Women are conferred with greater immunologic and survival benefits compared to men. Female sex steroids contribute to this sexual dimorphism. Furthermore, during human pregnancy when female sex hormones are elevated, neutrophil apoptosis is delayed. This study examines the specific effects of estradiol and progesterone on neutrophil apoptosis and function in healthy adult men and women. We also examined the contribution of these hormones to the persistence and resolution of an inflammatory response. Spontaneous apoptosis was significantly decreased in women compared with men. Physiologic doses of estradiol and progesterone caused a further delay in spontaneous apoptosis in both men and women but did not diminish Fas antibodyinduced apoptosis. The delay in apoptosis was mediated at the level of the mitochondria with decreased release of cytochrome c, which may alter caspase cleavage and activity. There were no associated alterations in neutrophil CD11b, but production of reactive oxygen intermediates (ROIs) in women was increased. Thus, female sex hormones mediate delayed neutrophil apoptosis in both sexes and enhance female intracellular production of ROIs. Modulating hormonal responses may be an effective therapeutic tool in combating inflammatory diseases. IntroductionFrom conception to senescence, women have a significant survival advantage. 1 Men are more susceptible to sepsis and subsequent morbidity and mortality than women of reproductive age. [2][3][4] The incidence of sepsis in postmenopausal women increases to levels almost equal to those seen in age-matched men. 5,6 The exact mechanism mediating this sexual dimorphism is unclear. However, female sex hormones have been implicated because they modulate the immune system under normal and stress conditions. 7 Following trauma or hemorrhage, female mice maintain their immune function, whereas male mice have significantly depressed responses. 8 Estradiol has been shown to be protective in organ ischemia-reperfusion injury and shock by preventing androgeninduced immunosuppression in male animals. 9-12 Thus, female sex hormones may be a useful adjunct in preventing trauma-induced immunosuppression and the associated increased susceptibility to sepsis. 13 Estrogen treatment, testosterone depletion, and testosterone receptor antagonists improve outcome in male animals following trauma and sepsis. 14 The exact role of changes in the estradiol-testosterone ratio in immune function requires further clarification. Estrogens are also cited as having a protective role in neurodegenerative and cardiac diseases through a variety of mechanisms including blockade of oxidation, antagonism of nitric oxide synthase activity, 15 and interference with the apoptotic process in a variety of cell systems.Altered neutrophil apoptosis has been implicated in the pathogenesis of several inflammatory conditions. 16,17 Excessively delayed neutrophil apoptosis is associated with the systemic inflammatory response syndrome (SIRS). This syndrome is also characterized by activated neutro...

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Labor is a mild proinflammatory state that is associated with fetal leukocytosis. Elective cesarean section has been linked with increased neonatal morbidity, which may be partially immune mediated. We hypothesized that labor may alter neutrophil phenotype and thereby decrease neonatal complications. We characterized neutrophil function and survival in normal neonates after either uncomplicated vaginal delivery (VD) or elective cesarean section (CS) without labor. Spontaneous neutrophil apoptosis is delayed in cord blood neutrophils of neonates after normal labor (VD) compared with CS, as assessed by propidium iodide DNA incorporation using flow cytometry. This demonstrates their ability to maintain an inflammatory response. CD11b expression on neonatal neutrophils after CS is decreased, providing further evidence of altered activation or priming. Lipopolysaccharide responsiveness, characterized by CD11b and apoptosis, is similar in VD and adults, but CS-derived neutrophils are unresponsive. Baseline TLR-4 levels are elevated in CS in contrast to the other groups, although expression is not up-regulated by lipopolysaccharide co-incubation. Neonatal neutrophil survival and function are altered by labor and may increase antibacterial function and neutrophilia. This suggests that labor of any duration may be immunologically beneficial to the normal term neonate.