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Genome-wide association study with 1000 genomes imputation identifies signals for nine sex hormone-related phenotypes. Ruth Katherine S,Campbell Purdey J,Chew Shelby,Lim Ee Mun,Hadlow Narelle,Stuckey Bronwyn G A,Brown Suzanne J,Feenstra Bjarke,Joseph John,Surdulescu Gabriela L,Zheng Hou Feng,Richards J Brent,Murray Anna,Spector Tim D,Wilson Scott G,Perry John R B European journal of human genetics : EJHG Genetic factors contribute strongly to sex hormone levels, yet knowledge of the regulatory mechanisms remains incomplete. Genome-wide association studies (GWAS) have identified only a small number of loci associated with sex hormone levels, with several reproductive hormones yet to be assessed. The aim of the study was to identify novel genetic variants contributing to the regulation of sex hormones. We performed GWAS using genotypes imputed from the 1000 Genomes reference panel. The study used genotype and phenotype data from a UK twin register. We included 2913 individuals (up to 294 males) from the Twins UK study, excluding individuals receiving hormone treatment. Phenotypes were standardised for age, sex, BMI, stage of menstrual cycle and menopausal status. We tested 7,879,351 autosomal SNPs for association with levels of dehydroepiandrosterone sulphate (DHEAS), oestradiol, free androgen index (FAI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, progesterone, sex hormone-binding globulin and testosterone. Eight independent genetic variants reached genome-wide significance (P<5 × 10(-8)), with minor allele frequencies of 1.3-23.9%. Novel signals included variants for progesterone (P=7.68 × 10(-12)), oestradiol (P=1.63 × 10(-8)) and FAI (P=1.50 × 10(-8)). A genetic variant near the FSHB gene was identified which influenced both FSH (P=1.74 × 10(-8)) and LH (P=3.94 × 10(-9)) levels. A separate locus on chromosome 7 was associated with both DHEAS (P=1.82 × 10(-14)) and progesterone (P=6.09 × 10(-14)). This study highlights loci that are relevant to reproductive function and suggests overlap in the genetic basis of hormone regulation. 10.1038/ejhg.2015.102
Progesterone: a novel adjunct to intravesical chemotherapy. Lewin J,Cooper A,Birch B BJU international OBJECTIVE:To investigate the effect of progesterone on multidrug-resistant urothelial cell lines, as the failure of intravesical chemotherapeutic drugs is often caused by multidrug resistance (MDR), mediated by the drug efflux pump P-glycoprotein (PGP), the function of which can be down-regulated by various compounds including steroid hormones. MATERIALS AND METHODS:Two urothelial cell lines (RT112S and MGH-U1S) and their MDR sublines (RT112R, to cisplatin; and MGH-U1R, a cell line expressing PGP) were used to assess the cytotoxic effects of progesterone, epirubicin and their combination. Cytotoxicity was assessed using a tetrazolium-based assay and in situ confocal microscopy. RESULTS:Cell lines sensitive to epirubicin (MGH-U1S, RT112S and RT112R) required a much lower dose of epirubicin to kill half the cells than did the MDR cell line. Progesterone was intrinsically cytotoxic to all cell lines with little difference among them. Combined therapy had no cumulative effect on epirubicin-sensitive cell lines, but reversed MDR in the MGHU1R cell line, both assessed by confocal microscopy and by the tetrazolium assay. CONCLUSIONS:Progesterone can reverse MDR in urothelial cells in vitro. This, combined with its effects on cell differentiation and apoptosis, together with its safety and tolerability compared to other MDR agents, suggests it may be a valuable adjunct to intravesical chemotherapy.
Immunohistochemical Differentiation of Plasmacytoid Urothelial Carcinoma From Secondary Carcinoma Involvement of the Bladder. Borhan Walaa M,Cimino-Mathews Ashley M,Montgomery Elizabeth A,Epstein Jonathan I The American journal of surgical pathology Plasmacytoid urothelial carcinoma (UC) is a rare variant of UC that can histologically mimic metastatic cancer involving the urinary bladder. A total of 45 cases of plasmacytoid UC were collected and reviewed histologically. The following immunohistochemical markers were performed: CDX2; polyclonal carcinoembryonic antigen (p-CEA); gross cystic disease fluid protein 15 (GCDFP-15); mammaglobin; estrogen receptor (ER); progesterone receptor (PR); GATA 3 and uroplakin II. In all cases, the plasmacytoid variant of UC lacked expression of ER and mammaglobin. In contrast, GCPDFP-15, PR, CDX2 and p-CEA showed positive staining in 11 (24.4%), 6 (13.3%), 8 (17.7%), and 22 (48.8%) cases, respectively. GCPDFP-15 was expressed in 4/8 female cases with 1 concurrently focally (+2) expressing PR. GATA 3 and uroplakin II was positive in 37/45 cases (82.2%) and 15/45 (33.3%) cases, respectively. A tissue microarray with 40 cases of infiltrating lobular carcinoma of the breast was stained for uroplakin II, and was negative in all cases. Tissue microarrays with 46 cases of gastric signet ring cell adenocarcinomas were all negative for GCDFP-15, ER, PR, GATA3, uroplakin II, and mammaglobin. A panel of stains including mammaglobin, ER, and uroplakin II is recommended to exclude metastatic lobular breast carcinoma to the bladder in cases where a conventional UC component is not present. Immunohistochemistry for CDX2 and p-CEA cannot be utilized to differentiate signet ring cell adenocarcinoma of the gastrointestinal tract from plasmacytoid UC; GATA3 or uroplakin II immunoreactivity can rule out a gastric primary given their negativity in signet ring cell adenocarcinoma of the stomach. 10.1097/PAS.0000000000000922
The prognostic role of steroid hormone receptor signaling pathways in urothelial carcinoma. Nagata Yujiro,Miyamoto Hiroshi Translational cancer research Emerging preclinical or clinical evidence suggests a vital role of nuclear receptor-mediated signals in modulating urothelial carcinogenesis and cancer growth. These include, but are not limited to, androgen receptor, estrogen receptors, glucocorticoid receptor, progesterone receptor, vitamin D receptor, retinoid receptors, and peroxisome proliferator-activated receptors, as well as orphan receptors. In particular, immunohistochemical studies in surgical specimens have demonstrated that increased or decreased expression of steroid hormone receptors, as well as alterations of their upstream or downstream signaling pathways, is often associated with oncologic outcomes in patients with bladder or upper urinary tract cancer. This review article summarizes and discusses available data indicating that steroid hormone receptors and related signals serve as biomarkers for urothelial tumors which further predict their recurrence and/or progression. 10.21037/tcr.2020.01.06
Analysis of the prognostic relevance of sex-steroid hormonal receptor mRNA expression in muscle-invasive urothelial carcinoma of the urinary bladder. Erben Philipp,Sikic Danijel,Wirtz Ralph M,Martini Thomas,Weis Cleo-Aron,Breyer Johannes,Otto Wolfgang,Keck Bastian,Hartmann Arndt,Bolenz Christian, Virchows Archiv : an international journal of pathology Muscle-invasive urothelial carcinoma of the urinary bladder (UCB) often recurs following radical cystectomy (RC). An altered expression of sex-steroid hormone receptors has been associated with oncological outcomes of UCB and may represent therapeutic targets. Here the expression of different hormone receptors was measured on mRNA levels in patients treated by RC and associated with outcomes. Androgen receptor (AR), estrogen receptor 1 (ESR1), and progesterone receptor (PGR) mRNA expression was assessed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) in RC samples of 87 patients with a median age of 66 (39-88) years. Univariate and multivariate analyses were performed to test associations with pathological and clinical characteristics as well as recurrence-free (RFS) and disease-specific survival (DSS). AR mRNA expression was lower in comparison with ESR1 and PGR expression (p < 0.0001). In univariate analysis, high expression levels of AR were associated with reduced RFS (HR 2.8, p = 0.015) and DSS (HR 2.8, p = 0.010). High AR mRNA expression and a positive lymph node status were independent predictors for reduced RFS (HR 2.5, p = 0.0049) and DSS (HR 3.4, p = 0.009). In patients with low AR mRNA expression, an increased ESR1 and PGR mRNA expression were associated with reduced RFS and DSS. High expression levels of AR are significantly associated with adverse outcome in patients with muscle-invasive UCB following RC. ESR1 and PGR expression status can further stratify patients with low AR expression into subgroups with significantly reduced RFS and DSS. Therapeutic targeting of AR may influence outcomes in patients with UCB. 10.1007/s00428-018-2496-9
The Estrogen Pathway: Estrogen Receptor-α, Progesterone Receptor, and Estrogen Receptor-β Expression in Radical Cystectomy Urothelial Cell Carcinoma Specimens. Tan Winston,Boorjian Stephen,Advani Pooja,Farmer Sara,Lohse Christine,Cheville John,Kwon Eugene,Leibovich Bradley Clinical genitourinary cancer OBJECTIVE:Bladder cancer has the sixth highest incidence in the United States. Treatment of metastatic bladder cancer is difficult, and mortality is certain. There are certain pathways in cancer growth and progression that are important in bladder cancer development. Recently, the estrogen pathway has been found to be a potential target for therapy. METHODS:We identified 410 patients treated with radical cystectomy for urothelial cell carcinoma between 1990 and 1994. We obtained representative paraffin-embedded tissue blocks for 336 (82.0%) of these cases and evaluated the expression and intensity of estrogen receptor (ER)-α, ER-β, and progesterone receptor by immunohistochemistry. RESULTS:Among the 12 ER-α-positive cases, median tumor ER-α expression was 10% (range, 10%-50%). In contrast to ER-α, all cases were ER-β-positive. Median tumor ER-β expression was 90% (range, 20%-100%). Nearly all cases had ER-β expression of ≥ 90% (175 [55.9%] with 90% and 103 [32.9%] with 100%). However, the intensity of ER-β staining varied from focal to moderate to marked in 64 (20.5%), 167 (53.4%), and 82 (26.2%) cases, respectively. Progesterone receptor expression was noted to be negative in all cases. CONCLUSIONS:ER-β is highly expressed in bladder cancer. Prospective validation of these data might further elucidate the utility of ER-β as a marker for prognosis or possible target for therapy. 10.1016/j.clgc.2015.04.001
The role of estrogens in female lower urinary tract dysfunction. Robinson Dudley,Cardozo Linda D Urology The urogenital tract and lower urinary tract are sensitive to the effects of estrogen and progesterone throughout adult life. Epidemiologic studies have implicated estrogen deficiency in the etiology of lower urinary tract symptoms that occur after menopause. Although the role of estrogen replacement therapy in the management of postmenopausal urinary incontinence (UI) remains controversial, its use in the treatment of women with urogenital atrophy is now well established. This review summarizes recent evidence of the urogenital effects of hormone therapy, particularly emphasizing management of postmenopausal UI and recurrent lower urinary tract infections. Estrogen therapy alone has little effect in the management of urodynamic stress UI, although in combination with an alpha-adrenergic agonist, it may improve urinary leakage. Estrogen therapy may be of benefit for the irritative symptoms of urinary urgency, frequency, and urge UI, although this effect may result from reversal of urogenital atrophy rather than a direct action on the lower urinary tract. The role of estrogen replacement therapy in the treatment of women with recurrent lower urinary tract infections remains to be determined, although there is now some evidence that vaginal administration may be efficacious. Low-dose, vaginally administered estrogens have a role in the treatment of urogenital atrophy in postmenopausal women and appear to be as effective as systemic preparations. 10.1016/s0090-4295(03)00676-9
Effects of pregnancy and progesterone on autonomic function in the rat urinary bladder. Tong Y C,Hung Y C,Lin J S,Hsu C T,Cheng J T Pharmacology Previous studies have shown that pregnancy is associated with a decrease in cholinergic function in the rabbit urinary bladder. The present study aimed at evaluating the effects of pregnancy on the autonomic function of the rat urinary bladder and to elucidate whether progesterone is responsible for such alterations. Female Wistar rats, 3 months old, were divided into four groups: (1) 2-week pregnant rats; (2) rats given daily intramuscular injections of progesterone 5 mg/kg for 2 weeks; (3) rats given intramuscular injections of vehicle for 2 weeks, and (4) controls. Cystometry showed a significant increase in bladder capacity in the pregnant rats. The wet weight of the pregnant rat bladder was also significantly increased. Histologic study revealed increased bladder wall thickness with interstitial edema and urothelium proliferative changes to a papillary configuration in these pregnant bladders. Bladder muscle strip study showed significantly reduced maximum contractile responses to acetylcholine and methoxamine in the pregnant and the progesterone groups. Muscarinic receptor binding study demonstrated reduced Bmax in the pregnant rats and rats receiving progesterone injections (control group Bmax = 57 +/- 11, pregnant group Bmax = 44 +/- 8, p < 0.05; progesterone group Bmax = 40 +/- 7, vehicle group Bmax = 58 +/- 9 fmol/mg protein, p < 0.05). The contractile response to lower concentrations (10(-6) mol/l to 10(-4) mol/l) of ATP was elevated in the pregnant rats.(ABSTRACT TRUNCATED AT 250 WORDS) 10.1159/000139282
Investigations of the estrogen (ER-ICA-test) and the progesterone receptor in the prostate and prostatic carcinoma on immunohistochemical basis. Wernert N,Gerdes J,Loy V,Seitz G,Scherr O,Dhom G Virchows Archiv. A, Pathological anatomy and histopathology Estrogen (ER) and Progesterone receptors (PR) were demonstrated immunohistochemically on frozen sections from 11 prostatectomy and 7 cystoprostatectomy specimens in the nuclei of various cell types. The periglandular fibrocytes and smooth muscle cells were extensively positive, the interglandular stromal cells were only partly so. Normal basal cells stained focally positive, hyperplastic basal cells stained extensively. The glandular secretory epithelium and atrophic glands were negative. The same findings were obtained in hyperplastic nodules. Both ER and PR also occurred in the urothelium of central prostatic ducts and of the prostatic urethra. The fibrous stroma around the ejaculatory ducts and seminal vesicles was extensively positive while the epithelium was negative. The smooth musculature of the seminal vesicles was only partly positive. On large field sections, the ER as well as the PR were numerically equally distributed throughout the inner zone of the prostate and the prostate proper. 12 prostatic carcinomas (G I-G III) were ER- and PR-negative. Estrogens may contribute to nodular hyperplasia by triggering a stromal proliferation with a secondary inductive epithelial growth. Obviously they do not act directly on prostatic carcinoma but inhibit growth via the hypophyseal-testicular axis. The biological significance of the PR in the prostate is unknown.
Role of steroid hormone receptors in formation and progression of bladder carcinoma: a case-control study. Mashhadi Rahil,Pourmand Gholamreza,Kosari Farid,Mehrsai Abdolrasoul,Salem Sepehr,Pourmand Mohammad Reza,Alatab Sudabeh,Khonsari Mehdi,Heydari Fariba,Beladi Laleh,Alizadeh Farimah Urology journal PURPOSE:To compare the expression rate of sex steroid hormone receptors of estrogen (ER), progesterone (PR) and androgen (AR) in normal urothelium and urothelial bladder cancer (UBC) and to evaluate the possible associations of these receptors expression with cancer progression and patient's survival. MATERIALS AND METHODS:We evaluated the clinical data and tumor specimens of 120 patients with pathologically confirmed primary UBC with 132 normal healthy controls. Both patients and controls selected from list of subjects who have been referred to Sina Urology clinic, and had a minimum of one year follow-up duration. Data collected from medical cords. For evaluation of expression, immunohistochemistry was performed on paraffin-embedded tissue sections using a monoclonal antibody for androgen, estrogen and progesterone receptors. Presence of at least 10% positive cells defined as positive expression. RESULTS:None of the control subjects showed AR expression, while 22% of the patients were AR-positive. ER/PR expressions were observed in 4.2%/ and 2.5% of the cases and in 2.3% and 1.5% of the controls, respectively. A statistically significant correlation was found between AR expression and tumor stage and grade (P &lt; .001). AR-positive patients showed a significantly poorer prognosis than AR-negative cases (log-rank test, P = .02, hazard ratio = 2.12; 95% confidence interval: 1.36-4.65). CONCLUSION:AR expression was significantly associated with higher grade and poorly differentiated tumors with unfavorable outcome. AR expression test might be useful as a diagnostic tool for determining the malignancy and outcome of UBC patients.&nbsp;
Unusual finding of endocervical-like mucinous epithelium in continuity with urothelium in endocervicosis of the urinary bladder. Cheah Phaik-Leng,Looi Lai-Meng,Lee George Eng-Geap,Teoh Kean-Hooi,Mun Kein-Seong,Nazarina Abdul Rahman Diagnostic pathology Endocervicosis in the urinary bladder is a rare benign condition. We present a case in a 37-year-old woman with classical clinical and pathological features of endocervicosis. The unusual observation of endocervical-like mucinous epithelium in continuity with the urothelium in addition to fully developed endocervicosis prompted immunohistochemical profiling of the case using antibodies to cytokeratins (AE1/AE3, CK19, CK7, CK5/6, CK20), HBME-1, estrogen receptor (ER) and progesterone receptor (PR) to assess the relationship of the surface mucinous and endocervicosis glandular epithelia. The surface mucinous epithelium, urothelium and endocervicosis glands were immunopositive for AE1/AE3, CK7 and CK19 while CK20 was only expressed by few urothelial umbrella cells. The surface mucinous epithelium was CK5/6 and HBME-1 immunonegative but showed presence of ER and PR. This was in contrast to the urothelium's expression of CK5/6 but not ER and PR. In comparison, endocervicosis glands expressed HBME-1, unlike the surface mucinous epithelium. The endocervicosis epithelium also demonstrated the expected presence of ER and PR and CK5/6 immunonegativity. The slightly differing immunohistochemical phenotypes of the surface mucinous and morphologically similar endocervicosis glandular epithelium is interesting and requires further clarification to its actual nature. The patient has remained well and without evidence of disease 18-months following transurethral resection of the lesion. 10.1186/1746-1596-6-56
Molecular mechanisms of development of the human fetal female reproductive tract. Cunha Gerald R,Kurita Takeshi,Cao Mei,Shen Joel,Robboy Stanley,Baskin Laurence Differentiation; research in biological diversity Human female reproductive tract development rests mostly upon hematoxilyn and eosin stained sections despite recent advances on molecular mechanisms in mouse studies. We report application of immunohistochemical methods to explore the ontogeny of epithelial and mesenchymal differentiation markers (keratins, homobox proteins, steroid receptors), transcription factors and signaling molecules (TP63 and RUNX1) during human female reproductive tract development. Keratins 6, 7, 8, 10, 14 and 19 (KRT6, KRT7, KRT8, KRT10, KRT14, KRT19) were expressed in a temporally and spatially dynamic fashion. The undifferentiated Müllerian duct and uterovaginal canal, lined by simple columnar epithelia, expressed KRT7, KRT8 and KRT19. Glandular derivatives of the Müllerian duct (uterine tube, uterine corpus and endocervix) maintained expression of these keratins, while tissues that undergo stratified squamous differentiation (exocervix and vagina) expressed KRT6, KRT14 and KRT10 during development in an age-dependent fashion. TP63 and RUNX1 were expressed prior to KRT14, as these two transcription factors are known to be upstream from KRT14 in developing Müllerian epithelium. In the vagina, KRT10, a marker of terminal differentiation, appeared after endogenous estrogens transformed the epithelium to a thick glycogenated squamous epithelium. Uroplakin, a protein unique to urothelium, was expressed only in the bladder, urethra and vaginal introitus, but not in the female reproductive tract itself. Mesenchymal differentiation was examined through immunostaining for HOXA11 (expressed in uterine mesenchyme) and ISL1 (expressed in vaginal mesenchyme). A detailed ontogeny of estrogen receptor alpha (ESR1), progesterone receptor (PGR) and the androgen receptor (AR) provides the mechanistic underpinning for the teratogenicity of estrogens, progestins and androgens on female reproductive tract development. Immunohistochemical analysis of differentiation markers and signaling molecules advance our understanding of normal development of the human female reproductive tract. These observations demonstrate remarkable similarities in mouse and human female reproductive tract development, but also highlight some key differences. 10.1016/j.diff.2017.07.003
Steroid Hormone Receptor Signals as Prognosticators for Urothelial Tumor. Disease markers There is a substantial amount of preclinical or clinical evidence suggesting that steroid hormone receptor-mediated signals play a critical role in urothelial tumorigenesis and tumor progression. These receptors include androgen receptor, estrogen receptors, glucocorticoid receptor, progesterone receptor, vitamin D receptor, retinoid receptors, peroxisome proliferator-activated receptors, and others including orphan receptors. In particular, studies using urothelial cancer tissue specimens have demonstrated that elevated or reduced expression of these receptors as well as alterations of their upstream or downstream pathways correlates with patient outcomes. This review summarizes and discusses available data suggesting that steroid hormone receptors and related signals serve as biomarkers for urothelial carcinoma and are able to predict tumor recurrence or progression. 10.1155/2015/840640
Progesterone induces the proliferation of urothelial cells in an epidermal growth factor dependent manner. Teng J,Wang Z Y,Bjorling D E The Journal of urology PURPOSE:We have previously reported that estrogen induced proliferation of urothelial cells is modulated by nerve growth factor (NGF). In this study we investigated whether progesterone induces urothelial cell proliferation and whether this effect is modulated by NGF or by epidermal growth factor (EGF). MATERIALS AND METHODS:Experiments were performed using human urothelial cells immortalized by human papillomavirus E6. Cell proliferation was determined using the alamarBlue (Trek Diagnostic, Westlake, New York) assay. Human papillomavirus were seeded in 48-well plates. They were incubated with 5% alamarBlue and different concentrations of progesterone, EGF or NGF in the presence or absence of neutralizing EGF or NGF antibody, K252a (an inhibitor of trkA, the high affinity receptor for NGF), Ru-486 (an antagonist of progesterone and glucocorticoid receptor) or ZK 137 316 (a specific antagonist of progesterone receptor). Immunoblotting was performed using specific antibodies for progesterone receptor, glucocorticoid receptor or EGF receptor. EGF content in conditioned medium was determined by enzyme-linked immunosorbent assay. RESULTS:In the presence of 10 nM to 1 microM progesterone urothelial cell proliferation was significantly increased 8.6% to 51.1%. This effect was abolished by ZK137 316 or by Ru-486. Hydrocortisone also induced urothelial cell proliferation. This effect was blocked by Ru-486 but not by ZK137 316. In addition, progesterone stimulated urothelial cell proliferation was inhibited by neutralizing EGF antibody but not by NGF antiserum or K252a. We also found that EGF synthesis and release by urothelial cells was increased by exogenous progesterone. This effect of progesterone was inhibited by ZK 137 316. CONCLUSIONS:These findings indicate that progesterone has the capacity to induce urothelial cell proliferation through its cognate receptor and this effect is mediated by EGF but not by NGF. 10.1097/01.ju.0000080704.75600.ee
Receptor isoforms that mediate estrogen and progestagen action in the female lower urinary tract. Tincello Douglas G,Taylor Anthony H,Spurling Susan M,Bell Stephen C The Journal of urology PURPOSE:Bladder symptoms can be ameliorated by sex steroids but to our knowledge the mechanism of action is unknown. Previous studies of steroid receptor expression in the bladder did not indicate receptor subtype expression. We report the distribution of estrogen and progesterone receptor isoforms in the female lower urinary tract. MATERIALS AND METHODS:Prospectively recruited women undergoing routine urogynecological or gynecological surgery provided cold cup biopsy samples from the bladder dome, trigone, and proximal and distal urethra. The samples were immediately frozen or fixed in formalin. After RNA extraction transcripts for estrogen receptor alpha and beta, and progesterone receptor A and B were noted on reverse transcriptase-polymerase chain reaction using isoform specific primers. The precise cellular localization of receptor proteins and their relative levels were assessed by immunochemistry in formalin fixed tissue sections with isoform specific antibodies. RESULTS:Nine premenopausal and 10 postmenopausal women were recruited into the study. Two postmenopausal women on hormone replacement therapy. Estrogen receptor alpha and beta, and progesterone receptor A and B transcripts were detected in whole bladder extracts. Nuclear estrogen receptor alpha immunoreactivity was present in squamous epithelium but absent from transitional epithelium. Estrogen receptor beta immunoreactivity was expressed in squamous and transitional cell epithelium. Nuclear progesterone receptor expression was present in urethral squamous epithelium only. Progesterone receptor expression was greater in premenopausal women and in postmenopausal women on estrogen. CONCLUSIONS:Estrogen receptor alpha and beta genes are transcribed in bladder tissue but only estrogen receptor beta is translated into protein, suggesting that the urothelium responds to endogenous estrogen via estrogen receptor beta. Progesterone receptor expression is confined to urethral squamous epithelium and the major isoform is progesterone receptor A. 10.1016/j.juro.2008.10.104
Estrogen and progesterone hormonal receptor expression in urothelial carcinoma of the bladder. Bolenz Christian,Lotan Yair,Ashfaq Raheela,Shariat Shahrokh F European urology 10.1016/j.eururo.2009.06.032
Sex steroid hormone receptors in bladder cancer: Usefulness in differential diagnosis and implications in histogenesis of bladder cancer. Imai Yasuo,Noda Shuhei,Matsuyama Chiaki,Shimizu Ayako,Kamai Takao Urologic oncology OBJECTIVE:In rare cases, differential diagnosis between bladder cancer (BC) and gynecological tract cancer (GTC) is difficult because of anatomical proximity and morphological similarity. We analyzed expression status of sex steroid hormone receptors in BC in this study. First, we investigated their usefulness as a histological marker for differential diagnosis. Second, we considered their roles in BC histogenesis. METHODS:Estrogen receptor α (ERα) and progesterone receptor (PgR) expression was investigated by immunohistochemistry in 125 BCs obtained by transurethral resection or biopsy, then in nonneoplastic background mucosa (trigone, fundus, and dome) of 33 total cystectomy samples. They were evaluated as positive when ≥ 1% of 500 subject cells were immunoreactive with moderate or strong intensities. RESULTS:ERα and PgR were positive in 38.4% and 3.2% of BCs, respectively, suggesting that ERα status alone could not definitely differentiate between BC and GTC. ERα expression was not significantly associated with age and sex of BC patients and histopathology of BCs. Although not significant, ERα expression was more frequent in higher grade (G1/G2 vs. G3/G4; P = 0.143) and marginally associated with advanced stage of BCs (pTis/pTa/pT1 vs. pT2/pT3, P = 0.056). ERα expression was significantly more frequent in background mucosa with ERα-positive BC (In the epithelium and stroma; both P < 0.001). ERα expression was continuously observed from normal to malignant epithelium in some cases. Although not significant, Brunn's nest or cystitis glandularis was more frequent in background mucosa with ERα-positive BC (P = 0.218). Analyses of nonneoplastic mucosa in cystectomy revealed that ERα was more frequently positive in urothelium of trigone, a predilection site for cystitis glandularis, than those of fundus and dome, with a significant difference between trigone and dome (P = 0.034). These data suggest that chronic inflammation may up-regulate ERα in the background epithelium, especially in trigone, and ERα expression in BC might be the reflection of bladder epithelium from which BC arose. CONCLUSIONS:Usefulness of ERα was limited in differential diagnosis between BC and GTC. ERα up-regulation might not play a critical role in the development of BC because it was already noted in the background bladder mucosa. 10.1016/j.urolonc.2019.01.023
Sex specific expression of progesterone receptor in mouse lower urinary tract. Savolainen Saija,Santti Risto,Streng Tomi,Gustafsson Jan-Ake,Härkönen Pirkko,Mäkelä Sari Molecular and cellular endocrinology Progesterone receptor (PR) was investigated immunohistochemically in the lower urinary tract of the male and female mouse. Estrogen receptor (ER)-subtype-deficient mice (ERKO, BERKO) were used to determine the possible regulation of PR expression in an ER-subtype-specific manner. PR was found to be co-expressed with ERalpha in cell nuclei of urothelium, lamina propria fibroblasts and smooth muscle cells in the female urethra. Only few PR positive cells were seen in female ERKO mice. Ovariectomy reduced and estrogen treatment restored the urethral PR expression in female wild type and BERKO mice. Thus, the expression of PR in the female urethra is estrogen-inducible via ERalpha. In male urethra, PR was co-expressed with ERbeta in the rhabdosphincter. In male, no evidence was obtained for the ER-linked control of the PR expression. No PR-positive cells were observed in the body of the bladder of either sex or any strain. 10.1016/j.mce.2004.11.008
Expression of steroid hormone receptors and its prognostic significance in urothelial carcinoma of the upper urinary tract. Kashiwagi Eiji,Fujita Kazutoshi,Yamaguchi Seiji,Fushimi Hiroaki,Ide Hiroki,Inoue Satoshi,Mizushima Taichi,Reis Leonardo O,Sharma Rajni,Netto George J,Nonomura Norio,Miyamoto Hiroshi Cancer biology & therapy To assess the expression status of steroid hormone receptors in upper urinary tract urothelial carcinoma (UUTUC), we immunohistochemically stained for androgen receptor (AR), estrogen receptor-α (ERα), ERβ, glucocorticoid receptor (GR), and progesterone receptor (PR) in 99 UUTUC specimens and paired non-neoplastic urothelial tissues. AR/ERα/ERβ/GR/PR was positive in 20%/18%/62%/63%/16% of tumors, which was significantly lower (except PR) than in benign urothelial tissues [57% (P < 0.001)/40% (P = 0.001)/85% (P = 0.001)/84% (P = 0.002)/13% (P = 0.489)]. There were no significant associations between each receptor expression pattern and histopathological characteristic of the tumors including tumor grade/stage. Kaplan-Meier and log-rank tests revealed no significant prognostic value of each receptor expression in these 99 patients. However, patients with UUTUC positive for either ERα or PR had a significantly higher risk of disease-specific mortality (P = 0.025), compared with those with UUTUC negative for both. PR positivity alone in pT3 or pT4 tumors was also strongly associated with the risk of disease-specific mortality (P = 0.040). Multivariate analysis further identified the expression of ERα and/or PR as a strong predictor for disease-specific mortality in the entire cohort of the patients (hazard ratio, 2.434; P = 0.037). Thus, in accordance with previous observations in bladder specimens, significant decreases in the expression of AR/ERα/ERβ/GR in UUTUC, compared with that in non-neoplastic urothelium, were observed. Meanwhile, the negativity of both ERα and PR in UUTUC as well as the negativity of PR alone in deeply invasive tumor was suggested to serve as a prognosticator. 10.1080/15384047.2016.1235667
Underlying mechanisms involved in progesterone-induced relaxation to the pig bladder neck. Fernandes Vítor S,Ribeiro Ana S F,Martínez-Sáenz Ana,Blaha Igor,Serrano-Margüello Daniel,Recio Paz,Martínez Ana Cristina,Bustamante Salvador,Vázquez-Alba David,Carballido Joaquín,García-Sacristán Albino,Hernández Medardo European journal of pharmacology Progesterone increases bladder capacity and improves the bladder compliance by its relaxant action on the detrusor. A poor information, however, exists concerning to the role of this steroid hormone on the bladder outflow region contractility. This study investigates the progesterone-induced action on the smooth muscle tension of the pig bladder neck. To this aim, urothelium-denuded bladder neck strips were mounted in myographs for isometric force recordings and for simultaneous measurements of intracellular Ca(2+) concentration ([Ca(2+)]i) and tension. On phenylephrine (PhE)-precontracted strips, progesterone produced concentration-dependent relaxations only at high pharmacological concentrations. The blockade of progesterone receptors, nitric oxide (NO) synthase, guanylyl cyclase, large conductance Ca(2+)-activated K(+) (BKCa) or ATP-dependent K(+) (KATP) channels reduced the progesterone relaxations. The presence of the urothelium and the inhibition of cyclooxygenase (COX), intermediate- and small-conductance Ca(2+)-activated K(+) channels failed to modify these responses. In Ca(2+)-free potassium rich physiological saline solution, progesterone inhibited the contraction to CaCl2 and to the L-type voltage-operated Ca(2+) (VOC) channel activator BAY-K 8644. Relaxation induced by progesterone was accompanied by simultaneous decreases in smooth muscle [Ca(2+)]i. These results suggest that progesterone promotes relaxation of pig bladder neck through smooth muscle progesterone receptors via cGMP/NO pathway and involving the activation of BKCa and KATP channels and inhibition of the extracellular Ca(2+) entry through L-type VOC channels. 10.1016/j.ejphar.2013.11.025
Sex hormones and the female urinary tract. Miodrag A,Castleden C M,Vallance T R Drugs Symptomatic clinical changes and urodynamic changes are apparent in the female urinary tract system during pregnancy, the menstrual cycle and following the menopause. The sex hormones exert physiological effects on the female urinary tract, from the ureters to the urethra, with oestrogens having an additional influence on the structures of the pelvic floor. High affinity oestrogen receptors have been identified in bladder, trigone, urethra and pubococcygeus muscle of women. Oestrogen pretreatment enhances the contractile response of animal detrusor muscle to alpha-adrenoceptor agonists, cholinomimetics and prostaglandins, as well as enhancing the contractile response to alpha-agonists in ureter and urethra. Progesterone on the other hand decreases tone in the ureter, bladder and urethra by enhancing beta-adrenergic responses. The dependence on oestrogens of the tissues of the lower urinary tract contributes to increased urinary problems in postmenopausal women. Urinary symptoms due to atrophic mucosal changes respond well to oestrogen replacement therapy. However, because they recur when treatment is stopped, continuous therapy with low dose natural oestrogens is recommended. Oestrogens may be of benefit in postmenopausal women with stress incontinence, but the doses necessary for clinical effect are higher than for the treatment of atrophic urethritis. The practice of adding a progestagen to long term oestrogen therapy to reduce the risk of endometrial carcinoma may, however, exacerbate stress incontinence by decreasing urethral pressure. Cyclical therapy with oestrogens may therefore be more appropriate particularly in women who are not suitable for surgery or have a mild degree of stress incontinence, along with other conservative measures such as pelvic floor exercises and alpha-adrenoceptor agonists. The place of oestrogen therapy in motor urge incontinence has not been determined. The risk of developing endometrial carcinoma as a result of long term high dose oestrogen replacement therapy must be borne in mind but remains to be clarified. However, oestriol has less of a uterotrophic effect compared to other oestrogens in standard therapeutic doses and is to be preferred. Side effects are usually dose related and tend not to be a problem with low dose therapy. 10.2165/00003495-198836040-00006
Ureteral endometriosis: clinicopathological and immunohistochemical study of 7 cases. Al-Khawaja Maha,Tan Puay-Hoon,MacLennan Gregory T,Lopez-Beltran Antonio,Montironi Rodolfo,Cheng Liang Human pathology Ureteral endometriosis is a rare yet important entity that can lead to renal failure due to silent obstruction of the ureter. Awareness of clinical and morphologic features can help in early detection and treatment. We analyzed the clinical, pathologic, and immunohistochemical findings of 7 cases of ureteral endometriosis. Mean age of patients was 51 years. All patients presented with hydroureter, accompanied in the most cases by hydronephrosis. Superimposed pyelonephritis was experienced by 2 of 7 patients. Most patients (4 of 7) had previously undergone total abdominal hysterectomy with bilateral salpingo-oophorectomy. In 6 of 7 cases, endometriosis involved the left ureter. The distal one third of the ureter was involved in 6 cases, whereas the middle third was involved in 1 case. In 4 cases, endometriosis was located extrinsic to the ureter, whereas in 3 cases, the ureter showed intrinsic involvement by endometriosis. One case showed simple endometrial hyperplasia. Surgical management included nephrectomy in 2 cases, distal ureterectomy with reimplantation in 3 cases, ureteral stent placement followed by ureteroureterostomy in 1 case, and relief of ureteral obstruction by resection of pelvic endometrioma in 1 case. Immunostains for cytokeratin-7 (CK7) and progesterone receptor (PR) were positive in all of the cases, whereas immunostains for estrogen receptor (ER) were positive in 83% of cases and immunostains for CK20 were negative in all cases. CA125 immunostains were positive in 67% of cases. The stromal cells were positive for CD10, ER, and PR immunostaining. Our findings suggest that the diagnosis of ureteral endometriosis is preceded in most cases by hysterectomy and bilateral salpingo-oophorectomy, possibly because of prior symptoms related to adenomyosis or pelvic endometriosis and that ureteral endometriosis has a strong predilection for involvement of the lower third of the left ureter. Ureteral endometriosis should be included in the differential diagnosis of obstructive ureteral lesions in women, particularly those involving the lower third of the left ureter, even in postmenopausal patients. Immunostains for ER, PR, CK7, CA125, and CD10 can be helpful in challenging cases. 10.1016/j.humpath.2007.11.011
Primary carcinoid tumor of the kidney with estrogen and progesterone receptor expression. Lin Chunhua,Wu Jitao,Gao Zhenli,Qu Guimei,Wang Wei,Yu Guohua Oncology letters Primary carcinoid tumors are uncommon neoplasms in the kidney. The current study presents a case of primary carcinoid tumor of the kidney in a 49-year-old female who suffered from painless gross hematuria for half a month. Left hydronephrosis, a horseshoe kidney and a space-occupying lesion of the left ureter were found by abdominal computed tomography scans and ultrasonic testing. Surgery was performed and an oval tumor was found under the left ureter; the tumor and left kidney were excised completely. The neoplasm was composed of solid nests of cells, trabeculae, adenoid structures and anastomosing cords in a loose and myxoid background. The tumor cells, which were consistent in volume, exhibited centrally oval nuclei with inconspicuous nucleoli, and eosinophilic finely granular cytoplasm. Upon immunohistochemical staining, the neoplastic cells were positive for AE1/AE3, vimentin, synaptophysin, chromogranin A, estrogen receptor and progesterone receptor, while being negative for epithelial membrane antigen, inhibin A, cluster of differentiation (CD)99, S-100 and CD10. Based on the histological characteristics, a diagnosis of primary carcinoid tumor of the left kidney was formed. The patient did not receive further treatment. The total follow-up period was 18 months after the surgery and repeated imaging examinations every 6 months revealed no recurrence. 10.3892/ol.2015.3167