Our study revealed that Tibetan males had larger brains than Tibetan females in both global GM volume and WM volume, which was consistent with that found in lowlanders such as Germany, American, Korean, Swiss, and Australian  as well as in our present Chinese Han subjects. Tibetan females had a larger proportion of GM volume than males, which was also found in previous studies on lowlanders [29, 30] but not in our present study on Han subjects. Moreover, Tibetan females had smaller regional cortical GM volume than males, with GM volume in the left pars opercularis in males and females had a significant positive correlation with forward digit span performance. In contrast, Tibetan females had larger regional CT than males and moreover, in females, CT values in these regions had significant negative correlations with altitude.
In our study, the accurate brain sites showing sex differences of CT were different between Tibetans and Han subjects, but they were all within the regions found in Germany aged 24.3 ± 4.3 years , in Korean females aged 19-36 years , and in American aged 7-87 years , with signiﬁcantly thicker cortices in females. In our study, although we got an opposite results in regional GM volume between Tibetans and Han, but the smaller regions in Tibetan females and the larger regions in Han females all overlapped and were consistent with the regions found in Germany aged 20-30 years . In addition, the regions that showing higher CT in the right superior temporal gyrus and left occipital lobe in our Han subjects also showed larger GM volume in America females aged 25.1 ± 4.5 years . In the present study, we have also analyzed brain structural differences between Han males and Tibetan males and brain structural differences between Han females and Tibetan females, and the results showed that the sex differences of brains were consistent with that found in our previous study in Tibetans and Han subjects .
Our study found that Tibetans females had significantly thicker regional cortical thickness than males and the correlation of regional CT with altitude existed in female but not male Tibetans by both regional and global analyses. (1) Firstly, these results suggest that HA environmental factors may affect easily on brain developments in female residents. In agreement with our results, depression and anxiety behaviors have been observed to increase with altitude of housing in female, but not male rats . In our previous study on sea-level residents after 4-week exposure at Qinghai-Tibet Plateau, both males and females showed significant differences in cerebral iron concentrations in deep gray matters in the brains after the HA stay, while the increased proportion of females (4%) was greater than males (2%) . Baum et al.  found that chronic intermittent hypoxia induced a higher Fosb gene expression in females than in males, reflecting stronger neuroplastic dynamics. (2) Secondly, these results suggest that females may have a better capacity to adapt to hypoxia. Some clinic and experimental data support this suggestion. When both male and female rats were reared at an altitude, red blood cell count, haematocrit, and plasma erythropoietin levels were lower in females than in males . A lot of studies showed that female animals with cerebral hypoxia-ischemia were less adversely affected relative to comparably injured males [14, 22, 42]. Clinical data also suggests females with cerebral hypoxia-ischemia exhibited less severe behavioral deficits compared to males . Charriaut-Marlangue et al.  reviewed that cohort studies have demonstrated a higher vulnerability in males towards neonatal ischemic and/or hypoxic-ischemic injury. Compared with female brains, male brains were poorly repaired after neonatal hypoxia-ischemia, and males have an increased incidence of long-term cognitive deficits. Female resistance to hypoxia can explain the lower female total mortality rate in infancy, childhood and adulthood .
The greater capacity for females to adapt to hypoxia may be related to the effects of circulating estrogen and progesterone. This two hormones have been shown greater in females living at HA than females who resident at lowlands . It has been shown that the resistance of females to ischemia is acquired after puberty  and is lost after menopause, which is in accordance with the protective effects of estrogen . Exogenous administration of estrogen has been shown to reduce ischemia-induced cerebral injury , and the protective effects may be through preventing neuron death  and related to its antioxidant properties . Estrogen can also increase regional CBF [50-52] and correlates directly with CBF velocity . Females have higher CBF compared with males in the left inferior frontal gyrus, bilateral middle temporal gyri, and left superior temporal gyrus [54, 55]. In addition, in animal models of neonatal hypoxia-ischemia, males are more sensitive to mitochondrial dysfunction, with increased mitochondrial permeability on the inner and outer membranes leading to a high amount of released proteins as compared to females . Taken together, the increased blood sex hormones, increased CBF, and relatively little mitochondrial permeability may contribute to female resistance to hypoxia. Females also have a better capacity to adapt to cold. For example, the vascular response to coldness at HA was smaller in females compared with males ; cold decreased the fatigue index of a sustained 2-min maximal voluntary contraction in males but not in females ; a significant benefit of temperature reduction in hypoxia ischemia was found in females but not in males .
In our study, sex differences of brains were found in the young adult residents at HA, which could be different from that in children or older peoples, as age-associated changes are sex-specific. A study has shown that men experienced greater volume decrement across age-groups than women, particularly in the dorsolateral prefrontal regions . Another MRI studied on healthy adults aged range 18-80 years showed that the greatest amount of atrophy in elderly men was in the left hemisphere, whereas in women age effects were symmetric .
The limitation in our study is that the inter-ethnic differences in brain structures can be large. We cannot draw a conclusion that gene and developmental environment which one dominantly determined the different pattern of sex differences between Tibetan and Han brains. Brain morphological differences between populations of different origins have been found in early neonate life  and in adults in terms of whole brain and region-specific volume [62-64]. Our previous study has revealed that, compared with Han subjects living at lowlands, Tibetans living on the Qinghai-Tibetan Plateau were associated with structural modifications in cortical thicknesses, curvature, and sulcus . Therefore, the global brain differences between these two populations may underlie the different pattern of sex differences between Tibetan and Han brains. The another limitation of this study is that we did not conduct neuropsychiatric tests in Han subjects, and thus cannot compare the neuropsychiatric ability between Tibetans and Han subjects.
In our study, females showed significant decreases of GM volume in the left pars opercularis and pars triangularis of Broca’s area, and GM volume in the left pars opercularis in Tibetans had a significant positive correlation with forward digit span performance. Previous study has found an association between impaired forward digit span performance and ischemia in pars opercularis . Moreover, stimulation of left Broca's area interfered with digit span, producing significantly more item than order errors . Forward digit span is a kind of verbal phonological short-term memory. MRI studies on articulatory suppression indicated that pars opercularis was involved in phonological short term-memory [67, 68]. Patients, who had a disability to make phonological judgements, showed lesions in the left Broca’s area . Therefore, the decreased GM volume of left pars opercularis of Broca area may be associated with poor phonological short term-memory in Tibetan females.