Sex differences and stress across the lifespan

Abstract

Sex differences in stress responses can be found at all stages of life and are related to both the organizational and activational effects of gonadal hormones and to genes on the sex chromosomes. As stress dysregulation is the most common feature across neuropsychiatric diseases, sex differences in how these pathways develop and mature may predict sex-specific periods of vulnerability to disruption and increased disease risk or resilience across the lifespan. The aging brain is also at risk to the effects of stress, where the rapid decline of gonadal hormones in women combined with cellular aging processes promote sex biases in stress dysregulation. In this Review, we discuss potential underlying mechanisms driving sex differences in stress responses and their relevance to disease. Although stress is involved in a much broader range of diseases than neuropsychiatric ones, we highlight here this area and its examples across the lifespan.

Figure 1

Programming and maturation of the sexually dimorphic brain and importance in lifelong sex differences in stress circuitry. Exposure of the male (XY) neonatal brain to estrogen (E) via central aromatization of testosterone (T) produced by the testes during this developmental window sets the stage for sex differences throughout life. Perturbations such as maternal stress can disrupt testosterone production and its ability to fully masculinize the brain, resulting in a mismatch between the gonad and brain later in life when activational T levels are present. Genes expressed on the X and Y chromosomes also drive differences in neurodevelopment and stress neurocircuitry that will result in pushing the male and female brain and HPA axis stress response further apart, these may include epigenetic modifiers such as miRNAs abundant on the X chromosome and histone demethylases on the Y. Studies in children with Turner syndrome (XO) and Klinefelter syndrome (XXY) indicate that X-linked gene dosage is important in morphological development of brain regions involved in stress regulation. During puberty, activational gonadal hormones produced in males and females further act on the blueprint established during early life to mature the sexually dimorphic brain. During this stage, T in the male also reduces the adrenal gland size and steroidogenic activity to promote an additional level for sex differences in stress responses. The aging brain receives significantly lower levels of gonadal hormones in women, and this, combined with additional cellular aging processes, produces unique sex differences in stress responsivity at this life stage. For women, there is an additional peak at this stage of life for presentation of stress-related disorders including schizophrenia and depression.

Figure 2

Sex differences in stress-related neuropsychiatric disease across the lifespan. Sex differences in response to prenatal and early life stress put males at an increased risk to present with neurodevelopmental disorders including ASD, ADHD, oppositional defiant disorder (ODD) and Tourette syndrome (TS). Males are also at greater risk of early onset schizophrenia. Although there are no sex differences in affective disorders before puberty, females show an increased risk in adolescence and throughout adulthood, especially if they have experience stress-related early life adversity or trauma. During peri-menopause and menopausal transition, women are at greater risk for presenting with schizophrenia, and affective disorders including depression.