Margaret McCarthy Ph.D.

SexX Matters

Is the Human Brain Sexually Differentiated?

Common biological processes across species inform us about human uniqueness.

Posted Apr 15, 2019

Whether men and women think and behave differently is both self-evident and endlessly debated. Most people intuitively believe that males and females on average have distinct brains—and if you talk to parents, they will say it was apparent from the earliest days. The key question is: Why do boys and girls act or think differently? 

Clues to this question are emerging from animal research, which attempts to isolate biological influences from social and cultural influences. Research on rodents has revealed a distinct biological process referred to as “sexual differentiation of the brain” which occurs during a critical developmental window. Put simply, this process assures that the gonadal sex of an individual (ovaries and testis) is in synch with brain sex.  Many people think the ovaries and testis are only important after puberty, but in males the testis synthesizes testosterone at high levels for a brief period during fetal development.  The fetal testosterone is released into the bloodstream and from there passes into the fetal brain.  Testosterone is a steroid that can modify any number of parameters important to brain growth. This includes stimulating the proliferation of new neurons and astrocytes in some parts of the brain while inducing their demise in others. Testosterone can also affect the connections between brain regions which will impact how information is processed and communicated later in life when the brain is mature.  Scientists refer to these developmental effects as “organizing” or “early life programming” because they will guide and restrict responses later in life.

For many years it was widely believed that sex differences in physiology and behavior were limited to the realm of reproduction and only occurred in those parts of the brain that directly controlled secretions from the pituitary, or mating and parenting behaviors.  This began to change in the 1990s with the discovery that steroids such as testosterone and estrogen are also present in parts of the brain that control learning and memory, or emotional responses like fear and anxiety. These studies focused on adult animals and while not a sex difference per se, demonstrated the ability of steroids in the mature brain to modify behaviors not involved in reproduction. It also lent credence to the notion that men and women behave the way they do because of the different steroids they experience as adults, i.e. high testosterone in men and cycling estrogen and progesterone in women. There was an important caveat, however. If this was true, then reversing the steroid profile of men and women should also reverse their behaviors and it was well known from animal studies that this is not the case. Instead, the influence of developmental steroid exposure, meaning high testosterone in fetal males, endures into adulthood as a form of early life programming that then determines the responsiveness to the post-puberty steroid profile. In other words, sexual differentiation of the brain during development is at least predictive, and at most, deterministic of adult behavior. 

Katrina Elena/stock photo iStock
Girl and Boy Twins
Source: Katrina Elena/stock photo iStock

This presents a problem when it comes to humans. First, most of us reject the notion that our thoughts and actions are dictated by events that occurred before we were born. Second, and more importantly, is that the human brain (and other species for that matter), is designed to develop in accordance with the environment it finds itself in, in order to predict the future. When a child is born their heart, liver, lungs, are all fully functional but the brain is just a blooming, buzzing confusion. This is by design as it allows the brain to imprint experience into its very fiber, to create connections and build circuits that will optimize performance in the future environment it expects to encounter. Here in lies the rub. From the moment they are born, boys and girls are treated differently. They are dressed differently, handled differently, and talked to differently. Behavioral expectations specific to gender are reinforced or punished both explicitly and implicitly over a period of decades as the brain matures, not reaching its full potential until the late 20s. How can we separate this powerful sculpting force on brain and behavior from the biological impact of steroid exposure experienced as a fetus?

The honest answer is we cannot fully separate them, and probably shouldn’t try. Ultimately the influence of experience on the developing brain is just as biological as the influence of steroids. But we can also look to so-called natural experiments in which the steroid exposure of development is out of synch with gonadal sex. This can occur in two main ways: 1) loss of function mutations in the receptors for testosterone or estrogen, or 2) loss of function mutations in the enzymes that synthesize steroids. The psychosexual profile of individuals with a genetic sex / hormonal sex mismatch has been intensely studied and, not surprisingly, caveats abound. There is no perfect experiment. Nonetheless, it is reasonable to conclude that there is consistent and pervasive evidence that testosterone exposure in utero is a contributing factor to sex differences in behavior, beginning in childhood. How large that influence is, varies by individual and in ways we still do not understand. Some argue that the influence is so negligible that it does more harm than good to give such a conclusion the imprimatur of science. Conversely, ignoring sex as a biological variable discards potentially valuable insights into the clinical evidence of gender bias in disorders of the brain. Moreover, government policies and societal acceptance of LGBTQ individuals can be enlightened and informed by a greater understanding of biological processes impacting male and female brain development.

This is my first blog post to Psychology Today, and I’m excited to contribute to the conversation about the human brain and behavior. As a scientist, I study the biological origins of sex differences in the brain to gain insight into the gender bias in rates of neurologic and neuropsychiatric disorders. Future posts will explore topics related to why boys are at greater risk of developmental disorders, how the sex chromosomes interact with steroids to affect the brain and why it is important that studies on sex differences in brain and behavior be expertly implemented and appropriately interpreted.