Estrogen Plays Key Role in Male Brain Development

By Jeffrey Norris

Not testosterone, but rather estrogen, the “female” hormone, is most directly responsible for the development of brain circuits in males that guide aggressive and territorial behaviors – at least in mice.

Nirao Shah

This latest discovery about sex hormones and behavioral and brain differences between the sexes appears online today (October 1) in the scientific journal Cell. The public may be largely unaware of the importance of estrogen for males, but in recent years scientists who study brain differences between sexes have identified a special role for estrogen in governing certain behaviors in male rodents. Now, for the first time, a new genetic strategy brought to bear by UCSF researcher Nirao Shah, MD, PhD, and graduate student Melody Wu has empowered the researchers to identify in cellular detail the male-female differences in the size, properties and functions of neural circuits within brain structures associated with sex specific behaviors. The researchers found that a naturally occurring, brief spike in testosterone secretion from the testes of a male mouse shortly after birth was sufficient to drive development of “male” brain circuits. Females do not secrete hormones after birth. Without the conversion of this testosterone burst into estrogen, much of male mouse brain circuitry develops similarly to normal female mice. Female mice provided with a shot of either testosterone or estrogen shortly after birth became “masculinized.” In humans, boys similarly secrete testosterone shortly after birth, Shah says.

Estrogen Is Made from Testosterone

Males and females, mice and humans, all make estrogen from testosterone, thanks to an enzyme called aromatase. Women have a lot more estrogen in the circulation, of course. Aromatase is familiar to many women with breast cancer. Breast cancer growth driven by estrogen is thwarted by giving women drugs known as aromatase inhibitors, which prevent the conversion of testosterone to estrogen. Shah modified the genetic code for the aromatase enzyme in mice, so that the cells making the modified enzyme could be detected with a tag. The engineered aromatase still functions normally. In earlier experiments, other researchers knocked out the enzyme entirely, and male mice lacking aromatase as a result failed to exhibit sex-specific behaviors. Male mice make so little estrogen that it’s tough to measure in the blood. But some of the testosterone secreted after birth travels to the brain, and if aromatase is present, then the testosterone can be converted to estrogen, leading to male-specific development within selected neural circuits. “Previously, we knew that aromatase was required, but we didn’t know where it was located,” Shah says. “The technique improved our ability to see the needle in the haystack. The biggest surprise is the select number of cells expressing this enzyme. From what we see, less than 0.1 percent of the cells in the mouse brain are estrogen-synthesizing cells.” The mouse brain contains about 100 million cells, he says. The research points to ways in which male and female mice respond differently and predictably to identical stimuli, particularly to chemical messages from other mice, called pheromones, for instance. The research also reveals that different behaviors are affected differently, depending on molecular differences in different parts of the brain.

Brain Differences in Men and Women

What lessons are there for humans? It may take many years of additional research to find out, Shah says. Naturally, mice are more instinctual than humans. But while it is difficult to overstate the roles of acculturation and socialization in human development, countless parents suspect that on average most girls and boys are inherently different when it comes to behavior. It may be that humans retain sex differences in brain circuitry left over from an earlier era of mammalian evolution. MRI images of humans reveal differences between men and women in the average size of certain anatomical features in the brain, but the opportunities to learn more about human brains and behavior through experimentation are somewhat limited. “You don’t have to have anatomical differences to have behavioral differences,” Shah says. “There may be genetic differences that you can’t see with MRI.” Shah hopes that what can be learned about differences in the brain circuitry and brain functions in male and female mice may one day provide clues about the origins of human diseases that arise in the brain. Males are more likely to be diagnosed with autism, attention deficit disorder and Parkinson’s disease, for instance. Females are more likely to suffer from Alzheimer’s disease, anxiety and depression. The scope of Shah’s research is expanding. He has just been awarded a five-year, $2.5 million “Pioneer Award” from the National Institutes of Health to blaze a new behavioral research trail. He will be studying how voles – rodents that resemble mice -- become and remain attached to one another. Unlike a mouse, a vole chooses one mate for life.

Estrogen Masculinizes Neural Pathwaysand Sex-Specific Behaviors

Melody V. Wu, Devanand S. Manoli, Eleanor J. Fraser, Jennifer K. Coats, Jessica Tollkuhn, Shin-Ichiro Honda,Nobuhiro Harada, and Nirao M. Shah

Cell, (Published online October 1, 2009)

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Related Links:

Shah Laboratory
UCSF Department of Anatomy