ASKA Pharma Medical Co.

Kawasaki, Japan

ASKA Pharma Medical Co.

Kawasaki, Japan
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Rege J.,University of Georgia | Nakamura Y.,Tohoku University | Satoh F.,Tohoku University | Morimoto R.,Tohoku University | And 5 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: Abroad analysis of adrenal gland-derived 19-carbon (C 19) steroids has not been reported. This is the first study that uses liquid chromatography-tandem mass spectrometry to quantify 9 C19 steroids (androgens and their precursors), estrone, and estradiol in the adrenal vein (AV) of women, before and after ACTH stimulation. Objective: The objective of this study was to define the adrenal androgen metabolome in women before and after ACTH infusion. Design: This was a retrospective study. Patients: Seven women, aged 50.4±5.4 years, with suspected diagnosis of an adrenal aldosterone-producing adenoma were included in the study. Methods: AV and iliac serum samples were collected before and after administration of ACTH (15 minutes). AV samples were analyzed using for concentrations of 9 unconjugated C19 steroids, estrone, and estradiol. Dehydroepiandrosterone sulfate (DHEA-S) was quantified by radioimmunoassay. Results: AV levels of DHEA-S were the highest among the steroids measured. The most abundant unconjugated C 19 steroids in AV were 11β-hydroxyandrostenedione (11OHA), dehydroepiandrosterone (DHEA), and androstenedione (A4). ACTH significantly increased the adrenal output of 9 of the 12 steroids that were measured. ACTH increased the mean AV concentration of DHEA-S by 5-fold, DHEA by 21-fold, A4 by 7-fold, and 11OHA by 5-fold. 11β-Hydroxytestosterone and testosterone were found to be potent androgen receptor agonists when tested with an androgen-responsive cell reporter model. Conclusion: The current study indicates that the adrenal gland secretes primarily 3 weak androgens, namely DHEA, 11OHA, and A4. Active androgens, including testosterone and 11β- hydroxytestosterone, are also produced but to a lesser degree. Copyright © 2013 by The Endocrine Society.

Nakamura Y.,Tohoku University | Satoh F.,Tohoku University | Morimoto R.,Tohoku University | Kudo M.,Tohoku University | And 9 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Context: 18-Oxocortisol (18-oxoF) is a derivative of cortisol (F) that is produced by aldosterone synthase (CYP11B2). The potential for this steroid as a biomarker for differentiating patients with aldosterone-producing adenoma (APA) from those with idiopathic hyperaldosteronism (IHA) has not been examined. Objectives: We measured 18-oxoF, aldosterone, and F in plasma from adrenal vein sampling (AVS) of patients with primary aldosteronism.Wecompared 18-oxoF levels and 18-oxoF/F ratios for their potential to differentiate APA from IHA. Design, Setting, and Subjects: This study measured 18-oxoF, F, and aldosterone in AVS obtained from patients with unilateral APA (14 cases) or bilateral IHA (seven cases, 14 samples total) using liquid chromatography-tandem mass spectrometry and RIA analyses. Results: The levels of 18-oxoF and the ratios of 18-oxoF/F, before and after ACTH stimulation, were significantly higher in blood-draining APA than in those from the contralateral adrenal glands and from adrenal glands with IHA. Conclusions: The 18-oxoF levels and ratios of 18-oxoF/F in AVS samples can be a clinically useful biomarker for differentiating APA from IHA and for determining the localization or lateralization of APA in patients with primary aldosteronism. Copyright © 2011 by The Endocrine Society.

Satoh F.,Tohoku University | Morimoto R.,Tohoku University | Ono Y.,Tohoku University | Iwakura Y.,Tohoku University | And 14 more authors.
Hypertension | Year: 2015

Adrenal venous sampling is currently the only reliable method to distinguish unilateral from bilateral diseases in primary aldosteronism. In this study, we attempted to determine whether peripheral plasma levels of 18-oxocortisol (18oxoF) and 18-hydroxycortisol could contribute to the clinical differentiation between aldosteronoma and bilateral hyperaldosteronism in 234 patients with primary aldosteronism, including computed tomography (CT)-detectable aldosteronoma (n=113) and bilateral hyperaldosteronism (n=121), all of whom underwent CT and adrenal venous sampling. All aldosteronomas were surgically resected and the accuracy of diagnosis was clinically and histopathologically confirmed. 18oxoF and 18-hydroxycortisol were measured using liquid chromatography tandem mass spectrometry. Receiver operating characteristic analysis of 18oxoF discrimination of adenoma from hyperplasia demonstrated sensitivity/specificity of 0.83/0.99 at a cut-off value of 4.7 ng/dL, compared with that based on 18-hydroxycortisol (sensitivity/specificity: 0.62/0.96). 18oxoF levels above 6.1 ng/dL or of aldosterone >32.7 ng/dL were found in 95 of 113 patients with aldosteronoma (84%) but in none of 121 bilateral hyperaldosteronism, 30 of whom harbored CT-detectable unilateral nonfunctioning nodules in their adrenals. In addition, 18oxoF levels below 1.2 ng/dL, the lowest in aldosteronoma, were found 52 of the 121 (43%) patients with bilateral hyperaldosteronism. Further analysis of 27 patients with CT-undetectable micro aldosteronomas revealed that 8 of these 27 patients had CT-detectable contralateral adrenal nodules, the highest values of 18oxoF and aldosterone were 4.8 and 24.5 ng/dL, respectively, both below their cut-off levels indicated above. The peripheral plasma 18oxoF concentrations served not only to differentiate aldosteronoma but also could serve to avoid unnecessary surgery for nonfunctioning adrenocortical nodules concurrent with hyperplasia or microadenoma. © 2015 American Heart Association, Inc.

Kinoshita T.,Toho University | Honma S.,ASKA Pharma Medical Co Ltd. | Shibata Y.,Gunma University | Yamashita K.,Tohoku Pharmaceutical University | And 6 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Context: Does adipose tissue produce steroid hormones like an endocrine organ? Object: To clarify whether adipose tissue produces sex steroid hormone like an endocrine organ, we estimated several key steroid hormone levels, as well as CYP17 and CYP19 activity, in ovariectomized, pre- and postmenopausal women by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Subjects and Methods: The subjects were 19 premenopausal (n = 12), postmenopausal (n = 4), and ovariectomizedwomen(n=3) aged 27-68 years. Serum, visceral adipose and sc adipose samples were taken from these subjects and stored at =70̊C. The levels of cortisol, cortisone, progesterone (Prog), androstenedione, dehydroepiandrosterone, estrone, estradiol (E2), and T in serum and adipose tissue wereestimatedsimultaneouslybyLC-MS/MS.CYP17andCYP19activity in tissueswereassayedwiththe use of 13C-labeled steroid precursors and LC-MS/MS-based estimation of the metabolites. Results: E2 and Prog levels in the sera of postmenopausal or ovariectomized women were less than 10% of those in premenopausal women. No marked variations were seen in other hormones. Estrone, androstenedione, dehydroepiandrosterone, and Prog levels in the visceral and sc tissues of postmenopausal and ovariectomized women were 9-60 times higher than those in serum, whereas E2 and T levels were 3- to 7-fold higher than those in serum, and cortisol and cortisone levels were 20% of those found for serum. CYP17 in adipose tissue was found to have 17-hydroxylase and 20,17-lyase activity, with each catalytic activity being essentially equal. Therefore, CYP17 in adipose tissue is of the testicular/ovarian type but not adrenal type, which has 17-hydroxylase activity dominant.Thepresence ofCYP19activity in adipose tissuewasapproximately3%of CYP17. Conclusion: Our findings suggest that adipose tissue acts as an endocrine organ, with CYP17 and CYP19 activity playing an essential role in sex steroid hormone biosynthesis. Copyright © 2014 by the Endocrine Society.

Nakamura Y.,University of Georgia | Nakamura Y.,Tohoku University | Rege J.,University of Georgia | Satoh F.,Tohoku University | And 6 more authors.
Clinical Endocrinology | Year: 2012

Context Although steroid hormones produced by the adrenal gland play critical roles in human physiology, a detailed quantitative analysis of the steroid products has not been reported. The current study uses a single methodology (liquid chromatography-tandem mass spectrometry, LC-MS/MS) to quantify ten corticosteroids in adrenal vein (AV) samples pre- and post-adrenocorticotropic hormone (ACTH) stimulation. Design/methods Three men and six women with a diagnosis of an adrenal aldosterone-producing adenoma (APA) were included in the study. Serum was collected from the iliac vein (IV) and the AV contralateral to the diseased adrenal. Samples were collected, before and after administration of ACTH. LC-MS/MS was then used to quantify serum concentrations of unconjugated corticosteroids and their precursors. Results Prior to ACTH stimulation, the four most abundant steroids in AV were cortisol (90%), cortisone (4%), corticosterone (3%) and 11-deoxycortisol (0·8%). Post-ACTH administration, cortisol remained the major adrenal product (79%); however, corticosterone became the second most abundantly produced adrenal steroid (11%) followed by pregnenolone (2·5%) and 17α- hydroxypregnenolone (2%). ACTH significantly increased the absolute adrenal output of all ten corticosteroids measured (P < 0·05). The four largest post-ACTH increases were pregnenolone (300-fold), progesterone (199-fold), 17α-hydroxypregnenolone (187-fold) and deoxycorticosterone (82-fold). Conclusion Using LC-MS/MS, we successfully measured 10 corticosteroids in peripheral and AV serum samples under pre- and post-ACTH stimulation. This study demonstrates the primary adrenal steroid products and their response to ACTH. © 2012 Blackwell Publishing Ltd.

PubMed | Kanagawa Cancer Center, Sapporo Medical University, Osaka University, Mie University and 6 more.
Type: Journal Article | Journal: The Prostate | Year: 2016

There is no consensus on blood adrenal androgen concentrations in men with different stages and pathological grades of prostate cancer. In this study, dehydroepiandrosterone (DHEA) concentrations in blood were examined by ultrasensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS). We analyzed the correlation between DHEA concentrations in blood and clinicopathological findings of prostate cancer.We analyzed 196 men (mean age 70 years) with prostate cancer. The patients underwent systematic needle biopsy, and peripheral blood sampling was conducted for measurement of DHEA. DHEA concentrations in blood were determined using LC-MS/MS method. Patient age, serum prostate-specific antigen, prostate volume measured by ultrasound, and DHEA levels in blood were compared with Gleason score and clinical stage by multivariate analyses.Median value of PSA and prostate volume were 11.5ng/ml and 27.7ml, respectively. Median concentration of DHEA in blood was 1,506.4pg/ml. There was no correlation between serum DHEA and clinical variables such as age, serum PSA, and prostate volume. In multivariate analysis, low serum DHEA levels in prostate cancer patients were significantly related to high Gleason score and advanced clinical stage. Serum PSA levels in prostate cancer patients were also significantly associated with high Gleason score and advanced clinical stage. High serum PSA and low serum DHEA levels were significantly associated with poor prognosis factors in men with hormone-nave prostate cancer.DHEA concentrations in blood were examined by newly developed ultrasensitive LC-MS/MS. We confirmed that low serum DHEA levels in prostate cancer patients were related to high Gleason score and advanced clinical stage. These results suggest that serum DHEA level may be a useful prognostic factor in prostate cancer patients.

Arai S.,Gunma University | Arai S.,Gunma Prefectural Cancer Center | Miyashiro Y.,Aska Pharma Medical Co. | Shibata Y.,Gunma University | And 4 more authors.
Steroids | Year: 2011

The mechanism accounting for the development of castration-resistant prostate cancer (CRPC) remains unclear. Studies in CRPC tissues suggest that, after androgen deprivation therapy (ADT), the adrenal androgens may be an important source of testosterone (T) and 5-alpha dihydrotestosterone (DHT) in CRPC tissues. To clarify the role of adrenal androgens in the prostatic tissues (prostatic tissue adrenal androgens) during ADT, we developed a high sensitive and specific quantification method for the levels of androgens in prostatic tissue using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Human prostatic tissues were purified using mixed-mode reversed-phase, strong anion exchange Oasis cartridges (Oasis MAX). Analysis of steroids was performed using LC-MS/MS after picolinic acid derivatization. The validation tests showed that our method of quantitative analysis was precise and sensitive enough for the quantification of dehydroepiandrosterone (DHEA), androstenedione, androstenediol, T, and DHT in the prostatic tissue. The levels of adrenal androgens in prostate cancer tissues after ADT were similar to those in untreated PCa. Especially, DHEA was the most existing androgen precursor in PCa tissues after ADT. The levels of DHEA were high in PCa tissues, irrespective of ADT. We assumed that DHEA played a significant role in the synthesis of T and DHT in PCa tissues after ADT. © 2010 Elsevier Inc.

PubMed | ASKA Pharma Medical Co., Yokohama City University, Gunma University and Kanagawa Cancer Center
Type: | Journal: Andrology | Year: 2016

There has been no consensus on the role of serum androgen concentrations in prostate cancer detection in men with prostate-specific antigen levels of 3-10ng/mL. In this study, testosterone and dihydrotestosterone concentrations in blood were examined by a newly developed method using ultrasensitive liquid chromatography with two serially linked mass spectrometers (LC-MS/MS). We investigated the correlation between serum androgen levels and Gleason scores at biopsy. We analyzed data of 157 men with a total prostate-specific antigen range of 3-10ng/mL who underwent initial systematic prostate needle biopsy for suspected prostate cancer between April 2000 and July 2003. Peripheral blood testosterone and dihydrotestosterone concentrations were determined by LC-MS/MS. Blood levels of testosterone and dihydrotestosterone were compared with pathological findings by multivariate analyses. Median values of prostate-specific antigen and prostate volume measured by ultrasound were 5.7ng/mL and 31.4cm

Takizawa I.,Niigata University | Nishiyama T.,Niigata University | Hara N.,Niigata University | Hoshii T.,Niigata University | And 3 more authors.
Cancer Letters | Year: 2010

The intracellular androgen metabolism and cell activity in prostate cancer cells with mutated (LNCaP-FGC) or wild-type (VCaP) androgen receptors in the presence of trilostane, an inhibitor of 3β-hydroxysteroid dehydrogenase, were examined. Trilostane suppressed the intracellular production of androstenedione, testosterone, and dihydrotestosterone from dehydroepiandrosterone in LNCaP-FGC cells. In both LNCaP-FGC and VCaP cell types, the prostate-specific antigen (PSA) levels in media were increased by trilostane alone in a concentration-dependent manner. Both cells pretreated with trilostane showed a dose-dependent decrease in PSA production with bicalutamide (P< 0.001). Trilostane should be used with particular concern when treating prostate cancer. © 2010 Elsevier Ireland Ltd.

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