The sex differences in IGF-1 levels reported in this study provide a potential basis for understanding the etiology of growth impairment in CD. The mechanisms responsible for growth impairment in CD may also apply in other chronic inflammatory diseases.
BA was lower than CA in our series of pediatric patients with CD, consistent with prior studies3,18
. The importance of BA in interpreting growth in such patients was further demonstrated by observed sex differences in height BA-Z, but not CA-Z scores. We did not observe sex differences in BA delay. In contrast, others found BA was significantly delayed in males, not females6
. This difference in results and its importance in explaining sex differences in growth impairment require clarification. We again identified sex differences in statural growth, as described in prior studies1,4,6–8
. Height BA-Z scores were significantly lower in males.
Our data show that IGF-1 levels are reduced in males compared with females, and the relationship between sex and IGF-1 levels was similar across TS’s 1–5. Griffiths et al reported that in a cohort of 100 TS 1 and 2 children with CD, males had lower height Z scores at the time of diagnosis of CD, achieved less catch up growth, and had lower ultimate height Z scores1
. Their report corresponds with our findings that sex differences in growth impairment are apparent even in pre-pubertal children. Taken together, the data suggest that sex differences in growth impairment are not driven by timing of diagnosis of disease in relation to timing of pubertal growth spurt in pediatric patients.
Inflammation has been shown to exert negative effects on growth. Several investigators have implicated inflammatory mediators in impacting the GH-IGF-1 pathway at various points19–27
. Multiple correlations have been reported between IGF-1 and IGFBP-3 and inflammatory markers in CD28–31
, as in our study. IGF-1 is more sensitive than IGFBP-3 to nutritional deprivation32
, whereas parallel reductions in IGF-1 and IGFBP-3 are more suggestive of defective GH action, i.e. deficiency or resistance. We measured urine GH levels as a screen for GH deficiency, and our results were not suggestive of GH deficiency in this cohort, consistent with other studies33–36
. We found an association between IGFBP-3 and CRP, but not with BMI. Additionally, the inflammatory markers remained significant predictors of IGF-1 levels after adjusting for BMI; BMI was not a significant predictor of IGF-1 in these models [data not shown]. BMI did not differ by sex in our study cohort and fails to explain the sex difference in IGF-1 levels. Hence, our results suggest that the observed reduction in IGF-1 levels in males compared with females is likely due to inflammation, rather than due to poor nutrition. Our data suggest that the effects of inflammation on hormone levels are more pronounced in males, and may explain the observed sex differences in IGF-1 and IGFBP-3 levels, even though inflammatory markers did not differ by sex. We are not aware of other reports of sex differences in IGF-1 and IGFBP-3 levels in CD for comparison.
Our data support that GH resistance associated with inflammation contributes to growth impairment in CD. The uGH/serum IGF-1 ratio was higher in TS 1 and 2 males, suggesting greater GH resistance in this group, and consistent with lower IGF-1 levels in males. It remains unclear why a sex difference in uGH/serum IGF-1 ratio was identified only at TS 1 and 2. Others have suggested that low estrogen concentrations could stimulate responsiveness to GH, whereas high concentrations, seen in adult females, could inhibit GH responsiveness37
. Therefore, sex differences in uGH/serum IGF-1 ratio at TS 3–5 with higher ratios in females might have been expected, but may have escaped detection because of possible sex differences in the effects of inflammation on growth. Perhaps the rise in testosterone with advancing pubertal stage in males offers a protective effect in TS 3–5 versus TS 1–2 males. However, IGF-1 levels were decreased in males compared with females across all TS’s. Therefore, the relevance of increased uGH/serum IGF-1 ratios requires further study.
Inflammation may also exert an adverse effect on sex hormone levels, contributing to impaired growth. Inflammatory markers correlated with testosterone levels in males, but not with estradiol levels in females. Since sex hormone levels predict IGF-1 levels, inflammation should have a greater negative impact on IGF-1 levels in males. We found weak evidence in support of a greater impact of modifying factors in males, and that sex modified the influence of sex hormone CA-Z scores on IGF-1 CA-Z scores, with the effect slightly stronger in males. In a rat model of colitis, no significant differences in 17B-estradiol concentrations in the colitic group versus controls were present in females38
, whereas testosterone was significantly reduced in colitic males. Correlations between disease state and androgens have been reported in other conditions. A reduction in testosterone has been observed in males with cystic fibrosis39
, and low androgen levels are present in juvenile rheumatoid arthritis40
and systemic lupus erythematosus41,42
. Finally, inflammatory cytokines, such as TNF-alpha, may induce reductions in testosterone as described in in vitro
Inflammation may also suppress pituitary hormone levels. Our results showed that pituitary hormone BA-Z scores were lower in TS 1 and 2 males. This finding may contribute to the sex difference in uGH/serum IGF-1 ratio in TS 1 and 2 children. Inflammatory markers correlated with LH BA-Z scores in males, but not with FSH BA-Z scores in females. Furthermore, sex modified the effect of CRP on pituitary hormone BA-Z scores. Higher levels of CRP were associated with lower pituitary hormone BA-Z scores in males, not females, suggesting that the impact of inflammation on hormone levels may differ by sex. In a rat model of colitis, investigators reported that the profile of plasma LH and FSH concentrations was similar to levels observed in control female rats38
, suggesting that hypopituitarism may not be the cause of growth impairment in CD36,45
. In contrast, others have reported diminished plasma LH and FSH levels in CD46,47
and cystic fibrosis, to a lesser extent in females than males48
. Thus, the existing evidence is mixed and deserves further study to advance our understanding of the impact of CD on hypothalamic-pituitary function and statural growth.