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  • br Conflicts of interest br Acknowledgements This

    2020-02-26


    Conflicts of interest
    Acknowledgements This study was funded by Kuwait University Research Administration (Project MI03/10).
    Introduction Epidemiological, experimental and biologic plausibility support a cardioprotective effect of estrogens in women [1]. Indeed, women are protected until the menopause from the development of coronary artery disease and lag behind men in the incidence of myocardial infarction and sudden death by 20 years [2]. The reasons for this protection are largely unclear, but ovarian hormones are implicated in this protective effect since at any age postmenopausal women have a greater cardiovascular risk than premenopausal and oophorectomized women not taking hormone replacement have an incidence of coronary artery disease similar to that of men of similar age [3]. A large body of evidence coming from observational studies suggests that s6 kinase replacement therapy and, with a more limited evidence, hormone replacement therapy are associated with a significant reduction in cardiovascular mortality and morbidity. This evidence, however, has not been supported by recent randomized studies, conducted mainly in elderly women, using conjugated equine estrogens alone and combined with medroxyprogesterone acetate [4], [5]. However, in the estrogen-only arm of WHI a trend to reduction of coronary heart disease was found in the age group 50–59 years missing scarcely a significance level [6]. This observation points at a crucial role of progestogen addition, which can antagonize the beneficial cardiovascular protective effect regarding the risk of coronary heart disease. In the studies using HRT the progestogen effects were assessed according to clinical endpoints, metabolic effects and influence on vascular markers in vitro or in vivo, respectively. The differentiation of the progestogens according to vascular effects in terms of clinical endpoints remains largely unclear. The most important trial, which allows the assessment of a progestogen effect based on clinical endpoints by comparison of estrogen-only therapy with a combined therapy, has only used one progestogen, i.e. medroxyprogesterone acetate (MPA) [4], [5]. In contrast the differential effect of the various progestogens in terms of metabolic action has been demonstrated in numerous studies, e.g. the well-known negative effect of androgenic progestogens on HDL-cholesterol in contrast to antiandrogenic progestogens [7]. As is generally known the progestogens can be characterised according to their partial effects on the androgen, glucocorticoid and mineralocorticoid receptor based on specific, mainly animal experimental models, as described detailed elsewhere [8]. With a distinct stimulating effect on the progesterone receptor and inhibiting effect on the estrogen receptor, dydrogesterone elicits a rather neutral behaviour concerning the other steroid receptors [8]. In terms of metabolic actions (lipids, carbohydrates, clotting factors) this must be considered an advantage, since otherwise progestogenic effects on the metabolic system were assessed rather negative. Thus neutral progestogens such as dydrogesterone are especially suitable for patients with metabolic syndrome, since the positive estrogenic effects are not antagonised [9]. In principal vascular systems can be influenced positively or negatively based on these partial progestogenic effects. For example, the specific, and in its chemical structure as yet unique progestogen drospirenone, can inhibit sodium/water retention in the renal distal tubuli by inhibition of the aldosterone receptor and thus influence blood pressure [10]. It could be shown clinically based on 24h ambulatoric blood pressure measurements that the usage of drospirenone in combination with estradiol can lower blood pressure in hypertensive patients and then can stabilise blood pressure [11]. However, for those risk patients also, e.g. dydrogesterone can be recommended, which also has been shown to lower the blood pressure in primarily hypertensive patients as measured by the same, at the moment best method for measurements of blood pressure.