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14© Дик Свааб, 2014 УДК 616.831-053.31-02:615.2/.3]:577.2
РАЗВИТИЕ МОЗГА ЧЕЛОВЕКА ДО РОЖДЕНИЯ: ВЛИЯНИЕ ЛЕКАРСТВ И ПОЛОВАЯ ДИФФЕРЕНЦИАЦИЯ
Дик Свааб
Нидерландский институт неврологии Королевской нидерландской академии искусств и наук, Мейбергдриф 47, 1105 ВА Амстердам, Нидерланды E-mail: d.f.swaab@nin.knaw.nl
Статья посвящена современному анализу данных молекулярно-биологических исследований о развитии мозга человека. Установлено, что наркотические вещества, лекарства, а также экологические факторы могут нарушать развитие мозга плода, что в конечном итоге становится причиной трудностей в обучении, а также служит основой многих видов расстройств поведения в более позднем возрасте. Врожденные дефекты такого рода известны как функциональные или поведенческо-тератологические. Поэтому женщины, которым для наступления беременности требуется проведение лекарственной терапии (например при лечении эпилепсии и депрессии), должны быть заранее осведомлены об указанных потенциальных проблемах.
Половая дифференциация мозга может также меняться под влиянием химических веществ в процессе внутриутробного развития. Последние данные развеяли сомнения в том, что гендерная идентичность и сексуальная ориентация программируются в структурах мозга еще в период эмбрионального развития человека. Половые органы также дифференцируются в первые месяцы беременности, в то время как половая дифференциация мозга происходит во второй ее половине. Поскольку процессы происходят в разное время, существует вероятность транссексуализации индивидуума (молекулярно-клеточные женские признаки могут формироваться в мозге мужских особей, и наоборот), что является отражением ошибочности суждения о полной свободе человека определенного пола (мужчина или женщина) в выборе сексуальной ориентации (гетеро-, би- или гомосексуальности). Такая точка зрения опровергается современными молекулярно-биологическими исследованиями и должна повлечь за собой пересмотр традиционных социальных и юридических представлений.
Ключевые слова: мозг человека, химическая дифференциация, половая дифференциация
HUMAN BRAIN DEVELOPMENT BEFORE BIRTH: INFLUENCE OF CHEMICALS AND SEXUAL DIFFERENTIATION
D.F. Swaab
Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef47, 1105BA Amsterdam, The Netherlands
Addictive substances, medication, and environmental substances can permanently disrupt fetal brain development, which might ultimately lead to learning difficulties as well as to many types of behavioral disorders in later life. Congenital defects of this kind are known as functional or behavioral-teratological defects. Women who wish to become pregnant and require drug treatment, e.g. for epilepsy or depression, must be made aware of the potential problems at an early stage so that the safest drug or alternative therapy is prescribed.
The sexual differentiation of the brain may also be influenced by chemicals during intra-uterine development. Variability has always been the motor of evolution and is still present — as evidenced in, e.g., sexual orientation and gender identity. There can be little doubt that our gender identity and sexual orientation are programmed in the structure of the brain while we are still in the womb and will last us for the rest of our lives.
Our sex organs are differentiated in the first months of pregnancy, while the sexual differentiation of the brain takes place in the second half of pregnancy. Since these processes occur at different times, what may happen, as it does in transsexuals, is that female structures are present in male brains and vice versa. The long-established idea that we are completely free to choose our gender-identity (i.e. the feeling to be male or female) or our sexual orientation (hetero-, bi- or homosexuality) is not only incorrect but has also been the cause of a great deal of misery.
Key words: human brain, chemicals differentiation, sexual differentiation
INTRODUCTION
The formation of brain cells shows a spurt during the intrauterine period and the first postnatal years of brain development. Around the age of 4, the brain contains the adult number of 100 billion neurons, which is twelve times the number of people on earth. The neurons are even outnumbered by glial cells, by no less than ten to one. Recent studies have shown that these cells, of which
humans possess more than any other organism, are crucial to the transfer of chemical messages and therefore to all brain processes, including the formation of long-term memory. There are 100 million billion synapses or, as Nobel Laureate Santiago Ramón y Cajal put it, 100 million billion neurons «hold hands». The neurons are linked by over one hundred thousand kilometers of nerve fibers. This network is so complex that it can only partly be
programmed on the basis of our genetic information [85]. Each brain is unique, due to genetic polymorphisms, self-organizing mechanisms and environmental epigenetic effects. The last two processes make that even the brains of identical twins are macroscopically different — already at the moment of birth [82, 102]. This review will focus (i) on the effect of chemicals on the developing brain, a topic that is also of the utmost importance in relation to medical treatment of pregnant women, and (ii) on sexual differentiation of the brain as an example of the enormous variability in all our properties. Variability has always been the motor of evolution and is still present, as evidenced by sexual orientation and gender identity. Also, sexual differentiation of the brain may be influenced by chemicals during intra-uterine development.
(I) DEVELOPMENTAL BRAIN DISORDERS CAUSED BY ENVIRONMENTAL FACTORS
Our brains develop with incredible rapidity before our birth and in the years immediately afterwards. Moreover, each tiny area of the brain and each cell type within that area develops at a different tempo. During this period of explosive growth, brain cells are extremely susceptible to a number of different factors. First, for the brain to develop normally, the unborn child needs sufficient nourishment. Sadly, we live in a world in which hundreds of millions of pregnant mothers live in an environment where they lack nourishment, which may lead to brain disorders such as schizophrenia and depression [72]. An unborn child's thyroid gland also needs iodine to function properly, but in China alone some 700 million people live in regions with an iodine shortage, which affects the growth of their children's brains [93].
Early brain development is determined, in general, by our genetic background and in detail by the activity of our nerve cells. These, in turn, are influenced by the availability of nutrients, chemical messengers from other brain cells (neurotransmitters), growth regulators, and hormones. In the second half of pregnancy, the unborn child's sex hormones regulate the sexual differentiation of the brain [4; see below]. Substances that enter the fetal system via the placenta can derail this delicate process. These substances may have been absorbed from the environment [92] or ingested by the expectant mother, such as for instance alcohol, nicotine or other addictive substances, and medication [36].
Chemicals, such as heavy metals, may also disrupt fetal brain development. The lead that is added to gasoline to reduce engine knocking enters the atmosphere and causes more children to be born with mental disabilities [57] and accounts for the 3-fold increase in the risk of hyperactivity at 7-8 years of age in boys and girls [78]. The dangers of mercury did not became apparent until the 1950s, when cats in the fishing villages around the Bay of Minamata in Japan started acting strangely and then dying and fish began to swim in bizarre patterns. The fishermen had been selling their best fish and keeping the worst specimens for the family pantry. As a result of the fish's high organic mercury content — mercury that proved to
come from a plastics factory — 6 percent of the children in the surrounding villages suffered serious brain damage before birth. The formation of their brain cells and the growth of brain tissue had been inhibited by the mercury, leading to mental disability. The adults in these villages also developed various forms of paralysis. A monument dedicated to all the life forms in the Shiranui Sea that fell victim to this disaster has now been erected in Minamata's environmental park. The park itself was built on twenty-seven tons of mercury-polluted sludge from the Bay of Minamata and dozens of sealed containers full of poisoned fish [62]. Even at low levels, mercury exposure is associated with a greater risk of ADHD [73]. Recently it has been found that traffic-related air polution is accompanied by a higher rate of autism [92].
Addictive Substances and Medication
Fortunately, the most severe developmental brain disorders that can arise early in pregnancy due to chemical compounds are rare. Examples of such serious teratological birth defects include spina bifida, the risk of which is increased by taking anti-epileptic drugs during pregnancy [98] and anencephaly, that is often associated with exposure to pesticides [49]. These defects, however, are just the tip of the iceberg in terms of the developmental brain disorders that can be caused by chemical substances during the entire pregnancy and in the postnatal years. Microscopic abnormalities are far more common than classic teratological abnormalities, and do not manifest themselves until later in life. Children affected in this way appear to be completely healthy at birth: the defects emerge later, when functional requirements are imposed on their brain systems. The children of pregnant women who smoke, for instance, are much more likely to have learning difficulties as well as behavioral problems in adolescence and reproductive problems in adulthood (see below). These disorders are known as functional disorders or «behavioral-teratological disorders».
Many chemical substances can reach the fetus and threaten its developing brain. Heavy metals in the environment, but also nicotine, alcohol, cocaine and other addictive substances, as well as medication taken during pregnancy, can disrupt the rapid development of the brain. Children exposed before birth to the drugs taken by their mothers not only display withdrawal symptoms after birth but can also be left with permanent brain damage. At the age of 10 years, children exposed intrauterinely to cocaine had a decreased head circumference, and showed behavior that was more withdrawn, anxious and depressed [71] and displayed less favorable adolescent functioning [9]. Adolescents exposed to cocaine before birth have a functional alteration in the prefrontal cortex in response to memory load and an altered connectivity of this brain region with the amygdala, changes that seem to be related to arousal dysregulation [55]. I have proposed that all substances that affect the adult brain can also influence the development of the fetal brain in the long term or even permanently. I have yet to see a single exception to this rule.
Alcohol
It was not until 1968 that French scientists established that drinking alcohol during pregnancy could impair fetal brain development [52]. However, the French publication went unnoticed until its rediscovery in 1973, with its finding dubbed «fetal alcohol syndrome» in English-language medical journals [39. 40]. To this day, a quarter of pregnant women in the Netherlands have the occasional glass of alcohol, even though drinking while pregnant can cause children to be born with undersized brains and severe mental disabilities. Drinking alcohol during pregnancy is also responsible for less severe damage, specifically in terms of learning and behavioral problems [36]. In early development, brain cells are created around the ventricles. They then migrate to the cerebral cortex where they develop and sprout fibers to establish contact with other brain cells. This migratory process of the fetal brain cells can be so severely disrupted by alcohol that the cells sometimes work their way through the cerebral membranes and end up outside the brain [40]. Alcohol also permanently activates the stress axis of the unborn child's brain, increasing the risk of depression and phobia [25].
Smoking
The potential harm that can be caused to an unborn child when its mother smokes during pregnancy is frightening. Smoking is the most common cause of neonatal death. It doubles the risk of sudden infant death syndrome (SIDS) [21]. In addition, a mother who smokes increases her child's risk of premature birth, low birth weight, impaired brain development, disturbed sleep patterns, poorer school performance [51], and obesity later in life [60, 84]. Her smoking affects not only her own thyroid function but also that of her child [76]. Her children run a higher risk of conduct problems [28], of attention deficit hyperactivity disorder (ADHD) [66], aggressive behavior, impulsiveness, speech defects, attention problems [37, 44] and, in the case of boys, impaired testes development and reproductive disorders [23]. Prenatal glucocorticoid exposure and maternal smoking during pregnancy independently increased the risk of nicotine dependency in adult daughters [83]. Children with fetal glucocorticoid exposure have a thinner rostral anterior cingulated cortex at the age of 6-10 years. This brain region is involved in affective disorders [15].
Around 12 percent of women in the Netherlands still smoke during pregnancy. Despite the known dangers, very few are able to give up smoking at this stage. Incidentally, trying to stop by using nicotine patches is also dangerous for the unborn child—animal studies have shown that nicotine in any form has a harmful effect on brain development. The dendritic changes identified in rats exposed to nicotine prenatally resembled neuroanatomical changes that are identified in rats who were given nicotine in adulthood [65]. In other words, it is not just all of the substances that constitute the smoke but also the nicotine itself that may cause developmental brain disorders.
Aspecific Effects
The functional teratological impact of medication sometimes comes to light by chance. In our institute, Majid Mirmiran studied whether the high level of REM sleep in fetuses is important for normal brain development. During this sleep stage, the brain is strongly activated, a pattern that already begins in the womb. Mirmiran carried out an experiment that inhibited REM sleep in rats by giving the rats either chlorimipramine (an antidepressant) or clonidine (a medicine used to combat high blood pressure and migraine). The experiment was conducted on two-to three-week-old rats at a stage at which the rats' brain development was comparable to fetal brain development in the second half of human pregnancy. After a short course of this treatment during their development, the adult animals had less REM sleep and were more fearful. Moreover, the sex drive in the grown male rats diminished, and they became hyperactive. In other words, a mere two weeks of exposure to these substances during their development caused permanent alterations in the brains and behavior of rats [63]. A subsequent study in Groningen looked at children whose mothers had been prescribed clonidine during their pregnancy eight years previously as a «safe» medication for high blood pressure and migraine. The children proved to have severe sleep disorders; some were even sleepwalkers [35]. One of the problems of functional teratological disorders, in other words, is that doctors must be able to determine, on the basis of animal studies, what disorders they need to look for in humans. What is more, the effects of the substances in question are aspecific. You cannot tell from a condition that manifests itself long after birth, such as a sleep disorder, exactly what substance taken during pregnancy caused the brain damage in question. Other examples of aspecific symptoms of functional teratology are learning disorders (caused by alcohol, cocaine, smoking, lead, marijuana, DDT, anti-epileptic drugs), depression, phobias and other psychiatric problems (diethylstilbestrol, smoking), transsexuality (phenobarbital, diphantoin), aggression (progestogens, smoking) and impaired motor skills (glucocorticoids, anti-epileptics, anti-depressives).
Additionally, chemical substances are thought to contribute to developmental disorders in which diverse factors play a role, like schizophrenia, autism, SIDS, and ADHD. Depending on her baby's genetic background, a woman who smokes during pregnancy may increase the chances of her child developing ADHD by a factor of nine [66]. The risk of ADHD is also increased when adrenal cortex hormones are administered during pregnancy to promote lung development in babies at risk of being born prematurely. This procedure has been found to impair brain development, potentially causing not only ADHD [41] but also a smaller brain, impaired motor skills, and a lower IQ [99]. These hormones are now administered much more sparingly.
Dilemma
One of the dilemmas doctors are confronted with is that patients with schizophrenia, depression or epilepsy
often continue to need treatment during pregnancy, because the mother's condition is potentially harmful, also to her child. Unfortunately, some anti-epileptics increase the risk of spina bifida [98] or transsexuality [16].
Anti-epileptics taken during pregnancy increase the risk of disturbed gross and fine motor skills, sentence skills and of autistic traits. Fortunately, no harmful effects of breast feeding were found [10, 90, 91]. It is best to treat epilepsy during pregnancy with a single drug in combination with folic acid. Some anti-epileptics are more harmful than others: valproate has been shown to impair neurodevelopment more than other epilepsy medications, such as carbomezapine [8, 90].
Around 2 percent of pregnant women take anti-depressants even when they only suffer from mild depression. Such drugs do not appear to increase the risk of serious birth defects, though the children born to these mothers tend to be somewhat underweight and slightly premature, score somewhat less well on the post-birth Apgar test, have subtle motor disorders and run a higher risk of developing autism [14, 56, 77, 89, 69]. However, there are also reports that do not find behavioral changes in these children at 18 months of age [3], and the reported disadvantages must be weighed against the problems that can result from a mother who suffers from stress during pregnancy. One study showed that maternal trait anxiety, depressive symptoms and stress had little negative influence on infant cognitive development [42]. However, another report showed that prenatal exposure to a moderately severe natural disaster is associated with lower cognitive and language abilities at 5 (1/2) years of age [52]. In addition, it was found that when a mother is fearful during pregnancy, this could permanently activate her baby's stress axis, thus increasing the risk of phobia, impulsiveness, ADHD, and depression later in life [59]. If at all possible, it is worth considering treating depression in pregnant women with alternative therapies, such as light therapy, transcranial magnetic stimulation, massage, acupuncture [58], or online therapy. Clearly, doctors treating such patients must carefully consider the options.
Mechanisms
Brain cells are created with incredible rapidity in the womb and shortly after birth, and this process continues, somewhat more slowly, until around the fourth year of life. Brain maturation goes on much longer; in the case of the prefrontal cortex it continues right up to the age of twenty-five [29]. Every facet of brain cell development can be disrupted by chemical substances during pregnancy. Disturbances to the migration of brain cells can lead to heterotopias, a condition in which groups of cells get lost somehow on their way to the cerebral cortex and get trapped in the white matter, a location where they cannot function properly. Substances regularly prescribed to pregnant women, such as benzodiazepines, can induce this condition [50]. Alcohol taken during pregnancy may also cause malformations (see above). Smoking and drinking alcohol during pregnancy alter the receptors for nicotine
and muscarine [20], and smoking marijuana during pregnancy can alter the dopamine receptors in the fetal brain [94] and may later have an adverse effect on school achievements [30].
Permanent effects on the developing brain have also been reported postnatally. For instance, repeated exposure to general anesthesia and surgery before the age of 2 is a risk factor in terms of developing learning disabilities [22] and ADHD [79]. The many other postnatal functional teratological effects that have been reported are not reviewed in the present paper.
(II) SEXUAL DIFFERENTIATION OF THE BRAIN IN THE WOMB
A Typical Boy or Girl?
Nothing would seem simpler than being able to tell at birth whether a child is a boy or a girl. Also the mechanism seems straight forward: gender is determined from the moment of conception: Two XX chromosomes will become a girl, an X and a Y chromosome will become a boy. The boy's Y chromosome starts the cascade that causes the male hormone testosterone to be produced. The presence or absence of testosterone makes the child develop male or female sex organs between the sixth and twelfth week of pregnancy. The brain differentiates along male or female lines in the second half of pregnancy, due to a male baby producing a peak of testosterone and a female baby not doing so. It is at that time that the feeling of being a man or woman—our gender identity—is fixed in our brains for the rest of our lives [4].
That our gender identity is determined already in the womb is a fairly recent discovery. Until the 1980s it was thought that a child was born a clean slate and that its behavior was then made male or female by social influences. This had huge consequences for the treatment of newborns with indeterminate sex organs in the 1960s and 1970s. It did not matter what sex you selected for your child, it was thought, as long as the operation took place soon after birth. The child's surroundings would then ensure that its gender identity adapted to its sex organ. Only since then have patient associations revealed how many lives were ruined by assigning a sex on the operating table that did not match the gender identity imprinted in the brain before birth [4]. The story of John-Joan-John shows how disastrous this approach could be [12]. When a little boy (John) lost his penis at the age of eight months due to a botched circumcision, it was decided to turn him into a girl (Joan). His testicles were removed while still an infant. He was dressed in girls' clothes, received psychological counseling from John Money, a sexologist from Philadelphia, received girls' toys (which he did not like) and was given estrogen during puberty. Money described the case as a great success: the child was said to have developed normally as a female [64]. When I remarked during a seminar in the United States that this was the only case I knew that showed that a child's gender identity could be changed by its environment after birth, Milton Diamond, a renowned sexuality expert, stood up and said that
Money's claim was completely unfounded. Diamond was acquainted with Joan; he knew that Joan had had his sex change reversed as an adult and had married and adopted children. A few years later Diamond made these findings public [17]. Sadly, John later lost everything he had on the stock market, suffered an unhappy separation from his wife, and in 2004 committed suicide [12]. This tragic story shows how strongly testosterone programs the brain in the womb. Removing this child's penis and testicles, giving him psychological counseling and administering estrogen during puberty could not change his gender identity.
That testosterone is indeed responsible for causing sex organs and brains to develop along male lines is apparent from androgen insensitivity syndrome (AIS). People with this condition produce testosterone, but their bodies are insensitive to it because of a mutation in the androgen receptor. As a result, both the external sex organs and the brain are feminized. Even if they are genetically male (XY), they become heterosexual women [95]. However, when girls are exposed to a high dose of testosterone in the womb due to congenital adrenal hyperplasia (CAH), the clitoris becomes so enlarged that they are sometimes registered as boys after birth. However, only in 1—3 percent of cases it later emerges that they did in fact acquire a male gender identity in the womb, and the risk for serious gender problems later on is 5%. The consensus is therefore that girls with CAH should be raised as girls even if they are masculinized [34].
The effect CAH can have in practice was shown clearly in a Dutch newspaper article by Jannetje Koelewijn (NRC Handelsblad, June 23, 2005). The parents of four daughters were overjoyed when their fifth child was a boy. But after a few months the child fell ill, and it was discovered the boy was in fact a girl with CAH. Doctors talked at length with the parents, Turkish Muslims, who refused to consider gender reassignment, partly on religious grounds. So the doctors decided to make the child more like a boy. The clitoris was made larger, to resemble a penis, and the child was given hormones to promote masculine development. The parents were delighted with this solution. But the brains of girls with CAH mostly develop along female lines (see above). It seems thus extremely likely that the «little boy» will later experience gender problems and will want to be a girl once more. When he enters puberty, he will also have to be told that he is infertile, that he will need testosterone treatment for the rest of his life, and that his uterus and ovaries will have to be removed.
A relatively new field is that of endocrine disrupters, i.e. compounds present in the environment that intervene in the interaction between endogenous sex hormones and the developing brain. This concerns, e.g., some pesticides, herbicides, plastic contaminants (such as phthalates), pharmaceuticals (such as DES) and dietary components (such as phytoestrogens). Animal experimental data show that these substances may alter reproductive-relevant or non-reproductive-relevant sexually-dimorphic behaviors [24]. Recent data are a cause of considerable concern about
such effects on human development in critical periods of development. As an example of a non-reproductive relevant effect is that in utero exposure to DES could lead to an increased risk of depression in adult life [68]. Prenatal exposure to phthalates, the anti-androgenic weakeners in plastics, is associated with less male-typical behavior in boys [87]. Intrauterine exposure to mild analgesics, which are anti-androgenic prostaglandin inhibitors, is a risk factor for the development of male reproductive disorders [47]. Moreover, boys with mothers exposed to pesticides during pregnancy, had smaller testicular volume and penile length at the age of 6-11, while girls showed earlier breast development [96, 97]. Prenatal ethanol is altering the sexual differentiation of the rat preoptic area [1]. What this all may mean for later gender-identity and sexual orientation for such children are not yet known.
In those rare cases where a child's sex is ambiguous and it is uncertain whether its brain has masculinized or feminized, a temporary gender may be assigned. Far-reaching interventions to turn such children into boys or girls should preferably be postponed until their gender identity has become clear through their behavior, or could take the form of reversible surgery. Germany is the first nation to legally recognize such intersex babies, allowing the parents to leave the sex designation blank on birth certificates [80].
Heterosexuality, Homosexuality, and Bisexuality
Alfred Kinsey's doctoral thesis on gall wasps did not attract any attention. However, after the publication of his report Sexual Behavior in the Human Male 1948, and five years later, Sexual Behavior in the Human Female, he became a celebrity. He devised the «Kinsey scale», which went from 0 to 6, 0 signifying exclusively heterosexual and 6 signifying exclusively homosexual. As a bisexual, Kinsey himself would have been classified as a «Kinsey 3». A person's position on this scale is determined in the womb by his or her genetic background and the effects of hormones and other substances on the developing brain. Studies of twins and families show that sexual orientation is genetically determined to a substantial degree, some even say up to 50%, but the genes in question have not yet been identified with certainty [67]. It is curious that a genetic predisposition for homosexuality should persist in populations over the course of evolution, given that this group reproduces so much less. One explanation for the persistance of homosexuality is that the genes involved do not merely increase the likelihood of homosexuality but even promote fertility in the rest of the family. Heterosexual individuals with the same genes produce a larger than average number of offspring, thus keeping these genes in the population [38].
In utero, hormones and other chemical substances importantly affect the development of our sexual orientation. Girls with the adrenal gland disorder CAH, which means they have been exposed to high testosterone levels in the womb, are more likely to become bisexual or homosexual [60]. Between 1939 and 1960, around
two million expectant mothers in the United States and Europe were prescribed the synthetic estrogen known as diethylstilbestrol (DES) in the belief that it would prevent miscarriages (which it did not do, in fact, but doctors like to prescribe and patients are always keen to be treated.) DES turned out to increase the likelihood of bisexuality and homosexuality in the daughters of women who were prescribed the drug [18]. Pre-birth exposure to nicotine also increases the likelihood of lesbian daughters [19]. In addition, it was found that the more older brothers a boy has, the greater the chance that he will be homosexual. Each older brother increases the odds of male homosexuality by approximately 33%. This 'fraternal birth order effect' is thought to be due to a mother's immune response to male substances produced by boy babies in the womb on the basis of the presence of his Y chromosome, a response that becomes stronger with each pregnancy [67]. Pregnant women suffering from stress are also more likely to give birth to homosexual children, because their raised levels of the stress hormone cortisol affect the production of fetal sex hormones [19].
Although it is frequently assumed that development after birth also importantly affects our sexual orientation, there is no proof of this whatsoever. Children of lesbian mothers and gay fathers are not more likely to become homosexual and are not different from children raised by heterosexual parents in terms of personality development, psychological development, and gender identity [32]. There is no evidence for the misconception that homosexuality is a «lifestyle choice» or that it is due to social learning.
The above-mentioned factors alter the development of the child's brain, e.g. the hypothalamus, an area that is important for sexual orientation. In 1990 Michel Hofman and I found the first brain difference in relation to sexual orientation: the brain's biological clock turned out to be twice as large in homosexual men as in heterosexual men. At the time we were actually looking for something else. I had previously discovered that Alzheimer's disease damages the biological clock, which explains why people suffering from this disorder wander around at night and doze during the day. I did some more studies to see if the same applied to other forms of dementia. In the case of AIDS dementia I found that the biological clock was twice as large as normal. Follow-up studies showed that this was not caused by AIDS; it was related to homosexuality [86]. In 1991, Simon LeVay [54] reported a second difference in hypothalamic structure between homosexual and heterosexual men, and in 1992 Allen and Gorski [2] found that the structure on top of the hypothalamus that connects the brain's left and right temporal lobes is larger in homosexual men.
Scans have also revealed functional differences in the hypothalamus with regard to sexual orientation. A study by Ivanka Savic of the Stockholm Brain Institute involved pheromones, the scented sex hormones that are given off in sweat and urine. Pheromones influence sexual behavior unconsciously. A male pheromone stimulates
activity in the hypothalamus of heterosexual women and homosexual men but does not provoke a response in heterosexual men. It seems that they are not turned on by male scents [75]. It was also found that lesbian women react differently to pheromones than heterosexual women [6]. Savic also showed that heterosexual women and homosexual men had more extensive functional connections between the amygdala and other brain areas than heterosexual men and homosexual women, proving that brain circuits function differently according to sexual orientation [74]. Functional scanning also showed changes of activity in other brain areas. In the case of heterosexual men and homosexual women, the thalamus and prefrontal cortex — structures of the reward circuitry — responded more strongly to a photograph of a female face, while in the case of homosexual men and heterosexual women these structures responded more strongly to a male face [45]. In other words, sexual orientation is determined by many structural and functional differences in the brain, all of which develop in the womb during the second half of pregnancy. They are not caused by the behavior of dominant mothers, the traditional scapegoats in this context. For the record: I made a habit over the years of asking the medical students I taught (usually in an auditorium filled with some 250 students) which of them did not have a dominant mother. No one ever raised their hand.
An important argument against the idea that homosexuality is a «lifestyle choice» or caused by environmental factors is the demonstrable impossibility of ridding people of their homosexuality — and this is not for want of trying: hormone treatments, castration, treatments that influence libido rather than sexual orientation, electroshock therapies as well as inducing epileptic insults. Prison sentences have proved equally ineffectual, as evidenced by the sad case of Oscar Wilde. Testicular transplants have been carried out, leading to a «success story» of a homosexual man allegedly having pinched the nurse's bottom after the operation. Psychoanalysis has also been tried, of course, as well as giving homosexuals apomorphine, a drug that induces nausea, in combination with homoerotic images, as a form of aversion therapy. The story goes that this did not diminish the men's erotic desires: its only effect was to make them start vomiting as soon as the therapist entered the room. Brain operations have also been performed on homosexual prisoners with a view to reducing their sentences if the treatment proved effective. Not surprisingly, the men all said that it had been effective [85]. Since none of these approaches has led to a well-documented change in sexual orientation, there can be little doubt that our sexual orientation is fixed by the time we reach adulthood and can no longer be influenced.
Transsexuality
Gender-identity disorder is rare: the prevalence is about 1:25000 [7]. Transsexuality is the most extreme form of gender-identity disorder and consists of the unshakable conviction of belonging to the opposite
gender. Transsexuals feel that they have been born into the body of the wrong gender and are desperate for a sex change or gender reassignment. Gender problems tend to become apparent at an early age. Mothers typically relate how their little boys dressed up in their frocks and shoes, were only interested in girls' toys, and mainly played with girls. But not all children with gender problems want to have a sex change later on in life. Only 23% of childhood gender problem cases will lead to transsexuality in adulthood [13]. In fact childhood gender variance is rather a predictor for homosexuality [80]. If necessary, puberty may be delayed with the help of hormones to gain extra time in which to decide whether or not to undergo treatment [11].
There are no indications that postnatal social factors might be responsible for this disorder. On the contrary, all the data indicates that gender problems arise in the womb. There is a strong genetic component to gender-identity disorders: a significant additive genetic component accounting for 62% of the variance, as found in a twin study [13]. Chromosomal abnormalities, polymorphisms of the genes for the estrogen receptor (ER)a, ERp, androgen receptor, aromatase and cytochrome P450 (CYP)-17 have all been mentioned in a number of studies [for references, see 66]. Gender-identity disorders may also be induced by abnormal fetal hormone levels. The risk is increased in case of congenital adrenal hyperplasia (CAH). It should be noted that, although the likelihood of transsexuality developing in CAH cases is 100 to 300 times higher than normal (in population, 1:25,000), the risk for transsexuality in CAH is still less than 1%, whereas the probability of serious gender problems in this group is 5,2%. The consensus is, therefore, that girls with CAH should be raised as girls, even if their genitals are masculinized [34]. In addition, a high prevalence of gender-identity problems has been reported in DES sons [43]. A formal study of these alarming data is certainly warranted. Moreover, in patients that were treated during pregnancy with medication that inhibits the breakdown of sex hormones, i.e. traditional anti-epileptics such as diphantoin or phenobarbital, a high prevalence of gender-identity disorders was observed [16]. There is also a fraternal birth order effect in the risk for transsexuality, pointing to an immunological mechanism [31].
The differentiation of our sex organs takes place in the first months of pregnancy, while the sexual differentiation of the brain occurs in the second half of pregnancy. Since these two processes take place at different times, the theory is that in the case of transsexuality, they have been influenced independently of one another. If this is the case, one would expect to find female structures in the brains of male-to-female transsexuals and male structures in the case of female-to-male transsexuals. And indeed, in 1995 our postmortem studies of donor brains yielded a small structure in which the usual sex difference was reversed. The brain structure in question is the bed nucleus of the stria terminalis (BST), an area that is involved in many aspects of sexual behavior. The central part of this nucleus, the BSTc, is twice as large in men as in women
and contains twice as many neurons. We found male-to-female transsexuals to have a «female» BSTc. The only female-to-male transsexual we could study — the material in question being yet rarer than the brains of male-to-female transsexuals — indeed proved to have a «male» BSTc. We were able to rule out that the reversal of the sex difference in transsexuals was caused by altered hormone levels in adulthood, and that the reversal must thus have happened at the developmental stage [48, 100]. Also other hypothalamic nuclei showed a sex reversal or an intermediate structure, such as the uncinate nucleus (=INAH3) the Intermediate nucleus (= SDN-POA) and the infundibular nucleus (= arcuate nucleus) [26, 27, 88]. MRI data showed signs of feminization in cortical thickness in untreated male-to-female transsexuals and signs of subcortical gray matter masculinization in untreated female-to-male transsexuals [101]. On the level of neurotransmitters, too, transsexual people display a reversal. The cerebral serotonin transporter asymmetry that is normally present in the mid-cingulate cortex in males, but not in females, is also absent in male-to-female transsexuals [47]. In 2008 the group headed by Ivanka Savic in Stockholm published a study involving functional brain scans of living male-to-female transsexuals. They had not yet been operated on, nor had they received hormone treatment. As a stimulus they were given male and female pheromones, scents that are not consciously perceived. In control groups, these pheromones were shown to produce different patterns of stimulation in the hypothalamus and other brain areas in men and women. The stimulation pattern for male-to-female transsexuals fell between that of men and women [5].
In 2007, Ramachandran and McGeoch published an interesting hypothesis and provisional research findings on transsexuality [70]. They believe that the neural body map of male-to-female transsexuals lacks a penis, while that of female-to-male transsexuals lacks breasts, because these body parts have not been programmed into the brain map during development. As a result, they do not perceive these organs as their own and want to get rid of them. Their provisional data do indeed show that transsexuals have a lower incidence of phantom penis/breast sensations than 'normal' individuals who have undergone amputation of the same appendage for medical reasons, such as cancer. Everything thus appears to indicate that early development of sexual differentiation in the brains of transsexuals is atypical. At the same time it is of course essential to make sure, before initiating treatment, that the desire for a sex change is not part of a psychosis, as it can be an occasional symptom of schizophrenia, bipolar depressions, and serious personality disorders [33].
CONCLUSIONS
Addictive substances, medication and environmental substances can permanently disrupt fetal brain development, leading to learning and behavioral disorders in later life. Congenital defects of this kind are known as functional or behavioral-teratological defects.
Tracing the connection between these disorders and the effects of chemical substances is difficult due to the length of time between the child's exposure to such substances in the womb and their effects, which may only manifest themselves when the child goes to school or—in the case of reproductive problems—perhaps twenty or thirty years later. Moreover, the conditions caused by these substances, such as learning and sleep disorders, are so aspecific that they cannot be used to identify the substance that caused the brain damage during pregnancy. On top of that, a single substance can produce different symptoms, depending on the stage of development at which the child was exposed to it. All of this is complicated even further by the fact that doctors, especially in the absence of reliable animal studies, do not know what disorders they should be looking for. With women who may require drug treatment during pregnancy, i.e. for epilepsy or depression, it is essential to discuss potential problems at an early stage so that if a pregnancy is planned, the safest drug or alternative therapy can be prescribed.
Sexual differentiation of the brain may also be influenced by chemicals ingested by the mother during intra-uterine development. Variability has always been the motor of evolution and is still present — as is evidenced, e.g., in sexual orientation and gender identity, programmed for the rest of our lives while we are still in the womb. Our sex organs differentiate in the first months of pregnancy, while sexual differentiation of the brain takes place in the second half of pregnancy. Since these processes take place at different times, it is impossible to determine, in those rare cases when children are born with indeterminate gender, whether the brain has developed along male or female lines. In the past, doctors have often
been far too quick to operate. They would «make» the baby a girl, to establish clarity for the parents and child. We now know from patients' associations that imposed gender identity frequently causes problems in later life. In cases of doubt regarding the sexual differentiation of the brain, it is better to assign a provisional sex until the child's behavior makes its gender identity clear. Some operations can be carried out in such a way as to be reversible.
Since our gender identity is determined so early on in development, it is not necessary to postpone a sex change until an advanced stage of adulthood to be sure that an individual really wants such a change. On the contrary, an early sex change has many advantages. Firstly, it is much better for someone to get used to their new gender before they have finished their education and settled into a career and a relationship. Also, obviously, it is easier to turn a man into a convincing woman before he has grown into a hulking six-footer with broad shoulders and a deep voice.
The long-established idea that we are completely free to choose our sexual orientation is not only wrong but has also caused a great deal of misery. It has led to people being punished for homosexuality, which all religions castigate as a sin — that is, as a wrong choice. But there is nothing optional about our sexuality, as it has been programmed in the womb. It is thus ridiculous to persist in attempts to «convert» homosexuals into heterosexuals, a practice that still goes on in countries like the United States and Britain.
Acknowledgements
I want to thank Mrs. W.T.P. Verweij for editing the English.
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Поступила 3 декабря 2013 г.
