Enzyme 5α-reductase Research Articles

A qualitative and quantitative analysis of polyphenolic compounds in five Epilobium spp. with a possible potential to alleviate benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is a widespread male disease, affecting more than 50 % of men over the age of 60 years. Inhibition of the enzyme 5α-reductase is a common treatment strategy for this condition. Such potential can be found in willow flowers (Epilobium spp.), which are known in folk medicine for treating of prostate ailments, mainly benign prostatitis, hypertrophy and prostatitis. Smallflower hairy willowherb (E. parviflorum), which is rare, is the most recommended for treating BPH. The aim. The aim of the study was to investigate the qualitative and quantitative content of polyphenols in five Epilobium species (E. adenocaulon Hausskn., E. hirsutum L., E. montanum L., E. parviflorum Schreb. and E. palustre L.) growing in Estonia, to find the most promising species in terms of chemical composition to alleviate BPH. Materials and Methods. The qualitative and quantitative analyses of polyphenols in herbs of Epilobium spp. were performed using HPLC/MS. All five species were collected from the pond's shore in Pilkuse village (Otepää municipality, Valga county, Estonia) in July 2008. Research results. It was found that 20 % ethanol was optimal for extracting polyphenolic compounds from the herb Epilobium spp. with subsequent UV chromatogram analysis at 350 nm. In the analyzed Epilobium species, 12 polyphenolic compounds were identified. Oenothein B, myricetin rhamnoside and myricetin glucoside were the principal polyphenolic compounds among other identified constituents in the Epilobium spp. herbs. E. montanum had the highest content of oenothein B. The highest was the total content of myricetin glycosides for all five compared species, the total content of quercetin glycosides was slightly lower, and the total content of kaempferol glycosides was the lowest. Conclusions. The content of polyphenols is highest in E. adenocaulon and the lowest in E. parviflorum. Thus, E. parviflorum does not offer the best therapeutic potential for the to relief of BPH in terms of the quantitative content of polyphenolic compounds

Sex hormone supplementation improves breathing and restores respiratory neuroplasticity following C2 hemisection in rats.

In addition to loss of sensory and motor function below the level of the lesion, traumatic spinal cord injury (SCI) may reduce circulating steroid hormones that are necessary for maintaining normal physiological function for extended time periods. For men, who comprise nearly 80% of new SCI cases each year, testosterone is the most abundant circulating sex steroid. SCI often results in significantly reduced testosterone production and may result in chronic low testosterone levels. Testosterone plays a role in respiratory function and the expression of respiratory neuroplasticity. When testosterone levels are low, young adult male rats are unable to express phrenic long-term facilitation (pLTF), an inducible form of respiratory neuroplasticity invoked by acute, intermittent hypoxia (AIH). However, testosterone replacement can restore this respiratory neuroplasticity. Complicating the interpretation of this finding is that testosterone may exert its influence in three possible ways: 1) directly through androgen receptor (AR) activation, 2) through conversion to dihydrotestosterone (DHT) by way of the enzyme 5α-reductase, or 3) through conversion to 17β-estradiol (E2) by way of the enzyme aromatase. DHT signals via AR activation similar to testosterone, but with higher affinity, while E2 activates local estrogen receptors. Evidence to date supports the idea that exogenous testosterone supplementation exerts its influence through estrogen receptor signaling under conditions of low circulating testosterone. Here we explored both recovery of breathing function (measured with whole body barometric plethysmography) and the expression of AIH-induced pLTF in male rats following C2-hemisection SCI. One week post injury, rats were supplemented with either E2 or DHT for 7days. We hypothesized that E2 would enhance ventilation and reveal pLTF following AIH in SCI rats. To our surprise, though E2 did beneficially impact overall breathing recovery following C2-hemisection, both E2 supplementation and DHT restored the expression of AIH-induced pLTF 2weeks post-SCI.

Steroidogenic activity and morphological characterization of prenatal testes and epididymis of guinea pig (Cavia porcellus)

The present study aims to establish the morphological, morphometric, and immunostaining patterns of the steroidogenic enzymes 17β-HSD and 5α-reductase and androgen receptors (AR) during the prenatal development of the male gonad and epididymis of Cavia porcellus. Fetuses at 22, 25, 30, 40, 45, 50, and 60 days of gestation (DG) were used. Specimens were dissected and subjected to macroscopic, histological, histomorphometric, and immunohistochemical analyses. Genital and scrotal protrusions were identified in 22 DG embryos. Gonocytes were identified at 25 DG and the formation of primary testicular cords was observed at 30 DG. Through anatomical evaluation, we observed differentiation of the epididymis into the head, body, and tail at 45 DG. During development, there is a progressive decrease in the diameters of the testicular cords and epididymal ducts. 17β-HSD enzyme immunostaining was observed in Leydig cells at all ages, while 5α-reductase was observed in Leydig cell cytoplasm and gonocytes at 40, 50, and 60 DG. AR shows gonocyte labeling at 30 DG. Thus, from the second trimester of pregnancy, it is possible to observe patterns of anatomical development, such as genital and scrotal prominence (22 DG), the appearance of gonocytes in the testicular cords at 25 DG, and the beginning of the organization of primary testicular cords at 30 DG, suggesting sexual differentiation. The 17β-HSD, 5α-reductase, and ARs play an essential role in sexual development and differentiation, presenting immunostaining at different reproductive process times.

Morphohistometric and steroidogenic parameters during testicular and epididymal differentiation in cavy (Galea spixii) fetuses

Sexual differentiation and steroidogenic mechanisms have an important impact on postnatal gonadal phenotypic development. Thus, establishing the activities that lead to male phenotypic development can provide a better understanding of this process. This study examined the prenatal development of cavies to establish morphological and histometric development patterns and protein and enzyme immunolocalization processes that are responsible for androgen synthesis in the testes and epididymis. Histological and histometric analyses of the diameter of the seminiferous cords and epididymal ducts of male fetuses on Days 25, 30, 40, and 50 were performed, as well as immunohistochemistry of the steroidogenic enzymes 5α-reductase and 17β-HSD, the androgen receptor, and the anti-Müllerian hormone (AMH). Our findings showed a cellular grouping of gonocytes from Day 30 onward that was characteristic of the seminiferous cord, which was not present in the lumen at any of the studied dates. From Day 50 onward, the differentiation of the three anatomical regions of the epididymis was evident, the head (caput), body (corpus), and tail (cauda), with tissue distinctions. Furthermore, the diameters of the seminiferous cords and epididymal ducts significantly increased with age. On Day 50, the tail showed the greatest diameter of the three regions. The Sertoli and Leydig cells exhibited AMH immunoreactivity at all dates. In addition, the Leydig cells and epididymal epithelial tissue were immunopositive for 5α-reductase, 17β-HSD, and the androgen receptor; therefore, these factors influenced the development and maintenance of the testis and epididymis during cavy prenatal development.

Exploring rat corpus cavernosum alterations induced by finasteride treatment and withdrawal.

Despite its efficacy for treating androgenetic alopecia, finasteride, an inhibitor of 5α-reductase (i.e., the enzyme converting testosterone, T, into dihydrotestosterone, DHT), is associated with several side effects including sexual dysfunction (e.g., erectile dysfunction). These side effects may persist after drug suspension, inducing the so-called post-finasteride syndrome (PFS). The effects of subchronic treatment with finasteride (i.e., 20 days) and its withdrawal (i.e., 1 month) in rat corpus cavernosum have been explored here. Data obtained show that the treatment was able to decrease the levels of the enzyme 5α-reductase type II in the rat corpus cavernosum with increased T and decreased DHT levels. This local change in T metabolism was linked to mechanisms associated with erectile dysfunction. Indeed, by targeted metabolomics, we reported a decrease in the nitric oxide synthase (NOS) activity, measured by the citrulline/arginine ratio and confirmed by the decrease in NO2 levels, and a decrease in ornithine transcarbamylase (OTC) activity, measured by citrulline/ornithine ratio. Interestingly, the T levels are negatively correlated with NOS activity, while those of DHT are positively correlated with OTC activity. Finasteride treatment also induced alterations in the levels of other molecules involved in the control of penile erection, such as norepinephrine and its metabolite, epinephrine. Indeed, plasma levels of norepinephrine and epinephrine were significantly increased and decreased, respectively, suggesting an impairment of these mediators. Interestingly, these modifications were restored by suspension of the drug. Altogether, the results reported here indicate that finasteride treatment, but not its withdrawal, affects T metabolism in the rat corpus cavernosum, and this alteration was linked to mechanisms associated with erectile dysfunction. Data here reported could also suggest that the PFS sexual side effects are more related to dysfunction in a sexual central control rather than peripheral compromised condition.

(009) Testosterone Management in Women with Hypoactive Sexual Desire Disorder Who Have Reduced 5α-Reductase Activity: A Unique Population

Abstract Introduction According to the Global Consensus Position Statement on the Use of Testosterone Therapy for Women, testosterone can significantly improve desire in menopausal women with hypoactive sexual desire disorder. Based on safety and efficacy of different formulations, the recommended treatment is 1/10th of a man’s dose, using a government approved topical testosterone gel or solution, or AndroFeme which is approved for use in menopausal women in Australia. There are, however, a subset of women without significant improvement in desire with this dose who experience improvement using higher doses of testosterone. These women have low or lower tertile dihydrotestosterone blood test values despite their total testosterone being above normal range or even in the upper tertile. The enzyme 5α-reductase converts testosterone to the more active form, dihydrotestosterone, that has a higher affinity for the androgen receptor than testosterone. 5α-reductase activity varies in different individuals. It is postulated that there are menopausal women with HSDD who have reduced 5α- reductase activity and therefore require a higher dose of testosterone from the gel or solution, or need a different testosterone formulation to realize clinical benefit. This subset of women do not appear to experience the usual adverse side effects of elevated testosterone (acne, thinning scalp hair, facial hair, aggressive behavior), in part because of low levels of dihydrotestosterone. Objectives This study examines the efficacy and safety of higher doses of testosterone using products government approved for men. Methods This is a retrospective chart review of menopausal women who were provided menopause management at our clinic focusing on women for whom 1/10th of a man’s dose of gel or solution did not provide symptom relief. Options included increasing the dose of gel or solution, or administration of an alternative delivery system of FDA approved (for men) testosterone including insertion of one or two 75 mg testosterone pellets (Testopel) or weekly intramuscular injection of testosterone cypionate (100 mg/ml – 0.1 ml or 10 mg). Results A total of 11 women (mean age 58 +/− 6 years) failed the usual 1/10th dose of topical testosterone gel for treatment of HSDD. Using testosterone pellet therapy, with 1-2 pellets implanted every 4-6 months, 6 patients had excellent desire as well as energy and self-confidence; 4 patients had excellent clinical response to weekly IM testosterone administration; 1 had improved symptoms by increasing the gel to 1 tube/4 days. While these treatments resulted in systemic levels of total testosterone outside the normal range for women (100 – 200 ng/dl), dihydrotestosterone values remained low or in the lower tertile (mean value 36 +/− 8 ng/dl; normal range 30 – 80 ng/dl). In general, side effects to be expected with higher doses of testosterone were not experienced despite elevated testosterone values. No patient complained of side effects consistent with excess testosterone other than mild facial hair. Conclusions In some women with reduced 5α-reductase activity, higher testosterone levels result in improved quality of life without expected negative side effects from higher physiologic levels of testosterone. Disclosure No.

Sex and seasonal differences in neural steroid sensitivity predict territorial aggression in Siberian hamsters

Many animals display marked changes in physiology and behavior on a seasonal timescale, including non-reproductive social behaviors (e.g., aggression). Previous studies from our lab suggest that the pineal hormone melatonin acts via steroid hormones to regulate seasonal aggression in Siberian hamsters (Phodopus sungorus), a species in which both males and females display increased non-breeding aggression. The neural actions of melatonin on steroids and aggressive behavior, however, are relatively unexplored. Here, we housed male and female hamsters in long-day photoperiods (LDs, characteristic of breeding season) or short-day photoperiods (SDs, characteristic of non-breeding season) and administered timed melatonin (M) or control injections. Following 10 weeks of treatment, we quantified aggressive behavior and neural steroid sensitivity by measuring the relative mRNA expression of two steroidogenic enzymes (aromatase and 5α-reductase 3) and estrogen receptor 1 in brain regions associated with aggression or reproduction [medial preoptic area (MPOA), anterior hypothalamus (AH), arcuate nucleus (ARC), and periaqueductal gray (PAG)] via quantitative PCR. Although LD-M and SD males and females displayed increased aggression and similar changes in gene expression in the ARC, there were sex-specific effects of treatment with melatonin and SDs on gene expression in the MPOA, AH, and PAG. Furthermore, males and females exhibited different relationships between neural gene expression and aggression in response to melatonin and SDs. Collectively, these findings support a role for melatonin in regulating seasonal variation in neural steroid sensitivity and aggression and reveal how distinct neuroendocrine responses may modulate a similar behavioral phenotype in male and female hamsters.

Biochemical and Histopathological evaluation of prostatic tissue under effect of Pterostilbene in benign prostatic hyperplasia rat model

Background: Benign prostatic hyperplasia [BPH] is the urologic condition that affects elderly men the most frequently Benign prostatic hyperplasia. Benign prostatic hyperplasia must be distinguished from
 lower urinary tract symptoms and benign prostatic enlargement. which refers to an enlarged prostate, benign prostatic hyperplasia is a purely histological term the development, maintenance, and secretory activity of the prostate and other sex-accessory tissues are stimulated by the presence of certain hormones and growth factors. the pathophysiology of Benign prostatic hyperplasia is significantly influenced by the activity of the enzyme 5α-reductase. It's important to remember that 5-αreductase is responsible for creating Dihydrotestosterone a stronger androgen. Pterostilbene Mostly found in blueberries and grapes and pterostilbene substance with a number of biological properties including anticancer properties. pterostilbene is a lipid-soluble molecule that exists in both cis and trans forms with the latter being more prevalent. The conventional medication for Benign prostatic hyperplasia utilized in this trial was finasteride which inhibits the 5α-reductase enzyme and lowers the amount of Dihydrotestosterone.
 Methods: Forty-eight male rats were divided into six groups; the control group consisted of eight rats who received subcutaneous injections of oil vehicle for a period of 42 days. The induction group consisted of eight rats who received subcutaneous injections of testosterone propionate for a period of fourteen days. The finasteride group consisted of eight rats who received finasteride 0.44 mg/kg by oral gavage for a period of twenty-eight days following the induction of Benign prostatic hyperplasia and Pterostilbene 200 group included 8 rats were given pterostilbene 200mg/kg by oral gavage for 28 days after 14 days of Benign prostatic hyperplasia induction. pterostilbene 100 group included 8 rats were given a pterostilbene 100mg/kg per day kg by oral gavage for 28 days after 14 days of induction Benign prostatic hyperplasia dose and the resveratrol group included 8 rats were given a resveratrol 100mg/kg per day kg by oral gavage for 28 days after 14 days of induction Benign prostatic hyperplasia After twenty-eight days.
 Results: Histological section of prostate Pterostilbene 200 were similar those in control negative revealed numerous variable sizes alveoli that filled with homogenous eosinophilic secretion, had normal epithelial and stromal tissue.
 Conclusion: Pterostilbene have a potent anti-proliferative effect by decrease the hyperplastic nodules for prostate and return epithelial cell to normal and have a very good scavenging activity for free radical [very good as antioxidant] in compare with Vitamin c and resveratrol.
 Aim of study: evaluate the effect of Pterostilbene as Anti proliferative on Benign prostatic hyperplasia and assess the antioxidant activity for Pterostilbene by DPPH Assay.

Overexpression of SRD5A3 in Hepatocellular Carcinoma and Its Molecular Mechanism: A Study of Bioinformatics Exploration Analysis with Experimental Verification

Background Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and more prevalent among males than females. However, the biological role of enzyme 5α-reductase (SRD5A3), which plays a critical role in the androgen receptor signaling pathway during HCC development, remains poorly understood. Methods ONCOMINE, GEPIA, UALCAN, and Kaplan–Meier Plotter were used to analyze the expression and prognostic value of SRD5A3 in HCC. STRING and Metascape were applied to analyze potential target and molecular pathways underlying SRD5A3 in HCC. A real-time quantitative reverse transcription-polymerase chain reaction was used to validate the downstream target expression of SRD5A3. Results The expression of SRD5A3 was significantly overexpressed in HCC tissues compared with normal tissues, while the expression of SRD5A1 and SRD5A2 were downregulated in multiple public datasets. It may be that the low methylation of the SRD5A3 promoter leads to its overexpression. The level of SRD5A3 tended to be higher expressed in clinical samples with advanced stage and positive node metastasis. Furthermore, the patients with higher SRD5A3 were remarkably associated with poorer overall survival and disease-free survival in the TCGA data. In addition, the increased mRNA expression of SRD5A3 could predict poorer overall survival in Kaplan–Meier Plotter database including different patient cohorts. Moreover, HCC patients with higher level of SRD5A3 had significantly shorter recurrence-free survival, progression-free survival, and disease-specific survival. Furthermore, enrichment analysis demonstrated that multiple processes, such as steroid hormone biosynthesis, lipid biosynthetic process, and androgen metabolic process, were affected by SRD5A1-3 alterations. In vitro experiments showed that the expression of SRD5A3 was increased in HCC tissues than that in adjacent tissues. SRD5A3 silencing promoted the expression of DOLK in two HCC cell lines. Conclusions This study identified SRD5A3/DOLK as a novel axis to regulate HCC development.

Pathogenesis of Androgenetic Alopecia

The pathogenesis of androgenetic alopecia (AGA) is a complex interplay of genetic, hormonal, and environmental factors. In scalp follicles of susceptible individuals, androgens promote miniaturization of hair and shorten hair growth in the anagen stage, ultimately leading to AGA. The major circulating androgen, testosterone, is converted to the more potent androgen dihydrotestosterone by the enzyme 5α-reductase (5αR). Androgen receptors (ARs) and 5αR are significantly more in balding scalp hair follicles than those from nonbalding follicles. Genetic predisposition plays a crucial role in AGA. Various genetic loci including AR gene and the ectodysplasin A2 receptor (EDA2R) (AR/EDA2R locus in Xq11-q12) have been strongly implicated. The basic pathology of AGA is progressive miniaturization of the terminal hair follicles and eventual conversion of terminal hair to vellus hair. The duration of the anagen phase diminishes progressively with each cycle, while the length of telogen phase remains constant or may be prolonged. This eventually results in a reduction of the anagen to telogen ratio. With each successive shortening of hair cycle, the length of each hair shaft is reduced, and it becomes too short for the growing hair to attain even the minimum length required to reach the skin surface, resulting in an empty follicular pore. Hair follicle miniaturization leads to conversion of terminal hairs into secondary vellus hairs. Although many mechanisms have been proposed, the actual mechanism of hair miniaturization has not yet been fully elucidated. This article attempts to collate the existing information regarding the pathogenesis of AGA.

Hydrogen Peroxide Stimulates Dihydrotestosterone Release in C2C12 Myotubes: A New Perspective for Exercise-Related Muscle Steroidogenesis?

Skeletal muscle is a tissue that has recently been recognized for its ability to produce androgens under physiological conditions. The steroidogenesis process is known to be negatively influenced by reactive oxygen species (ROS) in reproductive Leydig and ovary cells, while their effect on muscle steroidogenesis is still an unexplored field. Muscle cells are continuously exposed to ROS, resulting from both their metabolic activity and the surrounding environment. Interestingly, the regulation of signaling pathways, induced by mild ROS levels, plays an important role in muscle fiber adaptation to exercise, in a process that also elicits a significant modulation in the hormonal response. The aim of the present study was to investigate whether ROS could influence steroidogenesis in skeletal muscle cells by evaluating the release of testosterone (T) and dihydrotestosterone (DHT), as well as the evaluation of the relative expression of the key steroidogenic enzymes 5α-reductase, 3β-hydroxysteroid dehydrogenase (HSD), 17β-HSD, and aromatase. C2C12 mouse myotubes were exposed to a non-cytotoxic concentration of hydrogen peroxide (H2O2), a condition intended to reproduce, in vitro, one of the main stimuli linked to the process of homeostasis and adaptation induced by exercise in skeletal muscle. Moreover, the influence of tadalafil (TAD), a phosphodiesterase 5 inhibitor (PDE5i) originally used to treat erectile dysfunction but often misused among athletes as a “performance-enhancing” drug, was evaluated in a single treatment or in combination with H2O2. Our data showed that a mild hydrogen peroxide exposure induced the release of DHT, but not T, and modulated the expression of the enzymes involved in steroidogenesis, while TAD treatment significantly reduced the H2O2-induced DHT release. This study adds a new piece of information about the adaptive skeletal muscle cell response to an oxidative environment, revealing that hydrogen peroxide plays an important role in activating muscle steroidogenesis.

Expression of dihydrotestosterone synthases and androgen receptor in sheep oviduct ampulla and its regulation by estradiol and progesterone

Oviduct ampulla plays an important role in steroid hormone-regulated sperm-oocyte binding in female animals. Although studies have shown that androgen receptor are expressed in many species oviduct, the interaction among androgen receptor (AR), estradiol (E2) and progesterone (P4) in the sheep oviduct have rarely been reported. In this study, we evaluated the localization of two isoforms of dihydrotestosterone (DHT) sythetase enzymes 5α-reductase (5α‐red1, 5α‐red2) and AR in sheep oviduct ampulla by immunohistochemistry and immunofluorescence. Results showed that they were all distributed in oviduct epithelium layer. In epithelial cells, 5α‐red1, 5α‐red2 were expressed in cytoplast and nuclear, but AR were stained in nuclear. We also investigated their expression pattern in the sheep oviduct ampulla at different development stages of follicles (Large follicles stage; hemorrhagium, luteum and albicans of corpus stage) by molecular experiments. We found that 5α‐red1, 5α‐red2 and AR mRNA abundance and protein were expressed highest in corpus albicans stage and lowest in corpus hemorrhagium stage. In vitro, when sheep oviduct ampulla epithelial cells (SOAECs) were cultured and treated with different concentrations of E2/P4 (10−9–10−6 M), we found that E2 inhibited the expression of AR mRNA and protein, while P4 promoted this expression. In addition, when the SOAECs were treated with E2 (10−8 M) and/or its non-selective inhibitor ICI182780 (10−7 M) as well as with P4 (10−6 M) and/or its non-specific inhibitor RU486 (10−5 M), we found that E2 and P4 inhibited and promoted the expression of AR mRNA and proteins, respectively, via their nuclear receptor pathways. This study provides a basic insight for the further research of oviduct epithelium physiological function closely related to androgen.

Petroleum-derived naphthenic acids disrupt hormone-dependent sexual behaviours in male Western clawed frogs.

Naphthenic acids (NAs), the carboxylic acids found in petroleum, are of emerging concern as they contaminate coastlines after oil spills, leech into freshwater ecosystems of oil sands areas and have wide industrial applications. They are acutely toxic in fish and tadpoles and may be endocrine disruptors at sublethal levels. We characterized androgen-dependent courtship behaviours and their disruption by NAs in male Western clawed frogs, Silurana tropicalis. Courtship primarily consists of males producing low trills and achieving amplexus, a mating position where a male clasps a female. Adult males were exposed for 5days to 20mg/l NA and injected with human chorionic gonadotropin to induce calling. The duration of calling activity was significantly reduced by NA exposure. Other acoustic parameters such as dominant frequency, click rate and trill length were not affected. Vocalization and amplexus were both inhibited after NA exposure and restored after 2weeks of recovery in clean water. To determine possible disruption at the level of the testes, the effects of NA exposure on gene expression of key players in steroidogenesis was determined. Exposure to NAs decreased srd5a on average by ~ 25%. The enzyme 5α-reductase, encoded by srd5a, converts testosterone to its more bioactive form 5α-dihydrotestosterone (DHT), so NAs may be affecting this steroidogenic step. However, the observed upregulation of lhr, star and cyp17a1 suggests that NA-exposed males may be attempting to counteract the reduced potential to produce DHT. Yet, these NA-exposed frogs have dramatically reduced calling duration, so the observed upregulation of star and cyp17a1 is decoupled from the vocalizations. Calling duration and the ability of males to amplex females is reversibly disrupted by NA exposure, implying that environmental reduction and removal of NAs may help improve habitability of contaminated ecosystems.

Synthesis and Actions of 5α-Reduced Metabolites of Testosterone in the Nervous System

Neuroactive testosterone metabolites synthesized by enzymes 5α-reductase and 3α/3β-hydroxysteroid oxidoreductase are critical physiological modulators of the central nervous system (CNS) function. Indeed, as discussed in this review, they exert a variety of effects on myelination, brain maturation, neurotransmission, reproductive behavior, and the stress responses. The expression and synthesis of these enzymes as well as the levels of testosterone derivatives exhibit specific localized regional and sex differences in the CNS and are influenced under various physiological and neuropathological conditions. In addition, neuroactive metabolites of testosterone exert a variety of neuroprotective effects in several neuropathological animal models. Therefore, neuroactive testosterone metabolites might represent an interesting potential therapeutic option to treat some neurological disorders.

Treatment of Benign Prostatic Hyperplasia by Natural Drugs.

Benign prostatic hyperplasia (BPH) is one of the most common urinary diseases affecting men, generally after the age of 50. The prevalence of this multifactorial disease increases with age. With aging, the plasma level of testosterone decreases, as well as the testosterone/estrogen ratio, resulting in increased estrogen activity, which may facilitate the hyperplasia of the prostate cells. Another theory focuses on dihydrotestosterone (DHT) and the activity of the enzyme 5α-reductase, which converts testosterone to DHT. In older men, the activity of this enzyme increases, leading to a decreased testosterone/DHT ratio. DHT may promote prostate cell growth, resulting in hyperplasia. Some medicinal plants and their compounds act by modulating this enzyme, and have the above-mentioned targets. This review focuses on herbal drugs that are most widely used in the treatment of BPH, including pumpkin seed, willow herb, tomato, maritime pine bark, Pygeum africanum bark, rye pollen, saw palmetto fruit, and nettle root, highlighting the latest results of preclinical and clinical studies, as well as safety issues. In addition, the pharmaceutical care and other therapeutic options of BPH, including pharmacotherapy and surgical options, are discussed, summarizing and comparing the advantages and disadvantages of each therapy.

Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians.

Centenarians have a decreased susceptibility to ageing-associated illnesses, chronic inflammation and infectious diseases1-3. Here we show that centenarians have a distinct gut microbiome that is enriched in microorganisms that are capable of generating unique secondary bile acids, including various isoforms of lithocholic acid (LCA): iso-, 3-oxo-, allo-, 3-oxoallo- and isoallolithocholic acid. Among these bile acids, the biosynthetic pathway for isoalloLCA had not been described previously. By screening 68 bacterial isolates from the faecal microbiota of a centenarian, we identified Odoribacteraceae strains as effective producers of isoalloLCA both in vitro and in vivo. Furthermore, we found that the enzymes 5α-reductase (5AR) and 3β-hydroxysteroid dehydrogenase (3β-HSDH) were responsible for the production of isoalloLCA. IsoalloLCA exerted potent antimicrobial effects against Gram-positive (but not Gram-negative) multidrug-resistant pathogens, including Clostridioides difficile and Enterococcus faecium. These findings suggest that the metabolism of specific bile acids may be involved in reducing the risk of infection with pathobionts, thereby potentially contributing to the maintenance of intestinal homeostasis.

Inhibitory Activities of Dimeric Ellagitannins Isolated from Cornus alba on Benign Prostatic Hypertrophy.

Benign prostatic hypertrophy (BPH) is an intractable chronic inflammatory disease. We studied the efficacy of two ellagitannins, namely camptothin B (1) and cornusiin A (2) that were isolated from Cornus alba (CA) for the treatment of BPH, which is a common health issue in older men. The ellagitannins (1 and 2) were evaluated on its inhibitory activities of the enzyme 5α-reductase and tumor necrosis factor (TNF)-α, its interleukin (IL)-1β, IL-6, and IL-8 production, and its anti-proliferation and apoptosis induction in prostate cells that show hypertrophy (RWPE-1 cell). In inhibition of 5α-reductase, the ellagitannins (1 and 2) showed potential effects, compared to the positive control, finasteride. In the case of IL-1β, IL-6, IL-8, and TNF-α, 1 and 2 showed good inhibitory effects as compared to the control group treated with LPS. The ellagitannins (1 and 2) were also shown to inhibit proliferation of, and induce apoptosis in, the RWPE-1 cell. These results suggest that the ellagitannins (1 and 2) may be good candidates for the treatment of BPH.

A preliminary study on the mechanism of the neurosteroid-mediated ionotropic receptor dysfunction in neurodevelopmental toxicity induced by decabromodiphenyl ether

The mechanism of neurodevelopmental toxicity of decabromodiphenyl ether (BDE209) remains unclear. Recent evidence suggests that neurosteroids disorders play a vital role in BDE209 induced-neurodevelopmental toxicity. To explore the mechanism of it, pregnant ICR mice were orally gavaged with 0, 225, and 900 mg kg−1 BDE209 for about 42 days. Spatial learning and memory abilities of offspring were tested on postnatal day (PND) 21. Offspring were euthanized at PND26, the neuronal structure, neurosteroids level, and related proteins including neurosteroids synthase, ionotropic receptors and cAMP-response element binding protein (CREB) pathway were evaluated, as well as Ca2+ concentration and the mitochondrial membrane potential (Mmp). Our results showed that BDE209 impaired learning and memory abilities and disrupted neuronal structure. Meanwhile, BDE209 decreased the pregnenolone (PREG), dehydroepiandrosterone (DHEA), progesterone (PROG) and allopregnanolone (ALLO) levels in the serum and brain, as well as the mRNA and protein levels of cholesterol-side-chain cleavage enzyme (P450scc), steroid 17α-hy-droxylase (P450C17), 3β-hydroxysteroid dehydrogenase (3β-HSD) and steroid 5α-reductase of type I (5α-R) in the hippocampi. Also, BDE209 suppressed mRNA and protein levels of NR1, NR2A and NR2B subunits of the N-methyl-D-aspartic acid receptor (NMDAR) and α1 subunit of the Gamma-amino butyric acid A receptor (GABAAR), but increased the levels of β2 and γ2 subunits of the GABAAR in the hippocampi. Moreover, BDE209 increased the Ca2+ concentration and phosphorylation extracellular regulated protein kinases (P-ERK) 1/2 level, but decreased the P-CREB and Mmp level in the hippocampi. These results indicate that BDE209 exposure during pregnancy and lactation is possible to affect learning and memory formation of offspring by the neurosteroid-mediated ionotropic receptors dysfunction.

Steroidogenesis during prenatal testicular development in Spix's cavy Galea spixii.

Spix's cavy is a potentially good experimental model for research on reproductive biology and sexual development. The aim of the present study was to evaluate the ontogeny of the steroidogenic enzymes involved in testicular androgen synthesis during prenatal development. Testes were investigated on Days 25, 30, 40 and >50 of gestation. Immunohistochemistry and immunoblotting were used to establish the site and relative amount of androgenic enzymes, including 5α-reductase, cytosolic 17β-hydroxysteroid dehydrogenase (17β-HSDI) and mitochondrial microsomal 3β-hydroxysteroid dehydrogenase (3β-HSDII), throughout prenatal development. The testicular parenchyma began to organise on Day 25 of gestation, with the development of recognisable testicular cords. The mesonephros was established after Day 25 of gestation and the ducts differentiated to form the epididymis, as testicular cords were beginning to proliferate and the interstitium to organise by Day 30 of gestation, continuing thereafter. The androgen-synthesising enzymes 5α-reductase, 17β-HSDI and 3β-HSDII were evident in Leydig cells as they differentiated at all subsequent gestational ages studied. In addition, immunoblotting showed an increase in immunoreactivity for the enzymes at Days 30 and 40 of gestation (P<0.05) and a decrease at Day 50 of gestation (P<0.05). It is concluded that the increase in androgenic enzymes in Leydig cells coincides with the functional differentiation of the testes, and with the stabilisation and differentiation of mesonephric ducts forming the epididymis.

Dihydrotestosterone Induces Proliferation, Migration, and Invasion of Human Glioblastoma Cell Lines.

IntroductionGlioblastomas (GBM) are the most frequent and aggressive human brain tumors due to their high capacity to migrate, invade healthy brain tissue, and resist anticancer therapies. It has been reported that testosterone (T) levels are higher in patients with GBM than in healthy controls. It has also been dem{}onstrated that T induces proliferation, migration, and invasion of human GBM cell lines. T is mainly metabolized to 5α-dihydrotestosterone (DHT) by the enzyme 5α-reductase (5αR), but the role of this metabolite in GBM cells is unknown.MethodsThe expression of 5αR isoenzymes and AR in biopsies of GBMs was determined by the analysis of TCGA. U87 and U251 GBM cell lines were grown in supplemented DMEM. For evaluating the expression of AR in U251 and U87 cells, a RT-qPCR was performed. The cells were treated with T, DHT, finasteride (FIN), dutasteride (D), and the combined treatments, FIN+T and D+T or vehicle. After treatments, the viability was quantified by the trypan blue exclusion assay, the proliferation was evaluated by BrdU incorporation, and migration and invasion were analyzed by the scratch-wound and the transwell assays, respectively.ResultsIn a set of glioma biopsies from TCGA, we observed that SRD5A2 (5αR2) expression was higher in GBM and in low-grade gliomas than in normal brain tissue. We observed that DHT and T increased proliferation, migration, and invasion of human GBM cell lines: U87 and U251. F and D, drugs that inhibit 5αR activity, blocked the effects of T on GBM cells.DiscussionThese data suggest that T induces human GBM progression through its conversion into DHT. These results can be related to the chemical structure of DHT, which increases its affinity for AR and decreases five times the rate of dissociation compared to T. Also, it is possible that DHT mediates the effects of T on cell human GBM cells motility by changing the expression of genes involved in tumor infiltration.