Endocrine Disruptors and Estrogens in Human Prostatic Tissue.

Endocrine disruptors (EDs) are ubiquitous substances both in the environment and everyday products that interfere with the hormonal system. Growing evidence demonstrates their adverse effects on the organism, including the reproductive system and the prostate, owing to their (anti)estrogenic or antiandrogenic effects. Since EDs can interact with steroid hormone actions on-site, understanding the levels of intraprostatic EDs in conjunction with steroids may hold particular significance. The aim of this study was to develop and validate a method for determining estrogens, various groups of EDs (bisphenols, parabens, oxybenzone and nonylphenol) and phytoestrogens in their unconjugated and conjugated forms in prostate tissue by liquid chromatography-tandem mass spectrometry, and subsequently analyze 20 human prostate tissue samples. The method enabled 20 compounds to be analyzed: estrogens (estrone, estradiol, estriol), bisphenols (bisphenol A- BPA, BPS, BPF, BPAF, BPAP, BPZ, BPP), parabens (methyl-, ethyl-, propyl-, butyl-, benzyl- paraben), oxybenzone, nonylphenol and phytoestrogens (daidzein, genistein, equol) with LLOQs between 0.017-2.86 pg/mg of tissue. The most frequently detected EDs in prostate tissues were propylparaben (conjugated and unconjugated forms in 100 % of tissues), methylparaben (unconjugated in 45 % and conjugated in 100 %), ethylparaben (unconjugated in 25 % and conjugated in 100 % BPA (unconjugated in 35 % and conjugated in 60 % and oxybenzone (both forms in 45 % To the best of our knowledge, this is the first study detecting EDs, phytoestrogens and estriol conjugate (E3C) in the prostate. E3C was the most abundant estrogen in prostatic tissue. This highlights the need for further explorations into estrogen metabolism within the prostate.

The quantitation of 7beta-hydroxy-epiandrosterone in the plasma and seminal plasma of men with different degrees of fertility.

7beta-hydroxy-epiandrosterone (7beta-OH-EpiA) is an endogenous androgen metabolite that has been shown to exert neuroprotective, anti-inflammatory and anti-estrogenic effects. However, to the best of our knowledge no information is available about this androgen steroid in relation to sperm quality. We analyzed 7beta-OH-EpiA in plasma and seminal plasma using a newly developed isotope dilution ultra-high performance liquid chromatography - mass spectrometry method. Validation met the requirements of FDA guidelines. Levels of 7beta-OH-EpiA were measured in 191 men with different degrees of infertility. One-way analysis of variance followed by multiple comparison and correlation analysis adjusted for age, BMI and abstinence time were performed to evaluate the relationships between this steroid and sperm quality. Concentrations of 7beta-OH-EpiA in seminal plasma were significantly higher in severely infertile men in comparison with healthy men and slightly infertile men. The same trend was found when blood plasma was evaluated. Furthermore, plasma 7beta-OH-EpiA negatively correlated with sperm concentration (-0.215; p<0.01) and total count (-0.15; p<0.05). Seminal 7beta-OH-EpiA was negatively associated with motility (-0.26; p<0.01), progressively motile spermatozoa (-0.233; p<0.01) and nonprogressively motile spermatozoa (-0.188; p<0.05). 7beta-OH-EpiA is associated with lower sperm quality and deserves more research in that respect.

Serum and intratesticular sex steroids in azoospermic men: how do they correlate?

Five intratesticular sex steroids (testosterone, dihydrotestosterone, androstenedione, estradiol and epitestosterone) along with six serum hormones (LH, FSH, prolactin, SHBG, testosterone and estradiol) were determined in 84 non-obstructive azoospermic men, in order to evaluate to what extent serum and testicular tissue as well as individual hormones in the same material mutually correlate. With exception of androstenedione, tight correlations were found among tissue content of sex steroids, while only weak correlation was recorded between serum and testicular concentrations of major sex steroids testosterone and estradiol. It points to importance of measurement of intratesticular steroids in combination with examination of sperm parameters for assessment of testicular function and spermatogenesis.

[Robotic-assisted radical prostatectomy - results of 1500 surgeries]. / Roboticky asistovaná radikální prostatektomie - výsledky u 1500 operací.

INTRODUCTION: Prostate cancer is the most common malignant disease in men. The number of cases of prostate cancer has increased dramatically in recent 20 years. Radical prostatectomy is a surgical method for the first-line treatment of localised prostate cancer. We performed the first robotic-assisted radical prostatectomy on December 16th, 2005, achieved the boundary of 1000 robotic-assisted radical prostatectomies in 2012, and in 2015, we successfully completed the 1500th robotic-assisted operation on the prostate. METHOD: We retrospectively evaluated the oncological and functional results in 1,500 consecutive patients who underwent robotic-assisted radical prostatectomy at our institution between 20052015. The robotic system da Vinci Standard was used for the operations until November 2013, and subsequently the robotic system da Vinci Si HD. Mean age of the patients was 63.7 years (40 to 86); mean BMI was 27.7 (19.4 to 41.4); and mean preoperative PSA was 6.7 ng/ml (0.4 to 112.0). RESULTS: Pathological stage of the localised prostate cancer was found in 1125 (75%) men, and the stage of locally advanced cancer was found in 363 (24.2%) patients. We determined the Gleason score 7 in surgical specimens of 1150 (76.7%) men. 171 (11.4%) men underwent pelvic lymphadenectomy; metastases in the pelvic lymph nodes were detected in 36 (21.1%) patients. Urinary continence in the period of up to 1 year after the surgery was evaluated in 1218 (81.2%) patients in the group. 1119 (91.9%) men needed no incontinence pads or one safety pad one year from the surgery. Postoperative erectile function was evaluated in 447 (29.8%) men. One year from the surgery, 247 (55.3%) men were capable of a sufficient erection for sexual intercourse without any supportive therapy. Intraoperative complications according to the Clavien-Dindo classification were observed in 20 (1.3%) patients; complications within 3 months from the surgery were observed in 127 (8.5%) patients. CONCLUSION: Robotic-assisted radical prostatectomy is a clearly defined, safe and reproducible minimally invasive treatment of localised prostate cancer.Key words: prostate cancer robotic surgery radical prostatectomy complications.

Differences in bisphenol A and estrogen levels in the plasma and seminal plasma of men with different degrees of infertility.

The general population is potentially exposed to many chemicals that can affect the endocrine system. These substances are called endocrine disruptors (EDs), and among them bisphenol A (BPA) is one of the most widely used and well studied. Nonetheless, there are still no data on simultaneous measurements of various EDs along with steroids directly in the seminal fluid, where deleterious effects of EDs on spermatogenesis and steroidogenesis are assumed. We determined levels of BPA and 3 estrogens using LC-MS/MS in the plasma and seminal plasma of 174 men with different degrees of infertility. These men were divided according their spermiogram values into 4 groups: (1) healthy men, and (2) slightly, (3) moderate, and (4) severely infertile men. Estradiol levels differed across the groups and body fluids. Slightly infertile men have significantly higher BPA plasma and seminal plasma levels in comparison with healthy men (p<0.05 and p<0.01, respectively). Furthermore, seminal BPA, but not plasma BPA, was negatively associated with sperm concentration and total sperm count (-0.27; p<0.001 and -0.24; p<0.01, respectively). These findings point to the importance of seminal plasma in BPA research. Overall, a disruption of estrogen metabolism was observed together with a weak but significant impact of BPA on sperm count and concentration.

Steroids pretreatment in assisted reproduction cycles.

The objective is to present an overview of trials and appreciate the relevant data on the effect of steroids pretreatment (oral contraceptives, 17ß-estradiol and estradiol valerate) in assisted reproduction cycles. The subject of the study is to evaluate the clinical characteristics during steroids pretreatment cycles focused on the prevention of ovarian cysts, the positive contraceptive effect on the onset of regular period during long gonadotropin releasing hormone agonist protocol. In gonadotropin releasing hormone antagonist protocol the review is interested in supporting ovarian stimulation in low responders, the idea of cycle scheduling and improving treatment outcomes. The method is a review from MEDLINE/Pubmed database between 1994 and July 2012. We identified 15 randomised controlled trials (n=3069 patients). One trail (n=83 patients) assessed GnRH agonist protocol with or without steroids pretreatment, 8 trials (n=1884 patients) assessed GnRH antagonist protocols with or without steroids pretreatment and 6 trials (n=1102 patients) assessed GnRH antagonist protocols versus agonist ones with steroid pretreatment. Data demonstrates that oral contraceptives offer the effective prevention of functional ovarian cysts, the predictable onset of period during desensitisation. Existing data suggest that pretreatment with oral contraceptive pills or estradiol valerate give no advantage concerning number of oocytes or pregnancy rate. Pretreatment with oral contraceptive pills aiming to avoid weekend oocytes retrievals has to be more elucidated. In low responders oral contraceptive pill pretreatment may be beneficial in improving ovarian responses by reducing the amount of gonadotropins and the number of days required for ovarian stimulation. Current research indicates that also 17ß-estradiol may be encouraging pretreatment in low responders and in cycle scheduling. This article is part of a Special Issue entitled 'Pregnancy and Steroids'.

Hormones and endocrine disruptors in human seminal plasma.

Seminal plasma represents a unique environment for maturation, nutrition, and protection of male germ cells from damaging agents. It contains an array of organic as well as inorganic chemicals, encompassing a number of biologically and immunologically active compounds, including hormones. Seminal plasma contains also various pollutants transferred from outer environment known as endocrine disruptors. They interfere with hormones at the receptor level, act as inhibitors of their biosynthesis, and affect hormone regulation.In this minireview, the main groups of hormones detected in seminal plasma are summarized. Seminal gonadal steroids were investigated mostly with aim to use them as biomarkers of impaired spermatogenesis (sperm count, motility, morphology). Concentrations of hormones in the seminal plasma often differ considerably from the blood plasma levels in dependence on their origin. In some instances (dihydrotestosterone, estradiol), their informative value is higher than determination in blood.Out of peptide hormones detected in seminal plasma, peptides of transforming growth factor beta family, especially antimullerian hormone, and oligopeptides related to thyrotropin releasing hormone have the high informative value, while assessment of seminal gonadotropins and prolactin does not bring advantage over determination in blood.Though there is a large body of information about the endocrine disruptors' impact on male reproduction, especially with their potential role in decline of male reproductive functions within the last decades, there are only scarce reports on their presence in seminal plasma. Herein, the main groups of endocrine disruptors found in seminal plasma are reviewed, and the use of their determination for investigation of fertility disorders is discussed.

Penis augmentation by application of silicone material: complications and surgical treatment.

BACKGROUND: Complications resulting from enlargement of the penis by applications of unknown types of silicone and mineral oils are well described. Surgical removal of the tissue altered by inflammation leads to the development of defects of various sizes, often circular from the glans penis to the scrotum. The options of subsequent surgical treatment described in literature are not very extensive. Most defects are managed with skin grafting, rarely V-Y advancement or bilateral scrotal flaps. METHODS: We present a 36-year-old patient after application of unknown silicone material into the penis for cosmetic enlargement. After the application developed severe inflammation with ulceration and necrosis around the penis. Conservative treatment was not effective, therefore, the infiltrated skin with subcutaneous tissue of the entire penis was surgically removed. The resulting defect was covered by implantation of the penis under the skin of the scrotum. RESULT: There were no complications in the postoperative course, pain that was present before the surgery immediately subsided. Skin suture healed completely within 14 days. Three months after the surgery the patient returned to normal sexual life. CONCLUSIONS: Implantation of the penis under the skin of the scrotum is a fast, safe and effective method that can treat most of the circular skin defects of the penis. Scrotal skin is thin, soft, elastic and creates abundant and good cover around the entire penis.

[Obesity and male infertility]. / Obezita a muzská neplodnost.

The authors present a review on the effects of obesity on male fertility. Current scientific findings suggest an elevated risk of infertility among couples in which the male partner is obese. In obese men can be found reduced serum levels of androgens and SHBG and increased estrogen levels without compensatory increase in FSH. Among other impacts of male obesity that may contribute to increased risk of infertility are altered retention and metabolism of environmental toxins, lifestyle, sexual dysfunction, genetic factors, excessive secretion of hormones derived from adipose tissue, oxidative stress, sperm specific proteomic changes or elevated levels of cytokines. The increasing prevalence of obesity calls for greater clinical awareness of its impact on male fertility.

Responder analysis of the effects of denosumab on bone mineral density in men receiving androgen deprivation therapy for prostate cancer.

BACKGROUND: Denosumab, a fully human monoclonal antibody against RANK ligand, increased bone mineral density (BMD) and reduced fracture risk vs placebo in a phase 3 trial in men with prostate cancer on androgen deprivation therapy (ADT). The present analysis of this study evaluated BMD changes after 36 months in responder subgroups and in individual patients for three key skeletal sites (lumbar spine (LS), femoral neck (FN) and total hip (TH)) and the distal radius. METHODS: Men with nonmetastatic prostate cancer receiving ADT were treated with subcutaneous denosumab 60 mg (n=734) or placebo (n=734) every 6 months for up to 36 months in a phase 3, randomized, double-blind study. Patients were instructed to take supplemental calcium and vitamin D. For this BMD responder analysis, the primary outcome measure was the percentage change in BMD from baseline to month 36 at the LS, FN and TH as measured by dual-energy X-ray absorptiometry. BMD at the distal 1/3 radius at 36 months was measured in a substudy of 309 patients. RESULTS: At 36 months, significantly more patients in the denosumab arm had increases of >3% BMD from baseline at each site studied compared with placebo (LS, 78 vs 17%; FN, 48 vs 13%; TH, 48 vs 6%; distal 1/3 radius, 40 vs 7% (P<0.0001 for all)). BMD loss at the LS, FN and TH occurred in 1% of denosumab-treated patients vs 42% of placebo patients, and BMD gain at all three sites occurred in 69% of denosumab patients vs 8% of placebo patients. Lower baseline BMD was associated with higher-magnitude BMD responses to denosumab at the LS, FN and TH. CONCLUSIONS: In men with prostate cancer receiving ADT, significantly higher BMD response rates were observed with denosumab vs placebo. Patients with lower baseline T-scores benefited the most from denosumab treatment.

Testicular sperm aneuploidy in non-obstructive azoospermic patients.

BACKGROUND: Non-obstructive azoospermic (NOA) men can father children after testicular sperm extraction (TESE). Previous studies suggest that they may be at risk of producing chromosomally abnormal spermatozoa, but the number of sperm analysed per patient was usually very low. METHODS: Multicolour fluorescence in situ hybridization was used for detection of chromosome 13, 15, 16, 18, 21, 22, X and Y disomy and diploidy in sperm obtained from NOA men (n = 17) and control donors (n = 10). At least 500 testicular sperm were scored in each patient to increase the precision of our study. RESULTS: The mean frequency of overall disomy (2.32%) and diploidy (0.80%) found in 13 689 testicular spermatozoa of NOA patients was significantly higher than in the ejaculated sperm of normospermic control donors, disomy (0.62%) and diploidy (0.29%). A highly significant increase in frequencies of chromosome 15, Y and overall disomy (P < 0.001), and a significant increase in disomy of chromosome 13 (P = 0.002), 16 (P = 0.031) and 21 (P = 0.018), overall diploidy (P = 0.031) and diploidy caused by errors in meiosis I (P = 0.011) were observed in the NOA group. CONCLUSIONS: Testicular sperm samples of NOA patients show a higher incidence of numerical chromosomal abnormalities compared with ejaculated sperm of control donors. Appropriate genetic counselling is necessary in NOA men undergoing TESE.

The content of five sex steroids in human testis.

In order to assess whether intratesticular hormone content may be helpful for prediction of successful conception in men with fertility problems, five sex steroids, testosterone, dihydrotestosterone, androstenedione, estradiol and, for the first time epitestosterone, were measured in testicular tissue obtained by surgical retrieval from total 84 men. The group consisted of non-obstructive azoospermic men, aged 21-67 years who attended the centre for in vitro fertilization. Steroids after ether extraction and solvent partition were separated by high performance liquid chromatography and then measured by specific radioimmunoassays. The values varied considerably with means ± S.D. 2.43±2.47, 0.27±0.24, 0.080±0.13, 0.071±0.089 and 0.31±0.27 for testosterone, dihydrotestosterone, androstenedione, estradiol and epitestosterone, respectively.

Serum resistin levels in benign prostate hyperplasia and non-metastatic prostate cancer: possible role in cancer progression.

Resistin is a member of adipokine family involved in the regulation of inflammatory reactions and insulin sensitivity. In presented study its possible role in the development of benign prostate hyperplasia and prostate cancer was evaluated. Blood samples and prostate specimens were collected from 26 patients with benign prostate hyperplasia (BPH) and from 42 patients with prostate cancer (PCa) stage pT2 (n=18) and pT3 (n=24). Selected metabolic and biochemical parameters and serum resistin levels were measured and anthropometric measurements were performed as well as tissue immunohistochemistry for resistin. Serum resistin levels did not differ significantly between benign hyperplasia and prostate cancer but in cancer patients there was a trend towards decrease with higher cancer stage. Moreover, serum resistin levels were significantly lower in patients with seminal vesicle invasion in comparison to those without invasion. While in BPH serum resistin levels correlated with insulin resistance, inflammatory status and cortisol, in PCa positive correlation with F/T PSA ratio and cortisol was observed. Tissue immunohistochemistry did not show any differences in staining pattern between benign and neoplastic prostate tissue. We conclude that serum resistin levels do not significantly differ between patients with benign prostate hyperplasia and prostate cancer, but there is a trend towards decrease in resistin serum levels in advanced cancer cases.

Adiponectin as a potential marker of prostate cancer progression: studies in organ-confined and locally advanced prostate cancer.

Serum levels of adiponectin were measured in patients with benign prostatic hyperplasia and prostate cancer of pT2 and pT3 stage. Adiponectin ELISA assay, immunohistochemistry, and selected metabolic and biochemical parameters measurement was performed in 25 patients with benign prostatic hyperplasia and 43 with prostate cancer (17 patients with organ-confined and 26 patients with locally advanced disease). Serum adiponectin levels did not differ between prostate benign hyperplasia and cancer clinical stage T2, but was significantly higher in pT3 relative to pT2 group (14.51+/-4.92 vs. 21.41+/-8.12, P = 0.003). Tissue immunohistochemistry showed enhanced staining in neoplastic prostate glands and intraepithelial neoplasia relative to benign prostatic hyperplasia without distinction between disease grade and stage. Serum adiponectin levels are higher in locally advanced relative to organ-confined prostate cancer and may thus serve as an auxiliary marker providing further improvement for discrimination between pT2 and pT3 stages.

[Evaluation of the tumor extension before planned radical prostatectomy: a prospective study]. / Moznosti stanovení lokálního rozsahu karcinomu prostaty pred plánovanou radikální lécbou: prospektivní studie.

BACKGROUND: Study compares results of preoperative diagnostic methods with measurements of tumor extension in a specimen obtained by radical prostatectomy. METHODS AND RESULTS: One hundred forty-six patients with clinically identified cancer were enrolled in the study and subjected to radical prostatectomy. Each patient underwent transrectal sonography (TRUS), Power Doppler sonography with 3D reconstruction (3D-PDS), and the risk of the occurrence of locally advanced tumor was assessed using Partin tables. In subgroups of localized and locally advanced tumor, individual preoperative parameters were compared. ROC curves were generated for individual preoperative parameters and the area under the curve (AUC) was calculated. Multivariate logistic regression analysis was performed to determine independent predictors of extraprostatic tumor extension. A statistically significant difference between patients with localized and locally advanced tumor was observed in PSA levels (p < 0.014), PSA density (p < 0.004), DRE (p < 0.037), TRUS (p < 0.003), and 3D-PDS (p < 0.000). The highest AUC value was found for 3D-PDS 0.776, TRUS 0.670, and PSA density 0.639. According to multivariate analysis, independent preoperative predictors of extraprostatic tumor extension were PSA density, preoperative Gleason score 7, and 3D-PDS finding. CONCLUSIONS: Power Doppler sonography with 3D reconstruction represents the most reliable preoperative diagnostic tool in determining locally advanced tumor. Together with PSA density and the presence of aggressive tumor (Gleason score > or =7) in prostate biopsy, it is one of independent predictors of locally advanced prostate cancer.

Prostate-specific antigen: current status.

PSA is the most important of all tumor markers because it has significant applications in all aspects of the management of men with prostatic disease. Certainly, the most important utilization of PSA is for early detection of this most ubiquitous of all human neoplasms. In this article the authors describe the molecular forms of PSA and their characteristics, the factors influencing values of serum concentration of PSA, the problems of screening, and particularly the possibility to use PSA for detection of prostate carcinoma. A big problem in prostate carcinoma detection is the low specificity of PSA at the concentrations between 4-10 ng/ml, the so-called diagnostic gray zone, where the incidence of prostate carcinoma is only 25%. The authors evaluate the methods which make it possible to increase the sensitivity and/or specificity of PSA detection, such as PSA density, PSA density of the transition zone, PSA velocity, PSA doubling time, age-specific PSA, free PSA and, prospectively, the use of the RT-PCR technique.