Концентрация андрогенов и эстрогенов при доброкачественной гиперплазии предстательной железы The concentration of androgens and estrogens in benign prostatic hyperplasia

Background. The etiology of benign prostatic hyperplasia (BPH) has not been fully studied. The main role in the induction of prostate tissue proliferation is assigned to the metabolism of testosterone. Recently, it has been reported that one of the risk factors for BPH is a chronic violation of the blood supply to the prostate. The study objective is to determine the level of reproductive hormones in blood serum and prostate tissue when creating a model of chronic ischemia. Materials and methods. The model of chronic pelvic ischemia was created in 10 white non-linear mature rats by partial ligation of the inferior vena cava. The control group of the study consisted of 10 male rats of the same age. After 1.5 months, we performed a hormonal study in all rats (n = 20) determining the concentration of testosterone, dihydrotestosterone and estradiol in the blood and prostate tissue. Also, in all animals (n = 20), a morphological study of the prostate was performed. Results. We’ve found a significant increase in prostate mass in the main group of rats by 16.4 % (p <0.05). Animals with BPH and impaired blood supply to the prostate had changes in their hormonal status: increased levels of testosterone (p <0.05) and dihydrotestosterone (p >0.05) in the prostate tissue. Conclusion. Long-term ischemic disorders in the prostate may be a trigger for the development of BPH


Introduction
Benign prostatic hyperplasia (BPH) is one of the most common diseases in men over 50 years old [1][2][3][4][5]. Longlasting studies show that the pathogenesis of BPH remains unclear. The main role in the induction of prostate tissue proliferation is assigned to the metabolism of testosterone. According to modern concepts, an increase in the transformation of testosterone into its active metabolic analog-dihydrotestosterone has a pathogenetic value in prostatic hyperplasia [6][7][8].
Recently, it has been reported that one of the risk factors for BPH is a chronic violation of the blood supply to the prostate [9,10]. This condition can develop due to age-related changes in the pelvic vessels, atherosclerosis, etc. [11]. There are already studies in the literature that prove the deterioration of blood supply to the bladder and the development of its dysfunction in BPH [12]. Therefore, the study of the growth of hyperplastic prostate nodes against the background of chronic ischemia is an urgent issue of modern urology.
The study objective is to determine the level of reproductive hormones in blood serum and prostate tissue when creating a model of chronic ischemia.

Materials and methods
The research was experimental. The study included 20 white non-linear sexually mature rats. All the rats were 6 months old and weighed 200-250 g. All manipulations with animals were performed in accordance with the guidelines for the maintenance and use of laboratory animals [13].
The first step in the main group of animals (n = 10) was to create a model of chronic prostatic ischemia by disrupting venous outflow from the pelvic organs using dosed ligation of the inferior vena cava [12].
Then, 1.5 months after the ischemic effect on the prostate, we've performed a hormonal study in all rats (n = 20)determining the concentration of androgens (testosterone, dihydrotestosterone) and estrogens (estradiol) in the blood and prostate tissue. The level of hormones in the blood serum was determined by immunochemiluminescence on the access 2 device (Beckman Coulter, USA). To determine the concentration of androgens in the prostate tissue, we prepared a homogeneous substrate in the ratio of tissue / saline 1:10. This substrate was centrifuged at 3000 rpm for 5 min. The concentration of hormones was determined by an enzyme immunoassay (DRG Instrument GmbH, Germany) using an Artemis K-101 HTRF Microplate Reader (Berthold Technologies GmbH & Co. KG, Germany).
After the end of the experiment, a morphological study of the prostate gland of the studied animals (n = 20) was performed: mass determination and light microscopy of histological sections stained with hematoxylin and eosin.
Statistical processing of the material was carried out using the program Statistica 7.0. The reliability of differences between quantitative indicators was assessed using the Mann-Whitney test. The differences were considered significant at p <0.05.

Results
We found a significant increase in prostate mass 1.5 months after creating a model of chronic prostatic ischemia ( fig. 1). In the main group of animals, the prostate mass was 16.4 % higher (p <0.05).
Also, during the morphological study of prostate micro-preparations, we detected signs of glandular-fibrotic prostatic hyperplasia in the main group of rats. We did not observe any histological signs of BPH in the control group of animals.
In the blood of animals of both groups, the level of total testosterone did not significantly differ (p >0.05). Indicators of dihydrotestosterone in the blood serum of rats with ischemic prostate lesions were lower by 18.1 %, and estradiol by 20.8 % compared to the control group, but these values were not reliable (p >0.05). Indicators of androgen concentration in the blood of both groups of rats (in normal and in simulations of chronic ischemic prostate disease) are presented in table. We believe that significant differences in sex hormone indicators between the main and intact groups of rats were not achieved due to the short time of observation of the animals.
The indicator of total testosterone concentration in prostate tissue had significant differences between the two groups of animals, and was higher in rats with chronic ischemic prostate lesions by 22 % (p <0.05) ( fig. 2).
The level of dihydrotestosterone was also higher by 9.1 % in the main group of animals (89 ± 3 vs 81 ± 2), but these indicators didn't differ significantly (p >0.05). The concentration of estradiol in prostate tissue had no significant differences between the groups of experimental animals (p >0.05). Moreover, the concentration of estradiol in the prostate tissue in both the main group and the control group didn't reach the threshold value (<10 pg / g).

Discussion
As we know the metabolism of testosterone is associa ted with such conditions as obesity, age-related hypogonadism, hypertension, impaired glucose tolerance [14][15][16]. All these diseases are accompanied by a decrease in organ perfusion and the development of hypoxia. Since the diseases listed above and BPH are more common in older men, the relationship between them is obvious.
Our study shows that the main fact of long-term prostate ischemia provokes its prostatic hyperplasia. Hypoxia stimulates excessive formation of connective tissue. For this reason, we recorded a marked growth of the stroma with the formation of glandular-fibrous BPH in rats with the formed model of chronic ischemia.
The prostate is an organ that reacts to androgens [20]. There is a correlation between the expression of adrenoreceptors and the progression of BPH. Moreover, increased sensitivity to testosterone in prostate tissue with nodular hyperplasia significantly correlates with the level of IPSS and the volume of the gland [21]. Thus, long-term chronic prostatic ischemia can lead to changes in the expression of sex hormone receptors.
In our study, rats with BPH and impaired blood supply to the prostate had changes in their hormonal status: increased levels of testosterone (p <0.05) and dihydrotestosterone (p >0.05) in the prostate tissue. Based on the known information that testosterone and its metabolites provoke prostatic hyperplasia, which can be claimed that long-term ischemic disorders in the prostate can be a trigger factor for the development of BPH.

Conclusion
Chronic ischemic disorders in the prostate can be described as an independent pathogenetic factor in the development of BPH. Vascular damage leads to impaired blood flow and hypoxia, with increased tissue concentration of testosterone, which potentiates the development of BPH. When detecting reduced blood flow in the prostate vessels, it is sensible to include drugs that improve microcirculation in the complex of drug therapy.