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Try out PMC Labs and tell us what you think. Learn More. Biological differences between men and women contribute to many sex-specific illnesses and disorders. Historically, it was argued that such differences were largely, if not exclusively, due to gonadal hormone secretions. However, emerging research has shown that some differences are mediated by mechanisms other than the action of these hormone secretions and in particular by products of genes located on the X and Y chromosomes, which we refer to as direct genetic effects. This paper reviews the evidence for direct genetic effects in behavioral and brain sex differences.
We also discuss novel research being done on unique populations including people attracted to the same sex and people with a cross-gender identity.
As science continues to advance our understanding of biological sex differences, a new field is emerging that is aimed at better addressing the needs of both sexes: gender-based biology and medicine. Ultimately, the study of the biological basis for sex differences will improve healthcare for both men and women. Men and women are different in many ways. These differences include both biological phenotypes [e.
Some of these differences are influenced by environmental factors [ 3 ; 4 ]. Yet, there are fundamental differences between the sexes that are rooted in biology. Of particular interest are sex differences that have been identified in the brain. Although the brains of men and women are highly similar, they show consistent differences that have important implications for each sex. That is, brain sex differences uniquely affect biochemical processes, may contribute to the susceptibility to specific diseases, and may influence specific behaviors.
Such biological differences should never be used to justify discrimination or sexism. However, we believe that a thorough understanding of these differences can inform researchers and clinicians so that they can better address important issues. Two examples include how genetic sex can lead to differences between the sexes in the etiology and the progression of disease and how differences in neural development may result in differences in cognition and behavior. First, we will highlight some sex differences at the biological level and at the psychological level. Finally, we will discuss novel approaches to studying sex differences by focusing on unique groups of individuals: people with sex-chromosome variations e.
There are many biological differences between males and females that are beyond the obvious differences at a gross, macro level e. Specifically, there are several important physiological differences that have critical implications including the susceptibility to different diseases and the ability to metabolize different medications. In this section we will highlight some sex differences in neuroanatomy and neurochemistry. The two Women want sex Castella have similar but not identical brains. Most brain studies have focused on gross manifestations of these differences—namely the size of specific regions or nuclei.
Yet, there is mounting evidence of sex differences at a finer level including differences in synaptic patterns [ 5 ; 6 ] and neuronal density [ 7 ; 8 ; 9 ]. It is beyond the scope of this article to provide a comprehensive review of all known neuoranatomical differences. We have provided notable sex differences in the rat brain in Table 1.
There are also excellent resources for those who are interested in delving deeper into this topic [ 10 ; 11 ; 12 ]. Conflicting evidence concerning the examples reported here particularly in the SDN-POA exist, and the interpretation of the data is often more complicated than this summary implies. We have chosen to focus on neuroanatomical differences in the rat because the biological ificance and origins of these differences are much clearer than in humans.
Neuroanatomical differences in humans are also well-studied although ethical reasons preclude the experimental manipulations that have led to the findings detailed in Table 1. This ificantly limits the conclusions that can be drawn from any observations made in humans.
Although these neuroanatomical differences are intriguing, most are limited because the practical or functional ificance of these findings are unknown. Women want sex Castella the ificance of these differences is often difficult, even in rodents.
A highly relevant case study highlighted in their review concerns the sexually dimorphic nucleus of Women want sex Castella preoptic area SDN-POA. The preoptic area POA has been implicated in the regulation of male copulatory behavior [ 14 ], but the link if any between the sex difference in SDN-POA size and behavior remains elusive. Masculinizing the size of the SDN-POA in female rats does not result in a corresponding masculinization and defeminization of behavior [ 15 ]. Instead, the SDN-POA may be related to inhibition of female sexual behaviors [ 16 ; 17 ], which might not have been an obvious hypothesis given what was known about the POA ly.
As science and technology continue to advance, we will eventually know how to make sense of the mounting evidence of sex differences in the brain. For now, it is reasonable to suspect that such differences may help for observed sex differences in behavior, neurological diseases, and cognitive abilities. SDN-POA exist, and the interpretation of the data is often more complicated than this summary implies. Males and females exhibit different patterns of transmitting, regulating, and processing biomolecules.
Table 2 presents some of the neurochemical sex differences that have been identified. As a specific example, we focus below on the monoaminergic system, which has been implicated in several neurological diseases and mental disorders that differentially affect men and women.
Monoamines are a class of small-molecule neurotransmitters that are involved in the control of a variety of processes including reproduction and sexual behavior [ 51 ; 52 ], respiration [ 53 ], and stress responses [ 54 ]. Monoamines have also been implicated in numerous mental disorders, including ones that differentially affect men and women [ 55 ; 56 ].
Likewise, sex differences in the monoaminergic systems in the rat are well-documented. Reisert and Pilgrim provided a comprehensive review of arguments for the genetic bases of these differences [ 57 ]. Monoamines are subdivided into two groups—catecholamines and indolamines—based on their molecular structure. The main catecholamines are dopamine DAnorepinephrine NE and epinephrine, which are synthesized from the amino acid tyrosine.
Figure 1 highlights some of the known sex differences of the dopaminergic system. Regulation of dopamine can potentially control the levels of the other two catecholamines as they are Women want sex Castella from dopamine. A Chronic physical stress in sexually dimorphic responses. Dopamine DA activity is upregulated exclusively in males flight blue arrow while norepinephrine activity is upregulated exclusively in females yellow arrow [ 58 ].
Only males experience impaired memory. B Control of TH expression differs between the sexes. SRY, the testis determining gene, which is not found in females, directly regulates TH expression in males [ 49 ; ]. Aromatase activity is more responsive to dihydrotestosterone DHT in males than in females dark blue arrow [ ].
When the rats reach daythe direction of this difference is reversed. Catecholamines are released by the adrenal glands usually in response to stress, which affects males and females differently. For instance, chronic physical stress impairs memory in male rats only [ 58 ]. The sexes also show differing neurochemical responses: Dopamine activity is upregulated in males only whereas norepinephrine is upregulated in females only Figure 1A. Sex differences have also been found in the regulation and modification of dopamine see Figures 1B and 1C. Specifically, the enzyme tyrosine hydroxylase THwhich is involved in dopamine synthesis [ 59 ], is regulated by Sry —the male sex determination gene—which is not present in females.
Additionally, levels of norepinehrine in the amygdala differ between the sexes as a result of age. Thus, it is likely that brain catecholaminergic responses to stress might also differ between the sexes. Another monoamine is serotonin, which is an indolamine. Unlike catecholamines, serotonin is derived from the amino acid tryptophan. The serotonergic system shows sex differences Figure 2though many of these differences remain unlinked to behavioral differences between men and women. Nevertheless, differences in this system likely have consequences given the link between serotonin and numerous mental disorders [ 60 ; 61 ].
Serotonin 5-HT is sexually differentiated on multiple levels. In addition to the differences illustrated above, some of the loci that influence 5-HT levels in the blood are also sexually dimorphic [ 66 ].
In addition to biological differences, men and women differ in many psychological and behavioral aspects. For instance, men perform better on specific visuospatial aspects e. Furthermore, there is a large sex difference in sexual interests and behaviors, such as interest in casual sex, interest in multiple sex partners, and interest in visual-sexual stimuli e. Other examples are summarized in Table 3. Some contend that these differences are due to social systems and gender socialization [cf.
Nevertheless, biological traits likely contribute to many sex differences. Thus, a thorough understanding of the main determinants involved in expression of such sex differences can help us better explain the relationship between brain, Women want sex Castella, and environment. In addition, it allows us to determine how one's sex potentially influences the risk of developing disorders that manifest and progress differently in men and women. Such knowledge can better inform the treatment of these diseases.
Researchers have examined what contributes to the differences we see between males and females. Certainly for humans, social environments influence some of these differences. For instance, social stratifications e. However, social factors alone do not contribute to all differences seen between males and females—especially regarding biological differences [ ]. The life sciences have elucidated many factors that contribute to sex differences.
In this section, we briefly review the classical view that gonadal hormones contribute to most, if not all, sex differences after gonadal differentiation. We will then present some findings that have challenged this view. Sexual development in mammals can be divided into two main components: sex determination and sex differentiation [ ].
Unlike sex determination, sex differentiation is driven by gonadal hormones. It was widely believed that sex differences that emerged after sex determination were largely due to the actions of gonadal hormones. The classical view was based on decades of compelling research demonstrating the organizational and activation effects of gonadal hormones in vertebrates [ ; ].
For instance, the neonatal surge of testosterone in male rodents le to life-long changes in the synaptic pattern of the ventrolateral ventromedial hypothalamic nucleus [ 47 ]. Recently, it was found that gonadal hormones might not be the sole contributor to male- and female-typical development. Genes encoded on the sex chromosomes that directly act on the brain to influence neural developmental and sex-specific behaviors have been identified—an example of what we describe as direct genetic effects [ ; ].
When we use this term, we refer to effects arising from the expression of X and Y genes within non-gonadal cells that result in sex differences in the functions of those cells or target cells. Such direct genetic actions are wide-ranging and can include effects of locally produced hormones or other non-hormonal messenger molecules. For example, sex differences arising in the brain from differential paracrine secretion of neurosteroids would be considered a direct genetic effect. The commonality among these actions is that they are not dependent on mediation by hormones secreted by the gon.
In many cases, the identity of the messenger molecules have yet to be identified. This review will now focus on examples in which sex differences in behaviors are unlikely to be influenced by only the action of gonadal hormonal secretions and may in fact be due to direct genetic effects.
The idea that factors other than the gonadal hormone milieu could for sex differences first gained credence from research performed on the zebra finch. In zebra finches, males exhibit courtship behaviors that are unique to their sex.
Specifically, they possess the ability to sing a distinct courtship song. This male-specific ability has been attributed to several brain regions that are larger in males compared to females [ ; ]. Given the hypothesis that such differences must have been the result of sex-specific hormones, several researchers unsuccessfully attempted to alter the courtship behavior of finches by manipulating hormone levels [ ]. For example, it was shown that castrated male zebra finches were not ificantly different from intact male zebra finches in terms of song development [ ]. Furthermore, female zebra finches that developed testes continued to develop feminine song circuitry and did not exhibit masculine song behavior [ ; ].
Several other experimental manipulations led researchers to question the role of hormones. For instance, Jacobs et al. Interestingly, estrogen treatment was not able to cause full masculinization of the neural circuitry of the zebra finch song system the song circuitry was still smaller compared to control males [ ; ] and supraphysiological doses of estrogen were required for full masculinization [ ].
Similarly, it was shown that inhibiting the action of estrogen by using aromatase blockers in males did not completely prevent the male differentiation pathway [ ; ; ; ; ]. The discovery of a rare type of zebra finch provided further support for a new hypothesis Women want sex Castella sexual differentiation: The bilateral gynandromorphic finch has male-typical phenotypes on one half of the body e.
Each half of such finches is either entirely genetically male or genetically female.
Thus, each side contains the sex-specific genes necessary for the development of the corresponding sex-specific traits. In this model, while the gonadal hormonal actions in producing sex differences in the brain cannot be completely ruled out both sides of the neural song system were larger than that of normal femalestheir influences cannot fully explain the differences observed between the left and right sides of the brain. Given this explanation, the most reasonable theory is that endogenous genetic differences in the brain cells themselves can also contribute to the unequal differentiation of the two sides producing sex differences through their local action within the brain [ ].
Recent work on gynandromorphic chickens strengthens the case that the classical view largely does not apply to sexual differentiation in birds. Zhao et al. In mammals, transplantation of somatic cells from one sex into the gonad of the other sex reverses the sex identity of the donor somatic cells.
For example, XX cells can develop into functioning Sertoli cells while XY cells can become functioning granulosa cells [ ; ]. The host and donor somatic cells were exposed to the same hormones, but they responded differently based on their respective sex chromosome complement.
A second exception to the classical view that we highlight below concerns the development of the tammar wallaby. As with brain development, gonadal hormones drive the sex-specific development of the external genitalia in most mammals. Specifically, androgens promote the development of male genitalia.Women want sex Castella
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The Genetics of Sex Differences in Brain and Behavior