Cocoyam (Colocasia esculenta) modulates some parameters of testosterone propionate-induced rat model of benign prostatic hyperplasia.

The increased global prevalence of benign prostatic hyperplasia (BPH) and the promising potentials of functional foods in ameliorating it led to this study which reported the effect of aqueous ethanol extract of cocoyam (Colocasia esculenta) tuber on some biochemical indices in testosterone propionate (TP) induced benign prostatic hyperplasia (BPH) rats. Thirty male albino rats were randomly assigned into 6 groups of 5 rats each. Group 1 (negative control) received 3 mg/kg of TP and normal saline, group 2 (positive control) received 3 mg/kg of TP and 5 mg/kg of finasteride; groups 3, 4, and 6 rats received 3 mg/kg of TP and 100, 200 and 400 mg/kg of ethanol extracts of cocoyam respectively while group 5 (normal control) received olive oil + normal saline. The study lasted for 28 days. The negative control had increased prostate weight (p < 0.05), decreased body weight gain, prostatic superoxide dismutase, catalase and glutathione concentrations; no differences (p > 0.05) in the serum total cholesterol, triacylglycerol, Very Low Density Lipoprotein, High Density Lipoprotein, Low Density Lipoprotein concentration but increased (p < 0.05) prostate levels of interleukin 10, prostate specific antigen, testosterone, total proteins and malondialdehyde relative to the normal control. Finasteride or the C. esculenta tuber extract modulated most of these parameters as corroborated by histology of the prostate. The percentage yield of the C. esculenta tuber extract was 1.56% and 23 phenolic compounds were characterized in the tuber. The study showed the potentials of C. esculenta tuber in the management of BPH.

Linh Phu Khang Tue Tinh inhibited prostate proliferation in rats induced benign prostatic hyperplasia by testosterone propionate.

ETHNOPHARMACOLOGICAL RELEVANCE: Benign prostatic hyperplasia (BPH) is the hyperproliferation of the stromal and the epithelial cells within the prostatic transition zone. In recent years, phytotherapy have been studied with the concern for increasing quality of life, improving lower urinary tract symptoms (LUTS) as well as reducing prostate volume and the frequency of adverse events was similar to that of placebo. Linh Phu Khang Tue Tinh (LPKTT) capsules are formulated from 4 herbs widely used in traditional Vietnamese medicine - Panax notoginseng (Burkill) F.H.Chen - Tam that (radix), Crinum asiaticum L. - Náng hoa trang or giant crinum lily, Polygonum cuspidatum Willd. ex Spreng. (= Reynoutria japonica Houtt) - Cot cu khí or Japanese knotweed (radix), Oldenlandia herbacea (L.) Roxb. (formerly known as Hedyotis diffusa Spreng.) - Bach hoa xà thie^t thao or slender oldenlandia (herb). The preparation has been used in traditional Vietnamese medicine to treat nocturia, weak urine stream, urinary tract infection. According to modern studies, these herbs have anti-inflammation, antitumor, and antioxidant activities. AIMS OF THE STUDY: Evaluating the effects of LPKTT capsules on the development of BPH using a rat model of BPH induced by testosterone propionate (TP). MATERIALS AND METHODS: 60 male Wistar rats, 10-12 weeks of age, weight 200-250 g were separated into six groups: (G1) a normal control group that was taken orally phosphate-buffered saline (p.o.; PBS.) with corn oil (subcutaneous injection- Sc); (G2) a BPH model group that received PBS (p.o) with TP (Sc); (G3) a positive control group that received dutasteride (25 µg/kg BW/24 h, p.o.) with TP (Sc); (G4) a positive control group that received alfuzosin HCl (1.8 mg/kg BW/24 h, p.o.) with TP (s.c.) and (G5 and G6) LPKTT groups that received LPKTT at 289.8 or 869.4 mg/kg(p.o.) respectively, with TP (s.c.). BPH model was induced by Sc of TP, 3 mg/kg for 4 weeks. After that, rats were received NaCl/Dutasteride/Alfuzosin/LPKTT for the next 28 days. On the 56th day, assessed the results were through the indicators: micturition frequency, voided volume, total voided volume, the prostate and body weights, the ratio of prostate weight to body weight, prostate histology. RESULTS: LPKTT reduced micturition frequency and increased the voided volume when compared to the control group (p < 0.01). The results were equivalent to those of the alfuzosin ones (G4). LPKTT lowered prostate weight and the ratio of prostate weight to body weight when compared to the control group (p < 0.01). These reductions were the same in the dutasteride ones. Histomorphology in G5 and G6 also showed that LPKTT inhibited TP induced prostatic hyperplasia. The results were similar to that in the dutasteride group. Microscopic images of prostate in G5 and G6 were almost similar to that of G1. CONCLUSION: LPKTT capsules work to inhibit prostate proliferation in rats induced BPH by TP.

Psoralea corylifolia L. extract ameliorates benign prostatic hyperplasia by regulating prostate cell proliferation and apoptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Psoralea corylifolia L. seed (PCL), commonly known as "Poguzhi" or "BuguZhi", has been widely used to treat kidney yang deficiency in traditional Chinese medicine (TCM) where tonifying the yang deficiency is a representative understanding for treatment of hormonal deficiency disorders such as enuresis, oliguria, and prostatic diseases. Although PCL has been commonly used to treat problems of the urinary system, its efficacy against benign prostatic hyperplasia (BPH) has not yet been reported. AIM OF THE STUDY: In the present study, we aimed to assess the in vitro and in vivo efficacy of PCL against BPH, a condition which negatively impacts quality of life in men. MATERIALS AND METHODS: Normal human prostate cell lines, RWPE-1 and WPMY-1 cells, were stimulated with 10 nM dihydrotestosterone (DHT) to establish an in vitro BPH model. Subsequently, cells were treated with 100 or 200 µg/ml PCL, which inhibited cell proliferation without cytotoxicity, to evaluate the anti-BPH effect of PCL. Eight-week-old male Wistar rats were castrated, except for those in the control group (Con), and BPH was induced by subcutaneous injection of 10 mg/kg testosterone propionate (TP). Concurrent with daily TP injections, 5 mg/kg of finasteride (Fina) and 50 or 100 mg/kg PCL were orally administrated daily for four weeks, excluding the weekends. RESULTS: In DHT-stimulated RWPE-1 and WPMY-1 cells, expression of androgen receptor (AR) androgen signaling-related markers such as 5α-reductase 2 (5AR2), AR, and prostate-specific antigen (PSA) was upregulated, whereas 100 or 200 µg/ml of PCL treatment downregulated these markers. Furthermore, PCL significantly reduced the mRNA expression of anti-apoptotic genes and increased the mRNA expression of pro-apoptotic gene. In vivo, administration of PCL reduced prostate size and weight in TP-induced BPH rats. Moreover, histological alterations in epithelium thickness were significantly restored by the administration of PCL. Immunohistochemical analysis revealed increased expression of AR and proliferating cell nuclear antigen (PCNA) in TP-induced BPH prostates; these changes were suppressed by administration of 50 or 100 mg/kg PCL. CONCLUSIONS: We demonstrated the effect of PCL against BPH, mediated by the regulation of prostate cell proliferation and apoptosis, in DHT-stimulated normal human prostate cell lines and TP-induced BPH rats. These findings suggest that PCL could be a potential therapeutic agent against BPH.

Inhibitory Effect of Artemisinin on Testosterone Propionate Induced Benign Prostatic Hyperplasia.

BACKGROUND: Benign prostate hyperplasia [BPH] is an abnormal growth of prostate observed commonly in elderly males. Artemisinin has been reported to reduce the levels of testosterone. OBJECTIVE: This study is designed to evaluate the efficacy of Artemisinin on testosterone propionate [TP] induced benign prostate hyperplasia. MATERIALS AND METHODS: Male Wistar albino rats [n=24] were separated into four groups of six rats each. Group I served as control and distilled water using tween 80 as an emulsifying agent was administered subcutaneously. BPH was induced by testosterone propionate 3mg/kg [Group II], S.C. daily for 28 days. Group III was BPH + Finasteride treated group (10mg/kg orally for 28 days) and BPH + Artemisinin treated group (Group IV) (50 mg/kg orally for 28 days). RESULT: The study results showed significantly high levels of serum prostatic acid phosphatase (PAP), lactate dehydrogenase (LDH) and an elevation in prostate weight and prostatic index in Group II (BPH) when compared with Group I. The histopathological examination showed an increase in the epithelial proliferation of prostatic cells with involutions protruding into the lumen in BPH group when compared to the normal group. Treatment with Artemisinin (50 mg/kg) reduced the levels of PAP, LDH, prostate weight and prostatic index to a significant extent and restored the histoarchitectural features of the cells. CONCLUSION: The present study concludes that Artemisinin is efficacious in testosterone propionate induced BPH. This could be attributed, at least partly, to its anti-inflammatory property or its role in testosterone level reduction or as a Vitamin D receptor modulator.

Association between circadian rhythm disruption and polycystic ovary syndrome.

OBJECTIVE: To explore the association of circadian rhythm disruption with polycystic ovary syndrome (PCOS) and the potential underlying mechanism in ovarian granulosa cells (GCs). DESIGN: Multicenter questionnaire-based survey, in vivo and ex vivo studies. SETTING: Twelve hospitals in China, animal research center, and research laboratory of a women's hospital. PATIENTS/ANIMALS: A total of 436 PCOS case subjects and 715 control subjects were recruited for the survey. In vivo and ex vivo studies were conducted in PCOS-model rats and on ovarian GCs collected from women with PCOS and control subjects. INTERVENTION(S): The PCOS rat model was established with the use of testosterone propionate. MAIN OUTCOME MEASURE(S): Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), RNA sequencing, rhythmicity analysis, functional enrichment analysis. RESULT(S): There was a significant correlation between night shift work and PCOS. PCOS-model rats presented distinct differences in the circadian variation of corticotropin-releasing hormone, adrenocorticotropic hormone, prolactin, and a 4-h phase delay in thyrotropic hormone levels. The motif enrichment analysis of ATAC-seq revealed the absence of clock-related transcription factors in specific peaks of PCOS group, and RNA sequencing ex vivo at various time points over 24 hours demonstrated the differential rhythmic expression patterns of women with PCOS. Kyoto Encyclopedia of Genes and Genomes analysis further highlighted metabolic dysfunction, including both carbohydrate and amino acid metabolism and the tricarboxylic acid cycle. CONCLUSION(S): There is a significant association of night shift work with PCOS, and genome-wide chronodisruption exists in ovarian GCs.

Amelioration of testosterone-induced benign prostatic hyperplasia using febuxostat in rats: The role of VEGF/TGFß and iNOS/COX-2.

Benign prostatic hyperplasia (BPH) is a common male disorder. Febuxostat is a non-purine, selective inhibitor of xanthine oxidase (XO), which has a strong antioxidant capacity and pleiotropic pharmacological properties. This study's objective was to explore the potential ameliorative effects of febuxostat against testosterone-induced BPH in rats. Febuxostat (10 mg/kg/day, per os [p.o.]) prevented increased prostate index levels, serum levels of prostate-specific antigen (PSA), and testosterone levels compared to animals treated with testosterone alone, when administered for 28 days. Histological examination indicated that febuxostat dramatically ameliorated pathological changes in the prostate architecture compared to the testosterone group. Similarly, febuxostat markedly improved testosterone-induced oxidative stress by inhibiting the increase in lipid peroxide and nitrite content, and by reducing the level of depletion of reduced glutathione (GSH) and superoxide dismutase (SOD) activity, which significantly reduced the prostate content of pro-inflammatory cytokines, including tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6). Furthermore, febuxostat significantly reduced the prostatic content, both in terms of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) messenger ribonucleic acid (mRNA) levels, and of protein levels. Moreover, compared to the testosterone group, febuxostat's beneficial effects prevented the increase in growth factors, comprising vascular endothelial cell growth factor A (VEGF-A) and transforming growth factor beta (TGF-ß) protein levels. Its ameliorating effects were equal to those of finasteride, which is the most widely used remedy for BPH. In conclusion, this study provides novel evidence that febuxostat experimentally attenuates testosterone-induced BPH in rats, at least in part by inhibiting iNOS/COX-2 and VEGF/TGF-ß pathways.

Effect of acetogenin fraction of Annona muricata leaves on antioxidant status and some indices of benign prostatic hyperplasia in rats.

ABSTRACT Objectives: This work investigated the effect of acetogenin-rich fraction of Annona muricata leaves (AFAL) on antioxidant status and some markers of benign prostatic hyperplasia (BPH) in rats. Methods: BPH was experimentally induced in the rats by subcutaneous injection of testosterone propionate (TP, 3 mg/kg) for 28 consecutive days. The rats were administered orally different doses of AFAL (100 and 200 mg/kg) for 7 days. Prostate-specific antigen (PSA), prostate weight, relative prostate weight, prostate protein content and oxidative stress indices of the rats were evaluated. Results: It was observed that 200 mg/kg AFAL significantly reduced the PSA level, mean prostate weights and mean relative prostate weights of the test rats compared to the TP group, and the values were not significantly different from the normal control and group treated with a standard drug. The plant extract also significantly enhanced the antioxidant capacity of the test rats which were evidently compromised in the group that received the exogenous hormone alone. Histopathology of the prostate showed a marked recovery for the test rats after treatment with AFAL. Conclusion: Oral administration of acetogenin-rich fraction of Annona muricata leaves ameliorated TP-induced BPH in rats and significantly enhanced the antioxidant capacity of the rats.

D-Chiro-Inositol Treatment Affects Oocyte and Embryo Quality and Improves Glucose Intolerance in Both Aged Mice and Mouse Models of Polycystic Ovarian Syndrome.

Polycystic ovarian syndrome (PCOS) is the main cause of female infertility. It is a multifactorial disorder with varying clinical manifestations including metabolic/endocrine abnormalities, hyperandrogenism, and ovarian cysts, among other conditions. D-Chiro-inositol (DCI) is the main treatment available for PCOS in humans. To address some of the mechanisms of this complex disorder and its treatment, this study examines the effect of DCI on reproduction during the development of different PCOS-associated phenotypes in aged females and two mouse models of PCOS. Aged females (8 months old) were treated or not (control) with DCI for 2 months. PCOS models were generated by treatment with dihydrotestosterone (DHT) on Days 16, 17, and 18 of gestation, or by testosterone propionate (TP) treatment on the first day of life. At two months of age, PCOS mice were treated with DCI for 2 months and their reproductive parameters analyzed. No effects of DCI treatment were produced on body weight or ovary/body weight ratio. However, treatment reduced the number of follicles with an atretic cyst-like appearance and improved embryo development in the PCOS models, and also increased implantation rates in both aged and PCOS mice. DCI modified the expression of genes related to oocyte quality, oxidative stress, and luteal sufficiency in cumulus-oocyte complexes (COCs) obtained from the aged and PCOS models. Further, the phosphorylation of AKT, a main metabolic sensor activated by insulin in the liver, was enhanced only in the DHT group, which was the only PCOS model showing glucose intolerance and AKT dephosphorylation. The effect of DCI in the TP model seemed mediated by its influence on oxidative stress and follicle insufficiency. Our results indicate that DCI works in preclinical models of PCOS and offer insight into its mechanism of action when used to treat this infertility-associated syndrome.

Supraphysiological Levels of Testosterone Induce Vascular Dysfunction via Activation of the NLRP3 Inflammasome.

Background: Both supraphysiological and subphysiological testosterone levels are associated with increased cardiovascular risk. Testosterone consumption at supraphysiological doses has been linked to increased blood pressure, left ventricular hypertrophy, vascular dysfunction, and increased levels of inflammatory markers. Activation of the NLRP3 inflammasome contributes to the production of proinflammatory cytokines, leading to cardiovascular dysfunction. We hypothesized that supraphysiological levels of testosterone, via generation of mitochondrial reactive oxygen species (mROS), activates the NLRP3 inflammasome and promotes vascular dysfunction. Methods: Male, 12 week-old C57Bl/6J (WT) and NLRP3 knockout (NLRP3-/-) mice were used. Mice were treated with testosterone propionate [TP (10 mg/kg) in vivo] or vehicle for 30 days. In addition, vessels were incubated with testosterone [Testo (10-6 M, 2 h) in vitro]. Testosterone levels, blood pressure, vascular function (thoracic aortic rings), pro-caspase-1/caspase-1 and interleukin-1ß (IL-1ß) expression, and generation of reactive oxygen species were determined. Results: Testosterone increased contractile responses and reduced endothelium-dependent vasodilation, both in vivo and in vitro. These effects were not observed in arteries from NLRP3-/- mice. Aortas of TP-treated WT mice (in vivo), as well as aortas from WT mice incubated with testo (in vitro), exhibited increased mROS levels and increased caspase-1 and IL-1ß expression. These effects were not observed in arteries from NLRP3-/- mice. Flutamide [Flu, 10-5 M, androgen receptor (AR) antagonist], carbonyl cyanide m-chlorophenyl hydrazone (CCCP, 10-6 M, mitochondrial uncoupler) and MCC950 (MCC950, 10-6 M, a NLRP3 receptor inhibitor) prevented testosterone-induced mROS generation. Conclusion: Supraphysiological levels of testosterone induce vascular dysfunction via mROS generation and NLRP3 inflammasome activation. These events may contribute to increased cardiovascular risk.

Testosterone improves muscle function of the extensor digitorum longus in rats with sepsis.

Among patients with intensive care unit-acquired weakness (ICUAW), skeletal muscle strength often decreases significantly. The present study aimed to explore the effects of testosterone propotionate on skeletal muscle using rat model of sepsis. Male SD rats were randomly divided into experimental group, model control group, sham operation group and blank control group. Rats in experimental group were given testosterone propionate two times a week, 10 mg/kg for 3 weeks. Maximal contraction force, fatigue index and cross-sectional area of the extensor digitorum longus (EDL) were measured. Myosin, IGF-1, p-AKT and p-mTOR levels in EDL were detected by Western blot. Histological changes of the testis and prostate were detected by hematoxylin and eosin staining. We found that maximal contraction force and fatigue index of EDL in experimental group were significantly higher than in model control group. Cross-sectional area of fast MHC muscle fiber of EDL in group was significantly higher than in model control group. The levels of myosin, IGF-1, p-AKT and p-mTOR of EDL in experimental group were significantly higher than in model control group. In addition, no testicle atrophy and prostate hyperplasia were detected in experimental group. In conclusion, these results suggest that testosterone propionate can significantly improve skeletal muscle strength, endurance and volume of septic rats, and the mechanism may be related to the activation of IGF-1/AKT pathway. Moreover, testosterone propionate with short duration does not cause testicular atrophy and prostate hyperplasia in septic rats. Therefore, testosterone propionate is a potential treatment for muscle malfunction in ICUAW patients.

Developmental Programming: Contribution of Epigenetic Enzymes to Antral Follicular Defects in the Sheep Model of PCOS.

Prenatal testosterone (T)-treated sheep, similar to women with polycystic ovary syndrome (PCOS), manifest oligo-/anovulation, hyperandrogenism, and polyfollicular ovary. The polyfollicular ovarian morphology, a result of persistence of antral follicles, arises, in part, by transcriptional changes in key mediators of follicular development that, in turn, are driven by epigenetic mechanisms. We hypothesized that prenatal T excess induces, in a cell-specific manner, transcriptional changes in key mediators of follicular development associated with relevant changes in epigenetic machinery. Expression levels of key mediators of follicular development, DNA methyltransferases (DNMTs), and histone de-/methylases and de-/acetylases were determined in laser-capture microdissection-isolated antral follicular granulosa and theca and ovarian stromal cells from 21 months of age control and prenatal T-treated sheep (100 mg IM twice weekly from gestational day 30 to 90; term: 147 days). Changes in histone methylation were determined by immunofluorescence. Prenatal T treatment induced the following: (i) cell-specific changes in gene expression of key mediators of follicular development and steroidogenesis; (ii) granulosa, theca, and stromal cell-specific changes in DNMTs and histone de-/methylases and deacetylases, and (iii) increases in histone 3 trimethylation at lysine 9 in granulosa and histone 3 dimethylation at lysine 4 in theca cells. The pattern of histone methylation was consistent with the expression profile of histone de-/methylases in the respective cells. These findings suggest that changes in expression of key genes involved in the development of the polyfollicular phenotype in prenatal T-treated sheep are mediated, at least in part, by cell-specific changes in epigenetic-modifying enzymes.

Effect of Veratrum maackii on Testosterone Propionate-Induced Benign Prostatic Hyperplasia in Rats.

Veratrum maackii (VM), a perennial plant in the Melanthiaceae family, has anti-hypertensive, anti-cholinergic, anti-asthmatic, anti-tussive, anti-fungal, anti-melanogenesis, and anti-tumor activities. Here, we investigated the therapeutic effect of VM on benign prostatic hyperplasia (BPH) in human normal prostate cell line (WPMY-1) and a testosterone propionate-induced BPH animal model. WPMY-1 cells were treated with VM (1-10 µg/mL) and testosterone propionate (100 nM). BPH in rats was generated via daily subcutaneous injections of testosterone propionate (3 mg/kg) dissolved in corn oil, for 4 weeks. VM (150 mg/kg) was administered daily for 4 weeks by oral gavage concurrently with the testosterone propionate. All rats were sacrificed and the prostates were dissected, weighed, and subjected to histological, immunohistochemical, and biochemical examinations. Immunoblotting experiments indicated that WPMY-1 cells treated testosterone propionate had increased expression of prostate specific antigen (PSA) and androgen receptor (AR), and treatment with VM or finasteride blocked this effect. In rat model, VM significantly reduced prostate weight, prostatic hyperplasia, prostatic levels of dihydrotestosterone (DHT), and expression of proliferation markers such as proliferating cell nuclear antigen (PCNA) and cyclin D1, but increased the expression of pro-apoptotic Bcl-2-associated X protein (Bax) and the cleavage of caspase-3. VM administration also suppressed the testosterone propionate-induced activation of nuclear factor-kappaB (NF-κB). Our results indicate that VM effectively represses the development of testosterone propionate-induced BPH, suggesting it may be a useful treatment agent for BPH.

Endoglin inhibition by sodium acetate and flutamide ameliorates cardiac defective G6PD-dependent antioxidant defense in gestational testosterone-exposed rats.

Gestational androgen excess has been implicated in the development of cardiac dysfunction with poor mechanistic delineation. The role of sodium acetate on cardiac uric acid (UA) production and glucose-6-phosphate dehydrogenase (G6PD)-dependent antioxidant defense in pregnancy is not known. The study therefore sought to test the hypothesis that rats exposed to elevated testosterone in late pregnancy would have increased cardiac UA production and defective G6PD-dependent antioxidant defense. We also hypothesized that sodium acetate (SAc) or androgen receptor blocker, flutamide (Flu) would ameliorate these effects through endoglin inhibition. Twenty-four pregnant Wistar rats were treated (sc) with olive oil, testosterone propionate (0.5 mg/kg) singly or in combination with SAc (200 mg/kg; po) or Flu (7.5 mg/kg; po) in the late gestation between gestational day 14 and 19. The results showed that in the late gestation, testosterone exposure led to increased plasma and cardiac endoglin. In the heart of rats exposed to gestational testosterone there were elevated lactate dehydrogenase, adenosine deaminase, xanthine oxidase, uric acid (UA), cardiac injury markers and decreased G6PD-dependent antioxidant defense. However, either SAc or Flu comparably ameliorated these testosterone-induced effects. The data from the present study revealed that testosterone exposure in the late gestation causes elevated cardiac Eng that is accompanied by increased UA production and defective G6PD-dependent anti-oxidant defenses. Besides, the findings also suggest that the inhibitory effect of SAc or Flu on endoglin attenuates UA production and enhances the G6PD-dependent anti-oxidant barrier, thereby implying that endoglin may be a potentially novel therapeutic intervention for cardiac dysfunction particularly in pregnancy.

Quisqualis indica Improves Benign Prostatic Hyperplasia by Regulating Prostate Cell Proliferation and Apoptosis.

Quisqualis indica (QI) has been used for treating disorders such as stomach pain, constipation, and digestion problem. This study was aimed to evaluate the therapeutic efficacy of QI extract on treating benign prostatic hyperplasia (BPH) in LNCaP human prostate cancer cell line and a testosterone-induced BPH rat model. LNCaP cells were treated with QI plus testosterone propionate (TP), and androgen receptor (AR) and prostate specific antigen (PSA) expression levels were assessed by Western blotting. To induce BPH, the rats were subjected to a daily subcutaneous injection of TP (3 mg/kg) for 4 weeks. The rats in treatment group were orally gavaged with QI (150 mg/kg) together with the TP injection. In-vitro studies showed that TP-induced increases in AR and PSA expression in LNCaP cells were reduced by QI treatment. In BPH-model rats, the prostate weight, testosterone in serum, dihydrotestosterone (DHT) concentration and 5α-reductase type 2 mRNA expression in prostate tissue were significantly reduced following the treatment with QI. TP-induced prostatic hyperplasia and the expression of proliferating cell nuclear antigen (PCNA) and cyclin D1 were significantly attenuated in QI-treated rats. In addition, QI induced apoptosis by up-regulating caspase-3 and -9 activity and decreasing the B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein (Bax) ratio in prostate tissues of BPH rats. Further investigation showed that TP-induced activation of AKT and glycogen synthase kinase 3ß (GSK3ß) was reduced by QI administration. Therefore, our findings suggest that QI attenuates the BPH state in rats through anti-proliferative and pro-apoptotic activities and might be useful in the clinical treatment of BPH.

A Novel Potential Reproductive Effects of Pterocarpus marsupium Methanolic Extract on Testosterone Propionate Induced Polycystic Ovary Syndrome in Female Albino Rats.

OBJECTIVE: To investigate potential reproductive effects of Pterocarpus marsupium methanolic extract on testosterone propionate induced Polycystic Ovarian Syndrome (PCOS) in female albino rats. METHODOLOGY: PCOS was induced in female albino rats by daily injecting testosterone propionate for 15 days intraperitoneally. Animals are divided into five groups with six rats per group. Group 1: Control group received olive oil, Group 2: Testosterone propionate+natural recovery, Group 3: Testosterone propionate + a dose of clomiphene citrate (standard), Group 4 and 5: Testosterone propionate + low dose (200mg/kg) and high dose (400mg/kg) b.w respectively for 15 days. Various biochemical and histopathological investigations were assessed. RESULTS: Methanol extract of Pterocarpus marsupium was able to exert its protective effect successfully by restoring all the parameters to normal and diminishing the cysts found in ovaries. CONCLUSION: Pterocarpus marsupium showed potential reproductive effects on testosterone propionate induced PCOS female albino rats and could be used as an alternative therapy in the treatment of PCOS.

Administration of anabolic steroid during adolescence induces long-term cardiac hypertrophy and increases susceptibility to ischemia/reperfusion injury in adult Wistar rats.

Chronic administration of anabolic androgenic steroids (AAS) in adult rats results in cardiac hypertrophy and increased susceptibility to myocardial ischemia/reperfusion (IR) injury. Molecular analyses demonstrated that hyperactivation of type 1 angiotensin II (AT1) receptor mediates cardiac hypertrophy induced by AAS and also induces down-regulation of myocardial ATP-sensitive potassium channel (KATP), resulting in loss of exercise-induced cardioprotection. Exposure to AAS during adolescence promoted long-term cardiovascular dysfunctions, such as dysautonomia. We tested the hypothesis that chronic AAS exposure in the pre/pubertal phase increases the susceptibility to myocardial ischemia/reperfusion (IR) injury in adult rats. Male Wistar rats (26day old) were treated with vehicle (Control, n=12) or testosterone propionate (TP) (AAS, 5mgkg-1 n=12) 5 times/week during 5 weeks. At the end of AAS exposure, rats underwent 23days of washout period and were submitted to euthanasia. Langendorff-perfused hearts were submitted to IR injury and evaluated for mechanical dysfunctions and infarct size. Molecular analysis was performed by mRNA levels of α-myosin heavy chain (MHC), ßMHC and brain-derived natriuretic peptide (BNP), ryanodine receptor (RyR2) and sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) by quantitative RT-PCR (qRT-PCR). The expression of AT1 receptor and KATP channel subunits (Kir6.1 and SURa) was analyzed by qRT-PCR and Western Blot. NADPH oxidase (Nox)-related reactive oxygen species generation was assessed by spectrofluorimetry. The expression of antioxidant enzymes was measured by qRT-PCR in order to address a potential role of redox unbalance. AAS exposure promoted long-term cardiac hypertrophy characterized by increased expression of ßMHC and ßMHC/αMHC ratio. Baseline derivative of pressure (dP/dt) was impaired by AAS exposure. Postischemic recovery of mechanical properties was impaired (decreased left ventricle [LV] developed pressure and maximal dP/dt; increased LV end-diastolic pressure and minimal dP/dt) and infarct size was larger in the AAS group. Catalase mRNA expression was significantly decreased in the AAS group. In conclusion, chronic administration of AAS during adolescence promoted long-term pathological cardiac hypertrophy and persistent increase in the susceptibility to myocardial IR injury possible due to disturbances on catalase expression.

Neurotransmitter alteration in a testosterone propionate-induced polycystic ovarian syndrome rat model.

BACKGROUND: Polycystic ovarian syndrome (PCOS), one of the leading causes of infertility seen in women, is characterized by anovulation and hyperandrogenism, resulting in ovarian dysfunction. In addition, associations of several metabolic complications like insulin resistance, obesity, dyslipidemia and psychological co-morbidities are well known in PCOS. One of the major factors influencing mood and the emotional state of mind is neurotransmitters. Also, these neurotransmitters are very crucial for GnRH release. Hence, the current study investigates the status of neurotransmitters in PCOS. MATERIALS AND METHODS: A PCOS rat model was developed using testosterone. Twenty-one-day-old rats were subcutaneously injected with 10 mg/kg body weight of testosterone propionate (TP) for 35 days. The animals were validated for PCOS characteristics by monitoring estrus cyclicity, serum testosterone and estradiol levels and by histological examination of ovarian sections. Neurotransmitter estimation was carried out using fluorometric and spectrophotometric methods. RESULTS: TP-treated animals demonstrated increased serum testosterone levels with unaltered estradiol content, disturbed estrus cyclicity and many peripheral cysts in the ovary compared to control rats mimicking human PCOS. Norepinephrine (NE), dopamine, serotonin, γ-amino butyric acid (GABA) and epinephrine levels were significantly low in TP-induced PCOS rats compared to control ones, whereas the activity of acetylcholinesterase in the PCOS brain was markedly elevated. CONCLUSION: Neurotransmitter alteration could be one of the reasons for disturbed gonadotropin-releasing hormone (GnRH) release, consequently directing the ovarian dysfunction in PCOS. Also, decrease in neurotransmitters, mainly NE, serotonin and dopamine (DA) attributes to mood disorders like depression and anxiety in PCOS.

Prenatal Testosterone Exposure Leads to Gonadal Hormone-Dependent Hyperinsulinemia and Gonadal Hormone-Independent Glucose Intolerance in Adult Male Rat Offspring.

Elevated testosterone levels during prenatal life lead to hyperandrogenism and insulin resistance in adult females. This study evaluated whether prenatal testosterone exposure leads to the development of insulin resistance in adult male rats in order to assess the influence of gonadal hormones on glucose homeostasis in these animals. Male offspring of pregnant rats treated with testosterone propionate or its vehicle (control) were examined. A subset of male offspring was orchiectomized at 7 wk of age and reared to adulthood. At 24 wk of age, fat weights, plasma testosterone, glucose homeostasis, pancreas morphology, and gastrocnemius insulin receptor (IR) beta levels were examined. The pups born to testosterone-treated mothers were smaller at birth and remained smaller through adult life, with levels of fat deposition relatively similar to those in controls. Testosterone exposure during prenatal life induced hyperinsulinemia paralleled by an increased HOMA-IR index in a fasting state and glucose intolerance and exaggerated insulin responses following a glucose tolerance test. Prenatal androgen-exposed males had more circulating testosterone during adult life. Gonadectomy prevented hyperandrogenism, reversed hyperinsulinemia, and attenuated glucose-induced insulin responses but did not alter glucose intolerance in these rats. Prenatal androgen-exposed males had decreased pancreatic islet numbers, size, and beta-cell area along with decreased expression of IR in gastrocnemius muscles. Gonadectomy restored pancreatic islet numbers, size, and beta-cell area but did not normalize IRbeta expression. This study shows that prenatal testosterone exposure leads to a defective pancreas and skeletal muscle function in male offspring. Hyperinsulinemia during adult life is gonad-dependent, but glucose intolerance appears to be independent of postnatal testosterone levels.

Perinatal exposure to androgen excess and the effects on the rat uterine estradiol responsiveness.

Androgen exposure during sexual development induces alterations in steroidal target tissues. The objective of this study was to evaluate the uterine responsiveness to estradiol after perinatal androgenization. Pregnant Wistar rats were exposed to corn oil or testosterone propionate at 0.05, 0.1, or 0.2 mg/kg from gestational day 12 until postnatal day 21. Female offspring was challenged with estradiol (E2 ) after weaning (0.4 mg/kg) and at adulthood (10 or 100 µg/day), when the pituitary response was also evaluated. At adulthood, control and 0.05 mg/kg groups presented a uterine weight increment when exposed to 100 µg/day of E2 , 0.1 mg/kg group only responded to 10 µg/day of E2 , and the 0.2 mg/kg group showed increased uterine weight at both doses. The pituitary weight was similarly increased after estradiol stimulation in all experimental groups. In conclusion, testosterone propionate exposure induced an abnormal stimulation of uterine tissue growth by estrogen stimulus without affecting pituitary response. More studies are needed to clarify whether these alterations are capable of impairing the reproductive capacity of the female tract. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1460-1468, 2016.