NVP-CGM097 The most often used formula for

The most often used formula for calculating free NVP-CGM097 is the Coolens formula, which includes solving a second order polynomial [1], [2]. Coolens et al. [1] considered cortisol, CBG and albumin only and assumed the relevant reactions to be in equilibrium as well as conservation of the corresponding substances. Furthermore, the ratio of total albumin to its affinity for cortisol was assumed constant. Later Dorin et al. [2] developed an improved, cubic model with total albumin and its affinity for cortisol included as input variable and parameter, respectively, and by this excellent work demonstrated the importance of albumin concentration in cases with combined albumin and CBG deficiencies [2]. Nguyen et al. [3] extended the model further by considering two states of CBG: high-affinity, native CBG and low-affinity, elastase-cleaved CBG (CBG*), assuming equilibrium of the relevant reactions and conservation of the total amounts of the corresponding substances. This was elegantly generalized to a fourth order formula [3]. In their formula Nguyen et al. [3] ignored the actual enzymatic reaction cleaving CBG into CBG* and instead took the total amounts of each of CBG and CBG* to be conserved. 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 contrast 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.