Hamann S, Stevens J, Vick JH, Bryk K, Quigley CA, Berenbaum SA, Wallen K. Horm. Behav. 2014 Oct 2

DOI:10.1016/j.yhbeh.2014.09.013

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.  

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Summary    

Neuroscience research in human sex differences attracts controversy, whether samples studied are from the general population or patients with disorders (differences) of sex development (DSD). These investigations suggest multivariate contributions to “gendered” brain development and emphasize the importance of both nature and nurture. In addition to prenatal gonadal hormonal influences, early infancy and puberty may provide additional sensitive periods when hormones influence human neurobehavioral organization. Sex-linked genes could also contribute to sex-related variability in brain development, but most sex-related characteristics exhibit influences of socialization. 

The current report provides very suggestive evidence that 46,XY women with complete androgen insensitivity syndrome (CAIS) show patterns of brain activation (measured by functional magnetic resonance imaging [fMRI]) to sexually arousing stimuli similar to 46,XX women, with whom they share female-typical socialization and predominantly estrogenic postnatal hormonal exposure. Their fMRI responses were markedly different from XY men, with whom they share a Y chromosome complement and high prenatal and infant testosterone secretion. Women with CAIS lack functional androgen receptors, preventing a cellular response to testosterone; nevertheless, testosterone is aromatized to estradiol, resulting in a feminizing puberty that is mediated by normally functioning receptors for estrogen. 

These findings argue against the need for two X chromosomes or ovaries to determine feminine-typical brain responses in humans and reinforces the role of androgens and functioning androgen receptors in influencing masculine-typical brain development. Similarly, these data argue against a role for the aromatization of testosterone to estrogens in the masculinization of the human brain. 

The data, however, cannot rule out “activational” effects of hormones {1} or socialization effects, because all the women (typical and CAIS) were reared as girls and identified as women. The authors did not control for current hormonal status and the sample of woman were likely heterogeneous in terms of their hormonal state, i.e. some were naturally cycling and others were taking contraceptive pills. Despite this, the CAIS and typical women responded the same to the sexual arousal paradigm. An additional detail missing is the gonadal status of the CAIS women, although they likely had been gonadectomized relatively early given their age and prevalent clinical management practices in earlier years. 

Additional research would be necessary to rule out the activational effects of androgens (or estrogens), but the current study provides novel evidence that a 46,XY karyotype alone does not result in male-typical brain responses in humans. This may have implications for gender assignment practices in patients with 46,XY DSD conditions (other than CAIS). Although there is an association between the external appearance of the genitalia and the choice of gender assignment, there are clear secular trends in practice pointing toward an increased likelihood of affected 46,XY infants being reared as boys {2}. The explanation for this shift over time is unclear, but is not clearly evidence- based. Moreover, the impact on long-term health and quality of life outcomes of this shift in decision-making requires study. Finally, there are repeated anecdotal reports of women with CAIS supplementing estrogen replacement with testosterone for well-being and libido {3}; if this phenomenon can be confirmed in a clinical trial, then the task of discovering the mechanism of action of this effect still remains.  

Recommendation Citation: 

Sandberg D and Callens N: F1000Prime Recommendation of [Hamann S et al., Horm Behav 2014]. In F1000Prime, 17 Nov 2014; DOI: 10.3410/f.719717009.793501424. F1000Prime.com/719717009#eval793501424