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Testosterone and Cholesterol

7205-testcholesterolOf all the side effects associated with high-dose anabolic steroid use, the most immediately dangerous is the way they affect the cardiovascular system. Although a direct cause-and-effect relationship has never been established between steroid use and cardiovascular disease, many cases published in the medical literature point an accusatory finger at injudicious steroid use as being the primary cause of death from CVD. I’ve discussed in past columns how steroids can harm the cardiovascular system, but here’s a brief summary of a few of the mechanisms.

Taking steroids can lead to an enlarged heart that goes beyond that induced by exercise alone. That can set you up for future heart failure. Steroids can also damage the cells of the heart muscle, which, in turn, can put you at risk for a fatal electrical disturbance in heart rhythm known as an “arrhythmia.” Steroids are linked to higher blood pressure, which is the primary risk factor for strokes. The immediate cause of most heart attacks is an internal clot that obstructs a coronary artery. Steroids come into play because they promote internal clotting. Using steroids tends to thicken the blood due to overproduction of red blood cells, a condition known as polycythemia. Having too thick blood not only makes it harder to breathe but also boosts a person’s chances of having a stroke.

Steroids cause damage to the endothelium, which is the lining of blood vessels, decreasing how fast the blood vessels can dilate. Finally, steroid use may increase homocysteine, a metabolite of the amino acid methionine that is associated with damage to the endothelium.

Many of the negative effects are due to long-term use of steroids. The structural damage to heart cells comes under that heading. Steroids can also cause some rapid side effects, especially if taken in large amounts or in combination with other steroids in a cycle. Changes in blood-lipid profiles are a primary example.

Oral steroids potently affect an enzyme in the liver that degrades high-density lipoprotein, which is considered protective against cardiovascular disease. HDL ferries cholesterol from the blood back to the liver, where it’s degraded into bile. That’s the only way the body can rid itself of excess cholesterol, since cholesterol cannot be oxidized like fat. Steroids also boost low-density lipoprotein, the major cholesterol carrier in the blood, and having higher LDL is considered to be a major cause of atherosclerosis, especially when the LDL is oxidized.

Injectable steroids, in contrast to oral versions, are considered to be more benign in their effects on blood lipids, mainly because the injectables are not immediately metabolized in the liver, as the orals are. One study, for example, compared the effects of taking only six milligrams a day of Winstrol, a popular oral steroid, with 200 milligrams of testosterone enanthate, an injectable steroid. While the Winstrol was taken daily, the testosterone was injected once a week. After six weeks the Winstrol lowered beneficial HDL-2 by 71 percent. Those taking the injection showed lower levels of another subfraction, HDL-3, by only 9 percent. LDL rose by 29 percent with Winstrol but dropped 16 percent with the testosterone injection.

On the other hand, a recently published study suggests that the effect of only a single injection of testosterone on cholesterol is far more potent than was previously believed.1 To understand how that is possible, you need to know how cholesterol is produced. Cholesterol is produced in the liver. The rate-limiting enzyme for cholesterol synthesis, meaning the enzyme that determines how much and how fast cholesterol is produced, is HMG-COa reductase—HMG.

This is the enzyme that is inhibited by statin drugs, which are the primary drugs prescribed to treat cardiovascular disease. Statins effectively lower elevated blood cholesterol by inhibiting the activity of HMG. The body, however, has its own feedback mechanism, in that large amounts of LDL turn off the gene that produces HMG, which turns off cholesterol synthesis in the liver. The process depends on the activity of LDL cell receptors, which are involved in cell uptake of cholesterol. The more active the receptors are, the less cholesterol circulates in the blood. Once in the cell, cholesterol is used as a starting substance for a variety of vital functions in the body, including the stabilization of cell membranes and production of steroid-based hormones like testosterone, estrogen, cortisol and activated vitamin D.

In the new study 39 healthy volunteers, aged 18 to 50, got a 500-milligram injection of testosterone enanthate, which is equivalent to 360 milligrams of testosterone (that is, without the enanthate). This dose is considerably higher than what’s prescribed for the treatment of low testosterone. Although testosterone injections are rarely used to treat age-associated low T, when they are, the usual dose is about 100 milligrams, once a week. Doctors favor other forms of therapy because injections tend to peak after two days, then gradually decline. Using other forms of testosterone, such as creams, produces a lower level of in the blood but a more steady release of it.

The researchers measured the subjects’ total blood cholesterol at the start of the study to determine baseline values. Just two days after being injected with testosterone, the men’s blood cholesterol levels rose an average of 15 percent. After 15 days they dropped back to baseline. The researchers found that in 80 percent of the men the gene that controls the production of HMG in the liver increased by 80 percent within two days of their getting the testosterone injection, thus accounting for the rapid rise in blood cholesterol. There was no effect on liver function, as shown by no elevation in liver enzymes, so the effect was solely due to the testosterone-induced simulation of the gene for HMG in the liver.

To ensure that the effect was from the injection, the authors exposed isolated liver cells to an amount of testosterone equal to what the men in the study got. They observed that the testosterone did, in fact, promote increased activity of the HMG process in the liver cells. The higher cholesterol returned to baseline 15 days after the injection because of the body’s built-in feedback mechanism, whereby cholesterol controls its own synthesis by shutting that whole thing down. That is, higher blood cholesterol leads to a shutdown of liver cholesterol production as the gene for HMG is turned off.

There are a few factors to consider with this study. For one, as noted, unlike oral steroids, injected testosterone does not ordinarily lead to bad effects on blood lipids. If anything, dangerous LDL levels are reduced with testosterone injections, while HDL levels are barely affected. Why the difference between oral and injectable steroids?  One reason is that the orals potently boost the activity of the liver enzyme that degrades HDL, with 143 to 232 percent greater activity of the enzyme. Injectables don’t do that. Another difference is that some of the injectable testosterone is converted into estrogen through the activity of the enzyme aromatase, which is found all over the body.

Since many bodybuilders who use steroids are concerned about aromatase converting them into estrogen, they use other drugs, such as Arimidex, to block the aromatase. They do it to prevent various estrogen-related side effects, such as gynecomastia and water retention. The question is how that affects the protective cardiovascular benefits offered by estrogen. In one study, subjects were given a 280-milligram injection of enanthate per week. Other subjects got the same injection but also used an aromatase-inhibiting drug called testolactone. The third group in the study took the oral steroid methyltestosterone, at a dose of 20 milligrams a day. The study lasted for 12 weeks, and the researchers noted only small changes in the HDL levels in those who got only the testosterone injections. After four weeks, however, those who got the testosterone as well as the aromatase-blocking drug showed an average 25 percent drop in HDL. Those who took the oral steroid fared even worse, showing a 35 percent drop in HDL after a month.

The point here is that although the 500-milligram testosterone injection used in the study did cause a rapid rise in blood cholesterol after only two days, an injection that big would likely result in considerable conversion of the testosterone to estrogen by way of aromatase. The increased estrogen, in turn, would boost protective HDL, thus neutralizing most of the bad effects of the higher cholesterol levels induced by the injection. Of course, if a drug is also used that blocks aromatase, the protective effect is lost. Interestingly, another drug used to control estrogen, tamoxifen citrate—trade name Nolvadex—works not by inhibiting aromatase but rather by competitively interfering with estrogen binding to cell receptors. As such, using Nolvadex to control estrogen would not have as bad an effect on lipids as the aromatase-blocking drugs.

The final point to consider about this study is that the dose of testosterone used, 500 milligrams, is about five times greater than any dose used to treat low testosterone in men. The medical dose not only doesn’t cause problems with blood lipids but even reduces dangerous LDL levels. So the results of this study don’t pertain to those who are on any type of medically supervised testosterone therapy.


Editor’s note: Jerry Brainum has been an exercise and nutrition researcher and journalist for more than 25 years. He’s worked with pro bodybuilders as well as many Olympic and professional athletes. To get his new e-book, Natural Anabolics—Nutrients, Compounds and Supplements That Can Accelerate Muscle Growth Without Drugs, visit   IM

 1 Garevik, N., et al. (2012). Single-dose testosterone increases total cholesterol levels and induces the expression of HMG CoA reductase. Sub Abuse Treat, Prevent, and Policy. 7:12.

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