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Neoplasia (New York, N.Y.) Nov 2009Treatments for advanced prostate cancer (CaP) typically involve androgen deprivation therapy. However, most patients eventually develop castration-resistant CaP (CRPC)...
Treatments for advanced prostate cancer (CaP) typically involve androgen deprivation therapy. However, most patients eventually develop castration-resistant CaP (CRPC) for which highly effective therapies are limited. We explored the efficacy of a novel agent, HE3235, in inhibiting growth of CRPC in preclinical models. Castrated male mice were implanted subcutaneously with LuCaP35V CaP xenografts in the presence and absence of 5'-androstenediol (AED) and treated with HE3235. To investigate the effect of HE3235 on CaP tumor in the bone, castrated mice were injected intratibially with C4-2B CaP cells and treated with HE3235. Serum prostate-specific antigen (PSA) levels, tumor volume, immunohistochemistry, gene expression, and levels of intratumoral androgens were analyzed. HE3235 significantly prolonged the tumor doubling time of LuCaP35V, decreased androgen receptor expression, and lowered levels of intratumoral testosterone by approximately 89% and dihydrotestosterone by approximately 63% in both the presence and the absence of AED. HE3235 inhibited tumor growth in the bone environment. Weights of tumored tibiae of HE3235-treated animals were lower than those of control (P = .031), and normalized PSA levels were also significantly decreased at the end of study by HE3235 treatment (P = .0076). HE3235 inhibits the growth of subcutaneous CRPC as well as CRPC in the bone environment. Our data show that HE3235 exhibits a wide range of effects, including alteration of androgen receptor signaling and reductions in levels of intratumoral androgens. Our results support ongoing clinical investigations into the effectiveness of HE3235 in the setting of CRPC and warrants further studies into the mechanisms behind the effects of HE3235.
Topics: Androstanols; Animals; Antineoplastic Agents; Bone Neoplasms; Castration; Dihydrotestosterone; Gene Expression; Humans; Immunohistochemistry; Male; Mice; Mice, Nude; Neoplasm Metastasis; Prostatic Neoplasms; Receptors, Androgen; Reverse Transcriptase Polymerase Chain Reaction; Testosterone; Xenograft Model Antitumor Assays
PubMed: 19881957
DOI: 10.1593/neo.09960 -
Molecules (Basel, Switzerland) Jul 2022Multiple biological functions of extract were evaluated in the current work. Phytochemical components of the extract were detected by Gas Chromatography-Mass...
Molecular Interaction Studies and Phytochemical Characterization of L. Constituents with Multiple Biological Utilities as Antioxidant, Antimicrobial, Anticancer and Anti-Hemolytic Agents.
Multiple biological functions of extract were evaluated in the current work. Phytochemical components of the extract were detected by Gas Chromatography-Mass Spectrometry (GC-MS) and High-performance liquid chromatography (HPLC). Moreover, extract was estimated for antioxidant potential by 2,2-Diphenyl-1-picryl-hydrazyl-hydrate (DPPH) free radical scavenging, antimicrobial activity by well diffusion, and anticoagulant activity via prothrombin time (PT) and activated partial thromboplastin time (APTT). GC-MS analysis detected compounds including cholesterol margarate, stigmast-5-en-3-ol, 19-nor-4-androstenediol, androstan-17-one, pulegone-1,2-epoxide, isochiapin B, dotriacontane, hexadecanoic acid and neophytadiene. Chrysoeriol (15.36 µg/mL) was followed by kaempferol (11.14 µg/mL) and 7-OH flavone (10.14 µg/mL), catechin (4.11 µg/mL), hisperdin (3.05 µg/mL), and luteolin (2.36 µg/mL) were detected by HPLC as flavonoids, in addition to ferulic (13.19 µg/mL), cinnamic (12.69 µg/mL), caffeic (11.45 µg/mL), pyrogallol (9.36 µg/mL), -coumaric (5.06 µg/mL) and salicylic (4.17 µg/mL) as phenolics. Antioxidant activity was detected with IC 18 µg/mL, hemolysis inhibition was recorded as 79.8% at 1000 μg/mL, and PT and APTT were at 21.5 s and 49.5 s, respectively, at 50 μg/mL of extract. The acute toxicity of extract was recorded against PC3 (IC 97.99 µg/mL) and MCF7 (IC 80.21 µg/mL). Antimicrobial activity of extract was documented against , , , , , but not against black fungus . Molecular docking was applied using MOE (Molecular Operating Environment) to explain the biological activity of neophytadiene, luteolin, chrysoeriol and kaempferol. These compounds could be suitable for the development of novel pharmacological agents for treatment of cancer and bacterial infections.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Antioxidants; Hemolysis; Hemolytic Agents; Kaempferols; Luteolin; Mentha pulegium; Molecular Docking Simulation; Phytochemicals; Plant Extracts
PubMed: 35956775
DOI: 10.3390/molecules27154824 -
Arthritis Research & Therapy 2005In synovial cells of patients with osteoarthritis (OA) and rheumatoid arthritis (RA), conversion products of major anti-inflammatory androgens are as yet unknown but may... (Comparative Study)
Comparative Study
Androgen conversion in osteoarthritis and rheumatoid arthritis synoviocytes--androstenedione and testosterone inhibit estrogen formation and favor production of more potent 5alpha-reduced androgens.
In synovial cells of patients with osteoarthritis (OA) and rheumatoid arthritis (RA), conversion products of major anti-inflammatory androgens are as yet unknown but may be proinflammatory. Therefore, therapy with androgens in RA could be a problem. This study was carried out in order to compare conversion products of androgens in RA and OA synoviocytes. In 26 OA and 24 RA patients, androgen conversion in synovial cells was investigated using radiolabeled substrates and analysis by thin-layer chromatography and HPLC. Aromatase expression was studied by immunohistochemistry. Dehydroepiandrosterone (DHEA) was converted into androstenediol, androstenedione (ASD), 16alphaOH-DHEA, 7alphaOH-DHEA, testosterone, estrone (E1), estradiol (E2), estriol (E3), and 16alphaOH-testosterone (similar in OA and RA). Surprisingly, levels of E2, E3, and 16alpha-hydroxylated steroids were as high as levels of testosterone. In RA and OA, 5alpha-dihydrotestosterone increased conversion of DHEA into testosterone but not into estrogens. The second androgen, ASD, was converted into 5alpha-dihydro-ASD, testosterone, and negligible amounts of E1, E2, E3, or 16alphaOH-testosterone. 5alpha-dihydro-ASD levels were higher in RA than OA. The third androgen, testosterone, was converted into ASD, 5alpha-dihydro-ASD, 5alpha-dihydrotestosterone, and negligible quantities of E1 and E2. 5alpha-dihydrotestosterone was higher in RA than OA. ASD and testosterone nearly completely blocked aromatization of androgens. In addition, density of aromatase-positive cells and concentration of released E2, E3, and free testosterone from superfused synovial tissue was similar in RA and OA but estrogens were markedly higher than free testosterone. In conclusion, ASD and testosterone might be favorable anti-inflammatory compounds because they decrease aromatization and increase anti-inflammatory 5alpha-reduced androgens. In contrast, DHEA did not block aromatization but yielded high levels of estrogens and proproliferative 16alpha-hydroxylated steroids. Androgens were differentially converted to pro- and anti-inflammatory steroid hormones via diverse pathways.
Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Androgens; Androstenedione; Aromatase; Arthritis, Rheumatoid; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Cytokines; Dehydroepiandrosterone; Estrogens; Female; Humans; Inflammation; Inflammation Mediators; Macrophages; Male; Models, Biological; Osteoarthritis; Synovial Membrane; Testosterone
PubMed: 16207335
DOI: 10.1186/ar1769 -
The Journal of Clinical Endocrinology... Jan 2018Dehydroepiandrosterone sulfate (DHEAS) is the most abundant steroid in human circulation, and adrenocorticotropic hormone (ACTH) is considered the major regulator of its...
BACKGROUND
Dehydroepiandrosterone sulfate (DHEAS) is the most abundant steroid in human circulation, and adrenocorticotropic hormone (ACTH) is considered the major regulator of its synthesis. Pregnenolone sulfate (PregS) and 5-androstenediol-3-sulfate (AdiolS) have recently emerged as biomarkers of adrenal disorders.
OBJECTIVE
To define the relative human adrenal production of Δ5-steroid sulfates under basal and cosyntropin-stimulated conditions.
METHODS
Liquid chromatography-tandem mass spectrometry was used to quantify three unconjugated and four sulfated Δ5-steroids in (1) paired adrenal vein (AV) and mixed venous serum samples (21 patients) and (2) cultured human adrenal cells both before and after cosyntropin stimulation, (3) microdissected zona fasciculata (ZF) and zona reticularis (ZR) from five human adrenal glands, and (4) a reconstituted in vitro human 17α-hydroxylase/17,20-lyase/(P450 17A1) system.
RESULTS
Of the steroid sulfates, PregS had the greatest increase after cosyntropin stimulation in the AV (32-fold), whereas DHEAS responded modestly (1.8-fold). PregS attained concentrations comparable to those of DHEAS in the AV after cosyntropin stimulation (AV DHEAS/PregS, 24 and 1.3 before and after cosyntropin, respectively). In cultured adrenal cells, PregS demonstrated the sharpest response to cosyntropin, whereas DHEAS responded only modestly (21-fold vs 1.8-fold higher compared with unstimulated cells at 3 hours, respectively). Steroid analyses in isolated ZF and ZR showed similar amounts of PregS and 17α-hydroxypregnenolone in both zones, whereas DHEAS and AdiolS were higher in ZR (P < 0.05).
CONCLUSION
Our studies demonstrated that unlike DHEAS, PregS displayed a prominent acute response to cosyntropin. PregS could be used to interrogate the acute adrenal response to ACTH stimulation and as a biomarker in various adrenal disorders.
Topics: Adrenal Glands; Adrenocorticotropic Hormone; Adult; Aged; Case-Control Studies; Cells, Cultured; Dehydroepiandrosterone Sulfate; Female; Follow-Up Studies; Humans; Hyperaldosteronism; Male; Middle Aged; Pregnenolone; Prognosis
PubMed: 29126147
DOI: 10.1210/jc.2017-01525 -
Journal of Neurochemistry Sep 2017Little is known about the origin of the neuroactive steroids dehydroepiandrosterone sulphate (DHEAS) and pregnenolone sulphate (PregS) in the brain or of their...
Little is known about the origin of the neuroactive steroids dehydroepiandrosterone sulphate (DHEAS) and pregnenolone sulphate (PregS) in the brain or of their subsequent metabolism. Using rat brain perfusion in situ, we have found H-PregS to enter more rapidly than H-DHEAS and both to undergo extensive (> 50%) desulphation within 0.5 min of uptake. Enzyme activity for the steroid sulphatase catalysing this deconjugation was enriched in the capillary fraction of the blood-brain barrier and its mRNA expressed in cultures of rat brain endothelial cells and astrocytes. Although permeability measurements suggested a net efflux, addition of the efflux inhibitors GF120918 and/or MK571 to the perfusate reduced rather than enhanced the uptake of H-DHEAS and H-PregS; a further reduction was seen upon the addition of unlabelled steroid sulphate, suggesting a saturable uptake transporter. Analysis of brain fractions after 0.5 min perfusion with the H-steroid sulphates showed no further metabolism of PregS beyond the liberation of free steroid pregnenolone. By contrast, DHEAS underwent 17-hydroxylation to form androstenediol in both the steroid sulphate and the free steroid fractions, with some additional formation of androstenedione in the latter. Our results indicate a gain of free steroid from circulating steroid sulphates as hormone precursors at the blood-brain barrier, with implications for ageing, neurogenesis, neuronal survival, learning and memory.
Topics: Animals; Biological Transport; Blood-Brain Barrier; Brain; Capillary Permeability; Dehydroepiandrosterone Sulfate; Male; Pregnenolone; Propionates; Quinolines; Rats; Rats, Wistar
PubMed: 28665486
DOI: 10.1111/jnc.14117 -
Journal of Applied Physiology... Jan 2002The effectiveness of orally ingested androstenediol in raising serum testosterone concentrations may be limited because of hepatic breakdown of the ingested androgens.... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The effectiveness of orally ingested androstenediol in raising serum testosterone concentrations may be limited because of hepatic breakdown of the ingested androgens. Because androstenediol administered sublingually with cyclodextrin bypasses first-pass hepatic catabolism, we evaluated the acute hormonal response to sublingual cyclodextrin androstenediol supplement in young men. Eight men (22.9 +/- 1.2 yr) experienced in strength training consumed either 20 mg androstenediol in a sublingual cyclodextrin tablet (Sl Diol) or placebo (Pl) separated by at least 1 wk in a randomized, double-blind, crossover manner. Blood samples were collected before supplementation and at 30-min intervals for 3 h after supplementation. Serum hormone concentrations did not change with Pl. Serum androstenedione concentrations were increased (P < 0.05) above baseline (11.2 +/- 1.1 nmol/l) with Sl Diol from 60 to 180 min after intake and reached a peak concentration of 25.2 +/- 2.9 nmol/l at 120 min. Serum free testosterone concentrations were increased from 86.2 +/- 9.1 pmol/l with Sl Diol from 30 to 180 min and reached a peak concentration of 175.4 +/- 12.2 pmol/l at 60 min. Serum total testosterone concentrations increased above basal (25.6 +/- 2.3 nmol/l) from 30 to 180 min with Sl Diol and reached a peak concentration of 47.9 + 2.9 nmol/l at 60 min. Serum estradiol concentrations were elevated (P < 0.05) above baseline (0.08 +/- 0.01 nmol/l) from 30 to 180 min with Sl Diol and reached 0.14 +/- 0.02 nmol/l at 180 min. These data indicate that sublingual cyclodextrin androstenediol intake increases serum androstenedione, free testosterone, total testosterone, and estradiol concentrations.
Topics: Administration, Sublingual; Adult; Androstenediol; Body Composition; Cyclodextrins; Diet; Estradiol; Excipients; Hormones; Humans; Male; Testosterone; Weight Lifting
PubMed: 11744653
DOI: 10.1152/jappl.2002.92.1.142 -
Asian Journal of Andrology 2021This study aims to investigate whether clinical and biological preoperative characteristics of patients who were to undergo radical prostatectomy were associated with...
This study aims to investigate whether clinical and biological preoperative characteristics of patients who were to undergo radical prostatectomy were associated with impairment in patient-reported quality of life (QoL) and erectile dysfunction immediately before intervention. We evaluated patient-reported outcomes among 1019 patients (out of 1343) of the AndroCan study, willing to score the Aging Male Symptom (AMS) and the International Index of Erectile Function 5-item (IIEF-5) auto-questionnaires. Univariate linear regression and robust multiple regression were used to ascertain the relationship between demographic, clinical, and hormonal parameters and global AMS or IIEF-5 scores. As a result, most patients (85.1') of the Androcan cohort agreed to complete questionnaires. Significantly higher IIEF-5 global scores were found in non-Caucasian and obese patients, with larger waist circumference, metabolic syndrome, diabetes mellitus, cardiovascular disease, hypertension, high blood sugar, concomitant medications, and hypogonadism, while the AMS global score was significantly higher in patients with larger waist circumference, metabolic syndrome, high blood pressure, raised glycemia, and concomitant medication. The IIEF-5 global score was correlated to age, dehydroepiandrosterone (DHEA), fat mass percentage, and androstenediol (D5). The AMS global score was significantly correlated to DHEA, D5, and DHEA sulfate. Finally, the multivariate models showed that QoL and erectile function were significantly affected, before surgery, by symptoms and signs that are usually considered as pertaining to the metabolic syndrome, while sexual hormones are essentially correlated to erectile dysfunction.
Topics: Adult; Aged; Androgens; Erectile Dysfunction; Humans; Male; Metabolic Syndrome; Middle Aged; Preoperative Period; Prostatectomy; Quality of Life; Severity of Illness Index; Surveys and Questionnaires
PubMed: 33762475
DOI: 10.4103/aja.aja_3_21 -
The Journal of Steroid Biochemistry and... May 2022Endurance training is associated with physiological changes in elite athletes, but little is known about female-specific effects of endurance training. Despite the...
Endurance training is associated with physiological changes in elite athletes, but little is known about female-specific effects of endurance training. Despite the significant rise in female sports participation, findings from studies performed on male athletes are largely extrapolated to females without taking into consideration sex-specific differences in metabolism. Subsequently, this study aimed to investigate the steroid hormone profiles of elite female endurance athletes in comparison with their non-athletic counterparts. Untargeted metabolomics-based mass spectroscopy combined with ultra-high-performance liquid chromatography was performed on serum samples from 51 elite female endurance athletes and 197 non-athletic females. The results showed that, compared to non-athletic females, certain androgen, pregnenolone, and progestin steroid hormones were reduced in elite female endurance athletes, while corticosteroids were elevated. The most significantly altered steroid hormones were 5alpha-androstan-3alpha,17alpha-diol monosulfate (FDR = 1.90 × 10), androstenediol (3alpha, 17alpha) monosulfate (FDR = 2.93 × 10), and cortisol (FDR = 2.93 × 10). Conclusively, the present study suggests that elite female endurance athletes have a unique steroid hormone profile with implications on their general health and performance.
Topics: Adrenal Cortex Hormones; Androgens; Athletes; Female; Humans; Male; Metabolome; Steroids
PubMed: 35182726
DOI: 10.1016/j.jsbmb.2022.106081 -
European Child & Adolescent Psychiatry Jun 2014Autism is diagnosed on the basis of behavioral manifestations, but its biomarkers are not well defined. A strong gender bias typifying autism (it is 4-5 times more...
Autism is diagnosed on the basis of behavioral manifestations, but its biomarkers are not well defined. A strong gender bias typifying autism (it is 4-5 times more prevalent in males) suggests involvement of steroid hormones in autism pathobiology. In order to evaluate the potential roles of such hormones in autism, we compared the salivary levels of 22 steroids in prepubertal autistic male and female children from two age groups (3-4 and 7-9 years old) with those in healthy controls. The steroids were analyzed using gas chromatography-mass spectrometry and radioimmunoassay. Statistical analysis (ANOVA) revealed that autistic children had significantly higher salivary concentrations of many steroid hormones (both C21 and C19) than control children. These anomalies were more prominent in older autistic children and in boys. The levels of androgens (androstenediol, dehydroepiandrosterone, androsterone and their polar conjugates) were especially increased, indicative of precocious adrenarche and predictive of early puberty. The concentrations of the steroid precursor, pregnenolone, and of several pregnanolones were also higher in autistic than in healthy children, but cortisol levels were not different. Some steroids, whose levels are raised in autism (allopregnanolone, androsterone, pregnenolone, dehydroepiandrosterone and their sulfate conjugates) are neuroactive and modulate GABA, glutamate, and opioid neurotransmission, affecting brain development and functioning. These steroids may contribute to autism pathobiology and symptoms such as elevated anxiety, sleep disturbances, sensory deficits, and stereotypies among others. We suggest that salivary levels of selected steroids may serve as biomarkers of autism pathology useful for monitoring the progress of therapy.
Topics: Androgens; Autistic Disorder; Biomarkers; Case-Control Studies; Child; Child, Preschool; Female; Humans; Male; Saliva
PubMed: 24043498
DOI: 10.1007/s00787-013-0472-0 -
Fertility and Sterility May 1998To test the hypothesis that ovarian hormones in women with hyperandrogenism alter adrenocortical steroidogenesis.
OBJECTIVE
To test the hypothesis that ovarian hormones in women with hyperandrogenism alter adrenocortical steroidogenesis.
DESIGN
Combination of two prospective studies.
SETTING
Academic medical centers.
PATIENT(S)
Eighteen hyperandrogenic patients demonstrating hirsutism with either hyperandrogenemia, oligomenorrhea, or both. Eighteen healthy nonhirsute eumenorrheic untreated women served as controls.
INTERVENTIONS
Blood sampling basally and after acute adrenal stimulation with ACTH, before and after 20-24 weeks of leuprolide administration. Nine patients also received 0.625 mg/d of oral conjugated esterified estrogens and 10 mg of medroxyprogesterone acetate days 1-12 of the month (i.e., estrogen replacement therapy [ERT]), whereas the remaining nine did not.
MAIN OUTCOME MEASURE(S)
Before and after the administration of the GnRH agonist (GnRH-a), the basal concentrations of DHEAS; and the levels of androstenedione (A4), DHEA, androstenediol, 11 beta-hydroxyandrostenedione (11-OHA4), and cortisol before and 60 minutes after acute adrenal stimulation, were measured.
RESULT(S)
Levels of DHEAS, androstenediol, and 11-OHA4 decreased by 15%-30%, regardless of whether patients initially had or did not have DHEAS excess. However, only hyperandrogenic patients with elevated levels of DHEAS showed a significant decrease in basal DHEA levels. No statistically significant difference in the response of either androgen to ACTH (1-24) stimulation was noted with ovarian suppression, regardless of initial DHEAS level or use of ERT.
CONCLUSION(S)
We found no evidence that ovarian hormone secretion affected adrenal steroidogenesis, and those women with the highest adrenal androgen levels had the least response to GnRH-a suppression. These findings further support the concept of an intrinsic, and possibly primary, abnormality of adrenocortical steroidogenesis in a subset of hyperandrogenic women that is independent of ovarian abnormalities.
Topics: Adolescent; Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Adult; Androgens; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Estrogen Replacement Therapy; Female; Hirsutism; Humans; Leuprolide; Ovary; Prospective Studies
PubMed: 9591492
DOI: 10.1016/s0015-0282(98)00033-8