LC-MS-based urine metabolomics analysis of chronic subdural hematoma for biomarker discovery.

BACKGROUND: Chronic subdural hematoma (CSDH) is one of the most common neurosurgical diseases with atypical manifestations. The aim of this study was to utilize urine metabolomics to explore potential biomarkers for the diagnosis and prognosis of CSDH. METHODS: Seventy-seven healthy controls and ninety-two patients with CSDH were enrolled in our study. In total, 261 urine samples divided into the discovery group and validation group were analyzed by LC-MS. The statistical analysis and functional annotation were applied to discover potential biomarker panels and altered metabolic pathways. RESULTS: A total of 53 differential metabolites were identified in this study. And the urinary metabolic profiles showed apparent separation between patients and controls. Further functional annotation showed that the differential metabolites were associated with lipid metabolism, fatty acid metabolism, amino acid metabolism, biotin metabolism, steroid hormone biosynthesis, and pentose and glucuronate interconversions. Moreover, one panel of Capryloylglycine, cis-5-Octenoic acid, Ethisterone, and 5,6-DiHETE showed good predictive performance in the diagnosis of CSDH, with an AUC of 0.89 in discovery group and an AUC of 0.822 in validation group. Another five metabolites (Trilobinol, 3'-Hydroxyropivacaine, Ethisterone, Arginyl-Proline, 5-alpha-Dihydrotestosterone glucuronide) showed the levels of them returned to a healthy state after surgery, showing good possibility to monitor the recovery of CSDH patients. CONCLUSION AND CLINICAL RELEVANCE: The findings of the study revealed urine metabolomic differences between CSDH and controls. The potentially diagnostic and prognostic biomarker panels of urine metabolites were established, and functional analysis demonstrated deeper metabolic disorders of CSDH, which might conduce to improve early diagnose of CSDH clinically.

A Multivalent Peptoid Conjugate Modulates Androgen Receptor Transcriptional Activity to Inhibit Therapy-resistant Prostate Cancer.

Prostate cancers adapt to androgen receptor (AR) pathway inhibitors and progress to castration resistance due to ongoing AR expression and function. To counter this, we developed a new approach to modulate the AR and inhibit castration-resistant prostate cancer (CRPC) using multivalent peptoid conjugates (MPC) that contain multiple copies of the AR-targeting ligand ethisterone attached to a peptidomimetic scaffold. Here, we investigated the antitumor effects of compound MPC309, a trivalent display of ethisterone conjugated to a peptoid oligomer backbone that binds to the AR with nanomolar affinity. MPC309 exhibited potent antiproliferative effects on various enzalutamide-resistant prostate cancer models, including those with AR splice variants, ligand-binding mutations, and noncanonical AR gene expression programs, as well as mouse prostate organoids harboring defined genetic alterations that mimic lethal human prostate cancer subtypes. MPC309 is taken up by cells through macropinocytosis, an endocytic process more prevalent in cancer cells than in normal ones, thus providing an opportunity to target tumors selectively. MPC309 triggers a distinct AR transcriptome compared with DHT and enzalutamide, a clinically used antiandrogen. Specifically, MPC309 enhances the expression of differentiation genes while reducing the expression of genes needed for cell division and metabolism. Mechanistically, MPC309 increases AR chromatin occupancy and alters AR interactions with coregulatory proteins in a pattern distinct from DHT. In xenograft studies, MPC309 produced significantly greater tumor suppression than enzalutamide. Altogether, MPC309 represents a promising new AR modulator that can combat resistant disease by promoting an AR antiproliferative gene expression program.

Facile, Single-Step Synthesis of a Series of D-Ring Ethisterones Substituted with 1,4-1,2,3-Triazoles: Preliminary Evaluation of Cytotoxic Activities.

A series of new D-ring ethisterones substituted with 1,4-1,2,3-triazoles were obtained in a facile manner via click chemistry reactions. The new compounds were characterized by multinuclear NMR spectroscopy, mass spectrometry, IR and unequivocally by single crystal X-ray diffraction studies for compound 1. The cytotoxic activity of these derivatives was tested against a series of human cancer cell lines including human glioblastoma (U-251), human prostatic adenocarcinoma (PC-3), human colorectal adenocarcinoma (HCT-15), human mammary adenocarcinoma (MCF-7), human chronic myelogenous leukemia (K562), and human lung adenocarcinoma (SKLU-1). Derivatives (3, X=Cl) and (5, X=I) showed promising cytotoxicity activities for leukemia adenocarcinoma (K562) and lung adenocarcinoma (SKLU). CI50% of K562: 11.72±0.9 µM (3) and 24.50±1.0 µM (5). CI50% of SKLU: 14.9±0.8 µM (3) and 46.0±2.8 µM (5). In addition, DNA docking simulations showed that all compounds interact with DNA through crosslink instrastrand p-alkyl-like interactions.

Microbial transformation of oral contraceptive ethisterone by Aspergillus niger and Cunninghamella blakesleeana.

Ethisterone (17α-ethynyl-17ß-hydroxyandrost-4-en-3-one) (1) is a synthetic steroidal estrogen. It is extensively used as an oral contraceptive. The current study involves the structural transformation of ethisterone (1) by Aspergillus niger, and Cunninghamella blakesleeana. Fermentation of 1 with C. blakesleeana afforded two new polar metabolites, 17α-ethynyl-6ß,15ß,17ß-trihydroxyandrost-4-en-3-one, and 17α-ethynyl-7ß,15ß,17ß-trihydroxyandrost-4-en-3-one, while transformation of ethisterone with A. niger yielded a new metabolite, 17α-ethynyl-6α,17ß-dihydroxyandrost-4-en-3-one, along with a known metabolite, 17α-ethynyl-11α,17ß-dihydroxyandrost-4-en-3-one. Modern spectroscopic techniques were used to characterize the structures of all transformed products.

18F-labeled ethisterone derivative for progesterone receptor targeted PET imaging of breast cancer.

PURPOSE: A novel radiolabeled probe 1­(17­[18F]fluoro­3,6,9,12,15­pentaoxaheptadecyl­1H­1,2,3­triazole testosterone ([18F]FPTT) was synthesized and evaluated for PET imaging of progesterone receptor (PR)-positive breast cancer. METHODS: The ethinyl group of ethisterone, a PR targeting pharmacophore, was coupled with azide modified PEG-OTs by click chemistry to obtain the labeling precursor. The final [18F]FPTT was synthesized by a one-step nucleophilic substitution reaction with 18F. The in vitro stabilities of [18F]FPTT in saline or rat serum were determined after 2 h incubation. Then the in vitro cell binding, ex vivo biodistribution and in vivo imaging of [18F]FPTT were further investigated to evaluate the PR targeting ability and feasibility for the diagnosis of PR-positive breast cancer with PET imaging. RESULTS: [18F]FPTT was obtained in high decay-corrected radiochemical yield (78 ±â€¯9%) at the end of synthesis. It had high radiochemical purity (>98%) after HPLC purification and good in vitro stability. The molar activity of [18F]FPTT was calculated as 17 GBq/µmol. The microPET imaging of [18F]FPTT in tumor-bearing mice showed much higher tumor uptake in PR-positive MCF-7 tumor (3.9 ±â€¯0.20%ID/g) than that of PR-negative MDA-MB-231 tumor (1.3 ±â€¯0.08%ID/g). The high MCF-7 tumor uptake could be specifically inhibited by blocking with ethisterone (1.3 ±â€¯0.11%ID/g) or [19F]FPTT (2.20 ±â€¯0.17%ID/g), respectively. The biodistribution in estrogen-primed female SD rats of [18F]FPTT showed high uterus and ovary uptakes (8.31 ±â€¯1.74%ID/g and 3.79 ±â€¯0.82%ID/g at 1 h post-injection). The specific uptakes of uterus and ovary in normal rats were 3.52 ±â€¯0.29%ID/g and 3.22 ±â€¯0.50%ID/g respectively and could be inhibited by co-injecting of ethisterone. CONCLUSION: A novel [18F]FPTT probe based on ethisterone modification could be a potential diagnostic agent for PR-positive breast cancer.

Label-free sensitive luminescence biosensor for immunoglobulin G based on Ag6Au6 ethisterone cluster-estrogen receptor α aggregation and graphene.

A specific and label-free "on-off-on" luminescence biosensor based on a novel heterometallic cluster [Ag6Au6(ethisterone)12]-estrogen receptor α (Ag6Au6Eth-ERα) aggregation utilizing graphene oxide (GO) as a quencher to lead a small background signal was firstly constructed to detect immunoglobulin G (IgG) with a simple process and high selectivity. The efficient photoluminescent (PL) Ag6Au6Eth-ERα aggregation is strongly quenched by GO. In the presence of IgG, the PL of this system will be restored, and perceivable by human eyes under UV lamp excitation (365 nm). The quenching mechanism of GO on Ag6Au6Eth-ERα and enhancement mechanism of IgG on Ag6Au6Eth-ERα-GO were investigated in detail. Under the optimum conditions, the biosensor for high sensitive IgG detection expressed a wider linear range of 0.0078-10 ng/mL and a lower detection limit of 0.65 pg/mL with good stability and repeatability, which provided a new approach for label-free IgG detection.

Synthesis and preliminary evaluation of a 18 F-labeled ethisterone derivative [18 F]EAEF for progesterone receptor targeting.

To develop a novel progesterone receptor-targeting probe for positron emission tomography imaging, an ethisterone derivative [18 F]EAEF was designed and prepared in high decay-corrected radiochemical yield (30-35%) with good radiochemical purity (>98%). [18 F]EAEF is a lipophilic tracer (logP = 0.53 ± 0.06) with very good stability in saline and serum. In the biodistribution study, high radioactivity accumulation of [18 F]EAEF were found in uterus (5.73 ± 1.83% ID/g) and ovary (4.05 ± 0.73% ID/g) at 2 hr postinjection (p.i.), which have high progesterone receptor expression after treated with estradiol, while the muscle background has very low uptake (0.50 ± 0.17% ID/g). For positron emission tomography imaging, [18 F]EAEF showed high uptake in progesterone receptor-positive MCF-7 tumor (3.15 ± 0.07% ID/g at 2 hr p.i.) with good tumor to muscle ratio (2.90), and obvious lower tumor uptakes were observed in MCF-7 with EAEF blocking (1.84 ± 0.05% ID/g at 2 hr p.i.) or in progesterone receptor-negative MDA-MB-231 tumor (1.80 ± 0.03% ID/g at 2 hr p.i.). Based on the good stability and specificity of [18 F]EAEF, it may be a good candidate for imaging progesterone receptor and worth further investigation.

A Silver(I)-Estrogen Nanocluster: GSH Sensitivity and Targeting Suppression on HepG2 Cell.

A structure-determined silver nanocluster of [Ag10 (Eth)4 (CF3 COO)6 (CH3 OH)3 ]·3C-H3 OH (Eth = ethisterone) (1), is firstly demonstrated by self-assembly of silver salt and ethisterone. Due to the thiophilicity of silver(I) ions, complex 1 shows reactivity with glutathione (GSH) molecules in solution and induces the fluorescence quenching behavior. Thus, complex 1 can be used as a fluorescent sensor for GSH. In consideration of the higher level of GSH in cancerous cells, complex 1 presents significant tumor suppression reactivity toward the human hepatocellular carcinoma (HepG2) cells with IC50 value of 165 × 10-9 m. Especially, complex 1 displays 3.4-fold higher in vitro cytotoxicity to HepG2 cells than that of the normal CCC-HEL-1 cells, which makes complex 1 a potential targeting suppression agent for cancerous cells. The molecular design of complex 1 not only generates a new medicine-silver(I) cluster family, but also opens a new avenue to the targeting anticancer organosilver(I) materials.

Multivalent Peptoid Conjugates Which Overcome Enzalutamide Resistance in Prostate Cancer Cells.

Development of resistance to antiandrogens for treating advanced prostate cancer is a growing concern and extends to recently developed therapeutics, including enzalutamide. Therefore, new strategies to block androgen receptor (AR) function in prostate cancer are required. Here, we report the characterization of a multivalent conjugate presenting two bioactive ethisterone ligands arrayed as spatially defined pendant groups on a peptoid oligomer. The conjugate, named Multivalent Peptoid Conjugate 6 (MPC6), suppressed the proliferation of multiple AR-expressing prostate cancer cell lines including those that failed to respond to enzalutamide and ARN509. The structure-activity relationships of MPC6 variants were evaluated, revealing that increased spacing between ethisterone moieties and changes in peptoid topology eliminated its antiproliferative effect, suggesting that both ethisterone ligand presentation and scaffold characteristics contribute to MPC6 activity. Mechanistically, MPC6 blocked AR coactivator-peptide interaction and prevented AR intermolecular interactions. Protease sensitivity assays suggested that the MPC6-bound AR induced a receptor conformation distinct from that of dihydrotestosterone- or enzalutamide-bound AR. Pharmacologic studies revealed that MPC6 was metabolically stable and displayed a low plasma clearance rate. Notably, MPC6 treatment reduced tumor growth and decreased Ki67 and AR expression in mouse xenograft models of enzalutamide-resistant LNCaP-abl cells. Thus, MPC6 represents a new class of compounds with the potential to combat treatment-resistant prostate cancer. Cancer Res; 76(17); 5124-32. ©2016 AACR.

Investigation on the Interaction of Norgestrel with Human Serum Albumin Using Spectroscopy and Molecular-Docking Method.

The interaction of norgestrel with human serum albumin (HSA) was investigated by spectroscopy and molecular-docking methods. Results of spectroscopy methods suggested that the quenching mechanism of norgestrel on HSA was static quenching and that the quenching process was spontaneous. Negative values of thermodynamic parameters (ΔG, ΔH, and ΔS) indicated that hydrogen bonding and van der Waals forces dominated the binding between norgestrel and HSA. Three-dimensional fluorescence spectrum and circular dichroism spectrum showed that the HSA structure was slightly changed by norgestrel. Norgestrel mainly bound with Sudlow site I based on a probe study, as confirmed by molecular-docking results. Competition among similar structures indicated that ethisterone and norethisterone affected the binding of norgestrel with HSA. CH3 in R1 had little effect on norgestrel binding with HSA. The surface hydrophobicity properties of HSA, investigated using 8-anilino-1-naphthalenesulfonic acid, was changed with norgestrel addition.

Luminescent Ag6Au6 heterometallic ethisterone cluster and probe for estrogen receptor α.

A heterometallic cluster [Ag6Au6(ethisterone)12] of an unprecedented topology was synthesized and characterized. A sensitive and specific probe for estrogen receptor α (ERα) has been developed for the first time based on the enhancement of the Ag6Au6 luminescence.

Efficient synthesis of ethisterone glycoconjugate via bis-triazole linkage.

Synthesis of sugar based triazolyl azido-alcohols was accomplished via one pot click reaction of glycosyl alkynes with epichlorohydrin in aqueous medium. All the developed triazolyl azido-alcohols were further utilized for the synthesis of bis-triazolyl ethisterone glycoconjugates using CuAAC reaction. The developed triazole-linked ethisterone glycoconjugates would be crucial in androgen receptor pharmacology and chemical biology.

Click chemistry inspired highly facile synthesis of triazolyl ethisterone glycoconjugates.

Numerous deoxy-azido sugars 3 were prepared by the reaction of tosyl/bromo sugars with NaN3 in dry DMF under heating condition. The 1,3-dipolar cycloaddition of deoxy-azido sugars 3 with ethisterone 4 to afford regioselective triazole-linked ethisterone glycoconjugates 5 was investigated in the presence of CuI and DIPEA in dichloromethane or CuSO4·5H2O and sodium ascorbate in aqueous medium. All the developed compounds were characterized by spectroscopic analysis (IR, (1)H &(13)C NMR, and MS spectra). Structure of triazolyl ethisterone glycoconjugate 5a has been further confirmed by its Single Crystal X-ray analysis.

Combined oestrogen and progesterone for preventing miscarriage.

BACKGROUND: Historically, oestrogen and progesterone were each commonly used to save threatened pregnancies. In the 1940s it was postulated that their combined use would be synergistic and thereby led to the rationale of combined therapy for women who risked miscarriage. OBJECTIVES: To determine the efficacy and safety of combined oestrogen and progesterone therapy to prevent miscarriage. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (23 June 2013) CENTRAL (OVID) (The Cochrane Library 2013, Issue 6 of 12), MEDLINE (OVID) (1946 to June Week 2 2013), OLDMEDLINE (1946 to 1965), Embase (1974 to Week 25 2013), Embase Classic (1947 to 1973), CINAHL (1994 to 23 June 2013) and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials that assessed the effectiveness of combined oestrogen and progesterone for preventing miscarriage. We included one stratified randomised trial and one quasi-randomised trials. Cluster-randomised trials were eligible for inclusion but none were identified. We excluded studies published only as abstracts.We included studies that compared oestrogen and progesterone versus placebo or no intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and assessed trial quality. Two review authors extracted data. Data were checked for accuracy. MAIN RESULTS: Two trials (281 pregnancies and 282 fetuses) met our inclusion criteria. However, the two trials had significant clinical and methodological heterogeneity such that a meta-analysis combining trial data was considered inappropriate.One trial (involving 161 pregnancies) was based on women with a history of diabetes. It showed no statistically significant difference between using combined oestrogen and progestogen and using placebo for all our proposed primary outcomes, namely, miscarriage (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.32 to 2.80), perinatal death (RR 0.94, 95% CI 0.53 to 1.69) and preterm birth (less than 34 weeks of gestation) (RR 0.91, 95% CI 0.80 to 1.04). In terms of this review's secondary outcomes, use of combined oestrogen and progestogen was associated with an increased risk of maternal cancer in the reproductive system (RR 6.65, 95% CI 1.56 to 28.29). However, for the outcome of cancer other than that of the reproductive system in mothers, there was no difference between groups. Similarly, there were no differences between the combined oestrogen and progestogen group versus placebo for other secondary outcomes reported: low birthweight of less than 2500 g, genital abnormalities in the offspring, abnormalities other than genital tract in the offspring, cancer in the reproductive system in the offspring, or cancer other than of the reproductive system in the offspring.The second study was based on pregnant women who had undergone in-vitro fertilisation (IVF). This study showed no difference in the rate of miscarriage between the combined oestrogen and progesterone group and the no treatment group (RR 0.66, 95% CI 0.23 to 1.85). The study did not report on this review's other primary outcomes (perinatal death or rates of preterm birth), nor on any of our proposed secondary outcomes. AUTHORS' CONCLUSIONS: There is an insufficient evidence from randomised controlled trials to assess the use of combined oestrogen and progesterone for preventing miscarriages. We strongly recommend further research in this area.

Androgen receptor antagonism by divalent ethisterone conjugates in castrate-resistant prostate cancer cells.

Sustained treatment of prostate cancer with androgen receptor (AR) antagonists can evoke drug resistance, leading to castrate-resistant disease. Elevated activity of the AR is often associated with this highly aggressive disease state. Therefore, new therapeutic regimens that target and modulate AR activity could prove beneficial. We previously introduced a versatile chemical platform to generate competitive and non-competitive multivalent peptoid oligomer conjugates that modulate AR activity. In particular, we identified a linear and a cyclic divalent ethisterone conjugate that exhibit potent anti-proliferative properties in LNCaP-abl cells, a model of castrate-resistant prostate cancer. Here, we characterize the mechanism of action of these compounds utilizing confocal microscopy, time-resolved fluorescence resonance energy transfer, chromatin immunoprecipitation, flow cytometry, and microarray analysis. The linear conjugate competitively blocks AR action by inhibiting DNA binding. In addition, the linear conjugate does not promote AR nuclear localization or co-activator binding. In contrast, the cyclic conjugate promotes AR nuclear localization and induces cell-cycle arrest, despite its inability to compete against endogenous ligand for binding to AR in vitro. Genome-wide expression analysis reveals that gene transcripts are differentially affected by treatment with the linear or cyclic conjugate. Although the divalent ethisterone conjugates share extensive chemical similarities, we illustrate that they can antagonize the AR via distinct mechanisms of action, establishing new therapeutic strategies for potential applications in AR pharmacology.

Novel C,N-chelate platinum(II) antitumor complexes bearing a lipophilic ethisterone pendant.

The novel steroidal carrier ligand 17-α-[4'-ethynyl-dimethylbenzylamine]-17-ß-testosterone (ET-dmba 1) and the steroid--C,N-chelate platinum(II) derivatives [Pt(ET-dmba)Cl(L)] (L = DMSO (2) and PTA (3; PTA =1,3,5-triaza-7-phosphaadamantane)) have been prepared. Values of IC(50) were calculated for the new platinum complexes 2 and 3 against a panel of human tumor cell lines representative of ovarian (A2780 and A2780cisR) and breast cancers (T47D). At 48h incubation time complexes 2 and 3 show very low resistance factors (RF of <2) against an A2780 cell line which has acquired resistant to cisplatin and were more active than cisplatin (about 4-fold for 3) in T47D (AR+, AR=androgen receptor). Compound 1 retains a moderate degree of relative binding affinity (RBA=0.94%) for androgen receptors. The cytotoxicity of the non steroidal platinum analogues [Pt(dmba)Cl(L)] (dmba=dimethylbenzylamine; L=DMSO (4) and PTA (5)) has also been studied for comparison purposes. Theoretical calculations at the BP86/def2-TZVP level of theory on complex 3 have been undertaken.

Cytotoxicity, cellular localisation and biomolecular interaction of non-covalent metallo-intercalators with appended sex hormone steroid vectors.

A range of terpyridine platinum(II) metallo-intercalators with bioactive steroids attached has been created with the aim of localizing cytotoxic drugs. Complexes where the steroid does not interfere with access to the terpyridine are shown to retain potent cytotoxicity and show certain selectivity towards their natural receptors. Because the intercalation of the terpyridine moiety between the bases of the DNA is the origin of the biological activity, a dramatic decrease of the activity is observed when the access to the terpyridine unit is hindered by the steroidal unit.

Vitellogenin induction by a mixture of steroidal estrogens in freshwater fishes and relevant risk assessment.

The study method on combined effects of environmental contaminant mixture and ecological risk assessment was discussed. Batch tests were conducted to assess the in vivo potency of binary mixtures of estrogens using plasma vitellogenin concentrations in male crucian carp as the endpoint. The estrogenic potencies of 17beta-estradiol (E(2)) and 17alpha-ethynylestradiol (EE(2)) were determined following 14 day exposure to the individual chemicals and equipotent binary mixtures. A Nonlinear regression was obtained and 95% confidence limits of effect concentration were achieved using the bootstrap method. Concentration-response curve for fixed ratio binary mixtures of E(2) and EE(2) was compared with those for individual chemicals, using the biomathematical models of concentration addition (CA) and independent action (IA). A complete overlap was found for the CA predictions with the 95% confidence interval of the best-fit regression line of the observed responses, and the IA predictions was shown lower than the observations. The observed mixture effects were considerably higher than those of the hormone alone and far exceeded the 95% confidence interval of the estrogen regression lines. The predicted effects of binary mixtures at different mixture ratios indicated that the potential impact of components on mixture would depend predominantly on its concentration, the mixture ratio and its relative potency. Results suggested that E(2) and EE(2) acted together in an additive manner and the combined effects can be accurately predicted in whole range of exposure concentration by the models of CA and IA, the model of CA might be realistic, but more useful for ecological risk assessment.

Structure-activity relationships of synthetic progestins in a yeast-based in vitro androgen bioassay.

The recent identification of tetrahydrogestrinone (THG), a non-marketed designer androgen used for sports doping but previously undetectable by established mass spectrometry-based urine drug screens, and its production by a facile chemical modification of gestrinone has raised concerns about the risks of developing designer androgens from numerous marketed progestins. We therefore have used yeast-based in vitro androgen and progesterone bioassays to conduct a structure-activity study assessing the intrinsic androgenic potential of commercially available progestins and their derivatives, to identify those compounds or structures with the highest risk of forming a basis for such misapplication. Progestins had a wide range of androgenic bioactivity that was not reliably predicted for individual steroids by their progestin bioactivity. 17alpha-Hydroxyprogesterone and 19-norprogesterone derivatives with their bulky 17beta-substituents were strong progestins but generally weak androgens. 17alpha-Ethynylated derivatives of testosterone, 19-nortestosterone and 18-methyl-19-nortestosterone such as gestrinone, ethisterone, norethisterone and norgestrel had the most significant intrinsic androgenicity of all the commercially marketed progestins. Facile chemical modification of the 17alpha-ethynyl group of each of these progestins produces 17alpha-methyl, ethyl and allyl derivatives, including THG and norbolethone, which further enhanced androgenic bioactivity. Thus by using the rapid and sensitive yeast bioassay we have screened a comprehensive set of progestins and associated structures and identified the ethynylated testosterone, 19-nortestosterone and 18-methyl-19-nortestosterone derivatives as possessing the highest risk for abuse and potential for conversion to still more potent androgens. By contrast, modern progestins such as progesterone, 17alpha-hydroxyprogesterone and 19-norprogesterone derivatives had minimal androgenic bioactivity and pose low risk.

[Advances in the study of steroidogenic acute regulatory protein].

The steroidogenic acute regulatory (StAR) protein is an essential component in the regulation of steroid biosynthesis in adrenal and gonadal cells. The StAR protein has a high tissue specificity, located on the mitochondrial membranes of some relative cells. It regulates the transfer of cholesterin from extracellular into intracellular and plays a dominant role in steroidogenic synthesis. Recent studies have also shown that the transcription and expression of StAR are modulated not only through the cAMP-PKA dependent pathway, but also by multiple hormones and cytokines, which contributes to the regulation of cholesterin synthesis.