Postmenopausal confusion, also commonly referred to as postmenopausal brain fog, is a group of symptoms of

menopause Menopause, also known as the climacteric, is the time when Menstruation, menstrual periods permanently stop, marking the end of the Human reproduction, reproductive stage for the female human. It typically occurs between the ages of 45 and 5 ...

in which women report problems with

cognition Cognition is the "mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...

at a higher frequency during postmenopause than before. Multiple studies on

cognitive Cognition is the "mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...

performance following menopause have reported noticeable declines in greater than 60% of the patients. The common issues presented included impairments in reaction time and attention, difficulty recalling numbers or words, and forgetting reasons for involvement in certain behaviors. Association between subjective cognitive complaints and objective measures of performance show a significant impact on health-related quality of life for postmenopausal women. Treatment primarily involves symptom management through non-pharmacological treatment strategies. This includes involvement in

physical activity Physical activity is defined as any voluntary movement produced by skeletal muscles that requires energy expenditure.Global Recommendations on Physical Activity for Health, 2009. World Health Organization. Geneva, Switzerland. Accessed 13/07/2018 ...

and following medically supervised diets, especially those that contain

phytoestrogen A phytoestrogen is a plant-derived xenoestrogen (a type of estrogen produced by organisms other than humans) not generated within the endocrine system, but consumed by eating plants or manufactured foods. Also called a "dietary estrogen", it ...

s or

resveratrol Resveratrol (3,5,4′-trihydroxy-''trans''-stilbene) is a stilbenoid, a type of natural phenol or polyphenol and a phytoalexin produced by several plants in response to injury or when the plant is under attack by pathogens, such as bacterium, ba ...

. Pharmacological interventions in treating postmenopausal confusion are currently being researched.

Hormone replacement therapy Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. Effects of menopause can include symptoms such ...

(HRT) is currently not indicated for the treatment of postmenopausal confusion due to inefficacy. The use of HRT for approved indications has identified no significant negative effect on postmenopausal cognition. Although much of the literature references women, all people who undergo menopause, including those who do not self-identify as women, may experience symptoms of postmenopausal confusion.

History

Research on menopause as a whole declined with the end of the

Women's Health Initiative The Women's Health Initiative (WHI) was a series of clinical studies initiated by the U.S. National Institutes of Health (NIH) in 1991, to address major health issues causing morbidity and mortality in postmenopausal women. It consisted of three ...

(WHI) studies, but research on the treatment of symptoms associated with menopause—especially the treatment of cognitive decline—continues. The Study of Women's Health Across the Nation (SWAN), first started in 1996, continues to publish progress reports which include cognitive symptoms associated with menopausal transition, including those in postmenopause. , SWAN indicated, "Approximately 60% of midlife women report problems with memory during the enopause transition yet studies of measured cognitive performance during the transition are rare." Although there are many relationships between hormone levels in postmenopause and cognitive function, the previously favored HRT therapies (

estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

therapies) have been shown to be ineffective in specifically treating postmenopausal confusion. The use of hormone replacement therapies, once considered detrimental to cognition in postmenopausal women, has now been shown to have no negative effect when used properly for approved indications. There are no conclusive studies to support any pharmacological agents, but several potential drug candidates are still being explored.

Presentation

Menopause is a natural decline in the ovarian function of women who reach the age between 45 and 54 years. "About 25 million women pass through menopause worldwide each year, and it has been estimated that, by the year 2030, the world population of menopausal and postmenopausal women will be 1.2 billion, with 47 million new entrants each year." Postmenopause begins immediately following menopause (one year after the final

menstrual cycle The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that makes pregnancy possible. The ovarian cycle controls the production and release of eg ...

). Postmenopausal confusion is often manifested through the following cognitive symptoms: memory problems, forgetfulness, and poor concentration.

Confusion In psychology, confusion is the quality or emotional state of being bewildered or unclear. The term "acute mental confusion"

which is otherwise unexplained and coincides with the onset of postmenopause may be postmenopausal confusion.

Causes

Risk factors

Hypertension

A 2019 literature review identified

hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...

and history of

pre-eclampsia Pre-eclampsia is a multi-system disorder specific to pregnancy, characterized by the new onset of hypertension, high blood pressure and often a significant amount of proteinuria, protein in the urine or by the new onset of high blood pressure a ...

as significant risk factors for the accelerated decline of cognitive function in women during midlife. Although the mechanism remains unclear,

neuroimaging Neuroimaging is the use of quantitative (computational) techniques to study the neuroanatomy, structure and function of the central nervous system, developed as an objective way of scientifically studying the healthy human brain in a non-invasive ...

studies included in the review found that those with hypertension have evident structural changes in their brains; specifically,

gray matter Grey matter, or gray matter in American English, is a major component of the central nervous system, consisting of neuronal cell bodies, neuropil (dendrites and unmyelinated axons), glial cells (astrocytes and oligodendrocytes), synapses, and ...

brain volume decreased and

white matter White matter refers to areas of the central nervous system that are mainly made up of myelinated axons, also called Nerve tract, tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distr ...

hyperintensity volume increased.

Atherosclerosis and comorbidities

Atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...

and comorbidities such as

hyperlipidemia Hyperlipidemia is abnormally high levels of any or all lipids (e.g. fats, triglycerides, cholesterol, phospholipids) or lipoproteins in the blood. citing: and The term ''hyperlipidemia'' refers to the laboratory finding itself and is also use ...

and

diabetes mellitus Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained hyperglycemia, high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or th ...

have long been considered risk factors for cognitive decline because they have the propensity to cause the formation of

amyloid plaques Amyloid plaques (also known as neuritic plaques, amyloid beta plaques or senile plaques) are extracellular deposits of amyloid beta (Aβ) protein that present mainly in the grey matter of the brain. Degeneration (medical), Degenerative neuronal ...

(aggregates of misfolded, deleterious proteins) in the brain.

Insomnia

Many postmenopausal women report

insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...

. Studies have shown "associations between poor sleep quality and cognitive decline" in postmenopausal women as those with insufficient sleep, or with difficulty falling or staying asleep, reported decreased cognitive performance including "verbal memory,

attention Attention or focus, is the concentration of awareness on some phenomenon to the exclusion of other stimuli. It is the selective concentration on discrete information, either subjectively or objectively. William James (1890) wrote that "Atte ...

, and general cognition."

Depression

There is evidence linking depression and cognitive decline in postmenopausal women. Research suggests that increased

cortisol Cortisol is a steroid hormone in the glucocorticoid class of hormones and a stress hormone. When used as medication, it is known as hydrocortisone. Cortisol is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal corte ...

levels from depressive episodes may affect the

hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...

, area of the brain responsible for

episodic memory Episodic memory is the memory of everyday events (such as times, location geography, associated emotions, and other contextual information) that can be explicitly stated or conjured. It is the collection of past personal experiences that occurred ...

. Studies have also shown a correlation between depression and decreased cognitive performance including "

processing speed Processing is a free graphics library and integrated development environment (IDE) built for the electronic arts, new media art, and visual design communities with the purpose of teaching non-programmers the fundamentals of computer programmi ...

verbal memory Verbal memory is a term used in cognitive psychology which refers to memory of words and other abstractions involving language. A variety of tests is used to test verbal memory, including learning lists or pairs of words, or recalling a story after ...

, and

working memory Working memory is a cognitive system with a limited capacity that can Memory, hold information temporarily. It is important for reasoning and the guidance of decision-making and behavior. Working memory is often used synonymously with short-term m ...

" in postmenopausal women.

Hot flashes

There are studies indicating a correlation between frequency of

hot flash Hot flushes are a form of flushing, often caused by the changing hormone levels that are characteristic of menopause. They are typically experienced as a feeling of intense heat with sweating and rapid heartbeat, and may typically last from t ...

es in postmenopausal women and a deficit in verbal memory performance. It is suggested that faster blood flow in the brain or higher

levels from hot flashes may cause changes in the brain and affect information processing and memory.

Surgical menopause

A 2019 systematic review and meta-analysis identified surgical menopause, especially when performed at or before the age of 45, as a substantial risk factor for cognitive decline and

dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...

Cardiac procedures

Axial PSIR MRI of a brain with multiple sclerosis lesions

Cardiac procedures such as invasive cerebral and coronary angiography, coronary artery bypass graft surgery (CABG), surgical

aortic valve replacement Aortic valve replacement is a cardiac surgery procedure whereby a failing aortic valve is replaced with an artificial heart valve. The aortic valve may need to be replaced because of aortic regurgitation (back flow), or if the valve is narro ...

, and transcatheter aortic valve replacement (TAVR) have been found to increase the risk of cognitive decline in females as they been found to increase the incidence of brain

lesions A lesion is any damage or abnormal change in the tissue of an organism, usually caused by injury or diseases. The term ''Lesion'' is derived from the Latin meaning "injury". Lesions may occur in both plants and animals. Types There is no de ...

Mechanism

The mechanism of postmenopausal confusion is poorly understood due to simultaneous aging-related physiological changes, as well as differential diagnoses presenting with similar symptoms. Research remains ongoing.

Treatment

Overview

There are pharmacological and non-pharmacological considerations in improving the symptoms of postmenopausal confusion. Currently, no pharmacological agents are indicated to treat postmenopausal confusion, but research remains ongoing. Non-pharmacological strategies to manage postmenopausal confusion symptoms are utilized, with focus on diet and exercise.

Pharmacological

Hormone therapy

Hormone therapy Hormone therapy or hormonal therapy is the use of hormones in medical treatment. Treatment with hormone antagonists may also be referred to as hormonal therapy or antihormone therapy. The most general classes of hormone therapy are hormonal therap ...

, also known as estrogen therapy, was previously a common treatment for postmenopausal confusion. However, more recent research indicates that ''hormone therapy is not an effective treatment'' for postmenopausal cognitive symptoms. A 2008 Cochrane review of 16 trials concluded that there is a body of evidence that suggests that hormone replacement therapy is unable to prevent cognitive decline or maintain cognitive function in healthy postmenopausal women when given over a short or long period of time. Conversely, studies have also suggested that the use of hormone replacement therapy are unlikely to have negative cognitive effects when used for their approved indications. Previous research suggested that increases in blood flow to the hippocampus and temporal lobe occurred from hormone therapy, improving postmenopausal confusion symptoms. More recent research no longer supports this, and is inconclusive as to the true effects of estrogen on hippocampal volume as studies show results differing from improved cognition and maintained hippocampal volume when hormone therapy is administered during menopause to results showing no obvious beneficial results. Research focusing on adiponectin (ADPN) has yielded positive results in the development of possible treatments for postmenopausal confusion. A study has shown an association between higher levels of ADPN and increased cognitive performance in postmenopausal women. However, an ADPN receptor agonist has yet to be discovered.

Psychostimulant therapy

There is ongoing research regarding the efficacy of psychostimulant drugs such as lisdexamphetamine (Vyvanse) and

atomoxetine Atomoxetine, formerly sold under the brand name Strattera, is a selective norepinephrine reuptake inhibitor (sNRI) medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, cognitive disengagement syndr ...

(Strattera) in treating postmenopausal and menopausal confusion.

Non-pharmacological

Diet

Individuals play an important role in maintaining their cognitive health. One way to achieve this is by the promotion of healthy nutrition. In particular, the

Mediterranean diet The Mediterranean diet is a concept first proposed in 1975 by the American biologist Ancel Keys and chemist Margaret Keys. The diet took inspiration from the eating habits and traditional food typical of Crete, much of the rest of Greece, and s ...

, defined as being low in

saturated fat A saturated fat is a type of fat in which the fatty acid chains have all single bonds between the carbon atoms. A fat known as a glyceride is made of two kinds of smaller molecules: a short glycerol backbone, and fatty acids that each cont ...

and high in vegetable oils, showed improvement in aspects of cognitive function. This diet consists of low intake of sweets and eggs, moderate intakes of meat and fish, dairy products and red wine, and high intake of leafy green vegetables, pulses/legumes and nuts, fruits, cereal, and cold pressed extra virgin olive oil. Further analysis concluded that the Mediterranean diet supplemented by olive oil resulted in better cognition and memory as compared to the Mediterranean diet plus mixed nuts combination.

Supplementation

Soy isoflavones Isoflavones are a type of naturally-occurring isoflavonoids, many of which act as phytoestrogens in mammals. Isoflavones occur in many plant species, but are especially high in soybeans. Although isoflavones and closely-related phytoestrogens are ...

(SIF), a type of

which can be found in soybeans, fruits and nuts, has been shown to improve cognitive outcomes in recent postmenopausal women of less than 10 years. This suggests that the initiation of SIF may have a critical margin of opportunity when used at a younger age in postmenopausal women. In addition to improved cognitive functions and visual memory, no evidence of harm from SIF supplementation was revealed with the dose ranges tested in multiple trials. Analysis of multiple randomized controlled trials have brought attention to

black cohosh ''Actaea racemosa'', the black cohosh, black bugbane, black snakeroot, rattle-top, or fairy candle ( syn. ''Cimicifuga racemosa''), is a species of flowering plant of the family Ranunculaceae. It is native to eastern North America from the ext ...

and

red clover ''Trifolium pratense'' (from Latin prātum, meaning meadow), red clover, is a herbaceous plant, herbaceous species of flowering plant in the bean family, Fabaceae. It is native to the Old World, but planted and naturalised in many other regions ...

(which contain

) and its potential as an efficacious treatment of menopausal symptoms. Black cohosh did not reveal any evidence of risk of harm, but lack of good evidence cannot firmly conclude its safety. Overall, the results suggested that neither botanical treatments provided any cognitive benefits.

Resveratrol Resveratrol (3,5,4′-trihydroxy-''trans''-stilbene) is a stilbenoid, a type of natural phenol or polyphenol and a phytoalexin produced by several plants in response to injury or when the plant is under attack by pathogens, such as bacterium, ba ...

, another bioactive compound derived from plants, has also shown to improve cognitive performance in postmenopausal women. There are ongoing trials studying the cognitive benefits of resveratrol in early versus late postmenopausal women. Chronic

ginkgo biloba ''Ginkgo biloba'', commonly known as ginkgo or gingko ( ), also known as the maidenhair tree, is a species of gymnosperm tree native to East Asia. It is the last living species in the order Ginkgoales, which first appeared over 290 million year ...

supplementation has been shown to improve "mental flexibility" in "older and more cognitively impaired" postmenopausal women. However, a combined ginkgo biloba and

ginger Ginger (''Zingiber officinale'') is a flowering plant whose rhizome, ginger root or ginger, is widely used as a spice and a folk medicine. It is an herbaceous perennial that grows annual pseudostems (false stems made of the rolled bases of l ...

supplementation had no effect on memory or cognitive performance in postmenopausal women.

Dehydroepiandrosterone Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone precursor. It is one of the most abundant circulating steroids in humans. DHEA is produced in the adrenal glands, the gonads, and the brain. It funct ...

(

DHEA Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone precursor. It is one of the most abundant circulating steroids in humans. DHEA is produced in the adrenal glands, the gonads, and the brain. It functio ...

) supplementation may improve cognition in women with postmenopausal confusion but does not benefit those without cognitive impairment. More long-term studies are required to study the efficacy of DHEA and its role in cognition and postmenopausal women.

Exercise

Regular

physical exercise Exercise or workout is physical activity that enhances or maintains fitness and overall health. It is performed for various reasons, including weight loss or maintenance, to aid growth and improve strength, develop muscles and the cardio ...

may prevent symptoms of postmenopausal confusion. Studies have shown an association between exercise and "lower rates of cognitive decline" in postmenopausal women. On the other hand, an inactive lifestyle has been strongly associated with "higher rates of cognitive decline" in postmenopausal women.

Mind-body therapy

Studies have shown benefits of mind-body therapies in women with postmenopausal symptoms including cognitive impairment.

Mindfulness Mindfulness is the cognitive skill, usually developed through exercises, of sustaining metacognitive awareness towards the contents of one's own mind and bodily sensations in the present moment. The term ''mindfulness'' derives from the Pali ...

hypnosis Hypnosis is a human condition involving focused attention (the selective attention/selective inattention hypothesis, SASI), reduced peripheral awareness, and an enhanced capacity to respond to suggestion.In 2015, the American Psychological ...