WHEN JOSÉ CANSECO WAS ARRESTED AT THE MEXICAN BORDER for possession of a female fertility drug, baseball’s steroid scandal took a curious but predictable turn. It was Canseco who, after years of rumors, cast the brightest light on the prevalence of anabolic steroids in major league baseball, in his book, Juiced: Wild Times, Rampant ’Roids, Smash Hits, and How Baseball Got Big. Initially, though, the book was roundly booed—dismissed as the ravings of a vengeful malcontent who had squandered his talent. There was much truth in this assessment of Canseco the man. In his third year he became the first player ever to hit forty or more home runs and steal forty or more bases in one season. But his decline from that high point was precipitous, as he increasingly focused on swinging for the seats at the expense of his batting average and especially his (outfield) defensive skills. Within a few years of his historic feat, he was better known for having a ball bounce off his head for a home run. Nor did his seemingly blasé attitude endear him to fans or teammates. His first manager, Tony La Russa, then of the Oakland Athletics, came to particularly despise José. In an act of unprecedented spite, La Russa notified Canseco (through a second party) that he had been traded to the Texas Rangers while Canseco stood in the On Deck circle waiting to bat. It was telling that Canseco received little sympathy for his humiliation.
So the public, understandably, was not ready to take Canseco at his word. Soon after the publication of Juiced, however, its general veracity became apparent. Canseco himself admitted to being a long-time user, which surprised nobody. But he outraged the baseball community by implicating others by name, many of them All Stars, including his teammate Mark McGwire. By the time the steroid scandal resulted in a congressional investigation, Canseco’s seemingly wild claims were largely substantiated, which, of course, became the subject of his second book, Vindicated: Big Names, Big Liars, and the Battle to Save Baseball.
Anabolic steroids are popular with baseball players for the same reason they have long been popular in track and field (especially among sprinters), weight lifting, body building, and a host of other athletic endeavors: given the proper training regimen, they promote muscle growth. That is what “anabolic” in “anabolic steroid” refers to. All anabolic steroids are synthetic forms of androgens, particularly the hormone testosterone; that is, they are designed to mimic testosterone for the purpose of muscle building. In this they have a well-documented efficacy. But testosterone has many other effects aside from muscle building. In males, naturally produced testosterone promotes genital development, hair growth, and acne. It also has a host of effects in the brain that affect behavior, most notably libido, but also mood and aggression. These are all considered side effects by steroid users; they are actually just unwanted (by baseball players) but natural responses to this hormone. Many of these side effects are associated with adolescence, when testosterone levels naturally surge. In fact, in many ways, adult steroid users experience perpetual adolescence.
When testosterone levels are unnaturally elevated with synthetic steroids, some side effects become especially problematic. For example, a number of acts of violence have been attributed to so-called roid rage. But many of the undesirable effects of synthetic steroids are caused by their effects on natural testosterone. The body adjusts to the unnaturally high levels of testosterone by shutting down its own production of testosterone. Since synthetic testosterone can only be taken for a few weeks at a time without catastrophic consequences, testosterone levels are unnaturally low during the fallow periods, resulting in depression and low libido. Further complicating matters for users is the fact that one of the byproducts of testosterone metabolism is the estrogen estradiol. One of the consequences of the elevated levels of estradiol is the development of female-like breasts, commonly referred to as “man boobs.” High levels of estradiol and low levels of natural testosterone together are responsible for what is, in the macho world of athletics, one of the most undesirable consequences of steroid abuse: shrunken testicles. Even worse, though their libido remains elevated, many longtime users experience erectile malfunctions, a truly ironic case of “the spirit is willing but the flesh is weak.”
Which brings us back to Canseco’s border bust. Canseco was not only a snitch but a proudly self-proclaimed user and advocate of synthetic testosterone. He maintained his regular steroid regimen after his baseball career was over because he liked the way it made him look and feel. As such a longtime user, Canseco was especially vulnerable to shrinkage and limpness, not only when he had cycled off steroids, but as a more or less permanent state of affairs. At the time of his arrest, his sperm production had probably virtually shut down, hence the fertility drug.
What Canseco had in his possession was another hormone, called chorionic gonadotropin, which was purified from gallons of urine garnered from pregnant women. Gonadotropins stimulate the gonads to do what gonads do. What the gonads do is, of course, different in men and women. In women, gonadotropins stimulate the development of eggs in the ovary and the production of estrogens. In men, gonadotropins stimulate the production of sperm and androgens in the testes. That Canseco had pregnant-female-derived gonadotropins is simply because most pharmaceutical gonadotropins come from pregnant women. That he didn’t have a prescription is perhaps understandable.
Obviously, androgens are potent chemicals. In this chapter we will explore the reasons for this potency, especially their role in garden-variety gene regulation. This exploration of short-term gene regulation will provide some useful background for the discussion of epigenetic gene regulation in subsequent chapters.
Same Genes, Different Effects
Most of the time, most of your genes in most of your cells are silent; they just sit there, doing nothing. These silent genes must be activated in order to participate in protein production. Activation occurs when certain kinds of chemicals bind with their control panels, initiating the process of transcription as described in the previous chapter. These chemicals are called transcription factors. Sex steroids (androgens and estrogens) are important transcription factors. When Canseco is on his steroid cycle, the genes for which testosterone acts as a transcription factor are much more active than they are when Canseco is off his regimen. If we could equate gene activity with light levels, these androgen-sensitive genes would glow much brighter when Canseco was taking steroids.
But only in certain cells. In most of Canseco’s cells, the glow from these androgen-sensitive genes would remain dim, even when he was taking the steroids. Yet these steroids circulate widely in the blood, so in principle at least, every cell in his body would be exposed to the steroids. And every cell in Canseco’s body has the same genes. So why would only a minority of these cells glow when Canseco was using?
Testosterone and other sex steroids can only bind to genes after they have first bound to the proper receptors. But different kinds of cells have different kinds of receptors. So testosterone acts as a transcription factor only in those cells with androgen receptors. These androgen receptors reside in the gelatinous material inside the cell called cytoplasm. It is the testosterone-androgen receptor complex that moves from the cytoplasm to the cell nucleus and actually binds to the gene, thereby activating it. So we can largely predict which cells would glow when Canseco was using steroids by the presence or absence of androgen receptors. Some of the notable cell populations, or tissues, with androgen receptors are in the skin, skeletal muscles (biceps, triceps, and so forth), testicles, and the prostate gland. There are also androgen receptors in various parts of the brain, including the hypothalamus (which controls libido, among other drives) and the limbic system (which regulates emotions including aggression).1 So these are the cell populations where the androgen-sensitive genes will light up. The same genes elsewhere in the body will remain dim. This is the most basic way in which a gene’s activity is controlled by the cellular environment.
Canseco’s unnaturally high testosterone levels not only caused the shutdown of his testosterone production in the short term; in the long term, they caused a reduction in the androgen receptors in the androgen-sensitive cells. As such, ever higher doses were required to achieve the same effect on the muscles. And testicular shrinkage became an increasingly chronic condition, eventually permanent.
Even if we consider only Canseco’s androgen-sensitive cells, there is great variation in the effects of testosterone on cells in, say, the triceps muscle, compared with cells in the testicles or brain. In the triceps, testosterone stimulates the growth and proliferation of muscle fibers; in the testes, testosterone stimulates sperm development. What causes these divergent effects? In part they are due to the fact that testosterone interacts with different receptors and hence activates different genes in the triceps cells and in the testes cells. But even in those cases where the same genes are activated, the effects can be very different, simply because the cells in which these genes are activated are different. The varied responses among androgen-sensitive cells are testimony for cellular control over gene actions and effects.
From the Cellular to the Social
The activity of a gene, the degree to which it glows, is called gene expression. The control of gene expression is called gene regulation. So far we have considered gene regulation solely at the cellular level, the level at which the gene is most directly regulated. But the cellular environment itself is influenced by both the surrounding cells with which it directly interacts and cells in distant parts of the body with which it communicates through the blood. So gene regulation is often initiated from remote sites in the body. Androgen-sensitive genes in muscle cells are regulated by androgens produced in the testes.
Some of the most fascinating forms of gene regulation are initiated outside of the body. Social interactions are a particularly important source of gene regulation. For example, in animals from fish to humans, the outcome of competitive interactions can influence testosterone levels, with all the consequent effects on gene activity.2 So, too, can many other kinds of social interactions. When Canseco was informed of his trade while standing in the On Deck circle, his testosterone levels may have dipped. Though he didn’t seem outwardly bothered when the ball missed his glove and bounced off his head and over the fence for a home run, inside his body it was another story. The activity of a number of his genes—not just those sensitive to androgens—was temporarily altered by this embarrassing event. And to the extent that psychiatric interventions can meliorate the psychological effects of traumatic events like these, these interventions will cause alterations in the regulation of genes in his brain. In fact, any alterations in Canseco’s androgen levels resulting from athletic or other social interactions begin with alterations in gene expression in some of his brain cells. Let’s consider now how social interactions could alter androgen levels through changes in the expression of genes in these brain cells.
Recall that Canseco was busted for gonadotropins (GT). Though his were ultimately derived from the placenta of pregnant women, most GT in women and all GT in men are produced in a tiny gland at the base of the brain called the pituitary. But the production and release of pituitary gonadotropin levels are controlled by a small group of neurons in the hypothalamus.3 These neurons produce yet another hormone, called gonadotropin releasing hormone (GTRH).4 GTRH stimulates the release of GT, which stimulates the production of testosterone, a system called the hypothalamic-pituitary-gonadal axis, which I will henceforth refer to as the “reproductive axis.” If Canseco continues along his self-destructive path, he might eventually need to go further upstream along this reproductive axis to GTRH itself, though that hormone will prove much harder to procure.
A schematic diagram of the hypothalamic-pituitary-gonadal (HPG) axis. Diagram by the author.
The only way that social interactions could impact Canseco’s androgen levels is through his brain; that is, through effects on certain genes in certain brain cells. But the brain as we all know is a hugely complex organ. As such, we don’t want to go on a fishing expedition for the target cells. Fortunately, we have a logical place to begin to unravel the mechanism for the social control of testosterone levels: those GTRH neurons. It seems likely that any social influences on the brain that impact testosterone levels will be channeled through these neurons. We can then work backward from the GTRH neurons to those neurons that provide inputs, either directly or indirectly, to the GTRH neurons. It is in those neurons that project to the GTRH neurons where we are most likely to find the initial changes in gene expression that are caused by the social environment.
Such studies would require experiments that no one would think of conducting on humans. Fortunately, we have animal models for these investigations. Surprisingly, one of the best animal models is a fish, specifically, the African cichlid Astatotilapia burtoni from Lake Tanganyika. Males of this species compete for territories, a prerequisite for attracting females. Only a minority of males in a population can maintain territories, however; the rest are relegated to nonbreeding status. The territorial males and the nonterritorial males look quite different. Territorial males have bold black markings on their faces and are generally more colorful than nonterritorial males. Internally there are even more dramatic differences. Territorial males have much larger testes and higher testosterone levels than nonterritorial males. The GTRH neurons are also much larger in the territorial males than in the nonterritorial males.5
The social status of these fish can be manipulated, however, such that the territorial males are transformed into nonterritorial males and vice versa, with all of the consequent external and internal changes.6The alteration in size of the GTRH neurons reflects in part a change in the activity of the gene that codes for GTRH.7 A number of other genes are affected as well.8 Of particular note, the genes for both the androgen receptor and the GTRH receptor become less active.9 The net effect is a reduction in the rate of release of GT in the pituitaries of nonterritorial males, which causes a decrease in androgen production in the testes, with all of the effects we have previously detailed on androgen-sensitive genes, including those in the testes itself—hence Canseco-like shrinkage.
Lessons Learned from José’s Sad Saga
There is a moral in José Canseco’s misadventures with anabolic steroids, but it is only indirectly related to shrinkage. The moral pertains more directly to the remarkable sensitivity of genes to their cellular context. It is the cellular environment that determines how the genes for which testosterone is a transcription factor will respond. This sensitivity is not confined to testosterone-regulated genes; it is true of genes in general.
The cellular environment is itself influenced by other cells in the body, both local and remote. Moreover, the cellular environment is often influenced by events that occur outside of the body, including social interactions. So, many genes, including those responsive to testosterone, are ultimately socially regulated. The picture of gene action that emerges from Canseco’s saga is one of dependence, not that of an executive instructing its biochemical minions. It is a story of genes as much directed as directors. But this is gene action over the short-term. Perhaps things will prove different if we consider gene actions over the longer term. Maybe then their sensitivity to context, from the cellular to the social, diminishes. Maybe over the long-term the traditional view of genes makes more sense. It is to these longer-term gene actions, in stress-related genes, that we now turn.