In search of answers

Metabolic syndrome

Many risk factors for heart disease, stroke and type 2 diabetes overlap. Metabolic syndrome refers to a cluster of risk factors, including obesity, high blood pressure, high blood sugar and abnormal levels of fat (lipid) in the blood, that increases the likelihood of developing these conditions.

Oestrogen protects pre-menopausal women from the metabolic syndrome. So, women who experience early natural menopause are particularly likely to develop metabolic syndrome.

For example, researchers analysed the health records of more than 234,000 women who experienced a natural menopause between 30-60 years of age. About one in eight (11.7 per cent) had metabolic syndrome.

However, women who experience early natural menopause (40 years or younger) are about a quarter (27 per cent) more likely to develop metabolic syndrome than those with late menopause (50 years or older).

“Our findings show that age at natural menopause isn’t just a reproductive milestone – it’s a powerful indication of long-term cardiometabolic risk.

Recognising early menopause as a marker for metabolic syndrome gives clinicians a crucial window to identify at-risk women sooner and intervene earlier to prevent heart disease, diabetes and other complications,” says one of the study’s authors Dr Shefali Setia Verman, from the University of Pennsylvania.

Digestive health

A UK online survey of 564 people aged 44-73 found that more than nine out of 10 (94 per cent) perimenopausal and menopausal women experience gastrointestinal symptoms.

Bloating (77 per cent), constipation (54 per cent), stomach pain (50 per cent) and acid reflux (49 per cent) emerged as the most common digestive issues. Four in five (82 per cent) of those with gastrointestinal symptoms reported that the digestive problems began or worsened during the perimenopause and menopause.

Most women did not receive the support they felt they needed. Most (89 per cent) women with gastrointestinal symptoms tried self-management, such as dietary changes, stress management and supplements.

Only 53 per cent had sought professional support: 58 per cent of these felt that the professional support was inadequate. Indeed, 85 per cent wanted more information and help.

“Digestive health problems at midlife are often brushed aside, yet our research shows they are both widespread and impactful for women,” says Nigel Denby, lead author and registered dietitian and founder of Your Menopause by Harley Street at Home.

“By raising awareness of this hidden burden, we hope to encourage healthcare professionals to ask the right questions, validate women’s experiences and work towards better support and treatment options during menopause.”

The menopausal brain

Up to three in five perimenopausal and postmenopausal women report cognitive changes, such as brain fog and memory lapses, Nature Medicine noted in March 2025. The menopause may also influence the risk of developing Alzheimer’s disease.

A protein called apolipoprotein E (APOE) transports fats in the blood, helps the brain repair and influences the likelihood of developing Alzheimer’s disease. Geneticists identified several variations in the APOE gene including one known as APOE e4.

We inherit two copies of the APOE gene: one each from our biological mother and father. Having one APOE e4 variant doubles or triples the likelihood of Alzheimer’s disease. Someone with two APOE e4 variants is eight to 12 times more likely to develop Alzheimer’s disease than a person without a copy.

Two-thirds of Alzheimer’s disease patients are female; in part because women live longer than men. Women are more likely to develop age-related conditions, such as Alzheimer’s disease. But that’s not the whole story. For example, oestrogen helps brain cells take up glucose, which is the brain’s energy source.

As some nerves fire a thousand times a second, the brain needs a lot of energy. Indeed, the adult brain accounts for about two per cent of body weight, but consumes approximately 20 per cent of our glucose intake. When glucose levels fall too low, the brain starts “to consume its own tissue”, Nature Medicine commented. So, earlier menopause increases the risk for late-life decline in cognition and Alzheimer’s disease partly because the brain receives less glucose.

Alzheimer’s disease

Against this background, researchers followed 2,575 women aged on average 77.4 years for eight years and measured levels of proteins in their blood that are linked with inflammation.

A three-way relationship emerged. Firstly, the association between earlier menopause and faster memory decline was especially marked for women carrying the APOE e4 gene.

Secondly, higher levels of inflammation exacerbated the effect of earlier menopause on memory decline irrespective of APOE genes.

Thirdly, however, inflammation increased menopause-related memory decline more strongly in APOE e4 carriers than in non-carriers.

In other words, “APOE e4 and age-related inflammation strengthened the link between earlier age at menopause and faster memory decline, suggesting that these factors may be especially salient contributors to Alzheimer’s disease dementia risk in women with earlier menopause,” the authors concluded.

“Approximately 20 per cent of Alzheimer’s therapeutics in development target genetic and inflammatory factors. Yet, sex differences and female-specific risk factors like menopause are often overlooked in clinical trials.

Understanding how female biology influences Alzheimer’s disease risk is key to ensure we develop effective treatments for all individuals at risk,” says Madeline Wood Alexander, lead author, University of Toronto and Sunnybrook Research Institute.

Grey matter matters

Indeed, the brain changes markedly during the menopause. For example, several studies found reductions in the volume of grey matter in the frontal and temporal cortices, and the seahorse-shaped hippocampus of menopausal women.

These losses may contribute to worsening cognitive performance, particularly in verbal and visuospatial (visual form and location) memory during and after the menopause.

Meanwhile, white matter hyperintensities are bright spots on brain scans that often indicate damaged tissue typically following reduced blood flow.

Increased white matter hyperintensities are particularly common among women with early menopause or those with frequent hot flushes. The hyperintensities seem to be linked with, for example, cognitive decline, issues with balance and mood changes, and an increased risk of stroke and dementia.

Grey matter may partly recover after the menopause. The brain is not hard-wired like a computer and can create new nerves and connections (neuroplasticity). 

In addition, oestrogen binds to specific receptors (rather like a key fitting a lock) which switches on the pathways that lead to oestrogen’s biological action, such as controlling reproduction or glucose uptake by brain cells.

The number of oestrogen receptors may increase in response to declining hormone levels during and after the menopause. Nevertheless, “persistent disruptions” in metabolism and the connections between nerves and “suggest lasting effects on brain health”.

“This study represents the cumulative body of scientific knowledge relative to structural changes that take place in the brain during menopause,” says Dr Stephanie Faubion, medical director for The Menopause Society.

“This data will hopefully lead to a better understanding of the factors underlying some of the cognitive concerns experienced by women during the menopause transition so that we can ultimately identify effective therapies.”

Autoimmune diseases

Essentially, the immune system seeks and destroys bacteria, viruses, fungi, parasites, cancers and other threats to our health and wellbeing. The immune system also targets damaged tissue and so hastens wound healing and regulates inflammation.

The immune system recognises healthy cells, but does not attack (so-called tolerance). In autoimmune diseases, the immune system mistakenly attacks healthy tissue.

About three-quarters of people who have autoimmune diseases are females, and hormones probably contribute to a woman’s increased risk alongside environment and stress.

US researchers compared 889,413 postmenopausal women aged on average 60.5 years using hormonal replacement therapy (HRT) with the same number of non-users (controls). 

HRT users were about a quarter (27 per cent) more likely to experience an autoimmune disease after the menopause than controls: 9.0 per cent and 7.1 per cent respectively.

HRT increases in risk were observed for all autoimmune diseases except Graves’ disease and autoimmune hepatitis, which affect the thyroid gland and liver respectively. The increased risk ranged from three per cent for psoriasis to almost three times (2.90) for lichen sclerosus (both skin diseases).

“Our study found a statistical link between hormone therapy and autoimmune diseases, but the actual increase in absolute risk is relatively small and varies by condition. Because this was a retrospective database study, more research is needed before drawing firm conclusions."

"Hormone therapy remains a safe and important option for many women when used appropriately but, like any treatment, it should be individualised while we await more research on its possible links to autoimmune disease,” says lead author Dr Xuezhi Jiang, professor of obstetrics and gynaecology, Drexel University College of Medicine, Philadelphia.

The menopause is inevitable for almost every woman. But it seems that further research needs to uncover all the mysteries of the menopause.

Hopefully, however, recent and ongoing research will help community pharmacy teams support women experiencing “one of society’s most overlooked health challenges”.