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  • In the literature we can find two different modes of

    2019-07-11

    In the literature, we can find two different modes of action for estrogens: Firstly there is the commonly accepted genomic pathway. Estrogens pass the cell membrane due to their lipophilic character via diffusion and bind to estrogen receptors (ERs) in the cytoplasm. After binding a dimerization of two ERs takes place and the complex of two ERs and two steroid molecules is translocated into the nucleus where it acts as a transcription factor. Thus gene expression of estrogen-dependent proteins is activated. Secondly, estrogens also act in a non-genomic way that is mainly initiated at the membrane level. These non-genomic pathways gained more notoriety recently although such an action was described for the first time about 75 years ago [10], [11]. While the genomic pathway requires at least several minutes to initiate an effect, non-genomic actions can occur within seconds.
    Estrogens and the brain Interestingly some of the pathways of steroid actions in peripheral tissues are the same as in Azithromycin while others are different. One of the first descriptions of a steroidal effect in the brain was their sedative and analgetic effect [12], [13], [14], [15]. According to the widely accepted opinion, neurosteroids interact with classical steroid receptors and therewith regulate on a genomic level. However, now there are more indications that there is also a non-genomic, membrane-associated way of their action [16]. Neurosteroids have far less affinity to receptors than the usual steroid ligands. Rupprecht et al. suggest that a part of the neurosteroids could be retransformed to their precursor hormones, which can then activate the well-researched classical steroid pathway [17]. In the case of non-genomic activation, ligand-activated ion channels appear to play the key role, whereby GABAA receptors seem to be most important [16]. Toran-Allerand and coworkers showed that besides the above-mentioned effects E2 has multiple developmental impacts in brain. In cultures of different nerve cells, including NGF-differentiated PC12 cells, they showed that neurite growth was enhanced by E2 treatment and that the number of neurite branches is also increased (higher arborization) [18], [19]. Additionally they found that E2 could play an important role in the therapy of Alzheimer’s disease as well [20]. Moreover the effect of estrogens was not only researched in cell cultures but also in whole brains or different areas of the brain. E2 works in a neuroprotective way in the substantia nigra and also the cortex [21], [22], [23] and it leads to changes of nociception by influencing neuronal systemic areas [24], [25]. Additionally to Toran-Allerand’s results in cell culture systems it has been shown that estrogens increase synaptogenesis resulting in better learning and memory [26], [27], [28].
    Estrogen receptors and neuronal cells
    Sex hormone binding globulin – the missing link? Steroids cannot travel freely in blood due to their lipophilic character. That is why they are bound to binding globulins. Most steroids have their own binding globulin: glucocorticoids are bound to the corticosteroid binding globulin (CBG), Vitamin D is bound to the Vitamin D binding protein (DBP) and estrogens, as well as androgens, are bound to sex hormone binding globulin (SHBG). Binding globulins are mainly produced in the liver, from where they are released into the blood plasma to bind free steroids [53], [54]. More recently binding globulins have been found to play an active part in the actions of steroids [55], [56]. Between 2.2 and 5.1% of the steroids (except aldosterone) are free in the blood plasma [57]. This means that binding globulins carry from 35 to 67% of all. Interestingly, it has been shown that the binding globulins are not only produced in the liver but also in several other organs. SHBG for example is also expressed in female sexual organs like the uterus or ovaries, in nearly every other organ and also in the brain [58], [59], [60], [61], [62], [63]. Caldwell and coworkers were very interested in the localization of SHBG in hypothalamic structures of the brain. They found SHBG in magnocellular nuclei [63]. They further suggested a co-localization of SHBG and oxytocin. It is clear that the expression of SHBG is sex steroid dependent [64]. In neuronally differentiated PC12 cells we have previously showed that SHBG expression is not inhibited by the anti-estrogen tamoxifen [65]. It could therefore be estimated that the regulation of SHBG is not mediated via classical nuclear receptors but other transcription regulating mechanisms that should be researched in more detail. A second quite interesting fact is that SHBG seems to be internalized by cells. This has been shown by Porto et al. in breast cancer cells [66] but also in testes and prostate of rats [67]. But the uptake of SHBG did not only occur in typical sex steroid targets but also in the brain. Caldwell et al. showed the uptake of SHBG in hippocampal HT22 cells that were transfected with ERβ but not in ERα-positive cells [68] suggesting a special relationship between SHBG and ERβ.