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Introduction. About 10–20% of patients among women of reproductive age suffer from signs and symptoms of androgen excess in hyperandrogenism. Its skin symptoms may include hirsutism, acne, seborrhea and alopecia.Aim. To assess the effect of cyproterone acetate on skin symptoms of hyperandrogenism and improvement in the patients’ quality of life after treatment.Materials and methods. The study included 120 patients with skin symptoms of hyperandrogenism. The patients ranged in age from 18 to 35 years. The inclusion criteria were the main complaints of the patients as follows: acne, hirsutism and alopecia. The patients underwent a comprehensive clinical and laboratory examination. The drug of choice for the treatment of androgendependent dermatopathies was cyproterone acetate at a dose of 50–100 mg daily.Results and discussion. All patients were divided into three groups: 44 (37%) patients with hirsutism, 55 (53%) with acne, 12 (10%) with alopecia. Moreover, 32 (27%) patients had a mix of symptoms at the same time. Such patients were assigned to one of the groups depending on the predominant complaint. All patients were prescribed cyproterone acetate at a dose of 50-100 mg once daily, depending on the severity of symptoms from day 1 to day 10 of the menstrual cycle, and 54 (52%) patients were prescribed cyproterone acetate 20 mg and ethinyl estradiol 35 mg from day 1 to day 21 of the menstrual cycle. The study showed stabilization of the psychoemotional state, relief of anxiety, depressive disorders, enhancement of self-esteem and sociability, and improvement of the quality of life in its various manifestations in the majority of patients after the treatment.Сonclusion. When assessed using the dermatology life quality index questionnaires, all patients reported the stabilization of the psychoemotional state and the improvement in the quality of life after the treatment. The anxiety and depressive disorders decreased in 109 (91%) patients, which favourably influenced various areas of quality of life, enhanced self-esteem and sociability with a positive effect on personal relationships.

Introduction: 5α-reductase inhibitors have been proven useful for the treatment of prostate diseases, which can be due to the unregulated activity of 5α-reductase enzyme. This study was focused on determining the activity of four different derivatives of 17β-phenyl carbamoyl-androst-4-en-3-one 1–4 as inhibitors of 5α-reductase (5RD5A), to improve the effects of current drugs. Methods: In vitro effect of compounds 1-4 on the activity of the human prostate enzyme, 5α-reductase, was determined by measuring IC50 values, the concentration of a compound that inhibits the activity of 5RD5A2 by 50%. In vivo, the pharmacological effects of compounds 1-4 were identified in a hamster model of prostate hypertrophy. Results: The steroidal 17β-carboxamides 1, 3, and 4 (IC50 = 5±0.5, 0.112±0.045, 0.167±0.056 nM) significantly inhibited the in vitro activity of the 5RD5A2 enzyme with higher potency than finasteride, which is a drug known as a specific 5RD5A2 inhibitor (IC50 = 8.5±0.3 nM). Compounds 1, 3, and 4 were more potent than finasteride to decrease the size of hamster flank organs in castrated animals treated with testosterone. Also, compounds 1-4 were more effective than finasteride itself to reduce the weight of the prostate in the hamster model, without producing toxicological effects during the six days of treatment. Conclusion: In conclusion, the steroidal 17 β-carboxamides 1-4 were suitable inhibitors of human 5RD5A2 activity, in addition to being able to reduce prostate weight without causing toxicity. These steroids could, therefore, have promising therapeutic potential for the treatment of benign prostatic hyperplasia.

The taxane-based therapy provides survival benefit in patients with metastatic prostate cancer; however, the average survival is less than 20 months due to the partial taxane-related chemoresistance. Innovative strategies are needed to overcome the chemoresistance for improved patient survival. In this project, paclitaxel-resistance was developed on androgen-independent PC3 and androgen-dependent 22Rv1 and LNCaP human prostate cancer (PCa) cell lines to investigate the efficacy of methyl jasmonate (MeJa), an anti-cancer drug, in overcoming the chemoresistance. The PCa cell lines were maintained in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS) at 37?C under 5% CO2. The cell lines were exposed to the gradually increasing doses of paclitaxel. Since the resistance on LNCaP could not be achieved, the study was continued with 22Rv1 cell line. It was demonstrated that paclitaxel-resistant cell lines overexpress ABCB1. Resistance levels of cells and MeJa activity in all resistant and parental lines were measured using CellTiter-Glo? luminescent assay. Test results were compared with Student?s t-test or analysis of variance (ANOVA). P?0.05 (two-tailed) was considered to be significant. In conclusion, MeJa showed more cytotoxicity on paclitaxel resistant PC3 (PC3-PtxR) cells than resistant 22Rv1 (22Rv1-PtxR) cells. Detection of cytotoxic effects of MeJa in overcoming paclitaxel resistance may contribute to the development of alternative new compounds for the prevention or chemosensitization of resistance to chemotherapeutics such as paclitaxel.

Hypertrichosis is a rare condition characterized by excessive hair in areas of the body that are not predominantly androgen dependent. We can identify three main syndromes with congenital generalized hypertrichosis terminalis described in Mexico. The first is X-linked generalized hypertrichosis, an ultra-rare disease, with few cases reported to date. The second is Cantú syndrome, also known as hypertrichotic osteochondrodysplasia, which has a wide spectrum of clinical manifestations and is caused by pathogenic variants in ABCC9 and KCNJ8. The third is congenital hypertrichosis terminalis with or without gingival hyperplasia, which displays other features and involves several associated genes. The first two syndromes were described by the Mexican geneticist José María Cantú, and the concept of atavistic genes was invoked to explain the emergence of this outstanding trait. By understanding the genetic and pathophysiological basis of hypertrichosis, we can offer effective treatment to patients and help solve esthetic problems related to hair growth.

Background: Benign Prostatic Hyperplasia (BPH), and Prostate Cancer (PCa) are androgen-dependent diseases. PCa is associated with excessive signalling of the androgen receptor (AR) due to the binding of 5α-DHT and T. BPH is related to high levels of 5α-dihydrotestosterone (5α-DHT), biosynthesized from testosterone (T) by 5α-reductase (5RD5A). The inhibition of 5RD5A and the blockage of AR are targets for their treatment. In this study, the synthesis and determination of biological activity of the new N-cyclohexyl-3β-hydroxyandrosta-5,16-diene-17-carboxamide (6), N-cyclohexyl-3-oxoandrosta-4,6,16-triene-17-carboxamide (7), and N-cyclohexyl-3-oxoandrosta-4,16-diene-17-carboxamide (8) were carried out to find new drugs to improve these afflictions. Methods: The synthesis of 6 to 8 was confirmed by spectroscopic and spectrometric analyses. Competitive binding assays determined the affinity of 6 to 8 to the AR. The inhibitory activity of 5RD5A isoform 2 (5RD5A2) (IC50) was established by the conversion of [3H]-T to [3H]-5α-DHT and it was compared with finasteride (FIN). The pharmacological effect of 6 to 8 was determined on the weight of the prostate and seminal vesicles glands of castrated hamsters treated with T, and on the diameter size of their flank organs. Results: Compounds 7 and 8 bound lightly (ca. 15 %) to AR. Comparing to FIN (IC50 = 8.5 nM), 6 to 8 (IC50 = 0.169, 0.105 and 0.155 nM, respectively) showed higher potency as inhibitors of 5RD5A2. Compound 6 decreased the prostate and seminal vesicles weight, as well as the hamsters' diameter flank organs. However, 7 only decreased the diameter of flank organs. Surprisingly, 8 increased these pharmacological parameters. Conclusion: Androstane-17-caboxamide 6 is a 5RD5A2 inhibitor that reduces the weight of androgen-dependent glands such as the prostate, suggesting it could be a lead for new drugs to treat BPH and PCa.

The skin is the largest organ of the human body and is colonized by divergent microorganisms, with a majority of them being harmless and even helpful for humans. The development of molecular methods for the identification of microorganisms has led to a conception that the skin microflora is greatly diverse and variable. Innate and adaptive immune responses can change the microbiota, and, on the other hand, the microbiota is involved in an immune response. The degree of colonization of the skin by different microorganisms varies greatly depending on the body sites, as well as endogenous and exogenous factors. There are significant gender differences in skin structure and physiology, which is substantially influenced by sex hormones. The investigation of the skin microbial component in androgen-dependent dermatoses, such as acne and seborrheic dermatitis, will contribute to understanding the pathogenic mechanisms of these diseases and to developing effective methods of therapy.

Recent studies in mice demonstrate that a subset of neurons in the medial preoptic area (MPOA) that express galanin play crucial roles in regulating parental behavior in both sexes. However, little information is available on the function of galanin in social behaviors in other species. Here, we report that, in medaka, a subset of MPOA galanin neurons occurred nearly exclusively in males, resulting from testicular androgen stimulation. Galanin-deficient medaka showed a greatly reduced incidence of male–male aggressive chases. Furthermore, while treatment of female medaka with androgen induced male-typical aggressive acts, galanin deficiency in these females attenuated the effect of androgen on chases. Given their male-biased and androgen-dependent nature, the subset of MPOA galanin neurons most likely mediate androgen-dependent male–male chases. Histological studies further suggested that variability in the projection targets of the MPOA galanin neurons may account for the species-dependent functional differences in these evolutionarily conserved neural substrates.

Background: 5´ adenosine monophosphate-activated kinase (AMPK) is an essential regulator of cellular energy homeostasis which has been associated with different pathologies, including cancer. Precisely defining the role of AMPK in these processes necessitates the availability of a potent and selective inhibitor.Methods: High-throughput screening and subsequent chemical optimization led to the identification of the selective inhibitor BAY-3827. Cell proliferation and mechanistic assays, as well as gene expression analysis and chromatin immunoprecipitation were used to investigate the cellular impact of BAY-3827 and the crosstalk between lipid metabolism and androgen signaling in prostate cancer models. Also, fatty acid turnover was determined by examining lipid droplet formation.Results: BAY-3827 prevented phosphorylation of acetyl-CoA carboxylase 1 and showed strongest anti-proliferative activity in androgen-dependent prostate cancer cell lines. Analysis of genes involved in AMPK signaling revealed that the expression of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), fatty acid synthase (FASN) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2), all of which are involved in lipid metabolism, was strongly upregulated by androgen in responsive prostate cancer cell lines. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) analysis identified androgen receptor (AR) binding peaks in these genes. BAY-3827 strongly down-regulated the expression of lipase E (LIPE), cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B) and serine-threonine kinase AKT3 in the responsive prostate cancer cell lines. Also, the expression of members of the carnitine palmitoyl-transferase 1 (CPT1) family was inhibited by BAY-3827, and this was paralleled by impaired lipid flux.Conclusions: The availability of the potent and selective inhibitor BAY-3827 will contribute to a better understanding of the biological role of AMPK signaling in cancer, especially in prostate adenocarcinoma.

Objective: To explore the character of androgen-dependent dermopathy (ADD) in women with keloid scars. Methods: 100 girls and women aged 15-28 years were examined, of whom 47 were with «true» and 53 were with «false» keloids. The evaluation of keloid scars was carried out using the Vancouver Scale (Baryza MJ, Baryza GA, 1995), modified Fistal HH (2006). Hyperandrogenic skin conditions were evaluated using the dermatological acne index (DAI), the Ferriman-Galway scale and the trichoscopy method. Results: Acne was detected in 47 (100%) patients with «true» keloids and 40 (75.5%) patients with «false» keloids. Seborrheic dermatitis occurred in 32 (68.1%) cases of «true» and 27 (51.0%) observations of «false» keloids. In both groups of patients, the borderline condition between normal and excess haired, which in 22 (46.8%) patients with «true» keloids amounted to 10,5±1,2. Signs of androgenic alopecia were detected in 35 (74.5%) patients with «true» and 38 (71.7%) patients with «false» keloids. In «true» keloids, the density of hair in the androgen-dependent (parietal) area was lower than in patients with «false» keloid scars (171.3±14.6 vs. 273.2±17.5). The androgen-independent occipital area, the density of hair in patients with «true» scars was lower (191.3±11.2), than in patients with «false» keloids (241.0±18.5). In all patients with «true» keloids observed a combination of scarring with ADD. In 13 (24.5%) patients with «false» keloids correlation with ADD was not observed. Conclusion: The most typical ADD in women with keloid scars are the acne and androgenic alopecia, which occur respectively, in 100% and 74.5% of cases in «true», and in 75.5% and 71.6% with «false» keloids. Consequently, hyperandrogenic skin conditions in women may be risk factors for keloids and indicate a hormonal imbalance in this contingent of patients. Keywords: Androgen-dependent dermopathy, keloids , acne, androgenic alopecia.

Objective To compare the diagnostic accuracy of Ga-prostate-specific membrane antigen (PSMA)-HBED-CC PET/computed tomography (CT) imaging for the detection of androgen-dependent recurrent prostate carcinoma (ADPC) in Black South Africans (BSAs) versus White South Africans (WSAs) with increasing serum prostate-specific antigen (PSA) values below or equal to 10 ng/ml. Patients and methods A total of 61 patients with ADPC were prospectively included in the study (mean age: 66.7 years): 38 WSAs and 23 BSAs. Ga-PSMA-HBED-CC PET/CT imaging results obtained were related to serum PSA levels and to ethnicity. Results A total of 41 (67%) patients had a positive Ga-PSMA-HBED-CC scan result. Ga-PSMA-HBED-CC PET/CT positivity was significantly higher in patients with PSA values more than 2 ng/ml [32/38 (84%) patients] when compared with patients with PSA values less than 0.5 ng/ml [6/11 (55%) patients] or PSA values of 0.5-2 ng/ml [3/12 (25%) patients] (P=0.0001). Mean PSA values proved not significantly different in patients presenting with extrapelvic involvement when compared with those with intrapelvic involvement or between patients who presented with bone involvement versus those who did not on Ga-PSMA-HBED-CC PET/CT) (P≥0.147). Age, Gleason-scores, median PSA values, the frequency of a positive scan result, the frequency of bone involvement, and extrapelvic involvement proved similar in WSAs and BSAs (P≥0.417). Conclusion Ga-PSMA-HBED-CC PET/CT imaging identified a recurrence in 67% of the patients under study. Higher PSA levels were associated with Ga-PSMA-HBED-CC PET/CT positivity and the detection rate. Imaging results obtained proved similar in BSAs and WSAs, suggesting that the tumor burden and growth rate of ADPC are similar in both races.

Prostate cancer (PCa) is one of the most common malignancies affecting men worldwide. Androgen receptor (AR) has been a target of PCa treatment for nearly six decades. AR antagonists/degraders can effectively treat PCa caused by increased AR overexpression. However, all approved AR antagonists have similar chemical structures and exhibit the same mode of action on the protein. Although initially effective, resistance to these AR antagonists usually develops. Therefore, this calls for the identification of novel chemical structures of AR antagonists to overcome the resistance. Herein, we employed the synergetic combination of virtual and experimental screening to identify a flavonoid compound which not only effectively inhibits AR transcriptional activity, but also induces the degradation of the protein. Based on this compound, we designed and synthesized a series of derivatives. We discovered that the most potent compound 10e could effectively inhibit AR transcriptional activity, and possessed a profound ability to cause degradation of both full length- and ARv7 truncated forms of human AR. Notably, 10e efficiently inhibited the growth of ARv7 dependent prostate cancer cell-lines, which are completely resistant to all current anti-androgens. Compound 10e also showed strong antitumor activity in the LNCaP (androgen dependent prostate cancer cell line) in vivo xenograft model. These results provide a foundation for the development of a new class of AR antagonists.

We have recently described in this journal our detection of an anthropoid primate-specific, adrenal androgen-dependent, p53-mediated, ‘kill switch’ tumor suppression mechanism that reached its fullest expression only in humans, as a result of human-specific exposure to polycyclic aromatic hydrocarbons caused by the harnessing of fire – but which has components reaching all the way back to the origin of the primate lineage. We proposed that species-specific mechanisms of tumor suppression are a generalized requirement for vertebrate species to increase in body size or lifespan beyond those of species basal to their lineage or to exploit environmental niches which increase exposure to carcinogenic substances. Using empirical dynamic modeling, we have also reported our detection of a relationship between body size, lifespan, and species-specific mechanism of tumor suppression (and here add carcinogen exposure), such that a change in any one of these variables requires an equilibrating change in one or more of the others in order to maintain lifetime cancer risk at a value of about 4%, as observed in virtually all larger, longer-lived species under natural conditions. Here we show how this relationship, which we refer to as the lex naturalis of vertebrate speciation, elucidates the evolutionary steps underlying an adrenal androgen-dependent, human-specific ‘kill switch’ tumor suppression mechanism; and further, how it prescribes a solution to ‘normalize’ lifetime cancer risk in our species from its current aberrant 40% to the 4% that characterized primitive humans. We further argue that this prescription writ by the lex naturalis represents the only tenable strategy for meaningful suppression of the accelerating impact of cancer upon our species.

Background The physiological function of ADTRP (androgen‐dependent tissue factor pathway inhibitor regulating protein) is unknown. We previously identified ADTRP as coregulating with and supporting the anticoagulant activity of tissue factor pathway inhibitor in endothelial cells in vitro. Here, we studied the role of ADTRP in vivo, specifically related to vascular development, stability, and function. Methods and Results Genetic inhibition of Adtrp produced vascular malformations in the low‐pressure vasculature of zebrafish embryos and newborn mice: dilation/tortuosity, perivascular inflammation, extravascular proteolysis, increased permeability, and microhemorrhages, which produced partially penetrant lethality. Vascular leakiness correlated with decreased endothelial cell junction components VE ‐cadherin and claudin‐5. Changes in hemostasis in young adults comprised modest decrease of tissue factor pathway inhibitor antigen and activity and increased tail bleeding time and volume. Cell‐based reporter assays revealed that ADTRP negatively regulates canonical Wnt signaling, affecting membrane events downstream of low‐density lipoprotein receptor‐related protein 6 ( LRP 6) and upstream of glycogen synthase kinase 3 beta. ADTRP deficiency increased aberrant/ectopic Wnt/β‐catenin signaling in vivo in newborn mice and zebrafish embryos, and upregulated matrix metallopeptidase ( MMP )‐9 in endothelial cells and mast cells ( MCs ). Vascular lesions in newborn Adtrp −/− pups displayed accumulation of MCs , decreased extracellular matrix content, and deficient perivascular cell coverage. Wnt‐pathway inhibition reversed the increased mmp9 in zebrafish embryos, demonstrating that mmp9 expression induced by Adtrp deficiency was downstream of canonical Wnt signaling. Conclusions Our studies demonstrate that ADTRP plays a major role in vascular development and function, most likely through expression in endothelial cells and/or perivascular cells of Wnt‐regulated genes that control vascular stability and integrity.

To enhance the structural diversity of isoflavonoids and provide more derivatives for the biological screening, a semisynthetic mixture was generated by diversification of the crude extract of Radix puerariae (Pueraria montana var. lobata) through the chemical reaction with hydrazine hydrate. Eleven 3,4-diarylpyrazoles (1-11) and two 5-phenyl-6-benzyldihydropyridazinones (12 and 13) were isolated from the semisynthetic mixture, and their structures were identified by spectroscopic methods in combination with X-ray crystallographic analysis. Among them, nine compounds (5-13) were new derivatives. All the compounds were evaluated on the inhibitory activities against the prostate cancer cell lines LNCaP and PC3. Compounds 12 and 13 were found to exhibit much more potent inhibitory activities against the androgen dependent LNCaP cells than the androgen independent PC3 cells. Rapid synthesis of new 3,4-diarylpyrazoles and two 5-phenyl-6-benzyldihydropyridazinones with significant biological activity highlights the great potential of one-pot combinatorial modification for the diversification of natural products.

Munich Wistar Frömter (MWF) rats develop spontaneous albuminuria that is linked to autosomal genetic loci and inherit a nephron deficit in both female and male animals, respectively. However, albuminuria and kidney damage are clearly more pronounced in males. Here we tested whether androgens and the androgen receptor influence albuminuria in male MWF. We first demonstrated in a pilot study that orchiectomy (Ox) of male MWF led to a significant suppression of urinary albumin excretion (UAE), while continuous testosterone supplementation in MWF Ox led to UAE levels similar to sham-operated (Sham) MWF rats. Subsequently, we performed a comparative main study between male MWF and normal Wistar rats to evaluate the effect of the androgen receptor on UAE development in adult animals up to the age of 18 wk. MWF Sham developed a marked increase in UAE compared with Wistar Sham (48.30 ± 6.16 vs. 0.42 ± 0.08 mg/24 h, P < 0.0001). UAE was significantly lower in MWF Ox compared with MWF Sham (−55%, P < 0.0001). In MWF Ox animals supplemented with testosterone and treated with the androgen receptor antagonist flutamide (OxTF) UAE at 18 wk was even lower compared with MWF Ox (−71%, P < 0.01) and similar to age-matched female MWF. The mRNA expression of renal tubular injury markers Kim1 and NGAL was increased in MWF Sham compared with Wistar Sham ( P < 0.0008, respectively) and expression decreased significantly in MWF OxTF ( P < 0.0004, respectively). Thus, the sexual dimorphism in albuminuria development in MWF can be attributed to testosterone and the androgen receptor in male rats.

Predictors of site-specific metastasis after radical prostatectomy (RP) are unknown despite prognostic differences between metastatic sites. We performed RNA expression analysis for 19 genes known to be correlated with aggressive prostate cancer in primary tumors of 63 men pN+ at RP (N = 35 developing metastases after RP vs N = 28 without metastases after RP). Of the men developing metastases, 22 (62.9%) had bone metastases, 8 (22.9%) had nonregional nodal metastases, and 5(14.3%) had visceral metastases. Patients with nodal metastases had higher androgen receptor expression relative to other metastatic sites and nonmetastatic controls (P = .001). This may explain the favorable prognosis of nodal metastases as it may be more androgen dependent.

193 Background: Prostate cancer (PCa) is an androgen dependent malignancy. PCa patients initially respond to androgen ablation but eventually the disease becomes castrate resistant. MicroRNAs (miRs) are considered to be master regulators of gene expression and could be potential biomarkers and therapeutic targets for PCa. We previously showed miR-27a-3p to be an androgen receptor (AR)-modulatory oncomiR, with a role in PCa progression. Methods: RNA sequencing was carried out on xenograft tumours treated with an inhibitory antisense oligonucleotide for miR-27a (ASO-27a), or control. Differentially expressed genes were cross-referenced with publicly available patient tissue datasets. ASO-27a was transfected in a panel of PCa cell lines mirroring disease progression, to verify changes in transcriptional and translational levels. Immunohistochemical analysis of encoded proteins was undertaken in a cohort of 46 PCa patients with Gleason 3+4 or 4+3 disease and compared with normal tissue-control. Results: Putative target genes tested included the tumour suppressor HIP2, the oncogenes SRC3, YAP, and PAX3, which can act both as oncogene and tumour suppressor. MRNA or protein levels of the majority of those genes tested were upregulated after ASO-27a treatment of PCa cell lines. In 22Rv1 cells, HIPK2 mRNA levels were significantly upregulated with ASO-27a (p = 0.0137), while protein levels were downregulated . PAX3 mRNA levels were significantly reduced by ASO-27a in 22Rv1 cells (p = 0.0364), while protein levels were significantly increased (p = 0.0112). Immunohistochemically, PAX3 protein was lower in Gleason 7 tumours than in normal tissue, while YAP expression was higher in patients with Gleason 4+3, relative to those with 3+4. SRC3 immunostaining was slightly, but not significantly, higher in patients with 3+4 compared to 4+3. Conclusions: MiR-27a-3p is an AR-modulatory oncomiR in PCa, with potential as a therapeutic target. MiR-27a interaction with its target genes and especially HIPK2, YAP, SRC3 and PAX3 could provide the basis for therapeutic advance in screening and in the treatment of castrate resistant disease, through ASO-27a inhibition.

284 Background: The TMPRSS2:ERG gene fusion (T:E) is found in up to 70% of prostate cancers (PCa) and results in androgen dependent overexpression of ERG, promoting tumor growth. The early identification of T:E may be helpful even in low-risk PCa. Although T:E can be non-invasively detected in urine, its correlation with new imaging tools (MRI and high-frequency ultrasound) and clinical outcome remains vague.This study investigates T:E expression in patients scheduled for random/software-assisted MRI or micro-ultrasound (29Mhz) fusion biopsy. Methods: This is a prospective cohort study in patients with suspected PCa enrolled between 2016 and 2019, approved by local authorities with Prot. N. 336/19, 14/05/2019. Patients underwent systematic US-guided biopsy, plus targeted biopsy if they had ³1 suspicious lesion (PI-RADS V.2 >2) at mpMRI or PRIMUS >2 at MICRO-US. For each patient, 1 prostatic core from the highest PI-RADS or PRIMUS lesion was collected for T:E analysis (a core from the right lobe in negative patients). Histological analyses were performed by experienced genitourinary pathologists. RNA was extracted from a dedicated fresh biopsy and RT-PCR was performed with different primer couples to detect the most frequent T:E fusions. All amplified products were checked by sequencing. Results: The cohort consists of 92 patients (median PSA 7.13 ng/ml, IQR 5.25-11.04 - average age 65ys), 81 with a diagnosis of PCa after biopsy. mpMRI was performed on 63 (68.5%) patients and was positive in 58 (92%), who underwent fusion biopsy. T:E fusion transcripts were detected in 23.5% of individuals with a diagnosis of PCa. Among patients positive for T:E, those analyzed by MRI were 100% positive (73% PI-RADS ≥4), those analyzed by MICRO-US were 83% positive. Sensitivity of the T:E assay for any PCa was 23.5%, specificity 100%, with negative and positive predicting values of 15% and 100%. There was no correlation between T:E and family history, PSA, PIRADS, PRI-MUS and Gleason score. Conclusions: Our finding showed a 100% of specificity making T:E an attractive tool for early cancer detection. In the future, identification of T:E in semen could represent a screening test for clinical stratification of patients with suspected PCa.

e16517 Background: The combination of PCUR-101 (a synthetic form of the plant-derived medicinal agent, plumbagin) and surgical castration caused regression of androgen dependent tumors in mice. These promising pre-clinical results led to this first-in-human study of PCUR-101 in combination with androgen deprivation therapy (ADT) in men with metastatic, castrate resistant PCa (mCRPC). Methods: The goal of this phase I multicenter trial was to determine the safety profile, maximum tolerated dose (MTD), recommended phase II dose, clinical activity, and pharmacokinetic (PK) parameters of PCUR-101. A 3 + 3 dose escalation design was employed. Patients (pts) in cohorts of 3 were treated with escalating doses of PCUR-101 (50 mg – 200 mg) orally once daily continuously. Cycles were 28 days. Exploratory correlates of IL-6 and urine polyamines were also included. Results: 12 pts (median age 75 [range 63-86]) with mCRPC on ADT were treated in the dose escalation cohorts. No DLTs were observed during treatment and the MTD was not reached. The most frequent adverse events (AEs) included diarrhea (11 pts; all grade 1 or 2), nausea (7 pts; all grade 1 or 2), vomiting (4 pts; all grade 1 or 2) and constipation (3 pts; all grade 1 or 2). No objective responses were observed but 1 pt had PSA decrease by > 50%. Pts remained on study treatment for a median of 10 weeks (range 3-32 weeks). 5 pts, with stable disease, remain on active treatment. PK data could not be fully evaluated due to issues with the PK assay. Analyses of IL-6 and putrescine levels in pt samples indicate that, as compared to no treatment, PCUR-101 treatment in each cycle was associated with decreases in their levels. Reasons for treatment discontinuation included disease progression (n = 4), adverse event (n = 1; nausea and vomiting), subject withdrawal (n = 1), and investigator or sponsor decision (n = 1). After treating 12 pts, the sponsor decided to stop the trial in order to reformulate the study drug to allow for higher dosing and to redevelop the PK assay. Conclusions: At the doses evaluated, PCUR-101 combined with ADT was seen to be safe and may prolong disease stability in men with mCRPC. A second phase I study is planned using a new drug formulation and PK assay. Clinical trial information: NCT03137758.

The treatment landscape for prostate cancer has changed remarkably in the last few years, with several US FDA-approved drugs and a promising pipeline of new agents. The current paradigm of treatment for advanced prostate tumors, which are androgen dependent, is hormone ablation therapy. This can be achieved chemically through LHRH agonists or antagonists, or surgically through orchiectomy. Most tumors respond favorably to this treatment, but eventually the tumor develops a more aggressive castration resistant phenotype. This review will help the reader gain a better understanding of the current paradigm for treatment, efforts to overcome resistance, and the strategies for future development of targeted agents.

Activation of the epidermal growth factor pathway is important in prostate cancer development and the transcription of androgen receptor regulated genes. This study evaluated the potential activity of lapatinib in men with biochemically-relapsed androgen-dependent (stage D0) prostate cancer.Patients with a rising PSA after primary therapy for prostate cancer were enrolled. A PSA doubling time (PSADT)12 months was required. Lapatinib was administered at 1,500 mg orally daily. Outcome measures were changes in PSA kinetics. Primary tumor blocks were obtained and assessed for EGFR expression, EGFR Q787Q polymorphism, and Kras 38 mutational status.Forty-nine patients were enrolled (14 ineligible), resulting in 35 patients for analysis. No PSA response was observed; best response was stable disease (n = 28, 80.0%). Pretreatment average slope was 0.19 log (PSA)/month (PSADT = 3.70 months), in contrast to on-treatment average slope of 0.13 log (PSA)/month (PSADT = 5.44 months) using linear mixed effects models (P = 0.006). Median progression-free survival (PFS) was 17.4 months for the high EGFR group and 6.0 months for the low EGFR group (P = 0.50). Patients with Kras 38 mutation had shorter PFS than those without Kras 38 mutation (P = 0.09).Although no PSA responses (primary endpoint) was observed, lapatinib may have biologic activity in men with stage D0 prostate cancer as evidenced by a decrease in PSA slope in this non-randomized study. Additional trials assessing the role of EGFR overexpression and Kras wild type status in prostate cancer should be investigated.

A study was undertaken with an objective of two dimensional SDS-PAGE analysis of protein profile in tissues of all caput, corpus and cauda of epididymis in both castrated and normal bulls and identification of androgen dependent protein/s in the epididymal tissues of bull (Bos taurus). Two dimensional SDS-PAGE analysis for protein spots of different molecular weight (MW) with pI 3.5 to 7.35 and pI > 7.35 to 9.3 between the three regions in the normal and castrated bull as well as between normal and castrated bull of a particular region revealed significant differences. Similarly, comparison between the three regions of the normal and castrated bull epididymis for the number of protein spots irrespective of the MW in pI range of 3.5 to 7.35 and pI range > 7.35 to 9.3 revealed significant differences. The number of protein spots found to be significantly higher in caput, corpus and cauda epididymis of the normal bull when compared to similar region of the castrated bull epididymis. Most of the proteins, which are secreted, are having MW between 20 and 85 kDa. Six proteins, which are known to be highly dependent on androgens, are also of acidic in nature except for one protein having basic pH. A protein spot (pI: 6.55–6.85, and MW

Prostate cancer is an androgen dependent condition where Dihydrotestosterone promotes the growth of the neoplastic tissue. Androgen deprivation has been the mainstay of therapy for this condition. This can be achieved by surgical or medical means. Types of medical regimens are intermittent maximal or sequential androgen blockade.

At a population level female scalp hair growth shows features of regression with chronological ageing, although there is wide interindividual variation in timing and degree. The subjective assessment of hair loss is classically determined by hair density but it is apparent that other factors contribute to the clinical picture. Changes can occur in hair cycling, hair density, hair diameter and pigmentation, and possibly in structural qualities of the hair fibre. These changes are most pronounced in female pattern hair loss. Although conventionally considered as the female counterpart of male androgenetic alopecia the evidence that female pattern hair loss is androgen dependent is less clear cut than in men and it probably has a multifactorial basis. The emerging evidence implicating environmental factors is of particular interest as, unlike genes, such factors may be amenable to intervention. The clinical signs in women complaining of hair loss may be variable. In evaluating the patient complaining of hair loss, while true pathology must always be considered, the clinician needs to be aware of how age affects hair growth. These changes form the focus of this article.

Vocalizations used in aggressive and mating contexts often convey reliable information about signaller condition when physical or physiological limitations constrain signal expression. In vertebrates, androgens modulate the expression of vocal signals and provide a proximate link between male condition and signal form. In many songbirds, assessment of males is based on production of trills that are constrained by a performance trade-off between how fast notes are repeated and the frequency bandwidth of each note. In this study, we first recorded trills of male Neotropical singing mice (Scotinomys) to examine whether they show a similar performance trade-off, and then manipulated androgen levels to assess their role in modulating vocal performance. Lastly, we broadcast experimentally manipulated trills to females to determine whether they preferred versions resembling those of androgen-treated males. Singing mice showed a vocal performance trade-off similar to that of birds. Males treated with androgens maintained vocal performance, but castrated mice that were administered empty implants produced trills with lower performance. Females approached high-performance trills more rapidly and spent more time near corresponding speakers. Together, our results demonstrate that androgens modulate the production of physically challenging vocalizations, and the resulting signal variation influences female receiver response.

Historically, most studies of vertebrate central pattern generators (CPGs) have focused on mechanisms for locomotion and respiration. Here, we highlight new results for ectothermic vertebrates, namely teleost fish and amphibians, showing how androgenic steroids can influence the temporal patterning of CPGs for social vocalization. Investigations of vocalizing teleosts show how androgens can rapidly (within minutes) modulate the neurophysiological output of the vocal CPG (fictive vocalizations that mimic the temporal properties of natural vocalizations) inclusive of their divergent actions between species, as well as intraspecific differences between male reproductive morphs. Studies of anuran amphibians (frogs) demonstrate that long-term steroid treatments (wks) can masculinize the fictive vocalizations of females, inclusive of its sensitivity to rapid modulation by serotonin. Given the conserved organization of vocal control systems across vertebrate groups, the vocal CPGs of fish and amphibians provide tractable models for identifying androgen-dependent events that are fundamental to the mechanisms of vocal motor patterning. These basic mechanisms can also inform our understanding of the more complex CPGs for vocalization, and social behaviors in general, that have evolved among birds and mammals.

The potent immunomodulatory, anti-inflammatory and procoagulant properties of protein no. 4 secreted from the rat seminal vesicle epithelium (SV-IV) have previously been found to be modulated by a supramolecular monomer-trimer equilibrium. More structural details that integrate experimental data into a predictive framework have recently been reported. Unfortunately, homology modelling and fold-recognition strategies were not successful in creating a theoretical model of the structural organization of SV-IV. It was inferred that the global structure of SV-IV is not similar to that of any protein of known three-dimensional structure. Reversing the classical approach to the sequence-structure-function paradigm, in this paper we report novel information obtained by comparing the physicochemical parameters of SV-IV with two datasets composed of intrinsically unfolded and ideally globular proteins. In addition, we analyse the SV-IV sequence by several publicly available disorder-oriented predictors. Overall, disorder predictions and a re-examination of existing experimental data strongly suggest that SV-IV needs large plasticity to efficiently interact with the different targets that characterize its multifaceted biological function, and should therefore be better classified as an intrinsically disordered protein.

Background: Adenocarcinoma of prostate is an internationally important health problem of the man, particularly in developed countries. The aim of this exploratory study was to evaluate whether significant changes in the prostatic tissue levels of Zn, as an androgen dependent trace element and Br, Fe, Rb, and Sr, as androgen independent trace elements, exist in the malignantly transformed prostate. Methods and findings: Prostatic tissue levels of Br, Fe, Rb, Sr, and Zn as well as ratio of Zn content to other trace element contents were prospectively evaluated in 35 patients with adenocarcinoma and 37 healthy male inhabitants. Measurements were performed using 109 Cd radionuclide-induced energy dispersive X-ray fluorescent analysis Tissue samples were divided into two portions. One was used for morphological study while the other was intended for trace element analysis. Mean values ± standard error of means (M ± SEΜ) for mass fraction (mg/kg on dry mass basis) of trace element in the normal tissue was: Br 38.8 ± 5.6, Fe 118 ± 8, Rb 16.3 ± 1.1, Sr 2.5 ± 0.4, and Zn 1154 ± 119, respectively. M ± SEΜ for ratio of mass fractions were: Zn/Br 38.7 ± 6.4, Zn/Fe 11.2 ± 1.3, Zn/Rb 71.7 ± 9.0 and Zn/Sr 534 ± 83, respectively. The contents of Rb and Zn were significantly lower (approximately 2 and 8 times, respectively) and those of Br and Sr was significantly higher (2.7 and 2.2 times, respectively) in cancerous tissues than in normal tissues. Conclusions: There are great changes in trace element contents and their relationships in the malignantly transformed tissue of prostate.

Castration-induced involution of the normal prostate is caused by primary effects in the prostate stroma and vasculature, but if this is the case also in tumors is unknown.Androgen-independent AT-1 prostate tumor cells were therefore injected into the ventral prostate (VP) in Copenhagen rats. Seven days later when the growing tumor was surrounded by normal VP tissue the rats were castrated and the effect examined 3 and 7 days later.Castration reduced vascular density in the surrounding VP tissue and this was accompanied by tumor cell hypoxia, apoptosis, and temporarily retarded tumor growth. Castration-induced VP tissue regression occurred more rapidly in the contra-lateral than in the tumor-bearing lobe.Androgen-independent tumor cell respond to castration when growing in an androgen-dependent environment. The presence of a tumor influences the castration response in the surrounding normal tissue. The microenvironment determines how prostate epithelial cells respond to castration.

This article summarizes the importance of different targets such as 5α-reductase, 17β-HSD, CYP17A, androgen receptor and protein kinase A for the treatment of prostate cancer and benign prostatic hyperplasia. It is a well known fact that dihydrotestosterone (DHT) is associated with the development of androgen-dependent afflictions. At the present time, several research groups are attempting to develop new steroidal and non-steroidal molecules with the purpose of inhibiting the synthesis and biological response of DHT. This review also discusses the most recent studies reported in the literature that describe the therapeutic potential of novel compounds, as well as the new drugs, principally inhibitors of 5α-reductase.

Objective: To assess the effect of dihydrotestosterone (DHT) on the gene expression of c-fos and c-jun and on the proliferation of human non-transformed epithelial prostatic (HNTEP) cells. Methods: Cell proliferation (MTT) and c-fos and c-jun mRNA expression (RT-PCR) were determined in cells treated with DHT (10–8, 10–10, and 10–13M) or with control medium. Results: DHT 10–13 M had a significant stimulatory effect on cell proliferation (p < 0.05) and c-fos and c-jun gene expression when compared to cells treated with higher concentrations of this hormone (10–10 and 10–8M) or with the control group. Conclusions: Our data demonstrate that the increase in c-fos and c-jun expression and cell growth in HNTEP cells is maximal with the lowest DHT concentration (10–13M). These proto-oncogenes may play a role in the control of hormone responsiveness and cell proliferation in HNTEP cells.

Prostatic Tissue Level of some Androgen Dependent and Independent Trace Elements in Patients with Benign Prostatic Hyperplasia Benign prostatic hyperplasia (BPH) is an internationally important health problem of the man, particularly in developed countries. The aim of this exploratory study was to evaluate whether significant deficiencies in the prostatic tissue levels of Zn, as an androgen dependent trace element, and Br, Fe, Rb, and Sr, as androgen independent trace elements, exist in patients with BPH. For this purpose it was prospectively evaluated prostatic tissue levels of these trace elements in 32 patients with BPH and 32 healthy male inhabitants. Measurements were performed using 109Cd radionuclide-induced energy dispersive X-ray fluorescent analysis. Beside the measurements of Br, Fe, Rb, Sr, and Zn mass fraction the calculations of Zn/Br, Zn/Fe, Zn/Rb and Zn/Sr mass fraction ratios were also performed. There was no found significant difference in levels of Br, Fe, Rb, Sr, and Zn contents between BPH and intact prostate. In the hyperplastic prostates, we have only observed a significant increase in value of Zn/Fe mass fraction ratio (p

We and others have previously described that the androgen-responsive human prostatic carcinoma cell line LNCaP is resistant to TRAIL and that TRAIL-mediated apoptosis in LNCaP is PI3K/Akt-dependent. In this study, we found that LNCaP remained resistant to treatment with TRAIL after androgen deprivation even in the presence of the PI3K/Akt pathway inhibitor wortmannin. This resistance was determined by failure to form the TRAIL-DISC and by decreased TRAIL-R1 and TRAIL-R2 levels after androgen deprivation; the capacity of TRAIL to induce DISC formation was completely restored in the presence of DHT. TRAIL and wortmannin together accelerated processing of caspase-8 on the DISC and apparently the release of caspase-8 from the DISC into the cytoplasm. Surprisingly, we found that wortmannin decreased the total amount of TRAIL-R1, but not TRAIL-R2, in the cells as well as the amount of TRAIL-R1 precipitated by TRAIL. Our data suggest that TRAIL-DISC formation and sensitivity to TRAIL treatment are androgen-dependent in LNCaP.

Introduction. Hirsutism is a condition which results in excess of male pattern hair growth - the androgen dependent hair in females. Excessive hair growth usually starts around puberty. The aim of this study was to show the significance of hormonal diagnosis in female adolescent hirsute patients.Material and methods. The material consisted of medical documentation of 128 female adolescent patients aged 13–22 years who came for a consultation because of excessive male pattern hair growth (second degree of hirsutism according to the Ferriman-Gallwey scale) which they considered unacceptable. The history was indicative of considerable discomfort, decreased mood in subjects and low self-esteem (especially regarding patient’s femininity).Results. Results of the analysis were confronted with the results of a group of an equal number of participants.Conclusions. Hormonal tests in female patients with hirsutism were proven to constitute a major diagnostic element allowing for correct diagnosis of the cause of hirsutism, planning further tests and treatment methods.Considering its causes and effects, hirsutism in adolescent patients is a serious concern for developmental gynecology. This disorder is a endocrinological or gynecological problem, which influences patient's well-being.

carefully designed to control androgen exposure, evaluating the effects of dihydrotestosterone as the key androgen responsible for penile development. The protocol also employed smooth muscle biomarker measurements of the androgenic effects. The work provides evidence in support of the requirement of the neonatal testosterone surge for the differentiation of corpus smooth muscle cells and, thus, development of the penis. Notwithstanding their confirmation of androgen dependent penile development the investigators have made some striking observations that merit comment. 1 The localization of the androgenic effects on smooth muscle cells of the corpus cavernosum and not the corpus spongiosum suggests differential androgentargetingeffectsinpeniledevelopment.The investigators propose that this distinction is due to differences in the cellular composition and structure of the corpus cavernosum with specialized molecular interactions between endothelial cells of cavernous spaces and smooth muscle cells of trabeculae in thecorpuscavernosum.Chemicalmessagesoperating via intercellular communications are certainly possible and other investigative work has suggested molecular crosstalk between endothelial and smooth muscle cells in the penis. 2,3 Further investigative work in this model system offers to delineate the molecular interactions that may be in play. The finding of a significant reduction in PDE5a expression, also localized to the corpus cavernosum but notthecorpusspongiosum,uponandrogenwithdrawal in the neonatal period is also intriguing. The dependence of PDE5a expression on androgens has been disputed in prior investigations. 4,5 Evidence provided here 1 would support a contention that PDE5a expres

Androgen dependent epididymal proteins act as antigen to produce autoantibodies and affect normal fertility. In the present study, epididymal proteins were analyzed during the time of sexual maturation and their androgen dependency was studied in male albino mice. Epididymis of 21 days (Pre-pubertal), 45 days (Pubertal), 60 days (Post-pubertal), orchidectomized (15 days after surgery) and orchidectomized with testosterone-treated (15 days after treatment) mice were dissected out and analyzed. Caput, corpus and cauda epididymidis were separated and the protein extract was prepared with 0.1 M PBS for 10% SDS-PAGE analysis. Testosterone assay was performed in the experimental groups except the testosterone treated group. The electrophoretic analysis of proteins in caput, corpus and cauda epididymidis of orchidectomized animals showed the disappearance of several proteins as compared to the adult. However, the disappeared proteins started to reappear in testosterone treated animals. The results suggest that removal of testis depletes the testosterone level and causes significant alteration in epididymal proteins. These proteins need further investigation for the purpose of immunocontraception by using them as antigens.

Acute social defeat (SD) leads to transient and persistent physiological and behavioral changes. We examined the effects of acute SD on territorial urine marking and ultrasonic courtship vocalizations in DBA/2 male mice. Both behaviors are considered androgen dependent and are influenced by social status, with dominant mice displaying more of both behaviors. In Experiment 1, male mice that received SD displayed prolonged inhibition of territorial urine marking, relative to nondefeated control mice (NOSD). In addition, territorial marking increased with repeated tests. In Experiment 2, male mice that received 3 successive days of SD displayed fewer ultrasonic courtship vocalizations at 30 min. post-SD1 and 30 min. post-SD2, relative to NOSD mice. In Experiment 2, we also observed decreased territorial marking 4 weeks post-SD. In sum, SD induced prolonged inhibition of territorial marking, but had only transient effects on ultrasonic courtship vocalizations, suggesting that different mechanisms may mediate the maintenance of these behaviors.