Estradiol and the Brain

Estradiol is the most potent and most abundant estrogen in females and is the principal growth hormone required for their reproductive development. Estradiol supports growth of the vagina, the fallopian tubes, the endometrium and the cervical glands. The hormone is also required to maintain oocytes (eggs in the ovary) and triggers a series of events that lead to ovulation.

In males, a small amount of estradiol is produced in the testes and helps sperm to mature, as well as maintaining a healthy libido. Estradiol is one of two active metabolites of the male hormone testosterone. The other active metabolite of testosterone is dihydrotestosterone.

Estradiol and the brain

The developing brain expresses high levels of estradiol receptors (nuclear transcription factors), which regulate gene expression as well as acting at the membrane level to stimulate signalling pathways. Estradiol is therefore required for a lot more than reproductive processes in females. This versatile hormone regulates sexual differentiation of the brain, as well as providing protective effects in the bone, brain and cardiovascular system.

In the nervous system, this hormone has important effects on a range of brain areas involved in functions such as fine motor control, learning, memory, sensitivity to pain and motor coordination, as well protecting against stroke damage and Alzheimer’s disease.

Some of the effects of estradiol on brain function are described below.

Mood

Estrogens affect the serotonergic, dopaminergic, noradrenergic and cholinergic systems, which all play a role in mood. Research has shown that estrogen plays a role in depressive illness, demonstrating antidepressant effects in humans and influencing responses to antidepressant medication in animals.

Cognitive function

Verbal memory, spatial ability and fine motor skills are all influenced by estrogens and the strategies used to solve spatial or navigational puzzles differs between males and females.

Dementia

Open trials of estrogen therapy in women have demonstrated a prospective benefit of the therapy on cognitive function in women without dementia. Among elderly women who take post-menopausal estrogen replacement therapy, there is a lower incidence of death caused by Alzheimer’s disease compared with those who do not take ERT.

Pain

Murine studies have shown that different pain pathways are used in males and females, pathways that are regulated by the gonadal steroids and in particular, estrogen.

Stroke

In experimental models of stroke, estrogens play an important role in protecting against the damage caused by ischemia.

Estradiol and the menopause

In the central nervous system, estrogen has been shown to increase cerebral blood flow, provide anti-inflammatory effects, promote neuronal synapse activity and to exert both neuroprotective and neurotrophic effects on tissues in the brain.

The brain relies solely on blood flow as a source of energy to function and blood vessels make up around one third of the brain. Estrogen is known to increase cerebral perfusion by binding to endothelial receptors and stimulating nitric oxide release, which leads to vasodilation. At the neuronal synapse, estrogen increases levels of the neurotransmitters serotonin, dopamine and norepinephrine, as well as increasing the number of receptors for these chemicals. Estrogen has been shown to confer neuroprotective effects against oxidative stress, ischemic damage and the damage caused by amyloid protein, which is involved in the pathogenesis of Alzheimer’s disease. This hormone also promotes the growth and repair of neurons and stimulates the production of nerve growth factors.

Through these various mechanisms, estrogen has a large influence on emotions, mood and cognitive function, all of which may be affected during the menopause, when estrogen levels start to decline. Symptoms that may arise during the menopause include mood changes, memory problems and hot flushes. The prevalence of Alzheimer’s disease (which is more prevalent in women than men) has also been associated with a deficiency in estrogen in some studies.

Physicians should be aware of these associations when advising female patients about some of the symptoms they may experience during mid-life as well as educating them about the potential benefits of estrogen replacement therapy. Such benefits may include an overall improved sense of well-being, improved cognitive function and a reduced risk of Alzheimer’s disease.