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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 8 2820-2825
Copyright © 1999 by The Endocrine Society

Original Studies

Corticotropin-Releasing Hormone in Chimpanzee and Gorilla Pregnancies

Roger Smith, E. Jean Wickings, Maria E. Bowman, Anne Belleoud, Guy Dubreuil, Joanne J. Davies and Gemma Madsen

Mothers and Babies Research Center, John Hunter Hospital (R.S., M.E.B., J.J.D., G.M.), New South Wales 2310, Australia; Primate Center, Centre International de Reserches Medicales de Franceville (E.J.W., A.B., G.D.), Franceville, Gabon

Address all correspondence and requests for reprints to: Dr. Roger Smith, Mothers and Babies Research Center, John Hunter Hospital, Locked Bag 1, Hunter Region Mail Center, New South Wales 2310, Australia.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
In humans, the length of gestation and the onset of parturition have been linked to the exponential production of placental CRH and a late gestational decline in maternal plasma CRH-binding protein (CRH-BP). CRH has been shown to have direct effects on the myometrium and on the fetal adrenal, where it stimulates production of the estrogen precursor dihydroepiandrosterone sulfate. In vitro placental CRH production is stimulated by cortisol and inhibited by progesterone. To determine whether this mechanism might operate in other apes, we sampled eight chimpanzees and two gorillas through their pregnancies for CRH, CRH-BP, cortisol, estradiol, progesterone, and {alpha}-fetoprotein. We show that both chimpanzee and gorilla maternal plasma CRH concentrations rise exponentially as observed in the human. The gorillas exhibited a human-like antepartum fall in CRH-BP, whereas CRH-BP in the chimpanzee remained stable. Pregnancy-associated changes in cortisol, estradiol, progesterone, and {alpha}-fetoprotein were qualitatively similar to those observed in humans. Maternal plasma cortisol correlated with plasma CRH in both gorillas (r = 0.60; P < 0.05) and chimpanzees (r = 0.36; P < 0.02). Further, there was a strong correlation between plasma estradiol and the log of plasma CRH in the gorilla (r = 0.93; P < 0.0001) and in the chimpanzee (r = 0.72; P < 0.001), which is consistent with the hypothesis that placental CRH determines the placental production of estradiol by stimulating the production of fetal adrenal dehydroepiandrosterone sulfate. Plasma CRH and progesterone were positively correlated providing no in vivo support for progesterone inhibition of CRH release.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
IN HUMAN pregnancy, CRH is synthesized in the placenta and released into both the maternal and fetal circulations. Maternal plasma CRH increases exponentially as pregnancy advances to peak at the time of delivery. Maternal plasma CRH is elevated compared to gestational age-matched controls in women who are destined to deliver prematurely and is low in those who will deliver late (1, 2). Further, the human possesses a circulating binding protein for CRH (CRH-BP) the maternal concentrations of which fall in late pregnancy, and the CRH-BP may modify the biological action of CRH (3). The human myometrium expresses CRH receptors, and CRH may act via these receptors to regulate the processes of parturition (4, 5). Within the fetal circulation, levels of CRH also increase, although to a less marked extent (6, 7, 8, 9, 10). In the fetal circulation, CRH may have a role in stimulating production of dehydroepiandrostenedione sulfate (DHEA-S), either indirectly by stimulating fetal pituitary ACTH (11), which subsequently stimulates adrenal steroidogenesis (12), or directly by acting on the fetal zone of the adrenal, which has receptors for CRH. In vitro the fetal zone has been shown to respond to CRH by increased secretion of DHEA-S and production of the enzymes required for DHEA-S synthesis (13). As DHEA-S is an obligate precursor for placental estrogen production (14, 15), which mediates many of the key changes associated with delivery (16), CRH appears likely to play a central role in regulating human parturition. However, CRH is present only in the placentas of primates (17). The evolution of the role of placental CRH is, therefore, of interest. Limited information is available on CRH in the blood of pregnant primates other than man. In the baboon, an Old World monkey, two groups have reported that maternal plasma CRH is increased over nonpregnant concentrations but that levels peak in midgestation and do not exhibit the exponential rise observed in humans (18, 19). Limited data are also available on the rhesus, another Old World monkey (20). We were interested in whether species more closely related to man might possess patterns of secretion of CRH more closely related to our own and whether other insights into the function of placental CRH might be obtained by the study of such species. With this in mind we have followed the pregnancies of eight chimpanzees and two gorillas, correlating changes in maternal plasma concentrations of CRH and several potentially related hormones with gestational length. We report a strong association between maternal plasma CRH and estradiol. Our results support the concept that placental CRH drives the production of estradiol through an effect on fetal DHEAS production.


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

Pregnant chimpanzees and gorillas in the breeding colony of the Centre International de Reserches Medicales de Franceville (Gabon, West Africa) were studied. Prior approval for this study was obtained from the primate ethics committee of Centre International de Reserches Medicales de Franceville. Apes were housed in groups of 6–10 in large indoor rooms with daily access to outdoor recreation areas; they were fed ape pellets (SDS, UK) supplemented by fresh fruit.

Pregnancy was diagnosed using urinary CG levels (Abbott HCG Test, Abbott Laboratories, France) and was confirmed by ultrasound. Dates of sexual tumescences (scored daily in chimpanzees and observed in gorillas) and human fetal growth patterns were used as reference points to calculate the date of conception. Pregnant apes were sampled at 4–9 weeks (the first sample depended on the date of first ultrasound diagnosis) and 12, 18, 26, 30 and 32–33 weeks in chimpanzees and, in addition, at 34–35 weeks in gorillas. Postpartum samples were taken from five of the eight chimpanzees from 3–11 days after delivery. Animals were anesthetized by im injection of ketamine (10–15 mg/kg BW; Imalgene, Rhone-Merieux, France), delivered by blowpipe. They were submitted to a clinical examination, and fetal measurements were taken to monitor growth and fetal viability at each capture. Blood samples were taken from the femoral vein for routine biochemical and hematological parameters. Heparinized venous blood for determination of CRH and other hormones was immediately spun, and the plasma was aliquoted and stored at -50 C. Samples were transported on dry ice from Gabon, West Africa to Newcastle, Australia before assay.

CRH assay

Plasma samples assayed for CRH were extracted using silica glass powder (Vycor, Corning, Inc., Corning, NY) as previously described (19). Lyophilized samples were reconstituted in 0.5 mL RIA buffer [0.1 mol/L sodium phosphate (pH 7.45), 0.25% (wt/vol) BSA, 0.1% (vol/vol) 2-mercaptoethanol, and 0.02% (wt/vol) sodium azide]. Synthetic human (h) CRH (Auspep, Victoria, Australia) was used as the standard, chloramine-T-labeled [125I]Tyr0-hCRH was used as tracer, and Y2B0 was used as the anti-CRH antiserum (a gift from Prof. P. J. Lowry and Dr. E. Linton, University of Reading, Reading, UK). Separation of the antibody-bound tracer from unbound tracer was achieved with the addition of 50 µL of a suspension of donkey antirabbit antibody-coated cellulose (Sac-cel, Immuno Diagnostics, Tyne and Wear, UK). Extraction recovery was 107%. No correction of the data for extraction recoveries was made.

CRH-BP assay

Plasma samples were assayed for CRH-BP using a RIA. Human CRH-BP (Prof. P. J. Lowry, UK) was used as the standard. A standard curve was constructed by diluting a stock of 800 ng/mL CRH-BP in 10 serially doubling dilutions, resulting in known concentrations from 0.08–21.62 nmol/L. Triplicate 50-µL volumes of standards or samples were incubated at 4 C for 24 h with 50 µL sheep anti-CRH-BP antiserum (1:2500), followed by a 48-h incubation with 50 µL [125I]CRH-BP, with an activity of 20,000 cpm. Separation of the antibody-bound tracer from unbound tracer was achieved with the addition of 50 µL of a suspension of donkey antisheep antibody-coated cellulose (Sac-cel, Immuno Diagnostics, UK). The sensitivity of the assay was 0.81 nmol/L. The intraassay coefficient of variation was 12.2%.

Preparation of [125I]CRH-BP

CRH-BP was iodinated using a modification of the Iodogen method of Salacinski et al. (21). Briefly, 2 µg peptide in 50 µL 0.2 mol/L phosphate buffer, pH 7.4, were incubated with 200 µCi Na125I (Aust Radioisotopes, Lucas Heights, Australia) at room temperature for 30 min in an (5 µg) Iodogen-coated tube. The labeled peptide was purified over a 50 x 1-cm Sephacryl S200 (Pharmacia Biotech) column equilibrated with phosphate-buffered saline containing BSA (0.1%, wt/vol) and sodium azide (0.05%). The column was eluted with phosphate-buffered saline-0.1% BSA-0.05% azide at 10 mL/h, and 1-mL fractions were collected. Radioactivity eluting in the void volume was pooled and divided into aliquots for storage at -80 C.

Cortisol

Cortisol was measured using a paramagnetic particle chemiluminescent immunoassay (Access Cortisol Assay, Safoni Diagnostics, Pasteur, Australia). The assay sensitivity was 10 pmol/L, and the intra- and interassay coefficients of variation were 4.4% and 6.0%, respectively.

Progesterone

Progesterone was measured using a paramagnetic particle chemiluminescent immunoassay (Amerlite Progesterone Assay, Johnson & Johnson Clinical Diagnostics, Amersham Pharmacia Biotech, UK). The assay sensitivity was 0.3 nmol/L, and the interassay coefficient of variation was 7.4%.

Estradiol

Estradiol was measured using a RIA kit (Gamma-Beta Direct Estradiol kit, Immunodiagnostics Ltd., Boldon, UK). The assay sensitivity was 10 pmol/L, and the interassay coefficient of variation was 5.2%.

{alpha}-Fetoprotein (AFP)

AFP was measured using a kit (AFP Automated Immuno Enzymetric Assay, Tosoh, Tokyo, Japan). The assay sensitivity was 1 ng/mL, and the intra- and interassay coefficients of variation were 3.3% and 2.2%, respectively.

Statistical analysis

The grouped CRH data were analyzed using the Wilcoxon rank sum test. Correlation analysis was performed using the Microsoft Corp. Excel version 7.0 spreadsheet. Data are reported as the mean ± SEM unless otherwise stated.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Chimpanzee and gorilla studies

The eight chimpanzees delivered from 222–234 days gestation (mean ± SEM, 229 ± 1.3; n = 8). All delivered healthy infants with a mean weight of 1.9 ± 0.2 kg (±SEM) at the first postpartum examination (1–6 weeks). The two gorillas delivered at 253 and 261 days gestation; conditions prevented examination of the neonates, but both thrived.

CRH

The concentrations of plasma CRH immunoreactivity (CRH-IR) in the chimpanzee were undetectable before 100 days gestation and then increased exponentially to peak at term (Figs. 1Go and 2Go). At term, values ranged from 4.3–628.7 pmol/L, with a mean of 142.4 ± 55.6 pmol/L. Postpartum samples were below the limit of detection (1.9 pmol/L). Only one gorilla sample was obtained before 100 days gestation; however in both gorillas, CRH-IR levels rose exponentially from week 17 to peak at 436.4 and 2244.9 pmol/L in the last sample before delivery (Fig. 3Go). Postpartum samples could not be taken. Grouped CRH-IR concentrations in the last third of pregnancy in the chimpanzee were significantly lower than those in the gorilla for the same period (P < 0.02, by Wilcoxon rank sum test).



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  		Figure 1. Plasma CRH-IR concentrations in individual pregnant and postpartum chimpanzees. Individual animals are represented by different symbols, with the lines joining the concentrations at various gestational ages of the same animal.

 


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  		Figure 2. Mean plasma CRH and CRH-BP concentrations in pregnant and postpartum chimpanzees.

 


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  		Figure 3. Plasma CRH-IR and CRH-BP concentrations in individual pregnant gorillas. Individual animals are represented by different symbols, with the lines joining the concentrations at various gestational ages of the same animal.

 
CRH-BP

CRH-BP was stable throughout pregnancy in all eight chimpanzees (Fig. 2Go). Pregnant and nonpregnant concentrations were not significantly different [pregnant, 2560.7 ± 135.3 pmol/L (n = 43); nonpregnant, 2587.2 ± 392.0 pmol/L (n = 5)]. In the two gorillas studied, CRH-BP peaked at 126 and 192 days, then fell in late gestation (Fig. 3Go). The mean pregnant CRH-BP concentration in the gorillas was 3118.1 ± 223.9 pmol/L.

Cortisol

Chimpanzee plasma cortisol increased progressively throughout gestation, rising from a mean of 700.2 ± 52.7 nmol/L around the middle of pregnancy (81–120 days) to 1232.2 ± 46.5 at the end of pregnancy (201–240 days; Fig. 4Go). Similar increases in cortisol were also seen in the gorilla, peaking at 636 and 1075 nmol/L. Plasma cortisol correlated with plasma CRH throughout the pregnancies of both chimpanzees (r = 0.36; P < 0.02) and gorillas (r = 0.60; P < 0.05).



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  		Figure 4. Mean plasma cortisol concentrations in pregnant ({diamondsuit}) and postpartum ({blacktriangleup}) chimpanzees and pregnant gorillas ({blacksquare}).

 
Estradiol

Estradiol values rose progressively throughout gestation in the chimpanzee from 2009.5 pmol/L at week 4 to 17635.4 ± 1922.1 (n = 12) at the end of pregnancy (Fig. 5Go). The postpartum level was 28.6 ± 5.8 pmol/L. Very similar levels of plasma estradiol were observed in the two gorillas in which concentrations reached 19,550 and 21,600 pmol/L (Fig. 5Go). There was a moderate correlation between estradiol and CRH in the chimpanzee (r = 0.35; P < 0.05) and gorilla (r = 0.72; P < 0.02), but a much stronger correlation between estradiol and the log of CRH in both the chimpanzee (r = 0.72; P < 0.001; Fig. 6AGo) and gorilla (r = 0.93; P < 0.0001; Fig. 6BGo); both were closely related to gestational age.



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  		Figure 5. Mean plasma estradiol concentrations in pregnant ({diamondsuit}) and postpartum ({blacktriangleup}) chimpanzees and pregnant gorillas ({blacksquare}).

 


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  		Figure 6. Plasma estradiol strongly correlated with the log of plasma CRH in both chimpanzee (A; r = 0.72; P < 0.001) and gorilla (B; r = 0.93; P < 0.0001) pregnancies.

 
Other hormones

Progesterone rose markedly in the chimpanzee from a mean of 93.6 ± 13.4 nmol/L before 160 days to peak close to parturition at 354.2 ± 34.0 nmol/L (Fig. 7Go). Postpartum values were undetectable. Plasma progesterone concentrations in the gorilla were similarly raised, with levels reaching 478.0 and 355.0 nmol/L; one of the gorillas exhibited a decrease at the end of pregnancy (Fig. 7Go). Progesterone correlated with CRH in the gorilla (r = 0.63; P < 0.05) but not in the chimpanzee; however, a strong correlation was found between progesterone and the log of CRH in both the chimpanzee (r = 0.64, P < 0.001) and the gorilla (r = 0.85; P < 0.001). Plasma AFP concentrations rose in the first half of chimpanzee pregnancy, peaking at 228.3 ± 36.6 IU/mL between 160 and 200 days, and then fell before delivery in all chimpanzees (Fig. 8Go). Peak concentrations in the two gorillas also fell after reaching peaks of 122 and 137 IU/mL in the middle of pregnancy (Fig. 8Go).



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  		Figure 7. Mean plasma progesterone concentrations in pregnant ({diamondsuit}) and postpartum ({blacktriangleup}) chimpanzees and pregnant gorillas ({blacksquare}).

 


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  		Figure 8. Mean plasma AFP concentrations in pregnant ({diamondsuit}) and postpartum ({blacktriangleup}) chimpanzees and pregnant gorillas ({blacksquare}).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our results indicate that both the chimpanzee and the gorilla exhibit an exponential rise in maternal plasma CRH concentrations similar to that observed in humans. Further, a close association has been observed between maternal plasma estradiol and log plasma CRH in these species, which is consistent with the possibility that placental CRH drives the production of fetal adrenal DHEA-S, which, in turn, determines the placental production of estradiol. Maternal plasma cortisol was also weakly associated with plasma CRH, which would be anticipated if placental production of CRH is stimulated by cortisol as first suggested by Robinson et al. (22). However, a weak positive association was also observed with plasma progesterone, which would not support the inhibitory role previously postulated for this steroid (23, 24).

All pregnancies in both the chimpanzees and gorillas went to normal term delivery, leading to the birth of healthy offspring who thrived. Birth weights in the chimpanzees were normal, but weights in the baby gorillas could not be ascertained for fear of disturbing the maternal-infant relationships.

Maternal plasma CRH rose exponentially in the gorillas from 17 weeks to reach their highest concentrations in the last samples obtained before delivery. Log-linear transformation of the data produced straight lines for each individual, consistent with an exponential rise in the circulating concentrations. In the eight chimpanzees, maternal plasma CRH also rose in a manner consistent with an exponential rise, although concentrations were significantly lower than those observed in the gorillas (P < 0.02). Postpartum samples in the chimpanzee were undetectable. In this small group of chimpanzees and gorillas no premature or otherwise abnormal births were observed, and no correlation was observed between plasma CRH in individual animals and the length of gestation in that animal, although the range of deliveries was small (12 days for the chimpanzee and 8 days for the gorillas).

Plasma CRH-BP in the two gorillas followed a pattern similar to that described in humans with a fall late in pregnancy. In the chimpanzees no change in CRH-BP concentrations were observed related to gestational age; in particular, no late gestational fall was observed, and there was no significant difference between pregnant and nonpregnant levels. The lack of a late fall in CRH-BP may have been due to the lack of samples in the last weeks of pregnancy (deliberately restricted to avoid interfering with the parturient mother). An alternative explanation is that the late gestational fall in CRH-BP in the human and gorilla is related to increased clearance of CRH-BP due to the dimerization that occurs consequent to the occupancy of the CRH-binding site when CRH concentrations are elevated. As chimpanzee CRH concentrations are lower even at the end of pregnancy, the dimerization-induced clearance may not occur (25).

Cortisol levels increased during pregnancy in both the gorillas and chimpanzees. In the gorilla despite a large increase in plasma CRH, the increase in maternal plasma cortisol was modest compared to that in the chimpanzee and that observed in previous human studies (26). One possible explanation is a reduced ability of placental CRH to stimulate maternal pituitary ACTH secretion; however, restrictions on sample volume prevented further exploration of this and other possibilities. In the chimpanzee a more robust increase in maternal plasma cortisol was seen. In both species plasma cortisol correlated with plasma CRH, as has been previously reported in humans (chimpanzee: r = 0.36; P < 0.02; gorilla: r = 0.60; P < 0.05) (26, 27). These data are consistent with the hypothesis that glucocorticoids drive placental CRH production through a positive feedforward system that produces the exponential increase in CRH that has been observed in humans and is here reported in two other great apes (22).

Because CRH has been shown in vitro to stimulate synthesis of DHEA-S by the fetal zone of the adrenal, and DHEA-S is the precursor to placental estrogen synthesis, we also measured maternal plasma estradiol in the pregnant ape samples. In the chimpanzee, plasma estradiol correlated closely with the log of plasma CRH (r = 0.72; P < 0.001), and in the gorilla the correlation was remarkably high given the small number of samples available (r = 0.93; P < 0.001). These data are consistent with the hypothesis that placental CRH drives estrogen synthesis via its action in stimulating the synthesis of DHEA-S. The correlations observed are strongly related to gestational age.

Plasma progesterone increased throughout chimpanzee and gorilla pregnancy, as occurs in the human. It has been suggested that progesterone is a physiological inhibitor of placental CRH secretion (23, 24); however, no evidence to support this hypothesis could be provided in this study, in which both parameters increased concurrently. Both the estradiol and progesterone changes observed in the chimpanzees were similar to those previously reported (28, 29). We are unaware of similar data for the gorilla.

In the human it has been reported that AFP combined with plasma CRH is a more effective predictor of preterm delivery than CRH alone (McLean, M., personal communication). Although there were no preterm deliveries in this group of apes we report the changes in AFP that we observed and note that they in general follow a similar pattern to that observed in the human.

In summary, the changes in plasma CRH and CRH-BP observed in the chimpanzee and gorilla are very similar to those observed in the human. A close correlation was observed between maternal plasma CRH and plasma estradiol, supporting a putative role for plasma CRH in stimulating production of the estradiol precursor DHEA-S.

Received January 20, 1999.

Revised April 21, 1999.

Accepted May 5, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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X. Ni, Y. Hou, B. R. King, X. Tang, M. A. Read, R. Smith, and R. C. Nicholson
Estrogen Receptor-Mediated Down-Regulation of Corticotropin-Releasing Hormone Gene Expression Is Dependent on a Cyclic Adenosine 3',5'-Monophosphate Regulatory Element in Human Placental Syncytiotrophoblast Cells
J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2312 - 2318.
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X. Ni, R. C. Nicholson, B. R. King, E.-C. Chan, M. A. Read, and R. Smith
Estrogen Represses whereas the Estrogen-Antagonist ICI 182780 Stimulates Placental CRH Gene Expression
J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3774 - 3778.
[Abstract] [Full Text] [PDF]

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 Physiol. Rev.Home page
G. Gimpl and F. Fahrenholz
The Oxytocin Receptor System: Structure, Function, and Regulation
Physiol Rev, April 1, 2001; 81(2): 629 - 683.
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B. Sehringer, W. R. Schäfer, B. Wetzka, W. R. Deppert, R. Brunner-Spahr, E. Benedek, and H. P. Zahradnik
Formation of Proinflammatory Cytokines in Human Term Myometrium Is Stimulated by Lipopolysaccharide But Not by Corticotropin-Releasing Hormone
J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4859 - 4865.
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