Alzheimer's and HRT

With twice as many women than men suffering with Alzheimer's, what it the latest evidence in terms of Hormone Replacement Therapy (HRT) and protection? Dr Vikram Talaulikar and Professor Isaac Manyonda clarify things.

Dementia is now the biggest killer of women in the UK, surpassing heart disease, which remains the leading cause of death for men.

This progressively-worsening global pandemic is currently estimated to affect 50 million people worldwide, with projections suggesting it will increase to 132 million by 2050. The global costs of caring for dementia sufferers are estimated at US$800 billion per annum currently, projected to rise to US$2 trillion by 2030.

The human costs include profound disability and dependence for the afflicted and risk of developing depression and anxiety disorders for the carers. The four common types of dementia are: Alzheimer's Disease (AD); vascular dementia; Lewy body dementia; and fronto-temporal dementia. AD accounts for 70% of all cases, with a 1.8 to 1 female to male preponderance and whose onset coincides with the decline in oestrogen levels seen in the peri-menopause.

The hippocampus is the area of the brain that we use for learning and where memory is first formed. It is essential for declarative memory, that is, the conscious, intentional recollection of factual information, previous experiences and concepts. Hippocampal pathology is central to the development of AD and the hippocampal shape and volume can predict the onset of AD. The hippocampal area contains a large collection of oestrogen receptors. The hippocampus shrinks in the menopause and it is teleologically sound to link this to the well-documented decline in verbal memory and the decline in oestrogen levels. Thus, the menopause has a negative effect on hippocampal function.

With regards to AD, evidence suggests that if oestrogen replacement therapy is administered in the peri-menopausal period, there is a potential to prevent Alzheimer's Dementia (critical window theory). This is consistent with the accepted wisdom that, although the symptoms of dementia generally occur in later life, the disorder begins in midlife around the ages 40-65 years.

Some studies have explored the critical window theory for the potential benefits of supplying oestrogen replacement before the menopause. In a longitudinal cohort study, Shao et al. in 2012 showed that peri-menopausal oestrogen replacement within 5 years of the menopause, plus use for 10 or more years was significantly associated with a 35% reduced risk of AD [95% Confidence Interval CI 0.43-0.98]. This finding is supported by a few other prospective cohort studies. Oestrogen replacement started five or more years after the menopause was still associated with a 14% reduced, but not significant risk of Alzheimer's Dementia [95% CI 0.49-1.51].

Caution - combined oestrogen + synthetic progestogen therapy HRT (Hormone Replacement Therapy) may increase the risk of AD. The position of oestrogen as the effective prevention is shown by the result that peri-menopausal combined HRT (Oestrogen and Medroxyprogesterone acetate) within 5 years of the menopause and use for 10 or more years was associated with a non-significant reduced risk of Alzheimer's Dementia, while peri-menopausal oestrogen replacement therapy (ERT) within 5 years of the menopause and use for 10 or more years was associated with a statistically significant 35% reduced risk of Alzheimer's Dementia [95% CI 0.43-0.98]. Shao et al. 2012 also showed in their longitudinal cohort study of oral combined oestrogen + progestogens that menopausal HRT therapy 5 or more years after the onset of the menopause was associated with a 32% increased, but not significant risk of Alzheimer's Dementia [95% CI 0.78-2.24].

This was confirmed by the Women's Health Initiative Memory Study, a randomised placebo-controlled study of oral combined oestrogen and progestogens where menopausal HRT for 4 or more years after the menopause was associated with a significantly (double) increased risk of AD [Hazards Ratio 2.02, 95% CI 1.21-3.48]. It is accepted that ERT does not reverse established AD. Once a woman has developed AD, hormone replacement treatment, particularly combined oestrogen + progestogen (HRT), does not help, but might even worsen the condition.

Hormone Replacement Therapy is not associated with cognitive decline when women have recently started the menopause and they are non-diabetic.

It appears, therefore, that oestrogen is the key hormone for cognitive benefits and should be started early in menopause or peri-menopause. Progesterone (when required for womb lining protection), should ideally be the body-identical natural progesterone (Utrogestan) and should be administered in the lowest protective dose and duration required.

Evidence from in-vitro studies, animal experimentation and a growing body of human clinical studies suggests that estrogen could prevent up to 35% of cases of the disease, a significant proportion given the extent of the pandemic. We acknowledge that, on its own, this evidence is far from conclusive, but in the absence of any preventive or therapeutic interventions for AD, while definitive prospective randomised trials are awaited, we feel that women should be offered a simple, safe and cheap medicine which is oestrogen.

The UK government has recently declared that "prevention must be the heart of the NHS long-term plan", listing smoking, CVD (cardio-vascular disease) and obesity as its main targets. The dementia pandemic is not acknowledged as a target, perhaps in part because the existing focus is on current sufferers and resources are directed at further research. The progressively worsening nature of the dementia pandemic emphasises that, ultimately, non-sufferers will progress to be sufferers as they grow older. In such a scenario, the urgency of acknowledging and adopting an already existing potentially preventative strategy for AD - peri-menopausal estrogen therapy - cannot be exaggerated.

echo For more information, you can contact Professor Manyonda and Mr Talaulikar at the Menopause Clinic, London