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Interview: Roger Gorski

by Douglas Stein

DOCTORS SAY POSSIBLE TO CHANGE SEX OF BABY IN WOMB! MALE TRANSSEXUAL NURSES INFANT WITH MILK FROM OWN BREASTS TRANSSEXUALS CONTEMPLATE BRAINIMPLANT SURGERY TO COMPLETE SEX-CHANGE OPERATION The first statement is a banner headline from a popular American tabloid. The others could well appear in the same spot within a decade.

Underlying each of these astounding statements is fairly common knowledge that hormones secreted by the ovaries and testes play a crucial role in shaping male and female patterns of physical appearance and development. But only recently has a revolutionary idea begun to gain credence within the scientific community: that these same hormones mold the very architecture of male and female brains along significantly different lines. And these structural differences - laid down from fetal life to adolescence - are maintained and modified by sex hormones throughout life.

This explosive new area of brain research is generally called the study of the brain's sexual "dimorphism," meaning two distinct shapes or structures male and female. At the center of this controversial field is Roger Gorski, professor and chairman of the Department of Anatomy and Cell Biology of the University of California at Los Angeles School of Medicine, and director of the Laboratory of Neuroendocrinology of the Brain Research Institute. "Today," says Gorski, "there is a definite list of areas in the brain showing male female structural differences. In trying to understand neurobiology, you're much better off assuming a part of the brain is sexually dimorphic until you've proven it isn't."

Gorski did not set out to foment a sexual revolution in brain research, "or anything like it." Born in 1935 he loved the weather, "because in Chicago," he giggles, "if you don't like the weather, wait a few minutes - and it'll change." Born of a "modest, if not quite modest" Polish family, Gorski's only hope of attending the distinguished - and expensive - meteorological school at the University of Chicago was a scholarship exam. When he didn't make it he switched into biology, having been turned on to zoology. He entered the master's program at the University of Illinois at Champaign, where he began to assist "an animal science person." Suddenly he was correlating the electrical impulses in the brains of sheep with ovulation - and loving it. "You're really in neuroendocrinology," counseled a savvy adviser when Gorski was looking for a Ph.D. program, "so go to UCLA. That's a hotbed for it."

"I didn't wait," recalls Gorski. "I got into my 1947 DeSoto, drove straight to Los Angeles and the anatomy department, and was assigned to Charlie Barraclough." Having a mentor as freewheeling and creative as Barraclough - who often dazzled his students with jazz riffs - was a stroke of luck for Gorski. Not only did Barraclough initiate him in to the techniques of experimentally sex-reversing the reproductive functions of rats, but after they had worked together for two years, Barraclough went on sabbatical and never returned. Gorski wound up with Barraclough's research grant, his postdoc, and his technician. "So of course," laughs Gorski, "I did not leave. And I haven't left the field either."

Shortly after Barraclough's exit, Gorski had an epiphany. He was no longer just probing for differences in the small region of rats' brains that controlled hormone secretion, mating, and reproduction. He was trying, he realized, to fathom the very process of sexual differentiation of the brain itself. "We are all basically female," he argues. "If the chromosomally genetic male doesn't either see or respond to testicular hormones, he will have a female brain and body. Without hormonal action, the female pattern will emerge across the board in rat or man." Gorski saw that his career would focus on answering one basic question: How do sex hormones bring about the sexual differentiation of the brain?

In 1978, almost by accident, he made his landmark finding: that a previously uncharted area in the rat hypothalamus was five times as large in males as in females. This dramatic difference in size was due entirely to the impact of sex hormones on the developing brain. His discovery, which he christened the sexually dimorphic nucleus, or SDN, gave him an ideal model to study the effect of sex hormones on brain structure and function.

To this day the SDN is "far and away the area of greatest sex dimorphism yet found in the mammalian brain," says Gorski. Neuroscientists haven't confined their search for sex differences in brain structures to lab animals. Analyses of hundreds of human brains reveal striking structural differences in the brains of boys and girls, men and women. These may not only affect differences in sex behavior and attitudes but also underlie differences in such higher brain functions as memory, perception, cognition, imagination, and control of bodily movement. Psychologists, educators, and feminists argue that each sex's "intrinsic strengths," if not "intrinsic vulnerabilities," are the result of millennia of cultural pressures upon the infant, child, and adolescent to assume definite roles in play, work, and social situations. But now neuroendocrine physiologists and other researchers are beginning to demur.

So after three decades of research, where does Roger Gorski stand on this high-voltage issue? He is very, very cautious. "If you attribute particular behaviors or performance advantages - particularly cognition - to hormoneinduced changes in brain structure, to some people that's a very dangerous, sexist observation. People could certainly exploit that observation and act prejudicially in countless ways, saying females can't do this, males can't do that. But to me, since biological sex differences exist, the two sexes are better off knowing about them. One may argue about the value of societally induced sex differences, but biological sex differences are here to stay." Despite the "dangerous implications," Gorski is convinced the dimensions of the field he's pioneered will, if anything, grow larger and clearer. "All aspects of neurobiology may not turn out to be sexually dimorphic. But it seems unconscionable in this day and age that anyone would do a study without paying attention to sex."

Omni: What did your first studies in sexual differences focus on? Gorski: When I came to Barraclough's lab in 1959, he was looking at how the brain controlled ovulation. In the mid-Fifties he'd shown that a single injection of male sex hormone in female rodents during the early postnatal period would sterilize the females when they became adults. He had no proof of where the hormone acted. Together we injected female rats with testosterone - the major testicular hormone to block ovulation, then tried to restore it with electrode stimulation in different parts of the brain. We knew that stimulating the preoptic area of the hypothalamus normally causes female rats to ovulate if spontaneous ovulation is blocked. But the masculinized female failed to ovulate when we stimulated this area. This failure suggested that the preoptic area is a key brain site for hormone action in sexual differentiation.

Omni: How did you realize you were dealing with something far bigger than control of ovulation?

Gorski: We'd shown that if a newborn male rat is castrated and then given an ovarian transplant when he's grown, his brain will support ovulation. At that time I was preoccupied simply with the control of ovulation. I'll never forget the day [neuroscientist] Seymour Levine dropped into my lab after returning from England, where they'd performed similar studies. As we talked, it suddenly dawned on me that the neural control of ovulation was just the tip of the iceberg. We were actually dealing with a much more fundamental process: How does the brain differ between the sexes, and how do sex hormones bring about these differences? From that day I've devoted my career to these questions.

Omni: Don't most neuroscientists still think this sexual differentiation involves only the hypothalamus?

Gorski: To some, it makes no sense that there could be sex differences in other parts of the brain. I argue, how ever, that the brain is just part of the reproductive system and all of the reproductive system undergoes sexual differentiation. All mammals are basically female - including external genitalia, the internal sex organs excluding the gonads, and the brain. If you deny the developing brain exposure to testicular hormones during a precise time interval, you get a dramatic and permanent change. If the chromosomally genetic male either doesn't see or respond to testicular hormones, "he" will have a female appearance, including the outer sex organs and the brain.

Look at the influence of sex or gender identity on life-style. In evolutionary history it's generally the male who goes out to hunt and bring back the food. Wouldn't eons of this kind of activity lead to changes in male brain structure? To me sex differences are ubiquitous. The entire process of reproduction and the whole brain are geared toward survival of the species.

Omni: Why do male brains require estrogen, the so-called female sex hormone, to become masculinized?

Gorski: Other researchers have shown that the metabolic conversion of testicular testosterone to estrogen is a required step in masculinizing male brains. While it seems astonishing that estrogen masculinizes the male, it does reflect a common error: that estrogen is the "female" and testosterone the "male" sex hormone. That's not true. What is important is the ratio of these two hormones.

Omni: If estrogen masculinizes, does that mean in female babies there is no estrogen?

Gorski: Very logical, but no. In rats there is a special protein, called alpha fetoprotein, that binds the estrogen in the blood so that it cannot act biologically. Although in both sexes fetal blood levels of estrogen are high during pregnancy and shortly after birth, testosterone is not bound by alpha fetoprotein, so it enters the brain and, after being converted to estrogen within neurons, masculinizes them.

Omni: Does alpha fetoprotein also exist in humans? Gorski: Yes, but it doesn't appear to bind estrogen. I suspect there must be another biochemical substance or process that protects the brain of the human female fetus from the high estrogen levels of pregnancy. Actually, some scientists think that exposure to estrogen is necessary for the development of the female brain as well. They argue that the brain is actually neuter. And even in the female, estrogen is important for normal brain development. There's no question that enough estrogen will masculinize the brain - in the genetic male or female. Whether a female's brain is intrinsically female or requires a little estrogen to become truly female is a tricky question. Our studies show that for the female brain a little estrogen during development is good; too much is not.

Omni: Why is there such resistance to these sex differences? Gorski: Because the brain is still considered such a mysterious organ, many scientists find it hard to accept that it might be significantly different in males and females, and affected by something foreign to the brain like gonadal hormones. For years after I'd begun to look at the impact of steroids, I still viewed the brain as above all these interactions. Part of the reason was that the parameters studied were not all or none. While the standard posture of sexual receptivity for female sex behavior is lordosis, males, too, can show it. That means the equivalent neural circuitry for expressing lordosis exists in the male rat brain, too.

I had personally looked at hundreds of rat brains and never noticed structural differences. But almost all our studies focused on males one time or on females another time. I never directly compared the two. But my thinking began to change when in 1973, Geoffrey Raisman and Pauline Field showed that manipulating the sex hormone environment could change brain structure. They studied neural connections in rat brains and found that dendrites formed synapses quite differently in each sex in the areas they examined.

Omni: How did you discover the SDN?
Gorski: That's easy, I didn't! It was actually seen first by a postdoc, Larry Christensen. He'd decided to learn electron microscopy, and one day he came to my office and said he'd seen a major structural sex difference in the preoptic area of the rat brain. Because most of my studies of the last twenty years had centered on that very area, I laughed. Well, he took two slides - one male, the other female - and projected them on my wall. And there it was: The nucleus of the male was much bigger. In a minute he had me and everyone else in my lab convinced. It was so dramatic that once we recognized it, we didn't even have to magnify the slides to see the sex differences.

After that, I figured everyone looking for structural sex differences would find this one. This was the only time in my professional career I've been in a hurry to publish a paper. I was slightly paranoid that someone would beat us, because the discovery was so damn obvious. In retrospect, it's really amazing that someone not only could have, but should have, and didn't notice. There are brain atlases for surgery that assign coordinates as on a map to the various brain nuclei. They all had missed it. What does this say about science? That you can miss the truth because it's just too obvious? Or that we see what we expect to see, or not see.

The SDN is about five times bigger in males than females, and that size difference is due principally to the number of neurons. Giving the female testosterone for a prolonged period during fetal life completely sex - reverses the nucleus. If we castrate the male just after birth or treat him with an antiestrogenic agent, his nucleus becomes more comparable in size with that of the female, so we can sex-reverse brain structure by sex-reversing steroid input during the critical development period.

Omni: Are other hypothalamic areas larger in one sex or another? Gorski: The VMN [ventromedial nucleus], which is associated with both eating and aggression, has now been strongly implicated in control of female sex behavior. Because it is larger in males, you might say, Aha, this nucleus inhibits female sex behavior in males - keeps 'em straight, as it were. There are a couple of others, but the SDN is the area of greatest sex dimorphism of any mammalian brain region.

Omni: What does the SDN do?
Gorski: Life is sometimes bitter. For years we studied numerous sexually dimorphic functions, looking for their structural basis. Now we're sitting in the opposite camp. We have a very marked structural sex difference, but we still don't know what it does. How many neurons there are or where they may be located is much less important than what neurochemicals they produce or with what other neurons they connect. We still have to define these. We don't yet know whether the SDN facilitates or inhibits some reproductive process. Perhaps it inhibits female sex behavior in the male, suppressing female sexual behaviors like lordosis or attitudinal ones like the "maternal" instinct. Perhaps the neurons of the SDN are involved by influencing aggression or food intake. Perhaps it serves an integrative function, balancing hormonal, environmental, or sensory signals, like light or smell. Could we postulate that the SDN controls every sexually dimorphic function? Certainly we could, but we just as certainly could be wrong.

Omni: You often distinguish between centers for sexual behavior and others for control of hormones. Is the "center" concept valid?

Gorski: For a number of years the concept was robust in this field, because you could consistently change animal behavior by electrostimulating or lesioning a small brain area. But unfortunately, these centers overlap. The "center" for temperature regulation, for instance, is quite close to the "center" for sexual behavior. Sometimes a given nucleus can have multiple functions. Take the VMN, near the center of the hypothalamus. If you lesion it, animals cannot be sated; some of these rats become so fat they can barely move. But the same lesion gives you an extremely aggressive and furious rat. Normally, you handle rats without gloves, but when you destroy the VMN, you better wear lead gloves! And VMN lesions cause the female to show no sex behavior. So one "part" of the VMN may be concerned with female sex behavior, another with eating, a third with aggression. But that's an oversimplification. Each is not neatly enparcelated. The concept of the "center" is rarely accepted today.

Omni: The late Norman Geschwind compiled a body of work suggesting that testosterone, acting on the developing brain, encourages disordered neuronal growth and misconnections. The result, he argued, is that males are more prone to a range of nervous and immune system disabilities. What do you think of the "Geschwind thesis"?

Gorski: I support the general concept that during development sex hormones alter rates of neuronal migration, formation of connections, and even the shape of large-scale pathways. There is clearly a link between the nervous and immune systems and steroid hormones. Data that support Geschwind's thesis show that many problems - allergies, schizophrenia, and various learning disabilities - only manifest completely at puberty, when testosterone production reaches adult levels. It's quite possible that sex hormones have some "negative activational" role in nervous and immune system disorders.

But Geschwind's ideas don't really fit with the fact that the greatest effect of sex hormones on development is much earlier. We know testosterone influences the developing male brain primarily by being converted to estrogen. But I basically view this testosterone as just the male's means of getting estrogen up to his brain. So to accept Geschwind, I'd really have to argue that it's an excess of estrogen that's causing these neuroimmunological disabilities. That's a bit extreme.

Omni: You've said that the "complexity and ambiguity of neurobiology is an endless challenge." Nowhere does that seem more apparent than in the effects of sex hormones on human sexual orientation.

Gorski: There used to be a complete dichotomy in viewing the origin of sexual orientation: nature versus nurture, sex hormones versus environmental conditioning. Well, the last time I heard John Money talk, he said there is no controversy. Both play a role. The question is how much each contributes to one's sexual preference. We've talked about sexual dimorphism in the rat brain. It's a quasi-logical jump from brain structure to sexual orientation. But it is totally unfounded. In the lab we test sex behavior in a very artificial situation, treating it virtually as a reflex. We don't give the animals any chance to exhibit partner preference. We don't ask them if they enjoyed the encounter.

Animal sexuality is overwhelmingly dependent on sex hormones - much more than in humans. The differences between human and rat are so great you can't take data we've amassed on the sex behavior of the rat and freely apply them to humans. Some, Gunter Dorner in particular, have. However - and it is this however that brings me closer to Dorner - the process of sexual differentiation must apply to humans as it does to all mammals. I mean it follows the same course as it does in the rat. In humans you can - and do have genetic males look and act like females, and masculinized genetic females who, at least, resemble males.

Omni: Is there a strong biological basis in fetal hormone imbalances - as Dorner and others claim - for sexual behaviors labeled homosexuality, bisexuality, transsexuality?

Gorski: Arguing from the rat - which I just got finished saying you can't do - the transsexual is the most likely condition to be explained by hormones. That is, when an individual says, "I'm a woman in appearance, so why do I feel like a man?" Homosexuality is far more complex. Still, fetal hormone imbalances could - I'm not saying "do" - predispose a person to react one way or another to environmental stimulus.

I don't think anyone has ever success fully correlated hormone levels in adults with sexual behavior or preference. Virtually all of us seem to be secreting much more testosterone and estrogen than we need. Sex hormone levels are strongly influenced by genetic, ethnic, and racial factors. Although androgen levels in one ethnic group of men may be less than in the women of another ethnic group, that doesn't make those men less masculine than other males. We don't know, for instance, how genes affect the responsiveness of neurons to steroid hormones. Individual men of differing ethnic and racial back grounds might have a stronger or weaker response to the same quantity of testosterone, as they might to alcohol, cocaine, Valium, or any other drug.

Hormones produced by the gonads circulate in the blood. But these blood levels may be almost meaningless. What counts is how the person's individual physiology transforms the hormone into meaningful signals. At present in humans it's impossible to measure the sensitivity of neuronal receptors to hormones or their products.

Omni: Dorner claims that homosexual males typically show an "LH [luteinizing hormone] positive" response to an injection of synthetic estrogen that is in between that of heterosexual men and normally menstruating women. Is this response a valid index of homosexuality?

Gorski: Ovulation is caused by a marked surge of LH, and this surge is triggered by rising levels of estrogen produced by the ovary feeding back to the brain. The LH surge is the LH-positive response, which in rats is exclusively a female characteristic. But male monkeys normally show a positive response to an estrogen injection. So for humans, an LH-positive response may be an inappropriate index of homosexuality.

In humans you never know whether those labeled "homosexual" are responding differently than "normal" males to the estrogen injection because of some stress. Dorner's study was based, I believe, on a group of homosexuals he was already seeing. If he was "treating" them for their homosexuality, their possibly negative attitude toward their sexual preference could certainly bias his findings. The argument is often given that if you find a homosexual male with low testosterone, it's because he's under pressure. This stress is quite probably less for some one who lives openly gay, though I'm not completely sure of that.

Measuring hormones in adulthood won't tell you a damn thing about their levels in adolescence, childhood, or critical periods during fetal life. So you must base your interpretations on animal work. And to pick the rat over the monkey, as Dorner has done, seems extremely arbitrary. But there is another approach: to study so - called "human experiments of nature," people exposed to an incorrect prenatal hormone environment - with lasting results.

Omni: One such "experiment" is called the testicular feminizing male. What is the TFM?

Gorski: Here you have a genetic male whose testes, although undescended, still produce normal amounts of testosterone. But the TFM has genetically lost the androgen receptor all over the body - including the brain. This genetic male cannot respond to testosterone. So what is the phenotype [external characteristics] of this individual? Female! Female external sex organs, breasts, body fat distribution. The internal sex organs, however, are not female. Early in fetal life the testes produce another hormone, Mullerian duct inhibiting factor [MIF], that suppresses development of such female organs as the uterus and Fallopian tubes. MIF is not a steroid and doesn't need the androgen receptor to operate. Apparently MIF is normally secreted in the TFM, because those who function sexually as women often have to go to a clinician because intercourse is painful. That's because the deepest part of the vagina develops from the Mullerian duct, which both sexes possess in early embryonic life and which is suppressed by MIF.

The human male testes also normally secrete small amounts of estrogen. Because the TFM can't respond to testosterone during the prenatal period of sex differentiation, he develops as a female. And at puberty, when these testes become active, he responds to the increased quantity of estrogen, developing breasts and becoming sexually active as a female. These individuals rarely know they are male. They're born looking like girls, are treated by parents and peers as girls, and so act like girls. They are both phenotypically and psychosexually female.

Omni: In a sense, the opposite side of the coin is the female with congenital adrenal hyperplasia [CAH].

Gorski: These genetic females lack one or two key enzymes that convert androgens [from the adrenal glands] to cortisol, an adrenal hormone. So the adrenals keep on turning out masculinizing hormones. These girls are born with and - if the situation isn't corrected - develop masculine characteristics: enlarged clitoris, hirsutism, male shape and muscle pattern. A number of uncorrected girls were thought to be boys. Nevertheless, at puberty they do ovulate and menstruate.

Many CAH girls are identified just after birth. And by giving the missing hormones, you can easily eliminate the excess androgen. But these adrenal androgens may have affected the sexual differentiation of the brain during fetal life. Susan Baker and Anke Ehrhardt studied girls who were corrected shortly after birth and found them to have subtle masculine traits later in life. As adrenal-hyperactive girls, they were often tomboyish but still saw themselves as girls. As women, they are not merely disinterested in children but show an active aversion to infant care. Are they "tomboys" as adults? It's hard to tell, because a tomboyish woman may be more inclined toward masculine dress and hairstyle, but she probably will not want to play baseball or wrestle with the guys. Masculine behavior is more acceptable in a woman than feminine behavior in a man.

Omni: What about individuals with 5-alpha reductase deficiency - in childhood they're treated as girls, because that's what they look like, but who suddenly grow a penis at puberty?

Gorski: Testosterone can be converted into estrogen. The enzyme 5-alpha reductase transforms testosterone into an other hormone, dihydrotestosterone [DHT]. In human males DHT, not testosterone, is primarily responsible for the masculinization of the genitals. Genetic males with normal testosteroneproducing testes, but unable to make DHT, are born looking like girls and are raised as girls. At puberty when the testes start to produce high levels of testosterone, they do masculinize to a degree, perhaps because a greater quantity of testosterone over a longer time functions as a smaller amount of DHT over a relatively brief fetal period. Those producing high levels of testosterone actually change from girls to men! In the Dominican Republic there is a group [about 20] of these individuals. Most have become men, suggesting that the fetal hormone environment did masculinize their brains. In psychological interviews, many claim they "always knew" they were male.

On the surface, this phenomenon - people who are raised as girls but become men psychosexually - suggests that fetal hormones (or perhaps those at puberty) play an important role in psychosexual differentiation. There are, however, several controversial questions still unanswered. Were these individuals actually raised as girls? Did they be come males psychosexually because of a prenatal hormone effect, or did they just adjust their adult psychology to the fact that their bodies and genitalia masculinized? In other parts of the world, it's only those who become most malelike in physical appearance who become males. In this country, however, when this syndrome is detected, the "girls" usually have their testes removed. Is this the appropriate treatment? I wish I knew.

Omni: How might a fetal hormonal imbalance alter sexual orientation without affecting bodily development?

Gorski: We suspect there may be separate critical periods for development of various brain structures, sexual behavior, hormone feedback regulation, and all the outward manifestations of sexuality. I have no problem accepting that a temporary fluctuation of steroid hormones - via stress to the mother, ingested drugs, or just normal biological variability - might affect one aspect of brain development, but the body and everything else in the brain would be normal. Take the very macho, muscularly developed gay guy. We have no idea what his hormonal levels were like as a kid. To some people, gay or straight, male or female, a muscular guy is very attractive. Some gay men work to make their bodies conform to this sexually attractive ideal.

Omni: Why hasn't Dorner or others looked at ratios of testosterone and estrogen in homosexual men?

Gorski: Dorner certainly has a hypothesis to defend. But sure, hormone ratios are crucial in both sexes. And if you are going to prevent homosexuality, why limit it to males? If you found higher levels of whatever androgen in female fetuses, they'd theoretically have a greater chance of becoming lesbians. So why not treat these girls with progestins? Maybe because if you bungled the dose and timing, you'd "unfortunately" make them even more masculine!

Omni: Dorner not only feels that he is capable of correcting homosexuality but feels a strong need to.

Gorski: This is feasible only during fetal life and has to involve amniocentesis or other fetal testing. Since differentiation of the brain and genitalia is occurring by the same process, you could intervene toward the end of the second month. But should you? Most parents might simply want to prevent their offspring from being homosexual or transsexual. But I'm not sure they have that right. Behavior alone is not a disease. I suspect those people who so vehemently oppose abortion might be delighted with a Dornerstyle "corrective intervention."

And what kind of proof can we have that the baby would become gay? Obviously, we don't have any. When this interview comes out I'll get basically three types of letters. One: "My son or daughter had 'an accident' and is gay; what can or should I do?" Two: "I'm gay, and thank you for showing it's not my fault." Three: "I'm gay, and how dare you try to tell me it wasn't my choice?" Can't we accept that many people are perfectly happy being gay?

So back to it: If we could prevent homosexuality, should we? I don't think so, because we don't know the effects of sex hormones on aspects of brain development and function, such things as creativity or talent.

Some people, Geschwind in particular, have argued that the more lateralized, "masculinized" brain is a definite survival advantage. Well, in our society you can succeed professionally by being very good in a very limited way. Perhaps for the genius at money management or chess, "the more lateralized the better" holds true. But what about success and satisfaction in life, which are harder to grade on test scores? In creative endeavors, the more lateralized brain might be a distinct disadvantage. Many creative people have been gay. Would we lose that? Sex and sexuality are private and special, so we should not even be dealing with what other people think of our practices or preferences. Though I may be a bit of a hypocrite, because I'm pleased my three children seem quite normal.

Omni: How could your findings be applied to future sex-change operations? Gorski: We transplanted the male SDN into the female rat brain. These transplants survived well and enhanced [male sexual] behavior. So you can say that one can change sexual behavior with a brain implant. For the human male transsexual wanting to become female, it's fairly simple surgery to make effective female genitalia and permit a normal sex life, other than pregnancy. But remember, in the transsexual the brain is okay: it's the genitals that are "wrong." Now, suppose you're a female in a body with a male brain, or you claim that's how you feel. The current reconstruction of male genitalia is rather inefficient. It doesn't work erection-wise. Should we then entertain the idea of changing the brain of that female who wants to be a male, into a female brain that doesn't want to be a male?

Omni: How might sex hormones cause brain areas to differ in each sex? Gorski: We've shown that only half the neurons present at birth in the female SDN are alive on day seven. Sex steroids affect how many neurons end up in this part of the adult brain. Neurons are all born in an area lining the brain's ventricles and then migrate out. It's crazy, but sometimes younger neurons have to travel the farthest, go right through a region of older neurons to get to their destination. What tells a developing or migrating neuron where to end up? One theory has steroid hormones playing a key role in neuronal guidance. And what is a nucleus? Basically, it's an accumulation of neurons. They must, then, recognize their brothers, sisters, cousins. Maybe steroids play a pivotal role in what's called cell recognition. Finally, steroids may keep neurons alive by stimulating them to grow faster and make more connections.

What we now know about steroids tells us they act upon the DNA, or genome. In simplistic terms, steroids must be activating a survival gene keeping certain neurons alive. We're now trying to home in on and identify the genes these hormones must be activating and to isolate the "survival factors" these genes actually make.

And there's another way, too, that steroids might work. They could turn off a "suicide" process. Neurons survive be cause they often depend on factors like nerve growth factor [NGF]. Researchers recently pointed out that instead of asking how NGF normally works, you could turn the question around and ask, "Why do neurons die when you take NGF away?" Surprisingly, they found that cell death, occurring after you remove trophic factors, is often the result of additional protein synthesis. Nerve cells start making some thing extra, and that something extra kills them. This mechanism - removal of a substance [such as NGF] that inhibits a suicide gene - may be fairly common. We have to entertain the idea that the role of testosterone in the male SDN is to turn off a suicide gene. That a factor from the environment outside the brain, here testosterone from the testes, would lead to the survival of these neurons in the brain utterly fascinates me.

Omni: How will you study the effects of hormones on the developing brain? Gorski: By mixing DNA from the male's SDN with that of the female, it's possible to isolate molecules found only in the male SDN. With male SDNspecific DNA at hand we may identify relevant genes and proteins and begin to unravel the mystery of how hormones determine the structure and presumably the function of the brain.

Our field is in its infancy. By using noninvasive techniques, we will expand the list of sexual dimorphisms. Once we know whether a brain structure is on or off that list, we can begin to zone in on the effects of age, the Pill, endocrine abnormalities, nervous system disease, and the brain's structural identity. If we find wiring differences either in or between various brain regions, it would have a strong effect on how we think, feel, and respond to the world.

Clearly, defining the existence of structural sex differences is the prerequisite for studies that seem to be on everyone's mind: namely, those addressing the question of whether men and women have distinct and different in born strengths and weaknesses. But I'll tell you straight out: Sex differences in the structure of the human brain exist. And I for one strongly believe that some of them are shaped by the sex hormone environment. My position remains: It's sexually dimorphic until you've proven it isn't.