Perimenopause is a midlife transition state experienced by women that leads to reproductive senescence (loss of reproductive cells in the body).
As a psychoneuroendocrinologist, I’m interested in perimenopause because it affects mood and behavior. Perimenopause can contribute to depression and cognitive changes. It’s increasingly recognized that sex hormones like estrogen and testosterone are neuroprotective, i.e., protect the brain against insult and deterioration .
Women usually transition through perimenopause at an average age of 51.4 years. The process through to menopause, the final stage of perimenopause, takes 1–5 years from start to completion. This occurs after 12 months of amenorrhea (the absence of menstruation). Although primarily viewed as a reproductive transition, many symptoms of perimenopause are neurological in nature and occur as a result of estrogen depletion.
Functional Changes Observed in Perimenopause
The clinical definition of perimenopause focuses on functional changes in the reproductive system.
Reproductive senescence in women is defined by the depletion of oocytes (cells in the ovary). This is a process that begins at birth and continues until menopause is achieved.
The relatively wide age range (40–58 years) for menopause suggests that women either have a highly variable number of oocytes or that the rate of oocyte loss varies greatly between individuals. Perimenopause is characterized by increased variability in the length of the menstrual cycle and levels of circulating hormones. This is because there are fluctuations in the levels of hypothalamic, pituitary and ovarian hormones, resulting in ovulatory irregularities.
Estrogen is the primary female sex hormone and is a master regulator that functions in a number of key regions throughout the brain.
The role of estrogen in the brain – and its impact on mood and behavior – has been underappreciated until the last decade.
Estrogen affects specific neural circuits, those which (unsurprisingly) express a high number of estrogen receptors.
Although this distributed network of estrogen receptors forms the basis of the remarkable effects of estrogen in the brain, it can also be a point of vulnerability for the female brain.
During perimenopause, changes in levels of estrogen or its receptors networks result in a reduction in activity in key brain regions.
In many women, the brain compensates for these changes in estrogen levels during perimenopause. However, for some women this adaptive compensation is diminished, lacking or only expressed in some estrogen-regulated neural networks. Evidently, the main brain regions affected in the perimenopausal transition are heavily dependent upon estrogen to function effectively and, therefore, estrogen deficiencies give rise to a specific constellation of neuropsychiatric symptoms.
A substantial proportion of women (80%) are vulnerable to the neurological shifts that can occur during the perimenopausal transition.
Most women transition through perimenopause without long-term adverse effects. Yet some women emerge from this transition with an increased risk of neurological decline. Therefore, the presence, variability, intensity and duration of neurological perimenopausal symptoms could be warning signs for an increased risk of neurodegenerative diseases later in life. Neurological symptoms include:
The most frequent (often defining) feature of the perimenopausal transition is the hot flush.
This involves a disturbing and intense rise in body temperature, which is often sudden and short-lived, but can also last up to 60 minutes. It occurs in 75–80% of women in the perimenopausal phase and can continue for several decades (in less than 5% of women).
Hot flushes are generally caused by disruption to estrogen-regulated regions in the hypothalamus, which is the area of the brain that controls thermoregulation. This is a part of the brain with a high number of estrogen receptors.
Hot flushes can also cause severe stress and anxiety in many women, and can co-occur with the neurological symptoms outlined below.
Insomnia is a prevalent symptom of the perimenopausal transition and is frequently associated with the other symptoms.
The hypothalamus is the part of the brain that regulates sleep–wake cycles and relies heavily upon estrogen to function. A reduction in estrogen results in disruption of the regulation of sleep and circadian rhythms. Studies reveal that the prevalence of sleep disturbance is 28%-40% and sleep difficulties are maximal during late perimenopause and persist into postmenopause.
Subjective and objective memory deficits during the perimenopause have been well documented. Estrogen results in low activity in brain regions required for learning and memory function (e.g. prefrontal cortex, hippocampus, cingulate cortex).
These estrogen decrements affect verbal learning, verbal memory, working memory and fine motor skills. Such reduction in activity in the brain is associated with neurodegenerative diseases in later years.
There is an increased risk of depression in perimenopausal women, which can occur early in the perimenopausal transition. This even applies to women with no previous history of affective symptoms. The function of brain regions that regulate depression is byzantine.
Depression is also linked to a reduction of activity in the pons (which is affected by estrogen).
The experience of the perimenopausal transition can be highly variable. For some women intervention is necessary, and failing to intervene would be negligent.
When evaluating patients, I will identify the best strategy to maintain mood and neurological functioning in women during the perimenopausal and menopausal transition states.
Estrogen replacement therapy
Given that estrogen regulates key systems in the brain that contribute to perimenopausal symptoms, Estrogen replacement therapy is a logical choice.
Therapy has been shown to preserve activity in brain regions with estrogen-dependent neurological functions. It has also been shown to prevent a reduction in activity in cognitive brain regions and preserve memory function.
With regards to depression, the timing of the administration of estrogen therapy appears to be critical to the effectiveness of treatment, as treatment after perimenopause (5-10 years later) may be less effective.
Furthermore, in perimenopausal women with depression, estrogen replacement often has an antidepressant effect.
Nonetheless, many women do not choose Estrogen Replacement Therapy because the data on the benefits and risks of estrogen replacement therapy are complicated, controversial and confusing. The importance of seeking advice from qualified professionals so that therapy can be optimized and personalized remains paramount. This will allow for the best decision over how to deal with the symptoms of perimenopause.
 Behl C. Sex hormones, neuroprotection and cognition. Prog Brain Res. 2002;138:135-42.