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  • Despite a high affinity for progesterone and a

    2019-08-13

    Despite a high affinity for progesterone and a relatively high affinity for testosterone [7], the binding of progesterone and testosterone to CBG is often disregarded [1], [2], [3]. However, the concentrations of these two hormones varies considerably under both normal physiological and pathophysiological circumstances. There are concentration differences between women and men [8], [9] and for women during the menstrual cycles [10], [11] and pregnancy [12], [13]. For many women with polycystic ovaries or hirsutism increased levels of testosterone are observed [14]. In this paper we expand on the equilibrium considerations of cortisol\'s distribution in the blood by including testosterone and progesterone competing with cortisol in binding with CBG and albumin. In Rosiglitazone to earlier work [1], [2], [3], we include the enzymatic elastase reaction transforming native CBG into CBG*. The resulting equilibrium model can with small reductions be stated as a fourth order polynomial, which may serve as a new formula for calculating free cortisol. The goal of this paper is to (1) make an improved formula for calculating free cortisol, (2) quantify the amount of cortisol binding to proteins in the bloodstream competing with other steroid hormones, (3) investigate the influence of neutrophil elastase, (4) compare the predictions made by the proposed models to prior models by Coolens et al. [1], Dorin et al. [2], Nguyen et al. [3] under separate physiologically relevant circumstances, and (5) investigate and discuss the impact of variation in parameter and input variable values resulting from an intensive literature study.
    Methods
    Results
    Discussion In the present study we develop and validate a new static model for finding the concentration of free cortisol as well as determine the distribution of cortisol bound to albumin, intact and elastase cleaved CBG (CBG and CBG*, respectively). We suggest directly including elastase activity in the calculation of free cortisol with the approximated equilibrium dissociation constant given by the Michaelis–Menten constant (), the catalytic constant (), and the elimination constant () for the CBG* synthesis and elimination. If the level of elastase is unknown, but the level of CBG and CBG* is know, one is able to use the approximation . The results from fitting k (or more generally n) individually to the data of four normal individuals in Section 3.3 show that the model is able to fit data very well. The good performance of the model after fitting a common k = 0.63 for all four subjects shows that the model can be used as an improved method for estimating free cortisol. Additionally, by including the level of progesterone and testosterone in the model we are able to investigate the impact of these competitive steroids on cortisol distribution in the blood. A reduced version of the model is in the form of a fourth order polynomial and gives almost identical results as the static model for al investigations made (see Section 3). Even-though, there is a gender difference in the concentration of testosterone with normal young men having 17.7 ± 1.0 nM [49] and normal premenopausal women having 1.4 ± 0.2 nM [14] as well as an age-related change with elderly men having 12.1 ± 0.7 nM [49], our model suggests that testosterone does not influence the free cortisol concentration significantly when varied in a physiologically relevant range. On top of this, testosterone in the blood binds to sex hormone binding globulin (SHBG) [27], which is not included in the model presented here, possibly further cancelling out the potential effect testosterone could have on the free cortisol concentration. The affinity of human CBG for progesterone is of a considerable strength [81] with dissociation constants reported in the range of 11.1–85 nM [43], [7], [23], [81]. According to Cameron et al. [23] the binding of progesterone to both albumin and CBG do not influence the level of free cortisol significantly under physiological conditions despite the apparent contest between cortisol and progesterone in the binding to the transport proteins. Cameron et al. [23] attributes this to the relatively low concentration of progesterone relatively weak binding to both transport proteins [23]. Meyer et al. [81] argued that progesterone at high concentrations could become of importance in replacing cortisol [81]. Progesterone rises dramatically during pregnancy [12]. Meanwhile, both CBG and total cortisol rise as well with the rise in total cortisol probably being due to the rise in CBG [82]. Additionally, Nenke et al. [60] finds higher percentage of the uncleaved, high-affinity CBG in pregnant women and speculate that this could counteract the binding of progesterone [60]. Investigating these questions related to progesterone\'s impact, our simulations show that the static model predicts a rise in free cortisol not only when progesterone is varied independently as in Section 3.2.5, but also when the parameters X, X, X, and are set to typical values seen in pregnancy (see Section 3.4). Moreover, changes in predicted free cortisol and redistribution of bound cortisol are seen already at levels corresponding to levels seen for women in the luteal phase of the menstrual cycle (see Sections 3.2.5 and 3.4). The changes in relation to including progesterone in the model is of the same magnitude as changes due to variation of albumin in the normal range (see Sections 3.2.2, 3.2.5, and 3.4).