Estrogen actions

The classic view of estrogen actions in the brain was confined to regulation of ovulation and reproductive behavior in the female of all mamamalian species studied, including humans.

Burgeoning evidence now documents profound effects of estrogens on learning, memory, and mood as well as neurodevelopmental and neurodegenerative processes.

Most data derive from studies in females, but there is mounting recognition that estrogens play important roles in the male brain, where they can be generated from circulating testosterone by local aromatase enzymes or synthesized de novo by neurons and glia.

This is a comprehensive review of the effects of estradiol in the brain which (though a couple of years old) is loaded with information and reference.

Investigations in the hypothalamus first revealed sexually dimorphic effects of estradiol on synaptic remodeling, glial plasticity, and neuronal activity (including GABAergic interneurons and glutamatergic, cholinergic, and dopaminergic populations), as well as ER expression, intracellular signaling pathways, and transcriptional control, which could be related to the neuroendocrine control of reproduction and sex-specific reproductive behaviors.

However, it came as some surprise to find that similar sexually dimorphic responses to estradiol are present in brain regions that are not directly associated with reproductive success but are important for learning, memory, emotional responding, mood, and sensorimotor control, including the hippocampus, PFC, striatum, and amygdala.

An emerging theme for all these brain regions identifies sex-specific organization of susceptible neural circuitries at critical stages of development as a major factor underlying the sexually dimorphic effects of estrogens in the brain.

This is dependent to a large extent on a transitory surge of testosterone production in males during development, which, after its conversion to estradiol, masculinizes and defeminizes the brain; of particular significance is that the defeminizing actions result in the loss of capacity to respond to the feminizing actions of estradiol in adulthood.

In the hypothalamus, this achieves the necessary sex differences in functions to secure reproductive success, but for other brain regions this may be considered a disadvantage. Indeed, learning and experience may further modify certain circuitries to achieve similar outcomes for critical functions, such as cognition and sensorimotor integration, although they are attained by different mechanisms in male and female brains

These sex differences in connectivity and estrogen responsiveness have important implications for the different vulnerabilities of men and women to psychiatric and neurodegenerative conditions, especially under conditions of stress, where adaptive responses may result in a different degree of allostatic load in sex specific circuitries.

Together, these observations highlight the urgent need for a better understanding of the nature and origins of brain sex dimorphisms to realize the full potential of hormone-based therapies. Given the depth and breadth of the evidence for differential actions of estradiol in male and female brains, it is also important to redress the fact that the majority of preclinical studies still focus on estrogenic actions in the brains of ovariectomized female rodents, whereas menopausal women are the main focus of clinical studies; hence, data relate only to half the population.