Effects of Endogenous Sex Hormones on Lung Function and Symptom Control in Adolescents With Asthma

Mark D. DeBoer; Brenda R. Phillips; David T. Mauger; Joe Zein; Serpil C. Erzurum; Anne M. Fitzpatrick; Benjamin M. Gaston; Ross Myers; Kristie R. Ross; James Chmiel; Min Jie Lee; John V. Fahy; Michael Peters; Ngoc P. Ly; Sally E. Wenzel; Merritt L. Fajt; Fernando Holguin; Wendy C. Moore; Stephen P. Peters; Deborah Meyers; Eugene R. Bleecker; Mario Castro; Andrea M. Coverstone; Leonard B. Bacharier; Nizar N. Jarjour; Ronald L. Sorkness; Sima Ramratnam; Anne-Marie Irani; Elliot Israel; Bruce Levy; Wanda Phipatanakul; Jonathan M. Gaffin; W. Gerald Teague

Disclosures

BMC Pulm Med. 2018;18(58) 

In This Article

Results

Sample Features

The sample included 116 males and 71 females (Table 1). There were no significant differences between males and females with regard to age, racial/ethnic background, asthma severity, or corticosteroid treatment. There were 110 severe and 77 non-severe participants in the analytic cohort. Of these, 74 severe- and 30 non-severe participants had an ACQ < 1.0 as an estimate of poor control (67% and 39%, respectively).[24] Overall the sample was enriched in African Americans and severe asthma, with a high proportion with atopic sensitization. Among males, 84 (63%) were in pre−/early puberty and 32 (28%) in mid−/late puberty by Tanner stages of pubic hair development. Among females, 32 (45%) were in pre−/early puberty and 39 (56%) in mid−/late puberty by Tanner stages of breast development. 37 females (52%) were in pre−/early- and 34 (47%) in mid−/late adrenarche by Tanner stages of pubic hair. Adolescent females discordant for breast and pubic hair stages of development included 6 wherein pubic hair stage exceeded breast stage, and 1 wherein breast stage exceeded pubic hair (Additional File 1: Table S1).

Differences in Sex Hormones With Puberty

68 children in the sample had circulating sex hormones measured (45 males, 23 females). From pre−/early to mid−/late puberty, testosterone increased in males, and estradiol increased in females (Additional File 1: Figure S2A and Figure S2B). Likewise with puberty DHEA-S increased in males and DHEA-S, progesterone, and free testosterone increased in females (results not shown).

Supplementary Figure S2.

Sex hormone levels by Tanner stage for testosterone in males (A) and estradiol in females (B). Box plots are median and confidence intervals.

Differences in Lung Function With Puberty

For males, there was a tendency for lung function and the maximum bronchodilator response to improve with pubertal maturation, but these differences were not statistically significant (Table 2). By contrast in females, both the post-bronchodilator FEV1% and FVC % were significantly lower (by 8.9% and 9.1% respectively, p = 0.01 each) from pre−/early to mid−/late puberty as determined by breast development. In an analysis limited to severe females alone (n = 44), the lower FEV1 (%) from early to late puberty remained significant. Similarly, the differences by pubertal maturation remained when participants were stratified by overweight/obesity status (Additional File 1: Table S2-A-1 and Table S2-A-2). These differences by Tanner stage are attributable to breast and not pubic hair development, supporting a likely estradiol effect.

Differences in ACQ6 With Puberty

With regards to four week symptom control (Table 3), with males (n = 116) the ACQ6 was not significantly different from pre−/early to mid−/late puberty, whereas in females (n = 71) the ACQ6 was higher (worse) with puberty assessed by breast bud (p < 0.05) and by pubic hair development (p < 0.05). In males with severe but not non-severe asthma, the ACQ6 was lower (improved) with pubertal maturation, whereas the ACQ6 was higher with pubertal stage in females with both severe (n = 44) and non-severe (n = 37) asthma (p < 0.05 for both). Again, the differences by pubertal maturation remained when participants were stratified by overweight/obesity status (Additional File 1: Table S2-B-1 and Table S2-B-2).

Multi-variable Linear Regression of Lung Function and ACQ6 With Sex Hormones

Males. For males in the sample 6–18 years of age, lung function associated positively with log DHEA-S values (Table 4). The pre-bronchodilator FEV1% (β = 8.05; p = 0.01), post-BD FEV1% (β = 8.82, p = 0.008), and pre-BD FVC % (β = 8.33, p = 0.01) had strongly positive β coefficients. The ACQ6 had a negative β coefficient with higher log DHEA-S values (β = − 0.59, p = 0.007), indicating 4 week symptom improvement. These associations were driven largely by participant who were overweight/obese (Additional File 1: Table S3-A-1 and Table S3-A-2). The final model predicting ACQ6 included negative β coefficients for both log DHEA-S and testosterone, as well as the interaction of log DHEA-S with testosterone, an association not present when the cohort was stratified by overweight/obesity status. Circulating DHEA-S levels in males did not vary significantly when compared according to treatment with high-dose versus medium-dose inhaled corticosteroids (Additional File 1: Figure S3).

Supplementary Figure S3.

DHEA-S levels in boys with asthma treated with medium-dose and high-dose inhaled corticosteroids. Box plots are median and confidence intervals.

Females. For females 6–18 years of age, androgens associated positively, but estrogens negatively with lung function (Table 5). Free testosterone had a positive association with post-BD FEV1% (β = 3.99, p = 0.04). In contrast, estradiol had negative β coefficients for pre-BD FEV1% (β = − 0.47, p = 0.03), post-BD FEV1% (β = − 0.62, p = 0.0009), pre-BD FVC % (β = − 0.36, p = 0.04), and post-BD FVC % (β = − 0.33, p = 0.03). These associations were not significant in either group when stratified by overweight/obesity status (Additional File 1: Table S3-B-1 and Table S3-B-2). For the ACQ6, only log DHEA-S had a significant association, it varied positively (β = 0.49, p = 0.05) and the correlation was relatively weak. ACQ6 was not associated with age (Additional File 1: Table S4).

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