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Brain and Ovaries: Partners in Time
THE BRAIN-OVARIES CONNECTION
The human brain may well be the most complex biological structure on Earth. With its estimated 100 billion neurons and 100 trillion connections, it’s the crown jewel of our species and the source of all the qualities that make us human. It is the seat of intelligence, the interpreter of the senses, the supervisor of behavior, and the initiator of body movement.
To achieve all this, the brain is in close contact and integrated with every other part of the body, and very much shaped by all these interactions in return. For women, one of the most extraordinary and consequential connections is between our brain and our ovaries, its depth becoming clear when we take a peek at evolution. The survival of a species ultimately depends on reproduction and the relaying of its genes to future generations. Our body is optimized to support this capability, with the brain in the driver’s seat. This is important because human reproduction is complex, involving the many physiological, emotional, and behavioral interactions necessary to select a reproductive partner and then maintain the relationships that make it easier to raise offspring. As a result, the female brain has evolved to be not only intricately wired for reproduction but also deeply integrated with our ovaries to ensure all these mechanisms are in place.
THE NEUROENDOCRINE SYSTEM AND ITS ROUTES
These crucial connections are powered by the neuroendocrine system, a network that connects the brain to the ovaries and to the rest of our hormonal system, the complexity of which reveals a level of teamwork between these organs that few have sufficiently fathomed. That’s where we come in. Thanks to the close monitoring of estrogen by these regions, the brain can coordinate the myriad physical and mental functions necessary for reproduction and beyond. Straight ahead, a little primer: Neuroendocrine System Anatomy 101.
Route 1. The HPG
(Hypothalamic-Pituitary-Gonadal Axis)
Envision this system as a subway map with several stations, the brain at one end and the ovaries at the other, as we spotlight the most important routes and stops. The ovaries (aka gonads) are so strongly wired to the brain, specifically to two structures called the pituitary and hypothalamus, that medical textbooks identify these connections as a single entity: the hypothalamic- pituitary- gonadal axis, or HPG. The HPG is the pillar of the neuroendocrine system, dedicating itself to regulating reproductive behavior at all stages of life. As shown in figure eight major glands are part of the HPG. Picture each gland as a stop on Route 1.
1. Pituitary gland. The first station on the HPG is the pituitary The size of a pea, this small but mighty gland has a big job: it makes hormones that regulate the activity of all the other glands, the ovaries included. As a matter of fact, the most important hormones produced by the pituitary are FSH and LH—those same hormones that prompt ovulation during our reproductive years. The pituitary is also involved in making oxytocin (responsible for contractions during labor and lactation afterward), vasopressin (in charge of blood and water volume), and growth hormones (promoting the development of the entire human body, brain included).
2. Hypothalamus. This gland monitors the entire nervous system on behalf of the pituitary gland and flags anything requiring its special attention. This gland is a big deal, as it’s in charge of stimulating the production of LH and FSH by the pituitary, which results in the production of estrogen and progesterone in the ovaries. You could say it’s also head of homeostasis, controlling body temperature, sleep patterns, appetite, and blood pressure, therefore maintaining the body’s overall balance.
Figure 5. The Neuroendocrine System
3. Pineal gland. Located in the brain’s very center, this gland receives and conveys information about our environment’s current light-dark cycle and secretes the hormone melatonin accordingly. Like Mr. Sandman, we count on it to signal sleep.
4. Thyroid gland. Down in the neck, this butterfly-shaped beauty regulates metabolism and temperature. The thyroid produces two hormones you’re likely familiar with from your blood-test results: T3 (triiodothyronine) and T4 (thyroxine). Attached to the thyroid are four glands no larger than a grain of rice, called the These tiny glands attend to calcium regulation, which is important for bone health.
5. Thymus. Located in the upper chest, the thymus is like a bodyguard, producing white blood cells to fight infections and give abnormal cells the boot.
6. Pancreas. This organ-gland complex acts as a liaison between the hormonal and the digestive systems. The pancreas produces enzymes to assist digestion while also making two essential hormones to control the amount of sugar in the bloodstream, like the famous
7. Adrenal glands. This dynamic duo sits on top of your kidneys, producing hormones involved in regulating your metabolism, immune system, blood pressure, and stress response. Their claim to fame is adrenaline, a hormone that stops the body from caving during moments of flight or fight, but can also give you a burnout.
8. Ovaries. We reach our final station—the ovaries. In addition to holding the egg cells necessary for reproduction, the ovaries produce estrogen and progesterone under the hypothalamus’s supervision, as well as testosterone.
By examining the HPG pathways and its crucial components, we can see how this intricate system not only prepares the entire body to potentially host a pregnancy but also supports a range of behaviors leading up to that significant moment, from the sensation of butterflies in your stomach to feeling energized during a romantic courtship. In addition, by acting upon this system, estrogen in particular has been shown to boost metabolism, protecting us against weight gain, insulin resistance, and type 2 diabetes. Estrogen is also instrumental in maintaining bone health and in supporting the heart by keeping blood vessels healthy, possibly by keeping tabs on inflammation and cholesterol levels. On the downside, this connection is also responsible for the many physical, or bodily, symptoms experienced with the arrival of menopause. For instance, the risk of diabetes, osteoporosis, and heart disease all increase after menopause. Yet for all the good that estrogen does for a woman’s body, that’s nothing compared to what it does for her brain. So on to the next, and much less appreciated, brain-hormone route: inside the brain itself.
Route 2. The Brain-Estrogen Network
The neuroendocrine system doesn’t stop with the HPG. As shown in figure it communicates with many other key regions of the brain, which are referred to as the brain- estrogen network, as they are also susceptible to estrogen levels. The most notable stops on Route 2 are:
Figure 6. The Brain- Estrogen Network
1. Limbic system and brainstem. The limbic system is buried deep within the brain, snuggled just above the brainstem, which connects our brains to the spinal cord running down the rest of the body. Traced back to our evolutionary roots, these ancient parts of the brain are trained on instinctive behaviors and emotional responses. These impulses include stress, appetite, sleep/wake, feelings, and nurturing instincts.
2. Hippocampus. This seahorse-shaped structure is considered the memory center of the brain. Located in the limbic system, it is responsible for forming episodic memories, or memories of things you did in the past, like experiences from your childhood or your first day at work. The hippocampus also creates associations between our memories and our senses, connecting summer with the smell of roses—while helping us learn new things and aiding our sense of direction.
3. Amygdala. The hippocampus’s BFF, the amygdala, plays a central role in emotional responses, including feelings like pleasure, fear, anxiety, and anger. The amygdala also strengthens our memories with emotional content.
4. Cingulate cortex and precuneus. These neighboring regions of the brain’s cortical mantle are important for emotional processing, learning, social cognition, and autobiographical memory. The latter refers to our capacity to recall our personal history and events, like what we did on a specific date at a specific time.
5. Prefrontal cortex. This is a super-evolved section of the brain that helps us set and achieve goals. The prefrontal cortex assesses information from multiple brain regions and adjusts behavior accordingly. Doing so contributes to a wide variety of executive functions, including focusing one’s attention, controlling impulses, coordinating emotional reactions, and planning for the future. A heavy hitter, the prefrontal cortex is also involved in memory and language.
To summarize, the highly specialized HPG and brain-estrogen networks ensure that our brains and ovaries are closely connected, on an hour-to-hour basis, and that this connection has wide-ranging effects not only on the body but also on our emotions, sensations, and ability to think and remember. As a result, the health of the ovaries is linked to the health of the brain, and the health of the brain is linked to the health of the Western medicine separated a woman’s brain and ovaries into different disciplines and practices, but no woman in the world has the luxury of separating them in her own body. The hormones flowing back and forth between them spur these organs to develop as partners: they mature together, cross milestones together, and in many ways, age together, too. Thanks to just how far-reaching this interconnectedness is, any changes in hormonal quantity and quality can profoundly affect not only a woman’s reproductive health but also her physical and mental health.
THE FEMALE BRAIN RUNS ON ESTROGEN
Throughout the book, I am trying to reinforce the idea that there’s much more to estrogen than fertility. Beyond its role in reproduction, this versatile hormone is involved in a number of brain processes. That’s because the brains of people born with ovaries, scientists have learned in recent decades, are genetically engineered to respond preferentially to the estrogen made by said ovaries.
As it turns out, day in and day out, estrogen molecules slide right into the brain, searching for special receptors that are shaped precisely for this hormone. The receptors are like tiny locks, waiting for the right molecular key (estrogen) to turn them on. This is a vivid image for a crucial idea: women’s brains are hardwired to receive estrogen. Once it arrives, estrogen latches on to these receptors, activating a windfall of cellular activities in the process. Loaded with these receptors, our brains are ready-made to be estrogen-fueled.
A knowledge of this and of the workings of the neuroendocrine system makes it easier to understand how menopause can set off such a wild cascade of brain effects. If you’re a typical woman moving through your forties or fifties, your lifetime egg supply is running out; as that happens, the intricate, multi-hormone reproductive-signaling loop grows confounded, its triggers altered by the biology of change. Meanwhile, as the brain and ovaries start misreading each other’s demands for action, the brain frantically cranks up estrogen production or accidentally drops the ball instead, effectively throwing the brain-ovaries loop . . . for a loop. Eventually the ovaries stop making estrogen, and what used to be a long-term relationship comes to an end. The symptoms of menopause are then the challenging consequences of a brain full of receptors, receiving less and less of the fuel they need to take action.
It’s worth mentioning here that while women’s brains are wired to respond to estrogen’s activation, men’s brains are similarly calibrated for testosterone. This is important, as the quantity and longevity of each sex’s activator hormone differ, and testosterone doesn’t generally run out until late in life. This more gradual tapering-off process leads to andropause, the male equivalent of menopause. However, as the tabloids remind us, most men remain fertile until their seventies—which in a nutshell means that the testosterone receptors in men’s brains have more time to adjust. Women’s brains, on the other hand, don’t have that luxury.
As science has come to learn, the interaction between estrogen and women’s brains is quite complex and easily disrupted. For starters, estrogen itself isn’t as simple as it seems. The term “estrogen” actually refers to estrogens—not a single hormone but a class of hormones with similar functions. In chapter I mentioned that the type of estrogen we measure in blood is called estradiol. Estradiol is one of the main three types of estrogen. The other two are called estrone and
•Estradiol is the most potent and abundant type of estrogen during a woman’s reproductive years and the principal growth hormone required for reproductive development. It is produced mainly by the ovaries, and its levels are markedly reduced after menopause.
•Estrone is made by fat-rich adipose tissue and has a weaker effect than estradiol. After menopause, estrone is the main type of estrogen women’s bodies continue to produce.
•Estriol is the estrogen of pregnancy. It is present in nearly undetectable amounts whenever one is not pregnant.
When doctors talk about estrogen, they are usually referring to the combined effects of all three types. But when we’re talking about the interaction of estrogen with our brains, we are talking mainly about estradiol.
Estradiol: The Master Regulator of the Female Brain
Estradiol is so instrumental in a seemingly endless list of brain processes that it has gained the title of master regulator of the female brain. I can’t help but view estradiol as CEO of the Female Brain, Inc. It’s a genius commander in chief who knows all aspects of the business, inside and out. Estradiol’s most important functions include:
Estradiol plays a defensive role on our behalf by boosting the immune system and imbuing brain cells with the ability to overcome damage and aging.
growth. Not only does estradiol protect the brain cells we already have, but it helps grow new ones, while simultaneously prompting cell repair and new connections throughout the brain.
plasticity. Estradiol boosts the brain’s ability to respond and adapt to all sorts of changes, from updating our neuronal networks for learning and memory to preserving the brain’s ability to function in the face of damage.
This hormone has its hands in many pies, impacting multiple neurotransmitters , the brain’s chemical messengers for signaling, communicating, and processing information.
Estradiol has a positive effect on serotonin , a mood-balancing chemical that promotes happiness and pleasure, not to mention sleep. It also happens to be “nature’s Prozac,” delivering an antidepressant effect system-wide.
Estradiol supports the immune system and protects the brain from oxidative stress caused by harmful free radicals that can foster illnesses like inflammatory disease, cancer, and dementia.
health. Estradiol has positive effects on blood pressure and circulation, protecting both brain and heart against vascular damage.
This hormone also ensures that glucose, the brain’s main meal, is efficiently burnt as energy. Consequently, when estradiol is high, brain energy follows. By charging up brain function, estradiol influences everything from mobility to our cognitive abilities.
So far, so good. However, after menopause, estradiol leaves. She announces her retirement, firmly sets a course to wind down, and kicks up her heels. Estrone is then promoted to the task. Unfortunately, estrone can’t do what estradiol did. Without estradiol in town, the brain is driven to distraction. The connections between neurons aren’t powered as efficiently as before and tend to slow down. Over time, more connections are lost than renewed. Brain cells experience more wear and tear with less access to repair, which makes them age faster, too. Those happy and calming chemicals that kept our systems balanced don’t show up as often as before. It’s also more difficult to keep free radicals at bay, rendering the brain more vulnerable to inflammation, aging, and a variety of medical conditions. Bottom line, the loss of estradiol can be so impactful as to, at least temporarily, scramble the mind’s once-successful choreography of thought, emotion, and memory.
THE UPS AND DOWNS OF MENOPAUSE
The effects of estradiol’s mercurial behavior are particularly felt in the brain regions powered by this hormone, which experience these effects firsthand. The hypothalamus is the central node of this connection and takes the brunt of the impact. Since this gland controls body temperature, an instability in the supply of estradiol means that the brain can’t regulate body temperature correctly. Remember the hot flashes? Scientists believe that’s the hypothalamus going bonkers.
On top of losing hold over our internal temperature, the brain falters in the regulation of sleep and wakefulness. The result: we have trouble sleeping, with changes in our sleep rhythm and patterns. And since all these brain regions are in communication, the issues between the two can combine and whip up night sweats. The emotional amygdala or its neighbor, the memory-minding hippocampus, take their turns, too—prompting mood swings, forgetfulness, or both. The same goes with the prefrontal cortex, in charge of thinking and reasoning. Maybe the fog rolls in, and you have difficulty focusing or paying attention, or perhaps words don’t come to mind as easily as they used to. And let’s not forget the perpetual search for that elusive phone!
When we pull back the curtain on what’s going on inside the menopaused-out brain, some of its more peculiar symptoms suddenly don’t seem so strange anymore. The brain changes we reviewed at the beginning of this book likely make more sense, too. They are a reflection of the brain’s attempts to deal with the massive hormonal upheaval and accompanying remodeling underfoot. They suggest that as the brain is busy trying to cope with the consequences of the loss of estradiol, its defense mechanisms are temporarily lowered. The powerful shifts in brain chemistry and metabolism may then prompt the symptoms of menopause, while also rendering some women’s brains more vulnerable to a variety of medical stresses such as depression and cognitive decline.
With all that said, there’s more to menopause than its downsides. In fact, we’ve finished reviewing what could go wrong with menopause. It’s time to explore what could go
First off, menopause is a window not only of vulnerability but also of as it provides a critical time to detect any signs of medical risk and to intercede with strategies to reduce or altogether prevent that risk. By knowing when to look (during menopause) and what to look for (the brain changes and symptoms that can ensue), we can not only validate women’s experience of menopause but also address what to do about it. Taking better care of our brains during these years will serve both to bring the symptoms of menopause under control and to dramatically reduce any potential risk of future issues.
Just as important, while many women are vulnerable to neurological shifts during menopause, the majority of the female population gets through this transition without developing severe long-term problems. As we discussed in the previous chapter, symptoms like brain fog and hot flashes tend to ease and eventually fade away a few years into menopause. Personally, these considerations changed my approach to menopause and the focus of my research. Like most other scientists, when I started researching menopause, my initial goals were to understand the symptoms and health risks that menopause can bring about. I was looking for all sorts of things that could go wrong—energy declines, the loss of gray matter, Alzheimer’s plaques . . . all the baddies for which we wanted to find solutions. After all, entire bodies of literature portray menopause as a medical mess. But if menopause was such a catastrophe, no woman would be able to remain functional for another thirty years and beyond. So, my team and I set out to investigate.
We enrolled more participants and did even more brain scans. We gathered our data and sifted through it, determined to take in the bigger picture. Over time, as we dug deeper and broadened our sights, we learned about the good of menopause—not just the bad and the ugly that’s been the takeaway thus far. What we discovered is a broader and bolder story, one that in many ways turns out to be encouraging. I will share more about this in the next chapters, but for now, I want to show you some of our recent work providing evidence that menopause isn’t all about vulnerability.
If you recall from chapter our first discovery was that brain energy declines during the menopause transition. I am happy to report that we’ve made significant progress since those first before-and-after scans were taken. By expanding our studies both in size and duration, we found that, in some brain regions at least, the energy changes appeared to be temporary. For instance, while brain energy showed a dip during perimenopause and early postmenopause, its levels stabilized or improved years later. As shown in the figure below, some parts of the brain even showed a refreshing rebound in energy during the late postmenopausal stage, which starts approximately four years after the final menstrual period. Check out the arrows pointing to the frontal cortex below. Remember, this is the brain’s thinking and multitasking area.
Figure 7. Brain Energy Changes from Premenopause to Late Postmenopause
The menopause story brightened further with a late but lovely postmenopausal recoup in the brain’s gray matter. While gray matter tends to decline from the premenopausal to the postmenopausal stage, in some brain regions, this change appeared to plateau for quite a few women once menopause was completed. This also correlated with better memory after menopause. Do you remember how memory can decline during perimenopause, returning to close-to-baseline levels later on? Our data are right in synch with this timeline.
It’s important to underline that these are recent findings, all in the process of being confirmed on a global scale to reach firm and exact conclusions. While we work to make this happen, my takeaway is that menopause is a dynamic neurological transition that reshapes the landscape of the female brain in unique ways. There are hints and glimmers that this reshaping may include adaptations that help compensate for and maintain brain function, despite the drop in estrogen. In other words, the ovaries may close up shop, but the brain has its ways of carrying on. Many lines of evidence indicate that women’s brains have the remarkable, much underestimated, yet-to-be-celebrated ability to adapt to menopause. This information is just the beginning of unlocking menopause’s secrets and upgrading our experience of this important milestone in every woman’s life.
