No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Brain responses to sexual images in 46,XY women with complete androgen insensitivity syndrome are female-typical
Abstract
Androgens, estrogens, and sex chromosomes are the major influences guiding sex differences in brain development, yet their relative roles and importance remain unclear. Individuals with complete androgen insensitivity syndrome (CAIS) offer a unique opportunity to address these issues. Although women with CAIS have a Y chromosome, testes, and produce male-typical levels of androgens, they lack functional androgen receptors preventing responding to their androgens. Thus, they develop a female physical phenotype, are reared as girls, and develop into women. Because sexually differentiated brain development in primates is determined primarily by androgens, but may be affected by sex chromosome complement, it is currently unknown whether brain structure and function in women with CAIS is more like that of women or men. In the first functional neuroimaging study of (46,XY) women with CAIS, typical (46,XX) women, and typical (46, XY) men, we found that men showed greater amygdala activation to sexual images than did either typical women or women with CAIS. Typical women and women with CAIS had highly similar patterns of brain activation, indicating that a Y chromosome is insufficient for male-typical human brain responses. Because women with CAIS produce male-typical or elevated levels of testosterone which is aromatized to estradiol these results rule out aromatization of testosterone to estradiol as a determinate of sex differences in patterns of brain activation to sexual images, We cannot, however, rule out an effect of social experience on the brain responses of women with CAIS as all were raised as girls.
... The studies of sexual behavior and spatial skills in adults with CAIS also provide evidence for prenatal androgen effects on brain activation. In one study, control men had greater amygdala activation during the viewing of sexual images than did control women or women with CAIS (N = 39), with both groups of women providing similar arousal ratings after viewing the images (Hamann et al., 2014), consistent with sex differences in this task (Hamann et al., 2004). In another study, control men (N = 30) outperformed (i.e., had faster reaction times) and had greater parietal activation during a mental rotation task than did both control women (N = 29) and women with CAIS (N = 21) (van Hemmen et al., 2016), consistent with a relatively large literature on sex differences in spatial skills (reviewed in . ...
... Owing to the rarity of the diseases, age ranges are often large. For instance, ages ranged from 3 to 36 years in a structural study of individuals with CAH (Nass et al., 1997), and CAIS women were on average 38 years old compared to 28-year-old control women in a functional study (Hamann et al., 2014). This is usually addressed by covarying age in statistical analyses, but a single linear variable is unlikely to conceptually equate children and adults (Miller & Chapman, 2001). ...
... Regarding design, if the goal of a study is to detect neural mechanisms underlying prenatal androgen influences on behavior, then functional data should be collected while individuals are engaging in that behavior in the scanner; in other words, opportunities to detect prenatal androgen influences on brain function are maximized by examining behaviors that evidence prenatal androgen effects. This has been done in studies of CAIS on sexual behavior and spatial skills (Hamann et al., 2014;van Hemmen et al., 2016). In functional studies of CAH, however, the focus has been on emotion (Ernst et al., 2007;Mazzone et al., 2011), which shows a sex difference but not a clear pattern of prenatal androgen effects. ...
Sex hormones, especially androgens, contribute to sex and gender differences in the brain and behavior. Organizational effects are particularly important because they are thought to be permanent, reflecting hormone exposure during sensitive periods of development. In human beings, they are often studied with natural experiments in which sex hormones are dissociated from other biopsychosocial aspects of development, such as genes and experiences. Indeed, the greatest evidence for organizational effects on sex differences in human behavior comes from studies of females with congenital adrenal hyperplasia (CAH), who have heightened prenatal androgen exposure, female‐typical rearing, and masculinized toy play, activity and career interests, spatial skills, and some personal characteristics. Interestingly, however, neuroimaging studies of females with CAH have revealed few neural mechanisms underlying these hormone‐behavior links, with the exception of emotion processing; studies have instead shown reduced gray matter volumes and reduced white matter integrity most consistent with other disease‐related processes. The goals of this narrative review are to: (a) describe methods for studying prenatal androgen influences, while offering a brief overview of behavioral outcomes; (b) provide a critical methodological review of neuroimaging research on females with CAH; (c) present an illustrative analysis that overcomes methodological limitations of previous work, focusing on person‐specific neural reward networks (and their associations with sensation seeking) in women with CAH and their unaffected sisters in order to inform future research questions and approaches that are most likely to reveal organizational hormone effects on brain structure and function.
... In the present study, we explore gender and sexual orientation differences in 2D:4D ratio, and the relationship between the 2D:4D ratio and early versus late attention to sexually preferred stimuli in an eye-tracking paradigm. Chivers (2017), based on previous findings (Dawson & Chivers, 2016;Hamann et al., 2014;Vásquez-Amézquita et al., in press), hypothesised that lower prenatal androgenisation could be related to non-specific response patterns in terms of preferred gender, whereas greater prenatal androgenisation would be associated with greater gender-specific response. Therefore, we predicted that men and women of any sexual orientation with low (more masculinized) 2D:4D ratios would fixate faster (initial orientation) and longer (late attention) on bodies, and especially sexual areas (face, chest and pelvis) of sexually preferred stimuli than men and women with high ratios. ...
... There are two plausible and related explanations: 2D:4D ratio is not an accurate marker of prenatal androgen exposure (Bailey et al., 2016;Hampson & Sankar, 2012), or prenatal androgen exposure has a weak effect on sexual orientation and sexual behaviour, although that conflicts with recent evidence (i.e. Hamann et al., 2014;Zheng & Cohn, 2011). Berenbaum, Bryk, Nowak, Quigley, and Moffat (2009), who analysed XY men without normal exposure to prenatal testosterone due to androgen insensitivity syndrome, found that digit ratios were significantly higher in these men compared to typical men and similar to those of typical women, with moderate effect sizes but great withingroup variability. ...
... Even if there is a relationship between prenatal androgen exposure and 2D:4D ratios, there may be no association between digit ratios and some sexual dimorphic characteristics and behaviours, even though there is evidence suggesting both are influenced by prenatal sex hormones (e.g., Hamann et al., 2014). A possible explanation could be a difference of developmental timing between 2D:4D ratios and sex-typical characteristics (Cohen-Bendahana et al., 2005;Puts et al., 2004); if true, this could lead to a weak correlation between them, making 2D:4D a limited predictor of traits mediated by sex hormones such as sexual orientation and some sex-typical behaviours, which could be also influenced by additional factors, including postnatal hormone circulation, and socialisation (Chivers, 2017;Hamann et al., 2014). ...
Digit ratio (2D:4D) is a marker of prenatal androgenic exposure that is correlated with different behaviour patterns. Here, we explore the relationship between 2D:4D ratio and early versus late attention to sexually preferred stimuli using an eye-tracking paradigm with 78 androphilic or gynephilic men and women. We simultaneously presented preferred and non-preferred adult stimuli and assessed visual attention across time to first fixation and total duration fixation on entire body and three specific areas (face, chest and pelvis), and investigated whether digit ratio was related to visual attentional biases towards sexually preferred stimuli. As expected, participants tended to fixate faster and for more time on the preferred gender. However, we found no significant interactions between 2D:4D and attentional biases towards the preferred gender, for any measure of attention. These results suggest that attention towards the preferred gender is not related to the 2D:4D digit ratio.
... It is well documented that 46,XY individuals with CAIS due to AR mutations are phenotypically female (Meyer-Bahlburg, 1999;Zhu and Imperato-McGinley, 2004a;Byne, 2006;Gooren, 2006), and CAIS individuals are as satisfied with sexual function as normal women (Wilson et al., 2011). Moreover, recent studies using functional magnetic resonance imaging (fMRI) indicate that the brain functions in CAIS individuals are similar to normal females (van Hemmen et al., 2014;Hamann et al., 2014). This data collectively suggests that androgen action, but not the Y chromosome itself, is the primary factor in controlling male gender development. ...
... This sex deference in brain activation by a mental rotation test has also been reported by other investigators using fMRI analysis (Hoppe et al., 2012;van Hemmen et al., 2014). To date, using fMRI, a sex difference in brain activation has been observed via many other stimulations such as sexual images (Hamann et al., 2014), visual stress challenge (Goldstein et al., 2015), visual memory test (Spalek et al., 2015), novel voxel-wise measure of functional connectivity (Scheinost et al., 2015), visceral pain (Theysohn et al., 2014), etc. Taken together, these studies have provided strong objective evidence to support a sex difference in the functional organization of the brain in addition to the known sex difference in brain structures (Goy and McEwen, 1980;Sacher et al., 2013). ...
... They confirmed a sex-difference in neural activation during mental rotation in the control men and women group and revealed that individuals with CAIS had a female-like neural activation pattern, suggesting feminization of the brain in CAIS individuals. With similar approach, Hamann et al. (2014) reported that men and women were different in brain activation to sex-arousing stimuli and individuals with CAIS had highly similar neural activation as normal women by fMRI analysis. These results collectively argue against a direct role for sex chromosome complement and favor the influence of gonadal hormones on sexual differences in cognitive functions and behaviors. ...
Male sex development is a complex process of events involving genetic, epigenetic, and hormonal factors with androgens playing a major role. The formation of testes in 46,XY individuals establishes the male gonadal sex. Hormones produced by the testes, especially testosterone and anti-Mullerian hormone, play essential roles in male sex differentiation; conversely, defects in the production and action of these hormones result in disorders of sex development (DSD). In this chapter, the genetic, epigenetic, and hormonal factors controlling male sex determination and differentiation are reviewed. By discussing subjects with defects in androgen production and action, particularly those with 17beta-hydroxysteroid dehydrogenase-3 deficiency, 5alpha-reductase-2 deficiency, and androgen insensitivity syndrome, the roles of androgens in male sex differentiation, gender identity, and cognitive function are emphasized. The issue of the complex interaction of nature versus nurture is addressed.
... Human brain structure, specifically gray matter morphometry, has for instance been associated with fetal testosterone levels in boys at age 8-11 years in some, but not all, sexually differentiated brain regions (Lombardo et al. 2012), and with androgens (with unknown timing) in a study in boys with early androgen excess due to familial male precocious puberty (Mueller et al. 2011). In several species androgens masculinize and defeminize the brain after being aromatized to estrogens (reviewed in Baum 1979), whereas studies in human primates and rare clinical conditions in humans suggest that androgens act directly, that is, by activation of the androgen receptor (AR), in the development of the human brain (Cohen-Bendahan et al. 2005;Wallen 2005;Baum 2006;Hamann et al. 2014;van Hemmen et al. 2016). The absence of androgens during early development would induce female-typical neural development, although in mice a role for estrogens in feminizing the brain has recently been suggested (Brock et al. 2011). ...
... Despite testosterone concentrations within or above the male range (Melo et al. 2003;Doehnert et al. 2015), CAIS results in a female phenotype and nearly all women with CAIS are androphilic (sexually attracted to men), have a female gender identity, and show female-typical gender role behavior (Masica et al. 1971;Wisniewski et al. 2000;Hines et al. 2003). Two functional MRI (fMRI) studies in women with CAIS revealed a female-typical activation pattern in response to sexual images (Hamann et al. 2014) and during mental rotation (van Hemmen et al. 2016). This indicates that sex differences in regional brain function related to these tasks are most likely not directly driven by genetic sex, but rather reflect differences in sex hormone exposure. ...
... Taken together, the female-typical FA in women with CAIS is in agreement with previous findings in neural activity patterns in response to visual sexual stimuli and mental rotation performance (Hamann et al. 2014;van Hemmen et al. 2016). The present findings thus argue against a dominant role for sex chromosome Figure 1. ...
Sex differences have been described regarding several aspects of human brain morphology; however, the exact biological mechanisms
underlying these differences remain unclear in humans. Women with the complete androgen insensitivity syndrome (CAIS), who
lack androgen action in the presence of a 46,XY karyotype, offer the unique opportunity to study isolated effects of sex hormones
and sex chromosomes on human neural sexual differentiation. In the present study, we used diffusion tensor imaging to investigate
white matter (WM) microstructure in 46,XY women with CAIS (n = 20), 46,XY comparison men (n = 30), and 46,XX comparison women (n = 30). Widespread sex differences in fractional anisotropy (FA), with higher FA in comparison men than in comparison women,
were observed. Women with CAIS showed female-typical FA throughout extended WM regions, predominantly due to female-typical
radial diffusivity. These findings indicate a predominant role of sex hormones in the sexual differentiation of WM microstructure,
although sex chromosome genes and/or masculinizing androgen effects not mediated by the androgen receptor might also play
a role.
... They lack functional androgen receptors preventing the receptors to respond to androgens, developing a female physical phenotype, leading to a discrepancy between their genetic sex and genital appearance. Hamann et al. (2014) compared brain responses to images of heterosexual behavior, self-reported by all participants as sexually arousing, of CAIS women, typically developing women, and men. They showed that brain patterns of women with CAIS were highly like typically developing women but differed from brain patterns of men. ...
... A few studies reported a women's previous experience with watching visual sexual stimuli (Archer et al., 2006;Hamann et al., 2014;Woodard et al., 2013). Although not studied in fMRI research before, it might be interesting to examine whether women experienced with watching visual sexual stimuli are more sexually aroused by explicit sexual stimuli. ...
Abstract
Most of the neuroimaging studies on sexual behavior have been conducted with male participants, leading to men-based models of sexual arousal. Here, possible factors and methodological decisions that might influence brain responses to sexual stimuli, specifically for the inclusion of women, will be reviewed. Based on this review, we suggest that future studies consider the following factors: menstrual phase, hormonal contraception use, history of sexual or psychiatric disorders or diseases, and medication use. Moreover, when researching sexual arousal, we suggest future studies assess sexual orientation and preferences, that women should select visual sexual stimuli, and a longer duration than commonly used. This review is thought to represent a useful guideline for future research in sexual arousal, which hopefully will lead to a higher inclusion of women and therefore more accurate neurobiological models of sexual arousal.
... However, it is also possible that changes in psychosexuality observed across adolescence are organized by pubertal sex hormones. In this view, just as prenatal hormone action permanently alters psychology and behavior in rodents (Beatty et al., 1981;Gandelman, 1980;Isgor and Sengelaub, 1998;Matochik et al., 1994;Matsumoto et al., 2003;Sato et al., 2004) and humans (Hamann et al., 2014;Hines et al., 2004;Mueller et al., 2008;Resnick et al., 1986), peripubertal hormone action similarly exerts organizational effects that persist regardless of circulating hormone milieu in adulthood (for reviews, see Berenbaum and Beltz, 2011;Sisk and Zehr, 2005). ...
... If subsequent experimental work were to show that the timing of pubertal testosterone (rather than simply its presence or absence) modulated the magnitude of such organizational effects on neural structure and function, then this could be a viable mechanism by which earlier pubertal timing drives more maletypical psychosexuality in adulthood. There is evidence in humans that amygdalar function is sensitive to androgen exposure, such that increased androgen during early development predicts higher amygdalar activity in response to sexual images (Hamann et al., 2004(Hamann et al., , 2014. Thus, it is possible that amygdalar structure and function are also modulated by pubertal timing. ...
Evidence suggests that psychosexuality in humans is modulated by both organizational effects of prenatal and peripubertal sex steroid hormones, and by activational effects of circulating hormones in adulthood. Experimental work in male rodents indicates that sensitivity to androgen-driven organization of sexual motivation decreases across the pubertal window, such that earlier puberty leads to greater sex-typicality. We test this hypothesis in typically developing men (n = 231) and women (n = 648), and in men (n = 72) and women (n = 32) with isolated GnRH deficiency (IGD), in whom the precise timing of peripubertal hormone exposure can be ascertained via the age at which hormone replacement therapy (HRT) was initiated. Psychosexuality was measured with the Sexual Desire Inventory-2 (SDI-2) and Sociosexual Orientation Inventory-Revised (SOI-R). In both sexes, earlier recalled absolute pubertal timing predicted higher psychosexuality in adulthood, although the magnitude of these associations varied with psychosexuality type and group (i.e., typically developing and IGD). Results were robust when controlling for circulating steroid hormones in typically developing participants. Age of initiation of HRT in men with IGD negatively predicted SOI-R. We discuss the clinical implications of our findings for conditions in which pubertal timing is medically altered.
... Using a more scientifically unbiased approach to assess sexual response, and perhaps orientation in women with CAIS, a recent study focused on neural activation in response to viewing sexual images. Supporting the notion of predominantly heterosexual feelings in CAIS, it was found that women with this condition more closely resembled 46,XX heterosexual females than 46,XY males (Hamann et al., 2014). Functional MRI (fMRI) scans revealed that both 46,XY women with CAIS and 46,XX women had decreased amygdala activation when viewing nude male images or couples engaging in coitus. ...
... Functional MRI (fMRI) scans revealed that both 46,XY women with CAIS and 46,XX women had decreased amygdala activation when viewing nude male images or couples engaging in coitus. The results of this study were the first to establish that the brains of CAIS women more functionally resembled those of typical females, further indicating that testosterone responsiveness (and not the Y chromosome) is the most likely driver for establishing gynephilic preference and androphilic-typical brain activation toward sexual stimuli in humans (Hamann et al., 2014). ...
Sex differences in brain development and postnatal behavior are determined largely by genetic sex and in utero gonadal hormone secretions. In humans however, determining the weight that each of these factors contributes remains a challenge because social influences should also be considered. Cases of disorders of sex development (DSD) provide unique insight into how mutations in genes responsible for gonadal formation can perturb the subsequent developmental hormonal milieu and elicit changes in normal human brain maturation. Specific forms of DSDs such as complete androgen insensitivity syndrome (CAIS), congenital adrenal hyperplasia (CAH), and 5α-reductase deficiency syndrome have variable effects between males and females, and the developmental outcomes of such conditions are largely dependent on sex chromosome composition. Medical and psychological works focused on CAH, CAIS, and 5α-reductase deficiency have helped form the foundation for understanding the roles of genetic and hormonal factors necessary for guiding human brain development. Here we highlight how the three aforementioned DSDs contribute to brain and behavioral phenotypes that can uniquely affect 46,XY and 46,XX individuals in dramatically different fashions.
... Wallen and his colleagues again focused on the amygdala and determined that males have greater activation of this region in response to viewing sexual stimuli than do females (Hamman et al., 2004). Furthermore, 46, XY women with complete androgen insensitivity syndrome are female-typical in response to visual sexual stimuli, with less activation of the amygdala compared to males (Hamann et al., 2014). Thus, Wallen extended his research program to consider central effects and to consider how his research in monkeys translates to humans. ...
Eberhard (Ebo) Gwinner was a German ornithologist and chronobiologist. Following his doctorate in classical ethology, further formative experiences included postdoctoral training in biological rhythms and behavioral endocrinology. Gwinner combined these backgrounds to coin his trademark, integrative research on biological timekeeping under both natural and experimental conditions. He is most recognized for his seminal work and persistently authoritative monography on circannual rhythms. Gwinner also elaborated contributions of reproductive and adrenocortical hormones to avian annual cycle behavior, and his studies of multiple pacemaker interactions and the role of melatonin contributed majorly to understanding circadian systems. Gwinner pioneered many fields that unfolded beyond his lifetime, for example, research on light pollution and urbanization in wild organisms. Across subjects, much of his research revolved around bird migration, a topic that fascinated him throughout his lifetime and that he studied in daring and persistent experiments across continents.KeywordsCircannualCircadianMulti-pacemakerInternal resonanceMelatoninMigrationBehaviorBird
... Of course there are other methods to assess organizational hormone effects on the human brain, most prominently comparing individuals with endocrine conditions to unaffected individuals (e.g. congenital adrenal hyperplasia,Beltz et al., 2021; complete androgen insensitivity syndrome,Hamann et al., 2014; isolated gonadotropin-releasing hormone deficiency,Swift-Gallant et al., 2021;Shirazi et al., 2021;Shirazi et al., 2022) and also methods involving otoacustic emissions(McFadden & Pasanen, 1998) or auditory evoked potentials(McFadden & Champlin, 2000).Content courtesy of Springer Nature, terms of use apply. Rights reserved. ...
Objective
Organizational hormone effects on the human brain and behavior are often retrospectively assessed via morphological markers of prenatal (e.g., 2D:4D digit ratio) or pubertal (e.g., facial width-to-height ratio, fWHR) hormone exposure. It has been argued that markers should relate to circulating hormones particularly in challenging, dominance/status-relevant situations. However, meta-analytic research indicates that fWHR, a frequently used pubertal marker, is neither reliably sex-dimorphic nor related to steroid hormones. This casts doubt on fWHR’s validity for reflecting hormone levels. Ulna-to-fibula ratio (UFR), an alternative, long-bone-length-based pubertal marker, is sex-dimorphic and associated with dominance motivation. However, its hormonal associations were never tested before. We therefore explored UFR’s relationships to baseline and reactive hormone levels.
Methods
We measured ulna and fibula length as well as shoulder/waist/hip circumference of 81 participants (49 women; after exclusions) via anthropometry. Salivary hormone levels (estradiol, testosterone) at baseline and after a gross-motor one-on-one balancing contest were measured via radioimmunoassay.
Results
We replicated UFR’s dimorphism, unrelatedness to height, and correlations to other putative markers of organizational hormone effects. On an exploratory basis, we found UFR to be related to overall baseline testosterone and to competition-induced reactive surges in steroid hormones (estradiol, testosterone) overall and in women.
Conclusions
Our results hint at UFR’s relationship to baseline testosterone and may indicate functional connections between outcomes of pubertal organizational hormone effects and contest-induced steroid reactivity. Pubertal organizational hormone effects may prepare the endocrine system for dominance and status contests. However, the small sample and the exploratory nature of our research demands replication.
... In functional neuroimaging, patterns in women with CAIS do seem to be more in line with control women in activation while viewing sexually arousing stimuli (Hamann et al., 2014) and while performing a mental rotation task (van Hemmen et al., 2014). This similarity is generally assigned to the effects of sex hormones because, again, women with CAIS, being insensitive to testosterone, display a female-typical instead of a male-typical pattern. ...
Intersex conditions or disorders/differences of sex development (DSD) are conditions in which the development of chromosomal, gonadal and/or genital characteristics is atypical. Studies in individuals with DSD conditions may provide valuable insights on the roles played by sex chromosomes, sex hormones, sex anatomy and gender of rearing in the development of gender role and gender identity. An overview is given regarding various aspects that may be influenced in individuals with DSD conditions: play behaviour, activities, interests, cognitive functioning and brain development. Furthermore, we will highlight gender development across the DSD spectrum by describing the literature regarding gender identity and expression in individuals with DSD conditions. Gender dysphoria and gender change are more prevalent in individuals with DSD conditions. These findings have also been important in the debate around gender assignment in individuals born with ambiguous genitalia. In addition, we will describe sexual development, as sex-atypical physical appearance, hormone replacement therapy, past surgical interventions, and psychological issues may all affect sexuality. Recent developments show there is more room for gender diversity in society. A less binary approach to gender may also positively influence feelings regarding gender in variations of sex development.KeywordsDisorders of sex developmentDifferences of sex developmentIntersex conditionsGender role behaviourGender identityGender expressionGender assignmentGender dysphoriaGender developmentSexual development
... Another relevant condition is complete androgen insensitivity syndrome (CAIS), which is an immunity to the effects of androgens at all stages of development. Genetic males with CAIS typically report sexual orientations toward males (Wisniewski et al., 2000) and show neural responses to both male and female sexual stimuli, and therefore have female-typical sexual responses (Hamann et al., 2014). Thus, levels of early androgen exposure may affect not only the development of general sex differences, but also the formation of sexual orientation and sexual arousal patterns within each sex Breedlove, 2010). ...
In general, women show physiological sexual arousal to both sexes. However, compared with heterosexual women, homosexual women are more aroused to their preferred sex, a pattern typically found in men. We hypothesized that homosexual women’s male-typical arousal is due to their sex-atypical masculinization during prenatal development. We measured the sexual responses of 199 women (including 67 homosexual women) via their genital arousal and pupil dilation to female and male sexual stimuli. Our main marker of masculinization was the ratio of the index to ring finger, which we expected to be lower (a masculine pattern) in homosexual women due to increased levels of prenatal androgens. We further measured observer- and self-ratings of psychological masculinity–femininity as possible proxies of prenatal androgenization. Homosexual women responded more strongly to female stimuli than male stimuli and therefore had more male-typical sexual responses than heterosexual women. However, they did not have more male-typical digit ratios, even though this difference became stronger if analyses were restricted to white participants. Still, variation in women's digit ratios did not account for the link between their sexual orientation and their male-typical sexual responses. Furthermore, homosexual women reported and displayed more masculinity than heterosexual women, but their masculinity was not associated with their male-typical sexual arousal. Thus, women’s sexual and behavioral traits, and potential anatomical traits, are possibly masculinized at different stages of gestation.
... In addition, the presence of a Y chromosome in CAIS patients lacking androgen action may contribute to differences in neuronal networks involved in sexual desire. However, several neuroimaging studies have shown that CAIS patients have feminized brains ( (22,23,24), although some masculine features have been observed (25) consistent with a direct effect of Y chromosome genes. Thus, CAIS women may depend more on the central aromatization of testosterone to estradiol than non-CAIS women. ...
Complete androgen-insensitivity syndrome (CAIS), a disorder of sex development (46,XY DSD), is caused primarily by mutations in the androgen receptor ( AR ). Gonadectomy is recommended due to the increased risk of gonadoblastoma, however, surgical intervention is often followed by loss of libido. We present a 26-year-old patient with CAIS who underwent gonadectomy followed by a significant decrease in libido, which was improved with testosterone treatment but not with estradiol. Genetic testing was performed and followed by molecular characterization. We found that this patient carried a previously unidentified start loss mutation in the androgen receptor. This variant resulted in an N-terminal truncated protein with an intact DNA binding domain and was confirmed to be loss-of-function in vitro . This unique CAIS case and detailed functional studies raise intriguing questions regarding the relative roles of testosterone and estrogen in libido, and in particular, the potential non-genomic actions of androgens.
Learning points
N-terminal truncation of androgen receptor can cause androgen-insensitivity syndrome.
Surgical removal of testosterone-producing gonads can result in loss of libido.
Libido may be improved with testosterone treatment but not with estradiol in some forms of CAIS.
A previously unreported AR mutation – p.Glu2_Met190del (c.2T>C) – is found in a CAIS patient and results in blunted AR transcriptional activity under testosterone treatment.
... For instance, individuals with an XY karyotype and complete androgen insensitivity syndrome (CAIS), which results in insensitivity to androgens throughout the lifespan, typically report sexual orientations toward men with the same frequency as genetic women (Wisniewski et al., 2000), and do not differ from genetic females in a wide range of psychosexual measures, such as gender identity and gender role behavior in both childhood and adulthood (Hines et al., 2003). Additionally, individuals with XY karyotype and CAIS show neural responses to both male and female sexual stimuli, and therefore have female-typical (nonspecific) sexual responses (Hamann et al., 2014). Thus, if levels of early androgen exposure influence the development of sex differences, in general (Breedlove, 2010;Motta-Mena & Puts, 2017;Puts & Motta-Mena, 2018), then they could possibly also affect sex differences in the specificity of their sexual arousal. ...
Most men show sexual arousal to one, preferred sex, whereas most women respond to both sexes, regardless of their sexual orientation. A different research program indicates that men have lower second-to-fourth finger length ratios (2D:4D) than women, possibly because men are exposed to higher levels of androgens during prenatal development. We hypothesized that sex differences in sexual arousal patterns are influenced by prenatal androgen exposure and would thus be explained by sex differences in 2D:4D. We measured the sexual response patterns of 139 men and 179 women via genital arousal and pupil dilation to erotic videos, in addition to their 2D:4D. Compared to women, men showed stronger responses to one sex over the other, although this pattern was clearer in genital arousal than pupil dilation. Men also had lower 2D:4D than women. However, there was no evidence that sex differences in sexual arousal related to sex differences in 2D:4D. Thus, whichever factor explains sex differences in sexual arousal patterns may not be reflected in 2D:4D.
... The study of natural quasi-experiments in humans, or people in whom hormone production or action is congenitally altered such as those with congenital adrenal hyperplasia (CAH; Hines, 2010;Hines et al., 2004;Puts et al., 2008) or androgen insensitivity syndrome (Hamann et al., 2014;Hines et al., 2003), have proved critical to our understanding of hormone-driven organization of the brain and behavior. This paper presents the first examination of a human disease model wherein pubertal timing can be objectively determined to study links between peripubertal hormone exposure and adult phenotypes. ...
Experiments in male rodents demonstrate that sensitivity to the organizational effects of steroid hormones decreases across the pubertal window, with earlier androgen exposure leading to greater masculinization of the brain and behavior. Similarly, some research suggests the timing of peripubertal exposure to sex steroids influences aspects of human psychology, including visuospatial cognition. However, prior studies have been limited by small samples and/or imprecise measures of pubertal timing. We conducted 4 studies to clarify whether the timing of peripubertal hormone exposure predicts performance on male-typed tests of spatial cognition in adulthood. In Studies 1 (n = 1095) and 2 (n = 173), we investigated associations between recalled pubertal age and spatial cognition in typically developing men, controlling for current testosterone levels in Study 2. In Study 3 (n = 51), we examined the relationship between spatial performance and the age at which peripubertal hormone replacement therapy was initiated in a sample of men with Isolated GnRH Deficiency. Across Studies 1-3, effect size estimates for the relationship between spatial performance and pubertal timing ranged from. -0.04 and -0.27, and spatial performance was unrelated to salivary testosterone in Study 2. In Study 4, we conducted two meta-analyses of Studies 1-3 and four previously published studies. The first meta-analysis was conducted on correlations between spatial performance and measures of the absolute age of pubertal timing, and the second replaced those correlations with correlations between spatial performance and measures of relative pubertal timing where available. Point estimates for correlations between pubertal timing and spatial cognition were -0.15 and -0.12 (both p < 0.001) in the first and second meta-analyses, respectively. These associations were robust to the exclusion of any individual study. Our results suggest that, for some aspects of neural development, sensitivity to gonadal hormones declines across puberty, with earlier pubertal hormone exposure predicting greater sex-typicality in psychological phenotypes in adulthood. These results shed light on the processes of behavioral and brain organization and have implications for the treatment of IGD and other conditions wherein pubertal timing is pharmacologically manipulated.
... When adult, women with CCAH experience increased sexual arousal to women [58] together with increased sexual dysfunction [172], while retaining female gender identity [172]. 46,XY women lacking bioeffective androgen receptors (CAIS), in contrast, are born with intraabdominal testes, are indistinguishable from 46,XX girls and women in terms of body habitus (except for absence of body hair), as well as female gender identify and sexual orientation [173], and exhibit only one minor difference in fMRI-assessed neural responses to sexually arousing images [174]. The fMRI-related difference, however, is not male-like. ...
Indian rhesus macaque nonhuman primate models for polycystic ovary syndrome (PCOS) implicate both female hyperandrogenism and developmental molecular origins as core components of PCOS etiopathogenesis. Establishing and exploiting macaque models for translational impact into the clinic, however, has required multi-year, integrated basic-clinical science collaborations. Paradigm shifting insight has accrued from such concerted investment, leading to novel mechanistic understanding of PCOS, including hyperandrogenic fetal and peripubertal origins, epigenetic programming, altered neural function, defective oocytes and embryos, adipogenic constraint enhancing progression to insulin resistance, pancreatic decompensation and type 2 diabetes, together with placental compromise, all contributing to transgenerational transmission of traits likely to manifest in adult PCOS phenotypes. Our recent demonstration of PCOS-related traits in naturally hyperandrogenic (High T) female macaques additionally creates opportunities to employ whole genome sequencing to enable exploration of gene variants within human PCOS candidate genes contributing to PCOS-related traits in macaque models. This review will therefore consider Indian macaque model contributions to various aspects of PCOS-related pathophysiology, as well as the benefits of using macaque models with compellingly close homologies to the human genome, phenotype, development and aging.
... 157 One study found that brain activity only related to anticipation or expectancy was dependent on the menstrual cycle phase, such that the strongest anticipatory brain responses were recorded in women who were in their luteal phase; women in their follicular phase or women on oral contraceptives showed less modulation. 135 Two studies investigated the effect of sex steroid administration on VSS-induced brain activity and suggested that testosterone is the primary hormone modulating the strength of brain responses to VSS. 146,158 ...
The article consists of 6 sections written by separate authors that review female genital anatomy, the physiology of female sexual function and the pathophysiology of female sexual dysfunction but excluding hormonal aspects.
Aim. To review female sexual function - physiology and pathophysiology- especially since 2010 and to make specific recommendations with levels of evidence ( Oxford Centre) where relevant.
Conclusion. Despite numerous lab assesssments of female sexual function, genital assessments alone appear insufficient to characterise fully the complete sexual response.
... With the exception of emotion recognition, our and other studies indicate that women with XY chromosomes have a predominantly female typical cognitive profile. This harmonizes with MR imaging research on brain connectivity which shows a female-typical activation pattern when solving spatial tasks (van Hemmen et al., 2014), female-typical amygdala activation (Hamann et al., 2014), and an anatomy more similar to that of female controls than that of male controls (Savic et al., 2017) in females with CAIS. Women with CAIS, XYGD and XXGD also live in a female gender role (de Vries et al., 2007;Mazur, 2005), and, with few exceptions, identify as females (Brunner et al., 2015). ...
Background:
Many questions regarding the mechanisms behind sex differences in cognitive abilities are still unanswered. On a group level, men typically outperform women on certain spatial tasks, whereas women perform better on certain tests of memory and verbal ability. The prevailing theories concerning the biological predispositions for these and other differences in behaviour and brain function focus on early and prolonged exposure to sex hormones. There is, however, evidence of direct effects of sex chromosomes on sex-typical behaviour in other species.
Objectives:
To study the influence of sex hormones and sex chromosomes on cognition in women with Complete androgen insensitivity (CAIS) and Gonadal dysgenesis (GD).
Methods:
Eighteen women with CAIS, 6 women with 46,XYGD, and 7 women with 46,XXGD were compared with age-matched male and female controls on tests of spatial and verbal abilities, memory functions, and emotion recognition.
Results:
Women with CAIS, XYGD, and XXGD performed similar to female controls on cognitive tasks. However, on a test of emotion recognition, women with XXGD outperformed the other groups, whereas women with CAIS and XYGD performed similar to male controls.
Conclusion:
Our results support theories of androgen effects on cognitive abilities and suggest that factors related to sex chromosomes may influence emotion recognition. Implications of an atypical sex hormone situation and sex chromosome variation are discussed.
... Testosterone is seen as the gonadal hormone most pertinent to human sexual responsiveness [45,46]. Indeed, brains of genetic men without androgen function (complete androgen insensitivity syndrome, "46XY women") responded in a typical female-like fashion to visual erotic stimulation, that is, similar to male controls but at weaker strength [47]. Because in both 46XY and genetic women, there is less central testosterone function than in men; it was concluded that testosterone rather than genetic sex determines brain activity patterns during sexual stimulation. ...
Purpose of Review
The purpose of this study is to provide a comprehensive summary of the latest developments in the experimental brain study of human sexuality, focusing on brain connectivity during the sexual response.
Recent Findings
Stable patterns of brain activation have been established for different phases of the sexual response, especially with regard to the wanting phase, and changes in these patterns can be linked to sexual response variations, including sexual dysfunctions. From this solid basis, connectivity studies of the human sexual response have begun to add a deeper understanding of the brain network function and structure involved.
Summary
The study of “sexual” brain connectivity is still very young. Yet, by approaching the brain as a connected organ, the essence of brain function is captured much more accurately, increasing the likelihood of finding useful biomarkers and targets for intervention in sexual dysfunction.
... They even develop attractive breasts at puberty by peripheral metabolization of testosterone into estrogen [46]. As cerebral receptors will also be absent, androgen imprinting does not appear to happen in most of them and hence they develop unambiguous female GI [47]. Therefore, it is appropriate to raise CAIS boys as girls. ...
Sex assignment in 46XY genetic male children with congenital inadequacy of the penis (CIP) is controversial. Traditionally, children with penile length less than 2 cm at birth are considered unsuitable to be raised as males. They are typically re-assigned to female-sex and feminizing genitoplasty is usually done in infancy. However, the concept of cerebral androgen imprinting has caused paradigm shift in the philosophy of sex re-assignment. Masculinization of the brain, rather than length of the penis, is the modern criterion of sex re-assignment in CIP. This review summarizes the current understanding of the complex issue. In 46XY children with CIP, male-sex assignment appears appropriate in non-hormonal conditions such as idiopathic micropenis, aphallia and exstrophy. Female-sex re-assignment appears acceptable in complete androgen insensitivity (CAIS), while partial androgen insensitivity syndrome (PAIS) patients are highly dissatisfied with the assignment of either sex. Children with 5-alpha reductase deficiency are likely to have spontaneous penile lengthening at puberty. Hence, they are better raised as males. Although female assignment is common in pure gonadal dysgenesis, long-term results are not known to justify the decision.
... Une virilisation plus ou moins complète est également observée pour les individus XX souffrant d'hyperplasie congénitale des glandes surrénales (CAH) qui ont, dès le début de leur développement, une augmentation de la production de testostérone surrénalienne (Speiser & White, 2003). De façon plus flagrante, les individus XY n'ayant plus d'AR fonctionnel (AIS abordé précédemment) ont une structure cérébrale, un comportement et un profil cognitif « féminin » (Hamann et al. 2014;Hines et al. 2003). Il en est de même pour les hommes XY souffrant d'un déficit de production de la DHT (Collaer & Hines, 1995). ...
La déficience intellectuelle (DI) et les troubles du spectre autistique (ASD) sont deux troubles neurodéveloppementaux (NDD) présentant de nombreux chevauchements génétiques et phénotypiques ainsi qu’un biais de sexe important, avec plus de garçons atteints (1,4x plus pour la DI et 4x plus pour l'ASD). Au sein de notre laboratoire, le taux de diagnostic des patients souffrant de DI et/ou d’ASD est significativement plus élevé chez les filles que chez les garçons. De façon surprenante, nous n’avons pas observé de différence significative entre filles et garçons au niveau de la proportion de mutations pathogènes sur le chromosome X (5,3% versus 7,6%), confirmant ainsi que les mutations causales totalement pénétrantes sur ce chromosome ne peuvent pas expliquer la totalité de l’excès de garçons atteints de DI ou d'ASD. Nous avons donc choisi d’étudier une autre des hypothèses, plus environnementale, qui pourrait rendre le cerveau masculin plus susceptible au développement de NDD : le rôle des androgènes au cours du développement du cerveau. J'ai étudié l’effet de ces hormones masculines dans des précurseurs neuronaux humains (hNSCs) et observé que les androgènes augmentent la prolifération des hNSCs et les protègent contre la mort cellulaire en conditions stressantes. J'ai également mis en évidence que les androgènes, via leur récepteur (le récepteur aux androgènes), régulent une centaine de gènes dans les hNSCs avec, parmi eux, un enrichissement en gènes connus pour être différentiellement exprimés chez les individus avec ASD (dont NRCAM et FAM107A). La régulation de ces gènes par les androgènes pendant le développement du cerveau pourrait ainsi participer à la sensibilité accrue du cerveau masculin, exposé à d'autres facteurs génétiques et environnementaux, à développer une NDD.
... 157 One study found that brain activity only related to anticipation or expectancy was dependent on the menstrual cycle phase, such that the strongest anticipatory brain responses were recorded in women who were in their luteal phase; women in their follicular phase or women on oral contraceptives showed less modulation. 135 Two studies investigated the effect of sex steroid administration on VSS-induced brain activity and suggested that testosterone is the primary hormone modulating the strength of brain responses to VSS. 146,158 ...
The human female orgasm bestows the greatest pleasure without recourse to drugs. Despite numerous studies there are many aspects of the activity that are poorly understood. These include its neurophysiology and pharmacology, while even its typology, induction, and function(s) are contentious issues. It can be induced by a variety of agencies that include genital and non-genital sites and even by exercise. While there are similarities with the male orgasm, there are a few differences, the major one being that women can have repeated multiple orgasms while males cannot. Despite recurrent speculative claims in the literature, it does not mediate or facilitate sperm transport through its uterine contractions. Brain imaging that measures cerebral regional blood flow has revealed that there is no single orgasm center, but rather specific areas are either activated, inhibited, or unaffected during orgasm. However, no consensus has yet been achieved due to experimental procedural differences and data handling by researchers.
... Given the bulk of research showing an undifferentiated pattern of response to gender cues among androphilic women, a seventh hypothesis, an extension of the neurohormonal hypothesis for sexualorientation,isthatprenatalandrogenexposureisassociatedwith differentiationofresponsepatternsinthedirectionofpreferredgender, and lack of androgen exposure results in no differentiation. In a fMRI study comparing brain responses of androphilic genetically femalewomen, gynephilic genetically male, and androphilic genetic males with complete androgen insensitivity syndrome (CAIS) who were assigned a female gender at birth, and identify and live as women, showed gender-nonspecific brain responses among genetic females and CAISwomen (Hamann et al., 2014).CAIS women lack functional androgen receptors, and therefor their prenatal neurohormonal environment is very similar to natal genetic women's. Indeed CAIS women showed less specificity in brain responses than genetic, androphilic females. ...
Category-specific sexual response describes a pattern wherein the individual shows significantly greater responses to preferred versus nonpreferred categories of sexual stimuli; this pattern is described as gender specific for sexual orientation to gender, or gender nonspecific if lacking response differentiation by gender cues. Research on the gender specificity of women's sexual response has consistently produced sexual orientation effects, such that androphilic women (sexually attracted to adult males) typically show gender-nonspecific patterns of genital response and gynephilic women (sexually attracted to adult females) show more gender-specific responses. As research on the category specificity of sexual response has grown, this pattern has also been observed for other measures of sexual response. In this review, I use the Incentive Motivation and Information Processing Models as complementary frameworks to organize the empirical literature examining the gender specificity of women's sexual response at each stage of sexual stimulus processing and response. Collectively, these data disconfirm models of sexual orientation that equate androphilic women's sexual attractions with their sexual responses to sexual stimuli. I then discuss 10 hypotheses that might explain variability in the specificity of sexual response among androphilic and gynephilic women, and conclude with recommendations for future research on the (non)specificity of sexual response.
... In contrast, Kohler et al. reported that 46,XY female-raised individuals with Partial Androgen Insensitivity Syndrome (PAIS) were more likely to have sexual partners of the same and both sexes, thus further supporting the notion that androgen effects sexual orientation [21]. Interestingly, functional neuroimaging of 46,XY women with CAIS, typical (46,XX) women, and typical (46,XY) men has shown that brain responses of CAIS participants to various tasks (in which responses are usually different between men and women) are similar to typical women, and significantly different to that of typical males [8,38]. In spite of the findings of the latter investigations, however, there are recent studies reporting that psychosexual outcome in people with CAIS is more varied than previously believed. ...
Objective:
To report sexual orientation, relationship status and medical history of Iranian people with Differences of Sex Development (DSD) who were raised female.
Methods:
Our participants consisted of nineteen 46,XY individuals with Complete Androgen Insensitivity Syndrome (CAIS) and eighteen 46,XX individuals with Congenital Adrenal Hyperplasia (CAH) who were raised as females and older than 13years. As well as their relationship status and detailed medical history, an expert psychiatrist assessed their sexual orientation by a semi-structured psychiatric interview with them and, where applicable, their parents.
Results:
Five percent of CAH participants and 42% of CAIS participants were in a relationship, which was significantly different. All CAH individuals had been diagnosed at birth; 89% of CAIS had been diagnosed after puberty and due to primary amenorrhea and 11% were diagnosed in childhood due to inguinal hernia. Genital reconstructive surgery had been performed in 100% of CAH participants and 37% of CAIS. Regarding sexual contact experiences and sexual fantasies (androphilic, gynephilic or both), no significant differences were found. However, CAH females had significantly more gynephilic dreams (P=0.045).
Conclusion:
This study, notable as one of the rare from a non-western culture, described sexual, medical and socioeconomic status of 46,XX CAH and 46,XY CAIS individuals living in Iran. Although broadly in line with previous findings from Western cultures, Iranian CAH individuals had fewer romantic relationships, but in contrast to previous studies their sexual orientation was only different from CAIS in the contents of sexual dreams.
... A knockout of the androgen receptor in XY individuals (complete androgen insensitivity syndrome [CAIS] in humans) alters the body so that it looks completely like that of a female, proving that the masculine structure of many reproductive tissues requires androgen action in males. However, because the XY CAIS girl is reared as a female, one cannot easily separate the biologically and socially mediated effects of the mutation on many attributes that one might measure in CAIS women-for example, their brain function or susceptibility to disease (e.g., Hamann et al., 2014). In addition, differences in social or physical environments are expected to have lasting effects on the epigenome (DNA methylation and modifications of histones), so that the environment alters the readout of the genome (Szyf et al., 2008). ...
A general theory of mammalian sexual differentiation is proposed. All biological sex differences are the result of the inequality in effects of the sex chromosomes, which are the only factors that differ in XX vs. XY zygotes. This inequality leads to male-specific effects of the Y chromosome, including expression of the testis-determining gene Sry that causes differentiation of testes. Thus, Sry sets up lifelong sex differences in effects of gonadal hormones. Y genes also act outside of the gonads to cause male-specific effects. Differences in the number of X chromosomes between XX and XY cells cause sex differences in expression (1) of Xist, (2) of X genes that escape inactivation, and (3) of parentally imprinted X genes. Sex differences in phenotype are ultimately the result of multiple, independent sex-biasing factors, hormonal and sex chromosomal. These factors act in parallel and in combination to induce sex differences. They also can offset each other to reduce sex differences. Other mechanisms, operating at the level of populations, cause groups of males to differ on average from groups of females. The theory frames questions for further study, and directs attention to inherent sex-biasing factors that operate in many tissues to cause sex differences, and to cause sex-biased protection from disease.
... Further research should explore sexual orientation development over the life span in persons with DSD (Brunner et al, 2015), and include possible effects of changing hormone levels at puberty on sexual orientation (Berenbaum and Beltz, 2011). An important related question concerns the ways DSD affect patterns of sexual arousal (Hamann et al., 2014), given that these patterns play significantly different roles in male and female sexuality (Diamond, 2008). and nurture in sexual behavior development is particularly of importance when comparing different species (Wallen, 2005;Baum, 2006;Sisk, 2016). ...
The magnitude of sex differences in human brain and behavior and the respective contributions of biology versus socialization remain a topic of ongoing study in science. The preponderance of evidence attests to the notion that sexual differentiation processes are at least partially hormonally mediated, with high levels of prenatal androgens facilitating male-typed and inhibiting female-typed behaviors. In individuals with Disorders/Differences of Sex Development (DSD), hormonal profiles or sensitivities have been altered due to genetic influences, presumably affecting gender(ed) activity interests as well as gender identity development in a minority of the affected population. While continued postnatal androgen exposure in a number of DSD syndromes has been associated with higher rates of gender dysphoria and gender change, the role of a number of mediating and moderating factors, such as initial gender assignment, syndrome severity and clinical management remains largely unclear. Limited investigations of the associations between these identified influences and gendered development outcomes impede optimization of clinical care. Participants with DSD (n=123), recruited in the context of a Dutch multi-center follow-up audit, were divided in subgroups reflecting prenatal androgen exposure, genital appearance at birth and gender of rearing. Recalled childhood play and playmate preferences, gender identity and sexual orientation were measured with questionnaires and semi-structured interviews. Data were compared to those of control male (n=46) and female participants (n=79). The findings support that (a) prenatal androgen exposure has large effects on (gendered) activity interests, but to a much lesser extent on sexual orientation and that (b) initial gender of rearing remains a better predictor of gender identity contentedness than prenatal androgen exposure, beyond syndrome severity and medical treatment influences. Nonetheless,3.3% of individuals with DSD in our sample self-reported gender dysphoria from an early age and changed gender, which further underlines the need for thorough long- term follow-up and specific clinical support.
... Although the genetic composition between XX women and AIS women varies, female-typical sexual behavior has been observed to be similar in both groups. For example, a neuroimaging study indicated that when these two groups of women were presented with sexually arousing images, both groups exhibited less amygdala activation than male subjects [60]. ...
Sexual differentiation begins in utero with the sex chromosomes dictating subsequent endocrine and physiological effects. Distinctly timed events influence each subsequent developmental phase. Although the sex-dependent developmental paths typically occur in predicted patterns, individual and environmental variations may produce alterations in the expected sex-typical profiles. As aging progresses, males and females experience varying endocrine fluctuations, some with far-reaching consequences and the roots of these variations may be grounded in prior developmental events. In order to understand, study, and treat diseases and disorders that are impacted by sex, an appreciation of the mechanisms of organizational differences between the sexes is essential.
... 157 One study found that brain activity only related to anticipation or expectancy was dependent on the menstrual cycle phase, such that the strongest anticipatory brain responses were recorded in women who were in their luteal phase; women in their follicular phase or women on oral contraceptives showed less modulation. 135 Two studies investigated the effect of sex steroid administration on VSS-induced brain activity and suggested that testosterone is the primary hormone modulating the strength of brain responses to VSS. 146,158 ...
The article consist of six sections written by separate authors that review female genital anatomy, the physiology of female sexual function, the pathophysiology of female sexual dysfunction but excluding hormonal aspects.
Aim: To review the physiology of female sexual function and the pathophysiology of female sexual dysfunction especially since 2010 and to make specific recommendations accordng to the Oxford Centre for evidence based medicine (2009) "levels of evidence" wherever relevant.
Conclusion: Recommendations were made for particular studies to be undertaken especially in controversial aspects in all six sections of the reviewed topics. Despite numerous laboratory assessments of female sexual function, genital assessments alone appear insufficient to characterise fully the complete sexual response.
... Evidence for androgen effects on two aspects of sextyped brain responses comes from women with complete androgen insensitivity syndrome (CAIS) who have a Y chromosome but do not have effective androgen exposure (due to lack of functional androgen receptors). In two separate samples, women with CAIS had femaletypical brain responses to mental rotation [32 ] and to sexually-arousing stimuli [33]; their brain activation patterns were different than those of men and similar to those of typical women, consistent with their low androgen responsiveness and not with possessing a Y chromosome. ...
Many important psychological characteristics show sex differences, and are influenced by sex hormones at different developmental periods. We focus on the role of sex hormones in early development, particularly the differential effects of prenatal androgens on aspects of gender development. Increasing evidence confirms that prenatal androgens have facilitative effects on male-typed activity interests and engagement (including child toy preferences and adult careers), and spatial abilities, but relatively minimal effects on gender identity. Recent emphasis has been directed to the psychological mechanisms underlying these effects (including sex differences in propulsive movement, and androgen effects on interest in people vs things), and neural substrates of androgen effects (including regional brain volumes, and neural responses to mental rotation, sexually arousing stimuli, emotion, and reward). Ongoing and planned work is focused on understanding the ways in which hormones act jointly with the social environment across time to produce varying trajectories of gender development, and clarifying mechanisms by which androgens affect behaviors. Such work will be facilitated by applying lessons from other species, and by expanding methodology. Understanding hormonal influences on gender development enhances knowledge of psychological development generally, and has important implications for basic and applied questions, including sex differences in psychopathology, women's underrepresentation in science and math, and clinical care of individuals with variations in gender expression.
... Data suggest that subjective response patterns differ both with the nature of the assessment method and with the sexual content of the stimuli. That is, women's subjective responses to sexual stimuli are at times discordant with both their physiological responses and their stated sexual preferences, but these discrepancies are not found with certain types of sexual images (Chivers, et al., 2007;Hamann, et al., 2014;Spape et al., 2014). For example, heterosexual women will report subjective arousal to images depicting solo nude women, as well as to images depicting nude men, but Spape et al. (2014) recently showed that for sexual images with little contextual information, that depict only aroused genitals, women show subjective responses that correspond with both their stated sexual preferences and with their physiological responses. ...
Recent work suggests that a woman's hormonal state when first exposed to visual sexual stimuli (VSS) modulates her initial and subsequent responses to VSS. The present study investigated whether women's initial hormonal state was related to their subjective ratings of VSS, and whether this relationship differed with VSS content. We reanalyzed previously collected data from 14 naturally cycling (NC) women and 14 women taking oral contraceptives (OCs), who subjectively rated VSS at three hormonal time-points. NC women's ratings of 216 unique sexual images were collected during the menstrual, periovulatory, and luteal phases of their menstrual cycles, and OC women's ratings were collected at comparable time-points across their pill-cycles. NC women's initial hormonal state was unrelated to their ratings of VSS. OC women's initial hormonal state predicted their ratings for VSS with minimal contextual information and for images depicting female-to-male oral sex. Specifically, women who entered the study in the third week of their pill-cycle (OC-3 women) rated such images as less attractive at all testing sessions than did all other women. OC-3 women were also the only women to rate decontextualized VSS as unattractive at all testing sessions. These results corroborate previous studies in which women's initial hormonal state was found to predict subsequent interest in sexual stimuli. Future work, with larger samples, should more directly investigate whether OC-3 women's negative assessment of specific types of VSS reflects a reaction to the laboratory environment or a broader mechanism, wherein OC women's sexual interests decrease late in their pill-cycle.
Copyright © 2015. Published by Elsevier Inc.
Kim Wallen is an American behavioral neuroendocrinologist known for his studies on sex differences in behavior in rhesus macaques. His work has emphasized the importance of studying animals in naturalistic contexts to understand organizational and activational effects of hormones. Kim Wallen investigated the Organizational Hypothesis in a large study in which animals received flutamide or physiologically relevant doses of testosterone prenatally. He studied the effects of these hormonal manipulations on a wide variety of complex social behaviors. Wallen’s work has provided important information about the timing and sensitivity of social behaviors, hormones, the nervous system, and developmental milestones to prenatal androgens. His work in adult monkeys has challenged the notion that female monkeys are passive during sexual encounters, that females are always motivated to mate, and that androgens regulate female sexual desire. Kim Wallen’s findings have elucidated the importance of social factors and context in studying hormone-behavior relationships.KeywordsOrganizational HypothesisSex differenceSocial contextTestosteroneFlutamideEstrusPubertyVocalizationRough playMating
In this position paper, I argue that current ideological and sociocultural shifts in the use and meaning of the term gender have also reconfigured what biological sex means. Both terms have been made isomorphic and synonymic. The paper challenges this novel relationship, exploring its confounded history and unpacking how and why genderqueer theorists intentionally minimize body knowledge to enable expressive individualism. Linguistic, psychological and medical anthropology serve as tools of inquiry in my critique on why gender is now given the greater valence. Data from neurosciences are also used to refute notions of the body being just a “mute facticity,” as such theorists claim. Christian dogmas on sex and gender are also examined, as is the insistence on a binary model of humanity despite intersex births and the factuality of gender dysphoria. Christian incorrections, when perpetuated without ongoing analysis and change, continue what some call epistemic oppressions and hermeneutic injustices, contributing another layer to the problematic of sex and gender ideology as rendered today.
The origins of sex differences in human behavior have been extensively studied from various theoretical perspectives, and a growing body of evidence has suggested that organization of the brain, and subsequent sex-typed behaviors, are influenced by exposure to sex hormones and the expression of specific genes during early development. Methodological advances in the study of biological bases of sex differences have shed light on mechanisms that influence sex development across the life span, though many questions remain. This chapter provides a general overview of biological approaches to the study of sex differences, with summaries of findings to date and future directions. The emphasis of the chapter is on hormones because that has been the major focus of biological approaches to sex development for decades. The chapter also touches on genetics toward the end given some important emerging work disentangling hormonal effects from genetic effects.KeywordsAndrogensBrain functionBrain structureComplete androgen insensitivity syndromeCongenital adrenal hyperplasiaGender identityGender roleSexual differentiationSex determinationSexual orientation
Widespread sex differences in human brain structure and function have been reported. Research on animal models has demonstrated that sex differences in brain and behavior are induced by steroid hormones during specific, hormone sensitive, developmental periods. It was shown that typical male neural and behavioral characteristics develop under the influence of testosterone, mostly acting during perinatal development. By contrast, typical female neural and behavioral characteristics may actually develop under the influence of estradiol during a specific prepubertal period. This review provides an overview of our current knowledge on the role of steroid hormones in the sexual differentiation of the human brain. Both clinical and neuroimaging data obtained in patients with altered androgen levels/actions, i.e., congenital adrenal hyperplasia (CAH) or complete androgen insensitivity syndrome (CAIS), point to an important role of (prenatal) androgens in inducing typical male neural and psychosexual characteristics in humans. In contrast to rodents, there appears to be no obvious role for estrogens in masculinizing the human brain. Furthermore, data from CAIS also suggest a contribution of sex chromosome genes to the development of the human brain. The final part of this review is dedicated to a brief discussion of gender incongruence, also known as gender dysphoria, which has been associated with an altered or less pronounced sexual differentiation of the brain.
Background:
Spino-bulbar muscular atrophy is a rare genetic X-linked disease caused by testosterone insensitivity. An inverse correlation has been described between testosterone levels and empathic responses. The present study explored the profile of neural empathic responding in spino-bulbar muscular atrophy patients.
Methods:
Eighteen patients with spino-bulbar muscular atrophy and eighteen healthy male controls were enrolled in the study. Their event-related potentials were recorded during an "Empathy Task" designed to distinguish neural responses linked with experience-sharing (early response) and mentalizing (late response) components of empathy. The task involved the presentation of contextual information (painful vs. neutral sentences) and facial expressions (painful vs. neutral). An explicit dispositional empathy-related questionnaire was also administered to all participants, who were screened via neuropsychological battery tests that did not reveal potential cognitive deficits. Due to electrophysiological artefacts, data from 12 patients and 17 controls were finally included in the analyses.
Results:
Although patients and controls did not differ in terms of dispositional, explicit empathic self-ratings, notably conservative event-related potentials analyses (i.e., spatio-temporal permutation cluster analyses) showed a significantly greater experience-sharing neural response in patients compared to healthy controls in the Empathy-task when both contextual information and facial expressions were painful.
Conclusion:
The present study contributes to the characterization of the psychological profile of patients with spino-bulbar muscular atrophy, highlighting the peculiarities in enhanced neural responses underlying empathic reactions.
This chapter provides a developmental perspective to understanding neural and behavioral sex differences, focusing on cognition. There are sex differences in many skills, with sizes depending upon the aspect of cognition; the largest difference is in spatial skills. Differences arise in several ways, including social factors such as experience, genes, and sex hormones present during prenatal life and later in life (e.g., adolescence). There are sex differences in several aspects of brain structure and function, too, although most are small. The origins of these differences and their direct links to cognition are complex but beginning to be understood. Again, sex hormones seem to be a primary contributor. Future work should focus on genetic and hormonal influences on brain sex differences, the links between brain and behavioral (including cognitive) sex differences, and the ways in which brain sex differences are changed by gendered experiences.
Annotation. The purpose of this work — an analysis and a summary of results of scientific research on problems of molecular genetic mechanisms and human sex determination levels. Literature analysis was performed in scientometric databases of Google Scholar, MedLine, Web of Science, Scopus for 2014–2018. Sex determination is a complex multi-stage process secured by functional integration of genetic determinants, products thereof, and the conditions of individual development for its realization. Sexual differentiation occurs at genetic, gonadal, hormonal, somatic, psychological and social levels, and disorders at any of them may lead to deviations from normal sex determination.
Infants born prematurely may lack full term exposure to the prenatal milieu responsible for late-term sexual differentiation, with possible consequences on psychosexual development. This study assessed gender identity, sexual orientation, and adult sexual responses in men and women born either preterm or full term. An online survey was administered to 106 biological males (36 preterm) and 195 biological females (64 preterm). Preterm women identified less exclusively as heterosexual and preterm men reported higher sex interest and shorter orgasmic latency. Preterm birth may interfere with typical prenatal sexual differentiation, with potential effects on sexual orientation and adult sexual responsivity.
Men and women differ, not only in their anatomy but also in their behavior. Research using animal models has convincingly shown that sex differences in the brain and behavior are induced by sex hormones during a specific, hormone-sensitive period during early development. Thus, male-typical psychosexual characteristics seem to develop under the influence of testosterone, mostly acting during early development. By contrast, female-typical psychosexual characteristics may actually be organized under the influence of estradiol during a specific prepubertal period. The sexual differentiation of the human brain also seems to proceed predominantly under the influence of sex hormones. Recent studies using magnetic resonance imaging have shown that several sexually differentiated aspects of brain structure and function are female-typical in women with complete androgen insensitivity syndrome (CAIS), who have a 46 XY karyotype but a female phenotype due to complete androgen resistance, suggesting that these sex differences most likely reflect androgen action, although feminizing effects of estrogens or female-typical socialization cannot be ruled out. By contrast, some male-typical neural characteristics were also observed in women with CAIS suggesting direct effects of sex chromosome genes in the sexual differentiation of the human brain. In conclusion, the sexual differentiation of the human brain is most likely a multifactorial process including both sex hormone and sex chromosome effects, acting in parallel or in combination.
This report of a 46,XY patient born with a micropenis consistent with etiology from isolated congenital growth hormone deficiency is used to (1) raise the question regarding what degree testicular testosterone exposure to the central nervous system during fetal life and early infancy has on the development of male gender identity, regardless of gender of rearing; (2) suggest the obligatory nature of timely full disclosure of medical history; (3) emphasize that virtually all 46,XY infants with functional testes and a micropenis should be initially boys except some with partial androgen insensitivity syndrome; and (4) highlight the sustaining value of a positive long-term relationship with a trusted physician (R.M.B.). When this infant presented, it was commonly considered inappropriate to gender assign an infant male whose penis was so small that an adult size was expected to be inadequate, even if the karyotype was 46,XY, and testes were functional. Concomitantly, female gender assignment was considered the appropriate decision, believing that parental rearing in the assigned gender was considered the major factor determining established adult gender identity. Full disclosure of medical information was considered inappropriate. Progress in appreciating the complexities of gender identity development, which is not yet completely understood, and sexuality, coping ability, and outcome data has resulted in a change of practice in initial gender assignment. A 46,XY individual with functional testes and verified androgen responsiveness should be assigned and reared as male, regardless of penis size. Without androgen responsiveness, the multiple factors must be carefully considered and disclosed.
The role of gonadal steroids in sexual differentiation of the central nervous system (CNS) is well established in rodents, but no study to date has manipulated androgens prenatally and examined their effects on any CNS structure in a primate. Onuf's nucleus is a column of motoneurons in the sacral spinal cord that innervates the striated perineal muscles. This cell group is larger in males than in females of many species, due to androgens acting during a sensitive perinatal period. Here, we examined Onuf's nucleus in 21 adult rhesus monkeys, including control males and females, as well as males whose mothers had been treated with an anti-androgen or testosterone during gestation. We found a robust sex difference, with more motoneurons in control males than in females. The soma size of Onuf's nucleus motoneurons was also marginally larger in males. Treatment with the anti-androgen flutamide for 35-40 days during early gestation partially blocked masculinization of Onuf's nucleus: motoneuron number in flutamide-treated males was decreased relative to control and testosterone-treated males, but remained greater than in females, with no effect on cell size. A control motor nucleus that innervates foot muscles (Pes9) showed no difference in motoneuron number or size between control males and females. Prenatal testosterone treatment of males did not alter Onuf's nucleus motoneuron number, but did increase the size of both Onuf's and Pes9 motoneurons. Thus, prenatal androgen manipulations cause cellular-level changes in the primate CNS, which may underlie previously observed effects of these manipulations on behavior.
Introduction
The article consists of six sections written by separate authors that review female genital anatomy, the physiology of female sexual function, and the pathophysiology of female sexual dysfunction but excluding hormonal aspects.
Aim
To review the physiology of female sexual function and the pathophysiology of female sexual dysfunction especially since 2010 and to make specific recommendations according to the Oxford Centre for evidence based medicine (2009) “levels of evidence” wherever relevant.
Conclusion
Recommendations were made for particular studies to be undertaken especially in controversial aspects in all six sections of the reviewed topics. Despite numerous laboratory assessments of female sexual function, genital assessments alone appear insufficient to characterise fully the complete sexual response.
Introduction
Sex steroids are important in female sexual function and dysfunction.
Aim
To review the role of estrogens in the physiology and pathophysiology of female sexual functioning and the evidence for efficacy of estrogen therapy for female sexual dysfunction to update the previously published International Society of Sexual Medicine Consensus on this topic.
Methods
Panel members reviewed the published literature using online databases for studies pertaining to estrogen in female sexual function and dysfunction. Attention was specifically given to clinical trials that had reported on sexual function outcomes in women treated with estrogen.
Main Outcome Measures
Quality of data published in the literature and recommendations were based on the GRADES system.
Results
Observational studies that have considered relationship factors and physical or mental health have reported that these factors contribute more to sexual functioning than menopausal status or estrogen levels. Few clinical trials have investigated estrogen therapy with sexual function as a primary outcome. The available data do not support systemic estrogen therapy for the treatment of female sexual dysfunction. Topical vaginal estrogen therapy improves sexual function in postmenopausal women with vulvovaginal atrophy (VVA) and is considered first-line treatment of VVA. Oral ospemifene, a selective estrogen receptor modulator, is effective for the treatment of VVA and might have independent systemic effects on female sexual function.
Conclusion
For sexual problems, the treatment of VVA remains the most pertinent indication for estrogen therapy. When systemic symptoms are absent, estrogen therapy ideally can be administered by a vaginal preparation alone. Systemic estrogen therapy with combined estrogen and progestin in non-hysterectomized women is indicated for women who require treatment for vasomotor and/or other systemic estrogen deficiency symptoms. The improvement in well-being achieved by relief of vasomotor and other symptoms might improve libido in some women and abrogate further intervention.
Few studies have examined the impact of androgen insensitivity on human spatial learning and memory. In the present study, we tested 11 women with complete androgen insensitivity syndrome (CAIS), a rare genetic disorder characterized by complete absence of AR activity, and compared their performance against 20 comparison males and 19 comparison females on a virtual analog of the Morris Water Maze task. The results replicated a main sex effect showing that men relative to women were faster in finding the hidden platform and had reduced heading error. Furthermore, findings indicated that mean performance of women with CAIS was between control women and control men, though the differences were not statistically significant. Effect size estimates (and corresponding confidence intervals) of spatial learning trials showed little difference between women with CAIS and control women but CAIS women differed from men, but not women, on two variables, latency to find the platform and first-move latency. No differences between groups were present during visible platform trials or the probe trial, a measure of spatial memory. Moreover, groups did also not differ on estimates of IQ and variability of performance. The findings are discussed in relation to androgen insensitivity in human spatial learning and memory.
In 4 complete androgen insensitivity syndrome (CAIS) members of one family, 2 presented extreme and unusual clinical features: male gender identity disorder (case 1) and female precocious central puberty (case 2). The AR gene carried the mutation c.1752C>G, p.Phe584Leu. Gender dysphoria in CAIS may be considered as a true transgender and has been described in 3 other cases. Central precocious puberty has only been described in 1 case; Müllerian ducts in case 2 permitted menarche. Despite the common CAIS phenotype, there was a familial disparity for gender identity adequacy and timing and type of puberty. © 2015 S. Karger AG, Basel.
Neuroanatomical textbooks typically restrict the central nervous system control of sexual responsiveness to the hypothalamus, brainstem and spinal cord. However, for all its primitive functions human sex is surprisingly complex and versatile. This review aims to extend the neuroanatomy of sexual responsiveness by providing a comprehensive overview of the empirical evidence for cerebral cortical involvement. To this end I will structure relevant human brain research data to fit the sexual pleasure cycle template-wanting sex, having sex, inhibiting sex-arguing that going through these sexual response phases requires adequate shifting between functional cortical networks. The relevance of this notion for understanding certain sexual dysfunctions is discussed. Clin. Anat., 2015. © 2015 Wiley Periodicals, Inc.
© 2015 Wiley Periodicals, Inc.
Androgen insensitivity syndrome in its complete form is a disorder of hormone resistance characterised by a female phenotype in an individual with an XY karyotype and testes producing age-appropriate normal concentrations of androgens. Pathogenesis is the result of mutations in the X-linked androgen receptor gene, which encodes for the ligand-activated androgen receptor--a transcription factor and member of the nuclear receptor superfamily. This Seminar describes the clinical manifestations of androgen insensitivity syndrome from infancy to adulthood, reviews the mechanism of androgen action, and shows examples of how mutations of the androgen receptor gene cause the syndrome. Management of androgen insensitivity syndrome should be undertaken by a multidisciplinary team and include gonadectomy to avoid gonad tumours in later life, appropriate sex-hormone replacement at puberty and beyond, and an emphasis on openness in disclosure.
Sacred values, such as those associated with religious or ethnic identity, underlie many important individual and group decisions in life, and individuals typically resist attempts to trade off their sacred values in exchange for material benefits. Deontological theory suggests that sacred values are processed based on rights and wrongs irrespective of outcomes, while utilitarian theory suggests that they are processed based on costs and benefits of potential outcomes, but which mode of processing an individual naturally uses is unknown. The study of decisions over sacred values is difficult because outcomes cannot typically be realized in a laboratory, and hence little is known about the neural representation and processing of sacred values. We used an experimental paradigm that used integrity as a proxy for sacredness and which paid real money to induce individuals to sell their personal values. Using functional magnetic resonance imaging (fMRI), we found that values that people refused to sell (sacred values) were associated with increased activity in the left temporoparietal junction and ventrolateral prefrontal cortex, regions previously associated with semantic rule retrieval. This suggests that sacred values affect behaviour through the retrieval and processing of deontic rules and not through a utilitarian evaluation of costs and benefits.
In the twentieth century, the dominant model of sexual differentiation stated that genetic sex (XX versus XY) causes differentiation of the gonads, which then secrete gonadal hormones that act directly on tissues to induce sex differences in function. This serial model of sexual differentiation was simple, unifying and seductive. Recent evidence, however, indicates that the linear model is incorrect and that sex differences arise in response to diverse sex-specific signals originating from inherent differences in the genome and involve cellular mechanisms that are specific to individual tissues or brain regions. Moreover, sex-specific effects of the environment reciprocally affect biology, sometimes profoundly, and must therefore be integrated into a realistic model of sexual differentiation. A more appropriate model is a parallel-interactive model that encompasses the roles of multiple molecular signals and pathways that differentiate males and females, including synergistic and compensatory interactions among pathways and an important role for the environment.
Interest in biological substrates of sex-related variations in psychological and physiological characteristics has led to a search for biomarkers of prenatal hormone exposure that can be measured postnatally. There has been particular interest in digit ratio, the relative lengths of the second and fourth fingers (2D:4D), but its validity as a measure of prenatal androgen has not been established. We report the strongest evaluation of the value of 2D:4D as a biomarker for early androgen exposure. Individuals with 46,XY karyotype but no effective prenatal androgen exposure due to complete androgen insensitivity syndrome had digit ratios that were feminized: they were higher than those of typical men and similar to those of typical women. Nevertheless, the effect was modest in size, and there was considerable within-group variability and between-group overlap, indicating that digit ratio is not a good marker of individual differences in prenatal androgen exposure.
I. Introduction IN 1953 lohn Morris, an obstetrician at Yale University, reported a series of 82 individuals (80 cases collated from the literature and two cases of his own) who had a female phenotype despite the presence of bilateral testes (1). Since his initial description, studies of the endocrinology, pathophysiology, biochemistry, and molecular biology of the androgen insensitivity syndrome (AIS) have provided insights into the role of androgens in male sex differentiation, the mechanisms of androgen action, and aspects of the structure/function relationships of the androgen receptor. AIS is an archetypal example of a hormone resistance disorder. Androgens are secreted by the testes of these 46,XY individuals in normal or increased amounts; however, due to defective androgen receptor (AR1) function, there is loss of target organ response to the hormone, and the effects of androgens are reduced or absent. Clinical disorders of the AR are reported far more commonly than resistance disorders of other m...
We evaluated psychological outcomes and gender development in 22 women with complete androgen insensitivity syndrome (CAIS). Participants were recruited through a medical database (n = 10) or through a patient support group (n = 12). Controls included 14 males and 33 females, of whom 22 were matched to women with CAIS for age, race, and sex-of-rearing. Outcome measures included quality of life (self-esteem and psychological general well-being), gender-related psychological characteristics (gender identity, sexual orientation, and gender role behavior in childhood and adulthood), marital status, personality traits that show sex differences, and hand preferences. Women recruited through the database versus the support group did not differ systematically, and there were no statistically significant differences between the 22 women with CAIS and the matched controls for any psychological outcome. These findings argue against the need for two X chromosomes or ovaries to determine feminine-typical psychological development in humans and reinforce the important role of the androgen receptor in influencing masculine-typical psychological development. They also suggest that psychological outcomes in women with CAIS are similar to those in other women. However, additional attention to more detailed aspects of psychological well-being in CAIS is needed.
Men exhibit much higher levels of genital and subjective arousal to sexual stimuli containing their preferred sex than they do to stimuli containing only the nonpreferred sex. This study used event-related functional magnetic resonance imaging to investigate how this category-specific pattern would be reflected in the brains of homosexual (n = 11) and heterosexual (n = 11) men. Comparisons of activation to preferred sexual stimuli, nonpreferred sexual stimuli, and sports stimuli revealed large networks correlated with sexual arousal, spanning multiple cortical and subcortical areas. Both homosexual and heterosexual men exhibited category-specific arousal in brain activity. Within the amygdala, greater preference-related activity was observed in homosexual men, but it is unclear whether this is a cause or a consequence of their sexuality. In a subsequent analysis of regions hypothesized to support arousal, both participant groups demonstrated widespread increases in evoked activity for preferred stimuli. Aggregate data from these regions produced significant differences between stimulus types in 16 out of 22 participants. Significant activational differences matched reported sexual orientation in 15 of these 16 participants, representing an advance in psychophysiological measures of arousal.
Men are generally more interested in and responsive to visual sexually arousing stimuli than are women. Here we used functional magnetic resonance imaging (fMRI) to show that the amygdala and hypothalamus are more strongly activated in men than in women when viewing identical sexual stimuli. This was true even when women reported greater arousal. Sex differences were specific to the sexual nature of the stimuli, were restricted primarily to limbic regions, and were larger in the left amygdala than the right amygdala. Men and women showed similar activation patterns across multiple brain regions, including ventral striatal regions involved in reward. Our findings indicate that the amygdala mediates sex differences in responsiveness to appetitive and biologically salient stimuli; the human amygdala may also mediate the reportedly greater role of visual stimuli in male sexual behavior, paralleling prior animal findings.
This article reviews what is currently known about how men and women respond to the presentation of visual sexual stimuli. While the assumption that men respond more to visual sexual stimuli is generally empirically supported, previous reports of sex differences are confounded by the variable content of the stimuli presented and measurement techniques. We propose that the cognitive processing stage of responding to sexual stimuli is the first stage in which sex differences occur. The divergence between men and women is proposed to occur at this time, reflected in differences in neural activation, and contribute to previously reported sex differences in downstream peripheral physiological responses and subjective reports of sexual arousal. Additionally, this review discusses factors that may contribute to the variability in sex differences observed in response to visual sexual stimuli. Factors include participant variables, such as hormonal state and socialized sexual attitudes, as well as variables specific to the content presented in the stimuli. Based on the literature reviewed, we conclude that content characteristics may differentially produce higher levels of sexual arousal in men and women. Specifically, men appear more influenced by the sex of the actors depicted in the stimuli while women's response may differ with the context presented. Sexual motivation, perceived gender role expectations, and sexual attitudes are possible influences. These differences are of practical importance to future research on sexual arousal that aims to use experimental stimuli comparably appealing to men and women and also for general understanding of cognitive sex differences.
In this study, the authors investigated the hypothesis that women's sexual orientation and sexual responses in the laboratory correlate less highly than do men's because women respond primarily to the sexual activities performed by actors, whereas men respond primarily to the gender of the actors. The participants were 20 homosexual women, 27 heterosexual women, 17 homosexual men, and 27 heterosexual men. The videotaped stimuli included men and women engaging in same-sex intercourse, solitary masturbation, or nude exercise (no sexual activity); human male-female copulation; and animal (bonobo chimpanzee or Pan paniscus) copulation. Genital and subjective sexual arousal were continuously recorded. The genital responses of both sexes were weakest to nude exercise and strongest to intercourse. As predicted, however, actor gender was more important for men than for women, and the level of sexual activity was more important for women than for men. Consistent with this result, women responded genitally to bonobo copulation, whereas men did not. An unexpected result was that homosexual women responded more to nude female targets exercising and masturbating than to nude male targets, whereas heterosexual women responded about the same to both sexes at each activity level.
This chapter provides evidence that this distinction may have heuristic value in understanding the nature of steroidal influences on masculinization and defeminization. Across both types of mammals, defeminization was found to utilize estrogenic metabolites of androgens. However, the evidence of this requirement was stronger in altricial than precocial species. Unambiguous evidence of defeminization by nonaromatizable androgens was found only in the precocial rhesus monkey. The role of aromatization in masculinization was less clear, with little evidence in any species that mounting potential differentiated under either androgenic or estrogenic influence. When all aspects of male sexual and social behavior were considered, altricial species relied more on aromatization for masculinization than precocial species. No evidence was found in human males that the actions of estrogenic compounds were necessary for normal male sexual differentiation. These apparent differences between altricial and precocial species in the hormonal actions producing masculinization and defeminization might be an artifact of which species have become favored laboratory subjects.
Heterosexual women respond genitally to stimuli featuring both their preferred and nonpreferred genders, whereas men's genital responses are gender-specific, suggesting that gender cues are less relevant to women's sexual response. Instead, prepotent sexual features (exposed and sexually-aroused genitals), ubiquitous in audiovisual sexual stimuli, may elicit automatic genital responses, thereby leading to a nonspecific sexual arousal pattern in women. To examine the role of stimulus potency in women's sexual response, we assessed heterosexual women's and men's genital and subjective sexual arousal to slideshows of prepotent stimuli (erect penises and aroused vulvas), non-prepotent stimuli (flaccid penises and female pubic triangles), and sexually-neutral stimuli. Contrary to our hypotheses, both women and men demonstrated gender-specific genital and subjective sexual arousal, such that sexual arousal was greatest to prepotent male and female stimuli, respectively. This is the first study to demonstrate gender-specific genital responding in heterosexual women.
Both otoacoustic emissions (OAEs) and auditory evoked potentials (AEPs) are sexually dimorphic, and both are believed to be influenced by prenatal androgen exposure. OAEs and AEPs were collected from people affected by 1 of 3 categories of disorders of sex development (DSD) – (1) women with complete androgen insensitivity syndrome (CAIS); (2) women with congenital adrenal hyperplasia (CAH); and (3) individuals with 46,XY DSD including prenatal androgen exposure who developed a male gender despite initial rearing as females (men with DSD). Gender identity (GI) and role (GR) were measured both retrospectively and at the time of study participation, using standardized questionnaires. The main objective of this study was to determine if patterns of OAEs and AEPs correlate with gender in people affected by DSD and in controls. A second objective was to assess if OAE and AEP patterns differed according to degrees of prenatal androgen exposure across groups. Control males, men with DSD, and women with CAH produced fewer spontaneous OAEs (SOAEs) – the male-typical pattern – than control females and women with CAIS. Additionally, the number of SOAEs produced correlated with gender development across all groups tested. Although some sex differences in AEPs were observed between control males and females, AEP measures did not correlate with gender development, nor did they vary according to degrees of prenatal androgen exposure, among people with DSD. Thus, OAEs, but not AEPs, may prove useful as bioassays for assessing early brain exposure to androgens and predicting gender development in people with DSD.
Most men have a category-specific pattern of genital and subjective sexual arousal, responding much more strongly to erotic stimuli depicting their preferred sex than to erotic stimuli depicting their nonpreferred sex. In contrast, women tend to have a less specific arousal pattern. To better understand this sex difference, we used neuroimaging to explore its neural correlates. Heterosexual and homosexual women viewed erotic photographs of either men or women. Evoked neural activity was monitored via fMRI and compared with responses to the same stimuli in heterosexual and homosexual men. Overall, a network of limbic (as well as the anterior cingulate) and visual processing regions showed significantly less category-specific activity in women than men. This was primarily driven by weaker overall activations to preferred-sex stimuli in women, though there was also some evidence of stronger limbic activations to nonpreferred-sex stimuli in women. Primary results were similar for heterosexual and homosexual participants. Women did show some evidence of category-specific responses in the visual processing regions, although even in these regions they exhibited less differential activity than men. In the anterior cingulate, a region with high concentrations of sex-hormone receptors, subjective and neural category specificity measures correlated positively for women but negatively for men, suggesting a possible sex difference in the role of the anterior cingulate. Overall, results suggest that men tend to show more differentiated neural responses than do women to erotic photographs of one sex compared to the other sex, though women may not be entirely indifferent to which sex is depicted.
Complete androgen insensitivity syndrome (CAIS) is an X-linked genetic disorder affecting 46,XY individuals, characterized by the loss of function of the androgen receptor gene resulting in complete peripheral androgen resistance. Patients have a nonambiguous female phenotype with normal female external genitalia. Gonads are undescended testes (either intra-abdominal or inguinal), there is no uterus and the length of the vagina is usually very short. Gender identity is always female. This review focuses on the importance of accurate diagnosis of CAIS versus partial androgen insensitivity syndrome and other disorders of sex development by genotyping the androgen receptor, and raises issues of the optimal management of these patients. In the era of the Consensus Statement on Management of Intersex Disorders, we provide new insights into CAIS screening, surgical management of the gonads (balancing between hormonal production and malignancy risk) and of vaginal adequacy, and the ethics concerned with the disclosure to patients and their families.
The most appropriate treatment for intersex children remains a topic of debate, in part because of a lack of knowledge about the medical, operative, and psychosexual outcomes in affected adults. This study examined outcomes in 14 women diagnosed as having complete androgen insensitivity syndrome (CAIS). Women with CAIS provide an excellent opportunity to study the effects of estrogen on gender development in 46,XY individuals who are unresponsive to androgens. CAIS was diagnosed if testes were present along with normal external female genitalia in a 46,XY person, an androgen receptor gene mutation was identified, there was spontaneous feminization at puberty except for a lack of menses, virilization was not evident despite normal or high male testosterone levels, and axillary and pubic hair was much reduced or absent postpubertally. The women ranged in age from the late 20s to mid-60s when evaluated (average, 45 years).
Eight participants, 57% of the total, were at or above the 90th centile of control adult female height; the others were between the 50th and 75th centiles. Seven women exceeded ideal body weight by at least 15 kg, three of them by 80 kg or more. Most gonadectomies and vaginoplasties had been performed in adolescence or adulthood. Eight subjects, one a homosexual, did not require vaginoplasty. In no case was clitoroplasty necessary. Bone loss was documented in 43% of women. More than 80% had received some form of counseling. Nearly 80% of subjects were satisfied with their genitalia with regard to sexual function. A majority estimated their libido as being average or stronger. Ten of 13 reported being able to experience organisms. Only 1 of 14 women was substantially dissatisfied with her physical appearance, although 5 others were somewhat dissatisfied. In general, these women perceived themselves as being feminine throughout their development and had experienced female fantasies and experiences since adolescence. Half of the women were married at the time of the study. Five of them and one unmarried women had adopted children. Without exception the women were satisfied with their gender assignment. These women with CAIS have had generally satisfactory medical, surgical, and psychosexual outcomes. All of them were pleased at having been raised as females, and none desired gender reassignment.
While there has been increasing support for the existence of cerebral sex differences, the mechanisms underlying these differences are unclear. Based on animal data, it has long been believed that sexual differentiation of the brain is primarily linked to organizational effects of fetal testosterone. This view is, however, in question as more recent data show the presence of sex differences before the onset of testosterone production. The present study focuses on the impact that sex chromosomes might have on these differences. Utilizing the inherent differences in sex and X-chromosome dosage among XXY males, XY males, and XX females, comparative voxel-based morphometry was conducted using sex hormones and sex chromosomes as covariates. Sex differences in the cerebellar and precentral gray matter volumes (GMV) were found to be related to X-chromosome dosage, whereas sex differences in the amygdala, the parahippocamus, and the occipital cortex were linked to testosterone levels. An increased number of sex chromosomes was associated with reduced GMV in the amygdala, caudate, and the temporal and insular cortices, with increased parietal GMV and reduced frontotemporal white matter volume. No selective, testosterone independent, effect of the Y-chromosome was detected. Based on these observations, it was hypothesized that programming of the motor cortex and parts of cerebellum is mediated by processes linked to X-escapee genes, which do not have Y-chromosome homologs, and that programming of certain limbic structures involves testosterone and X-chromosome escapee genes with Y-homologs.
Statistical parametric maps are spatially extended statistical processes that are used to test hypotheses about regionally specific effects in neuroimaging data. The most established sorts of statistical parametric maps (e.g., Friston et al. [1991]: J Cereb Blood Flow Metab 11:690–699; Worsley et al. [1992]: J Cereb Blood Flow Metab 12:900–918) are based on linear models, for example ANCOVA, correlation coefficients and t tests. In the sense that these examples are all special cases of the general linear model it should be possible to implement them (and many others) within a unified framework. We present here a general approach that accomodates most forms of experimental layout and ensuing analysis (designed experiments with fixed effects for factors, covariates and interaction of factors). This approach brings together two well established bodies of theory (the general linear model and the theory of Gaussian fields) to provide a complete and simple framework for the analysis of imaging data.
The importance of this framework is twofold: (i) Conceptual and mathematical simplicity, in that the same small number of operational equations is used irrespective of the complexity of the experiment or nature of the statistical model and (ii) the generality of the framework provides for great latitude in experimental design and analysis.
Convincing evidence indicates that prenatal exposure to the gonadal hormone, testosterone, influences the development of children's sex-typical toy and activity interests. In addition, growing evidence shows that testosterone exposure contributes similarly to the development of other human behaviors that show sex differences, including sexual orientation, core gender identity, and some, though not all, sex-related cognitive and personality characteristics. In addition to these prenatal hormonal influences, early infancy and puberty may provide additional critical periods when hormones influence human neurobehavioral organization. Sex-linked genes could also contribute to human gender development, and most sex-related characteristics are influenced by socialization and other aspects of postnatal experience, as well. Neural mechanisms underlying the influences of gonadal hormones on human behavior are beginning to be identified. Although the neural mechanisms underlying experiential influences remain largely uninvestigated, they could involve the same neural circuitry as that affected by hormones.
A key question concerns the extent to which sexual differentiation of human behavior is influenced by sex hormones present during sensitive periods of development (organizational effects), as occurs in other mammalian species. The most important sensitive period has been considered to be prenatal, but there is increasing attention to puberty as another organizational period, with the possibility of decreasing sensitivity to sex hormones across the pubertal transition. In this paper, we review evidence that sex hormones present during the prenatal and pubertal periods produce permanent changes to behavior. There is good evidence that exposure to high levels of androgens during prenatal development results in masculinization of activity and occupational interests, sexual orientation, and some spatial abilities; prenatal androgens have a smaller effect on gender identity, and there is insufficient information about androgen effects on sex-linked behavior problems. There is little good evidence regarding long-lasting behavioral effects of pubertal hormones, but there is some suggestion that they influence gender identity and perhaps some sex-linked forms of psychopathology, and there are many opportunities to study this issue.
Cognitive neuroscientists increasingly recognize that continued progress in understanding human brain function will require not only the acquisition of new data, but also the synthesis and integration of data across studies and laboratories. Here we review ongoing efforts to develop a more cumulative science of human brain function. We discuss the rationale for an increased focus on formal synthesis of the cognitive neuroscience literature, provide an overview of recently developed tools and platforms designed to facilitate the sharing and integration of neuroimaging data, and conclude with a discussion of several emerging developments that hold even greater promise in advancing the study of human brain function.
We present a method for detecting event-related responses in functional magnetic resonance imaging (fMRI). The occurrence of time-locked activations is formulated in terms of the general linear model, i.e., multiple linear regression. This permits the use of established statistical techniques that correct for multiple comparisons in the context of spatially smooth and serially correlated data. Responses are modelled using event-related temporal basis functions. Inferences are then made about all components of the model, using the F-ratio at all voxels in the image, to produce a statistical parametric map (SPM{F}). This method allows for the experimental design to relate the timing of events to the acquisition of data to give a temporal resolution (with respect to the event-related response) far better than the scanning repeat time.
The 1959 publication of the paper by Phoenix et al. was a major turning point in the study of sexual differentiation of the brain. That study showed that sex differences in behavior, and by extension in the brain, were permanently sexually differentiated by testosterone, a testicular secretion, during an early critical period of development. The study placed the brain together in a class with other major sexually dimorphic tissues (external genitalia and genital tracts), and proposed an integrated hormonal theory of sexual differentiation for all of these non-gonadal tissues. Since 1959, the organizational-activational theory has been amended but survives as a central concept that explains many sex differences in phenotype, in diverse tissues and at all levels of analysis from the molecular to the behavioral. In the last two decades, however, sex differences have been found that are not explained by such gonadal hormonal effects, but rather because of the primary action of genes encoded on the sex chromosomes. To integrate the classic organizational and activational effects with the more recently discovered sex chromosome effects, we propose a unified theory of sexual differentiation that applies to all mammalian tissues.
Transsexuals harbor the strong feeling of having been born to the wrong sex. There is a continuing controversial discussion of whether or not transsexualism has a biological representation. Differences between males and females in terms of functional imaging during erotic stimuli have been previously described, revealing gender-specific results.
Therefore, we postulated that male-to-female (MTF) transsexuals may show specific cerebral activation differing from their biological gender.
Cerebral activation patterns during viewing of erotic film excerpts in functional magnetic resonance imaging (fMRI).
Twelve male and 12 female heterosexual volunteers and 12 MTF transsexuals before any treatment viewed erotic film excerpts during fMRI. Additionally, subjective rating of sexual arousal was assessed. Statistics were performed using the Statistical Parametric Mapping software.
Significantly enhanced activation for men compared with women was revealed in brain areas involved in erotic processing, i.e., the thalamus, the amygdala, and the orbitofrontal and insular cortex, whereas no specific activation for women was found. When comparing MTF transsexuals with male volunteers, activation patterns similar to female volunteers being compared with male volunteers were revealed. Sexual arousal was assessed using standard rating scales and did not differ significantly for the three groups.
We revealed a cerebral activation pattern in MTF transsexuals compared with male controls similar to female controls compared with male controls during viewing of erotic stimuli, indicating a tendency of female-like cerebral processing in transsexualism.
Controversy concerning the most appropriate treatment guidelines for intersex children currently exists. This is due to a lack of long-term information regarding medical, surgical, and psychosexual outcome in affected adults. We have assessed by questionnaire and medical examination the physical and psychosexual status of 14 women with documented complete androgen insensitivity syndrome (CAIS). We have also determined participant knowledge of CAIS as well as opinion of medical and surgical treatment. As a whole, secondary sexual development of these women was satisfactory, as judged by both participants and physicians. In general, most women were satisfied with their psychosexual development and sexual function. Factors reported to contribute to dissatisfaction were sexual abuse in one case and marked obesity in another. All of the women who participated were satisfied with having been raised as females, and none desired a gender reassignment. Although not perfect, the medical, surgical, and psychosexual outcomes for women with CAIS were satisfactory; however, specific ways for improving long-term treatment of this population were identified.
An anatomical parcellation of the spatially normalized single-subject high-resolution T1 volume provided by the Montreal Neurological Institute (MNI) (D. L. Collins et al., 1998, Trans. Med. Imag. 17, 463-468) was performed. The MNI single-subject main sulci were first delineated and further used as landmarks for the 3D definition of 45 anatomical volumes of interest (AVOI) in each hemisphere. This procedure was performed using a dedicated software which allowed a 3D following of the sulci course on the edited brain. Regions of interest were then drawn manually with the same software every 2 mm on the axial slices of the high-resolution MNI single subject. The 90 AVOI were reconstructed and assigned a label. Using this parcellation method, three procedures to perform the automated anatomical labeling of functional studies are proposed: (1) labeling of an extremum defined by a set of coordinates, (2) percentage of voxels belonging to each of the AVOI intersected by a sphere centered by a set of coordinates, and (3) percentage of voxels belonging to each of the AVOI intersected by an activated cluster. An interface with the Statistical Parametric Mapping package (SPM, J. Ashburner and K. J. Friston, 1999, Hum. Brain Mapp. 7, 254-266) is provided as a freeware to researchers of the neuroimaging community. We believe that this tool is an improvement for the macroscopical labeling of activated area compared to labeling assessed using the Talairach atlas brain in which deformations are well known. However, this tool does not alleviate the need for more sophisticated labeling strategies based on anatomical or cytoarchitectonic probabilistic maps.
In birds and mammals, differences in development between the sexes arise from the differential actions of genes that are encoded on the sex chromosomes. These genes are differentially represented in the cells of males and females, and have been selected for sex-specific roles. The brain is a sexually dimorphic organ and is also shaped by sex-specific selection pressures. Genes on the sex chromosomes probably determine the gender (sexually dimorphic phenotype) of the brain in two ways: by acting on the gonads to induce sex differences in levels of gonadal secretions that have sex-specific effects on the brain, and by acting in the brain itself to differentiate XX and XY brain cells.
Sexual arousal is category-specific in men; heterosexual men are more aroused by female than by male sexual stimuli, whereas homosexual men show the opposite pattern. There is reason to believe that female sexual arousal is organized differently. We assessed genital and subjective sexual arousal to male and female sexual stimuli in women, men, and postoperative male-to-female transsexuals. In contrast to men, women showed little category specificity on either the genital or the subjective measure. Both heterosexual and homosexual women experienced strong genital arousal to both male and female sexual stimuli. Transsexuals showed a category-specific pattern, demonstrating that category specificity can be detected in the neovagina using a photoplethysmographic measure of female genital sexual arousal. In a second study, we showed that our results for females are unlikely to be explained by ascertainment biases. These findings suggest that sexual arousal patterns play fundamentally different roles in male and female sexuality.
Previous research suggests that women's genital arousal is an automatic response to sexual stimuli, whereas men's genital arousal is dependent upon stimulus features specific to their sexual interests. In this study, we tested the hypothesis that a nonhuman sexual stimulus would elicit a genital response in women but not in men. Eighteen heterosexual women and 18 heterosexual men viewed seven sexual film stimuli, six human films and one nonhuman primate film, while measurements of genital and subjective sexual arousal were recorded. Women showed small increases in genital arousal to the nonhuman stimulus and large increases in genital arousal to both human male and female stimuli. Men did not show any genital arousal to the nonhuman stimulus and demonstrated a category-specific pattern of arousal to the human stimuli that corresponded to their stated sexual orientation. These results suggest that stimulus features necessary to evoke genital arousal are much less specific in women than in men.
A rapidly burgeoning literature documents copious sex influences on brain anatomy, chemistry and function. This article highlights some of the more intriguing recent discoveries and their implications. Consideration of the effects of sex can help to explain seemingly contradictory findings. Research into sex influences is mandatory to fully understand a host of brain disorders with sex differences in their incidence and/or nature. The striking quantity and diversity of sex-related influences on brain function indicate that the still widespread assumption that sex influences are negligible cannot be justified, and probably retards progress in our field.
Sexually arousing visual stimuli activate the human reward system and trigger sexual behavior. Here we performed event-related fMRI during visual processing of sexual core stimuli to pinpoint a neuronal correlate of sexual preference in humans. To dissociate gender of the stimulus from sexual preference, we studied male and female heterosexual and homosexual volunteers while they viewed sexual and nonsexual control stimuli. In contrast to previous work, we used core single-sex stimuli displaying male and female sexually aroused genitals. Since stimuli lacked any additional contextual information, they evoked no activity related to neuronal processing of faces, gestures or social interactions. Our prediction was that the sexual preference of the observer determines the neuronal responsiveness to pure male or female sexual stimuli in the human reward and motor system. Consistent with our prediction, the ventral striatum and the centromedian thalamus, showed a stronger neuronal response to preferred relative to non-preferred stimuli. Likewise, the ventral premotor cortex which is a key structure for imitative (mirror neurons) and tool-related (canonical neurons) actions showed a bilateral sexual preference-specific activation, suggesting that viewing sexually aroused genitals of the preferred sex triggers action representations of sexual behavior. The neuronal response of the ventral striatum, centromedian thalamus and ventral premotor cortex to preferred sexual stimuli was consistent across all groups. We propose that this invariant response pattern in core regions of the human reward and motor system represents a functional endophenotype for sexual orientation independent of the gender of the observer and gender of the stimulus.
Brain Aromatase, Estrogens, and Behavior Sexual differentiation of human behavior: effects of prenatal and pubertal organizational hormones
- J Balthazart
- G Ball
Balthazart, J., Ball, G., 2012. Brain Aromatase, Estrogens, and Behavior. Oxford University Press. Berenbaum, S.A., Beltz, A.M., 2011. Sexual differentiation of human behavior: effects of prenatal and pubertal organizational hormones. Front. Neuroendocrinol. 32 (2), 183–200.
- J Balthazart
- G Ball
Balthazart, J., Ball, G., 2012. Brain Aromatase, Estrogens, and Behavior. Oxford University
Press.
Men and women differ in amygdala response to visual sexual stimuli
- S Hamann
- R A Herman
- C L Nolan
- K Wallen
Hamann, S., Herman, R.A., Nolan, C.L., Wallen, K., 2004. Men and women differ in amygdala response to visual sexual stimuli. Nat. Neurosci. 7 (4), 411–416. http://dx.doi.
org/10.1038/nn1208.
- S Hamann
S. Hamann et al. / Hormones and Behavior 66 (2014) 724–730
Brain Aromatase, Estrogens, and Behavior
- J Balthazart
- G Ball
Balthazart, J., Ball, G., 2012. Brain Aromatase, Estrogens, and Behavior. Oxford University
Press.
Gender Development. Handbook of child psychology
- D N Ruble
- C L Martin
- S A Berenbaum
Ruble, D.N., Martin, C.L., Berenbaum, S.A., 1998. Gender Development. Handbook of child
psychology.