Male aggression is commonly pinned on testosterone, and estrogen is credited with imparting females with maternal instinct – but the true story of the sex hormones, and their roles in male and female behavior, is a lot more subtle. Here's why estrogen is an important hormone for males and females alike.

Photo Credit: Flickr user Singapore2010 - CC BY-NC 2.0

Many key differences between men and women can be chalked up to testosterone and estrogen, respectively. The sex hormones are responsible for the development of secondary sex characteristics during puberty – like body hair for men, and breasts for women – and influence our biology well into adulthood; circulating testosterone can lead to baldness in some men, and women's menstrual cycles are guided by monthly changes in circulating estrogen.

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But the extent to which sex hormones influence our day-to-day behavior is less clear (testosterone, for example, is often blamed for violent behavior in men, but studies suggest the connection between testosterone and male aggression is tenuous, at best). When it comes to studying the behavioral effects of sex hormones, humans can make for unreliable test subjects; culture has a way of confusing the balance between biology and custom.

Fortunately, model organisms like flies and mice engage in a number of innate, sexually dimorphic behaviors (i.e. behaviors typical of a particular sex). Two male mice, for example, both raised in solitude, will instinctively fight one another when introduced. Male and female mice, also raised in solitude, seem to know their respective roles when mating for the first time. And female mice show maternal instincts when raising their first pups, with nary a grandmother mouse to guide them. (Male flies, for their part, are also known to fight, and while the their courtship rituals are adorable, but there's no such thing as fly parenting).

Roy Niswanger CC BY-ND 2.0

Using model organisms, biologists have learned some surprising things about the relationship between testosterone, estrogen, and sexually dimorphic behaviors, and wholly debunked the facile notion that testosterone drives male behavior, while estrogen drives female behavior.

Testosterone, Estrogen, and Aromatase

On the molecular level, testosterone and estrogen are more similar than you may realize. Both are steroid hormones, a broad class of molecules derived from cholesterol. They're so structurally alike, testosterone can be converted into estrogen with a single enzyme, called aromatase, which is found in copious amounts in the ovaries.

Testosterone is converted to estradiol, one of the primary forms of estrogen, by just one enzyme, aromatase. Wikipedia user Boghog 2, Wikimedia Commons.

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Both testosterone and estrogen travel throughout the body via the bloodstream, and easily pass through the membranes of cells, permeating most tissues. Males tend to possess a lot more testosterone than females, and females more estrogen than males. But the biochemical pathways that produce and sense these hormones are found in both sexes. What's more, the last few decades have turned up several problems with pat interpretations of sex hormones, and the unilaterally male and female behaviors they purportedly influence.

For instance, castrating a male mouse (eliminating testosterone production) can decrease both its aggression towards other males, and its mating behavior towards females, but giving castrated male mice estrogen supplements can sometimes restore these male behaviors. (Obligatory disclosure: as with nearly all studies in mice, many of these effects depend on the strain of inbred laboratory mouse). Other studies support estrogen's carnal influence – male mice that lack the biological machinery to detect estrogen, for example, have been found to show little interest in mating with females, while dosing normal male mice with extra estrogen can induce mating behaviors in as little as 35 minutes.

Male hippos engaging in a typical male pastime: fighting. Nils Rinaldi. CC BY 2.0

These findings are confounded by two truisms of male physiology. The first is that the testes in male mice make testosterone, but not estrogen. The second is that virtually no estrogen can be detected in the bloodstream of male mice. Estrogen clearly influences male behaviors. If it's not in the blood stream, where does it originate – and where is it hiding?

Estrogen On The Brain

When scientists learned that aromatase could convert testosterone into estrogen, it provided a major clue in their search for a hidden source of male estrogen. The hormone, itself, was elusive – but researchers knew they could search for estrogen's point or origin by looking for aromatase.

Lo and behold, despite lacking estrogen in their bloodstream, male mice were found to possess aromatase in two brain regions commonly associated with sexually dimorphic behaviors: the hypothalamus and the amygdala. Testosterone easily passes from the bloodstream into the brain where, if there is aromatase lying around, it converts that testosterone into its own local estrogen supply. The discovery suggested that testosterone does not act alone. Estrogen, in some combination with testosterone, seemed to mediate male-typical behaviors by way of the hypothalamus and amygdala.

Females obviously produce plenty of estrogen, albeit at the same site where their testosterone is produced: the ovaries. There, the vast majority of testosterone is immediately converted to estrogen, which flows through the bloodstream and makes it into the brain.

Estrogen promotes maternal behaviors when it reaches the adult female brain. Seweryn Olkowicz.

Females have hypothalamuses, too, but the female hypothalamus promotes female-typical behaviors, such as "lordosis" (accepting a male mating attempt) and nursing, in response to estrogen. If both male and female mice end up with estrogen in the hypothalamus, something else must explain why their brains respond to the same hormone in distinct, sexually dimorphic ways.

Male Behavior is First Established in the Womb – by Estrogen

Many of the sexually dimorphic responses to estrogen can be traced all the way back to the earliest stages of development.

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The sex hormones begin to work on male and female biology in different ways as early as the first trimester of pregnancy. Just twelve weeks into human development (and a few days into mouse development), the genitals of both sexes have fully formed. As birth approaches, the ovaries lie dormant, but the testes in males jump into action, flooding prenatal male mice with testosterone.

At Left: Human fetus at 12 weeks. X. Compagnion.

One of the first organs to respond to this testosterone surge is the developing brain. Interestingly, while testosterone itself is important for what is called the "masculinization" of the male brain, local conversion of testosterone into estrogen is also required for this process.

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Masculinizing the neonatal mouse brain simply means shaping the young brain in preparation for executing male behaviors later in life. Male mice must be primed to mark and defend their territory, and procreate, once they reach adulthood. But without culture to instruct them, they must rely on male instincts bestowed upon them by their brains alone – brains that have bathed in testosterone since before birth.

You Need Estrogen To Build A Male Brain

In 2009, researchers in the lab of Nirao Shah at UCSF confirmed that estrogen was directly responsible for the early masculinization of the mouse brain, something others had observed more indirectly for decades. One key clue had come from the observation that testosterone could wire up male brain circuits independent of the androgen receptor, which normally detects testosterone.

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Importantly, the researchers showed that it was neurons possessing aromatase – i.e. neurons that could make estrogen out of testosterone – that displayed sexual dimorphism in their wiring in the adult brain. This implied that aromatase neurons in males had been exposed to estrogen early on, during the neonatal testosterone surge, shaping their own connections in the brain to one day promote male behaviors.

A neuron, wired into its appropriate circuit. Mike Seyfang CC BY-NC 2.0

In fact, artificially exposing young female mice to estrogen prior to birth could cause their aromatase neurons to wire up the same way they do in males. This neonatal estrogen treatment could also cause female mice to behave like males as adults. These females would mark their territory with urine just like males. An estrogen-treated female placed in close quarters with a male mouse would attack the latter before any attempts at mating had a chance to begin. The sex hormones in an adult mouse could only be properly interpreted by a brain that had developed as male or female much earlier in life. "Rather than the gonadal hormones telling the adult brain what do to," summarized Shah in a statement, "the brain interprets signals based on its prior history."

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This finding firmly laid to rest the belief that testosterone equals male behavior, and estrogen equals female behavior. Instead, the structure of the mouse brain influences how the brain responds to a given sex hormone, and that structure is determined by the brain's exposure, or lack thereof, to estrogen just around the time of birth.

Estrogen, Aggression, and Beyond

Recently, the Shah lab published some additional insights about estrogen-producing neurons in the male mouse brain. These 'aromatase-positive' neurons seem to control a male's willingness to fight a stranger mouse, but not the male's mating behavior. This was demonsrated by an experiment in which these neurons were selectively destroyed.

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In females, the same experiment reduced a female-specific form of aggression, in which females protect their pups from (generally pup-unfriendly) males. This finding raises all sorts of new questions, the biggest one being 'why do females have neurons that can produce estrogen when the ovaries take care of this in the first place?' Nevertheless, these particular neurons control sexually-dimorphic varieties of aggression, dependent on whether the neonatal testosterone surge provided a given mouse with the starting material to make estrogen in the brain.

Estrogen, clearly, is not just the female hormone, and testosterone is not the only hormonal fuel for either male or female aggression. As scientific techniques improve, it becomes more clear that sexually-dimorphic behavior is the result of complex interactions between sex hormones and neurons, over the space and time (i.e. body and age) of an animal's life.

An Important Caveat

Though these experiments, mostly done in mice, add to our general understanding of how sex hormones guide male and female behavior, the science of the human sexes can be easily misconstrued to reinforce cultural stereotypes about men and women.

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Human behavior is far from fixed the way mouse behavior is fixed, and the brains of men and women are more alike than they are different. However, this does not negate the fact that there are differences (of variable magnitude and importance) between the male and female brain – though the sex differences that are best correlated with sexual dimorphism in the brain all relate directly to reproduction.

Though direct evidence could be a long time coming, estrogen likely helps masculinize the male human brain, due to the ample presence of aromatase, our estrogen-producing enzyme, in the male hypothalamus, amygdala, and other brain regions. The behaviors resulting from the groundwork laid during development, layered with the strong influences of culture and experience, vary considerably in humans, but it will be very interesting to see how future scientists manage to bridge research on the mouse sexes and the human sexes.