Chapter 16: Sex and the Brain PDF

Chapter 16 Sex and the Brain SEXUAL DIMORPHISM and prefer toys such as dolls. Is this a product of Humans are sexually dimorphic (di, “two”; morph, learned gender social roles or something more “t...

Chapter 16 Sex and the Brain SEXUAL DIMORPHISM and prefer toys such as dolls. Is this a product of Humans are sexually dimorphic (di, “two”; morph, learned gender social roles or something more “type”). That is, we come in two styles. How one innately wired in the brain? conceptualizes these differences depends on one’s A study with vervet monkeys suggests that the perspective. Table 16.1 summarizes the major cat- choices of toys children make to play with are egories of sexual dimorphism. In this chapter, we more ingrained than some might think. Monkeys in focus on how the hormones change the morphol- large cages at the University of California, Los ogy of the brain and how this affects the behavior Angeles Primate Laboratory were allowed 5 minutes and sexuality. of exposure to individual toys classified as “mascu- line” (police car and ball) or “feminine” (doll and Pink and Blue pot). The amount of time they were in direct con- In general, men and women behave differently tact with each of the toys was recorded. Figure 16.1 and enjoy different activities. The etiology of shows a male and female monkey playing with the this difference remains a hotly debated topic. Is toys and the percent time that each gender spent it nature or nurture—genetic or environmental? in contact with the toys. These results show that With humans, it is almost impossible to tease out even nonhuman primates who are not exposed to these opposing causes. The signals a baby receives social pressure regarding toy preference will choose about its sexual identity start early—in the nurs- gender-specific toys. ery. Typically, boys favor construction and trans- If we remember the important role of plea- portation toys. Girls show less rough physical play sure in determining behavioral preferences, we can speculate that the monkeys spend more time with the toys they enjoy. Likewise, we can specu- late that the association between an object and the TABLE 16.1 pleasure is hardwired in the brain. Furthermore, some of this “wiring” must have arisen early in Different Ways of Conceptualizing human evolution before the emergence of our Sexual Dimorphism hominid ancestors. Perspective Example The Boy Who Was Raised as a Girl One of the more remarkable stories of sexually Chromosomal XX, XY dimorphic behavior involves a tragic story of a boy Gonadal Ovaries, testes raised as a girl. David was 8 months old in 1966 Hormonal Estrogen, androgens when his entire penis was accidentally burned beyond repair during a routine circumcision. Morphological Genitalia, body size, body shape Dr. John Money, a psychologist at Johns Hopkins Behavioral Nurturing, aggressive, hunter, Hospital with expertise in sexual reassignment, gatherer, etc. convinced the family to proceed with surgical Sexual Identity, orientation, preference sex change and raise the boy as a girl. Dr. Money believed that sexual identity/orientation developed 188 01546_ch16_p188-202.indd 188 12/26/12 1:47 PM  Chapter 16 l Sex and the Brain 189 Female with doll out in public as a boy. He stopped estrogen and A “Feminine” toys started testosterone. He had bilateral mastectomies and several operations to rebuild male genitalia. He eventually married in his twenties although he 30 could not have children. However, he battled with Contact (%) 20 depression and the demons from this childhood experience. In May 2005, at the age of 38, he killed 10 himself. 0 The significant point about this case is that in Doll Red pan spite of being raised as a girl and in spite of the presence of estrogen hormones and the absence Males of testosterone, David continued to have male Females pattern psychosocial and psychosexual devel- opment. Larger case studies are consistent with B “Masculine” toys David’s experience. One analysis of XY individu- als assigned female roles at birth due to a severe 30 pelvic defect (cloacal exstrophy) found that all showed masculine tendencies. Slightly more than Contact (%) 20 half chose to declare themselves male when older. 10 These studies suggest that something permanent happens in utero that determines sexual identity/ 0 Orange Police orientation. ball car Environment Male with truck It would be naive to dismiss the significance of environment on sexually stereotypical behav- FIGURE 16.1 l Male vervet monkeys spent more time in contact with “masculine” toys while females spent iors. History is replete with examples of men and more time with “feminine” toys. (From Alexander GM, women showing varying amounts of masculine Hines M. Sex differences in response to children’s toys in and feminine behavior that are clearly molded nonhuman primates (Cercopithecus aethiops sabaeus). by shifts in social norms. Kim Wallen reviewed Evol Hum Behav. 2002;23:467-479.) 30 years of research with rhesus monkeys and attempted to separate hormonal and social influ- after 18 months of age and children could adapt to ences. For example, rough and tumble play is a new sexual identity if the procedure was started one of the most robust sexually dimorphic behav- early enough. David provided an ideal case study as iors. Juvenile males wrestle more frequently he had an identical twin brother with a normal penis. than females in almost every rearing condition. Amazingly, Dr. Money reported in the medical However, if reared in a group with only males, they literature that the reassignment was a success, but (males or females?) actually engage in less rough it was in actuality a disaster. David, whose name play. Likewise, mounting behavior is seen more was changed to Brenda, did not want to wear with males than females. However, when reared dresses, or play with dolls. She preferred to play in isolated, same-sex environments, males display with guns and cars. She could beat up her brother less mounting while females display more such and threw a ball like a boy. Worst of all, this unusual behavior. behavior was not well received at school. She was Rust et al. looked at gender development in pre- relentlessly teased for her masculine traits. Brenda school children and the effect of an older sibling. was shunned by the girls and not accepted by the They discovered that having an older brother was boys. associated with greater masculine and less femi- By the time Brenda was 14 years old she was nine behavior in boys and girls. However, boys still unaware of the sexual reassignment and with older sisters were more feminine but not less remained distressed. A local psychiatrist who was masculine, whereas girls with older sisters were treating Brenda convinced the parents to reveal the less masculine but not more feminine. truth. Brenda recalls her reaction, “Suddenly it all Together, these studies suggest interplay made sense why I felt the way I did. I wasn’t some between hormones and environment. That is, sort of weirdo.” biologic factors predispose individuals to engage David immediately decided to revert to his in specific behaviors, which can be modified by genetic sex. Within several months, he began going social experience. 01546_ch16_p188-202.indd 189 12/26/12 1:47 PM  190 SECTION III l Behaviors CH3 Gonads CH3 CH3 CH3 The gonads (ovaries and testes) serve two CH3 major functions. First, they produce eggs or sperm to pass on DNA to the next HO generation. Second, they produce the sex Cholesterol hormones that not only promote the devel- opment of secondary sexual characteristics but also drive the behavior that increases the CH3 chances of an egg and sperm meeting. C O HORMONES O Figure 14.8 shows the classic experiment by Berthold who was the first to establish that the Progesterone testes contain a substance that controls the devel- opment of male secondary sexual characteristics. In Chapter 7, we discussed the relationship between OH the cortex, hypothalamus, pituitary gland, and end organ. Briefly, with input from the cortex, the hypothalamus produces gonadotropin-releasing hormone (GnRH), which in turn stimulates the O anterior pituitary gland to produce luteinizing Testosterone hormone (LH) and follicle-stimulating hormone (FSH). LH and FSH stimulate the gonads to produce the sex hormones. 5a-Reductase Aromatase Cholesterol is the precursor of all steroid hor- mones. Figure 7.7 shows the three major steroids OH OH synthesized from cholesterol: glucocorticoids, mineralocorticoids, and the sex steroids. The sex steroids are synthesized in the adrenals or gonads. Because the steroid hormones are lipid soluble and O HO H easily pass through the cell walls, they are released 17β-Estradiol (E2) as they are synthesized. 5a-Dihydrotestosterone (DHT) Testosterone, as shown in Figure 16.2, is con- verted into 17-b-estradiol (E2) and an androgen, FIGURE 16.2 l The sex hormones are synthesized 5-a-dihydrotestosterone (DHT). (An androgen is from cholesterol. Testosterone serves as a prohormone for 17-b-estradiol. a generic term for a hormone that stimulates or maintains male characteristics.) Amazingly, much of the androgen effects in the brain are actually transpire. Because the sex hormones can influ- implemented by 17-b-estradiol. For example, an ence neural function, they are sometimes called injection of estrogen to a newborn rat is more mas- neurosteroids in neuroscience literature. culinizing than an injection of testosterone. Why do the maternal estrogens not masculin- Differentiation and Activation ize all fetuses? One of the functions of a-fetopro- The development of sexual dimorphism is depen- tein during pregnancy is to bind with maternal dent on the sex hormones. The presence of testos- estrogens, which are then cleared through the terone at critical periods of time both masculinizes placenta. This protein, which does not bind testos- and defeminizes the brain. Likewise, the absence terone effectively, prevents estrogens from reaching of testosterone feminizes and demasculinizes the the brain. brain. In 1959 William C. Young et al. published We have discussed in other chapters how the a classic paper that rivals Berthold’s work with sex steroids can work directly on synaptic recep- roosters in helping us to understand the fundamental tors or indirectly through gene transcription (see principles of hormones and behavior. Figures 5.3, 7.1, and 7.3). These different effects To understand Young’s study it is impor- are summarized in Figure 16.3. The direct effects tant to be aware of the different sexual postures are fast, while the indirect effects take longer to males and females display at appropriate times. 01546_ch16_p188-202.indd 190 12/26/12 1:47 PM  Chapter 16 l Sex and the Brain 191 OH Direct effects HO Indirect Estrogen 17β-Estradiol (E2) effects receptor FIGURE 16.3 l Steroids can directly affect the transmitter synthesis/release or postsynaptic transmitter receptors. They can also indirectly influence gene transcription. (Adapted from Bear MF, Connors BW, Paradiso MA, eds. Neuroscience: Exploring the Brain. 3rd ed. Baltimore, MD: Lippincott Williams & Wilkins; 2007.) Female rodents will stand immobile and arch their lordosis when given estrogen and progesterone. backs: lordosis. Males will mount such a recep- However, they would mount other females when tive female. Females and males rarely (although given testosterone. The control group displayed the not completely) exhibit the opposite behavior. opposite behavior. Researchers use the presence or absence of lordo- This elegant experiment established a clear dis- sis and mounting as expressions of sexual behav- tinction between the differentiating effects of sex ior. For example, castration of a male stops his hormones during development and the activating mounting behavior. But this can be reinstated with effects during adulthood. The females exposed to injections of testosterone. testosterone in utero had alterations in the orga- Young’s group sought to understand the effects nization of their brains that prevented the normal of early and late exposure to sex hormones on sex- activation by female sex hormones as an adult. ual behavior. Their experiment, which is shown in Figure 16.4, started with injecting testosterone in Human Congenital Anomalies a pregnant female guinea pig. Their first observa- Occasionally, people are born with genetic altera- tion (not shown in the figure) was that female pups tions that give us insight into the differentiation exposed to high doses of androgens in utero were and activation of human sexual dimorphism. One born with masculinized external genitalia. such condition is congenital adrenal hyperplasia. The rest of the study focused on the female Children with this condition are exposed to exces- pups, which were allowed to mature and were then sive androgens due to overactive fetal adrenal spayed. Later, they were all given estrogen and pro- glands. Paradoxically, the condition is caused gesterone to stimulate female sexual behavior. Each by an impaired ability of the fetal adrenal gland was paired with a normal male guinea pig. Some- to produce cortisol. Because the pituitary fails to time later, the procedure was reversed. All were receive the appropriate negative feedback, it con- injected with testosterone and paired with a recep- tinues to secrete adrenocorticotropic hormone tive female. The results were striking. The females (ACTH), which in turn induces hyperplasia of the exposed to testosterone in utero failed to display androgen-producing cells of the adrenal cortex. 01546_ch16_p188-202.indd 191 12/26/12 1:47 PM  192 SECTION III l Behaviors A Normal Control pregnant Testosterone guinea administered pigs to pregnant guinea pigs Female pups allowed to mature and then spayed Later treated with female sex steroids B Lordosis No lordosis with receptive male Even later treated with male sex steroids C Mount No mounting receptive female FIGURE 16.4 l Guinea pigs exposed to testosterone in utero (A) fail to show feminine sexual behavior (B) when given female sex hormones and instead act like males (C) when given testosterone. As we might predict from Young’s studies with born as normal appearing females. The problem guinea pigs, human males are unaffected by the is caused by a mutation in the androgen recep- exposure to excess adrenal androgens in utero. tor. These individuals produce testosterone, but Females, on the other hand, are born with mascu- the cells are unable to recognize it. Consequently, linized external genitalia. Additionally, the females there is no activation of the genes necessary for tend to exhibit more rough and tumble play as chil- male characteristics. dren. As adults, they have an increased tendency to These individuals are born looking like normal prefer other females as partners. little girls and are raised as such (Figure 16.5). An extraordinary condition in men provides a Typically, the problem is only recognized when different example of anomalous sexual develop- they fail to menstruate in adolescence. Unfortu- ment. Androgen insensitivity syndrome (AIS) is nately, they are unable to conceive as they have a condition in which XY (male) individuals are failed to develop uteri, fallopian tubes, and ovaries. 01546_ch16_p188-202.indd 192 12/26/12 1:47 PM  Chapter 16 l Sex and the Brain 193 Treatment Revealing the diagnosis In the 1950s, the standard practice was to withhold the actual diagnosis from individu- als with AIS. They were told that childbear- ing was impossible, but not told they were genetically male. It was believed that such information would produce psychiatric disor- ders and possibly even thoughts of suicide. In the 1990s, the prevailing attitude shifted to full disclosure, and now it is the standard practice to reveal all the details to patients with this disorder. However, there remains a small cohort of women whose management FIGURE 16.5 l This person with complete was started in the era of less autonomy and androgen insensitivity syndrome has an XY who are still unaware of their diagnosis. genotype, but has developed unambiguous feminine Many patients can sense when the truth characteristics. (Courtesy of John Money.) is being withheld. In this age of the Internet, it is possible for curious patients to discover However, their behavior is unequivocally feminine. their own diagnosis. Some patients have Hines et al. examined the psychological develop- avoided further medical care or even com- ment of 22 XY individuals with complete AIS mitted suicide when finally discovering their compared with 22 XX normal controls and found true condition. When confronted with such a no differences on any measure of psychological patient, clinicians struggle with the appropri- outcome. They concluded that these results argue ate manner and timing of sharing the diagno- against the need for ovaries and two X chromo- sis, particularly with a patient who has been somes in the development of traditional feminine kept in the dark for so long. behavior. Likewise, it reinforces the importance of the androgen receptor in masculine development. It is an interesting thought that all humans (both men and women) would develop into women unless other hormones intervene. The default model for Control Estradiol mankind is a woman! NEURONAL CIRCUITRY Nerve Growth Gonadal steroids grow more than just testes and breasts—they also cause selective neuronal growth. As shown in Figure 16.3, gonadal steroids stimu- late gene expression through the androgen and estrogen receptors. These receptors, once bound with the hormone, also function as transcription factors, which, in turn, stimulate gene transcription and protein synthesis. Ultimately, the gonadal ste- roids can affect the nerve volume, dendritic length, spine density, and synaptic connectivity. Woolley et al. demonstrated this effect by admin- CA1 pyramidal cell CA1 pyramidal cell istering estradiol or placebo to ovariectomized rats and examining the structure and function of the FIGURE 16.6 l Ovariectomized rats treated with hippocampal cells. Figure 16.6 shows two CA1 estradiol display greater spine formation on CA1 pyramidal cells and a closer examination of their pyramidal cells from the hippocampus. (Adapted dendritic spines. The estradiol-exposed neurons from Woolley CS, Weiland NG, McEwen BS, et al. Estradiol increases the sensitivity of hippocampal had 22% more spines and 30% more N-methyl- CA1 pyramidal cells to NMDA receptor-mediated d-aspartate glutamate receptors than the con- synaptic input: correlation with dendritic spine trols. Furthermore, the treated neurons exhibited density. J Neurosci. 1997;17(5):1848-1859.) 01546_ch16_p188-202.indd 193 12/26/12 1:47 PM  194 SECTION III l Behaviors less electrical resistance to cellular input. So not A only did the estrogen change the structure of the neuron but also the function. Penis Growth Factor Proteins The astute reader might wonder about the role Anus of growth factor proteins with sex hormones and nerve plasticity. Indeed, there is considerable evi- dence linking gonadal steroids with growth factors Bulbocavernosus muscles such as brain-derived neurotrophic factor (BDNF). However, it is unclear if the sex hormones stimu- late the production of the growth factor protein, or work synergistically with them, or both. A study looking at the rat motor neuron sheds some light on this question. Cross section of lumbar spinal cord B The motor neurons projecting from the spinal Female Male cord to the skeletal muscles in rodents are generally similar for males and females. However, the male requires the additional innervation of the bulbocav- ernosus muscles around the penis, which are nec- essary for erections and copulation (Figure 16.7). Consequently, the motor neurons in the lumbar region of the spinal cord of the male rat (collec- tively called the spinal nucleus of the bulbocaver- nosus [SNB]) are approximately four times larger than in the female. These motor neurons regress in the female shortly after birth. Similar regression occurs with castrated males, although androgen SNB treatment will preserve the motor neurons. The dendrites of the motor neurons have exten- FIGURE 16.7 l A. The male rat has bulbocavernosus sive branchings that make connections spanning muscles that are needed to control the penis for several spinal segments. Cutting the SNB motor copulation. B. Cross sections of the female and male lumbar spinal cord show the presence of the spinal neurons results in regression of the dendrites. nucleus of the bulbocavernosus for the male, but not Previous research has shown that testosterone or the female (A. Adapted from Breedlove SM, Arnold AP. BDNF can limit the dendritic regression. Hormonal control of a developing neuromuscular Yang et al. took this a step further. They cut system. II. Sensitive periods for the androgen- the SNB motor neurons in castrated males. Then induced masculinization of the rat SNB. J Neurosci. 1983;3(2):424-432.) they put BDNF over the cut axons or administered testosterone, or both, in different groups of rats. A month later, the motor neurons were injected with the dynamic quality of the brain. The leader in this a marker that allows visualization of the dendrites research is Fernando Nottebohm at the Rockefeller and axons after the animal is sacrificed. Figure 16.8 University in New York. He and others wanted to represents a computer-generated composite sec- understand why male songbirds sing and females tion marking the presence of the SNB motor neu- seldom do. rons for the three groups of rats. The BDNF plus They initially looked at the syrinx (vocal cords) testosterone group preserved substantially more trying to find out the differences, but without suc- dendritic branching than seen with either alone cess. Later, they focused on the neuronal mecha- (similar to what would be seen in a normal con- nisms that control singing: the high vocal center trol). This suggests that BDNF and testosterone (HVC), robust nucleus (RA), and area X. These act synergistically to maintain the SNB motor nuclei send projections to the XII cranial nerve neuron morphology. which controls the syrinx. Lesions of the HVC bilaterally will silence a bird. Songbirds The big discovery came when they realized The study of the sexually dimorphic brain structures that the song nuclei are approximately three of the songbirds is one of the great stories of neu- times larger in males (Figure 16.9). This was the roscience—one that transformed our recognition of first discovery of sexual dimorphism in the brain. 01546_ch16_p188-202.indd 194 12/26/12 1:47 PM  Chapter 16 l Sex and the Brain 195 controlled by the testosterone. Evidence to support this include the following: Testosterone 1. The nuclei of the adult song system have high concentrations of testosterone. 2. Adult males with higher testosterone sing more than the adults with less testosterone. 3. Females given testosterone will sing more and show increased volume of their HVC and RA. 4. Drops in testosterone levels at the end of the breeding season correspond with the death of HVC neurons. BDNF Hypothalamus The hypothalamus is instrumental in regulating gonadotropin secretion. Specifically, the anterior aspect of the hypothalamus is known to control a wide variety of mating behaviors: desire, sexual behavior, and parenting. Lesions in this area can lead to alterations in sexual behavior. The preop- tic area (POA) in the rat is an area where signifi- Testosterone cant differences between the sexes are found (see and BDNF Figure 2.8). In the male rat, the POA is five to seven times larger than in the female. The differ- ence is so prominent that it can be accurately iden- tified with the naked eye. This region of the POA is called the sexually dimorphic nucleus of the preop- tic area (SDN-POA). Female rats given androgens will develop an SDN-POA approximately the size of that of a male. As with the SNB motor neurons, FIGURE 16.8 l Composite lumbar cross it appears that the androgens preserve the nerve sections showing the extent of spinal nucleus of the bulbocavernosus motor neurons that remain cells, which otherwise waste away. 1 month after surgical excision. Testosterone plus brain-derived neurotrophic factor preserved more of Humans the motor neurons than either alone. (Adapted from Allen et al. examined the anterior aspect of the hypo- Yang LY, Verhovshek T, Sengelaub DR. BDNF and androgen interact in the maintenance of dendritic thalamus in a postmortem analysis of 22 human morphology in a sexually dimorphic rat spinal brains: half of each sex. They focused their atten- nucleus. Endocrinology. 2004;145(1):161-168.) tion on an area that is the human equivalent of the rat SDN-POA. They identified four cell groupings within the anterior hypothalamus, which they called Furthermore, they showed that the size of the HVC the interstitial nuclei of the anterior hypothalamus correlates with the number of song syllables a male (INAH). They numbered the INAH from 1 to 4 and canary sings. reported that INAH-2 and INAH-3 are approximately Their next discovery has fundamentally altered twice as large in males compared with females. the way we think about the brain. Adult canaries Figure 16.10 shows the actual comparative micro- change their songs every year, which is accom- graphs through the INAH of males and females. plished by adding new syllable types and discarding others. Remarkably, this occurs through the birth Sexual Orientation and death of neurons in the song nuclei. Nottebohm Simon LeVay took this work one step further and et al. were the first to show that working neurons compared the INAH for females, heterosexual males, develop in adult warm-blooded vertebrates— and homosexual males. He confirmed the work by an idea that received a cool reception when first Allen et al., that is, two of the four interstitial nuclei presented in 1984. are sexually dimorphic. However, even more inter- The reason for discussing this topic in this esting, he found that INAH-3 was twice as large chapter is the fact that much of the differences in in heterosexual men as it was in homosexual men. the male canaries’ nuclei and song production are Although this provides compelling evidence that 01546_ch16_p188-202.indd 195 12/26/12 1:47 PM  196 SECTION III l Behaviors Male Female HVC HVC X X RA RA I XI XI I To syrinx To syrinx FIGURE 16.9 l The difference in the song nuclei in canaries explains why males sing but females rarely do. HVC, high vocal center; RA, robust nucleus. (Adapted from Nottebohm F. The road we travelled: discovery, choreography, and significance of brain replaceable neurons. Ann N Y Acad Sci. 2004;1016:628-658.) INAH 1 and 2 INAH 3 and 4 Paraventricular 3 1 nucleus Hypothalamus 4 2 3&4 1 3 4 1&2 2 Third ventricle Optic chiasm Paraventricular nucleus FIGURE 16.10 l Representative micrographs showing the interstitial nuclei of the anterior hypothalamus for women (top) and men (bottom). Note that INAH numbers 2 and 3 are less distinct in women. (From Allen LS, Hines M, Shryne JE, et al. Two sexually dimorphic cell groups in the human brain. J Neurosci. 1989;9(2):497-506.) 01546_ch16_p188-202.indd 196 12/26/12 1:47 PM  Chapter 16 l Sex and the Brain 197 sexual orientation is “hardwired,” we must be cau- 10,000 tious for there could be other explanations. For One female to male transsexual example, almost all of the homosexual men died of acquired immunodeficiency syndrome (AIDS), 8,000 whereas only approximately one-third of the het- erosexual men died of AIDS. Likewise, there Number of neurons was considerable overlap in the size of the nuclei 6,000 between groups, implying that it is impossible to predict the sexual orientation of any individual based on the measurement of his INAH-3. Other researchers have addressed this topic in 4,000 different species. Approximately 8% of the domes- tic male sheep display sexual preference for other males. A group in Oregon identified a cluster of 2,000 cells within the POA of the anterior hypothalamus (analogues to the INAH) that is significantly larger in rams than in ewes. They compared these nuclei 0 for rams with different sexual preferences and M F Male CAS Pre-men Post-men found it was twice as large in heterosexual rams to as it was in homosexual rams. Hence, an animal Female model that is consistent with the work by LeVay. More recently, a group in Amsterdam (the capi- FIGURE 16.11 l Postmortem analysis of the number of neurons in the INAH-3 nucleus for males tal of the sex trade industry) examined the INAH-3 (M), females (F), male-to-female transsexual, and nucleus from the brains of individuals with and castrated males due to prostate cancer (CAS). All without gonadotropin hormones compared with the women are separated by menopausal status in male-to-female transsexual individuals with com- the last two bars. One female to male transsexual pleted sex reassignment surgery. The volume of is included with the males. (Adapted from Garcia- Falgueras A, Swaab DF. A sex difference in the the INAH-3 nucleus was larger in the males com- hypothalamic uncinate nucleus: relationship to pared with females and transsexual subjects. Fur- gender identity. Brain. 2008;131:3132-3146.) thermore, they counted the neurons in the nucleus for each group and found a similar relationship as shown in Figure 16.11. Figure 16.12 is an example of one such observa- Taken together, the above studies suggest a tional study with humans. This was a study of more possible explanation for the continuum of human than 3,000 elderly people from one county in Utah. sexual behavior. Small differences in nuclei in the The objective was to test for the development of anterior hypothalamus produce significant differ- Alzheimer’s disease and see if a history of hormone ences in sexual identity and behavior. Early expo- sure to sexual hormones during critical periods or other environmental factors or genetics may alter Treatment HOMOSEXUALITY the development of nuclei that steer one’s sexual orientation and preferences. A few mental health professionals across the country offer treatment for individuals who PSYCHIATRIC DISORDERS want to be heterosexual rather than homo- Cognitive Decline sexual. Hardly any studies exist that establish There is considerable evidence that estrogens (and the effectiveness of such treatment. However, presumably testosterone) are neuroprotective. Robert Spitzer has published a survey of 200 Figure 16.6 shows the robust increase in spine for- individuals who claim to have changed their mation that can be induced by estrogen in hippocam- sexual orientation. Many reported chang- pal neurons. Presumably, such an arborization of ing from predominantly or exclusively homo- the neurons enhances neural connections. Research sexual to predominantly heterosexual. Few with rodents and nonhuman primates demonstrates reported complete changes. Is it possible beneficial effects of estrogen on cognition. Multiple that some motivated individuals were able to observational studies in humans have found that change their brain or were they not actually hormone replacement protects against the devel- homosexual at the start? Only prospective opment of Alzheimer’s disease, although there are studies will answer this controversial question. other risks of continued hormone replacement. 01546_ch16_p188-202.indd 197 12/26/12 1:47 PM  198 SECTION III l Behaviors 0.12 Women No HRT Point of Interest 0.10 Estimated incidence HRT Use 10 y 0.06 hormones of pregnancy trigger changes in the POA and hippocampus of the mater- 0.04 Men nal brain. These changes may explain why 0.02 mother rats perform better on tests of mem- ory (navigating a maze) than virgin rats of 0 similar age. Has nature developed a mecha- 65 70 75 80 85 90 95 100 nism to make mothers smarter caregivers? Age available for premature ejaculation. For example, FIGURE 16.12 l A prediction of the incidence of Alzheimer’s disease calculated from data collected the selective serotonin reuptake inhibitors make about men and women over 3 years shows the it harder to have an orgasm, although they are beneficial effects of sex hormones. HRT, hormone not U.S. Food and Drug Administration (FDA) replacement therapy. (Adapted from Zandi PP, approved for this indication. Carlson MC, Plassman BL, et al. HRT and incidence of Alzheimer’s disease in older women: the Cache Lack of interest in sex, on the other hand, is County Study. JAMA. 2002;288(17):2123-2129.) difficult to treat. Certainly, the qualities of the relationship, secondary medical conditions, and the presence of other psychiatric disorders have replacement therapy (HRT) was protective. Note strong influences on the joy of sex. However, some that the men (who presumably maintain adequate women find sex lacking. As many as one in three levels of sex hormones) fare better than the women women never or infrequently achieve orgasm dur- in terms of developing Alzheimer’s disease. Like- ing intercourse—the number is still only one in wise, the women who took HRT displayed a five with masturbation. Studies with twins show a dose–response effect. That is, the longer a woman genetic component to orgasmic ability. Estimated took HRT the less likely she was to develop heritability for difficulty achieving orgasm dur- Alzheimer’s disease. ing intercourse is 34%—on par with anxiety and Clinical trials of HRT and cognition have not depressive disorders (see Table 6.1). been as uniformly positive as we would hope. Dopaminergic mechanisms may play a large A review of the studies suggests that unopposed role in modulating sexual drive and orgasmic estrogen improves the verbal memory in women quality. As discussed in Chapter 12, the dopamine younger than 65 years. For older women, the pathways to the nucleus accumbens are active in results are neutral. Janicki and Schupf, in a recent motivated behavior. Dopamine agonists such as review of hormonal influences on cognition and the stimulant medications and cocaine are anec- Alzheimer’s progression, concluded that “overall dotally reported to enhance human sexual behav- data from epidemiologic studies, observational ior. More recently, genetic studies have shown that studies and clinical trials of HRT, studies of endog- different genotypes of the dopamine D4 receptor enous hormones, and evaluation of genetic vari- correlate more or less closely with sexual desire ants involved in estrogen biosynthesis and receptor and arousal. This suggests that biology as well activity indicate that estrogen plays an important as environmental signals (in close proximity to role in the pathogenesis of cognitive decline and Mr or Miss Right) interact to determine the sexual risk for Alzheimer’s Disease in both men and experience. women.” So while estrogen may not be the panacea The prospect of giving women an approved for preventing Alzheimer’s disease, it does appear medication to enhance sexual desire, although of to have some neuroprotective benefits. interest to the pharmaceutical industry and feared by domineering fathers everywhere, is currently Sexual Dysfunction not an option. The phosphodiesterase-5 inhibi- A survey of adults between the ages of 18 and 59 in tors (e.g., Viagra) have been tested in large tri- the United States found a high prevalence of sexual als for female sexual dysfunction and failed to dysfunction: 31% for men and 43% for women. enhance the interest any more than placebo. The The most common complaint for men was prema- testosterone patch, although effective for some ture ejaculation, whereas for women it was lack patients, failed to win the FDA approval owing to of interest. There are pharmacologic interventions safety concerns. 01546_ch16_p188-202.indd 198 12/26/12 1:47 PM  Chapter 16 l Sex and the Brain 199 Recent research suggests that a-melanocyte– solicitations, establishing that its effects are medi- stimulating hormone (a-MSH) may be, what ated centrally. Additionally, a-MSH activated the some call, a genuine aphrodisiac. We mentioned in Fos proteins (markers of gene expression) in the Chapter 11 that a large precursor neuropeptide in POA of the hypothalamus as well as the nucleus the pituitary gland, proopiomelanocortin (POMC), accumbens—areas that would be consistent with is cleaved to form active neuropeptides, which sexual pleasure. include ACTH, b-endorphin, and a-MSH (see Figure 16.13). a-MSH is the peptide that Mood Disorders also causes the skin to darken in patients with The lifetime prevalence of mood disorders in Addison’s disease and also suppresses appetite women is approximately twice that of men. (see Chapter 13). The story is told that a company Although the cause of this difference remains was testing a melanocortin product as a possible undetermined, one possible explanation is the sex tanning agent that did not require sun exposure. hormones—or more specifically, the fluctuation During early testing the medication triggered erec- in sex hormones. Figure 16.14 shows the altera- tions in most of the men. Eureka! Subsequently, a tions in estrogen levels for a hypothetical woman peptide analog of a-MSH called bremelanotide (a across her life span. The times of greatest risk for melanocortin receptor agonist) was developed for mood disturbances are during times of fluctuating further study. estrogen levels: menarche, premenstrual syndrome Research with animals has shown that bremela- (PMS), postpartum, and perimenopausal. notide enhances female sexual solicitation in rats. The correlation between dropping sex hor- The female rats became overtly flirtatious in a mones and depressive symptoms is not limited to rodent sort of way—even climbing through little women. The difference is the fluctuations. Men holes in the walls to get to the males. A study typically have stable testosterone levels. However, with married women in Iran (of all places) using when testosterone drops, psychiatric symptoms an intranasal spray to administer the medication become more prevalent. In one veterans admin- reported greater intercourse satisfaction in those istration (VA) study, the researchers followed up receiving the active medication. Unfortunately, the testosterone level and emergence of depressive testing has been halted due to increased blood pres- illness in men older than 45 for 2 years. They found sure in a few subjects. The company is considering that 22% of the hypogonadal men (total testoster- subcutaneous administration as a means to elimi- one