http://orcid.org/0000-0003-0970-8462
Abstract
Objective: Assess the association between serum sex hormone level and prostate volume in men with benign prostatic hyperplasia (BPH).
Material and methods: The study involved 239 BPH patients from January 2013 to June 2015 in our hospital. Each patient collected age, medical history, height, weight, body mass index, as well as a full examination of sex hormones, and transrectal ultrasound results.
Results: Estradiol (E2) was significantly associated with prostate volume (r = 0.151, p = .02) and transitional zone volume (r = 0.136, p = .035). The association was more significant after adjusting age and BMI (r = 0.253 and 0.250, p <.001). Patients were divided into two groups according to prostate volume and E2, respectively. E2 in patients with prostate volume ≤50 ml was significantly lower than those with prostate volume >50 ml. Prostate volume, transitional zone volume and age were all significantly higher in the patients with E2 ≥ 160 umol/l than those in the patients with E2 < 160 umol/l. Through logistics regression, E2 (p = .012, OR = 1.004) are the only independent risk factor for prostate volume.
Conclusions: E2 is significantly associated with prostate volume. High concentrations of E2 may be a risk factor for the large volume of prostate.
Introduction
Benign prostatic hyperplasia (BPH) is a common disorder among elderly men. While 50% of men beyond the age of 50 will develop histological BPH. It is characterized by the proliferation of epithelial and stromal cells, followed by enlargement of the gland [Citation1], leading to frequent micturition, difficulties in initiating micturition, nycturia, a poor stream of urine, and a prolonged duration of micturition. Lasting data suggests that by the year 2025, about 50 million Americans will suffer from BPH symptoms [Citation2], which in turn will raise healthcare expenses. So far, the etiology of BPH has not been fully explained [Citation3]. Then, aging, sex hormones, and growth factors are generally considered to play important roles in the development of BPH [Citation4]. It is worth mentioning the development of BPH is known to be sex steroid hormone-dependent. As we know, testosterone is converted to dihydrotestosterone (DHT) by the 5α-reductase enzyme, and higher DHT levels are associated with prostate enlargement [Citation5]. Additionally, 5α-reductase inhibitors have been shown to be effective for reducing prostate volume, thereby demonstrating the importance of testosterone in prostate growth [Citation6,Citation7]. The curative way of BPH is focused on hormone.
Although androgens are essential for maintaining normal morphology and the function of the prostate, Estrogens exert important biological function. The role of estrogen in the pathogenesis of BPH was firstly observed from the treatment of dogs with estrogen (in addition to androgens) leads to the development of BPH and LUTS BPH-related [Citation8]. Estrogen is important in BPH development as the prostate is often thought of as an estrogen target tissue. Estrogens and selective estrogen receptor modulators (SERMs) have been proved to directly and indirectly affect growth and differentiation of prostate [Citation1]. Estradiol (E2), a potent estrogen, has been shown to be a powerful inducer of prostatic proliferation [Citation9]. Despite the well-known association between sex hormones and prostate growth, few data that describe the relationship between prostate volume and serum E2 level in human body are available. The precise role of estrogen action directly affecting prostate growth and differentiation in the context of BPH is an understudied area and remains to be elucidated. The aim of our research was to assess the relationship between serum sex hormone level and prostate volume in men with BPH.
Methods
The study involved 239 patients from January 2013 to June 2015 in the Urology department of our hospital, diagnosed with BPH. Each patient collected age, medical history, height, weight, body mass index, as well as a full examination of sex hormones [E2; prolactin (PRL), progesterone (P), testosterone (T), luteinizing hormone (LH), follicle-stimulating hormone (FSH), serum prostate specific antigen (PSA), free serum prostate specific antigen (fPSA), and transrectal ultrasound results (prostate volume (PV); transitional zone volume (TZV); transitional zone index (TZI); intravesical prostatic protrusion (IPP))]. The patients with age <50 years old, the history of malignant tumor or the tumor with endocrine function, treated with hormone replacement or finasteride, were excluded from this study. The enrolled patients were informed of the purpose and course of the study, and gave their written consent to take part in it.
All serum samples were collected before 8 am in the morning after at least 10 h of fasting and nonsmoking. The analysis of the serum samples was performed using Hybritech calibrated Access tPSA and fPSA assays. Meanwhile, an enzyme-linked immunosorbent assay (ELISA) method was used to measure the levels of sex hormones (E2, PRL, P, T, LH, FSH, T, and LH). The ultrasound machine made by Siemens Sequoia 512 (Linear array probe 15L8W, frequency 3–8 MHz) was used to estimate prostate volume (ml). Images were obtained with the patient in the left decubitus position. The transverse and sagittal sections were recorded after marking the transition zone. The transverse and anteroposterior diameters of the total prostate and the transition zone at the largest cross-sectional area were used for various calculations. The superoinferior diameter of the prostate was measured on midline sagittal images and that of the transition zone was measured at the point of its largest diameter on the sagittal image. PV and TZV were calculated using the formula of volume estimation of an ellipsoid: volume = 0.52 × transverse diameter (mm) × anteroposterior diameter (mm) × superoinferior diameter (mm).
Statistical analysis was performed using SPSS Statistics version 21.0 (SPSS Inc., Chicago, IL). The data were presented as the mean ± SD. The distribution’s normality was examined using a one sample K–S test. Independent student’s t-test would be used when the data was consistent with normal distribution while Mann–Whitney U-test would be used when the data was not consistent with normal distribution. Correlations between the parameters were analyzed using Spearman’s correlation coefficient. Univariate and multivariate logistic regression were performed to search the risk factors of prostate volume, using enter and forward likelihood ratio method, respectively. The level of significance was set at p < .05. A p value < .05 was considered as statistically significant.
Results
A total of 239 patients were included in our study. The mean age of the enrolled patients was 71.39 ± 8.422 and the mean E2 level was 168.64 ± 89.665 pmol/l (). shows the correlation between prostate volume and sexual hormones. E2 was observed significantly associated with prostate volume (r = 0.151, p = .02) and TZV (r = 0.136, p = .035). Similarly, E2/T was also significantly associated with prostate volume (r = 0.163, p = .012) and TZV (r = 0.153, p = .018). However, the serum level of testosterone was not associated with prostate volume (r = −0.066, p = .308) and TZV (r = −0.076, p = .240).
Table 1. The baseline value of BPH patients.
Table 2. The association between prostate volume and sexual hormones.
It is clear that the prevalence of histologic BPH increases Obesity is a common comorbidity of BPH and also is an independent predictor of progression of LUTS [Citation10]. After adjusting BMI, the correlation between E2 and PV (r = 0.253, p < .001), TZV (r = 0.250, p < .001) was more significant. Meanwhile, E2/T was not associated with prostate volume (r = 0.119, p = .067) and TZV (r = 0.096, p = 0.138) adjusted by BMI ().
Table 3. The association between prostate volume and sexual hormones adjusted by age and BMI.
We analyzed the differential concentration of serum sexual hormones between the group with PV ≤50 ml and the group with PV >50 ml. It is found that E2 level was significantly upregulated in the group with PV >50 ml comparing with the group with PV ≤50 ml (n = 239, p = .019) while the ratio of E2/T was not sharply increased in the group with PV >50 ml (n = 239, p = .095) ().
Table 4. The comparison of sexual hormones between the group with PV ≤50 ml and the group with PV >50 ml.
Furthermore, we divided the patients according to serum E2 level. PV, TZV, and age in the patients with serum E2 level ≥160 pmol/l were significantly higher than those in the patients with serum E2 level <160 pmol/l, respectively ().
Table 5. The comparison of prostate volume between the group with E2 < 160 pmo/l and the group with E2 ≧ 160 pmo/l.
Univariate and multivariate logistic regression were performed to search the independent risk factors of prostate volume in BPH patients. By univariate analysis, it is revealed that only E2 (OR = 1.004, 95% CI 1.000–1.008, p = .028) was the risk factors for increasing prostate volume in BPH patients. Similarly, multivariate analysis showed E2 (OR = 1.004, 95% CI 1.001–1.008, p = .012) was the only independent risk factors for increasing prostate volume in BPH patients ().
Table 6. The univariate and multivariate analysis of hormone and prostate volume.
Discussion
Prostatic enlargement is one of the key features of clinical BPH. According to the Olmsted County study, there is an obvious association between the size of the prostate and the prevalence of LUTS according to age [Citation10]. Prostate size is also directly related to the risk of AUR and surgery for BPH. It is estimated that there is a 3-fold relative risk for urinary retention for men with prostates larger than 30 ml compared to those with prostates smaller than 30 ml [Citation11]. Results from the same study have estimated a 9-fold increase in the risk of prostate surgery for men with prostates larger than 30 ml [Citation12].
Although the development of the prostate is obviously an androgen-dependent process [Citation13], the mechanism of androgens on the development of BPH remains unclear. First, the incidence of BPH increases continuously during aging concomitantly with a decreased serum T levels [Citation14,Citation15]. Second, no correlation between serum T levels and prostate size has been found clinically [Citation1,Citation3,Citation16], which is similar with this study. Finally, treatment with androgens in hypogonadal patients does not appear to increase the risk of development of BPH/LUTS and, in some cases, LUTS is even improved by androgen replacement therapy [Citation16–18]. These observations indicated that androgens are not directly related to the development of BPH, which was supported by two hypotheses. The first one hypothesized that DHT intraprostatic concentrations, rather than circulating T levels, are implicated in the development of prostatic hyperplasia [Citation16]. Indeed, both androgen receptor (AR) and intraprostatic DHT concentrations remain stable during aging. Moreover, the saturation model theory proposed by Morgentaler and Traish [Citation19] hypothesize that the prostate is relatively insensitive to serum T level variations because the AR in prostate cells is normally saturated by relatively low androgens intratissue concentration. In these conditions, the AR can be fully activated in spite of the possible decrease in circulating T levels.
Since the incidence and development of BPH are not related to the serum T level, it may be hypothesized that other factors, such as growth factors, estrogen, inflammation, may play a key role in BPH etiology [Citation20]. Previous studies have found that estrogens directly and indirectly affect the growth of the prostate and the development of prostatic diseases. Estrogens are important regulators of prostatic stromal development [Citation21,Citation22]. The relationship between estrogens and prostate has been studied in animal models. Coffey et al. observed that the treatment of dogs with estrogen (in addition to androgens) leads to the development of BPH and LUTS BPH-related [Citation8]. Suzuki et al. showed that when Wistar rats were treated with testosterone and E2, prostate weight increased at a higher rate than with testosterone treatment alone, accompanied by higher DNA synthesis indices [Citation23]. Fujimoto et al. also reached the similar conclusion in C57BL mice [Citation24]. However, there are only several articles investigate the estrogens and prostate volume in BPH patients. Hammarsten et al. indicated the significant correlation between prostate volume and free E2 in the 159 patients living in Goteborg, Sweden [Citation25]. The sample volume of this study was relatively low and the patients’ age concentrated in 69–80 years old. Nukui et al. did the similar study in Japan and concluded that E2 and testosterone had significant correlation with prostate volume, especially in prostate volume >25 ml [Citation26]. The sample volume and patients’ age was close to our study. However, the prostate volume was lower than that in our study and the collection time of serum sample was different, which may be lead to the similar but not the same conclusion. The studies from the United States [Citation27] and Korea [Citation28] did not find the association between E2 level and prostate volume. This study was the first study for investigating the relationship between E2 and prostate volume in Chinese people.
In the estrogen pathway, estrogen receptors play an important role in modulating estrogen action. Estrogen action is mediated by two nuclear receptors: estrogen receptor-alpha (ERα) and estrogen receptor-beta (ERβ). ERα is a key mediator and putative therapeutic target for bladder complications of BPH. It has been reported that, while ERα is an oncogenic factor involved in cell proliferation and survival, ERβ is a protective factor that is anti-carcinogenic and pro-apoptotic. Recent experimental animal models on prostatic hyperplasia support estrogen receptors as critical factors in the prostatic hyperplastic response [Citation29]. E2 has been shown to promote prostate proliferation through activating ERα [Citation9] and cells expressing ERα were more prevalent in human BPH [Citation30]. Moreover, Park et al. suggested that the mechanism of estrogen-regulated cell growth and the role of stromal cells may be different in normal versus BPH prostates. Normal stromal cells predominantly used rapid E2 signaling, but BPH stromal cells used classical ER-signaling, which was inhibited by treatment with ER antagonist [Citation31]. To some extent, these may explain why the higher serum E2 level, the higher prostate volume in BPH patients.
There also exist some limitations in this study. We did not study the factors which could influence the estrogen metabolism, such as diet, smoking, alcohol intaking, metabolic syndrome, and leptin. We will do further prospective study in the near future. Moreover, serum levels of E2 do not necessarily reflect tissue levels of E2, which may be able to cause some ideas.
All of above, this is a large scale descriptive study, to the best of our knowledge, to investigate whether E2 is associated with the susceptibility to BPH. To our knowledge, we first reported the significant association between the serum E2 level and BPH after adjusting age and BMI in Chinese people. High concentrations of E2 may be a risk factor for a large volume of the prostate in BPH patients. Several possible mechanisms of the association between E2 level and BPH needed to be further elucidated. The factors that lead to the pathogenesis of BPH have not been clearly defined. In the future, additional studies should be conducted with to confirm these cascades.
Acknowledgments
The authors thank all patients for their ongoing participation in this study.
Disclosure statement
No potential conflict of interest was reported by the authors.
Additional information
Funding
References
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