Adrenal steroid levels during infancy associated with asthma at age 5 years
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Key takeaways:
- Pregnenetriol disulfate and 3a,21-dihydroxy-5b-pregnane-11,20-dione-21-glucoronide had inverse associations with asthma.
- The interaction effect of pregnanediol-3-glucorinide by sex was significant for girls.
Higher levels of urinary adrenal steroid metabolites during infancy were associated with lower odds for asthma at age 5 years, according to a study published in Annals of Allergy, Asthma & Immunology.
This protection against asthma may be due to these steroids suppressing type 2 inflammation, Kedir N. Turi, PhD, assistant professor of medicine, department of epidemiology and biostatistics, Indiana University, and colleagues wrote.
About 3 decades ago, Turi told Healio, a phenomenon known as “mini-puberty” was noted, where sex hormone-related biochemicals produced by the body increase between birth and age 3 months.
“Prior studies show these biochemicals, also known as adrenal steroids, play a role in lung development, regulation of the immune system, and explain differences in the prevalence of respiratory diseases between males and females throughout life,” Turi said.
However, an understanding of the role of these adrenal steroids during early life is lacking, he continued.
“We do not know why these adrenal steroid chemical levels rise right after birth and if they have any role in the development of chronic respiratory disease, such as asthma,” Turi said. “Our study aimed to fill this knowledge gap.”
Study design, results
The study included 264 children (62.1% boys, 68.6% white) from the INSPIRE birth cohort who had urinary metabolite data as infants. There were 43 children lost to 5-year follow-up and 65 lost to follow-up at 6 years.
Also, 76 of these children had metabolomics and nasal immune mediator data from age 2 months to 6 months. At 5-year follow-up, 60 (27%) children had an asthma diagnosis, and at 6 years, 50 (25%) of the children had the same.
Using an untargeted metabolomics approach, the researchers identified 11 adrenal steroid metabolites from a data set of more than 1,200 metabolites.
There were inverse associations between pregnanediol disulfate (adjusted OR = 0.32; 95% CI, 0.11-0.85), pregnenetriol disulfate (aOR = 0.2; 95% CI, 0.06-0.68) and 3a,21-dihydroxy-5b-pregnane-11,20-dione 21-glucuronide (aOR = 0.34; 95% CI = 0.14-0.75) and asthma at age 5 years.
The researchers noted that the adrenal steroid metabolites are from the same pathway and that they are highly correlated.
Multiple testing adjustments revealed associations between pregnenetriol disulfate and 3a,21-dihydroxy-5b-pregnane-11,20-dione 21-glucuronide and asthma at age 5 years.
In a concentration-dependent manner, asthma at age 5 years also was associated with increased concentrations of pregnenetriol disulfate and 3a,21-dihydroxy-5b-pregnane-11,20-dione 21-glucuronide.
This relationship between the age of the infant and pregnenetriol disulfate and 3a,21-dihydroxy-5b-pregnane-11,20-dione 21-glucuronide levels surges soon after birth, the researchers continued, with a peak at approximately age 2 months before declining.
At age 6 years, the associations between pregnenetriol disulfate and 3a,21-dihydroxy-5b-pregnane-11,20-dione 21-glucuronide levels and asthma outcomes remained consistent.
When the researchers analyzed the interaction effects of sex by adrenal steroid metabolites, with adjustment for multiple testing adjustments, only pregnanediol-3-glucuronide by sex interaction had a significant association with asthma at age 5 years.
There also was a significant difference between the effect of pregnanediol-3-glucuronide on asthma in girls and boys (aOR = 0.11; 95% CI = 0.02-0.51).
While this association between pregnanediol-3-glucuronide and asthma was significant for boys (aOR = 2.57; 95% CI = 1.06-6.38), it was not significant for girls (aOR = 0.28; 95% CI = 0.07-0.97).
Most of the associations between adrenal steroids and asthma in boys and girls were directionally consistent in the stratified analysis too, the researchers said, although boys (aOR = 3.06; 95% CI, 1.22-8.15) and girls (aOR = 0.32; 95% CI, 0.07-1.13) both had directionally opposite associations between pregnanediol-3-glucuronide and asthma.
Also, probably because of small sample sizes, multiple testing adjustments found that the associations within each sex strata between pregnanediol-3-glucuronide and asthma were not significant, the researchers said.
Multiple testing adjustments additionally found an inverse association between pregnenetriol disulfate and IL-13 (B = –0.36) and GM-CSF (B = –0.45).
Further associations included 3a,21-dihydroxy-5b-pregnane-11,20-dione 21-glucuronide with IL-4 (B = –0.29), IL-5 (B = –0.35), IL-13 (B = –0.26), granulocyte-macrophage colony-stimulating factor (B = –0.35), and fibroblast growth factor-beta (B = –0.24).
The differences in the association between pregnanediol-3-glucuronide and asthma for boys and girls led the researchers to evaluate sex by pregnanediol-3-glucuronide interaction effect and a sex-stratified analysis of the association between pregnanediol-3-glucuronide and nasal immune mediators (boys = 46; girls = 30).
The effect of the interaction between sex and pregnanediol-3-glucuronide was not significant on all immune response mediators, the researchers said.
All the coefficients of association between pregnanediol-3-glucuronide and immune mediators were negative for girls and positive for boys, or directionally opposite, except for IL-4, IL-5 and fibroblast growth factor-beta.
But after multiple testing adjustments, the researchers continued, all the sex-stratified association were insignificant except for the association between pregnanediol-3-glucuronide and IL-4 in boys.
Conclusions, next steps
Based on these findings, the researchers concluded that there were associations between higher urinary adrenal steroid metabolite levels during infancy (pregnenetriol [5-pregnene-3b,17a,20a-triol] disulfate and 3a,21-dihydroxy-5b-pregnane-11,20-dione 21-glucuronide) and lower odds for asthma at age 5 years.
“We were surprised to find that children who had higher adrenal steroid levels, measured just a few months after birth, were less likely to have asthma at age 5 years,” Turi said. “The children with higher levels of adrenal steroids also had lower levels of asthma-related immune mediators (cytokines).”
As a result, the researchers continued, adrenal steroid metabolites during infancy may have an effect on childhood asthma and its pathogenesis, with different effects on asthma risk based on sex.
“These findings are significant because they affirm that asthma pathogenesis begins during early life and is driven in part through altered biochemicals and immune responses,” Turi said. “It is also interesting that sex hormone biochemical precursors may explain some of the asthma risk differences between males and females.”
Turi noted that these findings are not yet clinically relevant for doctors.
“Our study is at the discovery phase,” he said. “More investigation is needed to understand why some children have lower levels of adrenal steroids and identify the mechanisms of the effects of adrenal steroids in driving the development of asthma.”
Turi and his colleagues also speculate that lower levels of adrenal steroids may be due to maternal and infant exposure to environmental factors.
“Our next step is to investigate whether adrenal steroid levels are altered by modifiable environmental exposures and whether reducing exposure may decrease the risk of asthma development,” he said.
“We also hope to conduct an experimental study using an animal model to illustrate the mechanism of effects of early-life adrenal steroids on the development of asthma,” he added.
For more information:
Kedir N. Turi, PhD, can be reached at knturi@iu.edu.
Perspective
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This epidemiological study shows that two metabolites in the adrenal pathway are associated with lower incidence of asthma, and it is a well-done study. In some ways, you have to be contextual and say, “Why do some people get asthma with the same environmental triggers and others don’t?” This could be part of that story.
Do people with high steroid levels have lower incidence of asthma? And if they had the right triggers, would they develop asthma? That is what this study seems to suggest, and it is not surprising. It does not explain why people have asthma, but it might explain why some people are more likely to have it than others despite the same environmental exposures. If the child has a predisposition to asthma, high steroid levels should reduce the risk for developing asthma.
The authors of the study suggest that higher levels of urinary adrenal steroid metabolites during infancy decrease inflammation, and that is very plausible. If this is the mechanism, a similar pattern should be seen in allergy, eczema and allergic rhinitis , which have a T2 immune basis. It would be interesting if this research could be extended to allergy, eczema and allergic rhinitis as well as to inflammatory disorders outside of that pathway such as inflammatory bowel disease. Such a strategy would provide insight, as each has a similar but different immune signature.
For example, TH1 is associated with inflammatory bowel disease, and TH2 is associated with eczema and allergy. All we have now is the hypothesis that high levels decrease inflammation in the airways, which is very plausible since these high levels can alter the frequency of other conditions with immune underpinning, not just asthma. Can you learn from these differences in hormone levels?
We give patients inhaled steroids to treat asthma. But if you give a patient with low levels of urinary adrenal steroid metabolites inhaled steroids at these early ages, would it prevent asthma in the long run? This is complex. We have to be very careful about giving steroids to young kids. Steroids alter the development of many organs. We may decrease the risk of one disease and increase the risk of another. You have to be a little thoughtful before going down that pathway. You’re talking about a lifetime risk here.
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