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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 5 1611-1614
Copyright © 1998 by The Endocrine Society

Original Studies

The Pathophysiology of Circulating Corticotropin-Releasing Hormone-Binding Protein Levels in the Human

P. J. Trainer, R. J. Woods, M. Korbonits, V. Popovic, P. M. Stewart, P. J. Lowry and A. B. Grossman

Department of Endocrinology, St. Bartholomew’s Hospital (P.J.T., M.K., A.B.G.), West Smithfield, London, United Kingdom EC1A 7BE; the Department of Biochemistry and Physiology, University of Reading (R.J.W., P.J.L.), Reading, United Kingdom RG6 6AJ; the Institute of Endocrinology (V.P.), 11000 Belgrade, Yugoslavia; and the Department of Medicine, University of Birmingham, Queen Elizabeth Hospital (P.M.S.), Edgbaston, Birmingham, United Kingdom B15 2TH

Address all correspondence and requests for reprints: Dr. P. J. Trainer, Department of Endocrinology, St. Bartholomew’s Hospital, West Smithfield, London, United Kingdom EC1A 7BE. E-mail: p.j.trainer{at}mds.qmw.ac.uk


   Abstract
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 Abstract
Introduction
 Experimental Subjects
 Materials and Methods
 Results
 Discussion
 References
 
To establish the factors that modulate circulating CRH-binding protein (CRH-BP) levels, we measured plasma CRH-BP in patients with a variety of endocrine and systemic disorders. CRH-BP was measured by RIA. Young women have higher plasma levels of CRH-BP than young men [females (n = 18), mean ± SEM, 145 ± 7; males (n = 20), 99 ± 6 ng/mL; P < 0.0001], but levels do not fall with the menopause or vary during the menstrual cycle and are unaffected by estrogen replacement therapy. Levels were lower in patients with liver disease than in healthy men (26 ± 3 vs. 99 ± 6; P < 0.0001) and were elevated in chronic renal failure compared to those in healthy women (211 ± 11.2 vs. 145 ± 7; P < 0.01). Levels were unaffected by fasting in men or women (male fasted, 97 ± 11; male fed, 97 ± 8; female fasted, 136 ± 9; female fed, 152 ± 10). Dexamethasone treatment lowered CRH-BP in all subjects (129 ± 8 vs. 111 ± 9; P < 0.003). Similarly, CRH-BP levels were lower in patients with Cushing’s syndrome (all female) than in healthy female controls (median, 82; range, 53–106; vs. median, 142; range, 101–190; P < 0.0001). In Cushing’s patients, an iv bolus of 100 µg human CRH further lowered plasma CRH-BP at 15 min (81 ± 5 vs. 50 ± 4; P < 0.0003).

Plasma levels of CRH-BP are higher in women than men, but this is unrelated to circulating estrogen levels. The low levels in liver disease and the high levels in renal failure support its hepatic origin and the kidneys as the route of clearance from plasma. The ability of glucocorticoids and exogenous CRH to lower plasma CRH-BP levels and of CRH-BP to modulate the bioactivity of circulating CRH suggest that the protein may be an important regulator of circulating CRH or related ligands.


   Introduction
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 Abstract
 Introduction
Experimental Subjects
 Materials and Methods
 Results
 Discussion
 References
 
CRH IS A 41-residue peptide that plays a pivotal role in the regulation of ACTH secretion (1). In addition, CRH is found extensively throughout the brain, where it may act as a neurotransmitter and as a central regulator of the stress response (2). More recent work has suggested that it may also be involved in the local tissue inflammatory response in diseases such as rheumatoid arthritis (3). Finally, there is increasing evidence for the involvement of CRH in the regulation of human parturition (4).

A high affinity 37-kDa binding protein for CRH has been purified from human plasma, and sequenced and cloned from human liver and rat brain complementary DNA libraries (5, 6). Rat and human CRH-binding protein (CRH-BP) are highly homologous, with a dissociation constant (Kd) of 0.1 ± 0.2 nmol/L. Plasma CRH-BP is hepatic in origin with additional gene expression detectable in brain and placenta. Circulating human CRH-BP contains 10 cysteine residues and a secondary structure consisting of 5 loops formed by the sequential disulfide bonding of adjacent residues (7). On a perfused pituitary cell column system, the bioactivity of CRH is reduced by coincubation with CRH-BP, whereas in vivo the presence of binding protein shortens the immunoreactive half-life of CRH (8, 9). The ability of CRH-BP to modulate the bioactivity of CRH suggests that the protein may be an important regulator of the hypothalamo-pituitary-adrenal (HPA) axis. Furthermore, there is increasing evidence that CRH-BP may bind with high affinity to peptide ligands distinct from CRH, although the precise nature of these ligands is currently unknown (10).

To establish the factors that modulate circulating CRH-BP levels and to better define the reference range, we measured plasma CRH-BP in normal subjects and in patients with a variety of endocrine and systemic disorders using a recently developed RIA.


   Experimental Subjects
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 Introduction
 Experimental Subjects
Materials and Methods
 Results
 Discussion
 References
 
All samples were collected at the endocrine investigation ward of St. Bartholomew’s Hospital, except for the patients with hepatic disease, who were studied in Birmingham, UK, and the postmenopausal women, who were studied in Belgrade, Yugoslavia. All of the women studied had regular menstrual cycles, except for the postmenopausal group, who had been amenorrheic for at least 1 yr. Ten male and 10 female nonobese (body mass index, <27 kg/m2) healthy volunteers (mean age, 25 yr; range, 20–33) were studied on 2 occasions, fasted and fed. Fasted samples were collected at end of a 12-h fast and at the time of the maximal cortisol response to a standardized 1000-Cal meal (11).

CRH-BP was measured in 10 female patients (median age, 54 yr; range, 23–70) with pituitary-dependent Cushing’s disease, and in a further cohort of 10 patients with Cushing’s disease before and after an iv bolus of 100 µg human CRH. The diagnosis of pituitary dependent-Cushing’s disease was established by failure to suppress plasma cortisol appropriately after low dose dexamethasone suppression test (0.5 mg every 6 h for 48 h), loss of the circadian rhythm of plasma cortisol, an exaggerated plasma cortisol response to an iv bolus of human CRH, and inferior petrosal sinus sampling demonstrating a central gradient for ACTH after CRH provocation. The diagnosis was confirmed in all cases at surgery. Plasma CRH-BP was also measured in a group of 7 healthy volunteers (4 males and 3 females; median age, 31 yr; range, 26–36) at 0900 h before and after oral dexamethasone at a dose of 0.5 mg precisely every 6 h for 48 h.

Fifteen patients (eight males and seven females; median age, 59 yr; range, 26–75) with renal disease had established chronic renal failure (median serum creatinine, 1087 µmol/L; range, 780-1742; reference range, <100 µmol/L) and were undergoing long term hemodialysis; they were sampled just before their twice or three times weekly hemodialysis. The patients with liver disease [n = 28; mean age, 48.9 ± 3 yr; serum bilirubin, 212 ± 61 µmol/L (reference range, 1–26); serum albumin, 27.8 ± 1.7 g/L (reference range, 34–51)] had histologically confirmed diagnoses in association with chronically disturbed serum liver function tests.


   Materials and Methods
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 Abstract
 Introduction
 Experimental Subjects
 Materials and Methods
Results
 Discussion
 References
 
All blood samples were collected in lithium heparin tubes, then immediately cold spun (250 x g, 10 min, 4 C) and separated, and plasma was frozen. Samples were stored at -20 C until assay.

Assays

CRH-BP RIA. Purified recombinant CRH-BP was radioiodinated by the glucose oxidase/lactoperoxidase method, and bound and free iodine were separated by gel filtration chromatography. CRH-BP stocks (3.48 mg/L) were prepared in aliquots of 0.5 mL in sheep serum and stored frozen at -20 C. Assay standards were prepared by dilution of stock aliquots in 0.05 mmol/L phosphate buffer, pH 7.4, containing 0.5% wt/vol BSA and 0.1% (wt/vol) sodium azide to obtain a range of concentrations from 0.9–464 µg/L. To 50 µL of the above buffer were added 50 µL standard or sample, 100 µL tracer containing 20,000 cpm [125I]CRH-BP, and 100 µL rabbit anti-CRH-BP antibody diluted 4,000-fold in the same buffer. Standards and samples were prepared in duplicate, and the assay was incubated for 16 h at 4 C before separation. Separation was achieved by a precipitating antibody consisting of 10% sheep antirabbit antiserum directed against the Fc fragment containing 0.5% (vol/vol) normal rabbit serum and 4% polyethylene glycol 6000 (Sigma, Poole, Dorset, United Kingdom). Inclusion of human CRH in standards or in human plasma samples in concentrations ranging from 1.6–25 µg/liter had no effect on CRH-BP measurements (12).

Statistics

All data were subjected to the Kolmogorov-Smirnov test of normality. Data with a Gaussian distribution were compared by paired and unpaired Student’s t test where appropriate; otherwise, the Mann-Whitney rank sum test was employed. Significance was taken as P < 0.05.


   Results
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 Abstract
 Introduction
 Experimental Subjects
 Materials and Methods
 Results
Discussion
 References
 
Plasma CRH-BP levels were higher in young females than in young men [females (n = 18), mean ± SEM, 145 ± 7; males (n = 20), 99 ± 6 ng/mL; P < 0.0001], but were not lower in postmenopausal women and were unaltered after 1 month of estrogen replacement therapy. Similarly, there were no differences in circulating CRH-BP levels measured on days 5, 10, 18, and 21 of the menstrual cycle in six women with regular menses (28 ± 2 days; data not shown).

Levels were lower in men with liver disease than in healthy men [liver disease (n = 28), 26 ± 3; healthy men (n = 20), 99 ± 6; P < 0.0001] and were elevated in patients with chronic renal failure compared to healthy women [renal failure (n = 10), 211 ± 11.2; healthy women (n = 18), 145 ± 7; P < 0.01; Fig. 1Go]. Fasting in men or women did not affect circulating CRH-BP levels [male (n = 10): fasted, 97 ± 11; fed, 97 ± 8; female (n = 10): fasted, 136 ± 9; fed, 152 ± 10; Fig. 2Go].



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  		Figure 1. Patients with chronic liver disease (n = 28) have lower plasma CRH-BP levels than healthy young women and men, whereas patients undergoing hemodialysis for chronic renal failure have higher levels (n = 18). The mean ± SEM are shown.

 


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  		Figure 2. Ten male and female subjects were studied on two occasions after fasting from midnight. On one occasion, a 1000-Cal meal (arrow) was served at 1200, and on the other occasion, no food was given. Plasma CRH-BP was measured every 20 min from 1100–1500 h. Feeding did not result in a change in plasma CRH-BP in either women or men despite a rise in plasma cortisol (data not shown). The mean ± SEM are shown.

 
Short term glucocorticoid therapy (dexamethasone, 2 mg/day for 48 h) reduced plasma CRH-BP in all subjects (n = 7; 129 ± 8 vs. 111 ± 9; P < 0.003; Fig. 3Go). The median 0900 h cortisol was 343 nmol/L (range, 212–766) before dexamethasone treatment, and in all subjects was undetectable (<50 nmol/L) at 48 h. Similarly, plasma CRH-BP levels were lower in female patients with untreated Cushing’s syndrome than in the healthy female controls [Cushing’s patients (n = 10): median, 82; range, 53–106; controls (n = 10): median, 142; 101–190; P < 0.0001]. In another cohort of patients with Cushing’s disease, an iv bolus of 100 µg human CRH further lowered plasma CRH-BP at 15 min (n = 10; 81 ± 5 vs. 50 ± 4; P < 0.0003; Fig. 4Go).



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  		Figure 3. Oral dexamethasone (0.5 mg every 6 h for 48 h) treatment lowers plasma CRH-BP in normal volunteers (n = 7).

 


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  		Figure 4. Mean plasma CRH-BP levels are lower in women with Cushing’s disease than in young women and fall further after the administration of human CRH. The mean ± SEM are shown.

 

   Discussion
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 Abstract
 Introduction
 Experimental Subjects
 Materials and Methods
 Results
 Discussion
References
 
Evidence is accumulating for the importance of CRH-BP as a modulator of the activity of the CRH-like peptides. We have previously shown that, in man, the half-life of human CRH is shorter than that of ovine CRH, which is not a ligand for human CRH-BP; in sheep, which do not have a circulating CRH-BP, no difference in half-life exists, which is compatible with our finding that both peptides had a longer half-life in sheep than in man. In a further study, in patients with Cushing’s syndrome, ovine CRH caused a more sustained ACTH response than human CRH, although no difference was seen in peak responses (13). We have also demonstrated that in normal volunteers an iv bolus of CRH induced a prompt fall in plasma CRH-BP levels (14). It is the dimerization of CRH-BP on association with CRH that appears to trigger the rapid clearance of CRH-BP from plasma by an as yet undetermined mechanism; this is unlikely to be renal, because the molecular size of the dimer (75 kDa) is sufficient to reduce its glomerular filtration to insignificant amounts. The change in its configuration may trigger its uptake at a specific receptor sites, i.e. CRH-BP may be acting as an "address" molecule (12). These data imply that binding to CRH-BP reduces the plasma half-life and bioactivity of CRH, a conclusion supported by the reduced ability of CRH to stimulate ACTH secretion when coincubated with CRH-BP in vitro (8).

It should be noted that CRH-BP, although affecting the half-life of CRH, is present in concentrations disproportionate to those of plasma CRH, implying that CRH may not be its most important peripheral ligand in males and nonpregnant women. CRH, as discussed above, is one member of a family of peptides involved in activation of the HPA axis, the inflammatory response, learning, and cognition. Other members of the family include fish urotensin and frog sauvagine, both of which are more potent than CRH at activating CRH-R2 receptors and bind with greater affinity to CRH-BP. Recently, Vale’s group identified, and named, in rat and man a further member of this family of peptides; urocortin has 45% homology to rat CRH and 63% homology to urotensin, and binds with high affinity to CRH-BP (15, 16). Several other members of the CRH family of peptides, and by implication ligands for CRH-BP, remain to be characterized in man. Aylwin and colleagues have reported ACTH-dependent Cushing’s syndrome and corticotroph hyperplasia caused by a CRH-like peptide secreted by a brain tumor, and we have evidence of an alternative ligand for the CRH-BP in the synovial fluid of patients with rheumatoid arthritis (17, 18). It has been speculated that the low levels of CRH in the cerebrospinal fluid of patients with Alzheimer’s disease may contribute to their cognitive impairment, a situation potentially exacerbated by the normal levels of CRH-BP and, by implication, even lower levels of free CRH. Displacement of CRH from its binding protein has been suggested as a possible treatment of Alzheimer’s disease (19). In rats and sheep, CRH-BP is limited to the brain, whereas in man it is also found in plasma; as under basal conditions plasma CRH is virtually undetectable, CRH-BP appears to be present in great excess. Thus, CRH-BP may have a number of roles, but only in the primate may its circulating level relate to modulation of the activity of plasma CRH or related peptides.

The lower levels documented here in patients with chronic liver disease are the first in vivo evidence for the liver as the principal source of circulating CRH-BP; this is supported by the human CRH-BP gene having been cloned from a human liver complementary DNA library and containing upstream the liver-specific regulatory elements LFA1 and LFB1 (20). The elevated plasma CRH-BP levels found in patients with chronic renal failure suggest a renal route of clearance from the circulation of nonligand-bound CRH-BP monomers.

This is the first study to document plasma CRH-BP levels to be higher in women than men, which might suggest an estrogen-dependent effect; however, the absence of a difference compared between pre- and postmenopausal women, the failure of estrogen therapy in postmenopausal women to restore CRH-BP levels to those in young women, and the lack of variation during the menstrual cycle would indicate otherwise. Suda et al. (21) failed to detect a difference between the sexes in plasma CRH-BP levels estimated by ligand binding to samples run on polyacrylamide gels.

CRH is secreted into the maternal circulation from placental trophoblasts, and its plasma levels rise exponentially in the last 60 days of pregnancy, which has led to speculation that CRH may be involved in the regulation and timing of parturition. McLean et al. (22) have offered compelling evidence for a role for plasma CRH-BP in the modulation of CRH activity in late pregnancy. In their study, the exponential rise in plasma CRH levels in very late pregnancy was accompanied by a 65% fall in plasma CRH-BP levels, thus suggesting a rise in CRH bioactivity. The difference in the CRH-BP levels between the sexes indicates a need to establish two normal ranges. Feeding is a potent physiological stimulant of the HPA axis (11, 23), and the absence of an effect of feeding on plasma CRH-BP levels suggests that CRH-BP is unlikely to be responsive to food intake and is therefore unlikely to play a role in the regulation of gastrointestinal function, although this must remain speculative at present.

Although the transient physiological rise in plasma cortisol after feeding is not associated with a change in CRH-BP, plasma CRH-BP levels are lower in patients with high chronic inappropriate elevation of plasma glucocorticoids due to Cushing’s syndrome and fall in response to the administration of 0.5 mg dexamethasone every 6 h for 48 h; these results are generally compatible with those of Suda et al. (24). The fall in plasma CRH-BP levels after an iv bolus of human CRH in the patients with Cushing’s syndrome is compatible with the fall documented in normal volunteers (14).

In conclusion, the higher plasma levels of CRH-BP in women do not appear to be estrogen dependent. The low levels in liver disease and high levels in renal failure support its hepatic origin and renal clearance, respectively. The ability of glucocorticoids and exogenous CRH to lower plasma CRH-BP levels, and of CRH-BP to modulate the bioactivity of CRH, suggest that the protein may be an important regulator of circulating CRH and possibly of other related ligands. Circulating CRH may be only one of a family of peptide ligands for CRH-BP that may be intimately involved in the inflammatory response (10). CRH-related peptides have been identified in inflamed joints of patients with rheumatoid arthritis, the plasma CRH-BP level is high in rheumatoid arthritis, and the CRH-BP gene contains at the extreme 5'-flanking region a number of Ig-like enhancer elements, such as nuclear factor-{kappa}ß (18). The modulation of CRH-BP, which binds to such ligands with high affinity, is also likely to play a role in mediating or limiting the inflammatory process, and understanding the factors that regulate its level are clearly important in advancing our knowledge of this process. It will now be of importance to study the precise regulation of CRH-BP in a variety of inflammatory conditions.


   Acknowledgments
 
We are most grateful for the excellent assistance of Debbie Grossman, Caroline Ramsey, Louise Conrich, and Kathy Maher.

Received September 5, 1996.

Revised December 17, 1997.

Accepted January 16, 1998.


   References
Top
 Abstract
 Introduction
 Experimental Subjects
 Materials and Methods
 Results
 Discussion
 References
 

  1. Vale W, Spiess J, Rivier C, Rivier J. 1981 Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science. 213:1394–1397.[Free Full Text]
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