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DHEA Dehydroepiandrosterone (pronounced dee-hi'-dro-epp-ee-ann-dro'-stehr-own), or DHEA as it is more often called, is a steroid hormone naturally produced in the adrenal gland. It is the most abundant steroid in the bloodstream and is present at even higher levels in brain tissue. DHEA levels are known to fall precipitously with age, falling 90% from age 20 to age 90. DHEA is known to be a precursor to the numerous steroid sex hormones (including estrogen and testosterone) which serve well-known functions. Although the specific mechanisms of action for DHEA are only partially understood, supplemental use of DHEA has been shown to have anti-aging, anti-obesity and anti-cancer influences. In addition, it is known to stabilize nerve-cell growth and is being tested in Alzheimer's patients. DHEA and Cancer Early reports from England [Bulbrook: 1962, 1971] suggested that DHEA was abnormally low in women who developed breast cancer, even as much as nine years prior to the onset or diagnosis of the disease. Of the 5000 women followed in the study, 27 developed cancer. Most of the 27 had abnormally low levels of DHEA. Many years later, Dr. Arthur Schwartz of Temple University found that supplemental DHEA significantly protected cell cultures from the toxicity of carcinogens. Cell cultures usually respond to powerful carcinogens with mutations (changes in DNA), transformations (changes in cell appearance), and a high rate of cell death. But when Schwartz added DHEA along with the carcinogen, all three of these effects were significantly diminished. DHEA and Glucose Metabolism Investigators have shown that DHEA inhibits glucose-6-phosphate dehydrogenase (G6PDH), an enzyme that breaks down glucose. There are two glucose-metabolizing pathways in the body, the catabolic, energy-yielding pathway and the anabolic, biosynthetic pathway. G6PDH happens to be the first enzyme in the biosynthetic pathway, the one which results in the synthesis of fatty acids and ribose (the sugar used in making deoxyribonucleic acid, or DNA). In simple language, G6PDH turns glucose into fat. DHEA and Aging The body's production of DHEA drops from about 30 mg at age 20 to less than 6 mg per day at age 80. According to Dr. William Regelson of the Medical College of Virginia, DHEA is "one of the best biochemical bio-markers for chronologic age." In some people, DHEA levels decline 95% during their lifetime � the largest decline of an important biochemical yet documented. DHEA levels are directly related to mortality (the probability of dying) in humans. In a 12-year study of over 240 men aged 50 to 79 years, researchers found that DHEA levels were inversely correlated with mortality, both from heart disease and from all causes. This finding suggests that DHEA level measurements can become a standard diagnostic predictor of disease, mortality and life-span. Furthermore, if animal results hold true, supplemental DHEA may prevent disease, reduce mortality, and extend life-span in humans. DHEA: The Buffering Steroid? DHEA may be unique among hormones for it's lack of specificity for hormone receptor sites. Just as vitamin E has never been shown to have a specific metabolic role (it is only proven essential as a general antioxidant), DHEA may serve an equally general purpose. "DHEA is the first example of a buffer action for hormones that I know of," states William Regelson. "It is a broad-acting hormone that only demonstrates itself under a specific set of circumstances. In that way, it is like a buffer against sudden changes in acidity or alkalinity. That is why when you get older, you're much more vulnerable to the effects of stress. As DHEA declines with age, you are losing the buffer against the stress-related hormones. It is the buffer action that [helps prevent] us from aging." The decrease of DHEA with age may result in gradual decline of a system for suppressing enzyme systems responsible for creating the building blocks of new cells, like lipids, nucleic acids (RNA and DNA) and sex steroids. The resulting rise in enzymatic activity in advanced age may be responsible for the proliferative events (cancer) and degenerative disease that become more frequent in advanced age. In this respect, DHEA might be best considered to be an anti-hormone, which might "de-excite" steroid-sensitive receptors that would otherwise lead to enhanced metabolic activity. DHEA Sulfate, the real thing! By the wizard Is there a common factor in aging and degenerative diseases? What if there were one single factor in the body that was found to be low in aging, cancer, heart disease, diabetes, obesity, osteoporosis and chronic fatigue? That factor has been found and confirmed by over 40,000 studies and publications. It is low blood levels of the hormone DHEA (Dehydroepiandrosterone). Dr. Julian Whittaker says of DHEA, "I can�t imagine practicing medicine without it." Why are doctors like Dr. Whittaker, Alan Gaby, Depak Chopra, Ward Dean and Robert Atkins all talking about DHEA? DHEA is produced by the adrenal glands, and is called the "Mother hormone" by top DHEA researchers because it is necessary in order to produce so many other hormones in both men and women. Whenever the body needs to produce hormones like estrogen, testosterone, progesterone or adrenalin, it calls on its stores of DHEA. DHEA levels peak at around age 20, and unlike any other hormone, show a linear decline with age in both men and women thereafter. DHEA is considered one of the most reliable measures of biological age. Next to aging, chronic stress is the biggest factor that causes a depletion of DHEA levels, since your body uses it up every time you make adrenaline. In one study of 5000 "normal, healthy" women, every single woman whose DHEA level was less than 10% of the normal level for their age, eventually developed and died of breast cancer. The low DHEA levels appeared up to 9 years ahead of the cancer diagnosis, however. Also, there was not a single woman with an above average DHEA level that developed cancer. Even in rats bred genetically to get cancer, DHEA supplementation blocked the development of cancer in 100% of all cases. A twelve-year-study of men between ages 50 and 79 found a 48% reduction in cardiovascular disease and 36% decrease in death from any cause associated with increased levels of DHEA. At Johns Hopkins, rabbits with atherosclerosis that were given supplemental DHEA showed a 50% reduction in the plaque in their arteries. An article in the New England Journal of Medicine concluded that DHEA protects against early death even in people without heart disease. Researchers at Temple University report that DHEA blocks factors which promote the growth of cancer cells as well as production of fat. According to one researcher there, "there isn�t any question, DHEA is a very effective anti-obesity agent." In mice, it reduces excess fat by 50% according to Longevity Magazine. Like GTF Chromium, it causes reduction in fat and increased lean muscle tissue even without any improvement in eating or exercise habits. Imagine what it could do if you combined DHEA and GTF Chromium (or a combination of citrin and chromium) with better diet and health habits! Old mice given DHEA supplements regain the vigor of youth, and their coats become sleek and glossy again. Even cancer, whether naturally occurring or artificially induced, disappears. Obese mice regain their normal weight. Immune function increases. Mice with diabetes improve dramatically. Why shouldn't people have access to these kinds of benefits, and perhaps even more, combining DHEA supplementation with other wonderful products like Chromium and Microwater. DHEA has been shown to improve memory in aging mice. DHEA levels in Alzheimer's disease patients are 48% lower than in people the same age without the disease. Why not combine DHEA supplementation with ginkgo, which has also been proven beneficial in these same people. A woman who had suffered her whole life from learning disabilities and poor memory was treated at the New York University School of Medicine with DHEA. On low doses, she showed improvement in learning and memory, as well as better sleep within one week. On higher doses, she showed further increases in short and long-term memory. At age 47 she was able for the first time in her life to successfully establish and operate her own small business. An article in Popular Science was titled "Could DHEA be the answer to prolonged life?" The article pointed out that Americans spend $100 billion each year to try to look younger. Now they can actually get younger. Many people report clearer thinking, higher energy levels, disappearance of aches and pains, weight loss, and many other rejuvenating benefits. This all makes sense because chronic stress that depletes DHEA also locks the body into a catabolic mode in which it progressively breaks down without cycling through an anabolic rebuilding phase. This can result in premature aging, muscle wasting, diabetes, fatigue, osteoporosis, undesirable redistribution of body fat, hypertension, fluid retention, lowered immune function and impaired mental function. Does any of this sound like anyone you know? Life Magazine stated "a leading U.S. authority on the hormone reports that in laboratory animals, high-dose DHEA feedings reduce body fat by one third, prevent atherosclerosis, alleviate diabetes, reduce the risk of cancer, enhance the immune response, inhibit development of certain autoimmune diseases and extend the normal life span of mice by 20%." A double-blind study on Lupus patients found that doctors were able to significantly reduce prednisone dosages in patients concurrently supplemented with high doses of DHEA. While the average person might take 5 to 10 mg, two or three times a day, those attempting to wean off dangerous steroids like prednisone may need to take up to 100 to 200 mg daily under a doctor's supervision. In the past, DHEA was only available by prescription, and only a handful of compounding pharmacies in the whole country were capable of filling the prescription. Furthermore, most medical doctors do not prescribe DHEA in the first place, so first you would have to search for a physician who knows anything about the product. Now, you can get real life-formed DHEA Sulfate, which is derived from bovine cholesterol. Why DHEA Sulfate? 90% of the DHEA in the human body is DHEA Sulfate. Most DHEA on the market is synthesized from petrochemicals, as this is the cheapest form. The better products are typically produced enzymatically from Diosgenin, derived from Mexican wild yam. The most absorbable form, however, is life-formed DHEA Sulfate, which is derived from bovine cholesterol. It has been shown to be about 6 times more absorbable than DHEA, because of the sulfate group. The sublingual route of absorption is also crucial for DHEA supplementation, because once it enters the GI tract, any DHEA that is absorbed will enter the portal blood system, which is filtered by the liver before it reaches the desired systemic destinations. Approximately 80% of the DHEA absorbed in the gut is broken down in the liver before it ever reaches the systemic blood supply. This also adds an additional burden on the liver, as well as reducing the effectiveness of the DHEA supplement. 7-Keto DHEA 7-Keto DHEA is more powerful than DHEA or DHEA-sulfate yet does not convert to testosterone or estrogen. 7-Keto DHEA, effects:
DHEA is not available for shipment to Germany, France or Canada. DHEA pas disponibles pour livraison � la France.
Technical Abstracts for 7-KETO�
Safety and pharmacokinetic study with escalating doses of 3-acetyl-7-oxo-dehydroepiandrosterone in healthy male volunteers Objectives: To evaluate the safety and pharmacokinetics of 3-acetyl-7-oxo-DHEA (3�-acetoxyandrost-5-en-7, 17-dione) given orally. Method: The participants received placebo (n=6) or 3-acetyl-7-oxo-DHEA (n=16) at 50mg/d for 7 days followed by a 7-day washout; 100mg/d for 7 days followed by a 7-day washout; and 200mg/d for 28 days. Results: There were no differences in the clinical laboratory values or in reported minor adverse experiences, between treatment and placebo groups. In general, blood hormone concentrations were unaffected by the treatment with 3�-acetyl-7-oxo-DHEA and remained within the normal range. No changes in vital signs, blood chemistry or urinalysis occurred during treatment with 3�-acetyl-7-oxo-DHEA compared to placebo. The administered steroid was not detected in the blood but was rapidly converted to 7-oxo-DHEA-S, the concentrations of which were proportional to dose. This steroid sulfate did not accumulate; plasma concentrations 12 hours after the 3�-acetyl-7-oxo-DHEA dose at 7 and 28 days on the 200mg/d dose were 15.8 and 16.3 �g/L respectively. The mean time to peak plasma level of 7-oxo-DHEA-S was 2.2 hours; the mean half life was 2.17 hours. The apparent clearance averaged 172 L/h, and the apparent mean volume of distribution was 540 L. Conclusions: These results indicate that 3�-acetyl-7-oxo-DHEA is safe and well tolerated in normal healthy men at doses up to 200 mg/d for 4 weeks.
A Randomized, Double-Blind, Placebo Controlled Study of 3-Acetyl-7-Oxo-Dehydroepiandrosterone in Healthy Overweight Adults Douglas S. Kalman, Carlon M. Colker, Melissa A. Swain, Georgeann C. Torina, and Qiuhu Shi Peak Wellness, Inc., and Greenwich Hospital, Greenwich, Connecticut, and North Shore University Hospital, Manhassett, New York ABSTRACT Objective: The purpose of this study was to determine the effects of 3-acetyl-7-oxo-dehydroepiandrosterone (7-oxo-DHEA) in healthy overweight adults. Methods: In a double-blind, placebo controlled protocol, 30 adults (28 women and 2 men; mean age, 44.5 + 11.5 years) with a mean body mass index of 31.9 + 6.2 kg/m2 were randomly divided into 2 groups of 15: Group 1 received 7-oxo DHEA 100mg twice daily and Group 2 received placebo for 8 weeks. All subjects participated in an exercise-training program 3 times per week. Each exercise session consisted of 60 minutes of cross-training (aerobic and anaerobic exercise) under the supervision of an exercise physiologist. ~1800 kcal/d (20 kcal/kg/d] by a registered dietitian. Subjects received biweekly dietary counseling to encourage compliance. Study participants underwent serum multiple-assay chemistry testing, as well as body composition, blood pressure, and dietary analysis at baseline, week 4, and week 8. Results: Of the 30 subjects who entered the study, 23 completed the 8-week protocol. Seven subjects dropped out for personal reasons unrelated to the study. Group 1 lost a significant amount of body weight compared with Group 2 (-2.88 kg vs -0.97 kg; P = 0.01) over the 8 weeks. Group 1 also achieved a significant reduction in body fat compared with Group 2 (-1.8% vs -0.57%; P = 0.02). The rate of change in body fat per 4-week interval in Group 1 was 3.1 times that in Group 2 (-0.88% vs -0.28%; P < 0.01). Group 1 also experienced a significant increase in triiodothyronine (T3) levels compared with Group 2 over the 8-week study period (+17.88 ng/dL vs 2.75 ng/dL; P = 0.04). There were no significant changes in levels of thyroid stimulating hormone (TSH) or thyroxine (T4) in either group. In addition, no significant changes were observed in vital signs, blood sugar, testosterone and estradiol levels, liver and renal function, or overall caloric intake during the study. No subjective adverse effects were reported throughout the study. Conclusions: The results of the study suggest that 7-oxo-DHEA combined with moderate exercise and a reduced-calorie diet significantly reduces body weight and body fat compared with exercise and a reduced calorie diet alone. In addition, 7-oxo-DHEA significantly elevated T3 levels but did not affect TSH or T4 levels, indicating that it does not adversely affect thyroid function in the short term. Publisher: Kalman, et al, Current Therapeutic Research Vol. 61(7), and pp 435-442, Copyright 2000 by Excerpta Medica, Inc.
Double-Blind, Placebo-Controlled, Randomized Clinical Trial Evaluating the Effects of Exercise Plus 3-Acetyl-7-oxo-dehydroepiandrosterone on Body Composition and the Endocrine System in Overweight Adults C Colker, M.D, G Torina, M Swain, D Kalman. Department of Medicine, Greenwich Hospital, Peak Wellness, Inc, Greenwich, CT 06830 3-Acetyl-7-oxo-dehydroepiandrosterone (7-Keto�) has been shown to normalize an induced hypothyroid state in lab animals and is also known to promote futile cycling. Regular exercise is known to help promote and maintain weight loss. Based on this information, 30 overweight (BMI 31.9 plusmn; 6.2) adults (Age 44.5 plusmn; 11.5) were randomized into a prospective, double-blind, placebo controlled eight week study. Fifteen subjects received 7-Keto� 100 mg twice per day whereas the other 15 subjects received a matching placebo. All subjects exercised three times per week, 60 minutes per session of cross-training (aerobic and anaerobic) under the supervision of an exercise physiologist. The exercise plus 7-Keto� group lost a significant amount of body weight as compared with the exercise plus placebo group (-2.88 kg, p=0.012). In terms of actual body composition changes, the exercise plus 7-Keto� group lost 1.8% body fat as compared to 0.57% for the placebo group (p=0.02). In terms of effects on the thyroid, triiodothyronine (T3) activity increased significantly in the group receiving 7-Keto� and not the placebo (+17.88 ng/dl vs. 2.75 ng/dl; p<0.05), there were no significant changes in either TSH or T4. There were no significant changes in blood sugar, testosterone, estradiol, liver, renal function tests, vital signs, or overall caloric intake over the eight week study. Nor were there any subjective adverse effects reported throughout the study. These results indicate that one hour of cross-training three times per week supplemented with 200 mg of 7-Keto� per day yields a significant reduction in both body weight and body fat. Journal of Exercise Physiology online, ISSN 1097-9751, Volume 2, Number 4, October 1999.
Clinical Safety and Endocrine Effects of 7-KETO� DHEA MH Davidson, C Weeks, H Lardy, K Maki, D Umporowicz. (SPON: DC Kvam). Chicago Center for Clinical Research, Chicago, IL 60610; Humanetics Corp., Minneapolis, MN 55426; and Univ. of Wisconsin, Madison, WI 53705 Supplemental dehydroepiandosterone (DHEA) has been postulated to have beneficial effects on heart disease, immune function and well-being. However, conversion of DHEA to sex hormones may cause unwanted side effects. 7-Keto� DHEA is a naturally occurring metabolite which has DHEA activity, but is not converted to sex hormones in vivo. The present study examined the effects of 7-Keto� DHEA on several endocrine and safety parameters in healthy adult men (18-49 years of age). 7-Keto� DHEA (n=18) or placebo (n=6) were administered for 8 weeks. The 7-Keto� DHEA dose was increased weekly to a maximum of 100 mg bid during the final 4 weeks of treatment. Levels of the hormones measured did not differ between groups (p>0.10) at baseline or during treatment. End-of-trial levels of dihydrotestosterone, estradiol, cortisol and insulin were not different from baseline values (p>0.10). A small reduction in total testosterone and a small, clinically insignificant, increase in free testosterone [27 + 5 vs. 31 + 8 pg/mL: p<0.01] were observed among men receiving 7-keto-DHEA. All hormone levels were within normal limits. This study shows that 7-Keto� DHEA is well tolerated at doses up to 200 mg/d and does not produce clinically important sex hormone changes in healthy men. Presented at Experimental Biology 98, April 19-22, 1998, San Francisco, CA. Ergosteroids: Induction of thermogenic enzymes in liver of rats treated with steroids derived from DHEA H Lardy, B Partridge, N Kneer and Y Wei, Institute for Enzyme Research, University of Wisconsin, Madison, WI 53705 Dehydroepiandrosterone (DHEA), an intermediate in the biosynthesis of testosterone and estrogens, exerts several physiological effects not involving the sex hormones. When fed to rats it induces the thermogenic enzymes mitochondrial sn-glycerol-3-phosphate dehydrogenase and cytosolic malic enzyme in their livers. Animals and humans, and their excised tissues, are known to hydroxylate DHEA at several positions and to interconvert 7a-hydroxy-DHEA, 7b-hydroxy-DHEA, 7-Keto� DHEA and the corresponding derivatives of androst-5-enediol. We report here that these 7-oxygenated derivatives are active inducers of these thermogenic enzymes in rats and that the 7-Keto� derivatives are more active than the parent steroids. We postulate that the 7a-hydroxy and 7-oxo derivatives are on a metabolic pathway from DHEA to more active steroid hormones. These steroids, including 7-Keto� DHEA, have potential as therapeutic agents because of their increased activity and because they are not convertible to either testosterone or estrogens. Proc. Natl. Acad. Sci., Vol. 92, pp. 6617-6619, July 1995.
The Effects of the Ergosteroid 7-KETO� DHEA on mitochondrial membrane potential: possible relationship to thermogenesis. V Bobyleva, M Bellei, N Kneer, and H Lardy Administered 7-Keto� DHEA is more effective than 3b-hydroxyandrost-5-en-7-one (DHEA) as an inducer of liver mitochondrial sn-glycerol-3-phosphate dehydrogenase and cytosolic malic enzyme in rats. Like DHEA, the 7-Keto� metabolite enhances liver catalase, fatty acylCoA oxidase, cytosolic sn-glycerol-3-phosphate dehyrogenase, mitochondrial substrate oxidation rate, and the reconstructed sn-glycerol 3-phosphate shuttle. The mitochondrial adenine nucleotide carrier is diminished by thyroidectomy and is restored to normal activity by administering 7-Keto� DHEA. The relationship between respiratory rate and proton motive force across the mitochondiral membrane was measured in the nonphosphorylating state. When treated with increasing concentrations of respiratory inhibitors liver mitochondria from rats treated with 7-Keto� DHEA or thyroid hormones show a more rapid decline of membrane potential than do normal liver mitochondria. Thus 7-Keto� DHEA induces an increased proton leak or slip as has been reported for the thyroid hormone by M.D. Brand (1990) Biochem. Biophys. Acta 1018, 128-133. This process may contribute to the enhanced thermogenesis caused by ergosteriods as well as by thyroid hormones. Archives of Biochemistry and Biophysics, Vol. 341, No. 1, May 1, pp. 122-128, 1997
Ergosteroids II: Biologically active metabolites and synthetic derivatives of DHEA H Lardy, N Kneer, Y Wei, B Partridge and P Marwa, Institute for Enzyme Research, University of Wisconsin, Madison, WI 53705 An improved procedure for the synthesis of 3b-hydroxyandrost-5-ene-7,17-dione, a natural metabolite of dehydroepiandrosterone (DHEA) is described. The synthesis and magnetic resonance spectra of several other related steroids are presented. Feeding dehydroepiandrosterone to rats induces enhanced formation of several liver enzymes among which are mitochondrial sn-glycerol 3-phosphate dehydrogenase (GPDH) and cytosolic malic enzyme. The induction of these two enzymes, that complete a thermogenic system in rat liver, was used as an assay to search for derivatives of DHEA that might be more active than the parent steroid. Activity is retained in steroids that are reduced to the corresponding 17b-hydroxy derivative, or hydroxylated at 7a or 7b, and is considerably enhanced when the 17-hydroxy or 17-carbonyl steroid is converted to the 7-Keto� derivative. Several derivatives of DHEA did not induce the thermogenic enzymes whereas the corresponding 7-oxo derivative compounds like 7-Keto� DHEA did. Both short and long chain acyl esters of DHEA and 7-Keto� DHEA are active inducers of the liver enzymes when fed to rats. 7-Oxo-DHEA-3-sulfate is as active as 7-Keto� DHEA or its 3-acetyl ester, whereas DHEA-3-sulfate is much less active than DHEA. Among many steroids tested, those possessing a carbonyl group at position 3, a methyl group at 7, a hydroxyl group at positions 1, 2, 4, 11, or 19, or a saturated B ring, with or without a 4-5 double bond, were inactive. Steroids 63:158-165, 1998
Dehydroepiandrosterone and 7-KETO� DHEA Augment Interleukin 2 (IL2) Production by Human Lymphocytes In Vitro R Nelson(1), M Herron(1), C Weeks(2), and H Lardy(3), (1)University of Minnesota, Minneapolis, MN, (2)Humanetics Corporation, St. Louis Park, MN, and (3)University of Wisconsin, Madison, WI. Combination anti-retroviral therapy can suppress HIV replication, but an immune modulator may be necessary to increase the number of CD4 cells. Infusion of IL-2 iv or sc can increase CD4 cell number, but inconvenience, cost, and dose-limiting toxicities are problematic. DHEA enhances IL2 production by activated mouse T cells and has been used in HIV infected patients. Here we compare DHEA and 7-Keto� DHEA for their ability to augment IL2 production by human lymphocytes in vitro, with the goal to identify an analog of DHEA with this immunomodulatory activity that is not metabolized to sex hormones. Mononuclear leukocytes isolated by gradient centrifugation from healthy volunteers were transferred to microfilter wells (105 /well) containing control medium or stimulus (PHA, 1.25 mg/ml, or OKT3 anti-T cell receptor antibody, 5 ng/ml, and + DHEA or 7-Keto� DHEA). After 24 hrs, supernatant fluids were collected and assayed for IL2 using an immunoassay kit (R&D Systems). Results are from a representative experiment in which 3 of 4 donors were "responders." IL2 in fluids from cultures incubated with OKT3 averaged 227 pg/ml. DHEA and 7-Keto� DHEA at 10-8 M augmented IL2 production in these OKT3-stimulated cultures by 88% and 103%, respectively. IL2 in fluids from cultures incubated with PHA averaged 583 pg/ml. DHEA and 7-Keto� DHEA at 10-9 M augmented IL2 production in these PHA-stimulated cultures by 78% and 68%, respectively. Presented at The 5th Conference on Retroviruses and Opportunistic Infections, February 1-5, 1998, Chicago, IL.
7-KETO� DHEA Improves Memory in Mice J Shi and H Lardy, Department of Biochemistry and Enzyme Institute, Univ. of Wisconsin, Madison, WI 53705 The correlation of decreased circulating DHEA sulfate with impaired memory during aging prompted Roberts and coworkers to test the influence of administered DHEA on retention of foot shock avoidance training. Immediate post training injection of DHEAS improved memory of old mice: it also reversed scopolamine-induced amnesia. We find 7-Keto� DHEA, a more active metabolite of DHEA, at 20 mg/kg body weight, abolished the effect of scopolamine on memory as tested in the Morris water maze procedure. DHEA was also tested at 20 mg/kg. Groups of 13 to 16 C57BL76 mice (35 gm) were trained to locate the pedestal in less than 15 seconds in three consecutive trials. Six days after treatment with 1 mg/kg scopolamine the average times (in seconds) to locate were: control 9.2+5.8 SE; scopolamine 21.8+21.6; scopolamine+DHEA 11.3+10.1; Scopolamine+7-Keto� DHEA 6.5+5.7. C vs. Sc p<0.032; Sc vs. DHEA+Sc p<0.10; Sc vs. 7-Keto� DHEA+ Sc p< 0.02. Additionally, aged, two year-old mice were tested one, two and four weeks after having been trained. At two weeks post training the times to rescue were: control 34 ec; DHEA 22 sec; 7-Keto� DHEA 7.6 sec. Tests at other times were comparable. Supported by Humanetics Corporation. Presented at Experimental Biology 98, April 19-22, 1998, San Francisco, CA.
Delta-5 Androstenediol is a natural hormone with androgenic activity in human prostate cancer cells H Miyamoto, S Yeh, H Lardy, E Messing, and C Chang It is known that andros-5-ene-3b-diol (Adiol), a precursor of testosterone (T), can activate estrogen target genes. The androgenic activity if Adiol itself, however, is poorly understood. Using a transient transfection assay, we here demonstrate in human prostate cancer cells that Adiol can activate androgen receptor (AR) target genes in the presence of AR, and that AR coactivator ARA70 can further enhance this Adiol-induced AR transcriptional activity. In contrast to this finding, an active metabolite of dehydroepiandrosterone, 7-Keto� DHEA, does not activate AR target gene in the absence or presence of ARA70. Thin layer chromatography analysis reveals that T, dihydrotestosterone, and 17-b-estradiol are undetectable in human prostate cancer DU145 cells after treatment with Adiol. Additionally, a proteolysis assay shows that a distinct ligand-receptor conformational difference exists between T-AR and Adiol-AR. Together the above findings and the fact that T, but not Adiol, can induce transcriptional activity in a mutant AR (mtAR708), suggests that, without being metabolized into T, Adiol itself may represent a natural hormone with androgenic activity in human prostate cancer cells. Because two potent antiandrogens, hydroxyflutamide (Eulexin), and bicalutamide (casodex), that are widely used for the treatment of prostate cancer, fail to block Adiol-mediated induction of AR transcriptional activity in prostate cancer cells, the effectiveness of so-called "total androgen blockage," a standard treatment for prostate cancer, may need to be reevaluated. Proc Natl Acad Sci, Vol 95, pp 11083-11088, Sept 98
An Acute Oral Gavage Study of 7-KETO� DHEA in Rats H Lardy, S Henwood, and C Weeks. University of Wisconsin, Madison, WI 53705; Covance Laboratories, Madison, WI 53705; and Humanetics Corporation, Minneapolis, MN, 55426. The present study was done to assess the tolerance of rats for 7-Keto� DHEA when administered as a single oral gavage dose. Five groups of Sprague-Dawley rats (Crl:CD (SD) BR VAF/Plus) (five/sex/group) were treated with 7-Keto� DHEA at a dose level of 0 (control), 250, 500, 1,000, or 2,000 mg/kg of body weight in a dose volume of 10 ml/kg. Food and water were provided ad libitum. All animals survived in good health to the scheduled end date on Day 15. The single oral administration of 7-Keto� DHEA had no apparent effects on body weight. Food consumption was significantly higher for all female treated groups during week two; however, the statistically significant differences were not considered to be clinical consequence. Treatment caused no apparent changes of gross or microscopic anatomical structures of nine different organs. This study demonstrated that the no-observable adverse effect level for a single oral dose of 7-Keto� DHEA in male and female rats was 2,000 mg/kg. Biochemical and Biophysical Research Communications 254, 120-123, 1999
An Escalating Dose Oral Gavage Study of 7-KETO� DHEA in Rhesus Monkeys S Henwood, C Weeks, and H Lardy. Covance Laboratories, Madison, WI 53705; Humanetics Corporation, Minneapolis, MN, 55426; and University of Wisconsin, Madison, WI 53705. To test the effects of 7-KETO� DHEA in Rhesus macaques the compound was administered by oral gavage to two male and two female monkeys. Dose levels of 250, 500, and 1,000 mg/kg body weight (BW)/day were administered on days 1, 3, and 5 respectively, and 1,000 mg/kg on days 7 through 11. Each group received the dose in a volume of 10 ml/kg BW. All animals survived to the scheduled end date on Day 12. No adverse clinical effects of 7-Keto� DHEA were observed at the 250 or 500 mg/kg doses. Females vomited on non-treatment days and all animals vomited on some days after being given the 100 mg/kg dose. Excessive salivation was observed before or immediately after dosing on days 9 through 11. Appearance, behavior and body weights were not altered by the treatments. Visual examination of all body cavities, and macroscopic examination of 42 different organs and tissues found no lesions or abnormalities. Biochemical and Biophysical Research Communications 254, 124-126, 1999
Mutagenicity Test With 7-KETO� DHEA in the Salmonella-Escherichia Coli / Mammalian-Microsome Reverse Mutation Assay C Weeks, H Lardy and S Henwood, Humanetics Corp, Minneapolis, MN 55426; University of Wisconsin, Madison, WI 53705; and Covance Laboratories, Madison, WI 53705. 7-Keto� DHEA is an analog of DHEA that cannot be metabolized to active androgenic or estrogenic hormones but retains and enhances the immunologic, memory-enhancing and thermogenic effects of DHEA. The objective of this study is to evaluate the toxicological profile of 7-Keto� DHEA using Salmonella and E. coli/mammalian microsome reverse mutation assays. Concentrations were 0.1 to 5.0 mg per plate with or without S-9 mix in S. typhimurium strains TA98, 100, 1535, and 1537 and E. coli WP2uvrA. No increase in the number of revertants per plate in any tester strain + S-9 was observed. Supported by Humanetics Corporation. Presented at Experimental Biology 98, April 19-22, 1998, San Francisco, CA.
Preclinical Toxicology Evaluation of 3-Acetyl-7-Oxo-Dehydroepiandrosterone (7-KETO� DHEA) C. Weeks, Humanetics Corp.; H. Lardy, Univ. of Wisconsin, Madison; and S. Henwood, Covance Laboratories. 7 Keto DHEA is an analog of DHEA which cannot be metabolized to active androgenic or estrogenic hormones but retains and enhances the immunologic, memory-enhancing and thermogenic effects of DHEA. The objective of these studies is to evaluate the toxicological profile of 7 Keto DHEA using Salmonella and E. coli/mammalian microsome reverse mutation assays, plus acute oral dose rat and subchronic oral dose monkey studies. For mutagenicity assays, concentrations were 0.1 to 5.0 mg per plate with or without S-9 mix in S. typhimurium strains TA98, 100, 1535, and 1537 and E. coli WP2uvrA. In the rat study, five groups of rats (five/sex/group) were given 0, 250, 500, 1000 or 2000 mg/kg in a single oral dose; animals were sacrificed on day 15 and necropsied. Rhesus monkeys (two/sex) were given oral doses of 250, 500 and 1000 mg/kg on days 1, 3, 5 respectively and 1000 mg/kg on days 7 through 11; animals were necropsied on day 12. No increase in the number of revertants per plate in any tester strain + S-9 was observed. In rats, the single oral no observable adverse effect dose was greater than 2000 mg/kg. Oral administration of 7 Keto DHEA to monkeys demonstrated no adverse clinical or anatomical pathology results. 7 Keto DHEA is now in clinical trials to further establish safety. Supported by Humanetics Corporation. Presentated at Experimental Biology 98, April 19-22, 1998 in San Francisco, CA.
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