Return to October 2000 Table of Contents ORIGINAL ARTICLE Safety and pharmacokinetic study with escalating doses of 3-acetyl-7-oxo-dehydroepiandrosterone in healthy male volunteers Michael Davidson, MD Drs. Davidson and Maki are with the Chicago Center for Ashok Marwah, PhD Clinical Research, Chicago, Ill.; Drs. A. Marwah, P. Marwah and Lardy are with the Institute for Enzyme Ronald J. Sawchuk, PhD Research and Department of Biochemistry, University of Kevin Maki, PhD Wisconsin, Madison, Wisc.; Dr. Sawchuk is with the Department of Pharmaceutics, College of Pharmacy, Padma Marwah, PhD University of Minnesota, Minneapolis, Minn.; and Dr. Charles Weeks, PhD Weeks is with Humanetics Corp., Chanhassen, Minn. Henry Lardy, PhD Medical subject headings: dehydroepiandrosterone sulfate; pharmacokinetics; prasterone; randomized controlled trials; steroids (Original manuscript submitted Apr. 17, 2000; received in revised form July 10, 2000 accepted July 10, 2000) Clin Invest Med 2000;23(5):300-10. © 2000 Canadian Medical Association Abstract the normal range. No changes in vital signs, blood chem- istry or urinalysis occurred during treatment with 3ß- Objectives: To evaluate the safety and pharmacokinetics acetyl-7-oxo-DHEA compared to placebo. The adminis- of 3-acetyl-7-oxo-DHEA (3ß-acetoxyandrost-5-ene- tered steroid was not detected in the blood but was rapid- 7,17-dione) given orally. ly converted to 7-oxo-DHEA-S, the concentrations of Design: A randomized, double blind, placebo-controlled, which were proportional to dose. This steroid sulfate did escalating dose study. not accumulate; plasma concentrations 12 hours after the Setting: The Chicago Center for Clinical Research. 3ß-acetyl-7-oxo-DHEA dose at 7 and 28 days on the 200 Participants: Twenty-two healthy men. mg/d dose were 15.8 and 16.3 mg/L respectively. The Study method: The participants received placebo (n = 6) mean time to peak plasma level of 7-oxo-DHEA-S was or 3-acetyl-7-oxo-DHEA (n = 16) at 50 mg/d for 7 days 2.2 hours; the mean half life was 2.17 hours. The appar- followed by a 7-day washout; 100 mg/d for 7 days fol- ent clearance averaged 172 L/h, and the apparent mean lowed by a 7-day washout; and 200 mg/d for 28 days. volume of distribution was 540 L. Outcome measures: Safety parameters, evaluated at Conclusion: These results indicate that 3ß-acetyl-7-oxo- each dose level, included measurement of total testos- DHEA is safe and well tolerated in normal healthy men terone, free testosterone, dihydrotestosterone, estradiol, at doses up to 200 mg/d for 4 weeks. cortisol, thyroxin and insulin levels. Analyses for 7-oxo- DHEA-3ß-sulfate (DHEA-S), the only detectable meta- bolic product of the administered steroid, were conduct- Résumé ed on plasma drawn from all subjects at 0.25, 0.5, 1, 2, 4, 6 and 12 hours after the final 100 mg dose of 3ß-acetyl- Objectifs : Évaluer l’innocuité et la pharmacocinétique 7-oxo-DHEA. de la 3-acétyl-7-oxo-DHEA (3ß-acétoxyandrost-5-ène- Results: There were no differences in the clinical labora- 7,17-dione) administrée par voie orale. tory values or in reported minor adverse experiences, Conception : Étude randomisée, à double insu, contrôlée between treatment and placebo groups. In general, blood par placebo et à dose croissante. hormone concentrations were unaffected by the treat- Contexte : Le Chicago Center for Clinical Research. ment with 3ß-acetyl-7-oxo-DHEA and remained within Participants : Vingt-deux hommes en bonne santé. 300 Clin Invest Med • Vol 23, no 5, octobre 2000 3-acetyl-7-oxo-dehydroepiandrosterone in healthy men Méthode d’étude : Les participants ont reçu un placebo demeurées à l’intérieur de la plage normale. Les signes (n = 6) ou de la 3-acétyl-7-oxo-DHEA (n = 16) à raison vitaux, la chimie sanguine ou les résultats d’analyses de 50 mg/j pendant 7 jours, suivis d’une période d’élim- d’urine au cours du traitement à la 3b-acétyl-7-oxo- ination de 7 jours, de 100 mg/j pendant 7 jours, suivis DHEA n’ont pas changé comparativement à ceux des d’une période d’élimination de 7 jours, et de 200 mg/j sujets qui ont reçu le placebo. On n’a pas détecté le pendant 28 jours. stéroïde administré dans le sang, mais il a été converti Mesures de résultats : Les paramètres d’innocuité éval- rapidement en 7-oxo-DHEA-S, dont les concentrations ués dans le cas de chaque dose ont inclus la mesure des ont été proportionnelles à la dose. Ce sulfate de stéroïde taux de testostérone totale, de testostérone libre, de dihy- ne s’est pas accumulé. Les concentrations plasmatiques drotestostérone, d’estradiol, de cortisol, de thyroxine et 12 heures après la dose de 3b-acétyl-7-oxo-DHEA à 7 et d’insuline. Le plasma prélevé chez tous les sujets 0,25, 0,5, 28 jours chez les sujets qui ont reçu la dose de 200 mg/j 1, 2, 4, 6 et 12 heures après la dernière dose de 100 mg de ont été de 15,8 et 16,3 mg/L respectivement. Il a fallu en 3b-acétyl-7-oxo-DHEA a été soumis à des analyses de moyenne 2,2 heures pour que le taux plasmatique de 7- dépistage du 7-oxo-DHEA-3b-sulfate (DHEA-S), le seul oxo-DHEA-S atteigne son maximum et la demi-vie produit métabolique détectable du stéroïde administré. moyenne a été de 2,17 heures. La clairance apparente Résultats : On n’a enregistré aucune différence entre les s’est établie en moyenne à 172 L/h et le volume moyen résultats d’analyses cliniques ou les expériences indésir- apparent de distribution s’est établi à 540 L. ables mineures déclarées chez les sujets traités par rap- Conclusion : Ces résultats indiquent que la 3b-acétyl-7- port à ceux qui ont reçu un placebo. En général, les con- oxo-DHEA est sans danger et bien tolérée chez les centrations d’hormones dans le sang n’ont pas été affec- hommes normaux en bonne santé à des doses qui peuvent tées par le traitement à la 3b-acétyl-7-oxo-DHEA et sont atteindre 200 mg/j pendant 4 semaines. Introduction particularly in the aged, is suggested to improve with DH E A su p p l e m e n t a t i o n , 7– 1 3 with possible benefits in Dehydroepiandrosterone (DHEA) is a steroid pro- muscle strength, mood ratings and memory perfor- duced by the adrenal cortex in response to stimula- mance. tion by adrenocorticotropin (ACTH)1, 2 and in the Several adverse experiences have been reported brain by pathways still to be elucidated.3 Most of the from the use of DHEA.12 , 1 4 Some involve alterations circulating DHEA is in its conjugated form, dehy- of sex hormone levels, resulting from transformation droepiandrosterone sulfate (DHEA-S), the most of DHEA to testosterone and estrogen.11, 1 5 Th e s e abundant steroid in human blood.1 Normal levels of steroid transformations may lead to acne, hair loss, DHEA-S vary with age; levels are high in the devel- facial hirsutism, mood changes, deepening of the oping fetus, nearly undetectable shortly after birth, voice and other signs of masculinization. DHEA ma y rise at adrenarch, peak at about age 25 years and then also affect the growth of prostate cancer in men and gradually decline.4, 5 On average, by age 75 years, breast cancer in women; the National Institute of circulating DHEA-S levels are only about 10% of Aging has issued a public service announcement their peak concentration. warning consumers about the use of DHEA be c a u s e Until the late 1970s, DHEA was considered a rela- of its sex steroid-associated side effe c t s . 16 tively inert compound whose main function was as There is need for a DHEA-like compound capable an intermediate in the bioconversion of cholesterol to of similar health maintenance benefits without the androgens and estrogens. Pioneering studies2, 6 st i m u - adverse effects. Fluasterone, a fluorinated form of lated research, which indicated that DHEAhas poten- DHEA, avoids the androgen-producing effects of tial benefits in treating a number of conditions, DH E A and is being developed as a drug. Another can- including systemic lupus erythematosus, cancer, didate is the natural metabolite, 7-oxo-DHEA wh i c h insulin resistance, cardiovascular disease, viral infec- is produced from DHEA via the 7a -hydroxy deriva- tions, osteoporosis and depression.7– 1 3 Because levels tive followed by its oxidation. 7-oxo-DHEA does not of DHEA and general health decline with age, it has activate the androgen receptor,17 is not converted to been postulated that DHEA replacement may help to an d r o g e n 18 and because of its carbonyl function on the maintain a more youthful state. Overall wellbeing, 7 position is not a substrate for the estroge n - f o r m i n g Clin Invest Med • Vol 23, no 5, October 2000 301 Davidson et al Metabolic functions of 7-oxo-dehydroepiandrosterone Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEA-S) are produced in human adrenal glands beginning at about 7 years of age (adrenarche). DHEA-S is the most abundant steroid (14 mg/L) in the blood plasma of humans at age 20 to 30 years and decreases steadily to about one-tenth that con- centration at age 70 to 80 years. DHEA is an intermediate in the biologic conversion of cholesterol to androgens and estrogens.