Antiandrogenic Activity Research Articles

Anti-androgenic, anti-oxidant and anti-apoptotic effects of the aqueous and methanol extracts of Pterorhachis zenkeri (Meliaceae): Evidence from in vivo and in vitro studies.

The aim of this study was to evaluate the effects of Pterorhachis zenkeri (Meliaceae) on sex organ growth in immature male rats and, oxidative stress and apoptosis markers in CCL-97 (R2C) Leydig cells. For the in vivo studies, 70 immature male Wistar rats (n=10/group) were treated for 2 or 4weeks with: distilled water (10ml/kg, per os) plus soya oil (1ml/kg, sc), bicalutamide (10mg/kg, per os), aqueous or methanol extract of P. zenkeri (10mg/kg or 62mg/kg, per os) or testosterone propionate (3mg/kg, sc). After each treatment period, body and sexual organ weights, plasmatic testosterone, total proteins and total cholesterol levels were measured. In the in vitro test, the effects of the methanol extract of P. zenkeri on cell viability, apoptosis, reactive oxygen species (ROS) production, intracellular calcium release and caspases 3/9 were assessed using CCL-97 Leydig cells. Pterorhachis zenkeri extracts decreased sex organ weights, plasmatic testosterone and protein levels in rats. In the in vitro studies, P. zenkeri inhibited apoptosis, ROS production, calcium release and caspase 3/9 activities. These results suggest that P. zenkeri has anti-androgenic, anti-oxidant and anti-apoptotic activities with methanol extract being the most active and could be an effective alternative for the management of androgen-related diseases.

Acid condensation products of indole-3-carbinol and their in-vitro (anti)estrogenic, (anti)androgenic and aryl hydrocarbon receptor activities

The objective of the study was to investigate the (anti)estrogenic, (anti)androgenic and aryl hydrocarbon receptor (AhR) agonistic activities of a mixture of acid condensation products of indole-3-carbinol, termed RXM, and to identify the compounds most responsible for the observed effects, using in vitro receptor-reporter gene transcriptional activation bioassays. For this, HPLC-fractions of RXM were prepared and tested. LC-MS/MS analysis was carried out for the identification of some of the acid condensation products. The RXM displayed weak estrogenic and anti-androgenic, and strong AhR agonistic properties. The fraction containing 3,3-diindolylmethane (DIM) displayed a weak estrogenic and relatively strong anti-androgenic activity. DIM was confirmed to be an androgen receptor (hAR) antagonist and a partial estrogen receptor (hERα) agonist. Also the fraction containing the trimer [2-(indol-3-ylmethyl)indol-3-yl]indol-3-ylmethane (LTr1) showed anti-androgenic activities. It was shown for the first time that DIM is not only estrogenic and anti-androgenic, but also possesses anti-estrogenic properties. Though indolo[3,2-b]carbazole (ICZ) is a potent AhR activator and was detected in the RXM, it did not contribute to AhR-agonist activity. Instead, fractions containing the trimers LTr1 and 5,6,11,12,17,18-hexahydrocyclonona[1,2-b:4,5-b′:7,8-b″]tri-indole (CTr), as well as some unidentified compounds showed the highest AhR activation. The fraction, containing the linear trimer LTr1, showed a weak anti-androgenic activity which has not been reported before. The study demonstrates the importance of a bioassay directed approach for identifying compounds that contribute most to the effects of mixtures.

Post-treatment of ozonated wastewater with activated carbon and biofiltration compared to membrane bioreactors: Toxicity removal in vitro and in Potamopyrgus antipodarum

Wastewater treatment plants are major point sources of (micro)pollutant emissions and advanced wastewater treatment technologies can improve their removal capacity. While abundant data on individual advanced treatment technologies is available, there is limited knowledge regarding the removal performance of ozonation combined with multiple post-treatments and stand-alone membrane bioreactors. This is especially true for the removal of in vitro and in vivo toxicity.Therefore, we investigated the removal of 40 micropollutants and toxicity by a pilot-scale ozonation with four post-treatments: non-aerated and aerated granular activated carbon and biological filtration. In addition, two stand-alone membrane bioreactors fed with untreated wastewater and one MBR operating with ozonated partial flow recirculation were analysed. Aqueous and extracted samples were analysed in vitro for (anti)estrogenic, (anti)androgenic and mutagenic effects. To assess in vivo effects, the mudsnail Potamopyrgus antipodarum was exposed in an on-site flow-through system.Multiple in vitro effects were detected in conventionally treated wastewater including estrogenic and anti-androgenic activity. Ozonation largely removed these effects, while anti-estrogenic and mutagenic effects increased suggesting the formation of toxic transformation products. These effects were significantly reduced by granular activated carbon being more effective than biological filtration. The membrane bioreactor performed similarly to the conventional treatment while the membrane bioreactor with ozonation had a comparable removal performance like ozonation.Conventionally treated wastewater increased the growth of P. antipodarum. Ozonation reduced the reproduction indicating a potential formation of toxic transformation products. In the post-treatments, these effects were compensated or remained unaffected. The effluents of the membrane bioreactors induced reproductive toxicity.Our results show that ozonation is effective in further reducing toxicity and micropollutant concentrations. However, the formation of toxicity requires a post-treatment. Here, ozonation coupled to granular activated carbon filtration seemed the most promising treatment process.

Notes from the NICU: Analyzing the Chemical Content of Commonly Used Medical Products

Notes from the NICU: Analyzing the Chemical Content of Commonly Used Medical Products

Effects of oral contraceptives on serum concentrations of adipokines and adiposity indices of women with polycystic ovary syndrome: a randomized controlled trial.

To compare the effects of oral contraceptives (OCs) with different progestins, including Levonorgestrel (LNG), Desogestrel (DSG), Cyproterone Acetate (CPA), and Drospirenone (DRSP) on adipokines levels and adiposity indices in women with polycystic ovary syndrome (PCOS). In this parallel randomized clinical trial, 120 women with PCOS randomly assigned to intervention with OCs containing LNG, DSG, CPA, or DRSP. Outcomes of interest, including serum concentrations of adiponectin, leptin, and resistin, and adiposity indices, i.e., body mass index (BMI), waist circumference (WC), obesity, central obesity, waist to hip ratio (WHR), waist to height ratio (WHtR), lipid accumulation product (LAP), a body shape index (ABSI), body roundness index (BRI), and visceral adiposity index (VAI), and lipid profiles were assessed at baseline, and 6months of treatment. This study showed no significant differences in serum concentrations of adipokines between the four study groups after 6months of treatment. Our results also showed that patients treated with various compounds of OC for 6months had no significant differences in their adiposity indices, except for LAP (p = 0.04), and VAI (p = 0.03). PCOS patients treated with OCs containing CPA had significantly a higher mean LAP, compared to those using products containing LNG. Besides, patients treated with OCs containing CPA had significantly a higher mean VAI, compared to those treated with OCs containing DRSP. This study demonstrated that OCs with low androgenic and antiandrogenic activities had identical effects on serum concentrations of adipokines, and adiposity indices, except LAP, and VAI parameters. IRCT20080929001281N3.

Antagonistic activity towards the androgen receptor independent from natural sex hormones in human milk samples from the Norwegian HUMIS cohort

In this paper, we investigated the possible presence of endocrine disrupting chemicals (EDCs) based on measuring the total estrogenic and androgenic activity in human milk samples. We used specific bioassays for analysis of the endocrine activity of estrogens and estrogen-like EDCs and androgens and androgen-like EDCs and developed a separation method to evaluate the contribution from natural hormones in comparison to that of EDCs to total endocrine activities. We extracted ten random samples originating from the Norwegian HUMIS biobank of human milk and analyzed their agonistic or antagonistic activity using the ERα- and AR CALUX® bioassays. The study showed antagonistic activity towards the androgen receptor in 8 out of 10 of the assessed human milk samples, while 2 out of 10 samples showed agonistic activity for the ERα. Further investigations demonstrated anti-androgenic activity in the polar fraction of 9 out of 10 samples while no apolar extracts scored positive. The culprit chemicals causing the measured antagonistic activity in AR CALUX was investigated through liquid chromatography fractionation coupled to bioanalysis and non-target screening involving UHPLC-Q-TOF-MS/MS, using a pooled polar extract. The analysis revealed that the measured anti-androgenic biological activity could not be explained by the presence of endogenous hormones nor their metabolites. We have demonstrated that human milk of Norwegian mothers contained anti-androgenic activity which is most likely associated with the presence of anthropogenic polar EDCs without direct interferences from natural sex hormones. These findings warrant a larger scale investigation into endocrine biological activity in human milk, as well as exploring the chemical sources of the activity and their potential effects on health of the developing infant.

Environmental relevant concentration of λ-cyhalothrin and 3-phenoxybenzoic acid caused endocrine-disrupting effects on male lizards (Eremias argus)

In the present study, the endocrine toxicity of LCT and PBA was investigated through exposure to Eremias argus for two weeks under environmental relevant concentration. RNA-sequencing identified 4442 and 4653 differentially expressed genes in lizard liver after LCT and PBA exposure. Four differentially expressed genes (hsd17β, ar, sult, ugt) related with hypothalamic-pituitary-gonadal axis were quantified by qPCR. The expression of genes associated with HPG axis in different tissues differed significantly. In LCT treatment group, ar, cyp17 and hsd3β genes involved in testosterone synthesis and transportation were significantly decreased in lizard testes, and the spermatogensis was inhibited in the testes, which indicated the anti-androgenic activity of LCT. After PBA exposure, the genes related with estradiol synthesis, transportation and metabolism, such as hsd17β, erα, ugt in lizard liver were important biomarkers and the significant decrease of estradiol level was highly correlated with hsd17β, erα, ugt gene expressions. The relative high binding affinity of PBA with ERα further demonstrated the anti-estrogenic activity of PBA. Our results elucidate the different toxic mechanism of LCT and PBA on lizard endocrine system at environmental relevant concentration. Pyrethroids metabolism may cause more seriously toxicity rather than detoxification.

Single-Cell Distribution Analysis of AR Levels by High-Throughput Microscopy in Cell Models: Application for Testing Endocrine-Disrupting Chemicals.

Cell-to-cell variation of protein expression in genetically homogeneous populations is a common biological trait often neglected during analysis of high-throughput (HT) screens and is rarely used as a metric to characterize chemicals. We have captured single-cell distributions of androgen receptor (AR) nuclear levels after perturbations as a means to evaluate assay reproducibility and characterize a small subset of chemicals. AR, a member of the nuclear receptor family of transcription factors, is the central regulator of male reproduction and is involved in many pathophysiological processes. AR protein levels and nuclear localization often increase following ligand binding, with dihydrotestosterone (DHT) being the natural agonist. HT AR immunofluorescence imaging was used in multiple cell lines to define single-cell nuclear values extracted from thousands of cells per condition treated with DHT or DMSO (control). Analysis of numerous biological replicates led to a quality control metric that takes into account the distribution of single-cell data, and how it changes upon treatments. Dose-response experiments across several cell lines showed a large range of sensitivity to DHT, prompting us to treat selected cell lines with 45 Environmental Protection Agency (EPA)-provided chemicals that include many endocrine-disrupting chemicals (EDCs); data from six of the compounds were then integrated with orthogonal assays. Our comprehensive results indicate that quantitative single-cell distribution analysis of AR protein levels is a valid method to detect the potential androgenic and antiandrogenic actions of environmentally relevant chemicals in a sensitive and reproducible manner.

P0937IMPACT OF TANNINS AS FOOD SUPPLEMENT IN A CKD POPULATION WITH RECURRENT URINARY TRACT INFECTIONS: PRELIMINARY DATA

Abstract Background and Aims Urinary tract infections (UTIs) are estimated to account for over 7 million office visits per year. UTIs are about 50 times more frequent in women than in men, however, in men the incidence steeply increases after 50 years of age for prostate involvement. UTI diagnosis is based on symptoms and urinalysis. Antibiotic therapy is often required in subjects with relapsing UTIs. Therefore, it would be useful to develop a therapeutic strategy based on natural active compounds, free from side effects (such as on renal function), that could counteract UTIs recurrence. For this purpose, tannins (TNs) could represent a valid therapeutic alternative. TNs are polyphenolic compounds known for their anti-inflammatory, antimicrobial and antioxidant effects. Recent studies highlighted how TNs intake can counteract UTI recurrence, improving the quality of life. The aim of our study was to evaluate the beneficial action of chestnut TNs administered as oral food supplement (OFS) in recurrent UTI patients. Method OFS was characterized by HPLC/DAD/MS analysis for its content in secondary polyphenolic metabolites and by Folin-Ciocalteau in vitro tests for its antioxidative and anti-free radical activity with stable radical DPPH•. For in vivo tests, 16 chronic kidney disease (CKD) patients (8 female and 8 males) who suffered from recurrent UTIs, were recruited. The OFS was administered in 2 cps/ day, for 9 weeks. Patients were evaluated at T0= baseline and T1= after 9 weeks of OFS treatment. We performed laboratory and urinary tests, and the quality of life (SCL-90R questionnaire) and body composition (bioimpedentiometry) assessment. All parameters and questionnaires were evaluated at T0 and T1. At the same time, oxidative stress (OS) and antioxidant defenses were monitored using CR4000 (FORD and FORT tests). Results HPLC/DAD/MS quali-quantitative analysis allowed for an in depth chemical characterization of the individual polyphenols present in the OFS: total tannins amount is 10.542mg/g, whereas total anthocyanins are 1.885mg/g. The Folin Ciocalteu assay results show a total polyphenols content of 68.7mg/g GAE; the antiradical activity by DPPH assay is 94% for a solution 0.519mg/mL of powder. The epidemiological features of the population were reported in Table 1 and it was divided into two subgroups, according to gender. Laboratory parameters were reported in Table 2. During the study, we observed a drop out of three female subjects because of gastrointestinal (GI) disorders (nausea, gastric heartburn). We did not find any significative change in body composition parameters after OFS treatment. We highlighted a significant reduction (Table 3) of ESR only in male patients (16,7± 2,2 mm/h vs 11,3± 1,5 mm/h, p=0,0062). The urinalysis, showed a significant reduction of leukocytes in both subgroups (male: 43,5 (1-450) n/uL vs 15 ± 5,7 n/uL p = 0,0391; female: 28,5 (1-990) n/uL vs 7 (1-91) n/uL p= 0,0625) but urinary bacterial flora, after OFS supplementation significantly decreased only in male subjects (428 ± 143,4 n/uL vs 34 (0- 450) n/uL p= 0,0156). Interestingly we observed a significant reduction of OS parameters after OFS treatment as reported in Table 4. We also observed a reduction of the anxious and depressive components in male subjects in the SCL-90R questionnaire. Conclusion TNs seem to exert an antimicrobial action in a gender dependent manner, useful to counteract the recurrence of UTIs. OFS contains Serenoa repens, a substance with peripheral, antispastic and antiandrogenic action that could induce nausea and vomiting. Female patients dropped out for GI disorders had lower body weight and SR probably were overdosed for their body mass. In male subjects, the decrease in anxiety and depression at the end of the study, could be linked to the improvement of the urinary symptomatology. A randomized clinical trial conducted a larger population is needed to confirm these findings and explain the correlation with gender.

Structure-based discovery of the endocrine disrupting effects of hydraulic fracturing chemicals as novel androgen receptor antagonists

Hydraulic fracturing (HF) technology is increasingly utilized for oil and gas extraction operations. The widespread use of HF has led to concerns of negative impacts on both the environment and human health. Indeed, the potential endocrine disrupting impacts of HF chemicals is one such knowledge gap. Herein, we used structure-based molecular docking to assess the binding affinities of 60 HF chemicals to the human androgen receptor (AR). Five HF chemicals had relatively high predicted AR binding affinity, suggesting the potential for endocrine disruption. We next assessed androgenic and antiandrogenic activities of these chemicals in vitro. Of the five candidate AR ligands, only Genapol®X–100 significantly modified AR transactivation. To better understand the structural effect of Genapol®X–100 on the potency of AR inhibition, we compared the antiandrogenic activity of Genapol®X–100 with that of its structurally similar chemical, Genapol®X–080. Interestingly, both Genapol®X–100 and Genapol®X–080 elicited an antagonistic effect at AR with 20% relative inhibitory concentrations of 0.43 and 0.89 μM, respectively. Furthermore, we investigated the mechanism of AR inhibition of these two chemicals in vitro, and found that both Genapol®X–100 and Genapol®X–080 inhibited AR through a noncompetitive mechanism. The effect of these two chemicals on the expression of AR responsive genes, e.g. PSA, KLK2, and AR, was also investigated. Genapol®X–100 and Genapol®X–080 altered the expression of these genes. Our findings heighten awareness of endocrine disruption by HF chemicals and provide evidence that noncompetitive antiandrogenic Genapol®X–100 could cause adverse endocrine health effects.

SAT-722 Structure-Based Discovery of Hydraulic Fracturing Chemicals as Novel Androgen Receptor Antagonists

Hydraulic fracturing (HF) technology is increasingly utilized for oil and gas extraction operations. The widespread use of HF has led to concerns of potential negative impacts on both the environment and human health. Indeed, the potential endocrine disrupting impacts of HF chemicals is one such knowledge gap. Herein, we used structure-based molecular docking to assess the binding affinities of 60 HF chemicals used in California to the human androgen receptor (AR). Five HF chemicals had relatively high AR binding affinity, suggesting the potential to disrupt AR effects. We next assessed androgenic and antiandrogenic activities of these chemicals in vitro. Of the five candidate AR ligands, only Genapol® X–100 was found to significantly reduce the AR transactivation by 22%. To better understand the structural effect of Genapol® X–100 on the potency of receptor inhibition, we compared the antiandrogenic activity of Genapol® X–100 with that of its structurally similar chemical, Genapol® X–080. Interestingly, both Genapol® X–100 and Genapol® X–080 elicited a significant antagonistic effect with 20% relative inhibitory concentrations (RIC20) of 0.43 and 0.89 μM, respectively. This indicated that Genapol® X–100 was more potent in inhibiting AR than Genapol® X–080, consistent with longer Genapol® X–100 chain length causing greater potency of AR activity inhibition. Furthermore, we investigated the mechanism of AR inhibition of these two chemicals in vitro. The result revealed that both Genapol® X–100 and Genapol® X–080 inhibited AR through noncompetitive binding mechanism. The effects of these two chemicals on the expression of AR responsive genes such as PSA, KLK2, and AR were also investigated. Genapol® X–100 and Genapol® X–080 notably altered the expression of these genes at relatively low concentrations of 0.5 µM to 1 µM. Using these integrated in vitro and in silico approaches, we identified HF chemicals as novel noncompetitive AR antagonists. Our findings heighten awareness of endocrine disruption by HF chemicals and provide evidence that noncompetitive antiandrogenic Genapol® X–100 could possibly cause adverse endocrine health effects in humans.

Effects of oral contraceptives on thyroid function and vice versa.

Thyroid gland dysfunction represents an epidemiologically relevant disease in the female gender, where treatment with oral contraceptives (OCs) is frequently prescribed. Although OCs are able to impact the thyroid gland function, scanty data have been released on this matter so far. The aim of this article was to review how hormonal OCs, including estrogen- or progesterone-only containing medications, interact with the hepatic production of thyroid-binding globulin (TBG) and, consequently, their effects on serum levels of thyroxine (T4) and triiodothyronine (T3). We also reviewed the effect of Levo-T4 (LT4) administration in women taking OCs and how they influence the thyroid function in both euthyroid women and in those receiving LT4. The estrogenic component of the pills is capable of increasing various liver proteins, such as TBG, sex hormone-binding protein (SHBG) and coagulation factors. On the other hand, the role of progestogens is to modulate estrogen-dependent effects mainly through their anti-androgenic action. In fact, a reduction in the effects of androgens is useful to keep the thromboembolic and cardiovascular risks low, whereas OCs increase it especially in women with subclinical hypothyroidism or in those treated with LT4. Accordingly, subclinical hypothyroidism is known to be associated with a higher mean platelet volume than normal and this increases cardiovascular risk due to platelet hyperactivity caused by incomplete thrombocytopoietic maturation.

A combination of spearmint and flaxseed extract improved endocrine and histomorphology of ovary in experimental PCOS

BackgroundPolycystic ovary syndrome (PCOS) is a complex reproduction and endocrine disorder of women in the reproductive age. Spearmint (Mentha spicata L.) has anti-androgenic activity and flaxseed (Linum usitatissimum L.) contains phytoestrogen and was reported to improve PCOS conditions. This study aimed to evaluate PCOS conditions following administration of a mixture of these two plants.MethodsTwenty-four rats with regular cycles were randomly divided into four groups as control (C) and treatment-control (TC) received a combination of spearmint extract (SE) + flaxseed extract (FE). PCOS was induced in PCOS and treatment (T) groups by a single intramuscular injection of estradiol valerate. The treatment group received a combination of SE and FE for 30 days, 7 weeks after injection of estradiol valerate. Estrous cycles were monitored for 10 days and in the last day animals were sacrificed, ovaries were collected for the histomorphometric study and the serum levels of progesterone, testosterone, estradiol, and dehydroepiandrosterone (DHEA) were measured.ResultSignificant rise in progesterone and a decrease in testosterone and estradiol with no significant change of DHEA in the T group, was observed in comparison with the PCOS group (P < 0.05). No significant difference noticed between T and control groups (C &CT) regarding evaluated hormones. A significant increase in primary, pre-antral and antral follicles noticed in the T group compared to the PCOS group. The number of cystic follicles decreased in the T group compared with the PCOS group. Granulosa layer thickness increased while the thickness of theca decreased significantly in the T group compared to the PCOS group (P < 0.05). No significant endocrine or histological differences noticed between C and TC groups.ConclusionA combination of flaxseed and spearmint extract improved the endocrine profile and the histomorphometric features of the ovary in the T group compared to the PCOS group.

The effect of type of oral contraceptive pill and duration of use on fresh and cumulative live birth rates in IVF/ICSI cycles.

Are there any differences in the fresh (LB) and cumulative live birth rates (CLBR) of women undergoing controlled ovarian stimulation (COS) for IVF/ICSI following pretreatment with different types of oral contraceptive pills (OCP) for different durations as compared to no-OCP? OCP administration for an interval of 12- to 30-day treatment period and with a 5-day washout period does not affect clinical pregnancy, LB nor cumulative LB in patients undergoing COS for an IVF cycle. The use of OCP is an effective way of treatment planning in IVF/ICSI cycles, but published evidence about its effect on pregnancy and LBR is inconsistent, some studies finding decreased rates but others no difference. This is a retrospective analysis carried out in a University-affiliated tertiary centre between January 2009 and December 2017. Overall, 4116 infertile women between 18 and 45years, who underwent their first ovarian stimulation cycle in our centre, were included. Patients were categorised into two groups as receiving OCP (n= 3517) or not (no OCP, n= 599). All patients with OCP pretreatment initiated controlled ovarian stimulation (COS) 5days post-pill. Overall, two types of OCP were used at the study's centre: ethinylestradiol (EE) 30μg/desogestrel 150μg, a third-generation progesterone; or EE 30μg/drospirenone 3mg, a fourth-generation progestin with mild antiandrogenic activity. A total of n= 4116 patients were analysed, (OCP n= 3517 and non-OCP n= 599). The use of OCP was independently associated with a small increase in the number of oocytes retrieved after adjusting for age, BMI, use of OCP, cause of infertility, initial dose (IU), type of gonadotropin, stimulation days, total stimulation units (total IU) (β 0.22, 95% CI 0.12-0.31). Cumulative LBRs were comparable between groups OCP versus non-OCP (32.4 versus 31.6%, P= 0.712). Following adjustment for age, BMI, infertility diagnosis, starting and total dose, type of gonadotropin, total days of stimulation, type of insemination, number of oocytes retrieved, day of transfer and number of embryos transferred in a multiple logistic analysis, patients using OCPs had a similar probability of achieving a LB as compared with patients not-using OCPs following fresh embryo transfer (ORadj 0.89, 95% CI 0.69-1.15) and a similar probability for CLBR after the use of fresh and frozen embryos (ORadj 0.94, 95% CI 0.73-1.21). No differences were observed in ovarian stimulation and clinical outcomes between drospirenone and desogestrel OCP groups. Limitations are related to the retrospective nature of the study; despite the sample size, the adjustments and the multivariable regression analysis conducted, we cannot exclude the presence of confounding bias. OCP administration was not randomly assigned, not allowing to exclude the presence of selection bias. Lastly, we only used two types of OCP with durations and washout periods as per institution protocol. Therefore, we cannot exclude that longer duration of administration, a different type of OCP or different pill-free interval might have had an alternative effect on LBR or CLBR; thus, the generalizability of this study's results should be considered with caution. Our study provides reassuring evidence that the use of 12-30days OCP for cycle programming, prior to IVF, does not decrease the chance of live birth and cumulative live birth rates. No external funding was used for this study. This research was performed under the auspices of 'Càtedra d'Investigació en Obstetrícia I Ginecologia' of the Department of Obstetrics, Gynaecology and Reproductive Medicine, Hospital Universitario Dexeus, Universitat Autònoma de Barcelona. The authors report no conflict of interest associated with the current study. NA.

Hypoxia modifies the response to flutamide and linuron in male three-spined stickleback (Gasterosteus aculeatus)

Hypoxia is a major stressor in aquatic environments and it is frequently linked with excess nutrients resulting from sewage effluent discharges and agricultural runoff, which often also contain complex mixtures of chemicals. Despite this, interactions between hypoxia and chemical toxicity are poorly understood. We exposed male three-spined stickleback during the onset of sexual maturation to a model anti-androgen (flutamide; 250 μg/L) and a pesticide with anti-androgenic activity (linuron; 250 μg/L), under either 97% or 56% air saturation (AS). We assessed the effects of each chemical, alone and in combination with reduced oxygen concentration, by measuring the transcription of spiggin in the kidney, as a marker of androgen signalling, and 11 genes in the liver involved in some of the molecular pathways hypothesised to be affected by the exposures. Spiggin transcription was strongly inhibited by flutamide under both AS conditions. In contrast, for linuron, a strong inhibition of spiggin was observed under 97% AS, but this effect was supressed under reduced air saturation, likely due to interactions between the hypoxia inducible factor and the aryl hydrocarbon receptor (AhR) pathways. In the liver, hypoxia inducible factor 1α was induced following exposure to both flutamide and linuron, however this was independent of the level of air saturation. This work illustrates the potential for interactions between hypoxia and pollutants with endocrine or AhR agonist activity to occur, with implications for risk assessment and management.

Pharmacological properties of fireweed (Epilobium angustifolium L.) and bioavailability of ellagitannins. A review

Summary Fireweed (Epilobium angustifolium L.) is a well-known medicinal plant traditionally used in the treatment of urogenital diseases, stomach and liver disorders, skin problems, etc. E. angustifolium extracts show anti-androgenic, antiproliferative, cytotoxic, antioxidant, anti-inflammatory, immunomodulatory, and antimicrobial activities. The unique combination of biological properties demonstrated by the results of some studies indicates that fireweed has a positive effect in benign prostatic hyperplasia (BPH) and potentially in the prostate cancer chemoprevention. However, the efficacy of E. angustifolium phytotherapy is still poorly tested in clinical trials, while numerous beneficial effects of extracts have been documented in the in vitro and in vivo tests. Fireweed is rich in polyphenolic compounds, particularly ellagitannins. Currently, polyphenols are considered to be modulators of beneficial gut microbiota. The literature data support the use of ellagitannins in the prostate cancer chemoprevention, but caution is advised due to the highly variable production of urolithins by the individual microbiota. A better understanding of the microbiota’s role and the mechanisms of its action are crucial for an optimal therapeutic effect. This paper aims to summarize and discuss experimental data concerning pharmacological properties of E. angustifolium and bioavailability of ellagitannins – important bioactive compounds of this plant.

A comparison of the effects of oral contraceptives on the clinical and biochemical manifestations of polycystic ovary syndrome: a crossover randomized controlled trial.

Do oral contraceptives (OCs) containing progestins with low androgenic or antiandrogenic activities have different effects to those containing levonorgestrel (LNG) on clinical, androgenic and metabolic manifestations of polycystic ovarian syndrome (PCOS)? The three OCs tested had similar effects on clinical findings of hyperandrogenism (HA), whereas products containing LNG were less effective on androgenic profiles and had detrimental effects on lipid profiles. Despite data available on the effects of OCs, the superiority of products with low androgenic or antiandrogenic progesterone components in comparison with older products used in women with PCOS has not been clarified. This study is a crossover randomized controlled six-arm trial, with all six arms including two 6-month treatment periods, one period with OCs containing LNG, and the other with one of three OCs containing desogestrel (DSG), cyproterone acetate (CPA) or drospirenone (DRSP). The trial was conducted between February 2016 and January 2018 and enrolled 200 patients with PCOS. Two hundred women with PCOS (ages 18-45years) were recruited at the endocrine outpatient clinic of the Research Institute for Endocrine Sciences (RIES) of the Shahid Beheshti University of Medical Sciences, Tehran, Iran. A blocking or stratification random allocation (block size = 6) using a computer-based random number generator was prepared to assign participants to treatment groups. Both the clinical examiner and data analyst were blinded to participants during the trial. Outcomes of interest, including anthropometric and clinical manifestations and hormonal, and biochemical parameters were assessed at baseline, after 3 and 6months of each treatment and after the washout period. This study detected a higher decrease in free-androgen index (FAI) levels after 3months of treatment with OCs containing DSG (95% CI: -2.3, -1.0), CPA (95% CI: -2.4, -1.1) and DRSP (95% CI: -2.6, -1.4), compared with products containing LNG (P< 0.001). Use of OCs containing DSG (95% CI: -3.6, -1.5), CPA (95% CI: -3.1, -0.8) and DRSP (95% CI: -3.4, -1.1) for 6months was associated with more decrease in FAI, compared with products containing LNG (P< 0.001). The study showed that use of OCs containing DSG, CPA and DRSP for 3-6months was associated with a higher increase of sex hormone-binding globulin (SHBG), compared with products containing LNG (P< 0.001). We also observed more decrease in dehydroepiandrosterone sulfate levels after use of OCs containing DSG (P= 0.003), CPA (P= 0.012) and DRSP (P< 0.001) for 6months, compared with products containing LNG. Our results showed that the use of OCs containing DRSP for 6months was associated with more improvement in acne, compared with products containing LNG (P= 0.007). Women treated with OCs containing CPA, and DRSP for 3months had higher TG and HDL levels and lower LDL levels, compared with those treated with products containing LNG (P< 0.05). After 6months of treatment, patients treated with OCs containing DRSP had a sharper decline in LDL levels and more increase in HDL levels, compared to those treated with products containing LNG (P= 0.001). Considering this trial was conducted in women diagnosed with Androgen Excess Society criteria, the results may not be generalizable for mild phenotypes diagnosed using Rotterdam criteria. Other limitations of the study include the high dropout rate, the lack of a gold standard androgen assay and the multiple end points. Our results support the views of clinicians, who suggest an OC with a low androgenic or antiandrogenic progestin, if available, to treat PCOS. This study was supported by the RIES, Shahid Beheshti University of Medical Sciences, Tehran, Iran. There are no conflicts of interest. IRCT201702071281N2. 21 February 2017. 21 March 2017.

Hypersexuality and pharmacological treatment options

Objectives. There are no standardised guidelines regarding the pharmacotherapy of compulsive sexual behaviour. The paper aims to review the available literature concerning the treatment of excessive sexual activity disorders. Specific mechanisms underlying hypersexuality and the consequent potential differences in its treatment were considered. Literature review. The classification of sexual disorders related to excessive sexual activity is rather problematic. Both DSM-5 and ICD-11 lack in a homogenous classification of this disorder. Currently, the safest and most beneficial drugs for patients with non-paraphilic disorders seem to be SSRI medications. Drugs presenting an antiandrogenic action (LHRH) are not recommended due to their side effects, apart from cases proceeding with severe symptoms. Promising results were obtained in a trial with naltrexone; yet, the study did not fulfil methodological norms. Other medications used in the treatment of hypersexuality are of minor importance; however, they may be used especially when psychiatric comorbidities are present. Conclusions. The best effects in the treatment of compulsive sexual behaviour are obtained with the combination of psychotherapy and SSRI drugs. Few methodologically correct studies have been performed. Most studies are carried out on small groups and fail to use methods which would enable to compare various therapeutic options. Research on the pharmacotherapy of non-paraphilic hypersexuality should be continued, especially regarding drugs which may act on the obsessive-compulsive mechanism.

Neonatal Exposure to Agonists and Antagonists of Sex Steroid Receptors Affects AMH and FSH Plasma Level and Their Receptors Expression in the Adult Pig Ovary.

Simple SummaryThe ovarian development and the establishment of ovarian reserve during fetal and/or neonatal life is critical for future reproductive success. Many environmental chemicals are known to negatively affect development and physiology of human and animal ovaries by interfering with endocrine systems, resulting in aberrant reproductive functions. The present study shows the long-term impact of neonatal exposure to agonists and antagonists of sex steroid receptors on AMH and FSH signalling in the ovary of adult pigs. Our findings suggest alteration in ovarian follicle recruitment from ovarian reserve arising from neonatal disruption of androgen/estrogen signalling induced by environmental endocrine active compounds. Everyday use of many endocrine disruptors is already prohibited after their harmful impacts on normal physiology have become known. Nevertheless, market introduction of new chemicals with potential deleterious influence on reproductive physiology has continued. Our outcomes confirm that a neonatal window plays an essential role in the physiological programming of ovarian function in adult pigs. The influence of environmental chemicals on this critical neonatal window needs to be investigated in order to gain a comprehensive view of deleterious interactions between endocrine disrupting chemicals and ovarian function.In this study piglets were injected with testosterone propionate (TP, an androgen), flutamide (FLU, an antiandrogen), 4-tert-octylphenol (OP, an estrogenic compound), ICI 182,780 (ICI, an antiestrogen) or corn oil (controls) between postnatal days 1 and 10 (N = 5/group). Then plasma anti-Müllerian hormone (AMH) and follicle stimulating hormone (FSH) concentration and the expression of their receptors were examined in the adult pig ovary. TP and FLU decreased plasma AMH and FSH concentration. In preantral follicles, TP resulted in upregulation of AMHR2 and FSHR expression, but decreased AMH protein abundance. FLU upregulated AMHR2 expression, while OP increased FSHR mRNA. In small antral follicles, OP upregulated ACVR1 and BMPR1A expression, while FLU increased BMPR1A mRNA. FLU and ICI resulted in upregulation of AMHR2 expression. TP and FLU upregulated AMH expression, while it was downregulated in response to OP or ICI. Moreover, OP and ICI resulted in downregulation of FSHR expression, while FLU decreased FSHR protein abundance. In conclusion, neonatal exposure to either agonist or antagonist of androgen receptor affected AMH and FSH signalling systems in preantral follicles. In small antral follicles these systems were influenced by compounds with estrogenic, antiestrogenic, and antiandrogenic activity. Consequently, these hormonal agents may cause an accelerated recruitment of primordial follicles and affect the cycling recruitment of small antral follicles in pigs.

In vitro estrogenic activity of binary and multicomponent mixtures with bisphenol A

Bisphenol A and its analogs are environmental contaminants with well known estrogenic and anti-androgenic activities. In studies of human biomonitoring, simultaneous exposure to multiple bisphenols was shown in different biological samples, at picomolar to low nanomolar concentrations. Evaluation of their combined toxicities will therefore be a more realistic and reliable predictor for estimation of health risks than evaluation of only the single chemicals. In the present study, estrogenic activities of individual bisphenols were evaluated, along with their binary and multicomponent mixtures including three- and four-component mixtures, using the Organisation for Economic Co-operation and Development validated transactivation assay with the hERα-Hela9903 cell line. Concentration-dependent estrogenic activity was confirmed for all of the tested bisphenols, in the nanomolar to micromolar range. Estrogenic activities of binary and multicomponent mixtures followed a concentration addition model. Although exposure to individual bisphenols remains below their effective doses, we demonstrate that as a mixture, they can contribute additively to toxicity. This study thus emphasizes the importance of mixture toxicity evaluation for risk assessment of compounds that act like the bisphenols.