Primary Research

The evidence base

The research behind my work

These research articles are a window into the thinking behind my work. I am drawn to studies that look at the body as an integrated system, and at menopause within its wider biological, environmental, and cultural context. This is where the picture becomes more nuanced — and often more useful.

Some of the research included here is not new but I have chosen to keep it here because it represents important turning points in my own understanding of the biological underpinnings of menopause, work that shifted how I think, how I look at symptoms, and how I support women in practice. It holds sentimental value!

What follows is a considered selection of research and ideas that have shaped how I approach clinical work, and how I interpret the patterns that emerge over time. It is not intended as a comprehensive library, but as a window into the depth behind the method.

Inflammation and insulin resistance partially mediate the relationship between age at menopause and depression in postmenopausal women

This study looked at more than 7,000 women over 60 in the US (NHANES 2005–2020) to understand how the age at menopause relates to depression in later life, and whether inflammation and insulin resistance help explain that link.​

What the researchers did
  • Included women aged 60+ who reported their age at menopause, use of hormone therapy, health conditions and lifestyle, and who completed the PHQ‑9 depression questionnaire (depression defined as PHQ‑9 ≥10).​
  • Measured blood C‑reactive protein (CRP) as a marker of chronic inflammation and calculated HOMA‑IR as a marker of…

Does Risk for Anxiety Increase During the Menopausal Transition?

3,000 women were followed for 10 years to ask a simple question: does the menopausal transition itself increase the risk of significant anxiety symptoms?

What was done
  • Participants were 42–52 years old at the start, pre‑ or early perimenopausal, and then assessed annually for a decade in the SWAN study.
  • Anxiety was measured as a cluster of four symptoms (irritability, nervousness/tension, feeling fearful for no reason, heart racing/pounding), rated for frequency over the past two weeks; “high anxiety” was defined as scores…

Anxiety as a risk factor for menopausal hot flashes

This long-term study followed 233 women from before menopause to after their final period to see how different types of anxiety relate to hot flushes. Anxiety was split into two parts: somatic anxiety (physical tension symptoms such as heart racing, sweating, trembling, bodily restlessness) and affective anxiety (worry, nervousness, fear).

  • Over 14 years, 72% of women reported moderate or severe hot flushes.
  • Somatic anxiety was a powerful predictor of hot flushes. After accounting for menopausal stage, women with higher somatic anxiety had about three times the…

Menopause and Alzheimer’s disease susceptibility: Exploring the potential mechanisms

This review looks at how menopause may increase the chance of developing Alzheimer’s disease, and which biological changes might be responsible. It notes that most people with Alzheimer’s are women, that earlier menopause is linked with higher dementia risk, and that most lab research on Alzheimer’s has been done in males, so the female midlife brain has been neglected.

Hormones and brain protection
  • Estradiol is described as strongly supportive of the brain: it helps nerve cells communicate, grow and repair,…

Sleep characteristics and white matter hyperintensities among midlife women

This study followed 122 late peri‑ and postmenopausal women (average age 59) to see how their sleep relates to early brain changes that raise the risk of stroke and dementia. Each woman wore a sleep‑tracking watch for three nights, then had a brain MRI to look for white matter hyperintensities (WMH) – small “bright spots” that indicate damage to tiny blood vessels and their surrounding brain tissue.

The key finding was that sleep fragmentation – how much time women were awake…

Postmenopausal sarcopenia and Alzheimer’s disease: The interplay of mitochondria, insulin resistance, and myokines

Postmenopausal sarcopenia and Alzheimer’s disease (AD) are linked through a shared muscle–brain metabolic pathway. It highlights that women make up around two‑thirds of AD cases and that more than 60% are postmenopausal, then argues that loss of skeletal muscle mass and function in this group is closely associated with increased risk of cognitive decline.​

Core pathophysiology
  • Menopause‑related oestrogen decline and ageing drive skeletal muscle changes: mitochondrial dysfunction, increased reactive oxygen species, chronic low‑grade inflammation, and insulin resistance characterised by reduced GLUT4‑mediated…

Brain aging shows nonlinear transitions, suggesting a midlife “critical window” for metabolic intervention

This study used MRI and body measures from more than 19,000 people to show that brain activity does not age in a straight line but goes through sharper “turning points,” with a key shift starting in the 40s. Comparison of metabolic, vascular, and inflammatory biomarkers implicates disrupted blood sugar regulation as the main driver of these transitions.

Links between where the brain ages fastest and patterns of gene expression point specifically to GLUT4 (the insulin‑dependent glucose transporter) and APOE…

Associations between moderate alcohol consumption, brain iron, and cognition

An analysis of whether “moderate” alcohol intake (even within current guidelines) is linked to higher iron in the brain and, in turn, to worse cognitive performance.

  • Using nearly 21,000 UK Biobank participants with brain MRI, the authors found that people drinking more than about 7 units of alcohol per week had higher iron levels in several deep brain regions (especially the basal ganglia), compared with lighter drinkers.
  • Higher brain iron was associated with poorer performance on tests of processing speed,…

Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer’s disease

Age‑related cognitive decline, including Alzheimer’s disease, can be understood as a myelin problem rather than only a “plaques and tangles” problem. Myelin is the fatty insulation around nerve fibres that makes brain signalling fast and efficient; in humans it continues to be built well into midlife, especially in frontal and temporal brain regions that support complex thinking. Because myelin is so metabolically expensive and turns over, it becomes increasingly vulnerable with age to oxidative damage, metabolic stress, and vascular insults, particularly…

No time to die: Evolution of a post-reproductive life stage

In a small number of animal species, females cease reproducing long before the end of their natural lifespan. A prolonged post‑reproductive life stage is exceptionally rare; strong evidence for it is currently confined to humans, Asian elephants, and four toothed whale species. At face value, this pattern appears to conflict with the expectation that evolution […]

Roles for osteocalcin in brain signalling: implications in cognition- and motor-related disorders

A hormone made by bone, osteocalcin, helps regulate blood sugar, mood, memory and movement by acting on the brain as well as the rest of the body. In animal and human data, low osteocalcin is linked with diabetes‑like metabolism, anxiety‑ and depression‑like behaviour, poorer learning and memory, and Parkinson’s‑like movement problems, while giving osteocalcin can improve these features in models. The authors propose that common age‑related issues such as osteoporosis, cognitive decline, sarcopenia, Parkinson’s disease and diabetes may…

Using copper to improve the well-being of the skin

Copper has two key properties that are being exploited in consumer and medical device products in the last decade. On the one hand, copper has potent biocidal properties. On the other hand, copper is involved in numerous physiological and metabolic processes critical for the appropriate functioning of almost all tissues in the human body. In the skin, copper is involved in the synthesis and stabilization of extracellular matrix skin proteins and angiogenesis.

This manuscript reviews clinical studies that…

Impacts of psychological stress on osteoporosis: clinical implications and treatment interactions

While osteoporosis and psychological stress occur via differing mechanisms, there are several potential molecular links that exist between a pathological response to stress and the development of bone disease. Although not a comprehensive list, these may include dysregulation of the HPA-axis and SAM pathway, inflammatory pathways, IGF signaling, estrogen, serotonin, GABA, and RANKL.

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SOURCE

Role of cortisol in the pathogenesis of postmenopausal osteoporosis: relationship to bone structure

Excess glucocorticoids are well recognised as a cause of osteoporosis; they inhibit osteoblast function and increase osteoblast and osteocyte apoptosis resulting in thinning of the trabeculae. The circadian rhythm of bone turnover, which is linked to cortisol rhythm, is abnormal in osteoporosis. Furthermore, some studies show abnormal cortisol metabolism in osteoporosis. The aim of our study was to evaluate the day–night rhythm of cortisol and to relate cortisol levels to bone micro-structure.

Methods: Postmenopausal women with vertebral fractures and…

Stress factors increase osteoporosis: a comparative assessment of osteocalcin and cortisol levels in menopausal women

Osteoporosis, a consequence of menopause in the biological cycle of women, emerges with the conclusion of reproductive capabi lities.
Hormonal changes during this phase contribute to the development of the disease. The study evaluated the relationship between stres s,
salivary cortisol levels, and osteocalcin, in postmenopausal women with osteoporosis.

The study involved a total of 30 postmenopausal volunteers diagnosed with osteoporosis. Stress levels were assessed using the NIH
stress score system to evaluate cortisol levels. Saliva and blood samples were analyzed using…

Association of menopausal vasomotor symptoms with increased bone turnover during the menopausal transition

The purpose of this study was to determine the longitudinal association between menopausal vasomotor symptoms (VMS) and urinary N-telopeptide level (NTX) according to menopausal stage.

We conclude that among early perimenopausal and late perimenopausal women, those with VMS had higher bone turnover than those without VMS. Prior to the final menstrual period, VMS may be a marker for risk of adverse bone health. 

…high bone turnover is associated with lower bone mineral density, faster bone loss, and poor bone…

Presence of vasomotor symptoms is associated with lower bone mineral density

Objective: To determine whether women with vasomotor symptoms (VMS) have lower bone mineral density (BMD) than women without VMS.

Design

We analyzed data from baseline to annual follow-up visit 5 for 2213 participants in the bone substudy of the Study of Women’s Health Across the Nation. At baseline, women were aged 42 to 52 years, had intact uterus and ≥1 ovary, were not using exogenous hormones, were not pregnant or lactating, and were pre- or early perimenopausal. Menopausal stage…

Endocrinal metabolic regulation on the skeletal system in post-menopausal women

Loss of estrogen results in reduced osteoblast mediated bone formation and enhanced osteoclastic resorption (Emmanuelle et al., 2021). Given the recent expansion of interest in understanding how these cellular processes are regulated via metabolic flux and bioenergetic capacity, there are several lines of indirect evidence that postmenopausal osteoporosis is a product of dysregulated intracellular metabolism in bone cells. 

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Osteoblast metabolism has been generally well characterized by our lab and others. This includes the…

Osteocalcin, a promising marker of osteoporosis: evaluation in post-menopausal females with osteoporosis

Background: Osteocalcin, has high affinity for calcium. In osteoporotic women, deficiency of calcium may lead to lowering of the formation of hydroxyapatite crystals. Thus, in the state of hypo mineralization, free osteocalcin available in the circulation. Therefore, present study was designed to evaluate significance of serum osteocalcin in diagnosis of osteoporosis, and relationship between Serum Osteocalcin and BMD (Bone mineral Density) in post-menopausal females with osteoporosis and without osteoporosis.

Methods: One hundred and forty seven post-menopausal women between age 45 to…

Menopause and cognitive impairment: A narrative review of current knowledge

A severe impairment of cognitive function characterizes dementia. Mild cognitive impairment represents a transition between normal cognition and dementia. The frequency of cognitive changes is higher in women than in men. Based on this fact, hormonal factors likely contribute to cognitive decline. In this sense, cognitive complaints are more common near menopause, a phase marked by a decrease in hormone levels, especially estrogen. Additionally, a tendency toward worsened cognitive performance has been reported in women during menopause. Vasomotor symptoms (hot flashes,…

Effects of ketone bodies in Alzheimer’s disease in relation to neural hypometabolism, β-amyloid toxicity, and astrocyte function

Brain hypometabolism precedes clinical signs ofAlzheimer’s disease: Frackowiak et al. (1981) found a decline in cerebral bloodflow and mean cerebral oxygen utilization, i.e., hypometabolism, which is correlated with the severity of dementia. Global oxygen extraction ratio was not increased, providing evidence against chronic ischemia. Shortly afterward deLeon et al. (1983) found that aged patients with senile dementia showed consistent diminutions in regional glucose use compared to elderly normal persons, also with significant correlation between hypometabolism and decreased cognitive functioning. Thirteen…

Menopausal hot flash frequency changes in response to experimental manipulation of blood glucose

An experimental study was conducted in 10 postmenopausal women taking hormone therapy (HT) between the ages of 38 and 55. Following a clinic visit to screen for general health and absence of diabetes, HT participants were asked to stop the medication for 7 to 10 days and to maintain a diary of hot flash frequency. When hot flashes were experienced at least four times per day in a consecutive 3-day period, participants were admitted to the General Clinical Research Center…

White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer’s Disease

White matter degeneration is a pathological hallmark of neurodegenerative diseases including Alzheimer’s. Age remains the greatest risk factor for Alzheimer’s and the prevalence of age-related late onset Alzheimer’s is greatest in females. We investigated mechanisms underlying white matter degeneration in an animal model consistent with the sex at greatest Alzheimer’s risk. Results of these analyses demonstrated decline in mitochondrial respiration, increased mitochondrial hydrogen peroxide production and cytosolic-phospholipase-A2 sphingomyelinase pathway activation during female brain aging. Electron microscopic and lipidomic analyses confirmed myelin…

Perimenopause as a neurological transition state

Estrogen-mediated regulation of the bioenergetic system: estrogen signalling supports and sustains glucose metabolism in the brain by regulating expression of glucose transporters, which results in increased glucose uptake, and by stimulating glucose metabolism, mitochondrial oxidative phosphorylation and ATP generation—collectively referred to as aerobic glycolysis. Glucose (1) is the primary metabolic fuel for the brain. Estrogen regulates the bioenergetic system in brain the through the estrogen receptors, GPER, ER-α and ER-β, and their activation of PI3K and downstream Akt and MAPK–ERK…

Low Estrogen Exposure and/or Defective Estrogen Signaling Induces Disturbances in Glucose Uptake and Energy Expenditure

Estradiol and its receptors are key players in the physiology and insulin production capacity of the β cells of pancreatic islets. Estradiol administration is associated with pancreatic islet hypertrophy and increased insulin release from the β cells in rats. Islet cells isolated from ovariectomized mice respond to glucose with a smaller insulin release than islet cells from intact mice. After menopause, estrogen loss decreases the insulin secretion, which is transitorily compensated by its reduced elimination. An estrogen deficient milieu endangers…

Estrogen: A master regulator of bioenergetic systems in the brain and body

Estrogen is a fundamental regulator of the metabolic system of the female brain and body. Within the brain, estrogen regulates glucose transport, aerobic glycolysis, and mitochondrial function to generate ATP. In the body, estrogen protects against adiposity, insulin resistance, and type II diabetes, and regulates energy intake and expenditure. During menopause, decline in circulating estrogen is coincident with decline in brain bioenergetics and shift towards a metabolically compromised phenotype. Compensatory bioenergetic adaptations, or lack thereof, to estrogen loss could determine risk…

Specifically formulated ketogenic, low carbohydrate, and carnivore diets can prevent migraine: a perspective

This article presents a hypothesis explaining the cause of migraines, suggesting that electrolyte imbalance, specifically a lack of sufficient sodium in the extracellular space of sensory neurons, leads to failed action potentials. The author argues that migraines are triggered when sodium channels fail to initiate action potentials, preventing communication between neurons. The article discusses the evolutionary perspective of the migraine brain, stating that migraineurs have a hypersensitive brain with more sensory neuronal connections, making them more reactive to environmental stimuli and…

A reassessment of diet and osteoporosis — Possible role for copper

Surprisingly little if any attention has been given to the role of copper in the aetiology of postmenopausal osteoporosis. For example, Freudenheim et al. (40). investigated relationships between usual intake of energy and 14 nutrients (but not copper) and the bone mineral content of US women 35-65 years of age in a longitudinal and cross-sectional study. They found interactions of bone loss with energy, calcium, phosphorus, protein, vitamin C, vitamin A, magnesium, zinc and a number of B vitamins. The…

Association between Body Fatness and Vitamin D3 Status in a Postmenopausal Population

Our data reflect that the high prevalence of vitamin D and vitamin D3 deficit observed in our postmenopausal population is generally correlated with BMI, in addition to anthropometric parameters such as hip and arm circumference and fat mass defined as fatness. According to our data, it seems that 25(OH)D3 is the vitamin D metabolite that is most closely related to the anthropometric parameters studied. Therefore, nutritional assessment and vitamin D3 supplementation policies are proposed, as well as related healthy habits to improve the…

Effect of vitamin E supplementation on chronic insomnia disorder in postmenopausal women

Chronic insomnia disorder is one of the most common problems in postmenopausal women, exacerbated by underdiagnosis and improper treatment.

This double-blinded, randomised, placebo-controlled trial was conducted to evaluate the potential of vitamin E to treat chronic insomnia as an alternative to sedative drugs and hormonal therapy.

The study enrolled 160 postmenopausal women with chronic insomnia disorder, divided randomly into two groups. The vitamin E group received 400 units of mixed tocopherol daily, while the placebo group received an identical…

Pause menopause with Rhodiola rosea, a natural selective estrogen receptor modulator

Rhodiola rosea extracts have been shown to enhance mood, cognitive function, and memory. Moreover, these extracts possess anti-stress, neuroprotective, cardiovascular-protective, and anticarcinogenic properties, which are particularly valuable to counteract some of the common health risks seen in women as they age. R. rosea is low in side effects compared to synthetic selective estrogen receptor modulators (SERMS).

Effects of myo-inositol supplementation in postmenopausal women with metabolic syndrome

Supplementation with myo-inositol may be considered a reliable option in the treatment of metabolic syndrome in postmenopausal women. The aim of this study was to evaluate whether myo-inositol, an insulin-sensitizing substance, may improve some features of metabolic syndrome in postmenopausal women. Methods: Eighty postmenopausal women affected by the metabolic syndrome were enrolled prospectively in the study and treated with diet plus supplementation of myo-inositol (2 g BID plus diet: intervention group) or with diet plus placebo (control group) for 6 months. They were…

From my Substack

I write regularly about menopause, symptoms, biology, and the wider story women are so often not told. If you want to go deeper into the thinking behind my work, you can start here.

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Sandra Ishkanes  Natural Menopause Specialist based in Brighton, serving clients worldwide via Online Consultations   
BSc Molecular Biology (King’s College London) | DipION | Functional Medicine Practitioner
Registered member, Association of Naturopathic Practitioners (ANP) – the UK professional body for accredited naturopathic and functional medicine practitioners. ANP members hold accredited qualifications, carry professional indemnity insurance, and follow a strict code of ethics.

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