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  • orexin Despite the sources of error


    Despite the sources of error discussed above, several trends have emerged and much valuable data are available regarding binding affinities of progestogens for different steroid receptors. All the progestogens bind to the PR with a high affinity, typically in the nanomolar range. For example the synthetic agonist R5020 was found to bind to the PR expressed in human or calf uterine cytosol with K values of 4.42nM and 5.6nM, respectively [16], [27]. In contrast, progestogens do not bind to the ER, as expected, due to the low homology between the ER ligand binding domain and the PR, although there are reports that some progestogen metabolites do bind the ER [2]. Consistent with the structural similarities between some progestogens and testosterone, several progestogens bind with relatively high affinity to the AR (Table 1), although the reported affinities vary greatly, most likely due to many of the factors described above. For example, some of the older generation progestogens such as MPA, norethisterone (NET) and levonorgestrel bind the AR with high affinity relative to metribolone [27], DHT [11], [30] and testosterone [18], [25]. However other researchers report that Prog, MPA, norethisterone-actetate (NET-A), cyproterone acetate and DHT all have similar and relatively high affinities for the AR [17], [23], [24] (Table 1). In contrast, DRSP, dienogest and TMG exhibit low RBAs [1], [6], [25], [31], while nestorone does not bind to the AR [12], [32]. It is not surprising that several progestogens structurally similar to Prog, bind to the MR, given the high affinity of Prog for the MR (K for Prog 1.69nM [23]). Indeed, TMG [25], [33] and DRSP (Table 1) [26], [27], [31], the latter derived from the MR antagonist spironolactone, both bind the MR with high affinity. These progestogens were specifically developed for their anti-mineralocorticoid properties for contraceptive usage [34] and for their predicted beneficial effects on blood pressure and cardiovascular function [26], [35], [36]. In contrast, many progestogens such as chlormadinone acetate, dienogest and NOMAC exhibit undetectable binding to the MR [1], [37], while MPA (K=197nM) and NET-A (K=229nM) bind weakly to the MR [2], [23]. Unlike for the PR, AR and MR, few progestogens bind to the GR with affinities in the significant pharmacological range. Of note, MPA has a high affinity in the nanomolar range for the GR (Table 1) [22], [25], [37], [38], with a K value of 10.8±1.1nM [22], significantly higher than the endogenous glucocorticoid orexin in humans [38]. Interestingly gestodene also binds the GR with a relatively high affinity, while progestogens such as NET, levonorgstrel, dienogest, TMG and DRSP, like Prog, bind the GR with low relative affinity [1], [6], [22], [25], [26], [38], [39].
    Potency, efficacy and biocharacter Potency, efficacy and biocharacter define the concentrations of progestogens required to cause or inhibit particular biological or physiological effects, the upper and lower limits of those responses, as well as how these change over a range of concentrations or doses [40]. These parameters are thus important for hormonal therapy. The current literature indicates that these parameters are substantially different in cell, tissue, animal, and clinical assays, both between progestogens and for the same progestogen.Pharmacologically, potency is defined as the concentration of ligand that induces half the maximal response, or EC50, while the efficacy refers to the maximal effect a ligand can elicit under defined experimental conditions. Efficacy also gives a measure of biocharacter of progestogens, which can vary from full agonist to partial agonist to different types of antagonism, depending on the extent to which a ligand can inhibit the response to a particular concentration of agonist (Fig. 2A and B) [2]. Potency, efficacy and biocharacter can only be accurately determined by performing dose response analysis and constructing a dose response curve (Fig. 2A) [2]. It is important to note that these parameters are not constant but are particular for a specific effect or response under defined conditions. In most clinical and animal assays, potency, efficacy and biocharacter are not evaluated by these pharmacological criteria. Evidence to date from ex vivo assays suggests that all progestogens act as full agonist for transcription via the PR, while their transcriptional activities via other steroid receptors vary from no activity, to partial agonist, full agonist, and varying levels of antagonism, in a cell- and promoter-specific manner. Although best described for G-protein coupled receptors [41], inverse agonists have also been identified for the PR [42], but have to our knowledge not been reported for progestogens. Biocharacter can vary depending on context. For example, decreasing SR concentrations can convert some progestogen agonists to antagonists [4]. In addition, whether a ligand is an agonist or antagonist can depend on cell type, such as the case for asoprisnil, the selective PR modulator [43]. These modulators have been suggested as therapeutic agents for the treatment of gynecological disorders. Some progestogens may display mixed agonist-antagonist activity, as has been reported for androgenic activity by cyproterone acetate [44]. However, the selective receptor-mediated effects of most progestogens remain to be investigated. Most of the progestogen biocharacter data have been defined in animal bioassays (Table 1) and are usually not fully explored by dose response analysis. They do not necessarily reflect activity or biocharacter via a particular SR, or that obtained in other assays in either the same or different species. The large number of inconsistencies reported for biocharacter (Table 1) most likely reflects species- and/or tissue-specific differences as well as difference in methodology.