Production Of Corticotropin-releasing Hormone Research Articles

The Regulation of Adrenocorticotrophic Hormone Receptor by Corticotropin-Releasing Hormone in Human Fetal Adrenal Definitive/Transitional Zone Cells

As gestation progresses, human fetal adrenals (HFA) initiate the production of cortisol, which increases placental corticotropin-releasing hormone (CRH) biosynthesis. While adrenocorticotrophic hormone (ACTH) is important for the onset of cortisol production, the late gestational surge in cortisol production occurs despite falling ACTH levels in the fetal circulation. The authors determine if CRH directly regulates the expression of the ACTH receptor (ACTHR) in HFA definitive/transitional zone (DZ/TZ) cells. DZ/TZ cells isolated from midgestation HFA were cultured before treatment with 0.01 nM to 100 nM CRH or ACTH. Cortisol was measured by radioimmunoassay. Real-time reverse-transcriptase polymerase chain reaction was used to measure ACTHR mRNA. Whole-cell ACTH binding studies were performed using I(125) (Tyr-23) ACTH. CRH produced a dose-dependent rise in cortisol production and caused a time-dependent increase in ACTHR mRNA levels between 12 and 24 hours. As little as 0.1 nM CRH induced ACTHR transcript by 12-fold at 24 hours. Together with ACTH 0.01 nM, 0.03 or 0.1 nM CRH increased ACTHR expression more than ACTH alone. Binding assays demonstrated a 3.5-fold increase in ACTHR protein at 48 hours with combined CRH and ACTH treatment. Physiologic levels of CRH seen in the late-gestation fetus stimulate DZ/TZ ACTHR expression. Since placental CRH production increases strikingly near the end of gestation, the authors suggest that CRH-induced ACTH receptor expression may increase TZ responsiveness to circulating ACTH and contribute to the late gestational rise in cortisol secretion by the HFA, participating in an endocrine cascade that is involved in fetal organ maturation and potentially in the timing of human parturition.

Adrenocorticotropin Hormone Stimulates Interleukin-18 Expression in Human HaCaT Keratinocytes

The hypothalamic-pituitary-adrenal (HPA) axis is activated by stress. This involves the production of corticotropin releasing hormone (CRH) with the subsequent release of proopiomelanocortin (POMC) peptides, of which adrenocorticotropin hormone (ACTH) is most important. Although the skin has the capacity to produce CRH and POMC peptides, the immunomodulatory roles of ACTH in skin are yet unknown. IL-18 has been known to affect cells involved in the inflammatory response. In this study, we aimed to identify the regulatory effect of ACTH on IL-18 expression of skin keratinocytes. Exposure of HaCaT cells to ACTH stimulated formation of IL-18 mRNA transcript and its protein products in a dose-dependent manner. Furthermore, we suggest that ACTH-induced IL-18 production is via the caspase-1 activation pathway, as IL-18 production induced by ACTH could be suppressed by caspase-1 inhibitor, and ACTH could increase caspase-1 activity. The effect of ACTH on IL-18 production was blocked by specific inhibitors of p38 kinase (SB203580) or extracellular signal-regulated kinase (ERK) (PD98059). In addition, ACTH-induced rapid phosphorylation of p38 kinase and ERK, and ACTH signaling occurred via melanocortin receptor 1 (MC1R) and receptor 2 (MC2R). These results suggest that ACTH stimulates IL-18 expression in human keratinocytes, which provides an insight into the interaction between ACTH and inflammatory mediators.

Complex Endocrinopathies in MEN-1: Diagnostic Dilemmas in Endocrine Oncology

Endocrine oncology is a complex area that must determine the site of a neoplastic process and the hormonal dysregulation that ensues. Patients with endocrine tumors often have delayed diagnosis because of the nonspecific and often subtle signs and symptoms. In patients with multiple endocrine neoplasia syndromes, diagnosis and clinicopathologic correlations can be even more challenging. We report a patient with multiple endocrine neoplasia type 1 (MEN-1) and a highly complex clinical story associated with multiple atypical lesions including two pituitary adenomas, a gonadotroph macroadenoma and a corticotroph microadenoma with Crooke's hyaline change and ectopic production of corticotropin-releasing hormone (CRH) from a thymic endocrine carcinoma. These lesions resulted in a highly complex clinical story, difficult diagnoses and questions about management. This case illustrates a number of clinically relevant challenges, including the diagnosis of pituitary adenomas in MEN-1, the difficulty in diagnosing Cushing's disease, and the large differential of pituitary pathologies in this disorder, double pituitary adenomas and other decoy lesions in Cushing's disease, the pathophysiology of Crooke's hyaline change in the pituitary, and the various causes of Cushing's syndrome associated with MEN-1.

Prepro-TRH 178–199 inhibits histamine- or restraint stress-induced activation of corticotropin releasing hormone production in rat hypothalamus

Under restraint stress conditions, prepro-thyrotropin releasing hormone (TRH) 178–199 suppresses adrenocorticotropic hormone (ACTH) secretion from the rat pituitary, which indicates that prepro-TRH 178–199 is a candidate endogenous corticotropin releasing inhibitory factor (CRIF). Restraint stress also activates the release of hypothalamic neuronal histamine, which increases both the expression of CRH mRNA in the paraventricular nucleus (PVN) and plasma concentrations of ACTH. The aim of this study was to determine whether prepro-TRH 178–199 modulates histamine- or restraint stress-induced activation of corticotropin releasing hormone (CRH) in the rat hypothalamus. Infusion of prepro-TRH 178–199 into the third cerebroventricle (i3vt) at a dose of 6 μg/kg significantly decreased the amount of CRH in the PVN, as compared to vehicle-treated controls ( p < 0.05), but did not affect the CRH amount in other hypothalamic regions. Restraint stress increased the amount of CRH in the PVN and ventromedial hypothalamic nucleus (VMH), as compared to non-restrained controls ( p < 0.05); this was attenuated by pretreatment with i3vt infusion of prepro-TRH 178–199 ( p < 0.05). I3vt infusion of histamine (270 nmol/rat) suppressed cumulative food consumption over 24 h, increased plasma ACTH concentrations, and increased the content of CRH in the PVN, as compared to vehicle-treated controls ( p < 0.05 for each); these effects were attenuated by pretreatment with prepro-TRH 178–199 ( p < 0.05). These results suggest that prepro-TRH 178–199 may regulate ACTH secretion by affecting basal and histamine- or stress-induced synthesis and/or secretion of CRH and ACTH by modulating histaminergic input to the PVN and VMH.

Glucocorticoids Down-Regulate Lipopolysaccharide-Induced de novo Production of Neurotensin mRNA in the Rat Hypothalamic, Paraventricular, Corticotrophin-Releasing Hormone Neurons

Objective: Intraperitoneal injection of the endotoxin lipopolysaccharide (LPS) produces inflammation accompanied by activation of the immune system and the secretion of cytokines. Cytokines stimulate the hypothalamo-pituitary-adrenal (HPA) axis to release the anti-inflammatory corticosterone which controls its own production by acting on the HPA axis. Upstream in the HPA axis are neuroendocrine corticotrophin-releasing hormone (CRH) neurons located in the paraventricular nucleus (PVN), whose multipeptidergic phenotype changes during inflammation: while CRH mRNA is up-regulated in these conditions, neurotensin (NT) mRNA expression is induced de novo. The negative feedback control of glucocorticoids on CRH production is well documented; however, their action on NT production in the PVN of the hypothalamus is poorly documented. The aim of this study was to determine if glucocorticoids modulate the de novo production of NT during inflammation. Methods: Using quantitative in situ hybridization histochemistry, we examined whether the absence (adrenalectomy) or excess (corticosterone implants) of glucocorticoids modulate de novo production of NT mRNA in the PVN during inflammation induced by LPS treatment. Results: A relatively low dose of LPS (50 µg/kg) that is not efficient to induce NT mRNA production in the PVN becomes efficient after adrenalectomy. Moreover, corticosterone excess reduces LPS-induced production of NT mRNA in the PVN. Conclusion: Glucocorticoids exert a negative control on NT mRNA production in the PVN of the hypothalamus, and this effect requires that NT mRNA production be triggered, such as during inflammation.

A Case of Congenital Adrenal Hyperplasia Combined with a Testicular Adrenal Rest Tumor and Adrenal Incidentaloma

The fundamental defect among patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylse deficiency is the inability to synthesize cortisol and aldosterone adequately. Ineffective cortisol synthesis signals the hypothalamus and pituitary to increase the production of corticotropin releasing hormone and adrenocorticotropic hormone, respectively. Consequently, the adrenal glands become hyperplastic. It is well known that an adrenal adenoma can develop from hyperplastic tissue under increased corticotropin stimulation of the adrenal cortex in patients that are suffering with CAH. The etiologic mechanism of adrenal incidentaloma remains uncertain, but several hypotheses have been suggested. A testicular adrenal rest tumor has been reported to form in association with the excessive secretion of adrenal androgen by inadequate control after adolescence in CAH. We present a case of poorly controlled salt-losing CAH due to 21-hydroxylase deficiency combined with a testicular adrenal rest tumor and adrenal incidentaloma.

Corticotrophin releasing hormone and the timing of birth

Corticotrophin-releasing hormone (CRH) is the hypothalamic peptide that controls the function of the pituitary-adrenal axis in response to stress. CRH is also expressed abundantly in the human placenta and is present in high concentrations in maternal and fetal plasma during late pregnancy. During pregnancy, CRH derived from the placenta is thought to play a crucial role in the regulation of fetal maturation and the timing of delivery, and CRH has also been implicated in the control of fetal-placental blood flow. Elevated CRH concentrations, as compared with gestational age matched controls, occur in patients in preterm labour. The exponential curve depicting the CRH increase is shifted to the left in women who will subsequently deliver preterm and to the right in women who will deliver post dates. This has led to the suggestion that CRH production is linked to a placental clock which determines the length of gestation. Clinically, maternal plasma CRH concentrations may be useful in identifying women at high risk of preterm delivery and CRH antagonists may be useful in preventing preterm labour. As significant CRH production by the placenta is restricted to primates, future research must take into account the species specificity of the mechanisms regulating parturition. A number of significant gaps remain in our knowledge of the function of this peptide in pregnancy. This review examines the current evidence regarding the role of CRH in human parturition.

Advances in understanding corticotrophin-releasing hormone gene expression

Glucocorticoids inhibit corticotrophin-releasing hormone (CRH) gene expression in the hypothalamic paraventricular nucleus (PVN), but stimulate expression in the placenta. In AtT20 cells (a model of PVN CRH production) cAMP produces a high level of promoter activity. Cyclic AMP stimulation occurs through the cAMP response element (CRE) and the caudal type homeobox protein response element (CDXARE). The CRE acts as part of a cAMP response unit that includes the hybrid steroid response element (HRE), ecdysone response element (EcRE), metal-responsive transcription factor-1 response element (MTFRE), ying yang 1 response element (YY1RE) and negative glucocorticoid response element (nGRE). Cyclic AMP acts on the HRE, EcRE and MTFRE to block YY1RE mediated inhibition of the CRE. Glucocorticoids acting at the nGRE inhibit cAMP activation of the CRE. In placental cells the CRH promoter has low intrinsic basal activity and cAMP causes a modest increase in activity. Stimulation by glucocorticoids and cAMP and inhibition by estrogen and estrogen receptor alpha occurs through the CRE. In AtT20 cells multiple response elements coordinate a response to cAMP and glucocorticoids while in placental cells the CRE acts in isolation. These differences in promoter function lead to responses that meet specific physiological needs.

Angst and the amygdala

Fear is an adaptation to danger, but excessive fear underlies diverse forms of mental anguish and pathology. One neural site linked to a sense of adversity is the amygdala, and one neuropeptide, corticotropin-releasing hormone (CRH), is localized within the central nucleus of the amygdala. Glucocorticoids enhance the production of CRH in this region of the brain, resulting in increased attention to external events and, when sustained for longer periods of time, perhaps contributing to anxious depression.

Cushing's Syndrome Due to Ectopic CRH Secretion by Adrenal Pheochromocytoma Accompanied by Renal Infarction

Ectopic production of corticotropin-releasing hormone (CRH) by a pheochromocytoma is an infrequent cause of Cushing's syndrome. We report the case of a 43-year-old man with Cushing's syndrome due to a CRH-producing adrenal pheochromocytoma. The patient had clinical and biochemical evidence of hypercortisolism in conjunction with high ACTH levels and non-suppressible serum cortisol levels on low-dose and high-dose dexamethasone suppression testing. In addition to these clinical features of one month's duration, the patient developed symptoms of pheochromocytoma including headache, hypertension that was resistant to conventional therapy and excessive sweating. Biochemical testing confirmed elevated 24-hour urinary catecholamines and metabolites. Abdominal CT revealed a 4.5 x 4 x 3.5 cm mass in the left adrenal gland. He underwent elective left adrenalectomy. Light microscopic and immunochemical studies revealed a pheochromocytoma that contained immunoreactive CRH and was negative for ACTH. Plasma ACTH and dexamethasone supression tests normalized after surgery. This is an unusual case of a CRH-secreting pheochromocytoma. This was complicated by renal infarction, illustrating further the complexity of Cushing's syndrome in a patient with pheochromocytoma caused by CRH hypersecretion.

Investigation of the corticotropin-releasing hormone-proopiomelanocortin axis in various skin tumours

Various types of external stress cause the skin and central neuroendocrine system to express corticotropin-releasing hormone (CRH)-proopiomelanocortin (POMC) axis-related hormones. However, the precise role of the CRH-POMC axis-related hormones in various skin tumours is unclear. This study examined expression patterns of the CRH-POMC axis-related hormones in skin tumours. The production of CRH, adrenocorticotropic hormone (ACTH) and alpha-melanocyte-stimulating hormone (alpha-MSH) in various tumour cell lines including HaCaT and primary keratinocytes was examined using an enzyme-linked immunosorbent assay. Immunohistochemical analysis of the skin tumours was also performed. CRH, ACTH and alpha-MSH were strongly expressed in malignant skin tumour cell lines such as G-361 and DX-3 (both malignant melanoma, MM). However, normal and haematological malignancy cell lines did not express the CRH-POMC axis-related hormones. Immunohistochemical analysis of the skin tumours showed that MM (80%), squamous cell carcinoma (SCC, 70%) and basal cell carcinoma (BCC, 10%) had strong immunoreactivity (++/+++) for CRH. Strong ACTH and alpha-MSH expression was observed in MM (70% and 50%, respectively), SCC (80% and 60%, respectively) and BCC (70% and 50%, respectively). We report that an increase in the level of the CRH-POMC axis-related hormones is associated with malignant skin tumours such as MM. These results highlight the importance of the CRH-POMC axis-related hormones in the malignant tendency of skin tumours.

Steroid hormone mediated regulation of corticotropin-releasing hormone gene expression

Corticotropin-releasing hormone (CRH), a 41 amino acid polypeptide, is expressed in many regions of central nervous system and peripheral tissues and mediates many physiological functions. Abnormal production of CRH is involved in some pathological processes. Among various endogenous factors that modulate CRH production, steroid hormones control CRH production by regulating its gene transcription. Although there is no classical steroid hormone response element in the CRH promoter, steroid hormones regulate CRH gene expression through protein-protein interaction or by binding directly to response elements.

Mirtazapine acutely inhibits basal and K(+)-stimulated release of corticotropin-releasing hormone from the rat hypothalamus via a non-genomic mechanism.

Originally described as a pivotal mediator of acute neuroendocrine responses to stress, corticotropin-releasing hormone (CRH) is currently envisioned as a peptide neurotransmitter involved in the pathogenesis of anxiety and depressive disorders; it has been postulated that antidepressant drugs are clinically effective insofar as they are able to reduce central CRH production and release. In this study we used a well validated in vitro model, i.e. acute rat hypothalamic explants, to investigate the effects of the antidepressant mirtazapine on the production and release of CRH from the hypothalamus in short-term experiments. CRH release was assessed through the measurement of CRH immunoreactivity in the incubation medium. We found that mirtazapine reduces in a concentration-dependent manner both basal and K(+)-stimulated CRH release in 30-min and 60-min experiments. Mirtazapine had no effect on CRH mRNA expression in 1-h and 3-h experiments; the intra-hypothalamic levels of peptide were not reduced, and even tended to increase, with respect to controls. Mirtazapine reduces CRH release from CRH-containing neurons in the rat hypothalamus through a mechanism independent from the modulation of CRH gene expression and peptide production.

Progesterone receptors A and B differentially modulate corticotropin-releasing hormone gene expression through a cAMP regulatory element.

Corticotrophin-releasing hormone (CRH) plays a major role in mechanisms controlling human pregnancy and parturition. Gene regulation by progesterone may be a key point in the control of placental CRH production. Studies in primary placental cells show that antagonism of progesterone activity or production by RU486 or trilostane leads to an increase in CRH promoter activity. This effect can be reversed by the addition of progesterone. Overexpression of progesterone receptor A (PR-A) or glucocorticoid receptor resulted in a decrease in CRH promoter activity following progesterone treatment, whereas an increase in promoter activity was observed with overexpressed PR-B. Studies including mutation of the cAMP regulatory element (CRE) confirm this site to be essential for the progesterone-mediated effects. In summary, our results demonstrate that progesterone regulates CRH gene transcription via a CRE in the CRH promoter and that PR-A and PR-B exhibit different actions in the regulation of CRH gene expression.

Distribution of corticotropin releasing hormone in the fetus, newborn, juvenile, and adult baboon.

Corticotropin releasing hormone (CRH) has previously been identified in extrahypothalamic tissues and may act in a paracrine fashion within these tissues. To date, CRH production and its role in the fetus and newborn have not been investigated. The aim of this study was to explore the distribution and ontogeny of CRH in extrahypothalamic tissues of the fetus, newborn, juvenile, and adult baboon. Pituitary, adrenal, kidney, liver, and lung tissues from baboons at 125 d gestation, 140 d gestation, 185 d gestation (term), juveniles, and adults were obtained at necropsy. The tissues were quantified for protein and immunoreactive CRH was determined by a RIA. CRH levels were normalized to the protein content of each tissue. CRH was present in all tissues and varied over a 100-fold range according to tissue type. The highest concentration of CRH was found in the pituitary, which did not differ with the gestation and/or age of the animal. In the lung tissues of 125- and 140-d gestation animals, CRH was greater than the term, juvenile, and adult lung (p < 0.02). CRH in the adrenal gland of the 125-d samples was greater than the other four ages tested (p < 0.02). Liver CRH levels were higher in the term animals compared with the juvenile baboons. Our study documents the existence of CRH in extrahypothalamic tissues of the baboon from 125 d of gestation to adulthood. Given its presence and distribution, we speculate that CRH may exert ongoing paracrine and/or autocrine actions in these tissues from the time of intrauterine life throughout adulthood.

Maternal and Fetal Hypothalamic‐Pituitary‐Adrenal Axes During Pregnancy and Postpartum

The principal modulators of the hypothalamic-pituitary-adrenal (HPA) axis are corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP). Corticotropin-releasing hormone is not exclusively produced in the hypothalamus. Its presence has been demonstrated at peripheral inflammatory sites. Ovulation and luteolysis bear characteristics of an aseptic inflammation. CRH was found in the theca and stromal cells as well as in cells of the corpora lutea of human and rat ovaries. The cytoplasm of the glandular epithelial cells of the endometrium has been shown to contain CRH and the myometrium contains specific CRH receptors. It has been suggested that CRH of fetal and maternal origin regulates FasL production, thus affecting the invasion (implantation) process through a local auto-paracrine regulatory loop involving the cytotrophoblast cells. Thus, the latter may regulate their own apoptosis. During pregnancy, the plasma level of circulating maternal immunoreactive CRH increases exponentially from the first trimester of gestation due to the CRH production in the placenta, decidua, and fetal membranes. The presence in plasma and amniotic fluid of a CRH-binding protein (CRHbp) that reduces the bioactivity of circulating CRH by binding is unique to humans. Maternal pituitary ACTH secretion and plasma ACTH levels rise during pregnancy-though remaining within normal limits-paralleling the rise of plasma cortisol levels. The maternal adrenal glands during pregnancy gradually become hypertrophic. Pregnancy is a transient, but physiologic, period of hypercortisolism. The diurnal variation of plasma cortisol levels is maintained in pregnancy, probably due to the secretion of AVP from the parvicellular paraventricular nuclei. CRH is detected in the fetal hypothalamus as early as the 12th week of gestation. CRH levels in fetal plasma are 50% less than in maternal plasma. The circulating fetal CRH is almost exclusively of placental origin. The placenta secretes CRH at a slower rate in the fetal compartment. AVP is detected in some neurons of the fetal hypothalamus together with CRH. AVP is usually detectable in the human fetal neurohypophysis at 11 to 12 weeks gestation and increases over 1000-fold over the next 12 to 16 weeks. The role of fetal AVP is unclear. Labor appears to be a stimulus for AVP release by the fetus. The processing of POMC differs in the anterior and intermediate lobes of the fetal pituitary gland. Corticotropin (ACTH) is detectable by radioimmunoassay in fetal plasma at 12 weeks gestation. Concentrations are higher before 34 weeks gestation, with a significant fall in late gestation. The human fetal adrenal is enormous relative to that of the adult organ. Adrenal steroid synthesis is increased in the fetus. The major steroid produced by the fetal adrenal zone is sulfoconjugated dehydroepiandrosterone (DHEAS). The majority of cortisol present in the fetal circulation appears to be of maternal origin, at least in the nonhuman primate. The fetal adrenal uses the large amounts of progesterone supplied by the placenta to make cortisol. Another source of cortisol for the fetus is the amniotic fluid where cortisol converted from cortisone by the choriodecidua, is found. In humans, maternal plasma CRH, ACTH, and cortisol levels increase during normal labor and drop at about four days postpartum; however, maternal ACTH and cortisol levels at this stage are not correlated. In sheep, placental CRH stimulates the fetal production of ACTH, which in turn leads to a surge of fetal cortisol secretion that precipitates parturition. The 10-day-long intravenous administration of antalarmin, a CRH receptor antagonist, significantly prolonged gestation compared to the control group of animals. Thus, CRH receptor antagonism in the fetus can also delay parturition. The HPA axis during the postpartum period gradually recovers from its activated state during pregnancy. The adrenals are mildly suppressed in a way analogous to postcure Cushing's syndrome. Provocation testing has shown that hypothalamic CRH secretion is transiently suppriently suppressed at three and six weeks postpartum, normalizing at 12 weeks.

Role of Psychosocial and Nutritional Stress on Poor Pregnancy Outcome

Epidemiological evidence suggests that maternal psychosocial stress, strenuous physical activity and fasting are independent risk factors for preterm birth and low birth weight. Data from clinical studies consistently demonstrate that women in preterm labor have significantly elevated levels of corticotropin-releasing hormone compared with age-matched control subjects. Because production of corticotropin-releasing hormone appears to be stress sensitive, this neuropeptide may play a critical role in the physiological mediation among stressful experiences, work stress and fasting and risk of preterm birth. In addition to the direct effect of elevated corticotropin-releasing hormone on the initiation of labor, it may have an immunomodulatory effect such that women with high levels of corticotropin-releasing hormone may be more susceptible to infection or the pathological consequences of infection. We review the epidemiological data linking maternal stress, physical stain and fasting to preterm birth and low birth weight and review the plausible biological pathways through which these exposures may increase risk of preterm birth. The timing of these exposures is considered important. Future research and clinical programs addressing these exposures must consider assessments and interventions before pregnancy.

Hormone trajectories leading to human birth.

The mechanisms regulating human parturition and labor remain unknown. This ignorance is expensive as preterm birth is responsible for 70% of neonatal mortality and 50% of cerebral palsy. Methods for the prediction of preterm birth and treatments for women in preterm labor have poor efficacy reflecting our limited knowledge of the mechanisms involved. Recent research has supported the view that parturition is a cascade of events that commences early in pregnancy and involves the mother, fetus, placenta, membranes, cervix and myometrium. Although a number of the key hormones and proteins involved have been identified, the relationships between these factors in time and tissues remain unclear. Placental production of Corticotropin-releasing hormone (CRH) is proposed as an early event regulating the cascade of events. Central to the onset of parturition will be a mechanism for progesterone withdrawal and estrogen activation in human. Two forms of progesterone receptor with opposing actions exist in the human myometrium. Progesterone receptor A (PR-A) is a dominant negative repressor of progesterone receptor B (PR-B). Preliminary studies strongly support the hypothesis that the onset of human parturition is initiated by rising concentrations of PR-A in the myometrium.

Maternal plasma corticotropin-releasing hormone trajectories vary depending on the cause of preterm delivery

Objective: Although second trimester maternal plasma corticotropin-releasing hormone concentrations are elevated in women who are destined to deliver preterm, the sensitivity and positive predictive value of an individual test of corticotropin-releasing hormone concentration is low. This poor screening performance may be due in part to the observation that the causes of preterm delivery are heterogenous, with potentially different effects on corticotropin-releasing hormone production. We have reanalyzed data from a previous cohort of women with multiple samplings to determine whether the trajectory of increase of placental corticotropin-releasing hormone provided more information than did a single sample. Study Design: In this cohort, where 2 to 4 samples that had been assayed for corticotropin-releasing hormone were available on 305 women, the general form of the exponential equation y = aebt was fitted to the corticotropin-releasing hormone data of each individual by the Gauss-Newton nonlinear least squares method, which generated the parameters, y-intercept and rate of rise, in corticotropin-releasing hormone concentration for each woman. Nonparametric statistical techniques, including bootstrapping, were applied to compare the results for the group of women who delivered at term with the group of women who delivered spontaneously preterm and the group of women who were delivered preterm by induction or cesarean delivery because of obstetric indication. Results: The 3 clinically defined groups have significantly different parameters, y-intercept and rate of rise, which describe the corticotropin-releasing hormone trajectory. The group that delivered preterm because of obstetric indications had a similar mean y-intercept but significantly greater mean rate of rise in corticotropin-releasing hormone concentration than the term group (0.3491 vs 0.1788; 95% CI, 0.2331-0.4615 vs 0.1394-0.2330). The group that delivered spontaneously preterm had a significantly greater mean y-intercept than the group that delivered preterm because of obstetric indication (17.08 vs 1.83; 95% CI, 5.89-28.43 vs 0.03-5.19) but a similar mean rate of rise to the group that delivered at term. Conclusion: These data suggest that spontaneous preterm delivery is associated with an abnormal setting of the production of corticotropin-releasing hormone that is present from very early in pregnancy, although women who experience an induced preterm delivery are characterized by rapidly rising placental corticotropin-releasing hormone concentrations. These data further suggest that clinical abnormalities that are associated with preterm delivery by induction or cesarean delivery are associated with abnormalities that lead to a rapidly increasing corticotropin-releasing hormone concentrations. Trajectories for corticotropin-releasing hormone provide information beyond that obtained from a single sample. (Am J Obstet Gynecol 2002;186:257-60.)

Neuropeptides: Modulators of immune responses in health and disease

Publisher Summary Glucocorticoids remain the most powerful of all anti-inflammatory agents, but their clinical application in chronic inflammation and autoimmune diseases is limited by systemic side effects. The challenge that needs to be addressed is to develop selective anti-inflammatory drugs with efficacy equal to or better than glucocorticoids. Immunoneuropeptides have exciting potential for development as a new generation of nonglucocorticoid anti-inflammatory drugs. One area of promise is the direct injection into inflamed tissue of small amounts of a long-acting compound or local implants of slow-release polymer beads impregnated with an anti-inflammatory agent. This would be a useful strategy for the application of low dose/high potency opioid or corticotropin-releasing hormone (CRH) analogs to exert anti-inflammatory effects without systemic release and consequent nonspecific effects. Expression of some immunoneuropeptides is responsive to glucocorticoids and catecholamines, and these neuropeptides can modulate the effects of stress on immune functions. Stress can influence the production of CRH and pro-opiomelanocortin (POMC) peptides from leukocytes and also determine T-cell differentiation into distinctive Th1/Th2 cytokine secretory profiles. Therefore, neuropeptides may be involved in mediating the effects of stress on production of specific cytokines with pro- or anti-inflammatory activity.