Interplay of Sex, Gender, and Environment in Psychiatric Disorders

Sex- and gender-based differences have been observed in the outcome of mental disorders. For example, the prevalence of depression, anxiety, or stress-related disorders are more in females while neurodevelopmental disorders such as Autism or Attention deficit hyperactivity disorder (ADHD) are more common in males. It is important to understand role of various factors like genetics, hormonal as well as environmental in such variations not only to provide better healthcare as well as prevention of mental disorders. Sex is largely driven by the biology while gender is determined by sex as well as the parenting, environmental, and cultural factors. Various sex-related hypothesis had been proposed for possible sex-based differences. The possible genetic mechanism is that females have two X chromosomes. One X chromosome is automatically and randomly inactivated, which leads to equal number of genes in males and females. However, 25% of genes escape inactivation on the inactivated X chromosome.[1] Expression of these genes at different times leads to sex-based differences. Expression of susceptibility genes may occur only under specific hormonal or environmental conditions over a time period.[2] Another possible theory is that at estrogen provides protection to females by reducing neuroinflammation starting after puberty till menopause.[3] Another mechanism proposed is that repeated early life trauma sensitizes the HPA axis. Furthermore, monthly hormonal fluctuation sensitizes the HPA-axis in females.[4] This may be one reason for more stress-related disorders in females. Maternal immune activation or early life inflammation negatively affects the male brain, but not females.[5] This may be possible reason for more neurodevelopmental disorders in males. However, only biological differences are not enough to produce these sex-based differences. Biological differences occur over a period of time. They interact with the environmental factors and cumulative stress over a period of time leading to onset of disorder. Several studies have reported gene–environment interaction leading to sex-based differences in mental health. Twin study of adolescent females reported the relationship between life events and risk for anxiety and depression. In the girls who had parents with history of depression, the occurrence of a stressful life event in the last year had significantly increased the risk of depression as compared to girls with no genetic risk.[6] Similarly, adoption study reported that the girls with genetic background of alcoholism when exposed to stressful environment in adopted family had high risk of developing alcoholism and depression both as compared to males who developed only alcoholism.[7] Gender and Environmental Interaction Large number of environmental factors, like individual adverse childhood experiences, social factors like poverty, deprived neighborhood, poor employment opportunities, or cultural factors like ethnic minorities, racism, or discrimination had been found associated with mental health problems in general. Gender based rules, expectations and cultural norms create stress, especially in females. Females are less likely to have educational opportunity, the same level of freedom as boys as well as employment opportunity and autonomy. Gender based differences in exposure to adverse experiences had been reported. The females are more likely to experiences adverse experiences then males. Females are more likely to report abuse and neglect as well as substance use and mental illness in family. Furthermore, gender-based differences in mental disorders have been reported with the similar exposure to stressful environment.[8,9] Sexual and verbal abuse have been associated with female smoking while adverse childhood experiences predict delinquency in boys.[10] Intimate partner violence in females has been found to be a significant risk factor for developing depression, abuse drugs, or attempt suicide. Child sexual abuse has been reported to be a risk factor for depression in adolescence.[11] Cultural expectations may become a source of stress like focus on male child, especially in southeast Asian countries. Studies from southeast Asia have reported a greater risk for postnatal depression in mothers who gave birth to a girl child. Especially if the mother already had girls and a boy was desired.[12] Effect of introduction of television on eating behavior has been assessed in a media naïve population. It was reported that there was increase in the rate of eating disorders in young girls. Furthermore, more focus on thinner body image and self-induced vomiting has been reported in young girls. This study demonstrated that the direct or indirect promotion of thinness as a symbol of beauty by media and fashion industries is now leading to a rise in eating disorders in the developing countries.[13] Similarly, environmental factors can also act as protective factors in spite of biological vulnerability. In adult twin females’ marriage like relationship was found protective for consumption of alcohol as well as development of depression as compared to unmarried twin girls in the presence of genetic vulnerability.[14] Hence, it is important to understand that large number of genes is implicated in severe mental disorders as per GWAS studies. Most genetic variants are nonspecific and associated with many disorders for example overall, 2/3 associations are common in schizophrenia, Bipolar disorder (BPD), and depression.[15] Polygenic risk scores analysis showed that by including more weakly associated genetic variants the prediction of mental illness improved. This suggests that large number of genes are involved in most mental disorders.[16] Similarly, same type of environmental factor has been associated with many disorders. Furthermore, everyone exposed to adverse environment does not develop the disorder. Therefore, any single factor is unlikely to cause mental disorder rather multiple environmental, genetic, and other biological exposure at different time point are responsible for the onset of disorder. For proper understanding of these factors, long-term follow-up studies with large representative samples are required with focus on assessments of biological factors, different types of environmental exposures, and psychopathology over the period of time.