CHAPTER 2
The Brain
When I was five, I asked my surgeon father—whom I considered the font of all knowledge—what my IQ was. After a brief silence, he answered me with a single trenchant sentence: “Intelligence is the ability to manipulate the environment.” I found that answer then, as now, fascinating. How we assess the world around us, and how we use experience to meet its challenges successfully, is one of the most interesting questions in all human biology. How do we become who we are? How do we remember things, file away experiences, learn new skills, grow in expertise?
Neurologists today are providing us with fascinating and provocative insights, one of which merited the Nobel Prize in medicine for 2000: experiences actually change the anatomy of the brain. From instant to instant, the physical shape of our nerve cells (neurons), the chemicals that we use to send messages from one neuron to another (neurotransmitters), and even the very molecules that make up the brain are all in flux. Each of our experiences is transmitted to our brain cells, stimulating the formation of new proteins, which actually increase and strengthen the connections between neurons. With repeated stimulation, whole networks of neurons develop that are specialized to process that particular kind of information. This translation of experience into structural changes is referred to as brain plasticity. It is how we learn; how we experience and interpret our environments; how we develop a history and an identity. It is how we become experienced, learning to fear some places, people, and circumstances and to delight in others. No matter how mystical and ephemeral our thoughts, feelings, insights, and emotions may seem, they are all consequences of physical events produced by our neurons and the communications between them.
How does all of this happen? And does it happen differently in men’s brains than in women’s? Are there essential differences in the brain that depend on biological sex?
SEX AND BRAIN STRUCTURE
Until recently, neurologists have assumed that the brain’s anatomy is identical in men and women, as with just about every other organ of the body. But the more we look (especially if we believe that there might, in fact, be something to find), the more we discover real differences in human organs as a function of biological sex. The brain is no exception.
The shape and size of the brain, as well as the numbers of its cells and the extent to which they are interconnected, differ between men and women. Scientists call these differences in anatomy sexual dimorphism (di means “two” and morph means “shape”).
Both animals and humans show sexual dimorphism in brain size and shape. Men’s brains are generally 15 to 20 percent larger than women’s, but women’s brains contain about 11 percent more neurons in one very specialized area of the cerebral cortex, just behind the eye, that is involved in recognizing tonal differences in language and music. Women also have more extensive connections between neurons and between the two halves of the brain than men. The right hemisphere of the brain, which houses the ability to understand the properties of three-dimensional objects in space, is larger in men. The left hemisphere controls speech. Other parts of the brain have differences that are mirror images, from hemisphere to hemisphere, depending on gender: the inferior parietal lobe (the part of the brain directly above the ear) is larger on the left in men and larger on the right in women. This part of the brain processes the information we receive through vision and touch. In the hypothalamus (the part of the brain that helps control hormonal levels), there is a collection of cells called the sexually dimorphic nucleus, which has almost twice as many cells in males as in females.
It’s well and good that neuroscientists have catalogued these differences and that they have, in some instances, a general notion of how they affect behavior, but what do they really understand about the genesis of these differences and why they should exist at all? The process is akin to assembling a jigsaw puzzle in the dark—scientists have identified some of the pieces and have even pushed a few together, but they haven’t really gotten a look at the whole picture.
Some sexually characteristic differences are determined before birth, as we know because differences in the patterns of interneuronal connections aren’t changed by postnatal hormonal influences. In animals, such differences can be caused before birth only by castrating males or by giving testosterone to females early in fetal development. Other differences in the size of some parts of the brain do occur under the influence of hormones in postpubertal life. Parts of the hypothalamus, for example, are larger in heterosexual males than in transsexual and homosexual males. These differences are not present at birth; they appear at only about four years of age and disappear again after fifty or sixty. Scientists believe these changes are the result of a complex interaction between experiences and hormones, a phenomenon we’re only just beginning to understand.
While we know that men’s and women’s brains have dramatic and very significant structural differences, we don’t know whether those differences translate into differences in behavior, aptitude, or cognition. Most of our information about brain sex differences comes from research in animals, where it is evident that not only the structure or shape of different parts of the brain but also certain behaviors are sex-specific. For example, the mating behavior of some species differs dramatically: the brilliantly colored South American male cowbird struts his bright plumage and sings loudly to attract the female, whose own tunes, if she sings at all, are neither as loud nor as complex. In the males who have the most complicated and loudest songs, a part of the brain called the vocal center is much larger than in the female.
But people are not songbirds, and the question of whether differences in human brain structure make men and women behave differently or have different talents is much less clearly answered. Certainly anatomical differences could explain some observed behavioral differences between the sexes; for example, if men’s brains are larger as a result of their inability to prune back extra (or defective) neurons during development, perhaps retaining damaged cells makes them more susceptible to impaired brain function in response to brain damage early on. On the other hand, the fact that men have more neurons may explain the earlier onset of dementia in women—the latter simply have fewer brain cells and are more impacted by their loss than are men. But at the moment, these ideas are only speculations—and exciting new hypotheses to test.
PROBING THE LIVING BRAIN
Thanks to powerful new techniques, neuroscientists are making enormous progress in mapping the anatomical and functional differences in the brains of men and women. Most of the information about the brain that I learned in medical school came from anatomists, who looked only at brain structure, and from physician-scientists, who matched—usually at autopsy—the damaged area with the patient’s specific defect.
The classic and groundbreaking case in brain mapping is that of Phineas Gage, a laborer in the late nineteenth century whose brain was pierced by an iron stake in a dynamiting accident. Incredibly, he survived, but he was “never really the same”; in fact, even after his wound had healed completely, his wife and co-workers found him almost intolerable. Gone was the quiet, hardworking day laborer; in his place was a rowdy, moody brawler prone to fits of rage. Gage’s wound was probably in the frontal lobe, in the part of the brain responsible for regulating emotion and affect. Another classic brain-mapping example is a patient whom Paul Broca studied; the patient couldn’t speak and was found upon autopsy to have damage in a small area in the front of the left side of the brain. Broca assumed, correctly it turns out, that this area was involved in the production of speech; to this day, we call this brain part “Broca’s area.” Carl Wernicke, using an associative technique, showed that another part of the brain is involved in picking the right words for communication. Wernicke had a patient who could speak but whose sequence of words (some of which were even made up) made no sense.
Neuroscientists owe a great debt to these early pioneers in the field, though the information from their crude if ingenious methods provided only a tiny part of the story. Today powerful new tools can simultaneously investigate both the structure and the function of the intact, living brain in real time, while patients are performing various activities and following commands. One of the most exciting is a noninvasive procedure called functional magnetic resonance imaging (functional MRI). Functional MRI can identify the areas of the brain that are associated with, for example, producing intelligible speech or developing an emotional response to a stimulus. One of the most important ideas that the new techniques have yielded is that no one specific location in the brain controls complex tasks like speech; rather, several areas may be involved. Even more intriguing, depending on the sex of the subject, those areas may be quite different.
Among the most accomplished investigators using functional MRI to sort out unique features of male and female brains are Sally and Bennett Shaywitz at Yale University. Their pioneering work has shown for the first time that quite literally men and women use different parts of their brains while thinking. They asked subjects to decide whether various nonsense syllables rhymed; the men’s brain activity was restricted to a small part of the left hemisphere near Broca’s area, while women used another area in addition located in the right side of their brains. Confirming this finding, Sandra Witelson at McMaster University in Hamilton, Ontario, has shown that this particular area of the right brain is larger in women than in men. Using the same technique as the Shaywitzes, Ruben Gur at the University of Pennsylvania School of Medicine found that even at rest men’s and women’s brains function differently: men’s limbic system (part of the brain involved in the experience of emotions) had higher activity in the portions thought to be involved with the perception of motion and action, while women’s limbic system was activated in newer, more recently evolved areas that have to do with the interpretation of expression and the nuances of speech.
Why do these differences exist and what implications might they hold for our understanding of male and female behavior? We do not know, but we have made astonishing progress in our understanding of the gender-specific brain and how it develops.
HOW DOES THE BRAIN BECOME MALE OR FEMALE?
At the beginning of its development, the fetus is neither male nor female, but early in the first trimester the sexes begin to develop differently. By the sixteenth week of life, in females, a tubular system called the Müllerian duct develops into a female genital system, complete with ovaries. In males, the Y chromosome activates the manufacture of a hormone that promotes the development of testes. Both the ovaries (when the fetus is three months old) and the testes (when the fetus is two months old) begin sex-specific hormone production.1 It is these sex hormones that make the brain either male or female by acting on its developing tissue at what is called a critical period, a brief period of time in development during which the brain is responsive to hormonal influences.
Hormones do not influence the brain as straightforwardly as you might think. Testosterone does not masculinize the fetal brain directly but enters the brain cells, where an enzyme2 called aromatase converts it into estrogen. Paradoxically, it is actually high intracellular concentrations of estrogen, formed from testosterone, that make the brain male. Without testosterone, there is not enough estrogen to impact the developing tissue. Maternal estrogen cannot act on the growing fetal brain, even though a great deal of it circulates in the fetal bloodstream; somehow the fetus is protected from its mother’s estrogen. Even the fetus’s own estrogen does not seem to penetrate the fetal cell very effectively. Without high intracellular levels of estrogen, then, the brain develops into that of a female.
Some scientists believe that the female brain is “neutral,” a default outcome that results from a developmental pattern that is not affected by hormones at all. Others believe that estrogen actively influences the development of the female brain but that much lower concentrations are required than those for the male brain to produce its sex-specific structure and function. In any case, through this marriage of genetics and hormone production, the brain is “hardwired” to be either male or female long before birth.
Continuing Brain Differentiation After Birth
Sex-specific development continues through puberty and is maintained by hormonal action for the rest of our lives. The differences in our brains remain apparent until old age, when they become less striking. It isn’t an exaggeration to say that the brain is as sexual an organ (if not more truly so) than the ovaries or testes.
At birth and during the first years of life, as the brain grows it undergoes periodic bursts of new cell formation, but as growth continues, many of these cells are “pruned back” and disappear. Interestingly, the developmental bursts occur in different parts of the brain at different times, probably critical times when input from the outside world can have an important and lasting impact on the brain function. If kittens are deprived of sight for the first three months of life by sewing their eyelids shut, they never regain vision, and parts of their brain development are stunted. This doesn’t happen to adult cats, whose brains are no longer in that window of time in which sensory input has such a dramatic developmental impact. Such periods of opportunity probably happen throughout normal postnatal life. Special skills or talents may suddenly appear: mathematicians, for example, develop their peak ability quite early in their lives. An enriched environment probably enhances the abilities of the developing infant, but scientists don’t know how, what, and when to present to the child to maximize its potential. Certainly infants living in deprived environments suffer from behavioral and intellectual handicaps, but for the most part the development of an infant is a reasonably sturdy process, relatively resistant to either the poverty or the richness of the environment.
Boys have larger brains than girls at birth, but boys are much more susceptible than girls to developmental disorders of the brain like mental retardation, impaired understanding of language, stuttering, autism, Tourette’s syndrome, tic disorders, attention-deficit/hyperactivity disorder, and nighttime bedwetting. Emese Nagy and associates at the University of Texas in Houston use something they call the “gender paradox” to explain this phenomenon: although boys have larger brains than girls, they point out that newborn boys also have lower metabolic rates—their body temperatures and heart rates are lower than those of newborn girls. This means that their brains may have a greater need for oxygen and energy and, simultaneously, a relative inability to provide it. Nagy believes that this paradox may explain the greater occurrence of all these disorders in males.1
DO MEN AND WOMEN HAVE DIFFERENT
INTELLECTUAL ABILITIES?
What about differences in intellectual ability and talents between men and women? Are they attributable to gender differences in brain structure? Unfortunately, this issue is so emotionally charged that many experts simply refuse to discuss it; others do so only very cautiously. Current science does indicate, however, that while no significant difference exists in overall intelligence, there are tiny but real differences between men and women in particular intellectual abilities and talents. Whether these differences are learned or are “hardwired” into the structure of the brain is very difficult to say. Most of the data about sex-specific thinking patterns and abilities come from animals, but there are striking parallels between what we find in rats and monkeys and what we observe in humans. The scientists who have just finished the definitive monograph from the National Academy of Sciences’ Institute of Medicine2 on gender-specific science point out several things about observed differences in the abilities of men and women:
• There’s a marked degree of overlap in specific abilities between the sexes; the most dramatic differences occur at the extremes, with the most talented individuals, rather than over the bulk of the population. For example, most world-class artists are men, although there are exceptions; among the Impressionists, Mary Cassatt certainly held her own. The same is true of celebrated composers and conductors, who are principally male.
• When mean scores for a particular task are calculated, the differences between men and women are significant, but they are smaller than the differences between the highest and lowest scores for people of the same sex.
• Observed differences between the sexes may apply only to a certain stage of life and disappear over time.
• How a particular ability is measured can affect the result depending on the sex of the subject. A recent study showed that women are less able than men to solve spatial problems, like working through a maze, if the testing is done with virtual reality systems, as in the training of astronauts. But additional factors that we have not yet discovered may be modulating these abilities.
Even with these qualifications, though, some real differences exist in the overall intellectual ability of men and women. These include the following:
• Women have superior “verbal abilities,” including spelling, grammar, fluidity of speech, writing, vocabulary, and oral comprehension. Women are not better at all components of verbal ability, but in any of these areas, where there is a superior performance, it is women who best men.
• Women remember things better than, whether verbal or non-verbal. For example, they are generally better at memorizing telephone numbers and at using landmarks to find their way back to a specific location.
• Women perform finely coordinated movements better than men; they can even repeat tongue twisters more fluently and accurately than their male counterparts.
• Boys’ ability to outperform girls in mathematics is striking. In Scholastic Aptitude Test (SAT) math scores above 500, boys do better than girls two to one; over 600, five to one; and at 700 or above, a whopping seventeen to one! Critics of these measurements point out that mathematical skills depend significantly on experience, and that more boys than girls are enrolled in advanced math classes. When the data are corrected for this one variable, the differences are actually much smaller, although boys still beat girls. In general, the two sexes seem to approach math problems with different strategies and abilities. Boys excel when they use spatial relationships, shortcuts, or choose among several alternative paths to solutions, whereas girls excel when the answers depend on verbal skills or remembering and understanding classroom-based information. It may be, then, that the alleged superiority of men in mathematics may have to do with the fact that they have more flexibility in strategic decision making than do women.
• There are differences in the way men and women remember the events of their own lives: women are more likely than men to recall childhood memories, particularly if they are associated with emotion, either in themselves or in others.
• Women are more sensitive than men to facial expressions.
• Men are better able to understand the movement of three-dimensional objects in space. For example, when men and women are asked what happens to the level of water in a glass when it is tilted, most men have the correct answer (the surface of the water remains parallel to the ground because of gravity), but one in two women get it wrong. Male and female rats learn tasks that have to do with spatial relationships quite differently. Just as with humans, female rats use landmarks to help them learn a new path, while males do not, even when they are available. (When her neighbor asked my daughter how to find the home of a mutual friend, she answered, “Go down Madison Avenue until you hit Prada, then turn left.”) Even more interesting, when men and women were asked to negotiate a maze in a virtual reality laboratory, functional MRI imaging techniques showed that men used the right (the “spatial” side) while women used the left (the “language” side) of their brains to complete the task.3
• Some scientists report that women’s ability to solve spatial tasks varies with the phases of their menstrual cycle. During menstruation, when estrogen levels are lowest, women have the most success with such challenges. Others have found that women with congenitally high levels of testosterone have an improved ability to perform spatial tasks. In contrast, when men experience a drop in testosterone, they lose some of their ability to solve these kinds of problems.
WHAT BEHAVIOR IS LEARNED
AND WHAT’S INNATE?
Many women don’t want to hear that their brains are different from those of men. It has taken centuries for us even to begin to catch up with the opportunities men enjoy. My daughter could be a brain surgeon if she chose to, but when I went to medical school thirty years ago, I never even considered the idea; brain surgery was for the men in my class.
Are the differences between men and women “hardwired” into our brains, or do they exist because of the roles society assigns to us? How much about us is inevitable and how much is learned? Do girls become “motherly” because they’re given dolls to play with? Are they less physically active than boys because they’re taught to be “ladylike”? My daughter recently observed a striking exchange between a mother and her four-year-old son on a New York street corner. The little boy’s eyes were brimming with tears, and he was clearly upset about something. “Boys don’t cry,” his mother chided him. “You might as well begin to understand that right now. So just suck it up.” As adults, when men don’t talk about their emotions, is it because they have learned not to or because an impassive response to something troubling is hardwired into their brain? A colleague of mine, New York pediatrician George Lazarus, believes that in spite of our best efforts to train them, girls and boys are different from the outset. He tells a story of parents who were determined to give their daughter the same opportunities as their sons and not to “close off” potential vocations by gender-specific lessons. They bought her four trucks to play with, and she received them enthusiastically, but one day neither she nor the trucks were anywhere to be found. Finally, her mother discovered her in her bedroom. As her mother entered, the little girl signaled her to be quiet. The trucks were placed carefully in a row on the pillows of the girl’s bed, with the covers drawn up over them. “Shhhh, Mommy! They’re sleeping,” she explained.
Every society sees boys and girls differently from the moment they’re born. They are valued differently and treated differently, and they are expected to play different roles and, in many instances, to achieve quite different goals. Our biology and our experiences combined define what we are, and we all have learned lessons that profoundly shape our behavior. The simple fact of being male or female is layered over with lessons about how males or females are valued and expected to behave in society. Separating what’s due to sex from what’s due to gender identity is often impossible, which makes it difficult for researchers to be certain about how immutably different men and women actually are. But as investigative techniques improve, scientists are becoming more certain about which differences are functions of biological sex and which may actually be a result of the ways a culture treats men and women.
Is Our Sense of Gender
“Hardwired” into Our Brains?
The fact that the brain is at least anatomically male or female early in development has provoked a tremendous amount of speculation about whether a person’s sense of sexual identity and of sexual preference are immutable, and whether doctors are justified in “reassigning” sex in individuals born with ambiguous genitalia. William Reiner, a urologist at the Johns Hopkins Children’s Center in Baltimore, has described a group of 27 children who were born with normal male chromosomes (X and Y) and normal testicles (indicating normal exposure to testosterone in the uterus) but no penises. All but two were castrated at birth and raised as girls, but in spite of this attempt to “reassign gender,” they all acted like boys in their rough-and-tumble play patterns. Fourteen of the 25 castrated children reassigned their own gender and said they were actually boys, one as early as five years old. The two children who were reared as boys were less psychologically maladjusted than the others and were well accepted by their male peers. This study would indicate that the “genderization” of the brain in the uterus produces a person’s sense of self as a man or woman, even when an environment “tells” the person precisely the opposite. Even being castrated at birth and raised as the other sex cannot change this inner experience of maleness or femaleness; it is “hardwired” into the brain.
More support for this notion comes from other variations in development. A defect called congenital adrenal hyperplasia, for example, causes girls to have an excess of male hormones. These children have a block in the chain of events through which the adrenal gland makes its final product, Cortisol. The chemicals that are made early in this chain of events resemble testosterone and are masculinizing. If their hormonal balance isn’t corrected, these girls may be so masculinized that their enlarged clitorises may be mistaken at birth for penises. At puberty, their ovaries begin to produce estrogen and they develop breasts and begin to menstruate. Nevertheless, exposure of their brains to these abnormal adrenal hormones during development has masculinized these girls. Indeed, although they apparently think of themselves as female, they engage in a great deal of activity thought to be more usual for boys and are characterized as having “tomboyish” behavior. As adults, several of them are not only uninterested in having children but actively dislike the idea of caring for children.
Another developmental anomaly also lends credence to the “hardwired” theory. There are genetic males (with an XY chromosome pair) who produce normal amounts of testosterone but whose bodies have no receptor for the hormone. (A receptor is a protein that functions as a “lock” into which a “key,” in this case a hormone, fits.) An individual may produce plenty of testosterone, but without a receptor he/she can’t use it. The person matures as a female, because the normal testis also produces small amounts of estrogen. At puberty, in fact, breasts develop, and the person becomes sexually active as a female, but lacking a uterus never menstruates. Since the brain was never masculinized in utero, the person not only looks like a female but feels like one, even with an XY chromosomal pair. This indicates that in spite of male or female genetic equipment, hormones and their prenatal impact on the developing brain provide the critical factor that makes us feel—and behave—like men or women.
Transgendered people are individuals who have no unusual features in their complement of hormones, in their hormones’ relative concentrations, or in their genitalia, yet feel that they are essentially the other sex. Conceivably, the usual timing or biology of their intrauterine brain development was somehow changed by a problem like maternal malnutrition, maternal stress, or maternal ingestion of some drug. Some scientists have suggested that homosexuality might be the result of a variation in the process of intrauterine brain genderization. Existing data certainly suggest that that might be the case, at least for some individuals.
In fact, maleness and femaleness may not be as immutable as was once thought. While we assume that sex is a result of whether a person has an XY or an XX chromosome, the hormones that are the consequence of that genetic equipment clearly have a profound and irreversible impact on gender identity. This impact is well substantiated by the natural experiments in children who develop without hormonal receptors for testosterone or have had intrauterine exposure to the excessive amounts of testosterone that I’ve just described. Maleness or femaleness is extremely fluid in other species; several kinds of fish change sex in response to their social rank! For example, when a male blue-headed wrasse (a coral reef fish) dies, the largest female in the group immediately begins to act like a male fish, actually converting to a male (with fully male gonads) within days. Other kinds of fish are hermaphrodites: they have two complete reproductive systems, can convert their sex within seconds, and even take turns in fertilizing each other’s eggs when coupling. In general, larger size seems to determine which fish more frequently plays the male role.
Even humans, for whom sex seems to be fixed, may have a whole spectrum of feeling and being “feminine” or “masculine.” Furthermore, the intensity of feeling one or the other may change during the course of human development, depending on the impact of hormones not only in utero but to some extent during postnatal development as well. Environmental challenges and circumstances may also play a very important role. “Masculine” characteristics like taking charge, organizing disparate group members into effective teams, and devising strategies to solve problems and achieve successes can predominate and be fostered among women if there are no males in the social network (such as is the case during a war, for example, when most males are away and women must take on their responsibilities), just as “feminine” tendencies to nurture, rescue, and foster the development of weaker, more dependent individuals may emerge among men when the occasion demands. In fact, drawing skills from both ends of the spectrum is often advantageous. In taking care of patients, I know that sifting and weighing evidence, making swift, informed decisions, and selecting appropriate therapies are essential ingredients for success, but so is a finely honed perception of what any single individual patient requires in terms of comfort and reassurance.
How will new scientific discoveries about the brain, hormones, and biological sex affect you? Researchers are studying the practical application of these discoveries on many issues, but one of the most important is diseases of the central nervous system. What scientists are learning provides doctors with insight into therapeutic maneuvers that will prevent and/or ameliorate those illnesses.
ESTROGEN AND THE BRAIN
Estrogen is not simply a reproductive hormone—it plays a much wider role in the body’s growth and maintenance. It is essential to adult men and women for the repair of tissues and organs. In fact, health care experts are considering using hormone replacement therapy to combat some of the changes of aging, including fading memory, for men as well as for women.
Estrogen binds to receptors (proteins that “lock onto” a molecule and modulate its activity in a cell) both on the cell membrane and deep within the cell. It has an affinity for specialized receptors inside the nucleus (the command center of the cell, which contains our genetic material and regulates the way the cell functions, grows, and repairs itself). There, in combination with other factors, estrogen “turns on” genes that direct the manufacture of new proteins. These new proteins can act within the cell itself or can be exported to influence other cells and tissues.
The varied actions of estrogen throughout the body are explained by specific differences in the estrogen receptors and by the presence or absence of specific co-factors (other proteins that enhance or facilitate the action of estrogen). These co-factors are not only age-specific (present only at one stage of development) but also tissue-specific.
It is estrogen that maintains the brain’s plasticity. As we’ve seen, every piece of new information from the outside world is processed over a unique pathway in the brain, a group of neurons recruited and modified to form a new network. Once established, the new pathway is preserved so that a “memory” of the information is stored in the tissue. It is actually possible to increase the volume of the brain by making new cells to master and retain information. By concentrating on and practicing their particular discipline, for example, musicians can increase the volume of the brain area involved in performing by as much as 25 percent! Estrogen is an essential modulator and facilitator of this process.
Estrogen receptors exist in many parts of the adult brain, and estrogen has specific effects on neurons. It increases the numbers of “spines” on the dendrites (the fingerlike projections from the body of a nerve cell). Through these spines neurons communicate with one another by chemical messages released across spaces called synapses. These chemicals are called neurotransmitters.
Estrogen is also an important regulator of many of the brain’s functions. It increases blood flow to the brain and enhances the brain’s use of glucose, which provides it with essential energy. In fact, cortical glucose metabolism is 19 percent higher in premenopausal women than in men of the same age.
The Role of Hormonal-Replacement Therapy (HRT)
in Memory Preservation and Alzheimer’s Disease
Understandably, doctors have become very interested in the importance of estrogen to women who are entering menopause. Studies have shown that rats that are estrogen deficient cannot learn new information; when their brains are examined, their neurons have significantly fewer dendrites than those of estrogen-replete rats. For this reason doctors recommend hormone-replacement therapy (HRT) for postmenopausal women who complain about a loss of memory or a declining ability to think through problems or even to concentrate on a task. (One of my patients calls it “fuzzy thinking.”) In perimenopausal and recently menopausal women, estrogen replacement often helps restore the ability to learn and hold on to new data, at least temporarily. A recent review of all existing studies on the impact of estrogen on brain function in postmenopausal women, however, was rather disappointing: the evidence of long-term improvement of women with Alzheimer’s disease who were treated with estrogen was not convincing enough for doctors to recommend estrogen for that purpose. Similarly, the results of studies testing whether HRT decreases women’s likelihood of developing Alzheimer’s disease were contradictory.
Throughout their lives, men have higher estrogen levels than postmenopausal women who are not on HRT. This may account for the differences in the clinical symptoms of men and women who have Alzheimer’s: women have more memory impairment and difficulty with language than men, in spite of equally severe deterioration in general cognition. Men with the disease are more likely to have problems with aggressive behavior; women are more likely to be depressed and emotionally labile. B. R. Ott, of Brown University School of Medicine, and his colleagues used single photon emission computed tomography (SPECT) to study blood flow to the brain and found that blood supply to the brain in men and women with Alzheimer’s is different.4 In affected men, blood flow was more frequently depressed in both sides of the brain, while in affected women it was decreased more often only on the left side of the brain.4 The reasons are unclear but may have to do with gender-specific differences in the distribution and characteristics of estrogen receptors.
“Designer Estrogens” and Their Complications
So-called “designer estrogens” are synthetic hormones that have been specifically manufactured to produce some of estrogen’s effects and to avoid others. The synthetically manufactured hormone tamoxifen, for example, binds to estrogen receptors in the breast and prevents estrogen from stimulating the production of breast tissue in patients who have developed or are at high risk for breast cancer. Another, raloxifene, has a positive impact on bone preservation. While these drugs can be very helpful for many patients, their effects on the brain are not fully understood, so they may introduce other problems into a course of treatment. These “estrogen analogues,” as chemists call them, may block estrogen’s important maintenance and repair work in the brain. Early study results have been somewhat reassuring: a study of women who were treated with raloxifene for three years showed no demonstrable deterioration in intellectual function.
STROKE IN MEN AND WOMEN
Cerebrovascular accidents (CVAs), more commonly known as strokes, are more frequent in men than in women, but they are more often fatal in women, who tend to be older when they occur. In one study, 25 percent of women who suffered a stroke died as a result, compared with 14 percent of men. Among those who survive, women seem to do worse than men: they have more impaired intellectual function, are less able to care for themselves, and have a higher rate of suicide. In one study of more than 37,000 stroke patients, the suicide rate was twice as high in the female victims, particularly the younger ones.
The risk for stroke is 20 percent higher in women who smoke. Oral contraceptives also increase the risk for stroke, although this risk has decreased with the pill’s current lower estrogen dose. Estrogen increases the tendency of blood to clot; its use is particularly dangerous in women who have an increased tendency to coagulate their blood because of abnormalities in their clotting mechanism. Patients with a history of clots in their veins or arteries, particularly those who have had a pulmonary embolus (a clot that circulates in the blood and blocks the blood supply to a certain part of the lung, causing the lung tissue to die), should not use estrogen replacement therapy in any form. The increased risk for a CVA (up to three times higher in oral contraceptive users than in nonusers) is almost entirely due to combining use of the pill with smoking, or to use by women with either high blood pressure or migraine headaches.
DEPRESSION
If hormones produce structural differences in the brain, might they also produce differences in men’s and women’s emotional behavior? After all, common sense suggests that hormones are important in regulating how we feel: ask any woman about moodiness, irritability, and even “cloudy thinking” just before her menstrual period.
How do hormones regulate mood? While the mechanism is not entirely clear, a growing group of researchers believe that hormones may influence communication between nerve cells. Neurons communicate, as we have seen, through messenger chemicals called neurotransmitters that are secreted by one cell and taken up by another. Several different kinds of chemicals are involved in interneuronal communication, including serotonin, acetylcholine, beta-endorphins, dopamine, and norepinephrine, among others. All of them seem to be involved in the regulation of mood. The amounts and distribution of these neurotransmitters differ in the normal brains of men and women, and aging changes them differently in the two sexes. In animals, estrogen affects the production rate and synaptic concentration of neurotransmitters, but its effects sometimes vary depending on the sex of the animal. In rats, for example, estrogen treatment improves the female’s ability to learn but has no effect in males, which respond better to thyroid hormone. In humans, though, estrogen increases the availability, the amount, and the strength of the response of neurons to serotonin; it also increases norepinephrine concentration and the number of receptors for this neurotransmitter in the brain.
Depression can manifest itself quite differently in different people. Some weep and are outwardly sad, some are cranky and easily fly off the handle, and others are so withdrawn that they sleep most of the time and have very little outward response to the world around them. Depressed women, much more than depressed men, suffer heightened anxiety, or an unreasonable fear of ordinary events (some as mundane as simply leaving the house). Other depressed women endure panic attacks, in which they are paralyzed by a feeling of impending doom and quite literally feel frightened almost to death. Depressed men, on the other hand, are more likely than depressed women to drink excessively or to exhibit violent, abusive behavior.
Do people inherit a tendency to become depressed? Absolutely. Studies of identical twins, even when one has been separated from the other by adoption, show that if one twin has a major depressive illness, the other is more likely to develop it than the average person. The sex of the twin seems to be important as well: fraternal twins of different sexes compared with identical or nonidentical twins of the same sex have a lower incidence of depression. Neuroscientists have not yet pinned down exactly how sex influences susceptibility to depression; it is not even certain that the gene(s) is/are carried on the X chromosome.
Depression is undeniably about twice as frequent in women as in men. This difference begins to emerge in midadolescence, and many researchers have suggested that this phenomenon is at least in part cultural, that society’s view and treatment of females affects self-esteem and creates feelings of sadness and worthlessness in women. Other data suggest that simply being a biological female is an important factor: the prevalence of depression in women is true in virtually every country of the world (except India3). Certainly social factors affect men and women differently—married men have less depression than married women, although marriage seems to provide better physical health to both sexes than to people who live alone. Living with children (especially three or more children) doesn’t increase the incidence of depression in men, but it does in women—except, interestingly, women in Mediterranean countries. (Some researchers think that this may be because mothers are more highly regarded in those countries than in the rest of the world.) Going to work seems to improve the mood of women who have dependent children; women who work and care for children have less depression than those who stay at home with relatively little adult contact.
Depression and HRT
In women, ovarian steroids (whether naturally occurring or taken as replacement therapy) have a direct impact on mood. Women with severe premenstrual tension find relief from oral contraceptives, which eliminate ovulation. In general, estrogen produces a sense of well-being, while elevated progesterone levels (the hormone produced in the second half of the menstrual cycle, from the ovary that has released a mature egg) are correlated with negative moods. This is dramatically apparent when women are given hormones either for birth control or to treat menopause-related conditions. Some of the progestins (synthetic hormones) in those medications are more disturbing than others to individual women. The depression and anxiety that accompany the progesterone phase of the cycle in women who use birth control pills can be eliminated or dramatically lessened by using a preparation with a different progestin.
The same sensitivity to progesterone is seen in many postmenopausal women who discontinue HRT because of an unpleasant reaction, not to estrogen (which gives them a sense of vigor and well-being), but to the particular progestin in their prescription, which makes them anxious and weepy. Some women are so sensitive that any progestin is intolerable; for these women, an intrauterine preparation that is not absorbed into the bloodstream is necessary. It is interesting that progestins and tranquilizers bind to the same site on the brain cell; blocking this site with progestins may increase irritability by making it impossible for calming agents (like diazepam [Valium]) to have an effect. Progestins may also interfere with serotonin-mediated systems. Medications that increase serotonin levels in the synapse (called selective serotonin-reuptake inhibitors or SSRIs; fluoxetine [Prozac] is the best known) are quite effective in treating serious cases of premenstrual tension, called premenstrual dysphoric disorder and classified by the American Psychiatric Association as a mental disorder.
Postpartum Depression:
When the “Baby Blues” Become Serious
Probably nowhere is the importance of hormones in stabilizing mood more evident than in postpartum depression. Postpartum depression affects one or two women in every thousand births and is related to the abrupt fall in estrogen and progesterone levels that happens within the first day or two of delivery. It is a very serious illness: psychiatric hospital admissions are more likely to happen just after childbirth than at any other time in life. These women are three hundred times more likely than others to become depressed again after delivery of another child. Their babies are often profoundly affected by their illness: they are withdrawn, cannot be comforted, and later in life become depressed themselves. In rare cases the symptoms of postpartum depression are so severe that the mother murders her own children in the throes of a real psychosis, which requires intensive treatment. (In most Western countries, except the United States, the disorder is well recognized as a chief mental illness: women who commit major crimes after delivery are sent for psychiatric treatment rather than to prison, as is the case here.)
Postmenopausal Depression
Estrogen deficiency may also play a role in the depression of postmenopausal women. Use of HRT seems to protect women from the depression that can affect some of them at about ten years after menopause. Other studies have shown that estrogen enhances the effect of SSRIs in relieving depression.
In the elderly estrogen-deficient patient, dementia and depression overlap. Inability to think clearly may actually be due to depression rather than dementia; conversely, about 30 percent of people with progressive dementia also show signs of severe depression. This is not true of younger patients. Whether HRT lessens the likelihood of depression in older women is controversial, but they do respond better to tricyclic antidepressants (such as amitriptyline or Elavil) than to SSRIs. In younger women, on the other hand, SSRIs (like Prozac) are more effective than tricyclics.
STRESS
Whenever you have an unpleasant experience, the resulting stress produces an increase in your adrenal gland’s output of adrenal glucocorticoids. The levels of these hormones in the bloodstream are controlled by an elaborate feedback mechanism that involves the hippocampal area of the brain, the pituitary, and the adrenal glands themselves. (Like the gonadal steroids, the adrenal glucocorticoids act directly on the brain itself.)
Levels of stress hormones are regulated differently in men and women. When a woman experiences an unpleasant stimulus, estrogen intensifies and prolongs the response of her adrenal glands. Even when young men are given a short course of treatment with estrogen, their response to stress increases! This estrogen link may explain why some girls become more susceptible to stressful conditions at puberty, which is also the age when depression in females begins to be so striking. It may also explain why in many women menopause, when fluctuations in estrogen and progesterone levels diminish, is often accompanied by more emotional stability and a new feeling of well-being. Some experts believe that the interaction between gonadal steroids and the body’s response to stress is the reason that diseases associated with increased amounts of emotional pressure (like post-traumatic stress disorder and autoimmune diseases) are more frequent in women than in men.
WHAT DOES THE NEW SCIENCE MEAN FOR YOU?
I’m a fifty-year-old woman and am starting to experience hot flashes, which I know are the beginning of menopause. Recently I’ve felt more out of sorts than usual and have had problems sleeping. Is there anything to be done about it?
If you are perimenopausal and are having severe mood swings, inability to concentrate, and sleep disturbance, oral contraceptives may provide you with a more stable level of estrogen and improve your symptoms.
My doctor wants to put me on one of the so-called “designer estrogens.” Is there anything in particular I should watch out for when taking these?
Don’t hesitate to ask your physician to explain any of the drugs she prescribes for you. If you are taking one of these synthesized hormones, be sure to notify her of any unusual side effects, like changes in your mood or your ability to think clearly and effectively or remember new information. It is relatively unlikely but still possible that these medications may be producing more problems for the brain than benefits.
I’ve got high blood pressure and am taking birth control pills. The little warning that came with the package says that there might be an increased risk of stroke in people like me. Do I need to worry?
You’re right—oral contraceptives are slightly chancier in patients who have high blood pressure or migraine headaches and are smokers. Talk with your doctor—these are important factors to consider when deciding which birth control method is right for you.
Sometimes my PMS is so bad that it derails my entire week. I know this isn’t unusual and I don’t mean to complain, but it’s getting exhausting. Ibuprofen takes care of the pain—can anything be done about the emotional roller coaster?
Premenstrual tension, particularly if severe, should prompt you to ask your doctor if an SSRI—a type of antidepressant—will help. Oral contraceptives might also help to stabilize your mood.
I was diagnosed with postpartum depression after both of my children were born; now I’m approaching menopause and am worried that it will return. Also, my daughter is pregnant. I’m wondering if I should mention the possibility of postpartum depression to her, so she’ll be better prepared than I was if it happens to her. Are there particular symptoms I should watch for?
The idea that menopause makes you susceptible to depression is not borne out by current information. Instead, menopause often ushers in a period of improved stability, enthusiasm for life, and serenity. But estrogen levels drift downward over a ten-year period following the cessation of menses, which is when older women may experience depression. If this happens to you, you might ask your doctor about HRT rather than an antidepressant, as the hormones may prove to be as effective as an antidepressant. If depression due to estrogen deficiency does become a problem and you elect to try an antidepressant instead of HRT, remember that women are helped more by SSRIs, while depressed men respond better to tricyclic medications like Elavil; ask your doctor how the antidepressant she prescribes for you works.
Your instincts about your daughter are right. Be vigilant after the birth of the baby, and talk with her frequently to get a sense of how she’s doing. A brief (two- or three-day) period of the “blues” is very common after delivery, but a lengthy and deepening sense of sadness demands attention from a doctor. Disturbing and repetitive thoughts about harming herself or the new baby are a signal that things are spiraling out of control; she shouldn’t be frightened or ashamed of sharing these feelings—they are symptoms of a chemical imbalance that can be treated, not signs of insanity or a criminal mind!
Depression is a labyrinthine illness that can be difficult to recognize, even in oneself. Many people may resist seeking medical attention for a prolonged case of the blues, but it is an illness and should be treated like one. Make sure your doctor or therapist discusses practical, “situational” treatments as well as medicinal ones. Getting out of the house more, feeling more useful (such as through paid or volunteer work), and sharing the burden of child care and housework, if you are a mother—all can be just as important as medication in reducing depression. Anxiety and agoraphobia (fear of open places) can be signs of depression in women; in these cases, antidepressants can be more helpful than sedatives (which can often produce a backlash of heightened anxiety or apprehension after wearing off and which are likely to be addictive).
My fourteen-year-old seems to vacillate between personalities: the sweet, confident child that she was and a tearful young woman with an acrid tongue. My husband feels that we should just leave her alone, but I’d like to do what I can for her, though she often barely acknowledges me.
Adolescence can be a very difficult time. Adolescent girls and their parents should bear in mind that changing hormone levels can bring about dramatic and very real challenges to self-confidence. Talking, emotional support, and seeking the help of counselors can be very helpful in working out some of these feelings before they become overwhelming for her and for the family.