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By: Mark Tallon

When we age the ability to control our quality of life becomes an issue for all of us. The application of aging research into the steroid dehydroepiandrosterone (DHEA) has helped our understanding of age induced losses of functional capacity, and has subsequently lead to the discovery of a relatively new compound "7-OXO-DHEA".

7 - Keto as it is more commercially known may have physiological actions that allow us to train well into old age. Recent studies suggest it may also have applications to a youthful, healthy, and physically active population. So the questions beckon; is there evidence to support 7-keto use over a broad spectrum of ages? And if so, how can it affect our physiques? And what lessons can be learnt from ageing science to keep us ahead of the dietary supplement market regarding the use of this novel compound?


The Scientific Facts Behind 7-Keto DHEA


The appliance of science to any functional context, in this case your health, performance and physique goals, are the mark of any good nutritional scientist. But as a scientist you can only base your assumptions on the scientific facts and fortunately for us this month we have plenty to work with; as the discovery of the DHEA metabolite "3b -Acetoxyandrost - 5 - ene-7, 17- dione" was discovered back in the late 1950's1 (and they wonder why we call it 7-Keto...imagine fitting that one on the label).

Because of this we have amassed a large volume of work in this often heavily chemical orientated, and sometimes confusing area of metabolism. In the past, 7-keto's closest relative DHEA gave us the initial and indeed pioneering insights into the potential benefits this class of compound can deliver. Clinical conditions such as: insulin resistance, cardiovascular disease, osteoporosis, and age-induced sarcopenia all have been positively influenced by the use of DHEA2-4.

Although considered relatively inert by the mid to late 90's, this view on DHEA was in for a radical change. The National Institute of Aging (web site) issued a public service announcement regarding its safety and warned consumers of its sex steroid associated side effects5. Because of the potential benefits to health, the search for a DHEA-like compound without the associated side effects was on. Although first identified in human urine in 19481 and tissues in 19546 it wasn't until the mid 90's when Dr. Henry Lardy began the excellent research on what he called "Ergosteroids"7.

The nomenclature of the ergosteroid family emerged due to their influences on energy metabolism; indeed this area in particular will form the core of our discussion on 7-keto. After a paper was released showing that DHEA could bring about a thermoginetic effect in rats, it wasn't long before both the nutraceutical and scientific world began the search for an effective and "safe alternative to ephedrine" for fat loss. In essence, a chemical that could confer the positive health benefits of DHEA.

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Feeding The Machine (Pharmacokinetics & Safety)

DHEA is a steroid produced by the adrenal gland7 and is the most abundant steroid in human blood8. There are always two things you should understand prior to the use of any sport / health supplement.


Safety of the product and the dose range proven to be safe.
Knowledge of how the supplement is taken up into the tissues and how quick it is excreted, "in-essence it's pharmacokinetic profile".
7-keto is a highly active derivative of DHEA and is one supplement of which its pharmacokinetic (dictionary) profile is needed if we want to ascertain when peak levels occur in plasma. This information will help prescribe the best possible rational for its time of use, dosage, and safety to optimise body compositional changes.

A series of trials have looked at both the safety and pharmacokinetics of 7-keto. In animal studies, 7-Keto was shown to be safe and in effect non-toxic to levels of 2000mg/kg in rats9 and 1000mg/kg in monkeys10. Toxicity was assessed by full-blood chemistry, blood cell counts and histological examination in 42 different tissues. Again caution must be taken until we see the human data; so what human data does exist? Davidson et al11 studied a series of doses ranging from 50mg/d (25mg twice daily) for 7 days; 100mg/d (50mg twice daily) for 7 days; and finally 200mg/d (100mg twice for 28 days). Results demonstrated that at all doses, 7-keto in comparison to a placebo presented no substantial impact on clinical blood markers of toxicity and health. This data was supported in further human trials12-13.

One other important point that really separates the function of 7-keto from DHEA, is the effects it has on androgenic and estrogenic compounds. In a landmark study14 investigating the androgenic activity of 7-keto, researchers unequivocally demonstrated that in human prostate cells 7-keto had no effect on androgen receptor (AR) activity. There are two problems in using this study to conclusively prove that 7-keto has no effect on AR activity.


This study is the primary study referenced to convince us that 7-keto has no androgenic effects, however the study uses cell lines (cells grown in a dish not in the body) to demonstrate this point.
Cell lines have a series of methodological problems in proving the data to be clinically relevant15.
The study / model uses abnormal cells (cancer cells) to prove there is no androgenic activity which makes it even more difficult to prove that similar non androgenic effects would be found in healthy human cells. Use of a model that relies on animal or human grafts using healthy tissues would have provided a more realistic view and an insight into the application of this therapeutic agent in a real world setting. Adding to this supposition recent data11 has shown free testosterone is significantly elevated (14.4% above baseline) following 7-keto administration. These values are a magnitude less than those associated with the direct use of DHEA and although significant constitute little clinical relevance. For these reasons an androgenic influence of 7-keto DHEA cannot be ruled out with 100% conviction therefore more research is needed in this area.

Pharmacokinetic data has revealed that based on a 100mg (200mg/d) dose, the highest tested to-date, is safe and peaks in concentration in plasma after around 2 hours and returns back to baseline after around 5-6 hours. We will come back to this later and link it in with some practical applications.

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Stimulating Resting Metabolism: UCP v Thyroid

OK, now to the important work... "fat loss" and 7-keto, how does it work? Is it the best derivative of DHEA to use for this purpose? And is there a synergistic effect between 7-keto and exercise in a normal population?

How Does It Work?

Before we can get into the evidence for 7-keto's use in fat loss lets look at some of the proposed mechanisms behind 7-keto's effects that may be of greater importance than those advertised by the popular press. The primary effect is said to be through the elevation of thyroid hormones namely triiodthyronine (T3). T3 is three to five times more active than T4 and generally increases the metabolism of carbohydrates, fats, and proteins. But how does T3 do this? Well, there are three mechanism but all are directly related to changes in mitochondrial efficiency thereby affecting ATP production, "our primary energy source". For simplicities sake as part of the process of energy production protons pass through a series of reactions that result in ATP, this is known as the electron transport chain (all occurring in the Mitochondria).

The structure and function of the mitochondria and it's membrane (see fig.3 below) can be influenced in a variety of ways that can result in decreased energy production. Imagine you have just finished a gruelling workout, you have a bucket (this is our mitochondria) of which we fill with a carbohydrate drink (lets say this is our energy) and you have a paper cup to take the carb drink from the bucket.



Yes, this is great, you are taking the carbs and cooling down... no problem. Now imagine the bucket is filled with holes. You still get your energy, but probably not as much, as the bucket would empty before you can get all you need, hence your efficiency at replenishing energy would be compromised. In the mitochondria a process known as proton leaking or futile cycling occurs that is in essence like our bucket with holes and in order for protons to work efficiently the integrity of the mitochondrial membrane must be maintained. The surface area is inherently leaky, you may say due to its lipid structure, and a variety of substances can effect the structure of the membrane included in the list is THYROID hormones16-17.

The second mechanism involves a direct effect on a series of enzymes (Malic enzyme (ME) & Glycero-3-phosphate dehydrogenase (GDH)) that facilitate energy production inside the mitochondria and when up-regulated gives an indication that there is mitochondrial uncoupling (defined as a disruption of the connection between food breakdown and energy production). Although these processes are linked and co-dependent; in many ways their mechanism of increasing thermogenisis or energy production are different.

A study investigating the influence of a number of DHEA derivatives, showed that these markers are upregulated in the livers of rats. However the 3b -Acetoxyandrost - 5 - ene-7, 17- dione or 7-keto DHEA used in the majority of fat loss supplements was not the most effective of all derivatives tested on the upregulation of these enzymes. The most influential derivative was 3b-7a-diol-A-17-one "so take note when buying your supplements". Bobyleva et al18 also confirmed the positive influence DHEA derivatives have on these markers of thermogenesis. Caution must be advised in the interpretation of this data, as these enzymes are isolated from the liver, therefore any suggestion that this is symptomatic of whole body thermogenesis including that of skeletal muscle is unfounded.

The third mechanism involves a series of proteins that facilitate the transport of protons across the inner mitochondrial membrane know as "Uncoupling Proteins or UCP's". These proteins act as membrane transports of protons, and in many ways uncouple energy production by oxidation and phosphorylation causing stored energy to be released as heat. Over the next few years you will see much more on this issue as many scientists now believe it is the UCP's that explain a large proportion of the genetic variability in resting metabolic rate19. As nutrition science advances and recognises the control mechanisms of UCP's don't be surprised if this is the next advance in the fat loss market. Recent evidence from a whole host of studies has started to shed light on the control of UCP's with reference to obesity20 and their up-regulation by thyroid hormones21.

There are a variety of UCP's that have been identified, however the most important for the sake of fat-loss are those found in the skeletal muscle and adipose tissue (UCP 2 and UCP3). De Lange et al21 was the first study to directly link elevations in thyroid (T3) and up-regulation of UCP3 in the gastrocenemius (calf) muscle. The data demonstrated a 12-fold increase in UCP3 density as well as 8% decline in muscle membrane potential (a indicator of uncoupling or loss of energy producing efficiency).

The use of 7-keto may have a significant impact on many of the associated mechanisms of fat loss, however I would suggest it is a combination of all of these factors that may lead to an up-regulation in resting metabolic rate. Most of the significant data regarding fat-loss is still passed down through animal studies and the use of powerful hormones that produce supra-physiological levels of T3 far higher than with the use of 7-keto human studies. The lack of direct human data in this area could easily be amended with a series of fairly simple studies. This would give us an indication of its potential as a significant fat-loss agent. I recently spoke to Dr. Zenk, one of the leading researchers in the field of Ergosteroids and 7-Keto DHEA, who is just in the process of completing one such study with 7-keto in which he assesses resting metabolic rate.


"From the preliminary data of our most recent study we have seen a significant increase in BMR in the order of 15 times that of placebo. This in combination with a similar clinical data make me feel that the primary effect of 7-Keto DHEA is via the activation of thermogenic enzymes on uncoupling oxidative phosphorylation rather than T3. We find this new data very encouraging for future studies on fat loss and the use of 7-keto DHEA"
- Dr. Zenk, MD CEO

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7-Keto & Exercise

The capacity of 7-Keto to significantly effect resting metabolic rate in humans as measure indirectly through body composition changes has only been studied in combination with exercise. Only one published human study to date has assessed the effects of 7-Keto on body composition in an adult population. Colker et al13 investigated a group of 30 overweight subjects (28 women, 2 male) randomly assigned into 2 groups. Group 1: 200mg/d 7-keto (100mg twice daily) and group 2: Placebo for 8weeks. Both groups undertook 3 x 60mins of cross training and instructed to follow a 1800 kcal/d diet.

Results of the study demonstrated the 7-Keto group reduced bodyweight by 4.4% over the course of the study as compared to only 0.51% in the placebo group (please note an error in the mean baseline placebo data if you get this paper) (see fig.4 below). The paper is relatively well designed but no information had been given regarding menstrual cycle phase. As most of the group were women fluctuations in bodyweight are frequently seen over the menstrual phase, and this could of easily be responsible for the difference between groups22. The other let down of the study was due to the use of fat callipers which have been shown to be highly variable in numerous studies, therefore the use of a DEXA scan or similar may have been a more reliable indicator of changes in body composition. As the study also took no measurement of metabolic rate the attribution of changes in bodyweight can only partly be attributable to the oxidation of bodyfat.



Although there are animal studies namely the Bobyleva et al study to show a significant impact of 7-Keto on thermogenisis and weight loss, there are also animal studies indicating no significant impact of 7-keto on bodyweight loss and even a possible increase in appetite with its use23. Although the theoretical premise of 7-keto's impact on fat loss is sound, data showing a noticeable physiological effect in human studies are at present scarce. Therefore until studies that use better methodologies for the assessment of the physiological impact of 7-Keto on body composition, caution must be taken regarding the significance of its use.

All About Longevity?

DHEA and its related compounds have been shown to decrease with age. Levels display a characteristic secretion pattern over a lifetime, with a surge during the prepubertal period, reaching a maximum at 25- 35 yr of age, followed by a continuous decline to steadily low levels with advancing age (andropause)24,25. Many studies have investigated the effects of DHEA in the elderly particularly related changes in IGF-1 production, body composition, muscle strength, and immune response26. The general concensus of the research papers have shown that in general replacement therapy using supplemental DHEA serves no scientific or clinical purpose whatsoever. Whether this is the case for 7-keto is unknown as its mechanism of action is very different to that of DHEA.

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At present we do not understand all aspects of 7-keto and associated DHEA derivatives; what we do know is the 7-keto like DHEA does decline with age27. What is uncertain is what this means with respect to thyroid function and body composition. The only data at present linking the possible therapeutic efficacy of 7-keto to ageing is in mice. Mice of old age were supplemented with 20mg/kg body weight and showed significant improvements in memory post treatment28.

The Future For 7-Keto

7-Keto has some great potential not only in the aging market but also as fat loss agent in its own right. "Based on the pharmacokinetic data the use 100mg 7-keto DHEA should be taken 1.5 - 2 hours before exercise, to help optimize the fat loss benefits followed with a secondary dose 5 hours after the first." There is clear data showing a decline in plasma concentrations with age. What effect this has on age related declines in thyroid function and memory is unknown. At present the conclusive data is lacking to fully back its use as a primary fat-loss agent for humans, but what information available is promising.

There were 2 papers released on products containing 7-Keto DHEA in 200229,30 but as these studies contained other bioactive agents including caffeine and L-Tyrosine (fat loss agent in their own right) I have not included them in this report. However they maybe useful as a source of further reading so have included them in the reference section. There have been a number of products claiming to be the answer to ephedrine over the past 2 years and although I believe ephedrine to be safe at certain doses as in the Boozer report31; there is a sub-section of the population that will be at risk from the use of such stimulants, and safer alternatives such as 7-keto may be just the answer.


Contact Mark James Tallon at mark@oxygenics.co.uk and view his web site at OxygeniX.com.

REFERENCES

1. Lieberman S, Dobriner K, Hill B.R, Fieser L.F, Rhoads, C.P. Identification and characterization of ketosteroids isolated from urine of healthy and diseased persons .J Biol Chem 1948; 172: 263 - 293
2. Kalimi M, Regelson W, Editors. The biological role of dehydroepiandrosterone (DHEA). Berlin: de Gruyter; 1990
3. Morales AJ, Haubrich RH, Hwang JY, Asakura H, Yen SS. The effect of six months treatment with a 100mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and women. Clin Endocrinology (Oxf) 1998; 49: 421 - 432
4. Barry NN, McGuire JL, Van Vollenhoven R. Dehydroepiandrosterone in systemic lupus erythematosus: relationship between dosage, serum levels,and clinical response. J Rheumatol 1998; 27: 2352 - 2356
5. National Institute on Aging. Pills, patches, and shots: Can hormones prevent aging? Washington: The Institute; December 1997
6. Fukushima DK, Kemp AD, Schneider R, Stokem M, Gallagher T. Studies in steroid metabolism XXV. Isolation and charectirisation of new urinary steroids. J Biol Chem 1954; 210: 129 - 137
7. Lardy H, Partridge B, Kneer N, Wei Y. Ergosteroids: Induction of thermogenic enzymes in liver of rats treated with steroids derived from dehydroepiandrosterone. Proc Natl Acad Sci 1995; 92: 6617 - 6619
8. Baulieu EE, Corpechot C, Dray F, Emiliozzi R, Lebeau MC, Mauvis-Jarvis P, Robel P.An adrenal-secreated androgen: Dehydroepiandrosterone sulfate. Its metabolism and a tentative generalization on the metabolism of other steroid conjugates in man. Rec Prog Horm Res 1965; 21: 411 - 500
9. Lardy H, Henwood SM, Weeks CE. An acute oral gavage study of 3b-acetoxyandrost-5-ene-7,17-dione (7-oxo-DHEA-acetate) in rats. Biochem and Biophys Res Com 1999; 254: 120 - 123
10. Henwood SM, Weeks CE, Lardy H. An escalating dose of 3b-acetoxyandrost-5-ene-7,17-dione (7-oxo-DHEA-acetate) in Rhesis Monkeys. Biochem and Biophys Res Com 1999; 254: 124 - 126
11. Davidson M, Marwah A, Sawchuk RJ, Maki K, Marwah P, Weeks C, Lardy H. Safety and pharmacokinetic study with escalating doses of 3-acetyl-7-oxo-dehydroepiandrosterone in healthy male volunteers, Clin Invest Med 2000; 23 (5): 300 - 310
12. Kalman DS, Colker CM, Swain MA, Torina GC, Shi Q. A randomised double-blind, placebo-controlled study of 3-acetyl-7-oxo-dehydroepiandrosterone in healthy overweight adults. Curr Thera Res 2000; 61 (7): 435 - 442
13. Colker CM, Torina GC, Swain MA, Kalman DS. Double-blind study evaluating the effects of exercise plus 3-acetyl-7-oxo-dehydroepiandrosterone on body composition and the endocrine system in overweight adults. J Ex Physiol (online) 1999; 2 (4): ISNN 1097 - 9751
14. Miyamoto H, Yeh S, Lardy H, Messing E, Chang C. Delta 5-androstenediol is a natural hormone with androgenic activity in human prostate cancer cells. Proc Natl Acad Sci 1998; 95: 11083 - 11088
15. Dixon SC, Knopf KB, Figg WD. The control of prostate-specific antigen expression and gene regulation by pharmacological agents. Pharma Rev 2001; 53: 73 - 91
16. Brookes PS, Hulbert AJ, Brand MD. The proton permeability of liposomes made from mitochondrial inner membrane phospholipids: no effect of fatty acid composition. Biophys Acta 1997; 1330: 157 - 164
17. Brookes PS, Hulbert AJ, Brand MD. The proton permeability of liposomes made from mitochondrial inner membrane phospholipids: comparison with isolated mitochondria. J Membr Biol 1997; 155: 167 - 174
18. Bobyleva V, Kneer N, Bellei M, Battelli D, Lardy H. Concerning the mechanism of increased thermogenesis in rats treated with steroids derived from dehydroepiandrosterone. J Bioenerg Biomembr 1993; 25: 313 - 321
19. Jekabsons MB, Gregoire FM, Schonfeld-Warden NA, Warden CH, Horwitz BA.T3 stimulates resting metabolism and UCP-2 and UCP-3 mRNA but not nonphosphorylating mitochondrial respiration in mice. Am J Physiol 1999; 277 (40): E380 - E389
20. Saito M, Ohashi A. Mitochondrial uncoupling protein as a target of pharmacotherapy for obesity. Nippon Yakurigaku Zasshi 2001; 118 (5): 327 - 333
21. De Lange P, Lanni A, Beneduce L, Moreno M, Lombardi A, Silvestri E, Goglia F. Uncoupling protein-3 is a molecular determinant for regulation of resting metabolic rate by thyroid hormone. Endocrinology 2001; 142 (8):3414 - 3420
22. Sutherland H, Stewart I. A critical analysis of the premenstrual syndrome. Lancet 1965; 1:1180
23. Lardy H, Henwood S, Weeks C. An acute oral gavage study of 7-keto DHEA in rats. Biochem and Biophys Res Com 1999; 254: 124 - 126
24. Orentreich N, Brind JL, Rizer RL, Volgeman JH. Age changes and sex differences in serum dehydroepiandrosteronesulphate concentrations throughout adulthood. J Clin Endocrinol Metab 1984; 59: 551 - 555
25. Belanger A, Candas B, Dupont A. Changes in serum concentrations of conjugated and unconjucated steroids in 40 to 80 year old men. J Clin Endocrinol Metab 1994; 79: 1086 - 1090
26. Carsson PR, Santro N, Elkind-Hirsch K. Postmenopausal dehydroepiandrosterone administration increases free insulin-like growth factor-I and decreases high-density lipoprotein: a six-month trial. Fertil Steril 1998; 70: 107 - 110
27. Marenich LP. Excretion of testosterone, epitestosterone, androstenedione and 7-keto dehydroepiandrosterone in healthy men of different ages. Probl Endokrinol 1979; 25 (4): 28 - 31
28. Shi J,Lardy H. 7-Keto DHEA improves memory in mice. Presented Exp Biol 1998; San Fransisco, CA
29. Zenk JL, Helmer TR, Kassen LJ, Kuskowski MA. The effects of NutraleanTM on weight loss: A randomised, Double Blind, placebo controlled trial. Current Therapeutic Research 2002; 63: 263 - 272
30. Zenk JL, Helmer TR, Kassen LJ, Kuskowski MA. The effects of Lean System 7TM on weight loss: A randomised, Double Blind, placebo controlled trial. In press 2003
31. Boozer CN, Daly PA, Homel P, Solomon JL, Blanchard D, Nasser JA, Strauss R, Meredith T.Herbal ephedra/caffeine for weight loss: a 6-month randomised safety and efficacy trial. Int J Obes Relat Metab Disord 2002; 26 (5): 593 -604



I added this article because it was more indepth than the first one.. I got this off of...

http://www.bodybuilding.com/fun/tallon1.htm

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