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  • br Genomic actions in the breast br Conclusion Clinical stud

    2019-07-04


    Genomic actions in the breast
    Conclusion Clinical studies suggest that progesterone and/or progestins may play a decisive role in the development of breast cancer in women using hormone therapy or oral contraceptives [3], [4]. However, this data are controversial to most experimental investigations in which progestins appear to act in part antiproliferative which supports the use of certain progestins as anticancer agents, e.g. MPA. The reason for this discrepancy remains unclear. Despite their widespread use, in vitro models have certain limitations: the choice of culture conditions can unintentionally affect the experimental outcome, and cultured health-related are adapted to grow in vitro; the changes which have allowed this ability may not occur in vivo. Many steroid-responsive cell lines were established from malignant effusions, which may not be fully representative of all solid tumors. The homogenicity of cell lines can be viewed as an advantage or disadvantage. It allows the study of cells which represent a tissue population, however, responses may not fully mimic those of the complex in vivo situation. Limitations of in vitro studies might be the high concentrations needed for an effective effect. Most data were obtained using rather high progestogen concentrations of 10−6M, since lower in vitro concentrations often do not show any relevant effect. The clinically relevant blood concentrations for the progestins most commonly used for HT, MPA and NET, are in the range of 4×10−9M to 10−8M for MPA [81] and around 10−8M for NET [82]. However, higher concentrations may be required in vitro in short-time tests in which the reaction threshold can only be achieved with supraphysiological dosages. Higher concentrations may also be reached in vivo in the vessel wall or organs compared to the concentrations usually measured in the blood.
    Funding This work was supported by grants to Xiangyan Ruan for scholarships in Clinical Pharmacology at the University of Tuebingen, Germany, by the following funding projects: Beijing Municipality Health Technology High-level Talent (No. 2009-3-52) and National Natural Science Foundation (No. 81172518).
    Introduction Hormone replacement therapy (HT) was exposed to a dramatic impact by the publications of the Women\'s Health Initiative (WHI) trial in 2002 [1] and the Million Women Study (MWS) [2] in 2003, affecting women\'s attitudes and physicians’ prescribing practice throughout the world. This caused a general decrease of HT use. Publications that raised a word of caution about discontinuing use of HT were disregarded [3]. Now, over 10 years after the first publication [1] there appears to be a revival or renaissance of HT, which seems to involve publications in leading medical journals [4], [5] and outstanding worldwide organizations such as the International Menopause Society and the Endocrine Society. It is now realized more and more that proper HT contributes to the well-being and function of women who have lost their ovarian function, improves or maintains physical and mental activity, and contributes to the quality of life [6]. This is mainly determined by estrogens. In order to avoid undue chronic stimulatory effects on the endometrium, control menstrual bleeding, avoid abnormal bleeding and avoid cancer development, the combination of the estrogen with a progestogen is needed. The present review will discuss some of the “newer” progestogens used for HT regarding their quality and effectiveness to uphold the favorable effects of estrogens and avoid undue proliferation at the endometrium, with risk of abnormal uterine bleeding (AUB) and oncological problems. The progestogens that will be discussed include dienogest (DNG), drospirenone (DRSP) and nomegestrol acetate (NOMAC).
    “Newer” progestogens Previously the question was raised regarding whether or not progestogens should be selected for HT use [7]. The answer was yes. Therefore, “newer” progestogens should be scrutinized, whether they are qualified to be considered for HT. One has to be aware that all progestogens are not equal. Besides progesterone, which is naturally produced in women in the ovaries (particularly the corpus luteum), in the placenta and to a certain extend in the adrenals, there are a variety of synthetic progestogens [Table 1]. One of these progestogens, dydrogesterone, is a retro-progesterone, and another, DRSP, is spironolactone derivative. We can then subdivide the rest of the progestogens on the basis of those that are related in chemical structure to progesterone and those structurally related to testosterone. The former group can be subdivided into 17α-hydroxyprogesterone derivatives and 19-norprogesterone derivatives, whereas the latter group (19-nortestosterone derivatives) can be divided into estranes and 13-ethylgonanes. The properties of the 17α-hydroxyprogesterone derivatives include mainly peripheral action, relatively moderate inhibition of gonadotropins, antiandrogenic effects, and good tolerability. Properties of 19-nortestosterone derivatives include high bioavailability and strong progestational effects on the endometrium.