Hodyl Nicolette A, Stark Michael J, Meyer Emily J, Lewis John G, Torpy David J, Nenke Marni A
Robinson Research Institute, University of Adelaide, Adelaide, 5000 Australia.
Robinson Research Institute, University of Adelaide, Adelaide, 5000 Australia; Women's and Children's Hospital, North Adelaide, 5006 Australia.
Eur J Obstet Gynecol Reprod Biol. 2020 Aug;251:129-135. doi: 10.1016/j.ejogrb.2020.05.034. Epub 2020 May 26.
Corticosteroid-binding globulin (CBG) binds and transports cortisol in the circulation in high cortisol-binding affinity (haCBG) and low affinity (laCBG) forms, the latter resulting from enzyme cleavage to target cortisol delivery at sites of inflammation. CBG also has substantial progesterone binding affinity, 3-fold less than cortisol. Progesterone and cortisol are important in the maintenance of pregnancy and in fetal development, respectively. The interactions of cortisol, progesterone and CBG affinity forms have not been studied together. We examined the interaction between progesterone and cortisol with CBG during fetal development.
A retrospective cohort analysis of 351 neonates born between January and December 2012 at the Women's and Children's Hospital, Adelaide, South Australia. Cord blood serum samples were collected immediately following delivery. Clinical data was provided by hospital records. Total cortisol, free cortisol, total progesterone, total CBG and haCBG were measured by immunoassay.
Cord blood total and free cortisol, and progesterone concentrations increased with gestational age. Cord blood progesterone concentrations were 100-fold luteal and 10-fold those in late pregnancy maternal circulation. The proportion of haCBG to total CBG was similar to that in healthy non-pregnant adults. However, free cortisol comprised approximately 15% of total cortisol, 3-fold higher than that in adults.
In a manner unique to fetal life, very high progesterone concentrations are capable of elevating free cortisol concentrations through competition with cortisol at CBG's hormone binding site, without altered binding affinity through CBG cleavage or altered CBG hormone-binding affinity. High circulating fetal progesterone concentrations compete for CBG binding with cortisol, leading to a 3-fold increase in the free cortisol fraction in cord blood. Higher free-to-bound cortisol may alter fetal cortisol distribution facilitating cortisol's roles such as neurodevelopment in concert with dehydroepiandrosterone (sulfate) and lung maturation, or support cortisol action at times of low ambient cortisol. This mechanism may underlie the known association between cortisol, progesterone and CBG, and be relevant principally in the fetal circulation due to the high progesterone concentrations encountered.
皮质类固醇结合球蛋白（CBG）以高皮质醇结合亲和力（haCBG）和低亲和力（laCBG）形式在循环中结合并转运皮质醇，后者是酶切作用的结果，目的是将皮质醇递送至炎症部位。CBG对孕酮也有相当高的结合亲和力，比皮质醇低3倍。孕酮和皮质醇分别在维持妊娠和胎儿发育中起重要作用。尚未对皮质醇、孕酮与CBG亲和力形式之间的相互作用进行共同研究。我们研究了胎儿发育过程中孕酮与皮质醇和CBG之间的相互作用。
对2012年1月至12月在南澳大利亚阿德莱德妇女儿童医院出生的351例新生儿进行回顾性队列分析。分娩后立即采集脐血血清样本。临床数据由医院记录提供。采用免疫分析法测定总皮质醇、游离皮质醇、总孕酮、总CBG和haCBG。
脐血总皮质醇、游离皮质醇和孕酮浓度随孕周增加而升高。脐血孕酮浓度在黄体期是母体循环晚期的100倍，是妊娠晚期的10倍。haCBG占总CBG的比例与健康非妊娠成年人相似。然而，游离皮质醇约占总皮质醇的15%，比成年人高3倍。
以胎儿期特有的方式，非常高的孕酮浓度能够通过在CBG的激素结合位点与皮质醇竞争来提高游离皮质醇浓度，而不会因CBG裂解或CBG激素结合亲和力改变而改变结合亲和力。胎儿循环中高浓度的孕酮与皮质醇竞争CBG结合，导致脐血中游离皮质醇分数增加3倍。较高的游离与结合皮质醇比例可能会改变胎儿皮质醇分布，促进皮质醇在与脱氢表雄酮（硫酸盐）协同作用下的神经发育和肺成熟等作用，或在环境皮质醇水平较低时支持皮质醇的作用。这种机制可能是皮质醇、孕酮和CBG之间已知关联的基础，并且主要与胎儿循环相关，因为胎儿循环中孕酮浓度很高。
