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

Discussion

In children enriched in severe asthma enrolled in the NIH/NHLBI SARP III study (n = 187), there were important differences in lung function and four-week symptom control between males and females with pubertal maturation. In males, lung function was not different and symptom control improved when comparing those in early vs. late puberty, whereas in females lung function and symptom control were worse. Circulating sex hormones changed with puberty; in males greater androgen levels associated with better lung function and ACQ6, while in females greater circulating estrogens had a weak but significant negative association with lung function. These results support the general hypothesis that with pubertal maturation asthma severity is likely to improve in males but worsen in females.[2] Furthermore our data suggest a beneficial effect of endogenous androgens on lung function growth and ACQ6 in males in later puberty; and that endogenous estrogens may have weak deleterious effects on lung function growth in girls.

A beneficial effect of androgens is suggested by the presence of fewer asthma symptoms in late Tanner stage males with severe asthma. In females the presence of more asthma symptoms in late adolescence either reinforces the benefit of androgens (given an absence of significant androgens in females) or supports a negative role for estradiol. These integrated, Tanner-stage-based measurements of the effect of sex hormones over time are complemented by the association between DHEA-S and fewer asthma symptoms (lower ACQ6) and higher pre- and post-albuterol FEV1% observed in boys. Given that GLI-based normal ranges of lung function are age-specific these maturational and hormone-associated measures appear to be present beyond the expected changes in lung function based on age alone. Furthermore, we did not note associations between ACQ6 and age in either boys or girls. Note that it is unlikely that the level of corticosteroid therapy caused the male/female discordance we observed because the males and females did not differ with regard to oral or inhaled corticosteroid dosing (Table 1). Furthermore treatment with high-dose corticosteroids did not suppress DHEA-S levels in males. Although the testosterone increase is quantitatively orders of magnitude greater than that of DHEA-S with puberty,[25,26] DHEA-S levels in our analysis were more strongly associated with better lung function and improved ACQ6 than was testosterone.

Of note, androgen receptors are expressed in bronchial smooth muscle tissue, and testosterone relaxes contracted airway smooth muscle, suggesting a beneficial effect of androgens on airway smooth muscle tone.[7] Additionally, DHEA-S inhibits human airway smooth muscle and airway fibroblast proliferation,[5] and may influence airway epithelial-to-mesenchymal transition,[6] suggesting that androgens may prevent adverse airway remodeling seen in severe asthma. Together, these affects could be associated with the lower asthma symptom scores we observed in association with increased DHEA-S and with late adolescence. Indeed a trial of androgen administration provided early data regarding safety and improved ACQ.[27] We noted associations between DHEA-S and lung function that were present in overweight/obese but not normal weight. This differential effect by weight status, which was seen only in boys, is of unclear significance and requires further investigation.

In females, subtle but significant discordance between loss of lung function observed in association with late puberty assessed by breast staging relative to pubic hair staging suggests that estrogen, which drives breast development, may be the main factor affecting lung function. Only females have a surge of estrogen or progesterone during puberty, and breast development is exclusively associated with this surge.[28] In our study the number of females with discordant pubertal examinations was small, whereas adrenal androgen effects confounded all assessments. We also cannot exclude an adverse effect of progesterone. For example, the effects of pregnancy on lung function may be either both estrogen and progesterone-dependent, and both hormones have been hypothesized to play roles in the worsening of lung function.[2]

These results likewise support disparate changes in lung growth between males and females with puberty that bear on the remarkable decline in hospitalizations and asthma severity seen in young adults.[3] Asthma prevalence appears to decline more in males than it does in females by the second decade of life,[1] a result which might be explained by disparate trends in airway growth due to sex hormones. Young adult females exhibit a "dysanaptic" pattern of airway growth which supports a pattern of anatomically "fixed" airflow limitation.[11] With regards to airway hyperreactivity, we found that the level of methacholine responsiveness actually fell in both males and females with Tanner stage, a finding differs from the results of Tantisera et al.[29] wherein females had increased methacholine responsiveness. The difference between the two studies may be due to sample differences, wherein the SARP III cohort is relatively enriched with African Americans and children with severe asthma.

It should also be noted that other hormonal changes during puberty could also affect lung function, including an increase in the degree of insulin resistance[30]—which itself is associated with increased risk of asthma in adults[31] and adolescent girls[32]—and elevations in stress hormones, including cortisol[33]—with such stress systems further associated with asthma risk.[34] While temporally related (i.e., during puberty), the processes of insulin resistance and stress response go beyond sex hormone regulation alone.[30,33] Unfortunately, the timing of our blood collection was not specifically in the early morning (thus not as helpful to assess cortisol regulation) or with fasting status (for assessing insulin resistance), and thus we were not able to assess how these processes may have interacted with changes in sex hormones. Nevertheless, because we were able to assess relationships between measured levels of sex steroids and outcomes important to asthma severity, our findings suggest a direct role for sex steroids themselves.

This cross-sectional analysis of the effects of puberty on asthma features is exploratory and intended primarily to identify specific hypotheses to be tested with longitudinal measurements. We would point out that the veracity of the results is limited by the cross-sectional analytic approach, and the relative paucity of children who were in the mid-Tanner stages (III/IV) at the time of enrollment and our lack of knowledge for most female participants of whether central puberty or adrenarche began first. We lacked data on some participant characteristics, including depression status—which could affect stress response[34]—and the fraction of excreted nitrosoxide (FeNO)—which would have permitted assessment of the relationship between hormone levels with activity of Th2-high airway inflammation.

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