferative effect, this was also investigated. Both CNP and the synthetic peptide VNP led to significantly reduced growth of HPrSMCs. Since previous studies of our group showed, a hormonal correlation between cGMP pathway components and testosterone in the rat prostate, the local concentration of testosterone (T) and estradiol (E2) in the prostate of BPH patients was investigated. Measurements showed that T was more concentrated than E2 in the human prostate, and the concentrations of T and E2 correlated positively. Since one of the causes of BPH is considered to be the decrease in serum T levels and concomitant hormonal changes between serum levels of T and E2 in males, this ratio in the prostate was considered. These changes in the T/E2 ratio are probably not reflected in the prostate, since the enzyme aromatase converts T to E2 and the ratio is therefore constant. An ex vivo rat model was used for functional experiments. Expression analyses revealed a similar expression profile among the three entities examined in this study. Among them, GC-B was expressed at significantly higher levels than the other GCs (GC-A and sGC); therefore, the rat prostate was considered suitable for demonstrating the effect of NPs on tissues. For the analysis, an extended code was used that evaluates the entire tissue. The tissue is converted into individual pixels, and thus, data points that allow a more precise analysis. The resulting results were converted into a movement score and allowed an accurate representation of the movement in the tissue. Experiments showed that CNP and VNP resulted in significant relaxation of rat prostate glands. The results of this thesis suggest that in addition to used PDE5 inhibitors, there are further possibilities to use the cGMP pathway in the treatment of BPH. Manipulation of this pathway shows fewer side effects in practice with PDE5 inhibitors, which severely affect the patient's life. Thus, additional activation of the cGMP signalling pathway via NPs or analogues should be considered for treatment of BPH. This signalling pathway not only leads to prostate relaxation, but also inhibits the proliferation of HPrSMCs. By targeting the CNP/GC-B signalling pathway, both characteristics of BPH could be addressed.