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Adrenocorticotropic hormone (ACTH or corticotropin) is a polypeptide hormone synthesised (from POMC, pre-opiomelanocortin) and secreted from corticotropes in the anterior lobe of the pituitary gland in response to the hormone corticotropin-releasing hormone (CRH) released by the hypothalamus. It consists of 39 amino acids. more...

Calcium folinate
Chenodeoxycholic acid
Choriogonadotropin alfa
Chorionic gonadotropin
Clavulanic acid

ACTH acts through the stimulation of cell surface ACTH receptors, which are primarily located on the adrenocortical cells. ACTH stimulates the cortex of the adrenal gland and boosts the synthesis of corticosteroids, mainly glucocorticoids but also mineralcorticoids and sex steroids (androgens). Together with ACTH the hormones lipotropin, melanocyte-stimulating hormone (MSH), β-endorphin and met-enkephalin are also released. ACTH is also related to the circadian rhythm in many organisms.

The half-life of ACTH in human blood is about 10 minutes.


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Maternal Depression and Risk for Postpartum Complications: Role of Prenatal Corticotropin-releasing Hormone and Interleukin-1 Receptor Antagonist - Statistical
From Behavioral Medicine, 6/22/99 by Karen H. Schmeelk

The pregnancies of 58 healthy adolescents (ages 13 to 19 years) were followed to examine links between symptoms of depression, corticotropin-releasing hormone (CRH), interleukin-I[BEta], (IL-1[Beta],), and IL-1 receptor antagonist (IL-1ra) as possible predictors of maternal and infant outcomes. Maternal psychological adjustment and medical complications during gestation, labor, delivery, and the postpartum period were monitored. Plasma samples collected during gestation were assayed for CRH, IL-1[Beta], and IL-1ra. During gestation, symptoms of maternal depression were found to be associated with lower levels of CRH; lower levels of CRH were associated with lower levels of IL-1ra. In addition, lower levels of IL-1ra predicted higher rates of maternal complications after childbirth. IL-1[Beta], detected in only 4 mothers, was not associated with any predictor or outcome measures. During gestation, CRH may induce circulating cytokine inhibitors without significantly affecting cytokine production or synthesis. Maternal symptoms of depression during gestation may attenuate the association between CRH and IL-1ra.

Index Terms: corticotropin-releasing hormone (CRH), depression, interleukin-1ra, neuroendocrine immune interactions, pregnancy

Many studies suggest that symptoms of depression are associated with decreases in functional and quantitative measures of immunity,[1] Changes in neuroendocrine system products, such as corticotropin-releasing hormone (CRH), have been proposed as plausible, although unconfirmed, pathways through which depression might compromise immunity.[2-4] This apparent link between depression, CRH, and immunity during pregnancy may be important to consider in predicting subsequent maternal and child health, but little empirical evidence of these relationships is available.[5]

During pregnancy, circulating levels of CRH are high. The levels begin to rise early in the first trimester and continue to rise until term.[6,7] During gestation, CRH is secreted by the maternal hypothalamus as well as by the syncytiotrophoblast and other layers of the placenta.[8] However, only placental CRH circulates in the blood. Placentally derived CRH is chemically identical to that produced in the hypothalamus,[4] but its production is not affected by negative feedback from ACTH or cortisol. The elevated levels of CRH during gestation are implicated in the release of placental peptides, such as oxytocin[9]; the maturation of the fetal hypothalamic-pituitary-adrenal (HPA) axis; and cellular processes linked to the placenta, fetal membranes, and decidua.[4] Higher than normal levels of CRH in early pregnancy are associated with the risk for preterm labor.[10,11] We recently reported that lower levels of CRH in pregnant adolescents were associated with a higher frequency of depressive symptoms.[12]

Correspondingly, immune-derived molecules (eg, cytokines) serve a number of important functions during pregnancy. Interleukin-1 (IL-1[Beta]), in particular, induces central and peripheral prostaglandin synthesis, which may affect uterine contractility and may potentiate the onset of labor.[13,14] Thus, if the maternal immune system is challenged (eg, through viral or bacterial exposure) and levels of IL-1[Beta] increase beyond optimal levels, induction of premature labor may occur. Some researchers have hypothesized that inhibition of IL-1[Beta] biosynthesis and signal transduction may be a factor in maintaining the fetus to term.[13,14] However, recent evidence points to a debate about whether prostaglandin production is a cause or consequence of labor. That is, a normal aseptic inflammatory response occurs after labor that may lead to similar levels of IL-1 and prostaglandins produced in the amniotic fluid and other compartments in both normal and preterm labor.

For normal pregnancies, prostaglandins may not initiate parturition, but in the case of infection, the secretion of inflammatory cytokines may stimulate the production of prostaglandins that could lead to preterm labor by mimicking a normal process.[15-17] Thus, something other than prostaglandins may play a role in the relationship between IL-1[Beta] and labor. It is noteworthy that IL-1[Beta] is the only cytokine for which there is an identified endogenous receptor antagonist, the interleukin-1 receptor antagonist (IL-1ra). Especially relevant is that IL-1ra levels in the circulation of pregnant women are elevated. IL-1ra levels rise throughout gestation,[18,19] possibly through the production by cells of the amnion, chorion, and decidua.[18] In vitro studies reveal that CRH may be capable of stimulating the production of IL-1ra in peripheral monocytes without co-stimulating production of IL- 1[Beta].[18] These findings suggest that CRH-induced production of IL-1ra during pregnancy might attenuate nonadaptive effects of IL-1[Beta] on the maintenance of the pregnancy.

In summary, the available findings suggest that pregnancy is an important developmental transition for evaluating the interrelationships among psychological states, endocrine and immune system products, and their contribution to predicting subsequent maternal and infant health. In this article, we describe research testing a model of the relationships among maternal depression, CRH, IL-1[Beta], and IL-1ra as predictors of preterm labor; complications during labor, delivery, and following childbirth; and infant health. A primary assumption of the model is that increased maternal depression, associated with lower CRH levels, leads to decreases in circulating IL-1ra. A secondary assumption is that depressed mothers may be more likely to show preterm labor and postpartum complications and that their children may have more complications at birth. We hypothesize that (a) levels of CRH and IL-1ra are positively associated and (b) the variability in the relations between CRH and IL-1ra more strongly predicts maternal and infant complications than either CRH or IL-1ra considered individually. Finally, we hypothesize that depression is associated with negative maternal and infant health outcomes through its effects on CRH and on CRH in association with IL-1ra.



Participants were 58 pregnant adolescents, 98% of whom were White, drawn from a larger sample of 78 in which 20 did not provide enough plasma for CRH and IL-1ra assay. They ranged in age from 13 to 19 years (M = 17.3; SD = 1.5). We recruited the participants in a prenatal clinic and a family practice and through community physicians affiliated with a hospital in a mid-Atlantic state. Forty-eight of the participants were unemployed; 57 were receiving some form of state or federal financial assistance; 52 were single; and 43 were living with at least one parent--18 with both biological parents, 17 with biological mother, 1 with biological father, and 7 with biological mother and stepfather or significant other. A criterion for recruitment into the study was that the adolescents must be free from chronic illness and severe mental health problems. When we obtained plasma for assessment of CRH, IL-1[Beta], and IL-1ra,[20] the women were between 9 and 21 weeks gestation (M = 14.9; SD = 2.7) in their first pregnancy.

Biological Assessments

We drew three 15-mL samples of whole blood into EDTA tubes between 8:30 AM and 9:00 AM, using a 21- or 23-gauge scalp vein needle inserted into a vein in the antecubital space. We took the samples at 20-minute intervals and placed them on ice. To maintain patency between venipunctures, we used heparin lock flush solution (100 USP/mL). The samples were centrifuged for 20 minutes at 3,000 RPM and the plasma was removed and stored in cryogenic vials at -80 [degrees] C until assayed.

We then followed procedures outlined by Denicoff et al[21] in determining plasma CRH levels in the 20-minute samples by radioimmunoassay (RIA). To each 1-mL sample, we added 3 mL of 100% methanol, then vortexed and centrifuged the mixture at 4,000 RPM at 4 [degrees] C for 5 minutes. We collected supernatants and lyophilized for 12 hours in a speed-vac without heat (Savant, Holbrook, NY).

We reconstituted the samples in 0.5-mL RIA buffer [0.063 M sodium phosphate (dibasic), 0.013 M sodium EDTA, 0.02% sodium azide, 0.1% triton x-100, 1% rabbit plasma, and 0.025 mg aprotinin/mL] and incubated them for 1 hour at 4 [degrees] C. We created standards by serially diluting a stock solution of CRH (Peninsula Labs, Belmont, CA) in RIA buffer to concentrations of 2,500, 1,250, 625, 313, 156, and 78 pg/mL. We centrifuged samples and standards at 3,000 RPM for 10 minutes at 23 [degrees] C and aliquoted 100 [micro]L of the aqueous phase into 12 x 75 mm polypropylene tubes in triplicate.

To each tube, we added 100 [micro]L of rabbit antirat/human CRH antibody (TS-3, National Institute of Child Health and Development) at a dilution of 1:15,000, then incubated the tubes for 48 hours at 4 [degrees] C. Next, we added 100 [micro]L of [[sup.125]I]CRH (Amersham, Arlington Heights, IL) to the mixture, vortexed it, and incubated it for another 24 hours at 4 [degrees] C. We added 50 mL of goat antirabbit gamma globulin (Peninsula, Belmont, CA) and incubated the mixture for 16 hours at 4 [degrees] C. Samples were then centrifuged, supernatant aspirated, and the pellet counted in a gamma counter (LKB Clinigamma) for 1 minute. We tested all samples in triplicate and calculated CRH concentrations (pg/mL) from log-logit regression analyses. The average intra-assay coefficient of variation was 8.1%, and the range of sensitivity was 19.5 to 625 pg/mL.

Immunoreactive IL-1ra (R&D Systems, Minneapolis, MN) and IL-1[Beta] (Medgenix, Belgium) were determined by ELISA. We conducted these tests in duplicate according to the manufacturers' protocols. The average intra-assay coefficients of variation and lower limits of sensitivity were 4.6% and 22 pg/mL, and 3.2% and 2 pg/mL for IL-1ra and IL- 1[Beta], respectively.

Labor and Delivery Assessment

A research nurse recorded labor and delivery complication scores and short-term infant outcomes from medical records. The attending physician determined preterm labor based on estimated gestational age (average of gestational age by dates, size, and sonogram). We derived two summary scores, following McCool and Susman,[22] representing (a) intrapartal complications (ie, abruption, meconium staining, cephalo-pelvic disproportion [CPD], eclampsia, preeclampsia, decreased fetal heart tone variability, and extended fetal bardycardia) and (b) postpartum complications (ie, anemia, hemorrhage, pelvic infection, urinary infection, pulmonary infection, wound infection, and other postpartum complications). For both measures, a higher number indicated a negative outcome (see Table 1 for details).

TABLE 1 Ranges, Means, and Standard Deviations for Labor and Delivery, Infant Outcome, and Depression Variables

Note. For an explanation of variable measurements, see the Method section.

Infant Outcome

Measures of infant outcome included gestational age (determined by the attending physician), Apgar scores, abnormalities, and risk factors for the infant at birth and at 24 hours postpartum scored from the Hollister newborn profile examination, resuscitation attempts (using oxygen, bag and mask, intubation, external cardiac massage, or other methods), and birth weight for gestational age. For abnormalities, resuscitation, and risk factors, a higher number indicates a negative outcome. For the Apgar test, scores are on a scale of 1 to 10, with 10 being a completely healthy infant.

Finally, we scored infant's weight as 1 if the infant was small, 2 if average, and 3 if large for gestational age, as determined by the attending physician. We dichotomized some of the complication scores (none = 0, some = 1) because of the lack of variability in scores, including abnormalities on the newborn profile exam, risk factors at 24 hours postpartum, resuscitation attempts, weight for gestational age, intrapartal complications, and postpartum complications.

A factor analysis identified two infant outcome factors: (a) abnormality and risk (ie, abnormalities, risk factors at birth and at 24 hours) and (b) immediate health (ie, average of 1-minute and 5-minute Apgar scores, resuscitation attempts). See Table 1 for means, standard deviations of the mean, and ranges for each variable.

Maternal Depression

We obtained summed symptom counts for major depression and dysthymia from the Diagnostic Interview Schedule for Children (DISC 2.1).[23] Our aim in administering the DISC was to establish a quantitative index of number of symptoms as opposed to establishing a diagnosis of depression. A research nurse trained in the administration of the DISC conducted the interview.

Analytic Strategy

We present descriptive statistics for plasma levels of CRH, IL-1[Beta], and IL-1ra first, followed by a description of bivariate correlations testing the relationships between the biological variables and maternal and infant complications. Finally, we used path models to test whether depression is associated with the relationship between CRH, IL-1ra, and birth complications or infant outcomes. We subjected CRH and IL-1ra values to log-transformation to normalize their respective distributions. For ease of interpretation, we present values used in the text and tables in concentration/volume units.


Plasma Levels of CRH, IL-1[Beta], and IL-1ra

Plasma levels of CRH ranged from 118.45 to 388.06 pg/mL (M = 231.42; SD = 57.15 pg/mL) and were consistent with the findings reported by Goland and colleagues.[7,24] IL-1ra levels ranged from 2.68 to 2,297.36 pg/mL (M = 381.41; SD = 481.57), a finding that was similar to the results reported by Greer et al[18] and Pillay et al.[19] We observed IL-1[Beta] levels greater than the detection limit of 2 pg/mL in only 4 of 58 participants; their levels ranged from 2.69 to 9.06 pg/mL (M = 5.29; SD = 2.73). Because of the range in gestational age among the participants (9 to 21 weeks gestation), we controlled analyses (including CRH and IL-1ra) statistically for gestational age, using standardized residuals computed by regression analysis, which represents the variability in CRH and cortisol that is independent of gestational age.

Are CRH and IL-1ra Associated?

Plasma levels of CRH and IL-1ra were significantly correlated, r(56) = .30, p [is less than] .05, which supports our original hypothesis.

Do CRH or IL-1ra Predict Labor and Delivery Complications or Infant Outcome?

Because only one participant experienced preterm labor, we did not use this variable in our analyses. Lower concentrations of CRH were related to greater numbers of postpartum complications, r(54) = -.268, p = .05, and lower levels of IL-1ra were related to greater numbers of postpartum complications, r(54) = -.359, p [is less than] .01, and fewer resuscitation attempts, r(54) = .287, p [is less than] .05.

Does Depression Influence Maternal Complications Through Effects on CRH and IL-1ra?

We used hierarchical multiple regression analysis to test paths in the model displayed in Figure 1. CRH and depression were found to predict significant levels of IL-1ra, [R.sup.2] = .325; F = 3.077; p = .05. As the path model in Figure 1 shows (numbers are betas), CRH significantly predicts IL-1ra, which in turn significantly predicts postpartum complications.


When we added depression and IL-1ra into the model, however, CRH did not directly predict postpartum complications (the addition of intrapartal complications as a predictor of postpartum complications did not significantly influence the model). These findings support our hypothesis that symptoms of depression are associated with maternal complications following childbirth through an association with CRH and IL-1ra levels.

Does Depression Affect Infant Outcomes?

The model did not significantly predict either of the infant outcome factors, abnormality and risk or immediate health, or intrapartal complications.


Our findings demonstrate an association between maternal depression, neuroendocrine immune processes, and maternal health following childbirth. They suggest a more complex and integrated role of CRH during gestation than has been previously considered. At a theoretical level, the findings open windows through which the mechanisms and developmental consequences of brain-behavior-immune interactions can be described.

Research has just begun to explore the developmental relevance of the findings emerging from studies of psychoneuroimmunology. For instance, age-related differences in the effects of cognitive and physical stressors on immunity have been reported.[25-28] In addition, exposure to immune stimuli in early life has been shown to have long-lasting effects on behavior and the activity of the HPA axis.[29,30]

A few studies have examined the implications of neuroendocrine-immune interactions in the context of human pregnancy.[31] Associations between the major hormones associated with pregnancy (mainly estradiol, progesterone, and cortisol) and immune factors (T-cell counts, cytotoxicity, cytokine production and inhibition) have been the main focus of these studies.[32,33] Most work in this field has examined these relationships in animals or human tissue, such as placenta or cell cultures. Our findings suggest that future studies should examine these relationships in vivo to reveal important clues regarding individual differences in maternal postpartum adjustment.

Our finding that increased IL-1ra was related to more resuscitation attempts in the newborns is interesting but currently unexplainable. One possibility is that excess IL-1ra may have a detrimental effect on fetal lung maturation or function.[34] However, we could find no evidence in the literature to support this interpretation. Replication of these findings and further investigation of the possible influence of neuroendocrine immune interactions on lung development are needed before any conclusions can be drawn.

Most of the women in this sample had uneventful pregnancies; none had miscarriages, and all but one delivered within 3 weeks of the expected date of delivery. All received consistent prenatal care, and they did not have any severe illnesses during pregnancy. However, because we have no record of any minor colds or infections that were not brought to the attention of a doctor, other factors may have influenced our results. Studies that focus on extremes of maternal depression or individuals at risk for depression during pregnancy might be an appropriate next step, especially in samples of women who are likely to receive the poorest prenatal care.

It should be noted that depression during pregnancy may or may not be related to postpartum depression. Studies examining postpartum depression generally select out those participants with preexisting depression. To add to the complexity of this issue, depression in adolescence, and specifically in our sample,[12] is usually an atypical form that is associated with a deficient HPA axis.[35]

Cortisol weakly stimulates placental CRH secretion; therefore, hyposecretion of cortisol may explain why a person with atypical depression may have decreased placental CRH secretion.[36] In addition, women with postpartum blues or depression have a suppressed HPA axis postpartum, and this depression has atypical features.[37] Possible explanations for this may be that (a) patients with atypical depression and resultant low placental CRH secretion may have further suppression postpartum following the hypercortisolism of the last trimester of pregnancy, with more pronounced psychological manifestations, or (b) patients with melancholic depression and resultant high placental CRH secretion may have a more marked postpartum adrenal suppression. These explanations are not mutually exclusive and should be examined further.

Our ability to draw firm conclusions would also be enhanced if we took multiple blood samples over the course of gestation. Knowing the timing of alterations in CRH during pregnancy would allow us to be more precise in stating when such alterations may be most detrimental to the fetus. Without these additional samples, the amount of variance accounted for in our model is limited. However, the magnitude of the results we have reported here is representative of effect sizes in human studies relating biological and behavioral variables. With the physiological complexity of pregnancy in mind, including additional variables in our model in the future may complete the model.

When CRH does not increase as it should during pregnancy, the implications for the mother and fetus may be serious. Because CRH (and other HPA products) can have suppressive effects on estrogen and progesterone, any modulatory control that CRH would normally have over these hormones could diminish.[2] An increase in estradiol without a concomitant increase in progesterone could cause increased production of prostaglandins, which could lead to preterm labor.[38]

An increase in estrogen may lead to impaired antibody production and decreased delayed hypersensitivity response in the child.[39] Because women usually produce more IL-1 during the luteal phase (and one can assume during pregnancy because at both times progesterone is increased), an increase in progesterone may allow more IL-1 to be produced.[40] IL-1[Beta] may, in turn, also affect progesterone production by blocking the stimulating effect of hCG, as it does in cultured luteal cells.[41] Finally, a hypoactive HPA axis is associated with a hyperactive immune system; during pregnancy that may lead to complications for both mother and fetus.[42]

In conclusion, pregnancy is a unique period of development for exploring neuroendocrine-immune interactions. The normal endocrine and immune milieu and environmental inputs, psychological stimuli, and social support during pregnancy are different from those when a woman is not pregnant. How individuals cope with the nature of these physiological, psychological, and environmental changes appears to have direct implications for maternal health and fetal/infant development.


The study was supported in part by grants from NICHD (R01 HD26004) and the W. T. Grant Foundation to Dr Susman and from the Pennsylvania State University (PSU) Center for Special Populations and Health to Dr Granger. Assays were facilitated by the PSU Behavioral Endocrinology Laboratory. We would also like to thank Jessica King for manuscript preparation and Jodi Heaton and Sam Listwak for greatly helping with this project.


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[40.] Lynch EA, Dinarello CA, Cannon JG. Gender differences in IL-[Alpha], IL-[Beta], and IL-1 receptor antagonist secretion from mononuclear cells and urinary excretion. J Immunol. 1994; 153:300-306.

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[42.] Chrousos GE The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med. 1995;332: 1351-1362.

Ms Schmeelk is a doctoral candidate in the Department of Biobehavioral Health at Pennsylvania State University in University Park, where Dr Granger is an assistant professor and Dr Susman is Jean Phillips Shibley Professor of Biobehavioral Health. Dr Chrousos is chief of the Section on Pediatric Endocrinology with the National Institute of Child Health and Development in Bethesda, Maryland.

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