Your Brain on Steroids: With Male Sex Hormones, Dose Size Matters
With Male Sex Hormones, Dose Size Matters


by Brenda Patoine

September, 2005

Congressional hearings questioning beefy baseball players about anabolic steroid use, along with the growing use of testosterone replacement therapy, have refocused attention on the good and bad effects of the family of so-called “male” sex hormones known as androgens (which are actually present in women in almost equal amounts).

Recent studies reiterate how diverse the effects are of these “androgenic/ anabolic steroids,” which include testosterone and its natural molecular cousins (such as dehydroepiandrosterone, or DHEA), as well as synthetic derivatives of testosterone (the anabolic steroids). Androgens of different stripes exert a number of different actions in the body and brain, depending on the steroid, dose, and person taking it.

In some studies, testosterone replacement has resulted in improvement in bone mass, muscle strength, and quality of life. And there is growing evidence for beneficial effects of physiological doses of androgens on learning, cognition and mood.

However, high doses of anabolic steroids are associated with an array of adverse psychiatric effects, including aggression, violent outbursts, hypomania, and depression. These symptoms generally become more prominent as the steroid dose increases, but they do not manifest in all users uniformly.

Aggression is the No. 1 reported symptom among anabolic steroid users. In animal studies, anabolic steroids dramatically increase aggression in doses and combinations that mimic street use. Moreover, in adolescent animals, steroids disrupt the normal development of aggression circuits in the brain and induce biological and behavioral changes that persist long after steroid use is stopped. 

The Difference Is the Dose

What accounts for such dramatic contradictions from the same family of hormones? The difference is in the dose, experts say. Testosterone replacement therapy typically uses a dose range of about 50 to 100 milligrams per week, whereas illicit anabolic steroids pack in 1000 milligrams a week or much more, with users often combining, or “stacking,” several drugs.

“When given in the ordinary physiological range, or even up to six times the normal range, androgenic steroids have very few of the adverse psychiatric effects associated with anabolic steroid use,” says Harrison Pope, a Harvard neuropsychiatrist who has studied patterns of anabolic steroid use and their psychological effects.

 “When you give somebody back testosterone that’s been depleted, what you’re essentially doing is bringing hormone levels back in check with what the system is used to,” says Rich Melloni, a neuropsychologist at Northeastern University who studies animal models of anabolic steroid use. “When you use anabolic steroids, you’re using not one, not two, but 10 to 100 times the dose. These high doses completely change the way the system behaves. If you do this during development, you’re setting up a long-standing change in the system.”

Angry Young Rodents

For 10 years, Melloni and his collaborators have injected some 1,200 adolescent hamsters with anabolic steroids in amounts and combinations that resemble street doses, then carefully have tracked their behavior and neural responses.

“The results are very clear-cut,” he says. “If you give animals steroids, they are tremendously more aggressive.”

The animal experiments helped settle the question of whether aggression in steroid users was more a phenomenon of environmental/social conditioning than a drug-induced effect. Still, the underlying neurobiology—the question of how steroids increase aggression— was not understood at all. Under a grant from the National Institute for Drug Abuse, Melloni’s group has now turned its attention to this question.

Their evidence points to two neurochemical systems in particular, vasopressin and serotonin, which act respectively as stimulator and inhibitor of aggression in the hamsters Melloni has studied.

“If anabolic steroids are part of the equation in adolescent development, the expression of brain circuits involved in stimulating aggression (i.e., vasopressin) are enhanced, and those circuits that are involved in suppressing aggression (i.e., serotonin) appear to be diminished,” he says. “You essentially are stepping on the gas for aggression while letting your foot off the brake.”

Two brain areas in particular, the anterior hypothalamus and the medial amygdala, “show consistent up-down changes in a number of the neurochemicals we’ve looked at,” he says. His group is now expanding the work to look at how other neurotransmitter systems, such as gammaaminobutyric acid and glutamate, may be involved in the intensified aggressive response.

The association between testosterone and human aggression has been the focus of considerable research, but there are few data on the influence of therapeutic replacement doses of testosterone on male aggressive behavior.

A 2004 British study by Daryl O’Connor and colleagues, published in The Journal of Clinical Endocrinology and Metabolism, found that healthy men treated with a relatively high dose of testosterone (1,000 mg/week) did not produce any detectable increase in aggressive behavior or changes in other nonaggressive or sexual behavior.

Aggression aside, it is increasingly clear that replacing natural levels of androgens does have psychological effects, says Neil MacLusky, a neuroendocrinologist at Helen Hayes Hospital in New York.

“The beneficial effects probably happen in the low physiological dose range,” he says. “You don’t need the kind of doses that one takes to get anabolic (muscle-building) effects.”

Right Androgen, Right Dose

MacLusky has studied the brain effects of DHEA, a “precursor” hormone that is made in the adrenal glands of men and women and can be converted into testosterone, estrogen, or other sex hormones.

“At physiological levels, DHEA does very little in the way of masculinization,” says MacLusky, referring to the effects other androgenics have on body hair growth and muscle mass. Importantly, though, DHEA does “have very pronounced effects in the brain, including synapse formation in the hippocampus,” he says.

His team’s most recent experiments show that DHEA and flutomide, a drug that blocks androgen receptors, work differently in the brain than they do elsewhere in the body. This finding suggests distinct pathways for the neural effects of these compounds.

“We don’t know how they’re working at this point, but they’re not working through the same receptors that are mediating the masculinizing effects of androgens,” MacLusky says. “This actually offers a tremendous opportunity, because one can envision treatment where the right doses of the right androgens could be taken by either men or women to achieve the beneficial effects on the brain, with none of the anabolic effects.”

The bottom line, experts say, is that not all androgens act the same, and that dose matters. There is a pervasive fear among researchers in this area that the recent media hype over anabolic steroids could produce a backlash against even legitimate medical uses of androgens.

“People see the bad things that can happen with athletes that inject massive amounts of these things over time and then conclude that androgen treatment is somehow going to be as bad or worse,” MacLusky says. “There is a risk that the prejudices against steroid treatment are really going to slow down research into the beneficial effects of hormones.”

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“If you give animals steroids, they are tremendously more aggressive,” says Rich Melloni, a neuropsychologist at Northeastern University who has conducted many experiments with adolescent hamsters.  Credit: Courtesy of Rich Melloni, Northeastern University