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Purpose of Review: We review the concepts surrounding prostate cancer prevention strategies with 5-alpha reductase inhibitors (5-ARIs) and the controversies associated with their use., Recent Findings: Updated data have shown no increased risk of death from the diagnosis of higher risk cancer; however, 5-ARIs remain controversial and not approved for prostate cancer prevention., Summary: The main theme of the review identifies the success of reducing insignificant prostate cancer and the controversy with the increased association of higher risk prostate cancer by approximately 20%. The reduction was shown to be most significant reduction in low-grade prostate cancer. The initial concern about 5-ARI use was that it could potentially increase high-risk prostate cancer leading to higher mortality in those men. Higher mortality has not been seen in follow-up data; however, 5-ARIs continue to have a black box warning and are not approved for prostate cancer prevention.

Background: Houttuynia cordata Thunb (HC) is a traditional herbal medicine widely used in Asia for the treatment of patients with alopecia, usually in combination with other two herbal medicines (Perilla frutescens var. acuta (PFVA) and green tea (GT)). However, the effect of this herbal complex has not been clearly demonstrated. We sought to determine the hair growth-promoting effect of this herbal complex (HC, PFVA, and GT) in the animal model., Methods: Six-week-old male C57BL/6 mice were randomly divided into four groups (negative control, finasteride (1 mg/kg) as a positive control, and two (200 and 400 mg/kg) concentrations of the herbal complex as experimental groups) and were fed its corresponding medications orally for 25 days. Hair growth was evaluated visually and microscopically. Western blot analysis for insulin-like growth factor (IGF)-1 and transforming growth factor (TGF)-β1 was performed., Results: The herbal complex exhibited hair growth-promoting activity in C57BL/6 mice. Grossly, the area of hair regrowth was 55.1 (±3.8) %, 70.2 (±6.3) % and 83.5 (±5.7) % in negative control, herbal complex 200 mg/kg and 400 mg/kg group, respectively. In histologic examination, the hair follicle count in deep subcutis was 2.6 (±0.7), 5.8 (±0.7) and 8.6 (±1.2) and the diameter of hair follicles was 11.9 (±5.0) μm, 17.4 (±3.9) μm and 22.8 (±5.2) μm in negative control, herbal complex 200 and 400 mg/kg group, respectively. The expression of IGF-1 was 0.14 (±0.01), 0.23 (±0.02) and 0.24 (±0.01) and the expression of TGF-β1 was 0.26 (±0.01), 0.19 (±0.02) and 0.15 (±0.01) in negative control, the 200 and 400 mg/kg group, respectively., Conclusions: This data provides adequate preliminary experimental evidence to support the hair regeneration effect of this herbal complex.

In teleosts, spermatogenesis is regulated by pituitary gonadotropins and sex steroids. 5α-dihydrotestosterone (DHT), derived from testosterone (T) through the action of 5α-reductase, has recently been suggested to play a physiologically important role in some fish species. In this study, gilthead seabream, Sparus aurata L., males received an implant of 1μgT/g body mass (bm) or vehicle alone and, 7days later, 1mg finasteride (FIN, an inhibitor of 5α-reductase)/kg bm or vehicle. Serum levels of T, 11-ketotestosterone (11KT), DHT and 17β-estradiol (E 2 ), and the mRNA levels of the main enzymes involved in their synthesis, were analysed. T promoted a transient increase in the serum levels of T, 11KT and E 2 but a decrease in those of DHT at day 15 following T injection, in accordance with the up-regulation of mRNA levels of the enzymes involved in T transformation to 11KT (coding genes: cyp11b1 and hsd11b) and the down-regulation of mRNA levels of the enzyme responsible for T transformation to DHT (coding gene: srd5a). Interestingly, a similar effect was observed when FIN was injected. However, when fish were injected with T and FIN successively (T+FIN), control levels were not recovered at the end of the experimental period (28days). DHT seems to regulate E 2 serum levels via the down-regulation of mRNA levels of aromatase (coding gene: cyp19a1a), which is needed for the transformation of T into E 2 . The testis histology, together with the proliferative rates recorded upon T, FIN or T+FIN treatment, suggests that DHT is involved in the onset of the meiotic phase of spermatogenesis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Benign prostatic hyperplasia (BPH) is the most common cause of lower urinary tract symptoms (LUTS) in older men. In this regard, recent studies have attempted to define the relationships between prostatic fibrosis, LUTS, and increased expression of transforming growth factor β1 (TGF β1) in BHP. Therapeutic approaches for BPH such as 5-α-reductase inhibitors and alpha-adrenergic blocking agents increase TGF β1 expression in the prostatic tissue. Here, we investigated the effects of the 5-α-reductase inhibitor-finasteride-on rat ventral prostate tissue, especially with regard to the tissue distribution and gene expression of fibrillar collagens. Adult Wistar rats (n = 15) were treated with finasteride (25 mg/kg/day) by subcutaneous injection for 7 and 30 days. Age-matched, vehicle-treated (n = 15) adult Wistar rats were used as control. Finasteride treatment reduced prostate size and increased the area of types I and III collagen fibers in the prostatic stroma. As expected, TGF β1 mRNA expression was upregulated by finasteride treatment. However, COL1A1 and COL3A1 mRNA expressions decreased after both 7 and 30 days of finasteride treatment, suggesting that finasteride treatment promotes prostate parenchyma and stroma changes, which lead to the observed types I and III collagen remodeling without de novo collagen synthesis. The upregulation of TGF β1 mRNA and protein associated with the 5-α-reductase inhibitor is more closely related to epithelial and stromal cell death pathways than to prostatic fibrosis., (© 2017 International Federation for Cell Biology.)

We have reported that testosterone-enanthate (TE) prevents the musculoskeletal decline occurring acutely after spinal cord injury (SCI), but results in a near doubling of prostate mass. Our purpose was to test the hypothesis that administration of TE plus finasteride (FIN; type II 5α-reductase inhibitor) would prevent the chronic musculoskeletal deficits in our rodent severe contusion SCI model, without inducing prostate enlargement. Forty-three 16-week-old male Sprague-Dawley rats received: 1) SHAM surgery (T 9 laminectomy); 2) severe (250 kdyne) contusion SCI; 3) SCI+TE (7.0 mg/week, intramuscular); or 4) SCI+TE+FIN (5 mg/kg/day, subcutaneous). At 8 weeks post-surgery, SCI animals exhibited reduced serum testosterone and levator ani/bulbocavernosus (LABC) muscle mass, effects that were prevented by TE. Cancellous and cortical (periosteal) bone turnover (assessed by histomorphometry) were elevated post-SCI, resulting in reduced distal femur cancellous and cortical bone mass (assessed by microcomputed tomography). TE treatment normalized cancellous and cortical bone turnover and maintained cancellous bone mass at the level of SHAM animals, but produced prostate enlargement. FIN coadministration did not inhibit the TE-induced musculoskeletal effects, but prevented prostate growth. Neither drug regimen prevented SCI-induced cortical bone loss, although no differences in whole bone strength were present among groups. Our findings indicate that TE+FIN prevented the chronic cancellous bone deficits and LABC muscle loss in SCI animals without inducing prostate enlargement, which provides a rationale for the inclusion of TE+FIN in multimodal therapeutic interventions intended to alleviate the musculoskeletal decline post-SCI.

Background: Phytotherapy is becoming a treatment option in management of diseases including benign prostatic hyperplasia (BPH). We have shown previously that methyl jasmonate (MeJA) ameliorated BPH, however the underlying mechanism of action remains unknown. This study was designed to investigate in mechanistic terms the protective role of MeJA in BPH., Methods: BPH was induced by daily injections of testosterone propionate (TP) (3mg/kg) for 28 days., Results: The weight and organo-somatic weight of prostate in BPH rats were 6.8 and 5.1 times higher than castrated-control group, respectively. Inflammatory markers; prostatic myeloperoxidase and total nitric oxide were significantly increased in BPH group. The activity of aniline hydroxylase (Phase I drug metabolizing enzyme) was significantly increased in BPH rats by 22%. In BPH group, immuno-histochemistry revealed strong expression of prostatic inducible nitric oxide synthase, cyclooxygenase-2 and Bcl 2 , while mild expression of p53 and Bax were seen. Serum triglyceride and total cholesterol were significantly increased, while HDL-c was decreased in BPH. Interestingly, MeJA and finasteride (singly or combination) attenuated inflammatory indices and induced apoptotic parameters in BPH rats., Conclusion: MeJA protects against TP-induced BPH via mechanisms that involve anti-inflammation, induction of apoptosis and inhibition of phase I drug metabolizing enzyme., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Acute sleep deprivation (SD) can trigger or exacerbate psychosis- and mania-related symptoms; the neurobiological basis of these complications, however, remains elusive. Given the extensive involvement of neuroactive steroids in psychopathology, we hypothesized that the behavioral complications of SD may be contributed by 5α-reductase (5αR), the rate-limiting enzyme in the conversion of progesterone into the neurosteroid allopregnanolone. We first tested whether rats exposed to SD may exhibit brain-regional alterations in 5αR isoenzymes and neuroactive steroid levels; then, we assessed whether the behavioral and neuroendocrine alterations induced by SD may be differentially modulated by the administration of the 5αR inhibitor finasteride, as well as progesterone and allopregnanolone. SD selectively enhanced 5αR expression and activity, as well as AP levels, in the prefrontal cortex; furthermore, finasteride (10-100 mg/kg, IP) dose-dependently ameliorated PPI deficits, hyperactivity, and risk-taking behaviors, in a fashion akin to the antipsychotic haloperidol and the mood stabilizer lithium carbonate. Finally, PPI deficits were exacerbated by allopregnanolone (10 mg/kg, IP) and attenuated by progesterone (30 mg/kg, IP) in SD-subjected, but not control rats. Collectively, these results provide the first-ever evidence that 5αR mediates a number of psychosis- and mania-like complications of SD through imbalances in cortical levels of neuroactive steroids.

The 18 kDa translocator protein (TSPO) is a five transmembrane domain protein that plays a crucial role in neurosteroid (e.g., allopregnanolone) synthesis by promoting the transport of cholesterol to the inner mitochondrial membrane. This protein is predominantly expressed in steroid-synthesizing tissues, including the central and peripheral nervous system, affecting stress-related disorders such as anxiety and depression. Recent studies have focused on the hippocampal dentate gyrus, which is very important for involvement of anxiety and depression. However, the exact role that TSPO plays in the pathophysiology of anxiety and depression and the involvement of the hippocampal dentate gyrus in regulating these behavioural effects remain elusive. This study used the lentiviral vectors mediating TPSO overexpression to assess the effects of TPSO overexpression in the hippocampal dentate gyrus on anxiolytic and antidepressant-like behavioural effects in mice. The expression of TSPO and the concentration of allopregnanolone in hippocampus tissues (3 mm in diameter around the injection site on both sides) were measured by Western blot and ELISA, respectively. The results indicated that microinjection of the LV-TSPO resulted in a significant increase in TSPO expression and allopregnanolone concentration in the hippocampus. Moreover, TSPO overexpression of the mouse hippocampal dentate gyrus generated significant anxiolytic and antidepressant-like behavioural effects in a series of behavioural models. These effects were completely blocked by the TSPO antagonist PK11195 (3 mg/kg, intraperitoneally) and the 5α-reductase inhibitor finasteride (5 mg/kg,intraperitoneally). Meanwhile, the increased allopregnanolone was also reversed by PK11195 and finasteride. In addition, neither PK11195 nor finasteride had an effect on the expression of TSPO. Overall, our results are the first to suggest that the overexpression of TSPO in the hippocampal dentate gyrus produced anxiolytic and antidepressant-like behavioural effects that are partially mediated by downstream allopregnanolone biosynthesis. Our results suggest that TSPO would be a potential anxiolytic and antidepressant therapeutic target., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: To explore the effects of Xialiqi Capsules(XLQ) on the expressions of the proliferating cell nuclear antigen (PCNA) and caspase-3 in the prostate tissue of the BPH rat model., Methods: Fifty male SD ratswereequally randomized into groups A (sham operation control), B (BPH model control), C (high-dose XLQ), D (low-dose XLQ), and E (finasteridecontrol) andthe BPH modelswere established by subcutaneous injection of testosterone propionate at 0.5 mg per kilogram of the body weight per day for 30 days after castration. After modeling, the animals in groups A and B were treated intragastricallywith normal saline, while those in C, D, and E with XLQ at 1.20 and 0.61 g per kilogram of the body weight per day or finasterideat 0.8 mg per kilogram of the body weight per day, respectively, all for 30 days. Then,the bilateral prostates were harvestedfrom the rats for calculation of the prostatic index (prostate wet weight/ body weight) and determination of the expressions of PCNA and caspase-3 in the prostate tissue by immunohistochemistry and immunofluorescence staining, respectively., Results: The prostate wet weight and prostate index were significantly increased in group B as compared with group A, (［1326±60］ vs［471±17］ g, P<0.01; ［2.89±0.18］ vs ［1.06±0.06］ mg/g, P<0.01), but decreased in groups C (［914±36］ g;［2.02±0.08］ mg/g), D (［1 099±46］g;［2.39±0.11］ mg/g), and E (［817±53］ g;［1.83±0.10］ mg/g)in comparison with B (P<0.01), with statistically significant differences among groups C, D, and E(P<0.01) and most significantly in E.The PCNA level in the prostate tissue wasremarkably higher in group B than in A, but lower in groups C, D and E than in B. The expression of caspase-3 was down-regulatedin group B as compared with A, but up-regulated in groups C, D and E in comparison with B, most significantly in E., Conclusions: Xialiqi Capsules can effectively reduce the prostate wet weight and prostatic index of in rats with BPH by inhibiting the level of PCNA and promoting the expression of caspase-3.

The inhibitory effect of maca extractant, lycopene, and their combination was evaluated in benign prostatic hyperplasia (BPH) mice induced by testosterone propionate. Mice were divided into a saline group, solvent control group and testosterone propionate-induced BPH mice [BPH model group, solvent BPH model group, benzyl glucosinolate group (1.44 mg/kg), maca group (60 mg/kg), lycopene treated (15, 5, and 2.5 mg/kg), maca (30 mg/kg) combine lycopene treated (7.5, 2.5, and 1.25 mg/kg), and finasteride treated]. Benzyl glucosinolate was used in order to evaluate its pharmacological activity on BPH to find out whether it is the major active component of maca aqueous extract. Finasteride was used as positive control. The compounds were administered once for 30 successive days. Compared with solvent BPH model group, BPH mice fed with maca (30 mg/kg) and lycopene (7.5 mg/kg) combination exhibited significant reductions in the prostatic index, prostatic acid phospatase, estradiol, testosterone, and dihydrotestosterone levels in serum. They also had similar histological compared with those aspects observed in the mice in the solvent control group. The results indicated that combination of maca and lycopene synergistically inhibits BPH in mice. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

The neurosteroid allopregnanolone (3α, 5α-tetra-hydroprogesterone: ALLO) elicits anxiolytic, anticonvulsant, and hypnotic anesthetic effects in vivo similar to those induced by other positive allosteric modulators of the GABA A receptor. Endogenous ALLO has been shown to be rapidly elevated in the brain by acute stress paradigms, such as immobilization, in animal models. The present study was designed to ascertain the role of neurosteroid biosynthesis in the anxiety-like behavior induced by immobilization stress. Mice were exposed to an immobilization stressor for 2 h. After 24 h, the mice that had been immobilized did not behave significantly differently in the elevated plus maze (EPM) test and in the elevated open platform (EOP) test than the mice that had not been immobilized. In contrast, finasteride-pretreated immobilization stressed mice did behave significantly differently in the EPM and EOP tests. These findings suggest that ALLO biosynthesis contributes to stress resistance. Furthermore, the ALLO mimetic drug alfaxalone appeared to antagonize the effects of finasteride by significantly changing the behavior in the EPM test or in the EOP test in finasteride (10 mg kg -1 )-pretreated immobilized mice. In addition, alfaxalone, unlike diazepam, did not affect the muscle tone of the mice, as measured by the grip strength test. These results suggest that alfaxalone is a promising anxiolytic candidate lacking benzodiazepine-like muscle-relaxant effects., (© 2017 Wiley Periodicals, Inc.)

Neonatal neuroactive steroids levels are crucial for brain development. Alterations of neonatal neuroactive steroids levels induce anxiolytic-like effects and improve exploration in novel environments in adulthood. These behavioural traits, i.e. sensation/novelty seeking, anxiety or impulsivity, are associated with vulnerability to drug use and abuse. Adolescence is also recognized as a particularly critical developmental phase to contribute to vulnerable phenotype. However, the influence of neuroactive steroids during development in the vulnerability to drug addiction has been poorly studied. The aim of the present experiment is to study the effect of early neonatal and adolescent manipulations of neuroactive steroids on the sensitivity to the stimulant effects of ethanol in adult male rats. Therefore, allopregnanolone or finasteride, an allopregnanolone synthesis inhibitor, were injected from postnatal day 5-9. In early adolescence, half of the subjects were injected with progesterone, the main allopregnanolone precursor, and the elevated plus-maze anxiety test was performed. Results indicated that early adolescent progesterone induced anxiolytic-like effects (increase in the percentage of entries and time in open arms). Neonatal finasteride administration decreased locomotor activity induced by ethanol in adolescent vehicle subjects. Interestingly, differences induced by neonatal treatments were not present in the animals that received progesterone in the early adolescence. In conclusion, neuroactive steroid manipulations in crucial stages of development could be playing an important role in behavioural effects of alcohol such as the sensitivity to locomotor stimulation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by multiple tics and sensorimotor abnormalities, the severity of which is typically increased by stress. The neurobiological underpinnings of this exacerbation, however, remain elusive. We recently reported that spatial confinement (SC), a moderate environmental stressor, increases tic-like responses and elicits TS-like sensorimotor gating deficits in the D1CT-7 mouse, one of the best-validated models of TS. Here, we hypothesized that these adverse effects may be mediated by neurosteroids, given their well-documented role in stress-response orchestration. Indeed, SC increased the levels of progesterone, as well as its derivatives 5α-dihydroprogesterone and allopregnanolone, in the prefrontal cortex (PFC) of D1CT-7 mice. Among these steroids, however, only allopregnanolone (5-15 mg/kg, IP) dose-dependently exacerbated TS-like manifestations in D1CT-7, but not wild-type littermates; these effects were countered by the benchmark anti-tic therapy haloperidol (0.3 mg/kg, IP). Furthermore, the phenotypic effects of spatial confinement in D1CT-7 mice were suppressed by finasteride (25-50 mg/kg, IP), an inhibitor of the main rate-limiting enzyme in allopregnanolone synthesis. These findings collectively suggest that stress may exacerbate TS symptoms by promoting allopregnanolone synthesis in the PFC, and corroborate previous clinical results pointing to finasteride as a novel therapeutic avenue to curb symptom fluctuations in TS.

White wax (WW) has been traditionally used to treat hair loss in China. However there has been no reporter WW and its extract responsible for hair growth-promoting effect on androgenetic alopecia. In this paper, we examined the hair growth-promoting effects of WW and policosanol of white wax (WWP) on model animal of androgenetic alopecia and the potential target cell of WW and WWP. WW (1, 10 and 20%) and WWP (0.5, 1 and 2%) were applied topically to the backs of mice. Finasteride (2%) was applied topically as a positive control. MTS assays were performed to evaluate cell proliferation in culture human follicle dermal papilla cells (HFDPCs). The inhibition of WW and WWP for 5α- reductase were tested in Vitro. Results showed more lost hairs were clearly seen in mice treated with TP only and TP plus vehicle. Mice which received TP plus WW and WWP showed less hair loss. WW and WWP showed an outstanding hair growth-promoting activity as reflected by the follicular length, follicular density, A/T ratio, and hair bulb diameter. The optimal treatment effect was observed at 10% WW and 1% WWP, which were better than 2% finasteride treatment. MTS assay results suggested that WW and WWP remarkably increased the proliferation of HFDPCs. Inhibitor assay of 5α- reductase showed that WW and WWP inhibited significantly the conversion of testosterone to dihydrotesterone, and the IC 50 values of WW and WWP were higher than that of finasteride. In Conclusion, WW and WWP could act against testosterone-induced alopecia in mice, and they promoted hair growth by inhibiting 5α-reductase activity and HFDPCs proliferation. DPCs is the target cell of WW and WWP., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Objective: We determined the role of the neurosteroid-sensitive δ subunit-containing γ-aminobutyric acid A receptors (δ-GABARs) in epileptogenesis., Methods: Status epilepticus (SE) was induced via lithium pilocarpine in adult rats, and seizures were assessed by continuous video-electroencephalography (EEG) monitoring. Finasteride was administered to inhibit neurosteroid synthesis. The total and surface protein expression of hippocampal δ, α4, and γ2 GABAR subunits was studied using biotinylation assays and Western blotting. Neurosteroid potentiation of the tonic currents of dentate granule cells (DGCs) was measured by whole-cell patch-clamp technique. Finally, the effects of inhibiting N-methyl-d-aspartate receptors (NMDARs) during SE on the long-term plasticity of δ-GABARs, neurosteroid-induced modulation of tonic current, and epileptogenesis were studied., Results: The inhibition of neurosteroid synthesis 4 days after SE triggered acute seizures and accelerated the onset of chronic recurrent spontaneous seizures (epilepsy). The down-regulation of neurosteroid-sensitive δ-GABARs occurred prior to the onset of epilepsy, whereas an increased expression of the γ2-GABAR subunits occurred after seizure onset. MK801 blockade of NMDARs during SE preserved the expression of neurosteroid-sensitive δ-GABARs. NMDAR blockade during SE also prevented the onset of spontaneous seizures., Significance: Changes in neurosteroid-sensitive δ-GABAR expression correlated temporally with epileptogenesis. These findings raise the possibility that δ-GABAR plasticity may play a role in epileptogenesis., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

Previous studies by our group have shown that low intra-prostatic dihydrotestosterone (DHT) induced BPH epithelial cells (BECs) to recruit CD8+ T cells. However, the influence of the recruited CD8+ T cells on BECs under a low androgen level is still unknown. Here, we found CD8+ T cells have the capacity to promote proliferation of BECs in low androgen condition. Mechanism dissection revealed that interaction between CD8+ T cells and BECs through secretion of CCL5 might promote the phosphorylation of STAT5 and a higher expression of CCND1 in BECs. Suppressed CCL5/STAT5 signals via CCL5 neutralizing antibody or STAT5 inhibitor Pimozide led to reverse CD8+ T cell-enhanced BECs proliferation. IHC analysis from Finasteride treated patients showed PCNA expression in BECs was highly correlated to the level of CD8+ T cell infiltration and the expression of CCL5. Consequently, our data indicated infiltrating CD8+ T cells could promote the proliferation of BECs in low androgen condition via modulation of CCL5/STAT5/CCND1 signaling. The increased secretion of CCL5 from the CD8+ T cells/BECs interaction might help BECs survive in a low DHT environment. Targeting these signals may provide a new potential therapeutic approach to better treat BPH patients who failed the therapy of 5α-reductase inhibitors.

This study aimed to identify the role of mouse fibroblast-mediated c-Jun and IGF-1 signaling in the therapeutic effect of finasteride on benign prostatic epithelial cells. BPH-1 cells, alone or with fibroblasts (c-Jun+/+ or c-Jun-/-), were implanted subcutaneously in male nude mice who were then treated with finasteride. The degrees of cell proliferation, apoptosis, and sizes of the xenografts were determined. BPH-1 cells were grown alone or co-cultured with mouse fibroblasts in the presence of finasteride and the level of IGF-1 secreted into the medium by the fibroblasts was determined. The proliferation-associated signaling pathway in BPH-1 cells was also evaluated. Fibroblasts and c-Jun promoted xenograft growth, stimulated Ki-67 expression, and inhibited BPH-1 apoptosis. Finasteride did not induce the shrinkage of xenografts in the combined-grafted groups despite repressing Ki-67 expression and inducing cell apoptosis. The addition of c-Jun-/- fibroblasts did not promote xenograft growth. In the absence of c-Jun and fibroblasts, finasteride did not alter xenograft growth, Ki-67 expression, or cell apoptosis. The in vitro results demonstrated that when BPH-1 cells were grown in monoculture, treatment with finasteride did not induce cell death and stimulated the expression of pro-proliferative signaling molecules, while in the presence of fibroblasts containing c-Jun, finasteride treatment repressed epithelial cell proliferation, the level of IGF-1 in the medium, and the activation of downstream pro-proliferative signaling pathways. Taken together, our results suggest that fibroblasts, c-Jun, and IGF-1 play key roles in mediating stromal-epithelial interactions that are required for the therapeutic effects of finasteride in benign prostate epithelial cells., Competing Interests: The authors have declared that no competing interests exist.

Benign prostatic hyperplasia (BPH) is one of the most common chronic diseases in male population, of which incidence increases gradually with age. In this study, we investigated the effect of chrysophanic acid (CA) on BPH. BPH was induced by a 4-week injection of testosterone propionate (TP). Four weeks of further injection with vehicle, TP, TP + CA, TP + finasteride was carried on. In the CA treatment group, the prostate weight was reduced and the TP-induced histological changes were restored as the normal control group. CA treatment suppressed the TP-elevated prostate specific antigen (PSA) expression. In addition, 5α-reductase, a crucial factor in BPH development, was suppressed to the normal level close to the control group by CA treatment. The elevated expressions of androgen receptor (AR), estrogen receptor α and steroid receptor coactivator 1 by TP administration were also inhibited in the CA group when compared to the TP-induced BPH group. Then we evaluated the changes in three major factors of the mitogen-activated protein kinase chain during prostatic hyperplasia; extracellular signal-regulated kinase (ERK), c-Jun-N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38). While ERK was elevated in the process of BPH, JNK and p38 was not changed. This up-regulated ERK was also reduced as normal by CA treatment. Further in vitro studies with RWPE-1 cells confirmed TP-induced proliferation and elevated AR, PSA and p-ERK were all reduced by CA treatment. Overall, these results suggest a potential pharmaceutical feature of CA in the treatment of BPH.

Electrophysiological recordings were used to investigate the role of the local synthesis of 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT) on synaptic long-term effects induced in the hippocampal CA1 region of male rat slices. Long-term depression (LTD) and long-term potentiation (LTP), induced by different stimulation patterns, were examined under the block of the DHT synthesis by finasteride (FIN), and the E2 synthesis by letrozole (LET). We used low frequency stimulation (LFS) for LTD, high frequency stimulation (HFS) for LTP, and intermediate patterns differing in duration or frequency. We found that FIN reverted the LFS-LTD into LTP and enhanced LTP induced by intermediate and HFSs. These effects were abolished by exogenous DHT at concentration higher than the basal one, suggesting a stimulus dependent increase in DHT availability. No effect on the synaptic responses was observed giving DHT alone. Moreover, we found that the inhibition of E2 synthesis influenced the HFS-LTP by reducing its amplitude, and the exogenous E2 either enhanced HFS-LTP or reverted the LFS-LTD into LTP. The equivalence of the E2 concentration for rescuing the full HFS-LTP under LET and reverting the LFS-LTD into LTP suggests an enhancement of the endogenous E2 availability that is specifically driven by the HFS. No effect of FIN or LET was observed on the responses to stimuli that did not induce either LTD or LTP. This study provides evidence that the E2 and DHT availability combined with specific stimulation patterns is determinant for the sign and amplitude of the long-term effects., (© 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Objective: The inhibition of glycolysis exerts potent antiseizure effects, as demonstrated by the efficacy of ketogenic and low-glucose/nonketogenic diets in the treatment of drug-resistant epilepsy. ATP-sensitive potassium (K ATP ) channels have been initially identified as the main determinant of the reduction of neuronal hyperexcitability. However, a plethora of other mechanisms have been proposed. Herein, we report the ability of 2-deoxy-d-glucose (2-DG), a glucose analog that inhibits glycolytic enzymes, of potentiating γ-aminobutyric acid (GABA)ergic tonic inhibition via neurosteroid-mediated activation of extrasynaptic GABA A receptors., Methods: Acute effects of 2-DG on the ATP-sensitive potassium currents, GABAergic tonic inhibition, firing activity, and interictal events were assessed in hippocampal slices by whole-cell patch-clamp and local field potential recordings of dentate gyrus granule cells., Results: Acute application of 2-DG activates two distinct outward conductances: a K ATP channel-mediated current and a bicuculline-sensitive tonic current. The effect of 2-DG on such GABAergic tonic currents was fully prevented by either finasteride or PK11195, which are specific inhibitors of the neurosteroidogenesis pathway acting via different mechanisms. Moreover, the oxidized form of vitamin C, dehydroascorbic acid, known for its ability to induce neurosteroidogenesis, also activated a bicuculline-sensitive tonic current in a manner indistinguishable from that of 2-DG. Finally, we found that the enhancement of K ATP current by 2-DG primarily regulates intrinsic firing rate of granule cells, whereas the increase of the GABAergic tonic current plays a key role in reducing the frequency of interictal events evoked by treatment of hippocampal slices with the convulsive agent 4-aminopyridine., Significance: We demonstrated, for the first time, that 2-DG potentiates the extrasynaptic tonic GABAergic current through activation of neurosteroidogenesis. Such tonic inhibition represents the main conductance responsible for the antiseizure action of this glycolytic inhibitor., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

The enzyme 5α-reductase (5αR) catalyzes the conversion of progesterone and testosterone into neuroactive steroids implicated in a wide array of behavioral functions. The prototypical 5αR inhibitor, finasteride (FIN), is clinically approved for the treatment of androgenic alopecia and benign prostatic hyperplasia. Recent evidence has shown that FIN, albeit generally well tolerated, can induce untoward psychological effects in a subset of patients; furthermore, this drug may have therapeutic efficacy for a number of different neuropsychiatric conditions, ranging from Tourette syndrome to schizophrenia. In rat models of these conditions, FIN has been shown to block the effects of dopamine receptors in the nucleus accumbens (NAcc), a key terminal of the dopamine mesolimbic system. The biological underpinnings of these effects, however, remain mostly elusive. To elucidate the neurochemical networks that may be responsible for the behavioral effects of FIN, we evaluated the proteomic profile of the NAcc following acute (100mg/kg, IP) and subchronic (7 days; 100mg/kg/day, IP) treatment with this drug, in comparison with vehicle treatment (n=5/group). Two-dimensional electrophoresis (2-DE) analysis coupled to mass spectrometry revealed significant changes in the expression of nine proteins (CRMP2, PSMD1, STX18, KCNC3, CYP255, GABRP, GABT, PRPS1, CYP2B3), which were further analyzed by ontological classification (PANTHER). These results point to a number of novel potential chemical targets of FIN, and may help elucidate the underpinnings of FIN's behavioral effects and therapeutic potential for neuropsychiatric disorders., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Palatable food is a strong activator of the reward circuitry and may cause addictive behavior leading to eating disorders. How early life events and sex interact in shaping hedonic sensitivity to palatable food is largely unknown. We used prenatally restraint stressed (PRS) rats, which show abnormalities in the reward system and anxious/depressive-like behavior. Some of the hallmarks of PRS rats are known to be sex-dependent. We report that PRS enhanced and reduced milk chocolate-induced conditioned place preference in males and females, respectively. Male PRS rats also show increases in plasma dihydrotestosterone (DHT) levels and dopamine (DA) levels in the nucleus accumbens (NAc), and reductions in 5-hydroxytryptamine (5-HT) levels in the NAc and prefrontal cortex (PFC). In male rats, systemic treatment with the DHT-lowering drug finasteride reduced both milk chocolate preference and NAc DA levels. Female PRS rats showed lower plasma estradiol (E 2 ) levels and lower DA levels in the NAc, and 5-HT levels in the NAc and PFC. E 2 supplementation reversed the reduction in milk chocolate preference and PFC 5-HT levels. In the hypothalamus, PRS increased ERα and ERβ estrogen receptor and CARTP (cocaine-and-amphetamine receptor transcript peptide) mRNA levels in males, and 5-HT 2 C receptor mRNA levels in females. Changes were corrected by treatments with finasteride and E 2 , respectively. These new findings show that early life stress has a profound impact on hedonic sensitivity to high-palatable food via long-lasting changes in gonadal hormones. This paves the way to the development of hormonal strategies aimed at correcting abnormalities in the response to natural rewards., (© 2015 Society for the Study of Addiction.)

Context: Among the 4-azasteroids, finasteride is biologically the most important compound having preventive effect against male pattern baldness (MPH) and benign prostatic hyperplasia commonly called enlargement of prostate gland., Objective: The microbial transformation of finasteride by fungus Aspergillus niger (ATCC 10549) has been investigated to obtain biologically more potent derivatives., Materials and Methods: Fermentation of finasteride was performed with filamentous fungus Aspergillus niger (ATCC 10549). This transformation resulted in the production of two transformed products, which were purified through column chromatography. In vitro lipoxygenase inhibitory potential was determined by incubating 20 mL of the enzyme with 10 mL of test sample (100 μM) in 0.1 mM (pH 7.0) phosphate buffer for 5 min at 258 °C followed by addition of 10 μL of substrate (linolenic acid) to reaction mixture and measuring the formation of complex spectrophotometrically., Results: Structure elucidation of biotransformed metabolites was ascertained through extensive 1D and 2D spectroscopic techniques. This study established the fact that A. niger promoted stereospecific dihydroxylation at C-11 and C-15 of finasteride. The resulting biotransformed metabolites were characterized as 11α-hydroxyfinasteride and 15β-hydroxyfinasteride, respectively. Finasteride along with transformed metabolites were analyzed for their in vitro lipoxygenase (LOX) inhibition assay. Among the tested compounds 15β-hydroxyfinasteride showed good activity with IC 50 value 112.56 ± 2.23 μM while inhibitory effect in case of 11α-hydroxyfinasteride was low with IC 50 value 186.05 ± 1.34 μM. Standard compound baicalein revealed IC 50 value being 22.0 ± 0.05 μM., Conclusion: The present investigation highlighted the fact that potentially active compound can be produced through the technology of biotransformation.

In a large clinical trial, finasteride reduced the rate of low-grade prostate cancer (PCa) while increasing the incidence of high-grade cancer. Whether finasteride promotes the development of high-grade tumors remains controversial. We demonstrated the role of fibroblasts and c-Jun in chemopreventive and therapeutic effect of finasteride on xenograft models of PCa. LNCaP (PC3) cells or recombinants of cancer cells and fibroblasts were implanted in male athymic nude mice treated with finasteride. Tumor growth, cell proliferation, apoptosis, p-Akt, and p-ERK1/2 were evaluated. In LNCaP (PC3) mono-grafted models, finasteride did not change the tumor growth. In recombinant-grafted models, fibroblasts and c-Jun promoted tumor growth; finasteride induced proliferation of LNCaP cells and repressed PC3 cell apoptosis. When c-Jun was knocked out, fibroblasts and/or finasteride did not promote the tumor growth. Finasteride inhibited p-Akt and p-ERK1/2 in mono-culture cancer cells while stimulating the same signaling molecules in the presence of fibroblasts. Reduced p-Akt and p-ERK1/2 were noted in the presence of c-Jun-/- fibroblasts. Fibroblasts and c-Jun promote PCa growth; finasteride further stimulates tumor growth with promoted proliferation, repressed apoptosis, and up-regulated pro-proliferative molecular pathway in the presence of fibroblasts and c-Jun. Stromal-epithelial interactions play critical roles in finasteride's therapeutic effects on PCa. Our findings have preliminary implications in using finasteride as a chemopreventive or therapeutic agent for PCa patients.

Studies with rodents and humans show the relationship between female sex hormones and cognitive/emotional tasks. However, despite the greater incidence of anxiety disorders in women, the data are still inconclusive regarding the mechanisms related to this phenomenon. We evaluated the effects of a classical anxiolytic/amnestic drug (diazepam; DZP) on female (at different estrous cycle phases) and male rats tested in the plus-maze discriminative avoidance task (PMDAT), that allows the concomitant evaluation of memory and anxiety-like behavior. Further, in order to investigate the role of progesterone and its metabolites in the effects of DZP in the PMDAT, female rats were pre-treated with the progesterone receptor antagonist mifepristone or the 5-alpha-reductase inhibitor finasteride. The main findings were: (1) DZP caused memory impairment and anxiolysis in both sexes, but only the highest dose induced the anxiolytic effect in females; (2) females in proestrus did not present the amnestic and anxiolytic effects of DZP (at 2.0 and 4.0mg/kg, respectively) and (3) the co-administration of mifepristone reestablished both amnestic and anxiolytic effects of DZP, while finasteride reinstated the amnestic effect in proestrus female rats. These results suggest that changes in the endogenous levels of progesterone and its metabolites are important in the modulation of emotional/cognitive behavior in female rats. Based on the influence on different aspects of DZP action, the mechanisms related to this modulation are probably linked to GABAergic transmission, but this point remains to be investigated. Further, the variation in therapeutic and adverse effects of DZP depending on sex and hormonal state is of great relevance considering the higher prevalence of anxiety disorders in women., (Copyright © 2016 Elsevier Inc. All rights reserved.)

In this study, protective actions of the sex steroid hormones, progesterone, testosterone, and 17β-estradiol, against oxygen-glucose deprivation (OGD)/reoxygenation-induced neuronal cell death were examined using rat organotypic hippocampal slice cultures. Progesterone, testosterone, and 17β-estradiol significantly attenuated neuronal cell death elicited by OGD/reoxygenation. While the neuroprotection conferred by progesterone was not affected by SU-10603, an inhibitor of cytochrome P45017α, finasteride, a 5α-reductase inhibitor that blocks the conversion of progesterone to allopregnanolone, partially reversed the neuroprotection induced by progesterone. The progesterone metabolite, allopregnanolone attenuated neuronal injury induced by OGD/reoxygenation. Pretreatment with letrozole, a cytochrome P450 aromatase inhibitor or 4-hydroxyphenyl-1-naphthol, a 17β-hydroxysteroid dehydrogenase 2 inhibitor showed no effect on testosterone-mediated neuroprotection, while finasteride completely abolished the protective action of testosterone. Treatment with 5α-dihydrotestosterone significantly suppressed neuronal injury. Pretreatment with mifepristone, a progesterone receptor antagonist and hydroxyflutamid, an androgen receptor antagonist significantly diminished the neuroprotective effects of progesterone and testosterone, respectively. ICI182,780, an estrogen receptor antagonist, showed no effect on neuroprotection mediated by 17β-estradiol. Pretreatment with actinomycin D or cycloheximide clearly abolished the neuroprotective effects of progesterone and testosterone, while actinomycin D and cycloheximide did not show any effect on neuroprotection mediated by 17β-estradiol. Taken together, progesterone protects neurons via progesterone receptor-dependent genomic pathway, and allopregnanolone is involved in progesterone-mediated neuroprotection. Testosterone and its metabolite 5α-dihydrotestosterone protect neurons via the genomic pathway of the androgen receptor. Metabolism of sex steroid hormones in the brain might complicate their protective actions in the brain., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Androgenetic alopecia (AGA) is characterized by a non-scarring progressive miniaturization of the hair follicle in predisposed men and women with a pattern distribution. Although AGA is a very prevalent condition, approved therapeutic options are limited. This article discusses the current treatment alternatives including their efficacy, safety profile, and quality of evidence. Finasteride and minoxidil for male androgenetic alopecia and minoxidil for female androgenetic alopecia still are the therapeutic options with the highest level evidence. The role of antiandrogens for female patients, the importance of adjuvant therapies, as well as new drugs and procedures are also addressed.

Liver failure is associated with a neuropsychiatric syndrome, known as hepatic encephalopathy (HE). Finasteride, inhibitor of neurosteroid synthesis, may improve the course of HE. The aim of our study was to investigate the influence of finasteride on mean and relative power density of EEG bands, determined by spectral analysis, in rat model of thioacetamide-induced HE. Male Wistar rats were divided into groups: (1) control; (2) thioacetamide-treated group, TAA (900 mg/kg); (3) finasteride-treated group, FIN (150 mg/kg); and (4) group treated with finasteride (150 mg/kg) and thioacetamide (900 mg/kg), FIN + TAA. Daily doses of FIN (50 mg/kg) and TAA (300 mg/kg) were administered during 3 subsequent days, and in FIN + TAA group FIN was administered 2 h before every dose of TAA. EEG was recorded 22-24 h after treatment and analyzed by fast Fourier transformation. While TAA did not induce significant changes in the beta band, mean and relative power in this band were significantly higher in FIN + TAA versus control group (p < 0.01). TAA caused a significant decline in mean power in alpha, theta, and delta band, and in FIN + TAA group the mean power in these bands was significantly higher compared with control. While in TAA group relative power was significantly decreased in theta (p < 0.01) and increased in delta band (p < 0.01) versus control, the opposite changes were found in FIN + TAA group: an increase in theta (p < 0.01) and a decrease in delta relative power (p < 0.01). In this study, finasteride pretreatment caused EEG changes that correspond to mild TAA-induced HE.

Endogenous levels of the neurosteroid (NS) allopregnanolone (AlloP) during neonatal stages are crucial for the correct development of the central nervous system (CNS). In a recent work we reported that the neonatal administration of AlloP or finasteride (Finas), an inhibitor of the enzyme 5α-reductase needed for AlloP synthesis, altered the voluntary consumption of ethanol and the ventrostriatal dopamine (DA) levels in adulthood, suggesting that neonatal NS manipulations can increase alcohol abuse vulnerability in adulthood. Moreover, other authors have associated neonatal NS alterations with diverse dopaminergic (DAergic) alterations. Thus, the aim of the present work is to analyse if manipulations of neonatal AlloP alter the DAergic response in the nucleus accumbens (NAcc) during alcohol intake in rats. We administered AlloP or Finas from postnatal day (PND) 5 to PND9. At PND98, we measured alcohol consumption using a two-bottle free-choice model (ethanol 10% (v/v)+glucose 3% (w/v), and glucose 3% (w/v)) for 12 days. On the last day of consumption, we measured the DA and 3,4-dihydroxyphenylacetic acid (DOPAC) release in NAcc in response to ethanol intake. The samples were obtained by means of in vivo microdialysis in freely moving rats, and DA and DOPAC levels were determined by means of high-performance liquid chromatography analysis (HPLC). The results revealed that neonatal Finas increased ethanol consumption in some days of the consumption phase, and decreased the DA release in the NAcc in response to solutions (ethanol+glucose) and food presentation. Taken together, these results suggest that neonatal NS alterations can affect alcohol rewarding properties., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The elevated plus maze test showed that GD-23 (N-carbobenzoxy-L-tryptophanyl-L-isoleucine amide), an original dipeptide ligand of TSPO, exerted anxiolytic effect when injected intraperitoneally at a dose of 0.5 mg/kg. This effect was completely blocked by the selective neurosteroid synthesis inhibitors, enzymes trilostane and finasteride. The same inhibitors do not prevent the anxiolytic effects of the benzodiazepine tranquillizer diazepam. The results of the study indicate the selective neurosteroidogenic mechanism of the anxiolytic action of GD-23.

Human immunodeficiency virus (HIV) is associated with motor and mood disorders, likely influenced by reactive microgliosis and subsequent neural damage. We have recapitulated aspects of this pathology in mice that conditionally express the neurotoxic HIV-1 regulatory protein, trans-activator of transcription (Tat). Progestogens may attenuate Tat-related behavioral impairments and reduce neurotoxicity in vitro, perhaps via progesterone's 5α-reductase-dependent metabolism to the neuroprotective steroid, allopregnanolone. To test this, ovariectomized female mice that conditionally expressed (or did not express) central HIV-1 Tat were administered vehicle or progesterone (4mg/kg), with or without pretreatment of a 5α-reductase inhibitor (finasteride, 50mg/kg). Tat induction significantly increased anxiety-like behavior in an open field, elevated plus maze and a marble burying task concomitant with elevated protein oxidation in striatum. Progesterone administration attenuated anxiety-like effects in the open field and elevated plus maze, but not in conjunction with finasteride pretreatment. Progesterone also attenuated Tat-promoted protein oxidation in striatum, independent of finasteride pretreatment. Concurrent experiments in vitro revealed Tat (50nM)-mediated reductions in neuronal cell survival over 60h, as well as increased neuronal and microglial intracellular calcium, as assessed via fura-2 AM fluorescence. Co-treatment with allopregnanolone (100nM) attenuated neuronal death in time-lapse imaging and blocked the Tat-induced exacerbation of intracellular calcium in neurons and microglia. Lastly, neuronal-glial co-cultures were labeled for Iba-1 to reveal that Tat increased microglial numbers in vitro and co-treatment with allopregnanolone attenuated this effect. Together, these data support the notion that 5α-reduced pregnane steroids exert protection over the neurotoxic effects of HIV-1 Tat., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: In the Prostate Cancer Prevention Trial, finasteride selectively suppressed low-grade prostate cancer and significantly reduced the incidence of prostate cancer in men treated with finasteride compared with placebo. However, an apparent increase in high-grade disease was also observed among men randomized to finasteride. We aimed to determine why and hypothesized that there is a grade-dependent response to finasteride., Methods: From 2007 to 2012, we randomized dynamically by intranet-accessible software 183 men with localized prostate cancer to receive 5mg finasteride or placebo daily in a double-blind study during the 4-6weeks preceding prostatectomy. As the primary end point, the expression of a predefined molecular signature (ERβ, UBE2C, SRD5A2, and VEGF) differentiating high- and low-grade tumors in Gleason grade (GG) 3 areas of finasteride-exposed tumors from those in GG3 areas of placebo-exposed tumors, adjusted for Gleason score (GS) at prostatectomy, was compared. We also determined androgen receptor (AR) levels, Ki-67, and cleaved caspase 3 to evaluate the effects of finasteride on the expression of its downstream target, cell proliferation, and apoptosis, respectively. The expression of these markers was also compared across grades between and within treatment groups. Logistic regression was used to assess the expression of markers., Findings: We found that the predetermined molecular signature did not distinguish GG3 from GG4 areas in the placebo group. However, AR expression was significantly lower in the GG4 areas of the finasteride group than in those of the placebo group. Within the finasteride group, AR expression was also lower in GG4 than in GG3 areas, but not significantly. Expression of cleaved caspase 3 was significantly increased in both GG3 and GG4 areas in the finasteride group compared to the placebo group, although it was lower in GG4 than in GG3 areas in both groups., Interpretation: We showed that finasteride's effect on apoptosis and AR expression is tumor grade dependent after short-term intervention. This may explain finasteride's selective suppression of low-grade tumors observed in the PCPT., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

GABAA receptors containing α4 subunits are widely implicated in acute ethanol sensitivity, and their spatial and temporal regulation prominently contributes to ethanol-induced neuroplasticity in hippocampus and cortex. However, it is unknown if α4-containing GABAA receptors in the thalamus, an area of high α4 expression, display similar regulatory patterns following ethanol administration, and if so, by which molecular mechanisms. In the current study, thalamic GABAA receptor α4 subunit levels were increased following a 6-week-, but not a 2-week chronic ethanol diet. Following acute high-dose ethanol administration, thalamic GABAA receptor α4 subunit levels were regulated in a temporal fashion, as a decrease was observed at 2h followed by a delayed transient increase. PKCγ and PKCδ levels paralleled α4 temporal expression patterns following ethanol exposure. Initial decreases in α4 subunit expression were associated with reduced serine phosphorylation. Delayed increases in expression were not associated with a change in phosphorylation state, but were prevented by inhibiting neuroactive steroid production with the 5α-reductase inhibitor finasteride. Overall, these studies indicate that thalamic GABAA receptor α4 subunit expression following acute and chronic ethanol administration exhibits similar regulatory patterns as other regions and that transient expression patterns following acute exposure in vivo are likely dependent on both subunit phosphorylation state and neuroactive steroids., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Hormones locally synthesized in the anterior pituitary gland are involved in regulation of pituitary cell renewal. In the pituitary, testosterone (T) may exert its actions per se or by conversion to dihydrotestosterone (DHT) or 17β-estradiol (E2) by 5α-reductase and aromatase activity, which are expressed in this gland. Previous reports from our laboratory showed that estrogens modulate apoptosis of lactotropes and somatotropes from female rats. Now, we examined the in vitro and in vivo effects of gonadal steroids on apoptosis of anterior pituitary cells from adult male rats. T in vitro did not modify apoptosis in anterior pituitary cells from gonadectomized (GNX) male rats. DHT, a non-aromatizable androgen, exerted direct antiapoptotic action on total anterior pituitary cells and folliculo-stellate cells, but not on lactotropes, somatotropes, or gonadotropes. On the contrary, E2 exerted a rapid apoptotic effect on total cells as well as on lactotropes and somatotropes. Incubation of anterior pituitary cells with T in presence of Finasteride, an inhibitor of 5α-reductase, increased the percentage of TUNEL-positive cells. In vivo administration of DHT to GNX rats reduced apoptosis in the anterior pituitary whereas E2 exerted proapoptotic action and reduced cells in G2/M-phase of the cell cycle. In summary, our results indicate that DHT and E2 have opposite effects on apoptosis in the anterior pituitary gland suggesting that local metabolization of T to these steroids could be involved in pituitary cell turnover in males. Changes in expression and/or activity of 5α-reductase and aromatase may play a role in the development of anterior pituitary tumors.

In the present study, a series of steroidal tetrazole derivatives of androstane and pregnane have been prepared in which the tetrazole moiety was appended at C-3 and 17a-aza locations. 3-Tetrazolo-3,5-androstadien-17-one (6), 3-tetrazolo-19-nor-3,5-androstadien-17-one (10), 3-tetrazolo-3,5-pregnadien-20-one (14), 17a-substituted 3-tetrazolo-17a-aza-D-homo-3,5-androstadien-17-one (26-31) and 3-(2-acetyltetrazolo)-17a-aza-d-homo-3,5-androstadien-17-one (32) were synthesized from dehydroepiandrosterone acetate (1) through multiple synthetic steps. Some of the synthesized compounds were evaluated for their in vitro 5α-reductase (5AR) inhibitory activity by measuring the conversion of [(3)H] androstenedione in human embryonic kidney (HEK) cells. In vivo 5α-reductase inhibitory activity also showed a significant reduction (p <0.05) in rat prostate weight. The most potent compound 14 showed 5AR-2 inhibition with IC50 being 15.6nM as compared to clinically used drug finasteride (40nM). There was also a significant inhibition of 5AR-1 with IC50 547nM compared to finasteride (453nM)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Secretions of chloride (Cl(-))- and bicarbonate (HCO3(-))-rich fluid by the seminal vesicles could involve cystic fibrosis transmembrane regulator (CFTR), which activity can be stimulated by cAMP generated from the reaction involving adenylate cyclase (AC). In this study, we investigated levels of CFTR, AC, and cAMP in the seminal vesicles under testosterone influence. Orchidectomized adult male rats received 7-day treatment with 125 or 250 μg/kg/day of testosterone with or without flutamide or finasteride. At the end of the treatment, animals were sacrificed and seminal vesicles were harvested for analyses of CFTR and AC protein expression level by Western blotting. Distribution of CFTR and AC in seminal vesicles was observed by immunohistochemistry. Levels of cAMP and dihydrotestosterone in seminal vesicle homogenates were measured by ELISA. Cystic fibrosis transmembrane regulator, AC, and cAMP levels increased with increasing doses of testosterone (P < 0.05 compared to nontreated orchidectomized rats). Cystic fibrosis transmembrane regulator and AC were expressed at the apical membrane of the epithelium lining the seminal vesicle lumen with higher expression levels observed in testosterone-treated rats than in non-treated orchidectomized rats (P < 0.05). The inhibitory effects of flutamide or finasteride on these parameters were greater in 250 μg/kg/day testosterone-treated rats than their effects in 125 μg/kg/day testosterone-treated rats. Higher dihydrotestosterone levels were observed in seminal vesicle homogenates after treatment with 250 μg/kg/day than with 125 μg/kg/day of testosterone (P < 0.05). Increased levels of CFTR, AC, and cAMP in seminal vesicles might contribute toward an increase in Cl(-) and HCO3(-) concentrations in the seminal fluid as reported under testosterone influence., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Endogenous neurosteroids that potentiate the gamma-aminobutyric acid type A (GABAA ) receptor are thought to enhance the generation of sleep spindles. This study tested the hypothesis that the 5α-reductase inhibitor finasteride, an agent associated with reductions in neurosteroids, would be associated with reduced sleep spindles in men referred for polysomnography., Methods: Spectral analysis and spindle waveform detection were performed on electroencephalographic (EEG) sleep data in the 11-16 Hz sigma band, as well as several subranges, from 27 men taking finasteride and 27 matched comparison patients (ages 18 to 81 years)., Results: No significant differences between groups were observed for spectral power or sleep spindle morphology measures, including spindle density, amplitude, duration, and integrated spindle activity., Conclusions: Contrary to our hypothesis, these findings demonstrate that finasteride is not associated with alterations in sleep spindle range activity or spindle morphology parameters., (Copyright © 2015 John Wiley & Sons, Ltd.)

Context: 5α-Reductase 1 and 2 (SRD5A1, SRD5A2) inactivate cortisol to 5α-dihydrocortisol in addition to their role in the generation of DHT. Dutasteride (dual SRD5A1 and SRD5A2 inhibitor) and finasteride (selective SRD5A2 inhibitor) are commonly prescribed, but their potential metabolic effects have only recently been identified., Objective: Our objective was to provide a detailed assessment of the metabolic effects of SRD5A inhibition and in particular the impact on hepatic lipid metabolism., Design: We conducted a randomized study in 12 healthy male volunteers with detailed metabolic phenotyping performed before and after a 3-week treatment with finasteride (5 mg od) or dutasteride (0.5 mg od). Hepatic magnetic resonance spectroscopy (MRS) and two-step hyperinsulinemic euglycemic clamps incorporating stable isotopes with concomitant adipose tissue microdialysis were used to evaluate carbohydrate and lipid flux. Analysis of the serum metabolome was performed using ultra-HPLC-mass spectrometry., Setting: The study was performed in the Wellcome Trust Clinical Research Facility, Queen Elizabeth Hospital, Birmingham, United Kingdom., Main Outcome Measure: Incorporation of hepatic lipid was measured with MRS., Results: Dutasteride, not finasteride, increased hepatic insulin resistance. Intrahepatic lipid increased on MRS after dutasteride treatment and was associated with increased rates of de novo lipogenesis. Adipose tissue lipid mobilization was decreased by dutasteride. Analysis of the serum metabolome demonstrated that in the fasted state, dutasteride had a significant effect on lipid metabolism., Conclusions: Dual-SRD5A inhibition with dutasteride is associated with increased intrahepatic lipid accumulation.

Neurosteroids exert diverse modulatory actions on dopamine neurotransmission and signaling. We previously documented that the enzyme 5α-reductase, which catalyzes the main rate-limiting step in neurosteroid synthesis, is required for the behavioral responses of Sprague-Dawley rats to non-selective dopaminergic agonists, such as the D1-D2 receptor agonist apomorphine. Specifically, systemic and intra-accumbal administrations of the 5α-reductase inhibitor finasteride countered apomorphine-induced deficits of sensorimotor gating, as measured by the prepulse inhibition (PPI) of the startle reflex; the classes of dopamine receptors involved in these effects, however, remain unknown. Prior rodent studies have revealed that the contributions of dopamine receptors to PPI regulation vary depending on the genetic background; thus, we analyzed the effect of finasteride on the PPI deficits induced by selective dopamine receptor agonists in Long-Evans (a strain exhibiting PPI deficits in response to both D1 and D2 receptor agonists) and Sprague-Dawley rats (which display PPI reductions following treatment with D2, and D3, but not D1 receptor agonists). In Long-Evans rats, finasteride opposed the PPI deficits induced by activation of D1, but not D2 receptors; conversely, in Sprague-Dawley rats, finasteride prevented the reductions in %PPI and accumbal dopamine extracellular levels caused by selective stimulation of D3, but not D2 receptors; however, the effects on %PPI were not confirmed by analyses on absolute PPI values. Our findings suggest that 5α-reductase modulates the effects of D1, but not D2 receptor agonists on sensorimotor gating. These data may help elucidate the role of neurosteroids in neuropsychiatric disorders featuring PPI deficits, including schizophrenia and Tourette syndrome., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background/aims: Bidens pilosa L. (Bp) is widely distributed in China and has been widely used as a traditional Chinese medicine. The aim of this study was to examine the effect of the extract of Bp on androgen deficiency dry eye and determine its possible mechanisms., Methods: Twenty-four rats were randomly divided into four groups: Group Con (control), Group Sal (physiological saline), Group Fin (oral finasteride), and Group Bp (oral finasteride and Bp). The dry eye model was established in group Fin and group Bp. Aqueous tear quantity was measured with phenol red-impregnated cotton threads with anesthesia. Tear film breakup time (BUT) and corneal epithelial damage were evaluated by fluorescein staining. Animals were sacrificed at 28 days, and ocular tissues (lacrimal gland and cornea) were evaluated with light microscopy; gene microarray analysis for inflammatory cytokines and Western blot were also performed., Results: Finasteride administration effectively induced dry eye in rats by 14 days after administration. Group Fin rats had significantly higher fluorescein staining scores and lower aqueous tear quantity and BUT than the group Con rats, and notable inflammatory cell infiltrates were observed in the lacrimal gland of group Fin rats. The fluorescein staining score, aqueous tear quantity and BUT significantly improved with Bp treatment in the group Bp rats, and the structures of the lacrimal gland were well maintained without significant lymphocyte infiltration. Cytokine antibody array data identified the cytokines B7-2/Cd86, IL-1β, IL-4, IL-6, IL-10, MMP-8, FasL, TNF-α and TIMP-1 as candidates for validation by Western blot. Expression levels of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α, in group Fin were upregulated compared with group Con. Levels of anti-inflammatory cytokines, such as IL-4 and IL-10, in group Fin were also upregulated compared with those in group Con. Compared with group Fin, IL-1β, FasL, and TNF-α were significantly decreased in group Bp., Conclusion: The extract of Bp appears to be effective for the treatment of androgen deficiency dry eye in rats by improving aqueous tear quantity, maintaining tear film stability, and inhibiting the inflammation of the lacrimal gland., (© 2016 The Author(s) Published by S. Karger AG, Basel.)

The enzymatic conversion of progesterone and testosterone by the enzyme 5alpha-reductase exerts a crucial role in the control of nervous function. The effects of finasteride in the brain, an inhibitor of this enzyme used for the treatment of human benign prostatic hyperplasia and androgenic alopecia, have been poorly explored. Therefore, the effects of a subchronic treatment with finasteride at low doses (3 mg/kg/day) and the consequences of its withdrawal on neuroactive steroid levels in plasma, cerebrospinal fluid and some brain regions as well as on the expression of classical and non-classical steroid receptors have been evaluated in male rats. After subchronic treatment (i.e., for 20 days) the following effects were detected: (i) depending on the compartment considered, alteration in the levels of neuroactive steroids, not only in 5alpha-reduced metabolites but also in its precursors and in neuroactive steroids from other steroidogenic pathways and (ii) an upregulation of the androgen receptor in the cerebral cortex and beta3 subunit of the GABA-A receptor in the cerebellum. One month after the last treatment (i.e., withdrawal period), some of these effects persisted (i.e., the upregulation of the androgen receptor in the cerebral cortex, an increase of dihydroprogesterone in the cerebellum, a decrease of dihydrotestosterone in plasma). Moreover, other changes in neuroactive steroid levels, steroid receptors (i.e., an upregulation of the estrogen receptor alpha and a downregulation of the estrogen receptor beta in the cerebral cortex) and GABA-A receptor subunits (i.e., a decrease of alpha 4 and beta 3 mRNA levels in the cerebral cortex) were detected. These findings suggest that finasteride treatment may have broad consequences for brain function., (© 2015 S. Karger AG, Basel.)

Background: Cogent evidence has shown that schizophrenia vulnerability is enhanced by psychosocial stress in adolescence, yet the underpinnings of this phenomenon remain elusive. One of the animal models that best capture the relationship between juvenile stress and schizophrenia is isolation rearing (IR). This manipulation, which consists in subjecting rats to social isolation from weaning through adulthood, results in neurobehavioral alterations akin to those observed in schizophrenia patients. In particular, IR-subjected rats display a marked reduction of the prepulse inhibition (PPI) of the startle reflex, which are posited to reflect imbalances in dopamine neurotransmission in the nucleus accumbens (NAcc). We recently documented that the key neurosteroidogenic enzyme 5α-reductase (5αR) plays an important role in the dopaminergic regulation of PPI; given that IR leads to a marked down-regulation of this enzyme in the NAcc, the present study was designed to further elucidate the functional role of 5αR in the regulation of PPI of IR-subjected rats., Methods: We studied the impact of the prototypical 5αR inhibitor finasteride (FIN) on the PPI deficits and NAcc steroid profile of IR-subjected male rats, in comparison with socially reared (SR) controls., Results: FIN (25-100 mg/kg, i.p.) dose-dependently countered IR-induced PPI reduction, without affecting gating integrity in SR rats. The NAcc and striatum of IR-subjected rats displayed several changes in neuroactive steroid profile, including a reduction in pregnenolone in both SR and IR-subjected groups, as well as a decrease in allopregnanolone content in the latter group; both effects were significantly opposed by FIN., Conclusions: These results show that 5αR inhibition counters the PPI deficits induced by IR, possibly through limbic changes in pregnenolone and/or allopregnanolone concentrations., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Finasteride and Dutasteride are 5α-reductase inhibitors used in the clinic to treat endocrine conditions and were recently found to modulate brain dopamine (DA) neurotransmission and motor behavior. We investigated if Finasteride and Dutasteride have a neuroprotective effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) male mice as a model of Parkinson's disease (PD). Experimental groups included saline treated controls and mice treated with saline, Finasteride (5 and 12.5 mg/kg) or Dutasteride (5 and 12.5 mg/kg) for 5 days before and 5 days after MPTP administration (4 MPTP injections, 6.5 mg/kg on day 5 inducing a moderate DA depletion) and then they were euthanized. MPTP administration decreased striatal DA contents measured by HPLC while serotonin contents remained unchanged. MPTP mice treated with Dutasteride 5 and 12.5 mg/kg had higher striatal DA and metabolites (DOPAC and HVA) contents with a decrease of metabolites/DA ratios compared to saline-treated MPTP mice. Finasteride had no protective effect on striatal DA contents. Tyrosine hydroxylase (TH) mRNA levels measured by in situ hybridization in the substantia nigra pars compacta were unchanged. Dutasteride at 12.5 mg/kg reduced the effect of MPTP on specific binding to striatal DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) measured by autoradiography. MPTP reduced compared to controls plasma testosterone (T) and dihydrotestosterone (DHT) concentrations measured by liquid chromatography-tandem mass spectrometry; Dutasteride and Finasteride increased plasma T levels while DHT levels remained low. In summary, our results showed that a 5α-reductase inhibitor, Dutasteride has neuroprotective activity preventing in male mice the MPTP-induced loss of several dopaminergic markers., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Prostate cancer is associated to a reactive stroma microenvironment characterized by angiogenic processes that are favorable for tumor progression. Senescence has been identified as a predisposing factor for prostate malignancies. In turn, the relationships between aging, reactive stroma, and the mechanisms that induce this phenotype are largely unknown. Thus, we investigated the occurrence of reactive stroma in the mouse prostate during advanced age as well as the effects of antiangiogenic and androgen ablation therapies on reactive stroma recruitment., Methods: Male mice (52-week-old FVB) were treated with two classes of angiogenesis inhibitors: direct (TNP-470; 15 mg/kg; s.c.) and/or indirect (SU5416; 6 mg/kg; i.p.). Androgen ablation was carried out by finasteride administration (20 mg/kg; s.c.), alone or in association to both inhibitors. The Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model was used as a paradigm of cancer-associated reactive stroma. The dorsolateral prostate was collected for α-actin (αSMA), vimentin (VIM), and transforming growth factor-beta (TGF-β) immunohistochemical and Western blotting analyses as well as for CD34/αSMA and CD34/VIM colocalization., Results: Senescence was associated with increased αSMA, VIM, and TGF-β expression as well as with the recruitment of CD34/αSMA and CD34/VIM dual-positive fibroblasts. These observations were similar to those verified in TRAMP mice. Antiangiogenic treatment promoted the recovery of senescence-associated stromal changes. Hormonal ablation, despite having led to impaired CD34/αSMA and CD34/VIM dual-positive cell recruitment, did not result in decreased stimulus to reactive stroma development, due to enhanced TGF-β expression in relation to the aged controls., Conclusions: Reactive stroma develops in the prostate of non-transgenic mice as a result of aging. The periacinar microvasculature is a candidate source for the recruitment of reactive stroma-associated cells, which may be derived either from perivascular-resident mesenchymal stem cells (MSCs) or from an endothelial-to-mesenchymal transition (EndMT) process. Thus, antiangiogenic therapy is a promising approach for preventing age-associated prostate malignancies by means of its negative interference in the development of reactive stroma phenotype from the vascular wall., (© 2015 Wiley Periodicals, Inc.)

Finasteride (FIN) inhibits neurosteroid synthesis and potentially improves the course of hepatic encephalopathy (HE). This study aimed to investigate the effects of FIN on brain oxidative stress and acetylcholinesterase (AchE) activity in acute thioacetamide-induced HE in rats. Male Wistar rats were divided into groups: 1. control; 2. thioacetamide-treated group (TAA; 900 mg/kg); 3. finasteride-treated group (FIN; 150 mg/kg); 4. group treated with FIN and TAA (FIN+TAA). Daily doses of FIN (50 mg/kg) and TAA (300 mg/kg) were administered intraperitoneally during three days and in FIN+TAA group FIN was administered 2h before every dose of TAA. FIN pretreatment prevented TAA-induced rise in malondialdehyde level in the cortex due to restoration of catalase activity and increased expression of superoxide dismutase 1 (SOD1) and induced an increase in malondialdehyde level in the thalamus due to reduction of glutathione peroxidase (GPx) and glutathione reductase (GR) activity. Although FIN pretreatment did not affect malondialdehyde level in hippocampus and caudate nucleus, hippocampal SOD1 expression was higher (p<0.05) and GR activity lower in FIN+TAA vs. TAA group (p<0.05). GPx activity was lower in caudate nucleus in FIN+TAA vs. TAA group (p<0.01). FIN pretreatment prevented TAA-induced rise in AchE activity in the thalamus and caudate nucleus and AchE activity correlates inversely in the thalamus (p<0.05) and positively in caudate nucleus (p<0.01) with malondialdehyde level. FIN has regionally selective effects on oxidative stress and AchE activity in the brain in acute TAA-induced HE in rats. The prooxidant role of FIN in the thalamus may be causally linked with inhibition of AchE.

Glucocorticoids and androgens have both been implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD); androgen deficiency in males, androgen excess in females, and glucocorticoid excess in both sexes are associated with NAFLD. Glucocorticoid and androgen action are regulated at a prereceptor level by the enzyme 5α-reductase type 2 (SRD5A2), which inactivates glucocorticoids to their dihydrometabolites and converts T to DHT. We have therefore explored the role of androgens and glucocorticoids and their metabolism by SRD5A2 upon lipid homeostasis in human hepatocytes. In both primary human hepatocytes and human hepatoma cell lines, glucocorticoids decreased de novo lipogenesis in a dose-dependent manner. Whereas androgen treatment (T and DHT) increased lipogenesis in cell lines and in primary cultures of human hepatocytes from female donors, it was without effect in primary hepatocyte cultures from men. SRD5A2 overexpression reduced the effects of cortisol to suppress lipogenesis and this effect was lost following transfection with an inactive mutant construct. Conversely, pharmacological inhibition using the 5α-reductase inhibitors finasteride and dutasteride augmented cortisol action. We have demonstrated that manipulation of SRD5A2 activity can regulate lipogenesis in human hepatocytes in vitro. This may have significant clinical implications for those patients prescribed 5α-reductase inhibitors, in particular augmenting the actions of glucocorticoids to modulate hepatic lipid flux.

Unlabelled: The literature reveals evidence for a gender specific outcome after major trauma and hemorrhage. Increased levels of male sex hormones such as testosterone and even more dihydrotestosterone (DHT) mediate negative effects on the posttraumatic immune response. Pretreatment with finasteride several days before trauma hemorrhage (TH) led to improved outcomes in mice. We hypothesized that finasteride mediates its protective effects also when administered after TH within the resuscitation process., Methods: Male C57BL/6N-mice underwent TH (blood pressure: 35 mmHg, 90 min) followed by finasteride application and fluid resuscitation. Plasma cytokines (MIP-1β, TNF-α, MCP-1, MCP-3, IL-6), productive capacity of alveolar macrophages (AM) and hepatic Kupffer cells (KC) and systemic DHT levels were determined 4 h and 24 h thereafter. Pulmonary and hepatic infiltration of PMN was determined by immunohistochemical staining., Results: Finasteride treatment resulted in reduced levels of systemic cytokines. This was accompanied by a reduced posttraumatic cytokine secretion of AM as well as Kupffer cells, thereby reducing hepatic distant organ damage as measured by reduced PMN infiltration. Systemic DHT levels were decreased following finasteride treatment., Conclusion: Finasteride exerts salutary effects on the pulmonary and hepatic immune response using a therapeutic approach following TH in mice. Therefore, finasteride might represent a potential agent following multiple trauma and hemorrhage., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Vascular endothelial growth factor (VEGF) plays a critical role in the pathogenesis of diabetic microvascular complications. Finasteride has been confirmed to decrease VEGF expression in prostate and prostatic suburethral tissue resulting in limiting hematuria from human benign prostatic hyperplasia. The purpose of this study was to evaluate the effects of finasteride on microvessel density (MVD), VEGF protein and mRNA expressions in the renal tissue of diabetic rats., Methods: Diabetic rats induced by streptozotocin were intragastrically given finasteride at 30 mg/kg body weight once a day for 4 weeks. Histomorphologic changes in kidney were observed under light microscope. Immunohistochemistry for CD34 and VEGF on kidney sections was performed to assess MVD and VEGF protein expression in glomeruli of rats, respectively. The VEGF mRNA expression in the renal tissue was examined using reverse transcription polymerase chain reaction analysis., Results: The glomerular tuft area, glomerular volume, MVD, VEGF protein expression in glomeruli and VEGF mRNA expression in the renal cortex tissue were significantly increased in diabetic rats and finasteride-treated rats when compared with controls (P < 0.01, P < 0.05). When compared with diabetic rats, the glomerular tuft area, glomerular volume, MVD, VEGF protein expression in glomeruli and VEGF mRNA expression in the renal cortex tissue of finasteride-treated rats were significantly decreased (P < 0.05, P < 0.01)., Conclusions: Finasteride reduces the VEGF expression and decreases the MVD in the renal tissue of diabetic rats, suggesting the therapeutic potential of finasteride on diabetic microvascular complications.