PROHORMONES AND THE ESTROGEN FACTOR

The introduction of prohormone supplements, capable of being actively converted into testosterone by naturally-occurring body enzymes, has made the term "anabolic supplement" a reality. Supplements such as androstenedione and others are termed "prohormones" because they serve as direct precursors for testosterone synthesis in the body. However, a less publicized effect of such supplements is their tendency to also be converted into estrogen.

Estrogen, like all hormones, has its good and bad effects. Though frequently termed a "female" hormone, this label is a misnomer, since it's also produced in men--though in far smaller amounts compared to women. The reason why men produce estrogen isn't completely understood, although some evidence indicates that it may play a role in sperm maturation. However, most of the effects of estrogen in men are negative, especially if the male hormonal scale tips more in the direction of estrogen compared to testosterone. What could tip this sex hormone scale in favor of estrogen in a man? Several factors may induce this condition. For example, testosterone is converted into estrogen by way of a ubiquitous enzyme located throughout the body, but especially in peripheral fat tissue called aromatase. Thus, just having abundant fat stores in the body increases the risk of having higher estrogen levels in men, and women, too, for that matter.

Normally most of the circulating testosterone in the blood plasma are bound to liver-produced proteins, such as sex-hormone binding globulin (SHBG) and to a lesser and weaker extent, albumin. But only the free or unbound testosterone (about 2% of the total amount in plasma) in active in the sense that it can interact with cellular androgen receptors.

When prohormone supplements are converted into testosterone by various enzymes in the liver and other tissues, they circulate in the blood as free and bound testosterone. As such, they are subject to conversion to estrogen whenever the enzyme aromatase is encountered. As the estrogen levels rise from this conversion, the testosterone/estrogen ratio (T/E ratio) tips toward estrogen. When that happens, several negative events related to higher body estrogen levels in men begin to occur. These estrogen-related effects include possible gynecomastia or male breast development. This is commonly seen in many athletes who use anabolic steroid drugs capable of being aromatized, such as testosterone injections.

Another possibility is benign prostatic hyperplasia (BPH) or prostate gland enlargement. Research shows that BPH results from a combined effect of a testosterone byproduct called dihydrotestosterone (DHT) and estrogen (0). Estrogen metabolites offer protective effects for women against cardiovascular disease onset presumably through the antioxidant activities of the 2-hydroxy metabolites.

In men, the failure to metabolize estrogen has been linked to reverse effects, including that of promoting increased internal blood clotting associated with both heart attacks and strokes. This was shown in many studies, including the long-term Framingham Heart study. In that study, men with the highest estradiol or unmetabolized estrogen levels showed the greatest risk of early heart attack.

There is a way, however, to harness the benefical cardiovascular effects of estrogen for men, which I'll reveal later. Recognition of the tendency for free testosterone to convert into estrogen has led to a search for natural alternatives to offset this notable problem. Drugs that inhibit aromatase, such as Testlac and Arimidex, are sometimes prescribed to for breast cancer preventive effects in women. But such drugs are extremely expensive, hard to obtain, and may impart undesired side effects of their own.

An over-the-counter supplement called chrysin, classified as a flavonoid, is found naturally in plants, and is often suggested as a natural, safe supplement to inhibit the aromatase enzyme that converts testosterone into estrogen. However, while the potency of chrysin is comparable to potent drugs such as Cytadren that also inhibit aromatase, these effects have thus far been shown to occur only in test tube studies. No one has yet determined the effectiveness of chrysin inhibition of aromatase in the human body. Some controversy even exists as to how well chrysin is absorbed into the body.

Obviously a substance that could curtail or even nullify some of the deleterious effects of estrogen would benefit both men and women. While women do naturally produce more estrogen that men, it's also true that in excess, estrogen has cancer-promoting effects in women, particularly in the breasts and reproductive tract. Such a estrogen-modifier would have to be safe, and not interfere with the beneficial effects of other hormones, such as testosterone. The question is: does such as substance exist? The vegetable cure Scientists have been aware for over a decade that certain foods contain naturally-occurring protective substances. Many such substances occur in plants and vegetables, and are often collectively referred to as phytochemicals or literally "plant chemicals." Cruciferous vegetables, such as broccoli, cabbage, and cauliflower contain some of the most potent protective phytochemicals yet discovered. These include sulforaphane, which works to prevent cancer by inducing a potent detoxifying enzyme system in the liver called phase-2 enzymes.

Another cruciferous phytochemical is called indole-3-carbinol(I3C). IC3 acts as an estrogen antagonist (2). Numerous studies published during the past decade conclusively show that I3C converts estrogen to safe metabolites , while also promoting estrogen inactivation and excretion (3). The dietary indoles found in cruciferous vegetables modify estrogen and promote its conversion into beneficial forms, such as 2-hydroxy and 2-methoxyestrogen (4). The synthesis of these "good" estrogens tends to decrease the production of "bad" estrogens that are linked to disease processes, including various cancers in both sexes (5).

Subsequent research revealed that indole-3-carbinol isn't the primary active ingredient that promotes beneficial estrogen synthesis. The process is actually a cascade effect, beginning with a phytochemical in cruciferous vegetables called glucosinolate, which is converted by enzymes into indole-3-carbinol. The indole-3-carbinol, in turn, is converted into the true active ingredient, diindolymethane (DIM) (6). Pure DIM was initially used in supplement form and given to animals in 1987 (7). Animal studies showed it to be both effective and nontoxic. When animals were exposed to carcinogens that initiated breast and colon cancers (8), the addition of DIM inhibited such cancers . Further research revealed that the mechanism behind these anticancer effects of DIM included reducing estrogen cell receptor activity (9); promotion of the "good' 2-hydroxy estrogens (10); and through supporting selective apoptosis, or programmed cell death, which allows the body to remove damaged cells prone to cancer (11).

Providing DIM to humans leads to an increased ratio of good 2-hydroxy estrogens to "bad" 16-hydroxyestrone. In fact, human studies showed that DIM resulted in a 75% increase in good estrogens with a 50% decrease in bad estrogens linked to disease onset. Other studies show that low levels of the beneficial 2-hydroxy estrogens are linked to breast cancers in both men (12) and women (13); uterine cancer (14); cervical cancer; and system lupus erythematosus (15), an autoimmune disease more common in women. Many previous risk factors for breast cancer development, such as obesity, high fat diets, and diets lacking omega-3 fatty acids are also characterized by a low-level 2-hydroxy synthesis in the body (16).

Since indole-3-carbinol (I3C) is capable of neutralizing excess estrogen and promoting its excretion, some supplement companies have incorporated I3C into their proprietary prohormone formulas. This, however, isn't effective. First, I3C is highly unstable and has a poor shelf life. Odds are good that any supplement containing this substance doesn't have much to begin with, and even less by the time a consumer purchases it. In addition, I3C, as noted, isn't the active chemical anyway; it's instead, DIM. I3C is converted into DIM through a process involving gastric hydrochloric acid (HCL). If a person is deficient in HCL, as commonly occurs in the elderly, I3C won't effectively convert into DIM. In contrast to I3C, DIM is highly stable, doesn't need any conversion in stomach acid, and is by far the most active phytochemical in promoting the synthesis of good, protective estrogens such as 2-hydroxyestrone (17). One problem does exist, however, with DIM: it's not soluble in water in its usual crystalline form. As such, it requires a special delivery system in order to be effective for supplemental purposes. Such a system exists in a special supplement called Diindolin.

Diindolin contains DIM associated with a special matrix that improves absorption. The daily usage of a 300 milligram dosage of Diindolin approximately equals the DIM obtainable from 2-4 pounds of raw broccoli. This supplement is clearly useful not only for people that just don't like cruciferous vegetables such as broccoli, but also don't want to eat several pounds of it each day to ingest beneficial levels of DIM.

By increasing the levels of beneficial 2-hydroxy estrogens, the testosterone/estrogen ratio is increased in favor of testosterone. More importantly from an anabolic point of view, the level of free testosterone rises in the blood with use of DIM. The mechanism behind this is that 2-hydroxy estrogens have a greater binding affinity for the blood proteins that "lock up" testosterone in the blood. Thus, these plasma binding proteins instead latch on to 2-hydroxy, leaving greater levels of free testosterone, including that produced through the use of supplemental prohormones. The 2-hydroxy estrogens promoted by DIM usage also increase testosterone synthesis through another mechanism. Estrogen, even more than testosterone itself, incurs a negative hormonal feedback loop to the pituitary gland, where the rate-limiting gonadotropin for testosterone synthesis, luteinizing hormone (LH) is synthesized and released. What this means is that high blood levels of estrogen, as may occur through aromatization of free testosterone, turn off the release of LH from the pituitary gland. This leads to a vicious biochemical cycle characterized by an imbalance between testosterone and estrogen in favor of the latter. These events, however, are nullified by 2-hydroxy, which doesn't provide the negative feedback message to the pituitary induced by estrogen. The net effect is greater testosterone synthesis in the Leydig cells of the testes, as well as lower levels of bad estrogen and all the effects that go with it. DIM differs from other natural substances currently touted to decrease estrogen levels, such as the soy isoflavones, genistein and diadzen. DIM, while promoting the synthesis of beneficial estrogens, such as 2-dehydroxy, isn't itself a phytoestrogen or an estrogen mimic as are the soy isoflavones. Thus, there is no danger of a paradoxical estrogen-agonist or pro-estrogen effect with DIM as can possibly occur in some cases with soy isoflavones. Diindolin also helps to burn fat through extending the activity of catecholamines, such as epinephrine and norepinephrine. These hormones help the body oxidize fat through interacting with beta-adrenergic fat cell receptors. This leads to an enzymatic cascade resulting in the release of free fatty acids into the blood. However, catecholamines are rapidly degraded by an enzyme called catechol-O-methyl transference (COMT). This same enzyme also metabolizes 2-hydroxy estrogens. An increase in 2-hydroxy estrogens, such as that induced by Diindolin, will promote a competitive inhibition effect with the catecholamine and COMT, leading to less rapid breakdown of catecholamines and thus enhanced fat mobilization. The implications of this process are that Diindolin will serve to potentiate the increased catecholamine secretion that normally occurs during exercise. It will also provide synergistic fat oxidizing effects when combined with a ephedrine-caffeine stack, since this stack works by also increasing the release of catecholamines.

Keeping DHEA honest DHEA, an adrenal androgen, was the first of the prohormone supplements to be marketed. The problem with DHEA, however, is that it isn't as direct a precursor for conversion into testosterone as is the supplements released later, such as androstenedione. DHEA, while capable of being converted into testosterone, can also take divergent pathways, such as conversion into estrogen or DHT. This is particularly true in men under age 40. Since DHEA also offers various health benefits, such as a heightened immune response and increased insulin sensitivity, the problem of possible conversion into estrogen by way of aromatase enzyme is a daunting one.

Diindolin can once again offer benefits by promoting the conversion of any estrogen produced as a result of DHEA usage into the beneficial 2-dehydroxy form, which if anything, would provide synergistic health benefits with DHEA usage. As noted earlier, Diindolin, through increasing 2-hydroxy synthesis, blunts the effects of estrogen in promoting prostate enlargement. It is synergistic with other phytochemicals that prevent prostate enlargement, such as saw palmetto (which blocks conversion of testosterone into DHT), green tea, pygeum africanum, and stinging nettle.

Diindolin may also increase insulin response. By potentiating catecholamines, Diindolin can increase carbohydrate clearance and "reset" the insulin system to a lower starting point. This effect, in turn, increases the response of insulin to high glycemic carbohydrates or simple sugars. Since such simple sugars are needed to promote uptake and absorption of creatine into muscle through a insulin-stimulated muscle creatine uptake carrier, the increased insulin response promoted by Diindolin serves to increase creatine supplemental efficacy. Diindolin also may increase workout recovery. Studies show that estrogen appears to limit muscle damage induced by intense training. The damage may be incurred by increased free radical release from the upgraded oxygen intake typical during exercise. These free radicals damage cell membranes, leading to an inflammation discernable as muscle soreness.

One of the good things about estrogen is that it is a potent free radical quencher. Evidence shows that you can obtain this same protective effect of estrogen minus the negative aspects with 2-hydroxy estrogen metabolites promoted by Diindolin. Studies show that dietary antioxidants, such as vitamin E, increase exercise recovery by minimizing the inflammatory effects of free radical release during exercise. The 2-hydroxy estrogens are even more potent in their free radical-quenching effect than vitamin E. Thus, by relieving muscle inflammation after exercise, Diindolin may speed exercise recovery. Add it all up and you can only draw one conclusion: the future of DIM or more precisely, Diindolin, looks bright!

(0)Farnsworth WE. Roles of estrogen and SHBG in prostate physiology.
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