Different strategies for preventing women's depression, dementia

Different strategies for preventing women's depression and dementia

Studies point out that sex steroids like estradiol affect women's brain health and the risk of depression and Alzheimer's disease throughout the lifespan.

Data from previous epidemiologic surveys have shown that there is a difference in the incidence of depression and Alzheimer's disease (the most common type of dementia) between the sexes (overall, the number of female patients is higher than that of males). This suggests that there are gender-specific biological mechanisms behind these two diseases. The risk of depression is highest in women during the reproductive years; in addition, women have an elevated risk of developing Alzheimer's disease after menopause.

Recent research evidence suggests that endogenous steroid exposure, exogenous steroid use, and genetic factors affect women's brain and mental health and may influence the risk of developing Alzheimer's disease in later life. In addition, depression is a known risk factor for Alzheimer's disease, although depression in women is commonly associated with hormonal changes in an individual's menstrual cycle (e.g., premenstrual anxiety disorder), pregnancy (e.g., perinatal depression), or menopause (e.g., perimenopausal depression), and there is a lack of research evidence on how these subtypes of depression affect the risk of developing Alzheimer's disease.

Recently, The Lancet Diabetes & Endocrinology, a subset of THE LANCET, published an important review indicating that sex steroids, such as estradiol, affect women's brain health and the risk of depression and Alzheimer's disease across the lifespan. The degree of risk for these two diseases is strongly associated with cumulative exposure to endogenous and exogenous steroids during a woman's reproductive years.

Estrogen, progesterone closely linked to female brain health

Sex steroids, such as estrogen, androgens, and progesterone, are major regulators that can have a wide range of effects on women's systemic systems. Although sex steroids are primarily produced in the female ovaries, their functions extend beyond the reproductive tract and can impact immune regulation, bone mass maintenance, vascular function, and brain function. Luteinizing hormone and estradiol are common and potent primary estrogens in the female body, with neurotrophic and neuroprotective effects on the brain. In addition, testosterone is a potent neuroactive androgen with neuroprotective properties that help regulate brain plasticity. Testosterone can act through the androgen receptor or through the estrogen receptor after conversion to estradiol by aromatase.

Sex steroids can affect neuronal activity by modulating neurotransmitter systems (e.g., serotonin, dopamine, glutamate, and gamma-aminobutyric acid [GABA]). The review emphasized that sex steroid receptors are widely expressed throughout the brain, including brain regions involved in learning and memory formation (e.g., hippocampus), emotion regulation and motivation (e.g., amygdala), and cognitive functions (e.g., prefrontal cortex). Changes in sex steroid levels throughout a woman's life are associated with structural and functional changes in the female brain and may influence a woman's susceptibility to depression and Alzheimer's disease. And in addition to changes in endogenous steroid levels throughout the lifespan, exogenous steroids ingested in the form of hormonal contraception and menopausal hormone therapy may further influence the female brain and the risk of developing both diseases.

The review emphasizes that the hippocampus plays an important role in learning, memory formation, and emotion regulation, and that changes in hippocampal morphology are a hallmark feature of depression and Alzheimer's disease. Notably, the hippocampus is particularly sensitive to changes in sex steroid levels. Thus, understanding how endogenous and exogenous steroid levels affect the hippocampus will contribute to the development of mechanistic models of depression and Alzheimer's disease risk in women.

Perimenopause or a key window of opportunity to prevent Alzheimer's disease

Overall, the risk of depression in women increases when sex steroid levels begin to rise during adolescence. Throughout the reproductive years, fluctuations in sex steroid levels during the menstrual cycle, during pregnancy, and during the transition to menopause may predispose some women to mood disorders that increase the risk of developing clinical depression. The review noted that brain changes associated with Alzheimer's disease begin to appear in midlife, coinciding with menopause. To date, menopause is the most widely studied specific risk factor for Alzheimer's disease in women, and some studies have proposed that the perimenopausal transition is a key window of opportunity for Alzheimer's disease prevention.

Alzheimer's Disease Risk May Be Lower With Longer Total Estradiol Exposure

Clinical researchers hypothesize that estradiol reduces signs of aging in the cerebrovascular and metabolic state of premenopausal women. Therefore, when estradiol levels decline during the menopausal transition, the effects of accelerated aging of the central nervous system and peripheral cells become apparent and may increase the risk of Alzheimer's disease.

The ability of the female brain to adapt to changes in estradiol levels during menopause may depend on a number of factors, including the extent of a woman's exposure to estradiol during her childbearing years. Some brain imaging studies have shown that the higher a woman's cumulative estradiol exposure over her lifetime, the lower her risk of developing Alzheimer's disease. In other words, the longer the reproductive period (the age interval between first menstruation and menopause), the more menstrual cycles, and the older the age at menopause, the longer the overall exposure to estradiol, which will likely reduce the risk of developing Alzheimer's disease. In contrast, natural or drug-induced premature menopause will result in a shorter reproductive life for women and may increase the risk of Alzheimer's disease.

The review emphasized that a woman's exposure to estradiol is further influenced by her reproductive history, exogenous hormone intake (in the form of hormonal contraception or menopausal hormone therapy), and genetics, all of which may affect brain health and the risk of developing Alzheimer's disease in later life. In addition, endocrine and metabolic disorders (e.g., polycystic ovary syndrome) can also affect a woman's lifetime levels of neutral steroid exposure. Overall, other important factors that influence women's brain health and risk of Alzheimer's disease in later life include overall health status, lifestyle factors (e.g., diet, nutrition, and sleep), and social determinants of health.