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The Journal of Steroid Biochemistry and... Nov 201311β-Hydroxyandrostenedione (11OHA4), which is unique to the adrenal, was first isolated from human adrenal tissue in the fifties. It was later shown in the sixties that...
11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione.
11β-Hydroxyandrostenedione (11OHA4), which is unique to the adrenal, was first isolated from human adrenal tissue in the fifties. It was later shown in the sixties that 11β-hydroxytestosterone (11OHT) was also produced by the human adrenal. Attention has shifted back to these adrenal androgens once more, as improved analytical techniques have enabled more accurate detection of steroid hormones. In this paper, we investigated the origin of these metabolites as well as their subsequent metabolism and examined a possible physiological role for 11OHA4 in prostate cancer cells. In H295R cells treated with forskolin and trilostane, etomidate, a reported cytochrome P450 11β-hydroxylase (CYP11B1) inhibitor, blocked the production of corticosterone, cortisol, 11OHA4 and 11OHT. The metabolism of androstenedione and testosterone by CYP11B1 and aldosterone synthase (CYP11B2) was assayed. Androstenedione was converted by CYP11B1, while the conversion by CYP11B2 was negligible. Both enzymes readily converted testosterone. The metabolism of these 11β-hydroxylated metabolites by 11β-hydroxysteroid dehydrogenase (11βHSD) types 1 and 2 was subsequently investigated. 11βHSD2 catalyzed the conversion of both 11OHA4 and 11OHT to their respective keto-steroids, while 11βHSD1 catalyzed the conversion of 11-ketoandrostenedione and 11-ketotestosterone to their respective hydroxy-steroids in Chinese hamster ovary cells. Investigating a functional role, steroid 5α-reductase types 1 and 2 converted 11OHA4 to 11β-hydroxy-5α-androstanedione (11OH-5α-dione), identified by accurate mass detection. UPLC-MS/MS analyses of 11OHA4 metabolism in LNCaP androgen-dependent prostate cancer cells, identified the 5α-reduced metabolite as well as 11-ketoandrostenedione and 11-ketotestosterone, with the latter indicating conversion by 17β-hydroxysteroid dehydrogenase. Downstream metabolism by 11βHSD2 and by 5α-reductase may therefore indicate a physiological role for 11OHA4 and/or 11OH-5α-dione in normal and prostate cancer cells.
Topics: Adrenal Glands; Androstenedione; Animals; COS Cells; Cell Line, Tumor; Chlorocebus aethiops; Cholestenone 5 alpha-Reductase; Humans; Tandem Mass Spectrometry
PubMed: 23685396
DOI: 10.1016/j.jsbmb.2013.04.010 -
Steroids Dec 2011Androstenedione (4-androstene-3,17-dione) is banned by the World Anti-Doping Agency (WADA) as an endogenous steroid. The official method to confirm androstenedione abuse...
Androstenedione (4-androstene-3,17-dione) is banned by the World Anti-Doping Agency (WADA) as an endogenous steroid. The official method to confirm androstenedione abuse is isotope ratio mass spectrometry (IRMS). According to the guidance published by WADA, atypical steroid profiles are required to trigger IRMS analysis. However, in some situations, steroid profile parameters are not effective enough to suspect the misuse of endogenous steroids. The aim of this study was to investigate the atypical steroid profile induced by androstenedione administration and the detection of androstenedione doping using IRMS. Ingestion of androstenedione resulted in changes in urinary steroid profile, including increased concentrations of androsterone (An), etiocholanolone (Etio), 5α-androstane-3α,17β-diol (5α-diol), and 5β-androstane-3α,17β-diol (5β-diol) in all of the subjects. Nevertheless, the testosterone/epitestosterone (T/E) ratio was elevated only in some of the subjects. The rapid increases in the concentrations of An and Etio, as well as in T/E ratio for some subjects could provide indicators for initiating IRMS analysis only for a short time period, 2-22h post-administration. However, IRMS could provide positive determinations for up to 55h post-administration. This study demonstrated that, 5β-diol concentration or Etio/An ratio could be utilized as useful indicators for initiating IRMS analysis during 2-36h post-administration. Lastly, Etio, with slower clearance, could be more effectively used than An for the confirmation of androstenedione doping using IRMS.
Topics: Administration, Oral; Androstenedione; Capsules; Doping in Sports; Female; Gas Chromatography-Mass Spectrometry; Humans; Male; Steroids; Time Factors; Urinalysis; Young Adult
PubMed: 21945895
DOI: 10.1016/j.steroids.2011.09.007 -
Disease Markers 2017Androstenedione (A4) is an adrenal and gonadal steroid biomarker, useful in the assessment of children in whom steroidogenic disorders are suspected. The first key step...
INTRODUCTION
Androstenedione (A4) is an adrenal and gonadal steroid biomarker, useful in the assessment of children in whom steroidogenic disorders are suspected. The first key step in the evaluation of a diagnostic test resides on confident reference intervals (RI). The lack of updated A4-RI with current methods in pediatrics may mislead A4 results and limit its diagnosis accuracy.
AIM
To provide A4 reference ranges in healthy children.
METHODS
Prospective, descriptive study. 283 children aged 4 days to 18 years were included. In children < 1 yr, A4 was measured directly in serum (NE-A4) and postorganic solvent extraction (E-A4) for the assessment of interfering steroids. The influence of chronological age (CA), gender, and Tanner stage (T) were investigated.
RESULTS
In the neonatal period, E-A4 was significantly lower than NE-A4; boys had higher NE-A4; sexual dimorphism disappeared after extraction procedure. In children older than 4 months, A4 concentration remained low until the age of 5 years. Thereafter, A4 increased significantly in association with CA and T ( = 0.65; < 0.001), obtaining the highest concentrations in children within pubertal ages without sexual dimorphism.
CONCLUSION
We recommend to perform solvent extraction in neonates and to take into account age and sexual development to properly interpret A4 results in childhood.
Topics: Adolescent; Androstenedione; Biomarkers; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Male
PubMed: 28592912
DOI: 10.1155/2017/9238304 -
Annals of Oncology : Official Journal... Jul 1997
Comparative Study
Topics: Aminoglutethimide; Anastrozole; Androstenedione; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Clinical Trials, Phase III as Topic; Female; Humans; Letrozole; Nitriles; Triazoles
PubMed: 9296213
DOI: 10.1023/a:1008282315089 -
Tumori 1995
Clinical Trial Randomized Controlled Trial
Topics: Androstenedione; Antineoplastic Agents; Aromatase Inhibitors; Breast Neoplasms; Estrogens; Female; Humans; Injections, Intramuscular; Middle Aged; Postmenopause; Treatment Outcome
PubMed: 7778222
DOI: 10.1177/030089169508100201 -
Pediatric Endocrinology Reviews : PER Sep 2004Estrogen has been shown to have an important role in skeletal maturation in both males and females. The use of aromatase inhibitors may provide a means to delay skeletal... (Review)
Review
Estrogen has been shown to have an important role in skeletal maturation in both males and females. The use of aromatase inhibitors may provide a means to delay skeletal maturation and increase final height in children with short stature. These medications have been used primarily in women with breast carcinoma and also in children with autonomous estrogen production, such as patients with McCune-Albright Syndrome. Several studies have evaluated the safety and metabolic effects in adults. A few studies in children have evaluated the efficacy and safety of these medications. These studies demonstrate a beneficial effect on bone age advancement and predicted adult height. Other studies have evaluated the effects on bone mineral density, lipid metabolism and adrenal function in children. This review summarizes the studies in the pediatric population and some of the metabolic effects in adults.
Topics: Adult; Aminoglutethimide; Androstenedione; Aromatase Inhibitors; Body Height; Child; Estrogens; Female; Growth Disorders; Humans; Letrozole; Male; Musculoskeletal System; Nitriles; Triazoles
PubMed: 16429098
DOI: No ID Found -
Medical Oncology (Northwood, London,... 2008Estrogen has been implicated in promoting breast cancer in a majority of women. Endocrine therapy controlling estrogen production has been the guiding principle in... (Review)
Review
Estrogen has been implicated in promoting breast cancer in a majority of women. Endocrine therapy controlling estrogen production has been the guiding principle in treating breast cancer for more than a century. A greater understanding of this disease at a molecular level has led to the development of molecules that inhibit estrogen production by inhibiting the aromatase enzyme, that is the primary source of estrogen in postmenopausal women. This review examines the evolution of aromatase inhibitor (AI) based therapies over the past three decades. The third generation aromatase inhibitors (anastrozole, letrozole and exemestane), which have been found to be extremely specific and effective in an adjuvant/neoadjuvant/extended adjuvant setting are discussed from a biochemical and clinical perspective. A comprehensive discussion of the past, present, and future of aromatase inhibitors is conducted in this review.
Topics: Aminoglutethimide; Androstadienes; Androstenedione; Aromatase Inhibitors; Breast Neoplasms; Clinical Trials as Topic; Fadrozole; Female; Humans; Letrozole; Nitriles; Triazoles
PubMed: 17973095
DOI: 10.1007/s12032-007-9019-x -
Endocrine-related Cancer Jun 1999Over the past decade several novel aromatase inhibitors have been introduced into clinical practice. The discovery of these drugs followed on from the observation that... (Review)
Review
Over the past decade several novel aromatase inhibitors have been introduced into clinical practice. The discovery of these drugs followed on from the observation that the main mechanism of action of aminogluthemide was via inhibition of the enzyme aromatase thereby reducing peripheral levels of oestradiol in postmenopausal patients. The second-generation drug, 4-hydroxyandrostenedione (formestane), was introduced in 1990 and although its use was limited by its need to be given parenterally it was found to be a well-tolerated form of endocrine therapy. Third-generation inhibitors include vorozole, letrozole, anastrozole and exemestane, the former three being non-steroidal inhibitors, the latter being a steroidal inhibitor. All are capable of inhibiting aromatase action by >95% compared with 80% in the case of 4-hydroxyandrostenedione. The sequential use of different generations of aromatase inhibitors in the same patients is discussed. Studies suggest that an optimal sequence of these compounds may well result in longer remission in patients with hormone receptor positive tumours.
Topics: Androstenedione; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Enzyme Inhibitors; Humans; Letrozole; Neoplasms, Hormone-Dependent; Nitriles; Triazoles
PubMed: 10731118
DOI: 10.1677/erc.0.0060259 -
The Journal of Steroid Biochemistry and... Sep 1992Exemestane (FCE 24304; 6-methylenandrosta-1,4-diene-3,17-dione) is a novel orally active irreversible aromatase inhibitor. Its in vitro and in vivo pharmacological... (Clinical Trial)
Clinical Trial Review
Exemestane (FCE 24304; 6-methylenandrosta-1,4-diene-3,17-dione) is a novel orally active irreversible aromatase inhibitor. Its in vitro and in vivo pharmacological properties have been compared to 4-hydroxyandrostenedione (4-OHA). In preincubation studies with human placental aromatase, exemestane, like 4-OHA, showed enzyme inactivating properties with a similar affinity (Ki 26 vs 29 nM) and a lower rate of inactivation (t1/2 13.9 vs 2.1 min). Conversely, when tested in pregnant mares' serum gonadotropin-treated rats, exemestane was more potent in reducing microsomal ovarian aromatase activity than 4-OHA, after both subcutaneous (ED50 1.8 vs 3.1 mg/kg) and oral dosing (ED50 3.7 vs greater than 100 mg/kg). No interference of exemestane on desmolase or 5 alpha-reductase activity was found. The compound did not show any relevant binding affinity to steroidal receptors, but slight binding to the androgen receptor (approximately 0.2% of dihydrotestosterone), like 4-OHA. In the first phase I trial, healthy postmenopausal volunteers were given single oral doses of exemestane, ranging from 0.5 to 800 mg, and plasma [estrone (E1), estradiol (E2) and estrone sulphate (E1S)] and urinary estrogens (E1 and E2) were measured up to 5-8 days. The minimal effective dose in decreasing estrogens was 5 mg. At 25 mg the maximal suppression was observed at day 3: plasma estrogens fell to 35 (E1), 39 (E2) and 28% (E1S), and urinary estrogens fell to 20 (E1) and 25% (E2) of basal values, these effects still persisting on day 5. No effects on plasma levels of cortisol, aldosterone, 17-hydroxyprogesterone, DHEAS, LH and FSH, and no significant adverse events were observed up to the highest tested dose of 800 mg exemestane.
Topics: 5-alpha Reductase Inhibitors; Androgens; Androstadienes; Androstenedione; Animals; Antineoplastic Agents; Aromatase Inhibitors; Humans; Lyases; Receptors, Steroid
PubMed: 1525055
DOI: 10.1016/0960-0760(92)90198-r -
Journal of Clinical Chemistry and... Oct 1982A specific radioimmunoassay for 4-androstene-3,17-dione (androstenedione) based on rabbit antisera to 6 beta-hydroxy-4-androstene-3,17-dione-6-hemisuccinate-bovine serum...
A specific radioimmunoassay for 4-androstene-3,17-dione (androstenedione) based on rabbit antisera to 6 beta-hydroxy-4-androstene-3,17-dione-6-hemisuccinate-bovine serum albumin conjugate was developed. Cross reaction by testosterone was eliminated by addition of experimentally established amounts of testosterone antiserum, which cross reacted by only 0.004 with androstenedione. The method has been used for simultaneous determination of androstenedione in both plasma and saliva of normal women under basal conditions and following dynamic tests. The plasma levels in normal women averaged 3.6 +/- 0.9 nmol/l and correlated (r = 0.93) with those found in saliva (0.353 +/- 0.089 nmol/l).
Topics: Androstenedione; Animals; Cross Reactions; Female; Humans; Rabbits; Radioimmunoassay; Saliva
PubMed: 7142915
DOI: 10.1515/cclm.1982.20.10.761