It seems that weekly we hear about some professional athlete who sullies himself and his sport through abuse of steroids. The melodrama unfolds, careers and statistics are brought low and asterisked, and everyone bemoans another fallen competitor. Yet there are millions of cases of steroid use that occur daily with barely a second thought: Millions of women take birth control pills, blithely unaware that their effects may be subtly seeping into and modulating brain structure and activity.



It is a huge experiment whose resolution will not be known for a while, but a new study in the journal Brain Research demonstrates that the effects are likely to be dramatic. It found that birth control pills have structural effects on regions of the brain that govern higher-order cognitive activities, suggesting that a woman on birth control pills may literally not be herself -- or is herself, on steroids.



The human brain is a remarkable structure, not least because of its seemingly infinite capacity for change, adapting millisecond by millisecond. Indeed, a structure with tens of billions of neurons, each of which has the ability to elaborate and branch and become more complex, while changing its activity in the process, is the very definition of change. This so-called neuroplasticity is a hallmark of the nervous system. It can, however, be augmented, boosted, by artificial means, and if we are not careful, the brain may go all catawampus.



Steroid hormones, which are excreted by endocrine organs such as testes and ovaries, flow in abundance throughout the bloodstream, reach target organs and structures, and exert powerful effects on them. To wit, the cock’s comb, the buck’s antlers, the lion’s mane, the blood-engorged uterus.



What of the mammal’s nervous system? It turns out that the brain is a veritable sponge for steroid hormones. In the male, the androgen testosterone (or a metabolite) binds to brain receptors and sculpts that structure into the aggression-promoting, sex-craving, risk-taking regulator with which we are all familiar. By the same token, the comparative lack of androgen hormones in the female produces the kinder, gentler, softer neural substrate that distinguishes itself from the male by dint of its vastly different behavioral repertoire.

Whereas the subtle structural effects of naturally-occurring steroid hormones and sex differences in the brain have been extensively studied, few studies have examined the role of synthetic hormones on changes in the human brain. What happens, then, when the female brain gets a significant and artificial dose of steroid hormone, either progesterone, estrogen or both? We know what happens below the waist, the pregnancies prevented. What happens above the neck, as this steroidal tsunami washes over the neural coastline?



It appears that the brain, that sensitive organ replete with steroid receptors, reacts to its hormonal milieu with startling structural modifications. Researcher Belinda Pletzer, of Paris-Lodron-University Salzburg, and her colleagues used MRI and voxel-based morphology to examine the brains of men; women on the pill; and “naturally cycling” women not on the pill.



The researchers found that males have considerably larger areas of gray matter in brain regions associated with learning and memory, known as the parahippocampal gyrus and hippocampus, as well as an area associated with emotional regulation, the amygdala. These data are consistent with many studies that provide evidence for gender differences in brain and behavior.



Further, naturally cycling women showed an increase in gray matter volume in the right fusiform/parahippocampal gyrus when circulating levels of estrogen and progesterone were low versus the phase when levels of these hormones were both high.



Does that increased gray matter translate into enhanced performance? It is not clear. Research into the hormonal regulation of cognition is extremely complicated. As Pletzer mentions, human fMRI studies have revealed that these areas are associated with spatial navigation abilities. Other work suggests that hippocampal–dependent spatial memory is enhanced by higher levels of estrogen. Under some conditions, however, estrogens have no effect or can even impair performance in rats.



Additionally, in Pletzer’s study, women using hormonal contraceptives showed larger gray matter volumes in the prefrontal cortex, pre- and postcentral gyri, the parahippocampal and fusiform gyri and temporal regions, when compared to naturally cycling women. The brain works like a neural beehive; the proper coordinated functioning of groups of tasked neurons are important to successfully accomplish a variety of mental tasks -- even the sensory processing and motor coordination needed for something as simple as picking up a hot cup of coffee without scalding oneself. Again, we do not know whether this increased gray matter translates into better or worse performance, but there likely is little good about treating a woman's brain like a spongy accordion.



Further, although the Pletzer data are suggestive, there are other methodological and interpretational issues worth considering. For example, the authors did not examine levels of circulating hormones in the male and female subjects (e.g., testosterone or estrogen, respectively). Such data would have been helpful in determining the timing of the neural structural effects.



Furthermore, the types of hormonal contraceptive were not examined, lumping them all into a vague “hormonal contraceptives” group. There is a high level of variability and differential ratios in levels of estrogen and progesterones in birth control pills.



Pletzer’s team, despite showing significant neuroanatomical alterations, did not perform behavioral or cognitive tests of their subjects that could have helped explain the meaning or functional consequences of the changes. Comparing other published work with the Pletzer study allows us to make inferences, but they are, at best, speculative given the unique details of the current research. There are pretty large differences in the structure of the brain that are attributable to cyclic fluctuations in natural hormones, and that appear to be due to unnatural concentrations of synthetic hormones. But since the authors did no cognitive testing of their subjects, we can only speculate about the behavioral effects.



Last, birth control pills also keep hormones low. So, there are two simultaneous events tugging at the data, a confound: the hormonal effects of the pills themselves, and the lowering of the normal hormones, both of which could bring about the structural effects. So even the actual hormonal basis underlying the reported structural differences remains unclear.



Still, overall, the Pletzer data do reveal some startling effects of oral contraceptive hormones. There are natural hormonal fluctuations that are a consequence of menstrual cycle oscillations, and which have organic effects of their own, but these have been a part of female mammals’ lives since time immemorial. Now, we are superimposing onto this sensitive substrate a steroid hormone cocktail with the potential of marking the brain in dramatic fashion.



The possibility that an accepted form of chemical contraception has the ability to alter the gross structure of the human brain is a cause for concern, even if the changes seem benign -- for the moment. In any event, women need to have all of the medical and now, neurobiological, information they can use in informing their personal contraceptive decisions. Like the rest of life, and like the steroid choices made by those ballplayers, there are costs and benefits. The benefits are well established; the costs, however, are still coming to light.