A Systematic Review of the Trace Element Concentrations in the Prostate Fluid of Normal Gland

Background: The prostate gland is subject to various disorders. The etiology and pathogenesis of these diseases are not well understood. Moreover, despite technological advancements, the differential diagnostics of prostate disorders has become progressively more complex and controversial. It was suggested that the measurement of Trace Elements (TEs) levels in Expressed Prostatic Fluid (EPF) may be useful as a biomarker. This suggestion promoted more detailed studies of the TEs concentrations in the EPF of healthy subjects. Objective: The present study evaluated by systematic analysis the published data for concentration of TEs analyzed in EPF of normal gland. Methods: The present systematic analysis included 1885 studies, all of which were published in the years from 1942 to 2019 and selected by searching the databases Scopus, PubMed, MEDLINE, ELSEVIER-EMBASE, Cochrane Library, and the Web of Science. The articles were analyzed and “Median of Means” and “Range of Means” were used to examine heterogeneity of TE concentrations in EPF of apparently healthy men. The objective analysis was performed on data from the 26 studies, with about 900 subjects. Results: The median of concentration means for such TEs as Bromine (Br), Cadmium (Cd), Coper (Cu), Iron (Fe), Rubidium (Rb), Strontium (Sr), and Zinc (Zn) in EPF of apparently healthy men were (mg/L): Br-2.86, Cd-0.146, Cu-0.416, Fe-8.3, Rb-1.13, Sr-1.22, and Zn-501. Conclusion: The study has demonstrated that the human prostatic secretion is a target fluid of human body for Cd, Fe, Sr, and Zn. Because of small sample size and high data heterogeneity, we recommend other primary studies.


Introduction
The prostate gland is subject to various disorders and of them chronic prostatitis, benign prostatic hyperplasia, and prostate cancer are the extremely common diseases of ageing men [1][2][3]. The etiology and pathogenesis of these diseases are not well understood. Moreover, despite technological advancements, the differential diagnostics of prostate disorders has become progressively more complex and controversial. This is particularly concerned with prostate cancer where the limitations and potential harms associated with the use of Prostate-Specific Antigen (PSA) as a diagnostic marker. The situation stimulates significant investigation of numerous novel biomarkers that demonstrate varying capacities to detect prostate cancer and can decrease unnecessary biopsies [4].
One of the main functions of the prostate gland is the production of prostatic fluid [46]. It contains a high concentration of Rb, Zn and some other TEs, in comparison with levels in blood serum and other human body fluids. The first finding of remarkably high levels of Zn in human Expressed Prostatic Fluid (EPF) was reported in the early 1960s [47]. After analyzing EPF expressed from the prostates of 8 apparently healthy men, aged 25-55 years, it was found that Zn concentrations varied from 300 to 730 mg/L. After this finding several investigators suggested that the measurement of Zn levels in EPF may be useful as a marker of abnormal prostate secretory function [48,49]. This suggestion promoted more detailed studies of the TEs concentrations in the EPF of healthy subjects and in those with different prostatic diseases, including prostate cancer .
TEs are vital for the normal functioning of the human body [71]. For example, Zn is an essential nutritional TE, especially in terms of proteins and nucleic acids metabolism. It is required for the catalytic activity of at least 300 enzymes, and is involved in the human immune system, in tissue repair, and in DNA syntheses.
The present study addresses the significance of prostatic fluid TEs levels as biomarker. Therefore, we systematically reviewed the available literature and performed a statistical analysis of TEs concentrations in EPF of normal gland, which may shed valuable insight into the etiology and diagnosis of prostate disorders.

Data sources and search strategy
Aiming at finding the most relevant articles for this review, a thorough comprehensive web search was conducted from Scopus, PubMed, MEDLINE, ELSEVIER-EMBASE, Cochrane Library, and the Web of Science databases between 1942 to November 2019, using the key words: trace element concentration, expressed prostatic fluid, and their combination. For example, the search terms for such TE concentration as Zn were: 'zinc concentration', 'Zn concentration', 'zinc content', 'Zn content', 'zinc level', 'Zn level' 'prostatic fluid zinc, 'prostatic fluid Zn, 'zinc of expressed prostatic fluid', and 'Zn of expressed prostatic fluid'. The language was not restricted. The titles from the search results were evaluated closely and determined to be acceptable for potential inclusion criteria.
Also, references from the selected articles were examined as further search tools. Relevant studies noted in the reference lists of each selected article were also evaluated for inclusion.

Eligibility criteria
Studies were included if the control groups were healthy human males with no history or evidence of andrologia or urologic disease and TEs were detected in samples of EPF. Studies were excluded if they were case reports or reviews. Studies involving subjects that were using Zn and other TEs supplementation were also excluded.

Data extraction
A standard extraction of data was applied, and the following available variables were extracted from each paper: method of TEs determination, number and age of health persons, samples preparing, mean and median of TEs concentrations, standard deviations of mean, and range of TEs concentrations.

Statistical analysis
Studies were combined based on means of TEs concentrations in EPF. The articles were analyzed and "Median of Means" and "Range of Means" were used to examine heterogeneity of TEs concentrations. The objective analysis was performed on data from the 29 studies, with about 900 healthy subjects.

Discussion
Samples of EPF are much more available for study than prostate tissue and can be obtained without damaging the prostate gland.

Information about TEs concentrations in prostatic fluid in different
prostatic diseases is of obvious interest, not only to more profoundly understand the etiology and pathogenesis of prostatic diseases, but also for their diagnosis, particularly for prostate cancer diagnostics. On the other hand, TEs of chemicals used for acid digestion can contaminate the EPF samples. Thus, when using destructive analytical methods, it is necessary to control for the losses of TEs, for complete acid digestion of the sample, and for the contaminations by TEs during sample decomposition, which needs adding some chemicals. It is possible to avoid these not easy procedures using non-destructive methods. Such method as XRF and, particularly, EDXRF is a fully instrumental and nondestructive analytical tool because a drop of EPF or other biological fluid is investigated without requiring any sample pretreatment or its consumption [52,[89][90][91]. In present study, in 14 articles Zn concentration in EPF samples was determined by the destructive analytical methods (13 articles-AAS and 1 article-ICP-AES) and in 10 articles nondestructive analytical methods were used for this purpose (2 articles-XRF and 8 articles-EDXRF).
Thus, published data allowed us to estimate the effect of acid digestion at the results of Zn determination in EPF on normal prostates (Table 3&4). In articles with destructive analytical methods the range of means for Zn concentration in EPF of normal prostates varied from 220mg/L to 825mg/L (ratio Mmax/ Mmin=3.75), with median of means 453 mg/L ( Table 3) Zn. There is some limitation in our study, which need to be taken into consideration when interpreting the results of this review.