Corticotropin-Releasing Hormone (CRH)-Binding Protein: Reduction in the Adrenocorticotropin-Releasing Activity of Placental but not Hypothalamic CRH*

Abstract

This study is the first to use CRH-binding protein (CRH-BP) purified from human plasma to investigate how the CRH-BP affects the physiological activity of CRH. After incubation at 37 C for 15 min, purified CRH-BP reduced the ACTH-releasing activity of synthetic human (h) CRH in a dose-dependent fashion; using hCRH and CRH-BP at concentrations commonly found in late gestational maternal plasma, (1.5 and 100 ng/mL, respectively) an average 76% reduction in ACTH release was obtained. No effect was observed under the same conditions on ACTH release induced by ovine (o) CRH, which does not bind to CRH-BP. Kinetic estimations are presented to show that the extent of binding of CRH to its BP (and, hence, the reduction in its bioactivity) depends on the time available for binding and the concentration of reactants. Equilibrium between CRH and its BP at the concentrations used in the bioactivity studies take place within 400 s. Since long term secretion of placental CRH into the peripheral circulation occurs during the third trimester of pregnancy, we suggest that the presence of circulating CRH BP may partly explain how markedly elevated plasma levels of CRH coexist with normal ACTH levels at this time. We also propose that stress-induced CRH release will not be similarly quenched by the CRH-BP in the hypothalamic portal system, as the concentration of CRH released will be high, and the exposure time before reaching pituitary corticotropes will be low. Using pituitary cells constantly bathed in BP premixed with hCRH or BP alone (to mimic the situations in pregnancy and nonpregnancy, respectively), we show that short concentrated pulses of synthetic CRH (10 ng in 5 s) or rat stalk median eminence extract (one tenth stalk median eminence in 5 s) retain their ability to induce ACTH secretion despite the presence of CRH-BP. It is, thus, possible that CRH can still exert its role as a stress hormone in late gestation.

CRF binding protein facilitates the presence of CRF type 2α receptor on the cell surface

“…Different functions have been proposed for CRF-BP (13). On one hand, CRF-BP exerts an inhibitory role by sequestering CRF peptide (9,(14)(15)(16). On other hand, a facilitatory role of CRF-BP on CRF-dependent neuronal plasticity depending on CRF 2 R in the rat ventral tegmental area (VTA) has been described (17,18).…”

Follicular Fluid Cortisol Releasing Hormone (CRH) Levels and Assisted Reproductive Treatment (ART) Outcomes

“…It is possible, for example, that the extraction methods used in the previous two studies did not separate all of the CRH from any binding protein present in the sample; in these circumstances, the CRH measurements obtained would underestimate the true levels present in follicular fluid. Methanol extraction, on the other hand, is known to extract CRH from body fluids with efficiency approaching 100% [15]. It is also possible that the CRH antibodies used in the three different RIA have differing cross-reactivities to the various molecular species of CRH, for example the CRH precursor, proCRH, and its intermediate metabolite, CRH 125−194 .…”

Has the mechanism by which the endocrine placenta scavenges the mother whilst sparing the foetus been unmasked?

“…We went on to discover, purify and clone a high affinity plasma binding protein (CRF-BP) that was present in the blood in sufficient concentrations to be capable of neutralising the biological activity of CRF in the peripheral circulation of both mother and foetus (Behan et al 1989). This provided an explanation for the protection of both maternal and foetal pituitary glands from the effects of placental CRF throughout most of pregnancy (Linton et al 1990). …”