Celsus described four of the five cardinal signs of inflammation 2000 years ago, and Eustachio discovered the adrenal glands almost 500 years ago, but not until 1936 did Selye note that in rats exposed to stressors, the adrenal glands were enlarged, and the thymus and lymph nodes shrunken.1–3 Cortisone, the active principle of the adrenal glands, was isolated by Kendall and Reichstein in the late 1940s and shown to suppress immune organs. These scientists, along with Hench, received the Nobel Prize in Physiology and Medicine, after Hench and colleagues showed that cortisone could ameliorate rheumatoid arthritis.4,5 In recent . . .

The Hypothalamic–Pituitary–Adrenal Axis and Immune-Mediated Inflammation

We report the existence of a 'placental clock', which is active from an early stage in human pregnancy and determines the length of gestation and the timing of parturition and delivery. Using a prospective, longitudinal cohort study of 485 pregnant women we have demonstrated that placental secretion of corticotropin-releasing hormone (CRH) is a marker of this process and that measurement of the maternal plasma CRH concentration as early as 16-20 weeks of gestation identifies groups of women who are destined to experience normal term, preterm or post-term delivery. Further, we report that the exponential rise in maternal plasma CRH concentrations with advancing pregnancy is associated with a concomitant fall in concentrations of the specific CRH binding protein in late pregnancy, leading to a rapid increase in circulating levels of bioavailable CRH at a time that coincides with the onset of parturition, suggesting that CRH may act directly as a trigger for parturition in humans.

A placental clock controlling the length of human pregnancy.

Glucocorticoids (GCs) are essential for the maintenance of homeostasis and enable the organism to prepare for, respond to and manage stress, either physical or emotional. Cortisol, the principal GC in humans, is synthesized in the adrenal cortex. It is released in the circulation in a pulsatile and circadian pattern. GC secretion is governed by hypothalamus and pituitary. The hypothalamus senses changes in the external and internal environment that may disrupt the homeostatic balance of the organism (i.e. stressors), and responds by releasing corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) from parvocellular neurons projecting from the paraventricular nucleus to the median eminence. These neurohormones are released into the anterior pituitary where they act synergistically via specific receptors (CRH-R1 and V1B receptor, respectively) to trigger the release of the adrenocorticotropic hormone (ACTH) from the corticotrope cells into the systemic circulation. In turn, ACTH exerts its actions on the adrenal cortex via specific receptors, type 2 melanocortin receptors (MC2-R), to initiate the synthesis of cortisol, which is released immediately into the systemic circulation by diffusion. Hypothalamic CRH and AVP, pituitary ACTH and adrenal GCs comprise the hypothalamic-pituitary-adrenal (HPA) axis. In this brief review, the HPA axis and the various factors that regulate its function are described.

Regulation of the hypothalamic-pituitary-adrenal axis.

A negative association between anemia and duration of gestation and low birth weight has been reported in the majority of studies, although a causal link remains to be proven. This paper explores potential biological mechanisms that might explain how anemia, iron deficiency or both could cause low birth weight and preterm delivery. The risk factors for preterm delivery and intrauterine growth retardation are quite similar, although relatively little is understood about the influence of maternal nutritional status on risk of preterm delivery. Several potential biological mechanisms were identified through which anemia or iron deficiency could affect pregnancy outcome. Anemia (by causing hypoxia) and iron deficiency (by increasing serum norepinephrine concentrations) can induce maternal and fetal stress, which stimulates the synthesis of corticotropin-releasing hormone (CRH). Elevated CRH concentrations are a major risk factor for preterm labor, pregnancy-induced hypertension and eclampsia, and premature rupture of the membranes. CRH also increases fetal cortisol production, and cortisol may inhibit longitudinal growth of the fetus. An alternative mechanism could be that iron deficiency increases oxidative damage to erythrocytes and the fetoplacental unit. Iron deficiency may also increase the risk of maternal infections, which can stimulate the production of CRH and are a major risk factor for preterm delivery. It would be useful to explore these potential biological mechanisms in randomized, controlled iron supplementation trials in anemic and iron-deficient pregnant women.

Biological mechanisms that might underlie iron's effects on fetal growth and preterm birth.

The clinical, biochemical, and radiological features of pituitary ACTH-dependent Cushing's syndrome (CS) [Cushing's disease (CD)] are often indistinguishable from those of occult ectopic ACTH-dependent CS (oEAS). We have evaluated, retrospectively, the results of simultaneous bilateral inferior petrosal sinus (IPS) ACTH sampling before and after CRH stimulation in 128 patients with ACTH-dependent CS: 107 patients with CD, 6 with oEAS, 1 with an adrenal adenoma, 1 with a pituitary gangliocytoma, and 1 with Nelson's syndrome; while, in the remaining 12, the source remains unclear. One hundred seven patients received human-sequence CRH (hCRH), and 11 received ovine CRH; another 6 patients underwent stimulation with desmopressin and hCRH, and 4 with desmopressin alone. A successful bilateral IPS catheterization and sampling (IPSCS) rate of 87.5% was obtained only after considerable experience had been gained. Sixty-nine patients with CD underwent successful bilateral IPSCS: the IPS-to-peripheral ratio of plasma ACTH value (IPS/P) rose from 9.5 +/- 1.4 to a maximum ratio of 55.8 +/- 7.5 in 67 patients, after CRH stimulation. The maximum ratio was obtained at 5 min in 60 of the 69 patients with CD; however, all 69 patients obtained a ratio of more than 2, at that time. In contrast, the 6 patients with occult ACTH-secreting neoplasms had a maximal IPS/P ratio of 1.3 +/- 0.16, and this did not change after CRH stimulation. A bilateral IPS/P ratio more than 2, obtained 5 min after CRH stimulation, had a sensitivity of 97% and a specificity of 100% in diagnosing CD. Two patients with proven active CD had an IPS/P ratio of less than 2. After successful bilateral IPSCS, the gradients between the IPS ACTH concentrations [IPS ACTH gradient (IPSG)] of more than 1.4, at 5 min after CRH stimulation, had a sensitivity of 83% in correctly lateralizing the pituitary microadenoma, compared with 72% sensitivity for magnetic resonance imaging (MRI) scanning. Furthermore, when IPSG and MRI findings were contradictory, IPSG was more often correct than MRI scanning. Although oEAS is a relatively uncommon cause of ACTH-dependent hypercortisolism (5.5% in our series), the accurate diagnosis of ACTH-dependent CS and localization of an intrapituitary microadenoma requires bilateral IPSCS with CRH stimulation, provided that the appropriate technical experience is available. hCRH is as effective a secretagogue as ovine CRH, and either may be used. The value of the combination of CRH and desmopressin stimulation requires more detailed investigation.

A Critical Analysis of the Value of Simultaneous Inferior Petrosal Sinus Sampling in Cushing’s Disease and the Occult Ectopic Adrenocorticotropin Syndrome

Late in the last trimester of human pregnancy, as plasma CRH levels rise, the concentration of circulating CRH-binding protein (CRH-BP) falls. We have investigated, using nonpregnant subjects, the hypothesis that CRH has a negative effect on plasma levels of CRH-BP. A specific RIA developed with the aid of recombinant binding protein has been used to measure CRH-BP. Subjects given iv infusions of human CRH for 10 h showed a sustained fall in plasma CRH-BP for the duration of the infusion. Intravenous bolus injection of human CRH produced a rapid reduction in CRH-BP levels to 54% of the basal value, whereas ovine CRH was without effect, even though both peptides are cleared from the plasma at similar rates and have similar effects on the pituitary-adrenal axis. The rapid clearance was concluded to be related to ligand affinity, as ovine CRH has a 200-fold lower affinity than human CRH for CRH-BP. We suggest that the rising levels of CRH are responsible for the reduction in CRH-BP concentrations observed in late pregnancy, and that this reduction is triggered by the binding of CRH-BP to its ligand.

Association of human corticotropin-releasing hormone to its binding protein in blood may trigger clearance of the complex.

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Association of human corticotropin-releasing hormone to its binding protein in blood may trigger clearance of the complex.