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Quest for better treatment for effects of menopause

May 29, 2008

During menopause, lack of oestrogens increases the risk of suffering cardiovascular diseases. For her doctoral thesis, University of the Basque Country researcher, Ainhoa Ruiz del Agua, studied the effects of substitute treatments and the genetic factors influencing the response to these therapies.

Menopause is a natural period in the ageing process of a woman. On ceasing the ovary function, the body gradually stops producing eggs and female sex hormones (amongst these being oestrogen and progesterone), responsible for regulating the menstrual cycle. Lack of oestrogens increases the risk of very important diseases with respect to premenopause, amongst these being osteoporosis and illnesses related to the cardiovascular system. Amongst these heart diseases atherosclerosis is the most important, being an illness characterised by the presence of plaques full of lipids (fats) along the walls of the arteries, and which restricts the blood flow, causing high blood pressure. If these plaques break, the result is a thrombosis that can block the artery, causing, amongst other things, heart attack.

To slow down the natural drop in oestrogen level and thus prevent associated problems, substitutive hormonal therapies are prescribed during the menopause, either orally or subcutaneously (with patches), as well as by treatments based on substances that modulate the oestrogen receptor, amongst these being raloxifene. However, the effects of these therapies are disputed, given that there are no definitive conclusions about their usefulness: research carried out to date shows their efficacy in preventing osteoporosis, but it has not been clarified if they are capable of reducing the risk of contracting heart disease. Moreover, the response amongst different women to the same treatment can vary according to environmental factors, population, diet and, of course, as a function of genetic factors.

Ms Ainhoa Ruiz del Agua's PhD thesis addressed these questions when she recently defended it at the University of the Basque Country (UPV/EHU): Oxidative stress biomarkers during postmenopause: effect of substitutive treatments. Dr Ruiz del Agua is a biochemistry graduate who is currently working as a researcher contracted by the Department of Physiology in the Faculty of Medicine and Odontology of the UPV/EHU. Her work was led by Ms María Begoña Ruiz Larrea and Mr José Ignacio Ruiz Sanz.
Treatment with diverse effects

The principal aim of the research is to determine the effect of substitutive treatments normally administered during postmenopause. Moreover, it aims to define the genetic markers that condition the response to each of the treatments. To this end, Doctor Ruiz del Agua analysed the response by a group of women from Bizkaia to two treatments: on the one hand, to raloxifene and, on the other, to a substitutive hormonal treatment combining estradiol (a type of oestrogen) and progesterone (another female sex hormone).

The conclusions of Doctor Ruiz del Agua's thesis point to raloxifene, while increasing the antioxidant activity of an enzyme known as arilesterase, which is beneficial, has a neutral effect on the cardiovascular system, given that it does not modifiy other cardiovascular risk markers, nor the characteristics of LDL ("bad" cholesterol) particles.

As regards combined hormonal therapy, Ruiz del Agua points to two main conclusions: it reduces one of the cardiovascular risk markers studied, which is beneficial, but it also reduces antioxidant activity of the serum, which means an adverse effect on the endothelial function (which avoids blood clots forming) and on the balance necessary between oxidant and antioxidant substances.
Genetic factors determining response to treatment

On the one hand, Doctor Ruiz del Agua states that the response to the treatments studied depends on the genetic burden of each patient, this response being favourable or otherwise, depending on the genetic variables carried by the women for the genes analysed.

In the case of hormonal therapies, carriers of the GG genotype (a combination highly frequent in the mpo gene) undergo a drop in the antioxidant activity of the serum, which means, in this sense, a favourable response to the treatment. In the case of raloxifene, only those women who, because of their genetic burden, are disfavoured for the antioxidant activity of arilesterase, gain benefit thanks to the treatment.

In short, this PhD presented at the UPV/EHU shows that certain aspects of treatments employed in postmenopausic women can be approached from an analysis of genetic polymorphisms, a fact which will contribute to the design of more personalised therapies for their application in postmenopause.

Elhuyar Fundazioa