Regulating Estrogen and Increasing Testosterone via Suicide Aromatase Inhibition: The Role of 3, 7-Keto DHEA:
* 3, 7-Keto DHEA is a naturally-occurring metabolite of dehydroepiandosterone (DHEA), and is a potent aromatase inhibitor with some very unique qualities. Aromatase is an enzyme that transforms testosterone into estrogen, and the more active aromatase is, the more estrogen will ultimately be present. Therefore, aromatase inhibitors significantly decrease the level of estrogen in the body. This is important as increased estrogen in men can signal the hypothalamic pituitary testicular axis (HPTA) to shut down the release of gonadotropin-releasing hormone (GnRH). GnRH signals the production of luteinizing hormone (LH), which signals the production of testosterone. Therefore, increased estrogen levels can lower endogenous testosterone production (21,29,31).
* 3, 7-Keto DHEA has demonstrated strong ability to lower estrogen, thus mitigating this effect. It has a high binding affinity (Ki value = 0.22 mM) to the aromatase enzyme, and binds in an irreversible manner, making it a suicide inhibitor of aromatase. Ki Values measure how efficiently a compound binds to its associated receptor. The lower the Ki value; the higher the binding affinity. This inhibition allows for the production of less estradiol (E2) and estrone (E1) and allows the user of the compound to maintain a higher level of testosterone; hence improving the Testosterone: Estrogen (T:E) ratio. The mechanism through which aromatase inhibitors raise testosterone is fairly simple; the HPTA senses low levels of estrogen, and because the body seeks to maintain homeostasis (it likes to maintain at least some estrogen, even in men), there is a concurrent increase in the amount of testosterone that is being produced, as a way to compensate for the low estrogen levels. The increased testosterone levels normally will result in increased estrogen since there is no estrogen being produced. Essentially, the brain is tricked into trying to produce more estrogen, so it releases more luteinizing hormone releasing hormone (LHRH) and subsequently more LH, leading to even higher testosterone levels (20,21-23).
* All aromatase inhibitors share this characteristic of positively altering the T:E ratio, and all will raise serum testosterone levels in men, which has been referenced in numerous studies. 3,7-Keto DHEA is comparable in potency to several other commonly available aromatase inhibitors. As explained above, a lower Ki value means higher potency, making it more potent than both Formestane and Exemestane, and very similar to androstentrione (ATD) (31,55). (See Figure 5)
Figure 5: POTENCY OF AROMATASE INHIBITORS, INCLUDING 3-DESOXY 7-KETO DHEA (KI VALUES)
* 3,7-Keto DHEA is unique from other commonly used aromatase inhibitors in sports supplements in that it is a natural metabolite of 7-Keto DHEA and it cannot directly bind to the androgen receptor. 3,7-Keto DHEA (like 7-Keto DHEA) also cannot convert to testosterone, estrogen, or progesterone via any type of enzymatic reaction, so by strict definition it cannot in any way be considered a prohormone. This clearly differentiates it from other recently banned products that allow for the direct conversion to a controlled substance in the body (in either in trace amounts or full-scale conversion). This can not occur with 3,7-Keto DHEA, as it is formed naturally in humans from 7-Keto DHEA and can be readily found in humans in the amount of 5-7 ug/day (23-24).
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