OR19-4 Pregnancy increases cleaved/low cortisol binding affinity corticosteroid-binding globulin (CBG) to a much greater extent than the intact/high binding affinity form of CBG; implications for estimates of cortisolemia

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR19-Female Reproductive Endocrinology
Sunday, June 16, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:00 PM
Room 102 (Moscone Center)
Marni A Nenke*1, Jui T Ho1, Vicki L Clifton2, Nicolette Hodyl2, Peter A Elder3, John G Lewis3 and David J Torpy4
1Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide SA 5000, Australia, 2Robinson Institute, University of Adelaide, Adelaide, SA 5005, Australia, 3Steroid and Immunobiology Laboratory, Canterbury Health Labs, Christchurch, New Zealand, 4Royal Adelaide Hospital, Adelaide SA, Australia
Background:  Pregnancy is a state of sustained physiological hypercortisolemia.  Plasma total cortisol, free cortisol and CBG all increase 3-fold by late gestation.1  The extent of rise in free cortisol is inconsistent with the parallel rise in CBG.  However, conventional CBG assays measure both high cortisol binding affinity, uncleaved CBG, and low affinity CBG which has been cleaved by tissue elastases to enable cortisol release.  A novel monoclonal ELISA can distinguish the cleaved from total CBG by employing an antibody to the exposed elastase sensitive loop.2

Hypothesis: That pregnancy induces a disproportionate rise in cleaved, low-affinity CBG, with a corresponding relative lack of rise in intact, high-affinity CBG, contributing to the extent of increase in free cortisol.     

Methods: Stored plasma samples from pregnant women which had been collected between 1400-1700h, serially through gestation, were assayed.  Total (cleaved plus uncleaved) and intact (uncleaved) CBG were assayed in parallel with specific monoclonal antibodies, using our in-house method.2  Total cortisol was assayed using a commercial immunoassay.

Results: 53 samples from 33 women were assayed, encompassing early (<15w, n = 13), mid (16-24w, n = 19), and late (>24w, n = 21) pregnancy.3  Total CBG levels in each interval were (mean ± SE) 1088 ± 167.9, 1117 ± 160 and 1125 ± 155 nmol/L, respectively. Corresponding intact CBG levels were 433.3 ± 27.0, 525.2 ±28.6 and 516.1 ± 46.7 nmol/L. Total cortisol levels increased throughout gestation 328 ± 23, 447 ± 38, 526 ± 33 nmol/L as expected.  Cleaved, low affinity CBG comprised 60.2%, 53.0% and 54.1% of total CBG across the three pregnancy intervals.

Conclusion: Cleaved, low cortisol binding affinity CBG comprises over 50% of total CBG in pregnancy compared to approximately 20% CBG in the non-pregnant state.4   The rise in intact high cortisol binding affinity CBG compared to non-pregnant individuals is much less than previously estimated using conventional assays, explaining the unexpectedly high free cortisol relative to total cortisol and total CBG in pregnancy.  High affinity CBG levels only rise moderately in pregnancy, less than 2-fold, compared to the non-pregnant state. This allows higher free cortisol levels to be achieved in pregnancy although a role for low affinity CBG in pregnancy is possible.

(1) Ho JT, et al., Clin Endocrinol 2007;66:869-877. (2) Lewis JG, Elder PA, J Steroid Biochem Mol Biol 2011; 127(3-5):289-94. (3) Hodyl NA, et al., Am J Respir Crit Care Med 2010;183:716-722. (4) Lewis JG, Elder PA, Clin Chim Acta 2013;416:26-30

Nothing to Disclose: MAN, JTH, VLC, NH, PAE, JGL, DJT

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This work was supported by the Gum Bequest, Royal Adelaide Hospital.