5α-reductase Activity Research Articles

Comparison of the response to treatment between Asian and Caucasian men with benign prostatic hyperplasia: Long‐term results from the combination of dutasteride and tamsulosin study

The Combination of Avodart and Tamsulosin study was a 4-year, randomized, double-blind study of the efficacy and safety of dutasteride and tamsulosin, alone or in combination, in men with moderate-to-severe benign prostatic hyperplasia. In this post-hoc investigation, we analyzed primary and secondary end-points from the Combination of Avodart and Tamsulosin study in Asian (n = 325) and Caucasian men (n = 4259). The incidence of acute urinary retention or benign prostatic hyperplasia-related surgery did not differ significantly between treatment groups in the Asian subpopulation. In Caucasian men, the incidence of acute urinary retention/benign prostatic hyperplasia-related surgery was significantly lower in the combination therapy group compared with the tamsulosin monotherapy group (P < 0.001), but not compared with dutasteride monotherapy. Combination therapy significantly increased the time to benign prostatic hyperplasia clinical progression and resulted in improved International Prostate Symptom Score, maximum urinary flow rate, quality of life, and reduced prostate volume in Asian and Caucasian men who received combination therapy compared with tamsulosin monotherapy. Combination therapy also significantly improved (P < 0.05) time to benign prostatic hyperplasia clinical progression, International Prostate Symptom Score, maximum urinary flow rate and quality of life versus dutasteride in the Caucasian subpopulation. The adverse-event profile was comparable between subpopulations. In conclusion, Asian and Caucasian men respond similarly to these treatments, despite apparent racial differences in 5α-reductase activity.

Synthesis and biological evaluation of novel unsaturated carboxysteroids as human 5α-reductase inhibitors: A legitimate approach

In the present study, novel steroidal 17a-substituted 3-cyano-17a-aza-D-homo-3,5-androstadien-17-ones (12–19) and 17a-substituted 17-oxo-17a-aza-D-homo-3,5-androstadien-3-oic acids (20–26) were synthesized from dehydroepiandrosterone acetate (6) along with 17-oxo-19-nor-3,5-androstadien-3-oic acid (30) through a multistep synthesis. Compounds were evaluated for their in vitro 5α-reductase inhibitory activity by measuring the conversion of [3H] androstenedione in human embryonic kidney (HEK) cells. In vivo 5α-reductase inhibitory activity was also determined using rat prostate weighing method. Compounds 21–23 and 25 showed potent inhibition of 5α-reductase II enzyme with IC50 values of 54.1 ± 9.5, 22.1 ± 2.4, 72.8 ± 2.3 and 26.5 ± 4.4 nM respectively as compared to Finasteride (30.3 nM) along with a significant (p < 0.05) reduction in rat prostate weight.

Effect of Dieckol, a component of Ecklonia cava, on the promotion of hair growth.

This study was conducted to evaluate the effect of Ecklonia cava, a marine alga native to Jeju Island in Korea, on the promotion of hair growth. When vibrissa follicles were cultured in the presence of E. cava enzymatic extract (which contains more than 35% of dieckol) for 21 days, E. cava enzymatic extract increased hair-fiber length. In addition, after topical application of the 0.5% E. cava enzymatic extract onto the back of C57BL/6 mice, anagen progression of the hair-shaft was induced. The treatment with E. cava enzymatic extract resulted in the proliferation of immortalized vibrissa dermal papilla cells (DPC). Especially, dieckol, among the isolated compounds from the E. cava enzymatic extract, showed activity that increased the proliferation of DPC. When NIH3T3 fibroblasts were treated with the E. cava enzymatic extract and the isolated compounds from the E. cava enzymatic extract, the E. cava enzymatic extract increased the proliferation of NIH3T3 fibroblasts, but the isolated compounds such as eckol, dieckol, phloroglucinol and triphlorethol-A did not affect the proliferation of NIH3T3 fibroblasts. On the other hand, the E. cava enzymatic extract and dieckol significantly inhibited 5α-reductase activity. These results suggest that dieckol from E. cava can stimulate hair growth by the proliferation of DPC and/or the inhibition of 5α-reductase activity.

963 HOW DOES 5α-REDUCTASE ACTIVITY CHANGE DURING THE PROGRESSION OF CASTRATION RESISTANT PROSTATE CANCER?

You have accessJournal of UrologyProstate Cancer: Basic Research V1 Apr 2012963 HOW DOES 5α-REDUCTASE ACTIVITY CHANGE DURING THE PROGRESSION OF CASTRATION RESISTANT PROSTATE CANCER? Takeo Kosaka, Akira Miyajima, Eiji Kikuchi, Takahiro Maeda, Hirohiko Nagata, and Mototsugu Oya Takeo KosakaTakeo Kosaka Tokyo, Japan More articles by this author , Akira MiyajimaAkira Miyajima Tokyo, Japan More articles by this author , Eiji KikuchiEiji Kikuchi Tokyo, Japan More articles by this author , Takahiro MaedaTakahiro Maeda Tokyo, Japan More articles by this author , Hirohiko NagataHirohiko Nagata Tokyo, Japan More articles by this author , and Mototsugu OyaMototsugu Oya Tokyo, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.1062AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Deregulation of the androgen-androgen receptor (AR) pathway is a hallmark of prostate cancer (PCA). Therapies targeting the androgen-AR axis at different levels including de novo steroid synthesis may be quite effective against PCA to improve the prognosis of patients. However, it has not been been fully elucidated how steroid-5α-reductase (SRD5As) contribute to the development of PCA or progression to castration-resistant prostate cancer (CRPC). In this study, we sought to determine the significance of dihydrotestosterone (DHT) and SRD5As activity in CRPC. METHODS Two human CRPC cell lines (C4-2 and C4-2AT6) were used in this study. C4-2AT6 was established from C4-2 grown in androgen ablated condition for six months. The expression of SRD5As was semi-quantified with qPCR. To ascertain the potential SRD5As activity, we cultured C4-2 and C4-2AT6 cells with the steroid precursors modified by stable isotope: 13C-[2,3,4]-androstenedione (13C-A-dione). The sequential biosynthesis of 13C-[2,3,4]-dihydrotestosterone (13C-DHT) and 13C-[2,3,4]-testosterone (13C-T) were analyzed by liquid chromatography/mass spectrometry (LC/MS). RESULTS The C4-2AT6 cells showed 0.48-fold decrease of SRD5A1, 1.4-fold increase in SRD5A2 and 2.6-fold increase in SRD5A3 expression than C4-2 cells. The DHT concentration (0.01 ± 0.008 pg/ml, p<0.001) detected by LC/MS in C4-2AT6 cultured supernatant was significantly lower than that of in C4-2 supernatant (0.46 ± 0.12 pg/ml). These results showed that DHT production was reduced in C4-2AT6 cells. LC/MS analysis can detect significant convergence of 13C-A-dione into 13C-DHT and 13C-T. The concentration of 13C-DHT/13C-T (DHT/T ratio) was thought to reflect the SRD5As activity. The concentration of 13C-DHT in C4-2 and C4-2AT6 was 779.6 ± 210.9 and 150 ± 58.5 pg/mL, respectively (p<0.001). The DHT/T ratio of C4-2 and C4-2AT6 cells was 0.07 ± 0.03 and 0.02 ±0.003, respectively (p<0.001), suggesting reduced SRD5As activity in C4-2AT6. The response of C4-2AT6 cells to DHT was significantly decreased, compared with C4-2 cells, indicating reduced dependency of mRNA expression of PSA and Nkx3.1 on DHT. CONCLUSIONS These results demonstrated that the direct evidences of the change of SRD5As activity, accompanied by the reduced ability to produce DHT in CRPC. These experimental models provide a bland new platform to investigate the significance of DHT and SRD5As in CRPC progression. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e392-e393 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Takeo Kosaka Tokyo, Japan More articles by this author Akira Miyajima Tokyo, Japan More articles by this author Eiji Kikuchi Tokyo, Japan More articles by this author Takahiro Maeda Tokyo, Japan More articles by this author Hirohiko Nagata Tokyo, Japan More articles by this author Mototsugu Oya Tokyo, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Effect of petroleum ether and ethanol fractions of seeds of Abrus precatorius on androgenic alopecia

Seeds of Abrus precatorius L., Fabaceae, are commonly used as purgative, emetic, aphrodisiac and in nervous disorder in traditional and folk medicines. In present study petroleum ether and ethanolic extracts of A. precatorius seeds are evaluated for reversal of androgen (testosterone by i.m route) induced alopecia in male albino wistar rats and compared to topical administration of standard antiandrogenic drug finasteride for 21 days. The results were reflected from visual observation and histological study of several skin sections via various parameters as anagen to telogen ratio and follicle density/mm area of skin surface. The animal of group 1 who were treated with only testosterone became alopecic on visual observation. Animals of Group 2, 3 and 4 who were treated with finasteride, petroleum ether and ethanolic extract of seed respectively topically along with testosterone (i.m) did not developed alopecia. To investigate the mechanism of observed activity, in vitro experiments were performed. Inhibition of 5α-reductase activity by extracts and finasteride suggest that they reversed androgen induced alopecia by inhibiting conversion of testosterone to dihydrotestosterone (potent androgen responsible for androgenic alopecia). So it may be concluded that petroleum ether and ethanolic extract of A. precatorius seed posses anti androgenic alopecia activity due to inhibition of 5α-reductase enzyme.

Anti-androgenic effect of sesquiterpenes isolated from the rhizomes of Curcuma aeruginosa Roxb.

Six sesquiterpenes: germacrone (1), zederone (2), dehydrocurdione (3), curcumenol (4), zedoarondiol (5) and isocurcumenol (6) were isolated from rhizomes of Curcuma aeruginosa Roxb. (Zingiberaceae). They inhibited 5α-reductase which converts testosterone to dihydrotestosterone (DHT). Germacrone (1) was the most potent (IC50=0.42±0.05mg/mL). Compound 1 was anti-androgenic in LNCaP cells when proliferation was testosterone-induced. The growth of flank gland of male Syrian hamsters is dependent on circulating androgen and when maintained with testosterone, 1 (3, 30, 100μg) inhibited growth but was ineffective against DHT. The similar activity profile was observed on the 5α-reductase inhibitor, finasteride (100μg) treatment group. The androgen receptor binding assay showed that 1 did not bind to the androgen receptor. In conclusion, 1 showed anti-androgenic effect on in vitro and in vivo assays. One of the possible mechanisms was inhibition 5α-reductase activity. Thus, 1 is a potential lead compound for treatment of androgen-dependent disorders.

Comparative GC-MS Based In vitro Assays of 5α-Reductase Activity Using Rat Liver S9 Fraction

α-Dihydrotestosterone (DHT) is the primary active metabolite of testosterone, catalyzed by 5α-reductase (5αR) in the skin, prostate, and liver. In this study, the 5αR activity in rat liver S9 fraction in the presence of a NADPH-generating system was evaluated and compared by gas chromatography-mass spectrometry (GC-MS)-based in vitro assays. Testosterone and a 5αR inhibitor, finasteride, were added to the S9 fractions and incubated at 37 o C for 1 h. Both testosterone and DHT were quanti- tatively measured and compared with two different GC-MS-based steroid profiling techniques. DHT was not detected by con- ventional GC-MS analysis in the absence of finasteride when the concentration of testosterone in the S9 fraction was less than 0.2 µM, whereas the isotope-dilution GC-MS (GC-IDMS) system was able to evaluate the 5αR activity. Because the S9 fraction contains more reactive enzymes and is easier to collect from tissues compared with a microsomal solution, the combination of the S9 fraction and GC-IDMS technique may be a promising assay for evaluating the 5αR activity in large-scale clinical studies.

Hair-Loss Preventing Effect of Grateloupia elliptica

This study was conducted to evaluate the effect of Grateloupia elliptica, a seaweed native to Jeju Island, Korea, on the prevention of hair loss. When immortalized rat vibrissa dermal papilla cells were treated with extract of G. elliptica, the proliferation of dermal papilla cells significantly increased. In addition, the G. elliptica extract significantly inhibited the activity of 5α-reductase, which converts testosterone to dihydrotestosterone (DHT), a main cause of androgenetic alopecia. On the other hand, the G. elliptica extract promoted PGE2 production in HaCaT cells in a dose-dependent manner. The G. elliptica extract exhibited particularly high inhibitory effect on LPS-stimulated IL-12, IL-6, and TNF-α production in lipopolysaccharide (LPS)-stimulated bone marrow-derived dendritic cells. The G. elliptica extract also showed inhibitory activity against Pityrosporum ovale, a main cause of dandruff. These results suggest that G. elliptica extract has the potential to treat alopecia via the proliferation of dermal papilla, 5α-reductase inhibition, increase of PGE2 production, decrease of LPS-stimulated pro-inflammatory cytokines and inhibitory activity against Pityrosporum ovale.

Quantitative determination of the representative triterpenoids in the extracts of Ganoderma lucidum with different growth stages using high-performance liquid chromatography for evaluation of their 5α-reductase inhibitory properties

► We develop the HPLC method for evaluating the 5α-reductase inhibitory potency of Ganoderma lucidum . ► Stage 5 is the prime stage for harvesting G. lucidum . ► The contents of ganoderic acid TR and DM in G. lucidum extracts could be a very useful indicator. For quantitative determination of 5 triterpenoid constituents, including one ganoderma alcohol (ganodermatriol) and four ganoderma acids (ganoderic acid TR, DM, A, and D), in the products of Ganoderma lucidum , an analytical system was developed using high-performance liquid chromatography. The mobile phase was a linear gradient of 2% AcOH/H 2 O–CH 3 CN, and the elution profile was monitored at 243 and 252 nm for ganoderma alcohols and acids, respectively. This system was applied to a quantitative determination of the constituents in the different stage of G. lucidum (BMC9049 strain). The analytical results indicated that the quantity and composition of these triterpenoids differed appreciably among various stages. The stage that showed the highest concentration of ganoderic acid DM and TR also showed the strongest 5α-reductase inhibitory activity. This stage (stage 5 of 6) is thus the prime stage for harvesting this strain. Further, the contents of 5α-reductase inhibitors such as ganoderic acid TR and DM in G. lucidum extracts could be a very useful indicator to assess their 5α-reductase inhibitory activity and verify their potency.

Synthesis and 5α-Reductase Inhibitory Activity of C21 Steroids Having 1,4-diene or 4,6-diene 20-ones and 4-Azasteroid 20-Oximes

The synthesis and evaluation of 5α-reductase inhibitory activity of some 4-azasteroid-20-ones and 20-oximes and 3β-hydroxy-, 3β-acetoxy-, or epoxy-substituted C21 steroidal 20-ones and 20-oximes having double bonds in the A and/or B ring are described. Inhibitory activity of synthesized compounds was assessed using 5α-reductase enzyme and [1,2,6,7-3H]testosterone as substrate. All synthesized compounds were less active than finasteride (IC50: 1.2 nM). Three 4-azasteroid-2-oximes (compounds 4, 6 and 8) showed good inhibitory activity (IC50: 26, 10 and 11 nM) and were more active than corresponding 4-azasteroid 20-ones (compounds 3, 5 and 7). 3β-Hydroxy-, 3β-acetoxy- and 1α,2α-, 5α,6α- or 6α,7α-epoxysteroid-20-one and -20-oxime derivatives having double bonds in the A and/or B ring showed no inhibition of 5α-reductase enzyme.

5α-reductase inhibition and hair growth promotion of some Thai plants traditionally used for hair treatment

Ethnopharmacological relevanceMany Thai traditional herbs have been used for hundreds of years for hair treatment and nourishment, including hair loss. However, scientific evidence about their mechanisms of action has not yet been elucidated. Aims of the studyThe purpose of this research is to define the possible mechanisms involved in hair loss treatment of the selected plants by determining the 5α-reductase enzyme inhibition and hair growth promoting activities, and the relationship between these two activities. Materials and methodsSeventeen Thai plants traditionally used for hair treatment were selected. The plants were dried, ground and extracted by maceration with ethyl alcohol. These extracts were further tested for 5α-reductase inhibition using enzymes from rat livers. Hair growth promoting activity was tested in C57BL/6 mice. ResultsCarthamus tinctorius L. was the most potent 5α-reductase inhibitor, with a finasteride equivalent 5α-reductase inhibitory activity (FEA) value of 24.30±1.64mg finasteride equivalent per 1g crude extract. Phyllanthus emblica L. was the second most potent inhibitor, with FEA of 18.99±0.40. Rhinacanthus nasutus (L.) Kurz. was the least potent 5α-reductase inhibitor (FEA 10.69±0.96). Carthamus tinctorius also was the most potent hair growth promoter in C57BL/6 mice. There were strong relationships between 5α-reductase inhibitory activity and hair growth promoting activity (r=0.719), and between 5α-reductase inhibitory activity and hair follicle count (r=0.766). ConclusionsEthanolic extract of Carthamus tinctorius was the most potent 5α-reductase inhibitor and hair growth promoter. This discovery may lead to the development of new alternative medicines for hair loss prevention and treatment.

5α-Reductase inhibitors, antiviral and anti-tumor activities of some steroidal cyanopyridinone derivatives

We herein report the 5α-reductase inhibitors, antiviral and anti-tumor activities of some synthesized heterocyclic cyanopyridone and cyanothiopyridone derivatives fused with steroidal structure. Initially the acute toxicity of the compounds was assayed via the determination of their LD50. All the compounds, except 3b, were interestingly less toxic than the reference drug (Prednisolone®). Seventeen heterocyclic derivatives containing a cyanopyridone or cyanothiopyridone rings fused to a steroidal moiety were synthesized and screened for their 5α-reductase inhibitors, antiviral and anti-tumor activities comparable to that of Anastrozole, Bicalutamide, Efavirenz, Capravirine, Ribavirin, Oseltamivir and Amantadine as the reference drugs. Some of the compounds exhibited better 5α-reductase inhibitors, antiviral and anti-tumor activities than the reference drugs. The detailed 5α-reductase inhibitors, antiviral and anti-tumor activities of the synthesized compounds were reported.

Localization of brain 5α-reductase messenger RNA in mice selectively bred for high chronic alcohol withdrawal severity

Several lines of evidence suggest that fluctuations in endogenous levels of the γ-aminobutyric acid (GABA)ergic neurosteroid allopregnanolone (ALLO) represent one mechanism for regulation of GABAergic inhibitory tone in the brain, with an ultimate impact on behavior. Consistent with this idea, there was an inverse relationship between ALLO levels and symptoms of anxiety and depression in humans and convulsive activity in rodents during alcohol withdrawal. Our recent studies examined the activity and expression of 5α-reductase ( Srd5a1), the rate-limiting enzyme in the biosynthesis of ALLO, during alcohol withdrawal in mice selectively bred for high chronic alcohol withdrawal (Withdrawal Seizure-Prone [WSP]) and found that Srd5a1 was downregulated in the cortex and hippocampus over the time course of dependence and withdrawal. The purpose of the present studies was to extend these findings and more discretely map the regions of Srd5a1 expression in mouse brain using radioactive in situ hybridization in WSP mice that were ethanol naïve, following exposure to 72 h ethanol vapor (dependent) or during peak withdrawal. In naïve animals, expression of Srd5a1 was widely distributed throughout the mouse brain, with highest expression in specific regions of the cerebral cortex, hippocampus, thalamus, hypothalamus, and amygdala. In dependent animals and during withdrawal, there was no change in Srd5a1 expression in cortex or hippocampus, which differed from our recent findings in dissected tissues. These results suggest that local Srd5a1 mRNA expression in WSP brain may not change in parallel with local ALLO content or withdrawal severity.

Hirsutism Score and the Severity of Hyperandrogenism Associated with Polycystic Ovary Syndrome in the South-Eastern Region of Turkey

This study investigated the severity of hirsutism and its correlation with serum total testosterone (tT) levels in 87 patients with polycystic ovary syndrome (PCOS) and 85 healthy control subjects from the south-eastern region of Turkey. A wide range of variability exists in both hirsutism and modified Ferriman-Gallwey (mFG) scores. Similar mFG scores and serum tT levels were found compared with previous studies of general populations, but lower scores than those previously reported from Turkey. The incidence of hirsutism was lower in hyperandrogenic PCOS patients compared with non-hyperandrogenic PCOS patients. There was no correlation between serum tT levels and the rate of hirsutism in patients with PCOS. Heritability, testosterone receptor sensitivity, 5α reductase activity or environmental/socioeconomic factors may play a role in the development of clinical hirsutism. Larger scale studies are needed to clarify which other factors may be responsible and to confirm these results.

Association of genetic variants in the two isoforms of 5α-reductase, SRD5A1 and SRD5A2, in lean patients with polycystic ovary syndrome

ObjectiveGiven its role in converting testosterone to dihydrotestosterone and cortisol to dihydrocortisol, 5α-reductase may be important in the pathophysiology of the polycystic ovary syndrome (PCOS). Increased activity of this enzyme has already been demonstrated in ovaries of affected women, and might be caused by genetic alterations. The aim of this study was to analyze representative genetic variants of both isoforms of 5α-reductase with regard to PCOS parameters in lean and obese women. Study designWe analyzed one single nucleotide polymorphism (SNP) (rs523349) of the isoform 2 (SRD5A2) and one haplotype of the isoform 1 (SRD5A1), consisting of the two SNPs rs39848 and rs3797179, in 249 women with PCOS and 226 healthy women using a 5′-exonuclease-assay. The genotypes were associated with anthropometric, metabolic and hormonal as well as functional tests in these women. ResultsIn the investigated haplotype of SRD5A1, the TA variant was associated with an increased frequency of PCOS (P=0.022) and an increased Ferriman–Gallwey Score (hirsutism) (P=0.016) in women with normal weight. The G allele at the examined position of the SRD5A2 showed a decreased frequency of PCOS (P=0.03) in women with normal weight. ConclusionOne of the keys in the development of the PCOS is hyperandrogenism, which might be caused by an increased 5α-reductase activity, as it is often seen in obesity. This mechanism might therefore be of importance in lean PCOS patients and contribute to the clinical findings.

A Novel SRD5A2 Mutation with Loss of Function Identified in Chinese Patients with Hypospadias

Objective: To investigate the functional change of SRD5A2 gene mutations identified in patients with 5α-reductase type 2 deficiency. Patients and Methods: Three unrelated subjects born with ambiguous genitalia were included. All patients were initially reared as girls, but they gradually exhibited variable degrees of virilization at puberty without breast development, followed by a change of gender role. Sequencing analysis of the SRD5A2 gene was performed and enzymatic activities of 5α-reductase type 2 were assessed. Results: Three compound heterozygous mutations in the SRD5A2 gene were identified: patient 1 with p.G203S/ c.655delT, patient 2 with p.Q6X/p.G203S, and patient 3 with p.G203S/c.755_756insT. Heterozygosity for the p.V89L polymorphism was also found in patients 2 and 3. The c.655delT mutation led to a complete loss of the enzymatic activity, whereas mutants p.G203S and c.755_756insT resulted in a reduction of the enzymatic activities by 60 and 90%, respectively. Conclusion: Two frameshift heterozygous mutations, c.655delT and c.755_756insT, led to a dramatic reduction in 5α-reductase activity, and the latter had not been reported previously. In addition, the heterozygous mutation (p.G203) identified in the 3 patients presumably suggests a founder effect in the Chinese population and may explain the similarity in phenotype among the patients.

Gas chromatography/mass spectrometry based hair steroid profiling may reveal pathogenesis in hair follicles of the scalp

A method of steroid profiling, including androgens, progestins, corticoids and sterols, was developed to evaluate the concentrations of steroids as well as the activities of the enzymes responsible for steroidogenesis in hair by gas chromatography/mass spectrometry. The extraction efficiencies of steroids from the hair matrix were improved by ultrasonication for 1 h at 50 °C. The overall recoveries ranged from 71 to 132%, with a limit of quantification for all analytes ranging from 1 to 50 ng/g. The devised method was used to identify the metabolic changes for both male-pattern baldness (MPB) and the drug efficiency of dutasteride, which inhibits 5α-reductase. Increased dihydrotestosterone levels and the dihydrotestosterone/testosterone (DHT/T) ratio, which is responsible for the 5α-reductase activity, were observed in the MPB patients. A dutasteride treatment resulted in decreases in the DHT and 5α-androstanedione concentrations and DHT/T ratio in the hair samples. Hair steroid profiling reflects the sebaceous status in the scalp and may be useful for monitoring the metabolic responses to both the disease and drug actions.

Screening of steroid 5-reductase inhibitory activity and total phenolic content of Thai plants

Steroid 5α-reductase is the enzyme responsible for changing androgen testosterone into the more potent androgen dihydrotestosterone (DHT). Overexpression of DHT can cause many disorders including androgenic alopecia and benign prostatic hypertrophy (BPH). The aim of this study is to determine which plants possess 5α-reductase inhibitory activity, and to evaluate the correlation between 5α-reductase inhibitory activity and total phenolic content of these plants. Ten kinds of Thai plants were collected from local areas and extracted with 95% ethanol. The yields of ethanolic extracts of these plants ranged from 2.22 to 16.05%, dry weight. In the present study the ability of the extracts to inhibit 5α-reductase enzyme has, for the first time, been calculated as finasteride equivalent 5α-reductase activity (FEA) value (mg finasteride per 1 g extract). FEA values are easier to understand and to compare their activity. FEA values of the extracts ranged from 5.56 to 17.59 mg finasteride per 1 g extract. The highest FEA value was found in Ocimum basilicum L. The red strain of Oryza sativa L. was the second most potent 5α-reductase inhibitor, with FEA value of 16.72. Total phenolic content of the extracts ranged from 32.00 to 370.85 mg gallic acid equivalent per 1 g extract. There was no correlation between 5α-reductase inhibitory activity and total phenolic content. Phytochemicals other than phenolic compounds may play an important role in enzyme inhibition. As the usual dosage regimen of finasteride for treating androgen-related disorders is 1 to 5 mg/d, regular intake of these fresh plants or their extracts may be beneficial in health promotion, prevention or treatment effect. Key words: Androgenic alopecia, benign prostatic hyperplasia, dihydrotestosterone, steroid 5α-reductase, testosterone, Thai plants, total phenolic content.

Recognition of 5α-reductase-2 deficiency in an adult female 46XY DSD clinic

The late presentation of steroid 5α-reductase-2 (SRD5A2) deficiency in females is poorly characterised. The ratios of 5α/5β-reduced metabolites of adrenal steroids in a urine steroid profile (USP) can give an indication of SRD5A2 deficiency, although the diagnostic cut-off for 5α/5β ratios are not clearly defined in genetically confirmed cases. The aim of this study was to establish the frequency of SRD5A2 deficiency in an adult clinic for disorders of sexual development (DSD) focussing on 46XY partially virilised adult female subjects. We investigated the relationship between USP results and SRD5A2 genetic sequence and determined the cut-off for USP 5α/5β-reduced steroid ratios compared with gene sequencing for the identification of SRD5A2 deficiency. USP and SRD5A2 genetic analyses were performed in 23 adult females, aged 19-57 years, with 46XY DSD and in four males with confirmed SRD5A2 deficiency. 5α-Reductase activity was assessed using the USP ratio of androsterone to aetiocholanolone (A/Ae), 5α-tetrahydrocortisol (5α-THF)/tetrahydrocortisol (THF) and 5α-tetrahydrocorticosterone to tetrahydrocorticosterone (5α-THB/THB). The SRD5A2 gene mutations were found in 10/23 (43%) females and in all four males. Totally, four novel mutations were identified. All mutation-positive subjects had A/Ae and 5α-THB/THB ratios below the lower limit of normal (100% sensitivity) while the sensitivity of 5α-THF/THF ratio was 90%. SRD5A2 deficiency is more prevalent than expected in the adult female 46XY DSD population. The clinical spectrum of this disorder may extend to a more female phenotype than previously considered to include individuals with little or no virilisation.

Increased Systemic Cortisol Metabolism in Patients With Schizophrenia and Bipolar Disorder

The hypothalamic-pituitary-adrenal (HPA) axis seems dysregulated and part of the pathophysiology in bipolar disorder and schizophrenia, but the underlying mechanisms are unknown. Recent evidence indicates that systemic cortisol metabolism influences blood cortisol levels and HPA axis functioning. Our objective was to estimate systemic cortisol metabolism by means of the activity of 5α-reductase, 5β-reductase, and 11β-hydroxysteroid dehydrogenase (11β-HSD) in patients with bipolar disorder and schizophrenia spectrum disorders compared to healthy controls. Inpatients and outpatients aged 18 to 65 years with DSM-IV bipolar disorder (n = 69) or schizophrenia (n = 87) were consecutively recruited to the catchment area-based Thematically Organized Psychosis Research (TOP) study. Healthy controls (n = 169) were randomly selected from statistical records from the same catchment area and were contacted by letter inviting them to participate. Spot urine samples were collected in a cross-sectional manner from November 2006 to November 2008. Urinary free cortisol and cortisone and their metabolites were analyzed with liquid chromatography tandem mass spectrometry and used as indicators of 5α-reductase, 5β-reductase, and 11β-HSD activity. The combined patient group had increased activity of 5α-reductase, 5β-reductase, and 11β-HSD2 (all P < .001) compared to controls. Elevated systemic cortisol metabolism was present in both schizophrenia (5α-reductase, 5β-reductase, and 11β-HSD2; all P < .001) and bipolar disorder (5α-reductase [P = .016], 5β-reductase [P = .001], and 11β-HSD2 [P = .007]). The results indicate increased activity of cortisol metabolism in patients with bipolar disorder and schizophrenia compared to healthy controls and suggest that increased systemic cortisol metabolism is involved in the pathophysiology and stress vulnerability in these severe mental disorders. The findings should be explored further in terms of potential new drug targets, and they add to the physiologic rationale for stress coping strategies in these patient groups.