Psychological distress and adjustment to disease in patients before and after radical prostatectomy. Results of a prospective multi-centre study.

The aim of this prospective multi-centre study was to evaluate the level of psychological distress (PD) and adjustment to disease in patients who underwent radical prostatectomy. Furthermore, the impact of urinary incontinence and erectile dysfunction on PD was assessed. Anxiety, depression and PD were evaluated using the Hospital Anxiety and Depression Scale in 329 prostate cancer patients before surgery as well as 3, 6 and 12 months after surgery. These results were compared with those of a male German general population reference group. Adjustment to disease was assessed using the Perceived Adjustment to Chronic Illness Scale. Patients reported low levels of PD at all points of assessment similar to population norms of age-matched German men. Persistent PD was seen in about 8% of the patients and 20% had PD at least two of the measurement points. Relevant predictors for PD after surgery were urinary symptoms and baseline PD. Adjustment to disease was highest before surgery and had significantly reduced at 3 and 6 months after surgery. In general, men are resilient to the experience of localised prostate cancer and adjust well psychologically after surgery. However, between 8% and 20% of patients could possibly benefit from mental health support.

Collecting system invasion and Fuhrman grade but not tumor size facilitate prognostic stratification of patients with pT2 renal cell carcinoma.

PURPOSE: The 7th edition of TNM for renal cell carcinoma introduced a subdivision of pT2 tumors at a 10 cm cutoff. In the present multicenter study the influence of tumor size as well as further clinical and histopathological parameters on cancer specific survival in patients with pT2 tumors was evaluated. MATERIALS AND METHODS: A total of 670 consecutive patients with pT2 tumors (10.4%) of 6,442 surgically treated patients with all tumor stages were pooled (mean followup 71.4 months). Tumors were reclassified according to the current TNM classification, and subdivided in stages pT2a and pT2b. Cancer specific survival was analyzed using the Kaplan-Meier method, and univariable and multivariable analyses were used to assess the influence of several parameters on survival. RESULTS: Tumor size continuously applied and subdivided at 10 cm or alternative cutoffs did not significantly influence cancer specific survival. In addition to N/M stage, Fuhrman grade and collecting system invasion also had an independent influence on survival. Integration of a dichotomous variable subsuming Fuhrman grade and collecting system invasion (grade 3/4 and/or collecting system invasion present vs grade 1/2 and collecting system invasion absent) into multivariate models including established prognostic parameters resulted in improvement of predictive abilities by 11% (HR 2.3, p <0.001) for all pT2 cases and 151% (HR 3.1, p <0.001) for stage pT2N0M0 cases. CONCLUSIONS: Tumor size did not have a significant influence on cancer specific survival in pT2 tumors, neither continuously applied nor based on various cutoff values. To enhance prognostic discrimination, multifactorial staging systems including pathological features should be implemented. The prognostic relevance of the variable subsuming Fuhrman grade and collecting system invasion should be considered for future evaluation.

Steroid hormone receptors: interaction with deoxyribonucleic acid and transcription factors.

Gene regulation by steroid hormones is mediated by binding of the hormone ligand to the corresponding receptor that triggers a complex set of interactions of the hormone receptors with each other, with DNA in chromatin, and with a variety of other proteins. In this review we attempt to summarize what is known about these interactions using as the main example the regulation of mouse mammary tumor virus transcription by glucocorticoids and progestins. We describe in some detail the interaction of monomers and homodimers of the steroid receptors with their recognition sequences, and the molecular mechanism used to discriminate between the responsive elements for glucocorticoids/progestins and estrogens. We then review the interactions between homologous and heterologous hormone receptors on complex hormone regulatory regions, before devoting some attention to the synergistic and inhibitory interactions of hormone receptors with other transcription factors. Finally we briefly summarize some of the possible mechanisms that modulate the molecular interactions of hormone receptors. In addition to ligand binding, these include receptor phosphorylation, changes in DNA topology, and the organization of DNA in nucleosomes. From this overview we draw the tentative conclusion that the specificity of the hormonal response in different cells results from a combination of developmental restrictions both in the accessibility of genomic sequence and in the repertoire of regulatory proteins present in each particular cell. In addition, the array of regulatory sequences in DNA and chromatin determines the precise nature of macromolecular interactions of the receptors that are modulated by their degree of phosphorylation.

[A rare renal tumour : Ectopic thyroid tissue in the kidney]. / Der seltene Nierentumor : Renales ektopes Schilddrüsengewebe.

During a nephrectomy of a nonfunctioning, tumour-bearing kidney we found ectopic thyroid tissue in the kidney. This location of ectopic thyroid tissue has not been described before. In general, ectopic thyroid tissue is uncommon and rather found in the cervical region or upper mediastinum. A 131-iodine whole-body scan is the most precise method to detect the presence of ectopic thyroid tissue. It is often difficult to distinguish between benign and differentiated malignant thyroid tissue.

Constitutive repression and nuclear factor I-dependent hormone activation of the mouse mammary tumor virus promoter in Saccharomyces cerevisiae.

To study the influence of various transactivators and the role of nucleosomal structure in gene regulation by steroid hormones, we have introduced mouse mammary tumor virus (MMTV) promoter sequences along with expression vectors for the glucocorticoid receptor (GR) and nuclear factor I (NFI) in Saccharomyces cerevisiae, an organism amenable to genetic manipulation. Both in the context of an episomal multicopy vector and in a centromeric single-copy plasmid, the MMTV promoter was virtually silent in the absence of inducer, even in yeast strains expressing GR and NFI. Induction was optimal with deacylcortivazol and required both GR and NFI. The transactivation function AF1 in the N-terminal half of GR is required for ligand-dependent induction and acts constitutively in truncated GR lacking the ligand binding domain. A piece of the MMTV long terminal repeat extending from -236 to +111 is sufficient to position a nucleosome, B, over the regulatory region of the promoter from -45 to -190 and another nucleosome over the transcription start region. The rotational orientation of the DNA on the surface of nucleosome B is the same as that previously found in animal cells and in reconstitution experiments. This orientation is compatible with binding of GR to two sites, while it should preclude binding of NFI and hence be responsible for constitutive repression. Upon ligand induction, there is no major chromatin rearrangement, but the proximal linker DNA, including the TATA box, becomes hypersensitive to nucleases. The transcriptional behavior of the MMTV promoter was unaffected by deletions of the genes for zuotin or SIN1/SPT2, two proteins which have been claimed to assume some of the functions of linker histones. Thus, despite the lack of histone H1, yeast cells could be a suitable system to study the contribution of nucleosomal organization to the regulated expression of the MMTV promoter.

Functional interaction of hybrid response elements with wild-type and mutant steroid hormone receptors.

Steroid hormone receptors can be divided into two subfamilies according to the structure of their DNA binding domains and the nucleotide sequences which they recognize. The glucocorticoid receptor and the progesterone receptor (PR) recognize an imperfect palindrome (glucocorticoid responsive element/progesterone responsive element [GRE/PRE]) with the conserved half-sequence TGTYCY, whereas the estrogen receptor (ER) recognizes a palindrome (estrogen responsive element) with the half-sequence TGACC. A series of symmetric and asymmetric variants of these hormone responsive elements (HREs) have been tested for receptor binding and for the ability to mediate induction in vivo. High-resolution analysis demonstrates that the overall number and distribution of contacts with the N-7 position of guanines and with the phosphate backbone of various HREs are quite similar for PR and ER. However, PR and glucocorticoid receptor, but not ER, are able to contact the 5'-methyl group of thymines found in position 3 of HREs, as shown by potassium permanganate interference. The ER mutant HE84, which contains a single amino acid exchange, Glu-203 to Gly, in the knuckle of ER, creates a promiscuous ER that is able to bind to GRE/PREs by contacting this thymine. Elements with the sequence GGTCAcagTGTYCT that represent hybrids between an estrogen response element and a GRE/PRE respond to estrogens, glucocorticoids, and progestins in vivo and bind all three wild-type receptors in vitro. These hybrid HREs could serve to confer promiscuous gene regulation.

[Laparoscopic surgery in urology: Taining and education]. / Laparoskopische Chirurgie in der Urologie: Training und Ausbildung.

Relatively long learning curves and, therefore, initially longer operating times compared to conventional procedures are still a matter of debate. Today, there are numerous possibilities for learning laparoscopic techniques and establishing one's own laparoscopic programs, including various pelvitrainers and virtual reality computer programs. One useful and realistic way involves "wet lab" training programs for ablative and reconstructive procedures using the pig model. Today, laparoscopic urological surgery includes procedures with low (e.g. laparoscopy for undescended testicles), intermediate (laparoscopic pyeloplasty) and high level (laparoscopic/endoscopic prostatectomy) complexity. Therefore, laparoscopy should be an integral part of training in urology. A defined number of possibly multi-institutional training centers with well structured educational programs are needed. The main goal should be the standardization of surgical procedures as well as educational training programs in order to shorten individual learning curves and generate common quality standards.

[In vitro effects of cAMP- and cGMP-stimulating drugs on the relaxation of the prostate smooth muscle tissue contraction induced by endothelin-1].

Results from experimental studies suggested a significance of the nitric oxide (NO)-cGMP- and cAMP-pathways in the control of the function of the smooth musculature of the human prostate. In addition, it has also been assumed that the vasoconstrictory peptide endothelin-1(ET-1) may play a role in the dynamic component of benign prostatic hyperplasia (BPH) and the so-called lower urinary tract symptomatology (LUTS). Nevertheless, up till now, little is known as to potential interactions between the contraction of prostatic smooth muscle mediated by ET-1 and the relaxation induced by NO and cGMP. Thus, it was the aim of the study to elucidate the effects of drugs interfering with the cGMP-pathway on the tension induced by ET-1 of isolated human prostate tissue, as well as contractile responses of isolated strip preparations to ET-1 and angiotensin-II (AT-II). Macroscopically normal human prostate tissue from the transition zone was obtained from male patients who had undergone surgery for localized cancer of the prostate or urinary bladder. Using the organ bath technique, the ability of ET-1 and AT-II to contract isolated prostate strips was evaluated. In another set-up, the effects of the NO-donor S-nitrosogluthatione (GSNO) and C-type natriuretic peptide(CNP), known as an endogenous ligand of the membrane bound guanylyl cyclase, (1 nM-1/10 microM) on the tension induced by 0.1 microM ET-1 of human prostate strips were investigated. The adenylyl cyclase stimulating agents forskolin and NO-donor natrium nitroprusside (NNP) were used as reference compounds. While AT-II failed to contract the prostate tissue, ET-1 induced stable and reproducible contractions of the tissue strips. The tension induced by 0.1 microM ET-1 was dose-dependently reversed by the drugs. The rank order of efficacy was forskolin >NNP>CNP(1 microM)>GSNO. R(max) values ranged from 55% (forskolin) to 35% (GSNO). Forskolin was the only compound which reached an EC50 value. Our results demonstrate that drugs in terfering with the cGMP- and cAMP-pathways can reverse the tension induced by ET-1. These findings are in support of the hypothesis that both cGMP and cAMP contribute to the control of the prostate smooth muscle tension and may provide new strategies for the future pharmacotherapy of LUTS und BPH.

Do we need new high-risk criteria for surgically treated renal cancer patients to improve the outcome of future clinical trials in the adjuvant setting? Results of a comprehensive analysis based on the multicenter CORONA database.

BACKGROUND: Since there is still an unmet need for potent adjuvant strategies for renal cancer patients with high progression risk after surgery, several targeted therapies are currently evaluated in this setting. We analyzed whether inclusion criteria of contemporary trials (ARISER, ASSURE, SORCE, EVEREST, PROTECT, S-TRAC, ATLAS) correctly identify high-risk patients. METHODS: The study group comprised 8873 patients of the international CORONA-database after surgery for non-metastatic renal cancer without any adjuvant treatment. Patients were divided into potentially eligible high-risk and assumable low-risk patients who didn't meet inclusion criteria of contemporary adjuvant clinical trials. The ability of various inclusion criteria for disease-free survival (DFS) prediction was evaluated by Harrell's c-index. RESULTS: During a median follow-up of 53 months 15.2% of patients experienced recurrence (5-year-DFS 84%). By application of trial inclusion criteria, 24% (S-TRAC) to 47% (SORCE) of patients would have been eligible for enrollment. Actual recurrence rates of eligible patients ranged between 29% (SORCE) and 37% (S-TRAC) opposed to <10% in excluded patients. Highest Hazard Ratio for selection criteria was proven for the SORCE-trial (HR 6.42; p < 0.001), while ASSURE and EVEREST reached the highest c-index for DFS prediction (both 0.73). In a separate multivariate Cox-model, two risk-groups were identified with a maximum difference in 5-year-DFS (94% vs. 61%). CONCLUSION: Results of contemporary adjuvant clinical trials will not be comparable as inclusion criteria differ significantly. Risk assessment according to our model might improve patient selection in clinical trials by defining a high-risk group (28% of all patients) with a 5-year-recurrence rate of almost 40%.

Inducible regulatory elements in the human cyclin D1 promoter.

To be able to elucidate the function of cyclin D1 in the control of cell cycle progression and its role as an oncogene in tumorigenesis, it is of paramount importance to understand the mechanisms involved in the regulation of its expression. In the present study, we have cloned the human cyclin D1 gene and analysed the structure and function of 3kb of its 5'-flanking region. Several regulatory regions involved in both basal level and serum-induced expression were identified, two of which turned out to be of particular interest. One of these regions is involved in serum induction and is located 848-944 bp upstream of the initiation site. In agreement with this result, in vivo footprinting revealed a novel, strongly inducible protein binding site around positions -928 to -921. A second constitutively occupied binding site was mapped to a potential CRE at position -52. Cotransfection experiments showed that the cyclin D1 promoter is inducible by c-Jun, and that this induction is mediated predominantly through the protected putative CRE at -52.

Progression of carcinoma cells is associated with alterations in chromatin structure and factor binding at the E-cadherin promoter in vivo.

E-cadherin has been identified as a tumor (invasion) suppressor gene, which is mutated in 50% of diffuse-type human gastric carcinomas. In other carcinomas, the expression of E-cadherin is down-regulated in the poorly differentiated cells such as from breast, bladder, lung and colon. We have here examined the in vivo properties of the genomic E-cadherin promoter in well and poorly differentiated carcinoma cell lines in order to gain insights into the mechanisms of E-cadherin down-regulation in tumors. In vivo footprinting analysis revealed that positive regulatory elements of the E-cadherin promoter (a GC-rich region, the CCAAT-box and a palindromic element) are specifically bound by transcription factors in E-cadherin-expressing but not in non-expressing cells. The tested cell systems include more than a dozen carcinomas cell lines as well as mammary epithelial cells where E-cadherin expression can be switched off by activation of a Fos-estrogen receptor fusion protein and rhabdomyosarcoma cells where E-cadherin expression was induced by transfection with E1A. Mapping of DNase I hypersensitive sites showed that the chromatin structure in the promoter region is loosened in expressing but condensed in non-expressing cells. Furthermore, the endogenous E-cadherin promoter is specifically methylated at CpG sites in the undifferentiated cells. We also show that the in vivo properties of the promoter in E-caherin-negative carcinoma cells are similar as in mesenchymal cells, i.e. fibroblasts or sarcoma cells. These data suggest that silencing of the E-cadherin promoter during epithelialmesenchymal transition and tumor progression is due to a loss of factor binding in vivo and to chromatin rearrangement in the regulatory region.

17beta-Estradiol induces cyclin D1 gene transcription, p36D1-p34cdk4 complex activation and p105Rb phosphorylation during mitogenic stimulation of G(1)-arrested human breast cancer cells.

MCF-7 human breast cancer cells express functional estrogen receptor and grow in response to estrogen stimulation. G(1)-synchronized MCF-7 cells, made quiescent by exposure to the HMG-CoA reductase inhibitor Simvastatin in estrogen-free medium, readily resume cell cycle progression upon stimulation with 17beta-estradiol (E(2)), even under conditions where polypeptide growth factor-triggered signal transduction pathways are inhibited by the continuous presence of Simvastatin in the culture medium. Under these conditions, cyclin D(1) gene transcription is transiently induced within the first 1-9 h of stimulation, as shown by the accumulation of cyclin D(1) mRNA and protein (p36(D(1))) in the cell and by enhanced expression of stably transfected D(1) promoter-luciferase hybrid genes. Estrogen-induced p36(D(1)) associates readily with p32(cdk2) and p34(cdk4), but not with p31(cdk5), which is however abundantly expressed in these cells. Only p36(D(1))-p34(cdk4) complexes are activated by E(2), as detected in cell extracts by immunoprecipitation with anti-D(1) antibodies followed by assessment of phosphotransferase activity toward the retinoblastoma (Rb) gene product and by analysis of p105(Rb) phosphorylation in vivo. An estrogen-responsive regulatory region has been mapped within the first 944 bp upstream of the transcriptional startsite of the human D(1) gene. Sequence analysis of this DNA region reveals that the cis-acting elements responsive to estrogen are likely to be different in this case from the canonical EREs.

Structural features of a regulatory nucleosome.

DNA sequences from the long terminal repeat of the mouse mammary tumor virus (MMTV-LTR) position nucleosomes both in vivo and in vitro. Here, were present chromatin reconstitution experiments showing that MMTV-LTR sequences from -236 to +204 accommodate two histone octamers in positions compatible with the in vivo data. This positioning is not influenced by the length of the DNA fragment and occurs in linear as well as in closed circular DNA molecules. MMTV-LTR DNA sequences show an intrinsic bendability that closely resembles its wrapping around the histone octamer. We propose that bendability is responsible for the observed rotational nucleosome positioning. Translational nucleosome positioning seems also to be determined by the DNA sequence. These data, along with the results from reconstitution experiments with insertion mutants, support a modular model of nucleosome phasing on MMTV-LTR, where the actual positioning of the histone octamer results from the additive effect of multiple features of the DNA sequence.

The mouse mammary tumour virus promoter positioned on a tetramer of histones H3 and H4 binds nuclear factor 1 and OTF1.

Modulation of eukaryotic gene expression is influenced by the organization of regulatory DNA-elements in chromatin. The mouse mammary tumor virus (MMTV) promoter exhibits regularly positioned nucleosomes that reduce the accessibility of the binding sites for sequence-specific transcription factors, in particular nuclear factor (NF1). Hormonal induction of the MMTV promoter is accompanied by remodeling of the nucleosomal structure, but the biochemical nature of these structural changes is unknown. Using recombinant histones, we have now assembled the MMTV promoter in particles containing either an octamer of the histones H3, H4, H2A and H2B or a tetramer of histones H3 and H4, and have compared the two particles in terms of structure, positioning, and exclusion of transcription factors. Using site-directed hydroxy radicals to map histone locations, two main nucleosome positions are found with dyads at position -107 and at -127. The same two main positions are found for particles containing only the H3/H4 tetramer, showing that the absence of H2A/H2B dimers does not alter positioning. The rotational orientation of the DNA double helix in both types of particles is essentially identical. However, the ends of the nucleosomal DNA as well as its central region are more accessible to cleavage reagents in the tetramer particle than in the octamer particle. In agreement with these structural features, the transcription factors NF1 and OTF1 were able to bind to their cognate sites on the tetramer particle, while they could not gain access to the same sites on the surface of the octamer particle. The DNase I digestion pattern of octamers treated with partially purified SWI/SNF complex from HeLa cells in the presence of ATP is indistinguishable from that of tetramer particles, suggesting that the SWI/SNF complex promotes ATP-dependent remodeling of the octamer particle but not of tetramer particles. These results are compatible with a hormone-induced removal of histone H2A/H2B during MMTV induction.

Interplay of steroid hormone receptors and transcription factors on the mouse mammary tumor virus promoter.

The mouse mammary tumor virus (MMTV) promoter, that responds to glucocorticoids and progestins, contains a complex hormone response element (HRE) in the long terminal repeat (LTR) region covered by a phased nucleosome. Hormone treatment leads to alterations in chromatin structure that make the HRE region more accessible to digestion by DNase I and permit binding of transcription factors, including nuclear factor I (NFI), immediately downstream of the HRE. NFI acts as a basal transcription factor on the MMTV promoter in vitro but competes with the hormone receptors in terms of binding to free DNA. In uninduced chromatin, the precise positioning of the DNA double helix on the surface of the histone octamer precludes binding of NFI to its cognate sequence while still allowing recognition of the HRE by the hormone receptors. We postulate that receptor binding to the nucleosomally organized MMTV promoter disrupts the chromatin structure enabling NFI binding and subsequent formation of a stable transcription complex. Whether the receptor remains bound to DNA during induction or is displaced by NFI is not conclusively known, but our evidence supports a "hit and run" mechanism. NFI is not the only factor involved in hormonally induced transcription of the MMTV promoter. Two degenerated octamer motifs located immediately upstream of the TATA box are recognized by the ubiquitous transcription factor OTF-1 (Oct-1, NFIII), and are also important. In vitro, mutations in these motifs do not influence basal transcription, but completely abolish the stimulatory effect of purified progesterone receptor. Progesterone receptor bound to the HRE facilitates binding of OTF-1 to the two octamer motifs. Thus, OTF-1 is a natural mediator of progesterone induction of the MMTV promoter and acts through cooperation with the hormone receptor for binding to DNA.

Chromatin structure modulates transcription factor binding to the mouse mammary tumor virus (MMTV) promoter.

The MMTV promoter contains a complex hormone responsive region (HRR) upstream of a binding site for the transcription factor nuclear factor I (NFI). Hormonal induction of MMTV expression requires the integrity of both the HRR and the NFI binding site. However, in vitro NFI acts as a basal transcription factor on the MMTV promoter that does not cooperate but rather competes with the hormone receptors in terms of binding to MMTV-DNA. Fragments that contain the HRR and the NFI binding site have been reconstituted into mononucleosomes. Steroid hormone receptors bind efficiently to these nucleosomes, NFI does not. Therefore it has been postulated that the chromatin structure may be responsible for the inability of NFI to bind to the chromosomally organized inactive MMTV promoter. In vivo DNaseI and methidium-propyl-EDTA-Fe(II) (MPE) digestion pattern indicate the presence of a nucleosome covering the HRR and the NFI binding site. Genomic footprinting shows that in vivo the rotational setting of the MMTV promoter DNA in this nucleosome is identical to that previously reported for reconstituted nucleosomes in which the major grooves of the NFI half palindromes are facing towards the histone octamer and appear not to be accessible to NFI. These results indicate that MMTV promoter sequences are determining nucleosome positioning in vivo and supports the concept that rotational positioning of DNA in this nucleosome constitutively represses the MMTV promoter.

Interaction of steroid hormone receptors with transcription factors involves chromatin remodelling.

The mechanism by which steroid hormones modulate promoter utilization is not clear. Evidence from transfection studies and cell-free assays points to an interaction of the hormone receptors with general transcription factors, as well as with sequence-specific transcription factors. Moreover co-activators or transcription intermediary factors, have been identified which could mediate some of the transcriptional effects of the hormone-receptor complex. However, in addition to this interaction of receptors with proteins directly involved in transcription, a participation of chromatin structure in gene regulation by steroid hormones is becoming increasingly evident. In the case of the MMTV promoter, the nucleosomal organization seems to be responsible for transcriptional repression prior to hormonal stimulation. This effect is due to occlusion by a nucleosome positioned on the MMTV promoter sequences in such a way that essential transcription factors cannot access their recognition sites. Following hormone induction, a remodelling of the nucleosome structure takes place which enables a whole complement of sequence specific transcription factors to assemble on the promoter. Since a complete occupancy of binding sites does not take place when the promoter is present as naked DNA, the nucleosomal organization appears to be required for the proper synergism between transcription factors following hormonal induction. According to this model, the positioning of a nucleosome sets the stage for constitutive repression and hormone induction of the MMTV promoter.

Transcriptional control by steroid hormones.

Gene regulation by steroid hormones leads to induction or repression of particular sets of genes. These effects are mediated by intracellular hormone receptors that, in the unliganded state, are maintained in an inactive form by unknown mechanisms possibly involving association with other cellular proteins. Induction of the mouse mammary tumor virus (MMTV) requires binding of the hormone receptor to a complex hormone-responsive element (HRE) located between 75 and 190 bp upstream from the start of transcription. The interaction of several receptor molecules with the four receptor binding sites in the HRE is highly cooperative on circular DNA molecules and each individual site is needed for optimal induction. In chromatin the HRE is precisely organized in phased nucleosomes. Following hormone treatment and receptor binding, changes in chromatin structure are detected that correlate with binding of transcription factors, including nuclear factor I, to the MMTV promoter. However, though nuclear factor I acts as a basal transcription factor on the MMTV promoter it does not cooperate with the hormone receptors in terms of binding to free DNA, and mutation of the nuclear factor I binding site does not eliminate hormonal stimulation. This residual induction is mediated by octamer motifs, upstream of the TATA box, that bind the ubiquitous transcription factor OTF-1. Mutation of these octamer motifs does not influence basal transcription in vitro, but completely abolishes the stimulatory effect of progesterone receptor.

History of direct vision internal urethrotomy.

Throughout medical history, the treatment of urethral strictures ranged from catheterization, the insertion of bougies, and the application of caustics to different methods of dilation, blind internal urethrotomy, and open surgery. The rise of endoscopy in the 19th century added the possibility of direct vision internal urethrotomy to this therapeutic spectrum. The development of this endourologic method is recapitulated from the first report in 1865 to the gold standard of cold knife urethrotomy in 1971 and later modifications (eg, advanced laser techniques).