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  • LP a levels are lowered by


    LP(a) levels are lowered by combined oral hormone therapy [80], [81], [82], [83], [84], whereas for most studies using transdermal HRT little or no changes have been observed [85], [86], [87].
    Oral versus transdermal administration In general most markers are influenced in a similar way by oral and transdermal hormone therapy although oral therapy may have a more faster and pronounced effect. The main difference between oral and transdermal administration may be confined to markers which are mainly or exclusively produced in the liver such as CRP, IL-6 and Lp(a). The former markers are elevated during oral therapy whereas the latter one is reduced. In a recent systematic review by Hemelaar et al. [88] of 72 randomized clinical trials potentially unfavourable changes seen with oral hormone therapy on the two important makers, CRP and activated protein C, are substantially smaller with non-oral hormone therapy. Own investigations on the comparison of transdermal versus oral combined estrogen/progestogen-therapy were published in detail elsewhere [89] and commented by an excellent editorial [90]. Concerning differentiated effects of the progestogens in this publication only speculations were possible on the comparison of oral and transdermal progestogen application, since up to now only norethisterone acetate and levonorgestrel can be applied transdermally (as combi-patches), which, as is generally known, are largely comparable pharmacologically. As stated above, there is no doubt that differences exist in terms of oral and transdermal application of the same progestogen, which can be clinically relevant. It appears of great interest to further research intensively on this topic.
    Limitations of marker measurements and practical recommendations Despite these limitations, however, in future also vascular markers may become a tool to predict risk and could be more useful to monitor therapy, like metabolic markers such as, e.g. lipids, the measurement of which is recommended as first line to predict risks [91]. Thus the different effects of the progestogens on Nogo-66 (1-40) as ‘surrogate markers’ must have a clinical significance, although the direct vascular hormonal actions are suggested to influence much stronger the cardiovascular outcome and prognosis. The significance of the vascular mediators is already clearly recognised. As an example the measurement of hsCRP has been already included in the official recommendations of the American Heart Association for the assessment of a middle cardiovascular risk in addition to the measurement of lipids [92]. In analogy also other vascular markers will follow for the recommendation in the clinical routine, especially as soon as the measurement will be able quickly and cost-sparingly.
    Introduction Autoimmune diseases encompass a wide spectrum of between 70 and over 100 different disorders affecting 5–10% of the world population [1], [2]. The disease induction and perpetuation of autoimmunity are multifactorial and complex. In general, autoimmune diseases are thought to result from an intricate interplay of genetic, epigenetic, gender, race, hormonal, environmental, and stochastic factors [2], [3]. The complexity of autoimmune mechanisms has been likened to a mosaic, where rearranging much of the same starting materials, such as pieces of genetic, hormonal, immunologic, and environmental factors in different orders, yield different pattern or a variation, of the same disease [4].
    Gender and autoimmunity Gender plays a critical role in the incidence and prevalence of autoimmune diseases. Females have a higher prevalence of autoimmune diseases [2]. In the prototypic autoimmune disorder, systemic lupus erythematosus (SLE), the female-to-male ratio is 10–12:1 [5]. This striking predilection for female occurs in both mice and man [2], [6]. SLE is not unique in this regard. In a variety of other autoimmune diseases such as Sjogren\'s syndrome, autoimmune thyroid disease (AITD) including Graves\' disease (GD) and Hashimoto\'s thyroiditis (HT), and scleroderma more than 80% of the affected are women [2]. Likewise, in rheumatoid arthritis (RA), multiple sclerosis (MS), and myasthenia gravis, the affected are 60–75% women [2]. The notion of X-chromosome dose effect has been unraveled with recent genetic studies. Using a single nucleotide polymorphism (SNP) genotype screen for X-chromosome abnormalities which are subsequently validated by karyotyping, Klinefelter syndrome (47, XXY) was found to be 10-fold more prevalent in males with SLE than in general population [7]. Indeed, having an extra X-chromosome like females, increases the risk of SLE in Klinefelter syndrome. Several lines of evidence from observational, experimental, and epidemiological studies indicate that being female per se or having an extra X-chromosome, confers a greater risk of developing both multi-organ and organ-specific autoimmune diseases [2], [4], [8].