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HRT in Vascular & Cardiovascular Diseases

Menopause is a time in a womans life that brings many changes. Due to hormonal changes, many of our body systems change. Lack of oestrogen has dramatic consequences on the female body, giving rise to some dysfunctions that could lead into pathologies in the long run. Osteoporosis is just one example.

The cardiovascular and the vascular system are influenced as well by the lack of oestrogen, and Hormone Replacement Therapy (HRT) may represent a help in dealing with those problems. Even though some women are still reluctant to use HRT, there is plenty of sustainable proof that the benefits are huge. Let’s see why HRT could help women with vascular/cardiovascular disease.

Peripheral Arterial Disease (PAD) affects a large number of people and is a cause of morbidity and mortality. The “family” of vasculopathies includes atherosclerotic occlusive disease, carotid artery occlusive disease, and abdominal aortic aneurysm. The prevalence of these diseases increases with age and usually are associated with the vascular risk factors such as cigarette smoking, hypertension, diabetes mellitus, and menopause. Although the prevalence of PAD is lower in women than in men, this trend changes with aging.

Medical treatment to counteract the disease, generally consists of lipid-lowering agents, platelet inhibitors, and HRT. The benefits of the first 2 drugs have been well documented; however, the use of hormone replacement therapy for the reduction of cardiovascular risk in postmenopausal women has been more difficult to demonstrate, with many recent clinical trials reporting some conflicting results. The 2 biggest study are Heart Estrogen Progestin Replacement Study (HERS) and Women’s Health Initiative (WHI).

The onset of peripheral arterial disease in women usually occurs 10–20 years later in women than in men. Menopause, whether surgically induced or naturally occurring, is considered an increased risk factor. But why does menopause increase the odds for women to develop vascular diseases? It is due to the lack of oestrogen which causes changes in lipid metabolism, glucose and also insulin metabolism, as well as direct arterial effects.

HRT has been demonstrated to have profound effects on the cardiovascular system, with plausible biological mechanisms which explains both the benefits and harms. Benefits usually result from oestrogen restoration and therefore reduction of all the problems caused by their reduction. HRT harms may arise from inappropriately high starting doses of the treatment causing transient increases in coagulation (defined as the process by which blood changes from a liquid to a gel, forming a blood clot) activation and adverse vascular remodelling. Observational studies of HRT suggest that there is a beneficial effect on the incidence of coronary heart disease (CHD). Any benefits of HRT seen in randomised clinical studies appears to be confined to those women within several years into the menopause, and it is clear from those trials that age at initiation of the therapy is a crucially important consideration. Women initiating HRT within 10 years of the menopause onset and below the age of 60, may achieve cardiovascular benefits, particularly regarding primary CHD prevention, whilst avoiding risks of stroke and venous thromboembolism.

Oestrogen plays numerous roles in the regulation of vascular endothelium, proliferation, and the inflammatory response.

In a small patient group, a study [7] identified the benefits of oestrogen on cholesterol. These investigators found that oral oestrogen increased HDL (the “good” cholesterol) and decreased LDL, but transdermal oestrogen did not have a similar benefit. Therefore, its not a matter of simply replacing the oestrogen but also the formulation in which the oestrogen is taken. In addition, the use of HRT has also been associated with changes in triglyceride (TG) levels.

There has been intense scrutiny on HRT and its effects on blood coagulation within the past few years after the study ‘HERS’ demonstrated an increased risk of venous thromboembolism with HRT treatment.

The ‘WHI’ study (16,608 women participating) was a randomised, placebo-controlled, double-blind trial designed to identify the potential risks and benefits of HRT. Results from the WHI, which were published in 2004, indicated a significant increase in the risk of adverse clinical vascular events in women receiving HRT compared to placebo.

The dose, type and route of administration of oestrogen determined its effects on triglycerides, which may be a particular risk factor for CHD in women. HRT has effects on body weight and body fat distribution. Body weight and fat distribution represent important risk factors for cardiovascular diseases. Although it is a popular misconception that HRT causes weight gain, most randomised trials have shown that as many women lose weight with HRT, and overall weight gain is usually greater with placebo than with HRT. The menopausal changes in body fat distribution are limited or sometimes even reversed by HRT administration.

Oestrogen, as we said before, has profound effects on the vasculature, including on the endothelial function, the inner layer of cells lining the inside of the blood vessels. Oestrogen causes vasodilatation by increasing the production of the potent vasodilator nitric oxide (NO). Oestrogen also reduces the release of the potent vasoconstrictor, endothelin-1. NO is involved in regulation of blood pressure, platelet function, inhibition of vascular smooth muscle proliferation and expression of adhesion molecules. It is therefore likely that the dose of oestrogen at initiation of therapy is most important in terms of beneficial or harmful effects on the vascular remodelling.

A common finding in the clinical trials with HRT has been reported as an increase in cardiovascular events in the HRT group in the early years of treatment, which appeared to diminish in later years. Thus, both HERS and WHI showed significant trends to reduction of CHD events over time with HRT, but any early increased risk led to no significant overall effects. One possible explanation for this finding is an increase in coagulation activation, which has an immediate effect on commencement of the therapy that is above all transient, it just requires time for the body to adapt. This effect could also be dose-dependent. Therefore, the dose of oestrogen at initiation is crucial for the cardiovascular outcome, and should be also dependent on the age of the participant.

So, this is as well a plausible metabolic basis that explains the effects of HRT on CHD risk, and can help to understand apparent contradictions between the findings of observational studies and those of randomised clinical trials. In older women, early CHD risk can be caused by increased coagulation activation and adverse vascular remodelling, usually resulting from an inappropriately high starting dose of oestrogen. Such effects are transient and diminish with increasing duration of use, in the same time the anti-atherogenic effects of HRT increase, resulting in eventual benefit. There is increasing evidence that the greatest benefit in preventing atheroma formation and progression is seen when HRT is initiated early in the post-menopause, and in most countries, this is exactly the target age group for HRT use. It may be possible to develop standard HRT regimens, initiated around the time of menopause, in such a way that they would be suitable to maximise the prevention of CHD in women.

Some quick fact and a resume:

  • Menopause by itself is a major risk factor for the development of CVD and PAD
  • Various HRT regimens can be chosen to adjust abnormalities on lipids metabolism, therefore reducing one risk factor
  • oral formulation of HRT may have beneficial effects for insulin and glucose metabolism, and potentially may help to prevent the development of diabetes mellitus
  • Contrary to what was previously perceived, HRT does not appear to increase vascular inflammatory processes
  • HRT seems to have beneficial effects on cardiovascular diseases outcomes if initiated in women before 60 years of age or anyway within 10 years of onset of the menopause
  • HRT may cause some cardiovascular harm through coagulation activation and abnormal vascular remodelling, but this is very dose-dependent, and these changes are transient since the body will in most cases adapt to this change.
  • The starting dose of HRT and the age in which is started is clearly of crucial importance to ensure cardiovascular benefits.


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