Differential Effects of Estrogen on Corticosteroid-Binding Globulin Forms Suggests Reduced Cleavage in Pregnancy

Abstract

Corticosteroid-binding globulin (CBG) is secreted as high-affinity CBG (haCBG), which may be cleaved by tissue proteases to low-affinity CBG (laCBG), releasing free cortisol. Pregnancy and the estrogen-based combined oral contraceptive pill (COCP) increase CBG concentrations twofold to threefold. The relative effects of these two hyperestrogenic states on the CBG affinity forms are unknown. We performed an observational study in 30 pregnant women, 27 COCP takers and 23 controls. We analyzed circulating total CBG, haCBG, laCBG, and free and total cortisol concentrations. In pregnancy, total CBG and haCBG were increased compared to controls (both P < 0.0001); however, laCBG concentrations were similar. In COCP takers, total CBG and haCBG were increased [802 ± 41 vs compared to controls (both P < 0.0001)], but laCBG was also increased (P = 0.03). Pregnancy and use of COCP were associated with a comparable rise in haCBG, but laCBG was lower in pregnancy (P < 0.0001). These results were consistent with an estrogen-mediated increase in CBG synthesis in both hyperestrogenemic states but with reduced CBG cleavage in pregnancy relative to the COCP, perhaps due to pregnancy-induced CBG glycosylation. Speculatively, increased circulating haCBG concentrations in pregnancy may provide an increased reservoir of CBG-bound cortisol to prepare for the risk of puerperal infection or allow for cortisol binding in the face of competition from increased circulating progesterone concentrations.

Analysis and validation of a new extended method for estimating plasma free cortisol including neutrophil elastase and competition from other steroids

“…Even with the higher levels of total CBG and lower percentage of CBG being on cleaved form during pregnancy [60] Women in 3rd trimester of pregnancy and women taking COCP (see figure 7e and 7f, respectively) are both examples of circumstances where the women have high levels of CBG and total cortisol [60]. The difference between the predictions by the model by Coolens et al [1] and the other models are greater for these two examples than for the remaining four.…”

“…Though the total level of CBG increases in pregnancy, the level of cleaved CBG does not, which results in a smaller ratio of cleaved CBG than normal (n CC * = 0.167) [60]. The increase in CBG during pregnancy is attributed to a direct estrogen-induced rise in production.…”

“…In pregnant women at term the concentration is approximately 541 nM [12]. CBG [59,60], cortisol [13,60], and testosterone concentrations [13] rise during pregnancy, while the concentration of albumin declines [61,62].…”

“…The increase in CBG during pregnancy is attributed to a direct estrogen-induced rise in production. In women using estrogen-based combined oral contraceptive pills (COCP) the total CBG level is similarly increased [63,60], but the level of cleaved CBG is also increased, though to a lesser degree (n CC * = 0.269 in COCP women vs n CC * = 0.433 in the normal control women) [60].…”

“…Additionally, estimated 24h mean input variable values in different population groups are shown; YM = young men, OM= old men, YWL= young women in the luteal phase, YWF= young women in the folicular phase, PW3T = pregnant women in the 3rd trimester, and COCP=women tacking estrogen-based combined oral contraceptive pills. The values are chosen by the relations described in section 2.2.2 and from values found in [77,63,45,60,61,78,58,13,10,12,11,79,49,14,80,48].…”