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What suppresses fever in pregnancy near term?

¹ Veterinary-Physiology, Justus-Liebig-University Giessen, D-35392 Giessen; and ² Johannes-Muller-Institut fur Physiologie, Humboldt Universität (Charité), D-10117 Berlin, Germany

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FEVER IS THE MOST COMMON MANIFESTATION of disease and is thought to be beneficial and even to assist survival in the face of infection. Thus investigations into agents that modulate fever (1, 5, 8) and periods when fever is suppressed (10) have clinical relevance and may have impact on many other physiological processes. The classical observation that fever is suppressed during the late stage of pregnancy stimulated a number of researchers to look for endogenous antipyretic mediators that are produced and released during the prepartum and the early postpartum period to cause the observed depression of a febrile response to various pyrogenic stimuli. Suppression of fever at term was first reported in 1978 (4), and, despite numerous attempts to find the mechanism, this remains a well-kept secret by nature. A change in the hormonal status alone cannot explain febrile refractoriness in pregnancy near term. At least in menopausal women receiving estrogen-replacement therapy, the altered thermoregulation induced by reproductive steroid therapy appears to occur via a mechanism distinct from a classic infection-induced fever (2). However, the neuropeptide arginine vasopressin (AVP) seemed to fulfill all criteria to act as an endogenous antipyretic substance during the late stage of pregnancy and in other physiological situations accompanied by a blunted febrile response. The ventral septal area, which is an area of the basal forebrain extending from the lateral aspects of the diagonal bands of Broca to the hypothalamic preoptic area, is innervated by vasopressinergic cell bodies in the bed nucleus of the stria terminalis and parvocellular neurons of the hypothalamic paraventricular nucleus. This brain area was identified as a putative site of action where AVP exerts its antipyretic activity. Microinfusions of AVP into this brain site produce antipyresis to injections of bacterial pyrogens via the V₁ receptor. Conditions that cause elevation of AVP in this area, including the late stage of pregnancy (3), are accompanied by reduced fever responses, whereas a decreased endogenous release of AVP is associated with enhanced fever. In addition, fever induced by bacterial pyrogens is increased when AVP antiserum or V₁-specific receptor antagonists are perfused into the ventral septal area (9). Within the ventral septal area the released AVP seems to stimulate septal neurons. This excitation is then transmitted via septofugal fibers to the hypothalamic thermoregulatory structures where it may inhibit the neuronal changes that can be induced by endogenous pyrogens, namely by PGE₂, which is traditionally regarded as the neural mediator of the febrile response.

The absence of fever in response to pyrogenic stimulation can be due to enhanced formation of endogenous antipyretics, but also to a depressed induction of endogenous pyrogens. In this volume, Mouihate et al. (7) provide the first experimental evidence that the second possibility (reduced activity of pyrogenic mediators) might be involved in the suppression of fever of pregnant rats near term. The enzyme cyclooxygenase (COX) is critically important for the formation of PGE₂, and the inducible form COX-2 is induced or upregulated by inflammatory stimuli (LPS or cytokines). The induction of COX-2 in thermoregulatory relevant brain areas after stimulation with exogenous or endogenous pyrogens is regarded as a critical step in the manifestation of a febrile response (6). Consequently, the authors of this manuscript investigated constitutive and LPS-induced COX-2 expression within the hypothalamus and demonstrate a significant reduction at near term compared with values before and after term. In addition, expression of the EP₃ receptor for PGE₂ was investigated based on evidence from literature that this receptor plays an important role in the generation of fever (11). The expression of the EP₃ receptor seemed, however, not to be impaired at near term. The findings of this study have importance beyond basic research in fever. The functional implications are valuable for obstetricians, reproductive physiologists, and neuroscientists.

	FOOTNOTES

10.1152/ajpregu.00311.2002

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