(1) Gender differences in airway behaviour occur throughout the human life span. Implicated in these differences are biological and sociocultural/environmental determinants related to sex and gender, respectively. Biological determinants of these gender differences in airway behaviour can be characterised as dimensional (related to structure/functional relationships), immunological, and hormonal. (2) Dimensional determinants: gender differences in airway dimensions relative to lung size and in structure/function relationships exist throughout the human life span and are characterised by higher flow rates for a given lung volume in girls and women than in boys and men. These differences are present in utero, have been demonstrated as early as one month of life, and persist through childhood into adulthood. Before puberty boys start to reduce their dimensional disadvantage and, in adolescent girls, the growth of their airways relative to their size (and air spaces) is slower than in adolescent boys. Nevertheless, the lungs of girls retain their dimensional advantages over the lungs of boys and these persist throughout their adult life. Thus, even though women remain on average shorter than men throughout adulthood, and even though the lungs of adult women remain smaller than those of adult men, they exhibit on average higher flow rates in relation to their lung size than men. (3) Immunological determinants of airway behaviour include atopy, probably the most important host determinant of airway behaviour. The phenotype biomarkers of atopy evolve differently with age. For instance, the acquisition of skin test positivity - that is, the increase in its prevalence rate with age - follows the same pattern in both sexes, being greater in childhood through early adulthood, but prevalence rates are lower in girls than in boys. Prevalence rates in both sexes coincide in the mid 20s and stabilise at a lower level in the 30s, after which they both fall at an accelerated rate in the 50s. Also, although prevalence rates averaged over the human life span show no sex differences, in those studies where age specific rates have been examined, these are higher in women in their reproductive years than those of men of the same age, but lower in girls than boys in childhood and again in women than men after the menopause. By contrast, sex differences in total serum IgE levels are present across the human life span, with levels in girls and women being consistently below those in boys and men at all ages. The evolution of total serum IgE also differs from that of skin test positivity, being highest in the first year of life, then decreasing rapidly to levels on average half those seen in childhood by the 30s and 40s and more slowly thereafter. Sex differences in allergen specific IgE are, however, less consistent. In one study of adults the only sex differences were for an outdoor allergen, grass, with lower levels in women than men. Gender differences in the determinants of the biomarkers of atopy other than allergen exposure (such as sibling and socioeconomic status, active and passive smoking, and occupational exposure) appear to have been less consistently examined. There is no evidence of gender differences in the relationship of skin positivity with sibling status. Higher and lower total serum IgE levels have been found in non-smokers than in smokers although gender differences do not appear to have been examined. The mechanisms of interaction between most environmental exposures and smoking remain to be explained. (4) Hormonal determinants. Throughout the human life span female airways are responsive to their sex hormones and to their cyclical fluctuations, supporting the hypothesis formulated by Havelock Ellis over a century ago that their airways are among the organs which exhibit secondary sex characteristics. These fluctuations impose a pattern of variation on airway behaviour to which male airways are not subjected. In the fetus and the neonate, given their more mature surfactant production, female airways (particularly the small airways) have an advantage over those of the male neonate in terms of airway patency as well as relative size. In childhood the airways of girls are less responsive to non-specific challenges such as methacholine, an advantage in part due to their dimensional advantages. This difference diminishes progressively towards adolescence. As girls enter the reproductive period of their life and their airways become subject to the cyclical fluctuation of their sex hormones, they exhibit premenstrual changes which include increases in their airway responsiveness to methacholine, in their chemosensitivity, in their ventilatory demands especially on exercise, and decreases in their spirometric lung function and transfer factor. These cyclical fluctuations are modified by the use of oral contraceptives. During pregnancy there appears to be a bidirectional interaction between the maternal and fetal immune systems. For instance, T cells in the cord blood of babies born to atopic mothers respond to aeroallergens as well as food allergens to which the mother was exposed during her pregnancy. Prenatal, perinatal and early life events also appear to be crucial in programming the fetal immune system as it hovers between the development or not of atopy and the asthma phenotype. During pregnancy the airways of the mother remain under the influence of her sex hormones, and there is also some evidence that the fetal sex hormones exert an influence on the mother's airway behaviour with her airways being less reactive if the fetus is male. After the menopause the level of airway reactivity decreases as does the risk of asthma, but this may reverse with hormone replacement therapy. Finally, despite the evidence that sex hormones influence many aspects of airway behaviour, the underlying physiological mechanisms remain poorly understood and the clinical implications poorly defined.
