A metabolomics study of Qianliexin capsule treatment of benign prostatic hyperplasia induced by testosterone propionate in the rat model.

A metabolomics investigation of the treatment effect of Qianliexin (QLX) capsules was conducted on rats with benign prostatic hyperplasia (BPH) induced by testosterone propionate. Establishment of the BPH model was confirmed using the prostatic index. Hematoxylin and eosin (HE) staining for TGF-ß, EGFR, collagen, IL-1 ß, TNF-α was performed and changes in urine volume were measured. Urine and serum samples were collected from three groups, including a control group, a BPH model group and a QLX-treated group and subjected to metabolomics profiling based on ultrahigh-performance liquid chromatography-mass spectrometry. Pharmacodynamics analysis showed that the QLX group had significantly lower histopathological damage, fibrosis damage, and inflammation and higher urine output compared with the model group. Twenty-two potential biomarkers were identified in urine samples and 23 metabolites were identified in plasma samples. Alterations in metabolic patterns were evident in all sample types. The treatment effects of QLX appear to involve various metabolic pathways including lipid metabolism, fatty acid metabolism and purine generation and significantly reduced the pathological symptoms and related biochemical indicators of BPH and improved the level of potential marker metabolites. This comprehensive study suggested that differential markers provided insights into the metabolic pathways involved in BPH and the treatment effects of QLX.

Protective role of diosmin against testosterone propionate-induced prostatic hyperplasia in Wistar rats: Plausible role of oxidative stress and inflammation.

Benign prostatic hyperplasia (BPH) is an important key health concern for aging men. Polyphenolic compounds have been found to possess important roles in the inhibition of numerous ailments that involve reactive oxygen species and inflammation. Diosmin is a citrus flavone that possesses antioxidant, anti-inflammatory, antiproliferative, and anticancer activities, so based on these properties of diosmin, we decided to evaluate its effect on testosterone propionate (TP)-induced BPH. A total of 30 Wistar rats were randomly assigned to five groups having six animals in each. This study was of 28 days in which TP (5 mg kg-1) was administered to induce BPH in the last 10 days of the study. It was found that diosmin at the doses of 20 and 40 mg kg-1 significantly reduced malondialdehyde and xanthine oxidase formation in a dose-dependent manner; however, it replenished catalase, glutathione (GSH), and GSH-dependent enzymes, that is, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase significantly against TP-induced BPH. Further, immunohistochemical study showed that diosmin alleviated inflammatory markers (nuclear factor kappa-light-chain-enhancer of activated B cells, cyclooxygenase-2, and interleukin-6). It was also found that diosmin downregulated the expression of androgen receptor and decreased the prostate-specific antigen concentration dose-dependently, significantly against TP-induced BPH. Diosmin also restored histoarchitecture of the prostate in a dose-dependent manner. Findings from the present study revealed the protective role of diosmin against TP-induced BPH in Wistar rats.

Androgens increase survival of adult-born neurons in the dentate gyrus by an androgen receptor-dependent mechanism in male rats.

Gonadal steroids are potent regulators of adult neurogenesis. We previously reported that androgens, such as testosterone (T) and dihydrotestosterone (DHT), but not estradiol, increased the survival of new neurons in the dentate gyrus of the male rat. These results suggest androgens regulate hippocampal neurogenesis via the androgen receptor (AR). To test this supposition, we examined the role of ARs in hippocampal neurogenesis using 2 different approaches. In experiment 1, we examined neurogenesis in male rats insensitive to androgens due to a naturally occurring mutation in the gene encoding the AR (termed testicular feminization mutation) compared with wild-type males. In experiment 2, we injected the AR antagonist, flutamide, into castrated male rats and compared neurogenesis levels in the dentate gyrus of DHT and oil-treated controls. In experiment 1, chronic T increased hippocampal neurogenesis in wild-type males but not in androgen-insensitive testicular feminization mutation males. In experiment 2, DHT increased hippocampal neurogenesis via cell survival, an effect that was blocked by concurrent treatment with flutamide. DHT, however, did not affect cell proliferation. Interestingly, cells expressing doublecortin, a marker of immature neurons, did not colabel with ARs in the dentate gyrus, but ARs were robustly expressed in other regions of the hippocampus. Together these studies provide complementary evidence that androgens regulate adult neurogenesis in the hippocampus via the AR but at a site other than the dentate gyrus. Understanding where in the brain androgens act to increase the survival of new neurons in the adult brain may have implications for neurodegenerative disorders.

Functional genomics may allow accurate categorization of the benzimidazole fungicide benomyl: lack of ability to act via steroid-receptor-mediated mechanisms.

Although benomyl and its metabolite carbendazim have been shown to adversely affect male reproduction, the mechanisms of action do not appear to involve the endocrine system. However, few studies have been conducted using currently proposed tests specifically focused on endocrine disruption. Here, potential estrogen- and androgen-mediated activity of benomyl was therefore investigated in vitro and in vivo. Benomyl and carbendazim proved negative for agonistic and antagonistic activity in reporter gene assays for the human estrogen receptor alpha and androgen receptor. In uterotrophic and Hershberger assays using Crj:CD(SD)IGS rats, benomyl (100, 300 or 1000 mg/kg/day, p.o., N = 6) did not exert agonistic effects. However, the highest dose decreased uterine weights in the uterotrophic assay, and decreased weights of some androgen-related tissues of castrated rats receiving a testosterone propionate (TP, 0.2 mg/kg) injection in the Hershberger assay; the effects were less severe than those with p,p'-DDE (100 mg/kg/day). When 4 mg/kg/day of TP was injected, decrease of organ weights due to benomyl was attenuated but still observed. Thus, its influence in some tissues was more potent than that of p,p'-DDE. Benomyl had no apparent effects on serum androgen levels. Microarray analysis of the gene expression profile in the ventral prostate of TP-injected castrated rats treated with benomyl indicated clear differences from the patterns observed with p,p'-DDE and flutamide. Taken together, these findings suggest the decreased organ weights observed in vivo to be caused by mechanisms that are not steroid-receptor-mediated, such as interfering with assembly of microtubules by benomyl. The study furthermore suggests that functional genomics may provide a reliable evidence for accurate categorization of test chemicals.

Evaluation of anti-androgenic activity of di-(2-ethylhexyl)phthalate.

DEHP is a widely used platiciser in the manufacture of PVC-based materials. It is known to disrupt the reproductive tract development in male rats. We have performed the Hershberger assay with DEHP on an immature castrated rat model to check if DEHP antagonise the testosterone propionate androgenic effect on the accessory sex organs development. DEHP significantly decreased the BC/LA muscles, the prostate, and the seminal vesicles relative weights from 100, 200, and 400 mg/kg bw/day, respectively. DEHP increased the liver relative weight from 100 mg/kg bw/day. A study was also performed on MDA-MB453 cell line stably transfected with pMMTVneo-Luc with DEHP and its major metabolites (MEHP and metabolites VI and IX) to identify anti-androgenic activity. Neither DEHP nor MEHP antagonised DHT activity in the MDA-MB453 transfected cells. In contrast, metabolites VI and IX were anti-androgenic in vitro. DEHP appeared not to be a 5alpha-reductase inhibitor and acted in an independent mechanism from the testicular production in the young rat.

Interactive effects of vinclozolin and testosterone propionate on pregnancy and sexual differentiation of the male and female SD rat.

In mammals, androgens are essential in directing mammalian sexual differentiation of the male phenotype. Administration of testosterone during this period alters female development in a male-like direction, whereas exposure to an androgen receptor antagonist like vinclozolin (V) demasculinizes and feminizes the male offspring. In the current study, we administered V (gavage at 200 mg/kg/day) and/or testosterone propionate (TP, sc, at 1 mg/rat/day), alone and in combination to Sprague-Dawley (SD) rats on days 14 through 19 of pregnancy, to determine if V would antagonize the effects of TP in the female and, conversely, if TP would antagonize the effects of V in the male offspring. These doses of TP and V were selected because they significantly alter sexual differentiation in the majority of female and male rat offspring, respectively, without producing severe toxicity in the dam or offspring. The study design is a 2 x 2 factorial (7 dams per group) including vehicle control, V, TP, and V + TP groups. As expected, individually, both V and TP reduced maternal weight gain and the V + TP group was affected in a cumulative fashion. Litter size on postnatal day (PND) 2 was reduced only by V + TP, whereas pup body weight was reduced in all three treated groups, the effect of V + TP again being cumulative. In female offspring, TP-induced alterations (i.e., increased anogenital distance [AGD] and fewer nipples, vaginal agenesis, hydrometrocolpos, induced prostate and bulbourethral glands, and levator ani muscle tissues) were all reversed by coadministration of V. In male offspring, V-induced alterations were only modestly antagonized by TP. At the dosage levels used herein, V + TP-treated male offspring had less well-developed nipples as infants and adults and a lower incidence of ectopic testis than did the V group. However, V-induced changes in reproductive organ weights, AGD, atrophic testes, vaginal pouch, and agenesis of the sex accessory tissues were not antagonized by concurrent TP treatment in male offspring. We observed that the combination of V and TP, two chemicals with opposing endocrine action, antagonized one another during sexual differentiation, especially in the female offspring and induced cumulative effects on maternal and neonatal toxicity. We suspect that antagonism of V by TP would be enhanced in the male if lower dose levels of V were used, but then the antagonism of TP by V in the female would likely be attenuated.

Biological profile of cortexolone 17alpha-propionate (CB-03-01), a new topical and peripherally selective androgen antagonist.

The aim of this study was to investigate the antiandrogenic activity of a new monoester of cortexolone, cortexolone 17alpha-propionate (CAS 19608-29-8, CB-03-01). Although the compound displayed a strong local antiandrogenic activity in hamster's flank organ test, it did not exhibit antiandrogenic activity in rats after subcutaneous injection, nor did it affect gonadotropins hypersecretion when injected to parabiotic rats. As topical antiandrogen, the steroid resulted about 4 times more active than progesterone (CAS 57-83-0) and, when compared to known antiandrogen standards, it was about 3 times more potent than flutamide (CAS 13311-84-7), about 2 times more effective than finasteride (CAS 98319-26-7) and approximately as active as cyproterone acetate (CAS 427-51-0). Its pharmacological activity seemed to be primarily related to its ability to antagonistically compete at androgen receptor level; nevertheless its primary pharmacological target needs to be further investigated. Its topical activity, along with the apparent absence of systemic effects, anticipates this compound to have the potential of representing a novel and safe therapeutic approach for androgen-dependent skin disorders.

Equol is a novel anti-androgen that inhibits prostate growth and hormone feedback.

Equol (7-hydroxy-3[4'hydroxyphenyl]-chroman) is the major metabolite of the phytoestrogen daidzein, one of the main isoflavones found abundantly in soybeans and soy foods. Equol may be an important biologically active molecule based on recent studies demonstrating that equol can modulate reproductive function. In this study, we examined the effects of equol on prostate growth and LH secretion and determined some of the mechanisms by which it might act. Administration of equol to intact male rats for 4-7 days reduced ventral prostate and epididymal weight and increased circulating LH levels. Using binding assays, we determined that equol specifically binds 5alpha-dihydrotestosterone (DHT), but not testosterone, dehydroepiandrosterone, or estrogen with high affinity. Equol does not bind the prostatic androgen receptor, and has a modest affinity for recombinant estrogen receptor (ER) beta, and no affinity for ERalpha. In castrated male rats treated with DHT, concomitant treatment with equol blocked DHT's trophic effects on the ventral prostate gland growth and inhibitory feedback effects on plasma LH levels without changes in circulating DHT. Therefore, equol can bind circulating DHT and sequester it from the androgen receptor, thus altering growth and physiological hormone responses that are regulated by androgens. These data suggest a novel model to explain equol's biological properties. The significance of equol's ability to specifically bind and sequester DHT from the androgen receptor have important ramifications in health and disease and may indicate a broad and important usage for equol in the treatment of androgen-mediated pathologies.