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Dehydroepiandrosterone (DHEA) (along with its sulfated metabolite, DHEA-S) is the most abundant naturally occuring steroid in human blood. It is produced in the adrenal cortex and can also be independently synthesized in the brain. Among the biological effects of DHEA are changes in the immune system, inflammation, lipid and carbohydrate metabolism, anticarcinogenic effects, neuroprotection, and antioxidant effects [1-2].
DHEA levels significantly decline with age, and this decline has been correlated to varying degrees with many of the complications associated with aging, such as cardiovascular disease and high cholesterol levels, insulin resistance and diabetes, obesity, and neurodegeneration [3-5]. In humans, DHEA has been reported to reduce body fat, alleviate angina, and reduce LDL ("bad") cholesterol, and it has also been used to treat cancer, multiple sclerosis, coronary artery disease, lupus, Alzheimer's, HIV/AIDS, depression, PMS symptoms, and osteoporosis [6-8]. It has antiproliferative effects on some human cancer cell lines . In animals, DHEA has been reported to decrease body fat and have beneficial effects in rodent models of diabetes, lupus, anemia, atherosclerosis, and breast, colon, lung, and skin cancer [3, 6, 9]. It also improves memory performance and has immunostimulating and antiglucocorticoid properties [10-11]. For these reasons, DHEA has been termed "fountain of youth" .
However, DHEA is not without its problems. For example, it converts to both estrogen and testosterone (and subsequently DHT), with the estrogenic conversion generally being greater . This also introduces exogenous hormones into the body, which makes cyclic use necessary. In animal studies, high doses of DHEA increase liver weight and the risk of liver cancer [2-3].
Luckily, many of the biological actions of DHEA may not be due to DHEA itself, but its metabolites. This is supported by numerous observations. First, some of the metabolites of DHEA share its properties but are considerably stronger . Second, a direct mechanism of action of DHEA has yet to be identified, indicating that the metabolites may be responsible for its effects . Third, large doses are generally required for DHEA to have an effect in animal studies, indicating that it may function as a precursor to more active steroids . Research has recently identified a number of DHEA metabolites which do not convert to androgens or estrogens or interact with sex steroid receptors but share many of the in vivo properties of DHEA, such as increased thermogenesis, neuroprotection and memory improvement, increased immune response, and improved cardiovascular health [4, 7, 10]. The most important of these are 7-oxo-DHEA (also known as 7-keto-DHEA), 7alpha-hydroxy-DHEA (7alpha-OH-DHEA), and 7beta-hydroxy-DHEA (7beta-OH-DHEA).
Among these DHEA derivatives, 7-oxo-DHEA is readily available as a supplement. 7-oxo-DHEA can be converted into both 7alpha-OH-DHEA and 7beta-OH-DHEA in humans, and in human liver microsomes, this occurs at an approximately 1:2 ratio [1, 13]. Both of these steroids can also be converted back into 7-oxo-DHEA , although once source indicates that the conversion of 7-oxo-DHEA to 7beta-OH-DHEA is irreversible . A number of enzymes from the 11beta-hydroxysteroid dehydrogenase (11betaHSD) family are responsible for this interconversion process, one or more of which has not yet been identified . Nevertheless, the effects of oral supplementation with 7-oxo-DHEA can be seen as the sum of some of effects of all three of these steroids, and also possibly the effect on enzyme competition with other steroids that convert via the same enzymes.
7-oxo-DHEA has been associated with weight loss in multiple human studies. Davidson et al. reported a study involving oral administration of 50-200 mg daily of 3-acetyl-7-oxo-DHEA (which is quickly hydrolyzed to 7-oxo-DHEA in the body) or placebo in 22 men. The body weight of the placebo group increased by 3.0 kg and the body weight of the treatment group decreased by .5 kg over a period of eight weeks, and the difference was statistically significant. This translates to a difference of one pound per week between placebo and treatment groups. However, the study was only designed to assess the safety of the substance, so it did not control for confounding variables . In another study, 30 overweight people were given either placebo or 100 mg of 7-oxo-DHEA twice daily for eight weeks. They exercised three times a week for a set period of time and were instructed to eat 1800 calories per day. Both groups lost weight, but weight loss was an average of 2 lbs greater per month in the 7-oxo-DHEA group (a statistically significant difference). Body fat decreased .89% per month in the treatment group compared to .29% per month with placebo, although this was measured by calipers, as opposed to a more reliable method .
In mice, rats, and dogs, DHEA has antiobesity effects and increases metabolic rate and thermogenesis. A decrease in body weight occurs without a change in food intake . Rats fed 7-oxo-DHEA weighed 10% less than control rats in one study . 7alpha-OH-DHEA also lead to a significant decrease in body weight in rats, an effect that was greater than that of DHEA . However, in a study in monkeys, 7-oxo-DHEA failed to have an effect on body weight over the course of a month, although this study was of very limited statistical power, and like the study mentioned above, was primarily intended to evaluate the possible toxicity and side effects of the compound .
There are a number of mechanisms which have been proposed by which 7-oxo-DHEA could increase fat loss. The first is potentiation of thyroid hormone activity and an increase in triiodothyronine (T3) levels. Thyroid hormones are important metabolic regulators, and often decrease when one goes on a diet, slowing metabolic rate and making weight loss efforts more difficult. In the second human study mentioned above, the group treated with 7-oxo-DHEA had significantly higher T3 levels, although they were still within the normal range . Another study examined the association between natural 7beta-OH-DHEA levels and T3 levels in 152 men and women, and found them to be significantly correlated, indicating a possible link between the two factors . 7-oxo-DHEA has also been reported to increase thyroid hormone levels in rats  and restore T3 and T4 levels in stressed mice .
7-oxo-DHEA, 7alpha-OH-DHEA, and 7beta-OH-DHEA all also increase the liver content of the thermogenic enzymes mitochondrial sn-glycerol-3-phosphate dehydrogenase and cytosolic malic enzyme, and all to a greater extent than DHEA . 7-oxo-DHEA is about 2.5 times as potent as DHEA in inducing these enzymes . These enzymes are also induced by thyroid hormone, and it is thought that either 7-oxo-DHEA or a metabolite acts in a similar manner to thyroid hormone. One observation on which this is based is that 7-oxo-DHEA and DHEA both still increase malic enzyme activity in hypothyroid rats, although one other study with DHEA did not have the same finding . Thus, induction of these enzymes may be due to a direct receptor effect, an increase in thyroid hormones and/or potentiation of thyroid hormone activity, or a combination, the last of which is most likely given the experimental evidence.
DHEA is well known to have antiglucocorticoid activity and increase the immune response. Both 7alpha-OH-DHEA and 7beta-OH-DHEA are more potent than DHEA in enhancing immune response and counteracting glucocorticoid-induced immunosuppression . In some tissues, one or both have been found to counteract the effects of cortisol and the synthetic glucocorticoid dexamethasone [20-21]. Dexamethasone increases the level of 7-hydroxylating enzymes in adipose tissue, and inflammation increased metabolism of DHEA to 7alpha-DHEA in the brain of rats, indicating that metabolism of DHEA through this route may be used as a natural feedback mechanism to stimulate the immune system . 7alpha-OH-DHEA increases resistance against lethal infection in animals and act as an antioxidant [2, 5]. The antiglucocorticoid action does not appear to be due to direct effects on the receptor, and is not yet well understood . 7-oxo-DHEA has also been found to mitigate the immune reduction seen in mice subjected to chronic stress, with the effect being greater than that of DHEA .
In the human liver, present evidence suggests that 7-oxo-DHEA is metabolized into 7alpha-OH-DHEA by the enzyme 11beta-hydroxysteroid dehydrogenase 1 (11betaHSD1). 11betaHSD1 also generally serves to convert inactive glucocorticoids to their active form, such as the conversion of cortisone to cortisol. It has been found that 7-oxo-DHEA competes with inactive glucocorticoids for the 11betaHSD1 enzyme . Thus, 7-oxo-DHEA may inhibit the production of cortisol by 11betaHSD1 in in vivo situations, and this may be involved to some degree in the antiglucocorticoid action of 7-oxo-DHEA and related compounds. Sulcova et al. performed a study in men involving transdermal administration of 25 mg 7-oxo-DHEA for five days, and circulating cortisol levels decreased by 7.4%, but the effect was not statistically significant, although it was close . Also, in the results reported by Davidson et al., cortisol levels decreased by 7.7% over eight weeks, but again this was not statistically significant . Thus, the present research suggests that 7-oxo-DHEA functionally reduces cortisol levels, but further research should be conducted to confirm this.
DHEA belongs to a class known as "neurosteroids" because it is synthesized de novo in the nervous system. It improves memory performance in aged and beta-amyloid peptide-injected mice . 7-oxo-DHEA, 7alpha-OH-DHEA, and 7beta-OH-DHEA all have neuroprotective properties and improve learning/memory in rodents to a greater degree than DHEA . 7-oxo-DHEA was found to reverse scopolamine-induced amnesia in young mice and improve memory in old mice as measured by the Morris water maze, and was described as much more effective than DHEA [7, 14]. DHEA acts as an antagonist at GABA-A receptors, improving cholinergic transmission, and it has been hypothesized that the effect of the metabolites may be due to the same mechanism . The antiglucocorticoid effects also result in neuroprotection .
Dosage and Administration
7-oxo-DHEA has been associated with a high degree of safety and a low incidence of side effects. One toxicological study at up to 2 g/kg orally daily found "no observable, serious, adverse effects on either male or female rats" . This study, along with another, found no significant increase in the weight of vital organs such as the liver . However, one study found 7-oxo-DHEA to increase liver weight in rodents (DHEA also has this effect) . Monkeys have also been given up 500 mg/kg daily without any adverse effects or changes in toxicological parameters (for a 175 lb. human, this would equate to 200 times the standard oral dose of 200 mg). 1000 mg/kg was associated with vomiting and salivation, but the vomiting also occured in the same animals on days that 7-oxo-DHEA was not administered, indicating that it may not have been due to the substance .
In human studies, 7-oxo-DHEA has been well tolerated, with no side effects reported at 200 mg orally [7, 15, 24]. Three studies have examined the effects of 7-oxo-DHEA on endrocrinological parameters. One found no significant change in blood sugar, testosterone, estradiol, or thyroid hormones other than T3, for which there was an increase. There were also no changes in tests of liver and kidney function or vital signs . The other studies, the Sulcova and Davidson studies mentioned earlier (involving 25 mg transdermally for 5 days and escalating doses to 200 mg for eight weeks respectively, both in males), found reductions in total testosterone of approximately 10%, while Davidson et al. found an increase in free (usable) testosterone of about 15%. Estradiol was also decreased over the course of the study by 66% and 8% in these studies, and the second difference was not statistically significant. Overall, the effects on endrocrinological variables were either small or inconsistent, and they always remained within normal parameters [7, 22].
The primary methods of administration for 7-oxo-DHEA are oral and transdermal (for an explanation of transdermal delivery, see this article). Transdermal administration offers multiple advantages. It has been found to be a very effective delivery method for DHEA [20, 22]. Since the half-life after oral administration of 7-oxo-DHEA is only about two hours , transdermal administration offers a more sustained release. In terms of which delivery method will be more effective, theoretical arguments have been presented both ways. Since transdermal administration is less likely to reach the liver, there will be less activation of thermogenic enzymes in the liver. On the other hand, 7-oxo-DHEA is metabolized to a large extent in the liver, so transdermal administration will result in more 7-oxo-DHEA reaching other tissues.
The oral dosage recommended in the literature is 200 mg (100 mg twice daily), although some have reported using higher doses. For oral use, it would ideally be taken multiple times throughout the day. Most have used a dose around 100 mg transdermally, although it is clear that even 25 mg transdermally exerts an effect.
In conclusion, 7-oxo-DHEA is a promising agent for fat loss and offers a variety of other potential benefits. It is also safe and generally free of side effects. Further research may find that 7-oxo-DHEA shares many of the other beneficial properties of DHEA.
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