Estrogen: The Other Male Hormone
By Helen Shen
Staff Writer
The recent case of Caster Semenya, a South African women’s track star now suspected of being intersex, has brought international media attention to the question of just what separates “maleness” and “femaleness.” At UCSF, researchers studying sex differences in mice have found surprising evidence that certain features of the male brain, as well as some male-specific behaviors, actually depend on the “female” hormone, estrogen.
The results, from the lab of Nirao Shah, are published in the October 2, 2009 issue of Cell, and provide new insights into how one hormone, estrogen, can have dramatically different effects on male and female brains.
While gender determination in humans can be complicated, in many animal species, males and females are distinguishable by clear sex-specific behavioral patterns. For example, a male mouse will attack another male introduced to its cage, whereas a female will not. Melody Wu, a graduate student in the Shah lab and lead author of the study, has found that estrogen is a key player in wiring, then activating, brain circuits that drive male aggression.
Estrogen and masculinity
Estrogen is commonly thought of as the canonical “female” hormone and testosterone the “male” hormone, but in fact the biochemical boundaries are not so clear. Although the testes produce only testosterone, the male brain is actually exposed to both hormones via the enzyme aromatase, which converts testosterone to estrogen. Surprisingly, previous research has shown that testosterone-derived estrogen is involved in controlling many male behaviors, including fighting.
But wait, if estrogen can make male mice behave “masculinely,” then why don’t females, with high circulating levels of estrogen, fight with males too?
The key, as Wu and colleagues have discovered, has a lot to do with timing. Males are exposed to estrogen early in life, when females are not, causing their brains to be wired differently. This sets the stage for estrogen exposure later in life to have vastly different effects on male and female brains, and in turn, on fighting behavior.
A two-step process—neonatal and adult effects of estrogen
Brain development: For the first few weeks after birth, the ovaries produce no estrogen, and the developing female brain is not exposed to sex hormones. In males, however, the testes produce a surge of testosterone immediately after birth that exerts a powerful influence on the brain.
Hypothesizing that the early hormonal surge is an important determinant of brain maleness, the researchers mimicked this in neonatal females with testosterone injections. Sure enough, anatomical evidence showed that later in life, the brains of these females looked male-like, in specific areas thought to control fighting.
Remarkably, the same effects were observed in females injected with estrogen neonatally, strongly suggesting that, even in males, the circuits controlling aggression are masculinized not by testosterone, but by its aromatized product, estrogen.
Hormonal activation: Still, even with the right male-like brain circuits in place, as adults, these females did not fight quite like males. A second boost of testosterone in adulthood, again mimicking male levels, was able to fully “activate” the masculinized circuits, leading females to display full male-like aggression. Further testing once again pointed to estrogen, derived from testosterone, as being an active agent driving male-typical aggression.
So, can this mechanism account for any behavioral differences between men and women? Perhaps not. According to Wu, “the direct correlation of these findings to humans is still unclear, especially since there are certainly enormous cultural and social factors that contribute to human behavior.” However, “these exciting results give us a better understanding of the general principles of how the brain is wired… and how some of those developmental mechanisms can influence adult behavior.”
Shah further notes that studying interactions between sex hormones and the nervous system in mice could one day shed light on why many common neurological and psychiatric illnesses, such as multiple sclerosis and autism, are more prevalent in one sex than the other.
This article appeared in the October 8, 2009 issue of Synapse.