Your Brain on Estrogens

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Estrogens represent a group of sex hormones usually known as “woman hormones”. But newer research has begun to show that they are much more than that. Although the science on this front is relatively still in its infancy, estrogens appear to play an important role in brain function, both in females, as well as in males.

(This post is part of our series “Hormone Effects on the Brain“)

The topic of estrogens and their effects in the body and brain is a complex one, which means that we have a lot of ground to cover today. To make it easier to follow, we’ve split the post into the following sections:

general characteristics of estrogens (what they are, how & where they are produced, mechanisms of action)
general effects of estrogens
neural effects of estrogens

Before we jump right into it, there’s one thing we need to clarify. This article uses the terms “male” and “female” to refer to the genetic sex of an individual as determined by the presence of absence of the Y chromosome in mammalian species.

General characteristics of estrogens

In order to understand how estrogens produce their effects, we need to know a bit about their properties.

What are estrogens?

The first and most obvious one is what exactly are they? We already know they’re hormones (which, if you remember from our introductory post, means that they are released into the bloodstream and travel throughout the body, influencing the activity of all cells with the right receptors). Additionally, from a chemical point of view, estrogens are steroids. That means they have four rings of atoms arranged in a certain configuration, like in the image below.

More importantly, steroids are lipids, which means they are hydrophobic and soluble in other fats. And you know what else is made out of fat in your body? The protective cover of your cells, i.e. the cellular membrane. Putting this together, it means that estrogens can freely pass through the cellular membrane. As we’ll see later, this is important for their mechanisms of action and consequently, it determines what kind of effects they can have.

There are four main types of estrogens which have been identified so far: estrone, estradiol, estriol, and estetrol. Same meat, different gravy, right? Well, yes and no. In theory, all of these hormones bind to similar receptors and produce similar effects. But there are differences in their potency and the time period when they circulate through the body.

Estradiol is the most potent form of estrogen, as well as the most commonly found one in both premenopausal females, as well as in males. After menopause, estradiol levels drop significantly in females and estrone becomes the dominant hormone. It is less clear how these levels change with age in males, but current reports indicate no significant reduction. Finally, estriol and estetrol are produced mainly during pregnancy, by the placenta and fetal liver, respectively. Their physiological function is currently far from clear.

How are estrogens produced?

At their core, all steroid hormones, estrogens included, are derived from cholesterol. The transformation of cholesterol into steroid hormones occurs via complex pathways, with multiple steps performed by various enzymes.

More directly speaking, the immediate precursor of estrogens are androgens (i.e. testosterone & androstenedione). This synthesis occurs under the effect of an enzyme called aromatase.

Where are estrogens produced?

In order to find out where estrogens are produced, we need to find out where aromatase dwells, because, as we’ve already established, without aromatase, there are no estrogens. As you might expect, the main seat of estrogen production is in the ovaries. However, aromatase is also expressed in the testicles, placenta, brain, adipose tissue, some blood vessels, skin, and bones.

In other words, estrogens are produced throughout the body. In postmenopausal females, the extragonadal sources become the primary ones for estrogen production, while in males the testicles continue to produce estrogens during old age.

How do estrogens act?

There are two mechanisms of action for estrogens:

the first is a more direct one and involves binding to specific receptors on the cellular membrane. This triggers other molecules inside the cellular membrane and leads to a cascade of relatively fast effects;
the second involves direct action inside the cell. If you remember, we mentioned in the beginning that, as steroids, estrogens can pass through the cellular membrane. Once inside the cell, they can also pass through the nuclear membrane and make their way to our genes. There estrogens can directly influence gene expression and thus produce long-lasting effects.

General effects of estrogens

Now that we have a clearer picture regarding the basics of estrogens, we can finally turn our attention to what effects they produce. We’ve seen that these hormones are produced far and wide in the human body, so it should come as no surprise that they also affect many organs.

The most obvious and well-known effects of estrogens are related to reproduction and sexual development. In females, estradiol acts as a growth hormone for the reproductive organs. Additionally, it is responsible for ovulation, it prepares the endometrium for the implantation of the fertilized ovum, and some studies suggest it might even be important for sustaining the pregnancy. In males, it prevents sperm cells from dying. Estrogens are also important for the development of secondary sex characteristics in females.

They act on the skeletal system by limiting the final height in both sexes through promotion the ossification of the bone growth zone (epiphyseal closure). Estrogens help in maintaining bone density. This is why osteoporosis is more common in post-menopausal females.

In the cardiovascular system, estrogens have protective effects, which translate into decreased overall risk of heart disease for females. However, they also promote blood clotting. As a consequence, during pregnancy, when estrogen levels increase dramatically, females face a much higher risk of venous thromboembolism.

Estrogens are also anti-inflammatory, they support lung function, reduce bowel motility, are involved in pigmentation, etc. And they have other roles which have not yet been fully elucidated.

Neural effects of estrogens

Among these partially clear roles are the ones on the nervous system. Unfortunately, what we know about this significantly outweighs what we don’t know yet, but we’ll try to give you a picture of the current research.

What do we know?

The first thing is that estrogens are present in the brain of many mammalian species (including mice, rats, and humans), both in males, as well as in females.

Another piece of information is that various neuropsychiatric disorders, including schizophrenia, Parkinson’s disease, or Alzheimer’s disease have sex-specific incidences (that is, they are more common in either males or females). Given that estrogen concentrations are higher in females and that, as we said before, this hormone is present in the brain, researchers developed the hypothesis that these sex-specific differences are mediated by estrogens.

Finally, research in mice and rats has demonstrated that, in the fetal brain, testosterone is transformed in estradiol in the brain. Estradiol, in its turn, goes on to induce structural brain changes before birth, essentially masculinizing the brain. It’s important to note here that sexual dimorphism (i.e., sex-specific differences) in the brain does not automatically imply cognitive differences. In fact, as performance measures show similar results between males and females, scientists hypothesize that the structural differences are a way for the brain to preserve optimal functioning under very different hormonal circumstances. Basically, due to biological constraints related to reproduction (fluctuating estrogen levels on relatively short time scales in females), male and female brains need to take different routes in order to arrive at the same destination.

What don’t we know?

Well, in short, everything else.

For one, it’s unclear whether estrogens have the same effects in the male and the female brain. We have already seen above that estradiol induces structural differentiation in the male, but not in the female brain. But in addition to that, some studies suggest a neuroprotective role of estrogens in females (hence, for example, lower rates of Alzheimer’s disease in this group premenopause, but increased postmenopause, when estrogen levels drop dramatically), but not in males. Further research is necessary in this direction.

Secondly, we don’t know whether estrogens have the same effects in all brain regions. Again, studies suggest that, for example, neuronal death and synapse generation are promoted by estradiol in some regions, while they are inhibited in others. The behavioural implications of these findings are also unclear. Why exactly estrogen behaviour is sex- and region-specific in the first place remains also unclear.

Most importantly, while it’s clear that neuropsychiatric disorders affect males and females differently, researchers are only beginning to uncover the role played by estrogens in these disorders, as well as how these hormones can be used as effective treatments.

Conclusion

As we’ve already seen, today’s topic is complicated and full of unknowns. But if there’s something you take away, it could be the following:

estrogens are not “just woman hormones”, but they have important physiological roles both in females and males;
they’re also not “just sex hormones”, but hormones which affect many organ systems in the body, including the brain, and they could be an important factor in the understanding and treatment of neuropsychiatric disorders.

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