Sex-differentiated changes in C-reactive protein from ages 9 to 21: the contributions of BMI and physical/sexual maturation.

In the absence of acute infection, the acute phase reactant C-reactive protein (CRP) is a marker of low-grade systemic inflammation that is associated with chronic illness and mortality in adulthood (Ridker, 2007; Shah et al., 2009). Currently, CRP > 3 mg/L is considered a uniform marker of disease risk in both women and men. However, imposing sex-differentiated criteria for CRP remains an ongoing topic of debate, because women—who typically have a longer life expectancy than men—nevertheless tend to be over-represented in the CRP > 3 mg/L group (Khera et al., 2005). This debate is currently missing a critical piece of information: When and why do sex differences in CRP emerge? Here, we examine the developmental origins of sex differences in CRP from ages 9 to 21—when marked physical and behavioral changes of adolescence could contribute to diverging trajectories of CRP in females versus males. Trajectories of CRP: Do Sex Differences Emerge During Late Adolescence? Longitudinal research describing trajectories of CRP is notably missing, but cross-sectional work suggests that mean levels of high-sensitivity (hs)-CRP undergo no (McDade et al., 2005) or only small (Cook et al., 2000; Ford et al., 2003) age-related increases from middle childhood to mid-adolescence (approximately ages 5–15), temporary accelerations in the rate of increase into young adulthood (Ford et al., 2003), and mostly linear increases throughout adulthood (O’Connor et al., 2009). Cross-sectional studies also suggest that, compared to men, women typically have higher mean CRP and likelihood of CRP > 3 mg/L [(Ford, 1999; Ford et al., 2004; Khera et al., 2005; Lakoski et al., 2006); for an exception, see Rifai and Ridker, (2003)]. Sex differences in CRP concentrations before young adulthood have not been consistently examined or reported, although one nationally representative study suggests that female-male differences emerge only after age 15, when the aforementioned accelerated temporary increases in CRP are primarily driven by females (Ford et al., 2003). Correlates of CRP Several factors could contribute to sex-differentiated trajectories of CRP during adolescence. Adiposity/obesity/Body Mass Index (BMI)is strongly associated with CRP in both sexes (Dowd et al., 2010; Skinner et al., 2010), but more strongly in women than in men (Visser et al., 1999; Williams et al., 2004; Khera et al., 2009). Sex-differentiated BMI-CRP associations have not been examined or reported earlier in life, but, considering puberty-related shifts in body composition, adolescence could mark the beginnings of such sex-differentiated associations. After puberty, percent body fat is typically greater in women than in men (Gallagher et al., 1996), and the known inflammatory action of fat deposits could contribute to greater CRP in women (Wozniak et al., 2009). Physical/sexual maturation also results in increased exposure to sex hormones, with potentially different consequences for females and males. External administration of sex hormones (e.g., estrogen) has at least some proinflammatory effects and can increase in females with the use of oral contraceptives (Williams et al., 2004). Endogenous exposure to sex hormones also increases with the onset of puberty and with pregnancies, but its effects on inflammatory markers and overall disease risk in females are less well understood (Eskes and Haanen, 2007). In turn, testosterone increases approximately tenfold more in males than in females during adolescence (Granger et al., 2004), and has anti-inflammatory effects. Thus, unlike later in life when decreases in testosterone contribute to increases in males’ disease risk, adolescent increases in testosterone could protect males from elevated CRP (Laaksonen et al., 2003). Apart from sex hormones, behavioral changes of adolescence—including the onset of sexual activity and involvement with multiple sexual partners for some adolescents—could also lead to new vulnerabilities to inflammatory processes, perhaps especially in females with the onset of vaginal intercourse (Hooton et al., 2000; Dielubanza and Schaeffer, 2011). Other correlates could contribute to changing levels of CRP over time, but sex differences in associations between these correlates and CRP have not consistently been reported. Substance use, especially nicotine use tends to be positively associated with CRP (O’Connor et al., 2009), and increases during adolescence. The impact of alcohol and illegal drugs on inflammatory processes is less well understood, with some research suggesting that alcohol use is negatively associated with CRP (O’Connor et al., 2009). Ethnicity, including indigenous/Native ethnic background, is robustly correlated with elevated CRP in Canadian and Australian samples (e.g., Retnakaran et al., 2006; Wang and Hoy, 2006), but has not been examined in samples of U.S. children.