Binary and multi-class classification for androgen receptor agonists, antagonists and binders.

Androgens and androgen receptor regulate a variety of biological effects in the human body. The impaired functioning of androgen receptor may have different adverse health effects from cancer to infertility. Therefore, it is important to determine whether new chemicals have any binding activity and act as androgen agonists or antagonists before commercial use. Due to the large number of chemicals that require experimental testing, the computational methods are a viable alternative. Therefore, the aim of the present study was to develop predictive QSAR models for classifying compounds according to their activity at the androgen receptor. A large data set of chemicals from the CoMPARA project was used for this purpose and random forest classification models have been developed for androgen binding, agonistic, and antagonistic activity. In addition, a unique effort has been made for multi-class approach that discriminates between inactive compounds, agonists and antagonists simultaneously. For the evaluation set, the classification models predicted agonists with 80% of accuracy and for the antagonists' and binders' the respective metrics were 72% and 78%. Combining agonists, antagonists and inactive compounds into a multi-class approach added complexity to the modelling task and resulted to 64% prediction accuracy for the evaluation set. Considering the size of the training data sets and their imbalance, the achieved evaluation accuracy is very good. The final classification models are available for exploring and predicting at QsarDB repository (https://doi.org/10.15152/QDB.236).

Terapia de privación de andrógenos y obesidad mórbida: ¿tienen en común el riesgo cardiovascular por síndrome metabólico? / Androgen Deprivation Therapy And Morbid Obesity: Do They Share Cardiovascular Risk Through Metabolic Syndrome?

Antecedentes: A pesar de que el uso de la terapia de privación de andrógenos (TPA) ha producido una mejora en la supervivencia de hombres con cáncer de próstata avanzado, el hipogonadismo resultante se asocia con efectos negativos acusados, comparables a los que se observan en la obesidad mórbida, estando el riesgo cardiovascular entre los más letales. Objetivos: Evaluar el síndrome metabólico, las anomalías metabólicas y el riesgo cardiovascular en pacientes con cáncer de próstata sometidos a TPA, sin TPA y con obesidad mórbida. Métodos: Se trata de un estudio transversal que incluye a 79 hombres con cáncer de próstata, de los cuales 54 están sometidos a TPA y en 25 está ausente esta terapia, incluyéndose también a 91 pacientes con obesidad mórbida agrupados por sexo y edad. Para definir el síndrome metabólico empleamos los criterios de la Federación Internacional de Diabetes (FID). Se compararonl as anomalías metabólicas, los marcadores metabólicos y la puntuación Framingham entre los pacientes en terapia TPA, sin terapia TPA y con obesidad mórbida con el fin de predecir el riesgo de enfermedad coronaria a 10 años. Resultados: Los pacientes en terapia TPA presentaron una incidencia mucho mayor de diabetes y obesidad centralizada, así como mayores niveles de colesterol total y lipoproteínas de baja densidad (LBD), en comparación con los varones eugonadales. El riesgo cardiovascular medio fue significativamente superior en pacientes sometidos a TPA (39,97±12,53% vs. 26,09±14,80%; p = 0,021). Los sujetos con obesidad mórbida tenían un mayor riesgo de enfermedad coronaria a 10 años, comparable a la de los pacientes sometidos a TPA (p = 0,054). Conclusión: Este estudio apunta a que en los pacientes sometidos a TPA la preponderancia de anomalías metabólicas y riesgos cardiovasculares es mayor, siendo similar a la observada en sujetos con obesidad mórbida. Es posible que ambos procesos tengan en común el riesgo cardiovascular por vía de síndrome metabólico (AU)

Background: Although the use of androgen deprivation therapy (ADT) has resulted in improved survival in men with advanced prostate cancer, the resulting hypogonadism is associated with profound adverse effects comparable to those found in morbid obesity, being cardiovascular risk among the most lethal. Objectives: Evaluate metabolic syndrome, metabolic abnormalities and cardiovascular risk in patients with prostate cancer under ADT, not under ADT and morbid obese men. Methods: This is a cross-sectional study that involves 79 men presenting prostate cancer, of whom 54 under ADT and 25 not under ADT and 91 morbidly obese patients paired by sex and age. To define metabolic syndrome, we used the International Diabetes Federation (IDF) criteria. Metabolic abnormalities, metabolic markers and Framingham score to predict the ten year coronary heart disease risk were compared among patients under ADT, not under ADT and morbid obese. Results: Patients under ADT presented significantly greater occurrence of diabetes and central obesity and higher levels of total cholesterol and low density lipoprotein (LDL) compared to eugonadal men. The mean cardiovascular risk was significantly higher in patients under ADT (39.97±12.53% vs. 26.09±14.80%; p = 0.021). Morbidly obese subjects had increased ten year coronary heart disease risk; comparable to patients under ADT (p = 0.054). Conclusion: This study suggests that patients under ADT show higher prevalence of metabolic abnormalities and cardiovascular risk similar to those found in morbidly obese subjects. It is possible that both processes share cardiovascular risk through metabolic syndrome (AU)

Widely used pesticides with previously unknown endocrine activity revealed as in vitro antiandrogens.

BACKGROUND: Evidence suggests that there is widespread decline in male reproductive health and that antiandrogenic pollutants may play a significant role. There is also a clear disparity between pesticide exposure and data on endocrine disruption, with most of the published literature focused on pesticides that are no longer registered for use in developed countries. OBJECTIVE: We used estimated human exposure data to select pesticides to test for antiandrogenic activity, focusing on highest use pesticides. METHODS: We used European databases to select 134 candidate pesticides based on highest exposure, followed by a filtering step according to known or predicted receptor-mediated antiandrogenic potency, based on a previously published quantitative structure-activity relationship (QSAR) model. In total, 37 pesticides were tested for in vitro androgen receptor (AR) antagonism. Of these, 14 were previously reported to be AR antagonists ("active"), 4 were predicted AR antagonists using the QSAR, 6 were predicted to not be AR antagonists ("inactive"), and 13 had unknown activity, which were "out of domain" and therefore could not be classified with the QSAR ("unknown"). RESULTS: All 14 pesticides with previous evidence of AR antagonism were confirmed as antiandrogenic in our assay, and 9 previously untested pesticides were identified as antiandrogenic (dimethomorph, fenhexamid, quinoxyfen, cyprodinil, λ-cyhalothrin, pyrimethanil, fludioxonil, azinphos-methyl, pirimiphos-methyl). In addition, we classified 7 compounds as androgenic. CONCLUSIONS: Due to estimated antiandrogenic potency, current use, estimated exposure, and lack of previous data, we strongly recommend that dimethomorph, fludioxonil, fenhexamid, imazalil, ortho-phenylphenol, and pirimiphos-methyl be tested for antiandrogenic effects in vivo. The lack of human biomonitoring data for environmentally relevant pesticides presents a barrier to current risk assessment of pesticides on humans.

Decision trees versus support vector machine for classification of androgen receptor ligands.

With the current concern of limiting experimental assays, increased interest now focuses on in silico models able to predict toxicity of chemicals. Endocrine disruptors cover a large number of environmental and industrial chemicals which may affect the functions of natural hormones in humans and wildlife. Structure-activity models are now increasingly used for predicting the endocrine disruption potential of chemicals. In this study, a large set of about 200 chemicals covering a broad range of structural classes was considered in order to categorize their relative binding affinity (RBA) to the androgen receptor. Classification of chemicals into four activity groups, with respect to their log RBA value, was carried out in a cascade of recursive partitioning trees, with descriptors calculated from CODESSA software and encoding topological, geometrical and quantum chemical properties. The hydrophobicity parameter (log P), Balaban index, and descriptors relying on charge distribution (maximum partial charge, nucleophilic index on oxygen atoms, charged surface area, etc.) appear to play a major role in the chemical partitioning. Separation of strongly active compounds was rather straightforward. Similarly, about 90% of the inactive compounds were identified. More intricate was the separation of active compounds into subsets of moderate and weak binders, the task requiring a more complex tree. A comparison was made with support vector machine yielding similar results.

Androgen administration to aged male mice increases anti-anxiety behavior and enhances cognitive performance.

Although androgen secretion is reduced with aging, and may underlie decrements in cognitive and affective performance, the effects and mechanisms of androgens to mediate these behaviors are not well understood. Testosterone (T), the primary male androgen, is aromatized to estrogen (E(2)), and reduced to dihydrotestosterone (DHT), which is converted to 5alpha-androstane, 3alpha, 17beta-diol (3alpha-diol). To ascertain whether actions of the neuroactive metabolite of T, 3alpha-diol, mediates cognitive and affective behaviors, intact, aged male C57/B6 mice (24 month old) as well as young, intact and gonadectomized (GDX; 12 week old) mice were administered s.c. T, 3alpha-diol, E(2), or sesame oil vehicle (1 mg/kg; n=4-5/group) at weekly intervals and 1 h later mice were tested in the activity box, roto-rod, open field, elevated plus maze, zero maze, mirror maze, dark-light transition, forced swim, or Vogel tasks. Mice were trained in the inhibitory avoidance or conditioned contextual fear and were administered hormones following training and then were tested. After the last test occasion, tissues were collected for evaluation of hormone levels and effects on gamma-aminobutyric acid (GABA)-stimulated chloride flux. T, 3alpha-diol, or E(2) increased anti-anxiety and antidepressant behavior of aged, intact mice in the open field, light-dark transition, mirror maze, and forced swim tasks. T or 3alpha-diol, but not E(2), enhanced anti-anxiety behavior in the elevated plus maze, zero maze, and the Vogel task, and increased motor behavior in the activity monitor, latency to fall in the Roto-rod task, and cognitive performance in the hippocampally-mediated, but not the amygdala-mediated, portion of the conditioned fear task and in the inhibitory avoidance task. Anti-anxiety and enhanced cognitive performance was associated with regimen that increased plasma and hippocampal 3alpha-diol levels and GABA-stimulated chloride flux. Similar patterns were seen among young, adult GDX but not in intact mice. Thus, 3alpha-diol can enhance affective and cognitive behavior of male mice.

Comparison of in vitro and in vivo screening models for androgenic and estrogenic activities.

Identification of nuclear receptor-mediated endocrine activities is important in a variety of fields, ranging from pharmacological and clinical screening, to food and feed safety, toxicological monitoring, and risk assessment. Traditionally animal studies such as the Hershberger and Allen-Doisy tests are used for the assessment of androgenic and estrogenic potencies, respectively. To allow fast analysis of the activities of new chemicals, food additives, and pharmaceutical compounds, high-throughput screening strategies have been developed. Here, a panel of mainly steroidal compounds, screened in different in vitro assays, was compared with two human U2-OS cell line-based CALUX (Chemically Activated LUciferase eXpression) reporter gene assays for androgens (AR CALUX) and estrogens (ERalpha CALUX). Correlations found between the data of these two CALUX reporter gene assays and data obtained with other in vitro screening assays measuring receptor binding or reporter gene activation (CHO cell line-based) were good (correlation coefficients (r2) between 0.54 and 0.76; p < 0.0001). Good correlations were also found between the in vitro and in vivo data (correlation coefficient r2 = 0.46 for the AR CALUX vs. Hershberger assay and r2 = 0.87 for the ERalpha CALUX vs. Allen-Doisy assay). The variations in the results obtained with the reporter gene assays (CALUX vs. CHO cell line based) were relatively small, showing the robustness of these types of assays. Using hierarchical clustering, bioactivity relationships between compounds but also relationships between various bioassays were determined. The in vitro assays were found to be good predictors of in vivo androgenic or estrogenic activity of a range of compounds, allowing prescreen and/or possible reduction of animal studies.

OECD validation of the Hershberger assay in Japan: Phase 3. Blind study using coded chemicals.

The Organization for Economic Co-operation and Development (OECD) has initiated the development of new guidelines for the screening and testing of potential endocrine disrupters. The Hershberger assay is one of the assays selected for validation based on the need for in vivo screening to detect androgen agonists or antagonists by measuring the response of five sex accessory organs and tissues of castrated juvenile male rats: the ventral prostate, the seminal vesicles with coagulating glands, the levator ani and bulbocavernosus muscle complex (LABC), Cowper's glands, and the glans penis. The Phase 1 feasibility demonstration stage of the Hershberger validation program has been successfully completed with a single androgen agonist and a single antagonist as reference substances. The Phase 2 validation study was performed, employing a range of additional androgen agonists and antagonists. Recently, the Phase 3 validation study was conducted and performed in several International laboratories. Three Japanese laboratories have contributed to the blind study using coded materials of Phase 3 validation. Four coded test substances in the agonistic version and seven substances in the antagonistic version were orally administered by gavage for 10 consecutive days, respectively. In the antagonist version of the assay, 0.2mg/kg/day of testosterone propionate (TP) was coadministered by subcutaneous injection. All five accessory sex reproductive organs and tissues consistently responded with statistically significant changes in weight within a narrow window in both versions. Therefore, the Japanese studies support the Hershberger assay as a reliable and reproducible screening assay for the detection of androgen agonistic and antagonistic effects.

Evaluation of a rapid in vitro androgen receptor transcriptional activation assay using AR-EcoScreen cells.

An accurate and reliable in vitro assay system has been needed for first tier screening of endocrine disrupting chemicals. For the purpose, we previously developed stable AR-EcoScreen cell lines to assess androgen receptor (AR)-mediated transcriptional activation. In this report, we evaluated AR-EcoScreen cell lines as the phase I of prevalidation study by determining the intra-laboratory reproducibility, assay stability, and overall protocol performance of AR-EcoScreen assays. Forty compounds recommended by the ICCVAM were tested for AR agonist and antagonist activity. The mean coefficient of variation (CV) for intra-assay reproducibility in the AR agonist assay was 4.35% for 5alpha-dihydrotestosterone (DHT), and that for the antagonist assay was 5.51% for hydroxyflutamide. The detection limit of the agonist assay was 2.3x10(-11) M for 5alpha-dihydrotestosterone. Furthermore, we examined the overall performance of the method by comparing the predicted result with the ICCVAM classification. Thus, the overall sensitivity, specificity, and accuracy of the agonist assay were 89%, 94%, and 91%, respectively. For the antagonist assay, these values were 94%, 100%, and 96%, respectively. In summary, we concluded that AR-EcoScreen method was ready to proceed to the phase II prevalidation study to asses the inter-laboratory variability and transfer of the protocol.

17 Alfa-Hidroxiprogesterona como marcador de sospecha de hiperplasia adrenal congénita leve y tardía en el síndrome androgénico cutáneo: estudio sobre 84 pacientes / 17-alpha hydroxy-progesterone as a marker for late congenital adrenal hyperplasia (mild form) in the cutaneous androgenic syndrome: a study of 84 patients

Se estudió un grupo de 84 mujeres (promedio de edad 24 años, rango 16 a 37) que consultaron por alguna manifestación del síndrome androgénico cutáneo (75 por ciento acné, 15 por ciento alopecia y 10 por ciento hirsutismo). De este grupo de enfermas, el 54 por ciento presentaba asociado algún tipo de dismenorrea (principalmente oligomenorrea 45 por ciento). Se pudo comprobar que un 52 por ciento de ellas presentaba valores elevados de la 17 alfa-hidroxiprogesterona (x= 1,48 ng/ml), lo cual abrió la sospecha de una hiperplasia adrenal congénica de presentación tardía y leve como causa de androgenismo cutáneo. Este diagnóstico se pudo comprobar en un 7 por ciento por pruebas funcionales, además de haber observado un 8,3 por ciento de poliquistosis ovárica y un 9,5 por ciento de hipotiroidismo

17 Alfa-Hidroxiprogesterona como marcador de sospecha de hiperplasia adrenal congénita leve y tardía en el síndrome androgénico cutáneo: estudio sobre 84 pacientes / 17-alpha hydroxy-progesterone as a marker for late congenital adrenal hyperplasia (mild form) in the cutaneous androgenic syndrome: a study of 84 patients

Se estudió un grupo de 84 mujeres (promedio de edad 24 años, rango 16 a 37) que consultaron por alguna manifestación del síndrome androgénico cutáneo (75 por ciento acné, 15 por ciento alopecia y 10 por ciento hirsutismo). De este grupo de enfermas, el 54 por ciento presentaba asociado algún tipo de dismenorrea (principalmente oligomenorrea 45 por ciento). Se pudo comprobar que un 52 por ciento de ellas presentaba valores elevados de la 17 alfa-hidroxiprogesterona (x= 1,48 ng/ml), lo cual abrió la sospecha de una hiperplasia adrenal congénica de presentación tardía y leve como causa de androgenismo cutáneo. Este diagnóstico se pudo comprobar en un 7 por ciento por pruebas funcionales, además de haber observado un 8,3 por ciento de poliquistosis ovárica y un 9,5 por ciento de hipotiroidismo (AU)

Guest editorial: Generic names for steroid hormones and related substances.

PIP: To aid communication and information retrieval, avoid ambiguity, and keep imprecise information out of print, a system of nomenclature is proposed for steroid hormones and similar compounds. A 3-way cross-clas sification of these substances is proposed, subdivided into hormones and drugs, classified by metabolic stage into agents and metabolites, and then classified by relation to endocrine effect. Compounds belong to 1 of the gorups called androgens, estrogens, gestagens, or corticosteroids if they possess 1 or more of these characteristics: 1) typical biological activity; 2) typical structure, such as steroid skeleton with 19, 18, or 21 carbon atoms; 3) structure derived invivo by metabolic conversion from another member of the same group. Hormones are biologically active agents secreted by endocrine glands. Metabolites are derived from hormones or drugs by metabolic conversion in vivo. The term "gestagens" is preferred to the more widely used "progestogens" to avoid attaching both the prefix "pro" and the suffix "gen" to the same stem with the same connotation and to permit the consistent use of the prefix "pro" or "pre" to indicate prohormones or prehormones, such as "proestrogens." "Progestin" is an obsolete term used for the corpus luteum hormone before progesterone had been identified and named. "Corticoids" should not be used as a synonym for corticosteroids. Comments on the proposed table are invited.^ieng