Developmental,estrogen induced infravesical obstruction is reversible in adult male rodents

PURPOSE: We treat neonatally estrogenized rats and aromatase over expressing AROM+ male mice with infravesical obstruction using the specific aromatase inhibitors finrozole and letrozole, and analyzed whether developmentally induced alterations in urodynamics and rhabdosphincter are reversible in adulthood. MATERIALS AND METHODS: Adult estrogenized rats and AROM+ mice were treated with aromatase inhibitors for 6 weeks. Maximal and mean bladder pressure, the urinary flow rates and electromyography activity were recorded from the proximal rhabdosphincter. In addition, proximal rhabdosphincter thickness in the AROM+ mouse was measured and correlated with seminal vesicle size and serum testosterone concentrations. RESULTS: Finrozole and/or letrozole treatment significantly increased the mean maximal flow rate plus or minus SD in AROM+ mice (4.7 +/- 2.0 versus 13.3 +/- 4.4 ml. per minute, p = 0.0004) and in estrogenized rats (18.4 +/- 6.18 versus 31.1 +/- 10.85 ml. per minute for finrozole p = 0.005) and 32.4 +/- 14.3 for letrozole, p = 0.005), while bladder pressure slightly decreased. The reappearance of transient repolarization, indicating urethral lumen opening, coincided with an increased flow rate on electromyography in the proximal rhabdosphincter in rats. Relative thickness of the proximal rhabdosphincter (p = 0.007), seminal vesicle size (p = 0.0002) and mean serum testosterone concentration (472.5 +/- 230.35 versus 3,065.6 +/- 1,994.67 pg./ml., p = 0.0002) were restored after finrozole treatment in AROM+ mice. CONCLUSIONS: Current findings indicate that alterations in urodynamics, seminal vesicle size, and rhabdosphincter size and function in developmentally estrogenized male rodents are reversible when treated with aromatase inhibitor.     

PTEN and ERG expression in MRI-ultrasound guided fusion biopsy correlated with radical prostatectomy findings in men with prostate cancer

Background

Conventional systematic prostate biopsies (SBx) have multiple limitations, and magnetic resonance imaging (MRI)-ultrasound fusion targeting is increasingly applied (fusion biopsies [FBx]). In our previous studies, we have shown that loss of the tumor suppressor gene phosphatase and tensin homolog (PTEN) in radical prostatectomy (RP) specimens predicts poor disease-specific survival, and in active surveillance (AS), PTEN loss in SBx predicts an adverse AS outcome, although SBx PTEN status does not correlate well with the corresponding RP status. Here, we have hypothesized that PTEN and erythroblast transformation-specific related gene (ERG) status in FBx correlate better with RP than they would in SBx.

Methods

A total of 106 men, who had undergone FBx and subsequent RP in a single center between June 2015 and May 2017 were included. Fifty-three of the men had concomitant or previous SBx's. All biopsy and RP specimens were collected, and tissue microarrays (TMA) were constructed from RP specimens. Immunohistochemical stainings for PTEN and ERG expression were conducted on biopsies and RP TMAs and results were compared by using Fisher's exact test.

Results

The immunohistochemical predictive power of FBx, determined by the concordance of biopsy PTEN and ERG status with RP, is superior to SBx (77.6% vs 66.7% in PTEN, 92.4% vs 66.6% in ERG). FBx was superior to SBx in correlation with RP Gleason Grade Groups and MRI prostate imaging reporting and data system scores.

Conclusion

FBx grading correlates with RP histology and MRI findings and predicts the biomarker status in the RP specimens more accurately than SBx. A longer follow-up is needed to evaluate if this translates to better prediction of disease outcomes, especially in AS and radiation therapy where prostatectomy specimens are not available for prognostication.

     

Androgen metabolism in control and neonatally estrogenized male mice.

Reduction, oxidation, and aromatization of androgens were studied in the male genital tract of untreated control and neonatally estrogenized mice. This study shows regional differences in 5 alpha-reductase and 17 beta-hydroxysteroid oxidoreductase activities in untreated male genital tract; 3 alpha/3 beta-hydroxysteroid oxidoreductase (3 alpha/3 beta-HSOR) activity varied little between tissues. Neonatal treatment with diethylstilbestrol (DES, 2 micrograms/pup/day on days 1 through 5) caused an alteration in the androgen metabolism of the male genital tract, resulting in apparent decreased net accumulation of dihydrotestosterone (DHT). This developmentally-induced 5 alpha-reductase deficiency may play a role in the long-term inhibitory effects of early estrogenization by DES in the growth and function of male sex accessory glands. No aromatase activity could be demonstrated in the male genital tract of control or neonatally estrogenized mice.     

A dose‐dependent dual effect of oestrogen on voiding in the male mouse?

OBJECTIVES: To explore the effect of different degrees of oestrogenization on male voiding, by treating adult castrated and 5alpha-dihydrotestosterone (DHT)-maintained male mice with different doses of oestrogens, as exposure of male mice to excessive amounts of oestrogens can cause bladder outlet obstruction (BOO); in addition, male mice lacking oestrogen receptor (ER)alpha (ERKO) or ERbeta (BERKO) were studied to assess the importance of ER subtypes. MATERIALS AND METHODS: Castrated, DHT-maintained adult mice were treated with 17beta-oestradiol (E(2); 50 and 250 microg/kg) or oestrone (E(1); 5, 50 and 500 microg/kg) daily for 10 days. Control mice were treated only with the vehicle. BERKO and ERKO mice, and their wild-type littermates used as their controls, remained untreated. Under anaesthesia, the bladder and distal urethra were exposed to record simultaneously the bladder pressure and urinary flow rate from the distal urethra. RESULTS: E(2)-treated mice showed obstructive voiding, seen as increased bladder pressure, decreased average flow rate and prolonged micturition time. This was also evident when a high dose (500 microg/kg) of E(1) was used. After treatment with a dose of 50 microg/kg, the urodynamic variables were similar to those in the control mice. Surprisingly, after treatment with a low dose (5 microg/kg) all urodynamic variables improved. There was a minor increase in the bladder pressure in BERKO mice; ERKO mice had a significantly lower urinary flow rate. CONCLUSIONS: High doses of oestrogens caused BOO in castrated, DHT-maintained male mice. A small dose of E(1) had a positive effect on voiding, suggesting that oestrogens are needed for normal male voiding. Reduced urinary flow rates in ERKO mice suggest that oestrogen effects on voiding are mediated at least partly via ERalpha.     

Multiple structural and functional abnormalities in the p450 aromatase expressing transgenic male mice are ameliorated by a p450 aromatase inhibitor

The present study was undertaken to analyze the effect of a P450 aromatase inhibitor (finrozole) on 4-month-old transgenic mice expressing human P450 aromatase (P450arom) under the human ubiquitin C promoter (AROM+). AROM+ mice present several dysfunctions, such as adrenal and pituitary hyperplasia, cryptorchidism, Leydig cell hypertrophy and hyperplasia, and gynecomastia. The present study demonstrates that these abnormalities were efficiently treated by administration of a P450arom inhibitor, finrozole. The treatment normalized the reduced intratesticular and serum testosterone levels, while those of estradiol were decreased. The body weight and several affected organ weights were normalized with the treatment. Histological analysis revealed that both the pituitary and adrenal hyperplasia were diminished. Furthermore, the cryptorchid testes present in the untreated AROM+ males descended to scrotum, 4 to 15 days after inhibitor treatment. In addition, the disrupted spermatogenesis was recovered and qualitatively complete spermatogenesis appeared with the inhibitor treatment. This was associated with normalized structure of the interstitial tissue, as analyzed by immunohistochemical staining for Leydig cells and macrophages. One of the features was that the Leydig cell hypertrophy was markedly diminished in the treated mice. AROM+ mice also present with severe gynecomastia, while the development and differentiation of the mammary gland in AROM+ males was markedly diminished with the inhibitor treatment. Interestingly, the mammary gland involution was associated with the induction of androgen receptor in the epithelial cells, while estrogen receptors were still detectable in the epithelium. The data show that AROM+ mouse model is a novel tool to further analyze the use of P450arom inhibitors in the treatment of the dysfunctions in males associated with misbalanced estrogen to androgen ratio, such as pituitary adenoma, testicular dysfunction, and gynecomastia.     

Levocetirizine for treatment of immediate and delayed mosquito bite reactions

People frequently experience whealing and delayed papules from mosquito bites. Various antihistamines have previously been tried for the treatment of this condition. We performed a double-blind, placebo-controlled, cross-over study with levocetirizine 5 mg and matched placebo in 30 adults who were sensitive to mosquito bites. On the third treatment day the subjects received two Aedes aegypti bites on the forearm. The size of the bite lesions and the intensity of pruritus (visual analogue scale) were measured. Bite symptoms could be analysed in 28 subjects at 15 min and in 8 subjects at 24 h. Levocetirizine decreased the size of wheals by 60% (p < 0.001) and accompanying pruritus by 62% (p < 0.001) compared with placebo. The effect of levocetirizine increased in a linear fashion with the size of wheals and was most significant in the subjects with largest bite lesions. Levocetirizine also decreased the size of 24-h bite lesions by 71% (p=0.008) and accompanying pruritus by 56% (p=0.016). These results show that prophylactic levocetirizine 5 mg is an effective treatment for both immediate and delayed mosquito bite symptoms and is especially effective in subjects with large wheals.     

Indirect androgenic control of citrate accumulation in rat ventral prostate

Androgenic control of citrate metabolism was studied by measuring the conversion of (2-14C)acetate or (6-14C)glucose to (14C)citrate and 14CO2 in the ventral prostate of the rat. The decarboxylation of (2-14C)acetate showed that androgen preferentially increased (14C)citrate oxidation, probably to meet the increased energy demands of cellular synthetic reactions. This led to the decreased accumulation of (14C)citrate from (2-14C)acetate. On the other hand, both the production of (14C)citrate and the formation of 14CO2 from (6-14C)glucose were decreased by castration and increased by testosterone, this being mainly due to the androgenic control of pyruvate dehydrogenase. These changes were more marked and rapid than those in oxygen consumption, in (2-14C)acetate oxidation, or in the total content of prostatic citrate that was maintained by testosterone. Glucose as the main source of citrate in testosterone-treated rats can thus be replaced by alternative substrates in castrated rats. The rate of citrate accumulation could be more dependent on the number of secretory cells than their hormonal activation.     

Histopathological evidence for an association of inflammation with ductal pin-like lesions but not with ductal adenocarcinoma in the prostate of the noble rat

BACKGROUND: Chronic inflammation may contribute to the development of prostate cancer. The goal of this study was to determine the possible association of prostatic inflammation, prostatic intraepithelial neoplasia (PIN)-like lesion, and prostate cancer, and to assess the androgen and estrogen dependency of the early steps of carcinogenesis. METHODS: Noble rats were treated with testosterone and estradiol implants for 13, 18, or 26 weeks. Hormone dependency of the lesions was studied in a subset of animals by removing hormone implants for 3 weeks after 15 weeks treatment time. RESULTS: After treatment for 13 weeks, acute and chronic inflammation was found in the dorsolateral prostate lobes and both inflammation and PIN-like lesions were present in the periurethal area of the prostate in all animals (n = 8). Following hormone exposure for 18 and 26 weeks, inflammation in the prostate remained, and adenocarcinomas in the periurethal prostate area with no adjacent inflammation were observed in all 18 animals studied. When both hormone implants were removed after 15 weeks, PIN-like lesions progressed further to adenocarcinoma only in two of seven animals. When only the estradiol implants were removed, three of five animals developed adenocarcinomas. CONCLUSIONS: Even though adenocarcinomas were not morphologically associated with inflammation, PIN-like lesions preceding adenocarcinoma were found in close association with inflammation, pointing towards a possible initiator role of inflammation in the early steps of prostatic carcinogenesis. Further, these results indicate that both androgens and estrogens together play a significant role in the induction of inflammation and prostatic cancer in this model.     

Developmental estrogenization and prostatic neoplasia

The association of estrogens with benign prostatic hyperplasia and prostatic cancer has been widely studied, but no conclusive evidence exists for a role of estrogens in prostatic disease. This paper reviews the literature and describes studies which have sought to show a correlation of estrogens and alterations in the prostates of humans and experimental animal models. Using the developmentally estrogenized mouse model, we propose an alternative role for estrogens as a predisposing factor for prostatic diseases: estrogen exposure during development may initiate cellular changes in the prostate which would require estrogens and/or androgens later in life for promotion to hyperplasia or neoplasia. Thus, the critical time for estrogen action would be during the development of the prostatic tissue. We further suggest that estrogen-sensitive cells may remain in the prostate and be more responsive to estrogens later in life or less responsive to the normal controlling mechanisms of prostatic growth. © 1994 Wiley-Liss, Inc.