5α-reductase Activity Research Articles

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.

Steroid Metabolism in Children and Adolescents With Obesity and Insulin Resistance: Altered SRD5A and 20α/20βHSD Activity.

Alterations in glucocorticoid metabolism may contribute to the development of obesity and insulin resistance (IR). Obesity in turn affects the androgen balance. The peripheral metabolism of steroids is equally an important determinant of their bioavailability and activity. The aim of this study was to evaluate steroid metabolism in obese children and to define which enzyme alterations are associated with IR. Clinical characteristics and anthropometric measurements were determined in 122 obese children and adolescents (72 girls, 50 boys) aged 8 – 18 years. 26 of them (21.3%) were diagnosed with IR (13 boys, 13 girls). Routine laboratory tests were performed and 24h urinary steroid excretion profiles were analyzed by gas chromatography/mass spectrometry. Positive relationship between 5α-reductase (SRD5A) activity and IR was found. According to the androsterone to etiocholanolone (An/Et) ratio the activity of SRD5A was significantly increased in obese children with IR, but the difference remained insignificant once the 5α-dihydrotestosterone to testosterone (5αDHT/T) ratio was considered. Furthermore, this relationship persisted in boys but was not observed in girls. The activity of 20α-hydroxysteroid dehydrogenase (20αHSD) and 20β-hydroxysteroid dehydrogenase (20βHSD) was reduced only in obese girls with IR. Conclude, in the context of obese children and adolescents with IR, we surmise that increased SRD5A represents a compensatory mechanism to reduce local glucocorticoid availability. This phenomenon is probably different in the liver (restriction) and in the adipose tissue (expected increase in activity). We show significant changes in 20αHSD and 20βHSD activity in obese girls with IR, but it is difficult to clearly determine whether the activity of these enzymes is an indicator of the function in their ovaries or adrenal glands.

Synthesis, in silico, and in vivo anti-inflammatory evaluation of 3β-cinnamoyloxy substituted pregna-4,16-diene-6,20-diones derivatives

Pregnane derivatives have been studied mainly for their 5α-reductase activity. However, the anti-inflammatory activities of such compounds are still poorly explored. In the search for new anti-inflammatory agents, seven new pregnane derivatives 6a-g, with cinnamic acid esters at C-3 were prepared and fully characterized. The anti-inflammatory activity of compounds was assessed in TPA induced mice ear model. From them, compound 6 b was the most active to reduce edema, with an ED50 of 0.017 mg/ear. Also, Molecular Docking and Molecular Dynamics studies were performed to identify a potential molecular target related to the inflammatory process. The in vivo results suggest that 6 b could be a potent anti-inflammatory compound, while in silico studies suggest its interaction with some critical enzymes in the inflammatory response.

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.

Chemical characterization and 5α-reductase inhibitory activity of phenolic compounds in goji berries

Lycium fruits have a high content of phenolics as bioactive constituents with various pharmacological effects, but there is a lack of comparative analysis and chemical profiling of phenolics in Lycium fruit varieties. An ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MSE) combined with chemometrics was developed to characterize the phenolics in fruits from four Lycium species, including Lycium barbarum L. (LBL), L. chinense Mill. (LCM), L. barbarum var. auranticarpum (LBA) and L. ruthenicun Murr. (LRM). 63 phenolics were identified according to reported tandem mass fragmentation patterns and the UNIFI scientific informatics platform. Nine phenolics (5, 18, 20, 29, 31, 37, 41, 43, 60) were common and predominant components among four types of Lycium fruit. The partial least squares discriminant analysis (PLS-DA) and the orthogonal partial least squares discriminant analysis (OPLS-DA) were analyzed on the basis of a matrix created from 653 sets of data, and 20 Lycium fruits were classified into four groups. Further analysis identified that phenolics profiles were characteristic for each Lycium species, and five markers (13, 29, 31, 35, 99) could be utilized for fruit identification. Subsequently, inhibitory activity against 5α-reductase of phenolic extracts of Lycium fruits showed that LBL extract was the relative better effective, followed by LCM, whereas LBA and LRM showed no activity, which might be associated with the high contents of marker compounds (29, 31, 35, 43, 71, 99) in LBL. These findings will provide guidance for the development of Lycium phenolics with beneficial properties for the prevention and treatment of Benign prostatic hyperplasia (BPH).

PROSTATOPROTECTIVE EFFECT OF MACLURA POMIFERA OIL EXTRACT AND THE WAY IT IS IMPLEMENTED

Relevance. In the experiment, it was shown that in rats with a sulpiride induced prostate hyperplasia (SGP) which was treated by the Maclura Pomifera oil extract (OEM), a prostatic index is normalized, biochemical indicators and morphofunctional state of the prostate are improved. However, the mechanism of implementing corrective influence remains unknown. Objective: to exam the contribution of hormonally mediated signaling pathways of the mechanism of pharmacological effect of oil extract in the form of rectal suppositories at the experimental hyperplasia of the prostate in rats. Materials and methods. On 60 rats of both sexes, acute toxicity of the active substance was studied with intragastric administration of OEM (dose on the active substance 5000 mg/kg, n = 12) or suppositories mass with OEM (dose for the active substance of 1500 mg/kg, n = 12). Under rectal administration, toxicity was investigated with the introduction of OEM (dose of the active substance 1000 mg/kg, n = 12) or suppositories mass with OEM (dose for the active substance 300 mg/kg, n = 12). A group of intact control amounted to 12 rats. The SGP model was created in rats (age 9-11 months, body mass 330-360 g, n = 18) by sulpiride (40 mg / kg, i.p., 30 days). The rats of the control group (n = 6) were obtained with 0.5 ml of 0.9% NaCl, i.m. From 31 to 51 days of the experiment, rats in the therapeutic mode were treated with OEM suppositories (380 mg/kg, n = 12) or a reference drag Prostaplant Forte (35 mg/kg, n = 6) once a day. The testosterone (Tc) and E2 content, level 5α-dihydrotestosterone (5α-DHT) were determined by the immunoferment method in serum. In the prostate homogenate, the content of 5α-reductase (5αR) was studied, as well as the concentration of androgenic (AR) and estrogenic (Erα) receptors. Results. Toxic influence on the internal organs and deaths of animals after the introduction of the maximum possible amounts of OEM was not observed. The use of suppositories with OEM in rats with SGP normalized the content of sex hormones. Significant inhibition of 5αR activity and a decrease in the content of AR, as well as an increase in the content of ERα, were detected. The group with the introduction of the Prostaplant forte was observed similar improvements. It was assumed that the implementation of the antiproliferative effect of the MEM is carried out due to the coexpression of the ERα and ERβ, which leads to the blocking of the ERα ability to react to the ligand (estrogen) and to a decrease in cell proliferation. Conclusions. 1. Extract of Maclura refers to the ІV class of toxicity with intragastric and rectal administration (low-toxic substances). 2. The use of suppositories with OEM in rats with SGPH normalizes the functional activity of the prostate, which is confirmed by the normalization of the content of sex hormones. 3. Extract of Maclura in the prostate cells inhibits 5α-reductase activity, reduces androgen receptors and the testosterone ratio/androgen receptors as the same to drugs with 5α-reductase inhibition action. 4. Phytosuppositories with OEM in a dose of 380 mg/kg do not inferior on the efficiency of the prostatoprotective action of the referens drag Prostaplant forte in a dose of 35 mg/kg.

Metabolism of testosterone during weight loss in men with obesity

ObjectiveMen with obesity often have low total and, with increasing adiposity, also low free testosterone (T) levels, which can partially restore during weight loss. Although this is partly explained by lower sex hormone binding globulin (SHBG) production and hypothalamic-pituitary downregulation, it is still not unravelled whether changes in androgen metabolism contribute to this phenomenon. Therefore, early changes in urinary excretion of T and its metabolites, during weight loss, in men with obesity are investigated. DesignLongitudinal study. MethodsFourteen men with obesity (age 52(45–60)years, BMI 42.6(41.8–44.8)kg/m²) underwent gastric bypass surgery (GBS). Before surgery and 3 weeks, 6 weeks, 6 months and 1 year thereafter, 24 h urine and fasting serum samples were collected. Serum T and estradiol (E2) levels were analyzed using LC-MS/MS and urinary metabolites of T with GC-MS/MS. ResultsAlready three weeks after GBS, serum SHBG and total T levels increased and remained increased as compared to baseline (all,p < 0.0125). Gonadotropins and (free) E2 levels were unchanged, serum E2/T ratio decreased (p < 0.0125). Total amount of urinary T increased non-significantly with mean increases of 53 % one year after GBS (p = 0.026). Urinary E2/T, estrone/T, 3α-androstanediol/T and androsterone/T ratios decreased after GBS (p < 0.0125). ConclusionsRestoration of circulating T levels during weight loss in this population is not only brought about by normalization of circulating SHBG levels, but increased production of and alterations in T metabolism also contribute. More specifically, relative decreases in aromatization and lower 5α-reductase activity might also be involved in restoring T levels in men with obesity.

Estrogenic and antiandrogenic activities of methoxyflavans isolated from the fruit of Mauritia Flexuosa (Moriche Palm).

Moriche palm is consumed as both a fresh fruit and processed food in Peru and Brazil. Although its fruit contains phytoestrogens, the active compounds have not yet been identified. Therefore, we purified moriche palm extract (MPE) and identified compounds exhibiting estrogenic and antiandrogenic activities. Estrogenic activity was assessed by the estrogen-dependent growth of MCF-7 cells and increases in uterine weights in mice. Antiandrogenic activity was evaluated by 5α-reductase inhibitory activity and prostate-specific antigen (PSA) expression in LNCaP cells. In vivo antiestrogenic activity was also assessed based on testosterone-induced prostate growth in castrated mice. Four methoxyflavans were isolated from MPE and all, except for 7,4'-dihydroxy-5-methoxyflavan, promoted MCF-7 cell growth, indicating estrogenic activity. Uterine and ovary weights increased in mice orally administered MPE (400mg/kg) for 2weeks. Regarding antiandrogenic activity, among the four methoxyflavans isolated, 6,7,4'-trihydroxy-5-methoxyflavan (1 µg/ml) suppressed the mRNA and protein expression of PSA in LNCaP cells. Furthermore, prostate growth was suppressed in mice orally administered MPE (200mg/kg) for 2weeks. All methoxyflavans inhibited 5α-reductase activity with IC50 less than 10 µg/ml. Collectively, the present results demonstrated that orally administered MPE exhibited estrogenic and antiandrogenic activities. Methoxyflavans, particularly 6,7,4'-trihydroxy-5-methoxyflavan, appear to be the active compounds for these activities. PRACTICAL APPLICATIONS: The fruit of Mauritia flexuosa (moriche palm) has been used for beverages and processed foods. Although it is said to contain phytoestrogens, the active compounds have not yet been identified. In this study, we isolated and identified methoxyflavans exhibiting estrogenic and antiandrogenic activities. Among them, 6,7,4'-trihydroxy-5-methoxyflavan appeared to be the most effective compounds for these activities.

Steroid metabolome profiling of follicular fluid in normo- and hyperandrogenic women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a heterogeneous disease defined by the presence of at least two of the following features: hyperandrogenism, oligoanovulation (OA), and polycystic ovarian morphology (PCOM). Hyperandrogenism is considered the cornerstone of PCOS. However, the most prevalent phenotype in Chinese women with PCOS is OA + PCOM [normo-androgenic PCOS (NA-PCOS)]. It has been reported that PCOS women have higher androgen levels in follicular fluid (FF), but whether NA-PCOS women have the same intrafollicular steroid profiles as hyperandrogenic PCOS (HA-PCOS) women has not been explored.In this study, we analyzed 17 steroids in stimulated size-matched ovarian follicles (16−18 mm) from 166 controls and 141 PCOS women [87 NA-PCOS and 54 HA-PCOS women, defined by a single serum testosterone (T) immunoassay measurement] using liquid chromatography tandem mass spectrometry, and investigated their relationship with baseline characteristics. No significant differences in intrafollicular steroid levels and product/precursor ratios between NA-PCOS and HA-PCOS women were observed, though HA-PCOS women had significantly higher serum luteinizing hormone and T levels than NA-PCOS women. NA-PCOS and HA-PCOS women had significantly higher levels of androstenedione (AD), T and free androgen index, higher enzyme activity of P450c17 (AD/17OH-progesterone), 3βHSD2 (17OH-progesterone /17OH-pregnenolone) and P450c11 (corticosterone /11-deoxycorticosterone), lower levels of pregnenolone, 17OH-pregnenolone and 11-deoxycorticosterone, and decreased enzyme activity of P450aro (estrone/AD and estradiol/T) and 5α-reductase (dihydrotestosterone/T) in FF than controls. NA-PCOS women had significantly higher intrafollicular cortisol levels and lower 11βHSD2 (cortisone/cortisol) activity than controls. Baseline serum T levels were slightly correlated with intrafollicular estrogens (E1: r = 0.192, p = 0.019; E2: r = 0.248, p = 0.002; E3: r = 0.248, p = 0.002) and androgens (DHEAS: r = 0.276, p = 0.001; AD: r = 0.185, p = 0.032; T: r = 0.173, p = 0.044) in controls and PCOS women respectively. Serum anti-Müllerian hormone (AMH) levels and antral follicle count (AFC) were correlated with intrafollicular cortisol (AMH: r = 0.380, p = 0.000; AFC: r = 0.177, p = 0.036) and corticosterone (AMH: r = 0.212, p = 0.048; AFC: r = 0.219, p = 0.009) levels in PCOS women.In conclusion, NA-PCOS and HA-PCOS women had statistically similar steroid metabolome profiles in FF, both of which showed a generally decreased steroidogenesis and hyperandrogenism compared to controls.

Synthesis and Study of Some 17a-aza-D-homo Steroids as 5α-Reductase Inhibitors.

Tremendous advances have been made in the development of new pharmacotherapuetic agents and less invasive techniques to help men with lower urinary tract symptoms. The use of 5α-reductase inhibitor (5-ARI) is restricted to the patients with large prostate volumes, whose symptoms are refractory to antiandrogens or α-adrenergic blockers. Out of the various synthesized 5-reductase inhibitors with different substituents on the steroidal nucleus, esters have been found to exhibit high anti-androgenic activity. In our attempt to find new, safer and potent 5-ARI and our continued interest in azasteorids, esters of 17a-Aza-D-homo-5-androsten-3β-ol with synergistic effect were synthesized and characterized using different analytical techniques. The compounds were evaluated for their 5α-reductase inhibitory activity in-vivo by their effect on serum androgen level by ELISA assay procedure. The interaction with receptors was studied using an advanced docking programme to predict the correlation of the synthesized compounds with actual biological activity. The target compounds (6-12) showed increased anti-androgenic activity as compared to finasteride and control, which imply that the target compounds are effective in inhibiting 5α-reductase. Particularly, compound 6 showed the highest inhibitory activity and greater affinity for the 5- AR receptor with the highest dock score. The results of these studies when compared with Finasteride showed increased solubility and dissolution of target compound 6. Compound 6 showed immense potential with improved efficacy and better bioavailability, thus makes it a suitable candidate for further studies and optimal formulation.

Indole Alkaloids from Hosta plantaginea and Inhibition of Steroid 5α-Reductase Activities In Vitro

A new indole alkaloid (1), together with eight known indole alkaloid derivatives (2–9), was isolated from Hosta plantaginea for the first time. The structures of compounds 1–9 were elucidated on the basis of comprehensive spectroscopic analyses and references. Compounds 1–9 were evaluated for their inhibition of steroid 5α-reductase activity in vitro. Among them, compounds 1 and 2 showed important inhibition of steroid 5α-reductase activities.

Premature Adrenarche in Girls Characterized By Enhanced 17,20-Lyase and 17β-Hydroxysteroid Dehydrogenase Activities.

Girls with premature adrenarche (PA) may have a higher risk of developing polycystic ovary syndrome (PCOS) and metabolic syndrome. The biological purpose of adrenarche is unknown and the role of novel biosynthetic pathways remains unclear. To compare the urinary steroid metabolome and enzyme activities of girls with PA to age-matched control girls and to published steroid values of girls with normal adrenarche and of women with PCOS and their newborn daughters. Prospective observational study from 2009 to 2014. Academic pediatric endocrinology referral center. Twenty-three girls with PA and 22 healthy, age-matched girls. Steroid metabolites in 24-hour urine samples, including 4 progesterones, 5 corticosterones, aldosterone, 13 androgens, 2 estrogens, 14 glucocorticoids, and enzyme activities represented by metabolite ratios. Girls with PA had a higher body mass index (mean standard deviation scores 0.9 vs -0.3, P = 0.013). Androgen excretion was higher in PA girls than in control girls (median 3257 nmol/24 hours vs 1627 nmol/24 hours, P < 0.001), in particular metabolites from alternate androgen pathways. The amount of progesterone, corticosterone, aldosterone, estrogen, and cortisol metabolites were similar between groups. Activities of 17β-hydroxysteroid-dehydrogenase and of 17,20-lyase were higher in girls with PA. Activities of 3β-hydroxysteroid-dehydrogenase, 21-hydroxylase, and 5α-reductase activity were not different between groups, in contrast to published results on girls with normal adrenarche or PCOS females. Metabolites and enzymes involved in alternate androgen pathways appear to be markers of PA. Prospective studies should assess whether steroid production in PA also differs from adrenarche at normal timing and persists into adulthood.

Acute Valproate Exposure Induces Sex-Specific Changes in Steroid Hormone Metabolism in the Cerebral Cortex of Juvenile Mice.

Valproic acid (VPA), an antiepileptic and mood stabilizer, modulates neurotransmission and gene expression by inhibiting histone deacetylase activity. It is reported that VPA may affects the steroid hormone level. In this study, VPA-induced acute metabolic alterations were investigated using liquid chromatography-tandem mass spectrometry in prepubertal mice brain. In VPA-treated (400 mg/kg in saline solution, intraperitoneal) mice, cortisol levels were increased (female: P < 0.004, male: P < 0.003) and 17β-estradiol levels were decreased (Both P < 0.03). Furthermore, in the VPA-treated male mice, dihydrotestosterone levels were increased (P < 0.02) and testosterone were decreased (P < 0.002). The 4-hydroxylase activity was upregulated in the female VPA-treated mice (P < 0.01) and the 5α-reductase activity was increased in the male VPA-treated mice (P < 0.003). These results indicate sex specific differences in VPA-induced steroid metabolism in the brain cortex.

Childhood Trauma Is Nominally Associated With Elevated Cortisol Metabolism in Severe Mental Disorder.

ObjectiveIndividuals exposed to childhood trauma display longstanding modifications of the Hypothalamic–Pituitary–Adrenal (HPA) axis, as well as cognitive impairments. Schizophrenia spectrum disorder (SZ) and bipolar disorders (BD) are characterised by higher prevalence of childhood trauma, abnormal HPA axis, and cognitive dysfunction. Elevated cortisol metabolism was recently demonstrated in both disorders. However, it is yet to be established if childhood adversity is associated with cortisol metabolism in this population, and how this may be associated with cognitive function.MethodsOne-hundred-and-fourteen participants with a DSM-IV SZ or BD diagnosis took part in the study. Diagnoses were evaluated by the Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I). Estimated cortisol metabolizing activity (5α-reductase and 5β-reductase) was assessed by urinary free cortisol, and metabolites. All patients underwent cognitive assessment and completed the Childhood Trauma Questionnaire.ResultsEstimated 5β-reductase activity was elevated in participant with childhood physical abuse (r = 0.26, p = 0.005). After adjusting for age, sex and diagnosis, physical abuse was still nominally associated with elevated 5β-reductase. Moreover, only high 5α-reductase activity was negatively correlated with working memory and executive performance (r = −0.23, p = 0.01; r = −0.19, p = 0.05, respectively), however this disappeared after adjusting for age, sex and diagnosis. Cortisol metabolism did not mediate the association between childhood trauma and cognitive function.ConclusionsOur study indicates that childhood physical abuse is associated with elevated cortisol metabolism (5β-reductase) in adults with a SZ or BD disorder. However, our study did not support cortisol metabolism as a mediator between childhood trauma experiences and cognitive function within these disorders.

OR11-02 Distinctive Neuroendocrine Changes and Menstrual Dysfunction in Early Postmenarchal Daughters of Women With PCOS

PCOS is a complex genetic disease with strong familial aggregation - ~40% of reproductive-age sisters have elevated testosterone (T) levels and other features of the syndrome. Beginning in infancy, daughters of affected women (PCOS-d) have elevated anti-Müllerian hormone (AMH) levels and evidence for global increases in 5α-reductase activity. Peripubertally, PCOS-d have increased T levels. Peripubertal overweight and obesity (OB) girls also have elevated T but not AMH levels.We initiated a prospective study of PCOS-d and OB to test the hypothesis that only PCOS-d are at increased risk to develop PCOS. Herein, we present the baseline assessments in 14 PCOS-d, 14 OB, and 18 lean control girls (LC) aged 11-16 yrs who were enrolled within 2-yrs of menarche. PCOS-d mothers fulfilled NIH criteria, OB and LC mothers had no history of irregular menses or clinical hyperandrogenism. Morning blood sampling was performed for hormone levels. Free T was calculated from total T and SHBG. Ovarian MRI was performed to assess morphology. Data are mean ± SD, α=0.05.By design, age did not differ between the groups, but BMI z-score was higher in OB compared with PCOS-d and LC (1.3±1.1 PCOS-d v 2.0±0.6 OB v 0.1±0.7 LC, P<0.0001). The prevalence of irregular menses (cycles ≤ 21d or ≥ 45d apart) was significantly increased only in PCOS-d (61% PCOS-d, 23% OB, 19% LC, Χ 2 P=0.03). Total T levels did not differ between the groups. SHBG levels were decreased in PCOS-d and OB (23±16 PCOS-d v 30±16 OB v 56±15 LC, nmol/L, P<0.0001), resulting in a trend toward increased free T levels in these groups (0.6±0.3 PCOS-d v 0.6±0.5 OB v 0.4±0.2 LC, ng/dL, P=0.06). DHEAS levels were higher in PCOS-d and OB compared with LC (135±35 PCOS-d v 150±68 OB v 88±46 LC, ug/dL, P=0.05). AMH levels, follicle counts and ovarian volume did not differ.GnRH analog (GnRHa,10 µg/kg SC) stimulation was performed in 9 PCOS-d and 13 OB. Both baseline LH levels (7.6±4.4 PCOS-d v 3.7±2.1 OB, mIU/mL, P=0.01) and LH responses to GnRHa were significantly increased in PCOS-d (LH AUC: 2110±1132 PCOS-d v 1047±808 OB, P=0.01). Baseline FSH and FSH AUC did not differ. Post-GnRHa 17-OHP levels did not differ.Early postmenarchal PCOS-d but not OB have evidence for increased GnRH-mediated LH release, a cardinal feature of PCOS disordered gonadotropin secretion. The increased prevalence of irregular menses in PCOS-d is consistent with this change. In contrast, androgen levels are similarly increased in both groups. These findings align with genomewide association studies implicating gonadotropin secretion and action in PCOS pathogenesis and suggest that neuroendocrine alternations in gonadotropin release are a core causal pathway in PCOS. Moreover, these findings provide further support for our hypothesis that PCOS-d but not OB are at increased risk for PCOS. Longitudinal studies are ongoing to test this hypothesis at 2-yrs postmenarche when the diagnosis of PCOS can be established.

Anti-Acne Vulgaris Effects of Pedunculagin from the Leaves of Quercus mongolica by Anti-Inflammatory Activity and 5α-Reductase Inhibition.

Quercus mongolica (QM)—a member of the Fagaceae family—has been used as traditional medicine in Korea, China and Mongolia as a treatment for inflammation of oral, genital or anal mucosa and for external inflammation of skin. To treat acne vulgaris (AV), we evaluated the inhibition of inflammatory cytokines (IL-6 and IL-8) of QM leaf extract (QML) and its main compound, pedunculagin (PD) in vitro and 5α-reductase inhibitory activity by western blotting. As results, QML and PD showed potent NO production inhibitory activity compared with the positive control (PC), NG-monomethyl-L-arginine (L-NMMA). QML and PD was also showed the decreases of IL-6 and IL-8 compared with the PC, EGCG and exhibited potent 5α-reductase type 1 inhibitory activities compared with the PC, dutasteride.

Glucocorticoid metabolism and the action of 11 beta-hydroxysteroid dehydrogenase 2 in canine congestive heart failure

The enzyme 11-beta-hydroxysteroid dehydrogenase isoenzyme 2 (11BHSD2) is responsible for converting the active glucocorticoid cortisol to inactive cortisone and in the renal medulla protects the mineralocorticoid receptor (MR) from activation by cortisol. Derangements in 11BHSD2 activity can result in reduced conversion of cortisol to cortisone, activation of the MR by cortisol and, consequently, sodium and water retention. The objective of this study was to examine glucocorticoid metabolism in canine congestive heart failure (CHF), specifically to evaluate whether renal 11BHSD2 activity and expression were altered. Dogs were prospectively recruited into one of two phases; the first phase (n=56) utilized gas chromatography-tandem mass spectrometry to examine steroid hormone metabolites normalised to creatinine in home-caught urine samples. Total serum cortisol was also evaluated. The second phase consisted of dogs (n=18) euthanased for refractory CHF or for behavioural reasons. Tissue was collected from the renal medulla for examination by quantitative reverse transcription polymerase chain reaction, immunohistochemistry and protein immune-blotting. Heart failure did not change urinary cortisol:cortisone ratio (P=0.388), or modify renal expression (P=0.303), translation (P=0.427) or distribution of 11BHSD2 (P=0.325). However, CHF did increase excretion of 5α-tetrahydrocortisone (P=0.004), α-cortol (P=0.002) and α-cortolone (P=0.009). Congestive heart failure modifies glucocorticoid metabolism in dogs by increasing 5α-reductase and 20α-hydroxysteroid dehydrogenase activity. Differences between groups in age, sex and underlying disease processes may have influenced these results. However, 11BHSD2 does not appear to be a potential therapeutic target in canine CHF.

Effect of Pregnenolone Derivatives on the Selective Inhibition of 5α-Reductase 2 Activity

Background:Benign prostatic hyperplasia and prostate cancer are androgen-dependent diseases, and dihydrotestosterone (DHT), a 5α-reduced metabolite of testosterone (T), has been implicated as a causative factor in the progression of these diseases. The 5α-reductase enzyme (5α-R) converts T to DHT, which is responsible for increasing cell proliferation, and hence inhibition of this enzyme could lead to potential treatments for these afflictions.Objective:This study focused on evaluating the biological activity of three series of pregnenolone derivatives as inhibitors of 5α-R and as antiandrogens on androgen-dependent glands.Method:To determine the biological activity of these compounds, we evaluated the effect of each one on suppressing the activity of both types of isozymes of 5α-R (1 and 2) by 50% (IC50). Using animal studies, we assessed the effect of these derivatives on the weight of the prostate, seminal vesicles, and diameter of the flank organs of castrated hamsters previously dosed with 1 mg/Kg T.Results:In vitro experiments showed that derivatives 1f, 2b, and 3d were very effective inhibitors of the activity of 5α-R2, showing IC50 values of 21.8, 20, and 15 nM, respectively. Derivatives 2b and 3b showed a lower inhibition effect on 5α-R1.:The data also indicated that derivatives 2b, 1f, 3b, and 3d were very active in reducing prostate weight in the hamster model of benign prostatic hyperplasia.Discussion:Pharmacological experiments showed that pregnenolone derivatives possess an antiandrogenic effect because of the inhibition of DHT production in androgen-dependent glands.Conclusion:The pregnenolone derivatives studied suppressed type 2 5α-reductase activity and because of this, the weight and dimension of androgen-dependent organs were decreased.

New chlorophenolic glycoside from Curculigo orchioides and their activities on 5α-reductase

Two new chlorophenolic glucosides curculigines P (1) and Q (2), together with seven known compounds (3–9), were isolated from the dried rhizomes of Curculigo orchioides. Their structures were determined by spectroscopic methods including 1 D, 2 D NMR and MS. All the isolated compounds were evaluated on 5α-reductase activity by a HaCaT-based bioassay. Compounds 1–9 showed varying degrees of inhibiting activity against 5α-reductase, while compound 1 indicated the most potent inhibitory effect.

Maternal Glucocorticoid Metabolism Across Pregnancy: A Potential Mechanism Underlying Fetal Glucocorticoid Exposure

Across pregnancy, maternal serum cortisol levels increase up to 3-fold. It is not known whether maternal peripheral cortisol metabolism and clearance change across pregnancy or influence fetal cortisol exposure and development. The primary study objective was to compare maternal urinary glucocorticoid metabolites, as markers of cortisol metabolism and clearance, between the second and third trimester of pregnancy. Secondary objectives were to test associations of total maternal urinary glucocorticoid excretion, with maternal serum cortisol levels and offspring birth weight z score. A total of 151 women with singleton pregnancies, recruited from prenatal clinic at the Pittsburgh site of the Measurement of Maternal Stress (MOMS) study, had 24-hour urine collections during both the second and third trimesters. Between the second and third trimester, total urinary glucocorticoid excretion increased (ratio of geometric means [RGM] 1.37, 95% CI 1.22-1.52, P < .001), and there was an increase in calculated 5β-reductase compared to 5α-reductase activity (RGM 3.41, 95% CI 3.04-3.83, P < .001). During the third trimester total urinary glucocorticoid excretion and serum cortisol were negatively correlated (r = -0.179, P = .029). Mean total urinary glucocorticoid excretion across both trimesters and offspring birth weight z score were positively associated (β = 0.314, P = .001). The estimated activity of maternal enzymes responsible for cortisol metabolism change between the second and third trimester of pregnancy. Additionally, maternal peripheral metabolism and clearance of cortisol may serve as a novel mechanism affecting fetal cortisol exposure and growth.