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Differential Effects of Estrogen on Corticosteroid-Binding Globulin Forms Suggests Reduced Cleavage in Pregnancy
Marni A Nenke1, Anna Zeng2,3, Emily J Meyer1
1Endocrine and Metabolic Unit, and.
Insights
Pregnancy and oral contraceptives both increase high-affinity corticosteroid-binding globulin (CBG). However, pregnancy shows lower low-affinity CBG compared to oral contraceptive use, suggesting altered CBG processing.
Area of Science:
- Endocrinology
- Reproductive Biology
- Proteomics
Background:
- Corticosteroid-binding globulin (CBG) exists in high-affinity (haCBG) and low-affinity (laCBG) forms, influencing free cortisol levels.
- Hyperestrogenic states like pregnancy and combined oral contraceptive pill (COCP) use significantly elevate CBG concentrations.
- The differential impact of pregnancy versus COCP use on CBG affinity states remains unclear.
Purpose of the Study:
- To compare the effects of pregnancy and COCP use on circulating concentrations of total CBG, haCBG, and laCBG.
- To investigate potential differences in CBG cleavage between these two hyperestrogenic conditions.
Main Methods:
- Observational study involving 30 pregnant women, 27 COCP users, and 23 controls.
- Analysis of serum total CBG, haCBG, laCBG, free cortisol, and total cortisol levels.
- Statistical comparison of CBG parameters across the three groups.
Main Results:
- Both pregnancy and COCP use significantly increased total CBG and haCBG compared to controls.
- Pregnancy was associated with similar laCBG levels as controls, while COCP users showed increased laCBG.
- Despite comparable increases in haCBG, pregnancy exhibited significantly lower laCBG than COCP use.
Conclusions:
- Estrogen drives CBG synthesis in both pregnancy and COCP use.
- Pregnancy is associated with reduced CBG cleavage compared to COCP use, potentially due to glycosylation.
- Elevated haCBG in pregnancy may serve as a cortisol reservoir for infection defense or to counteract progesterone competition.
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.
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