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

Methods

Severe Asthma Research Program

Details of the SARP III network, recruitment targets, enrollment and characterization procedures, and the longitudinal protocol have been previously published.[15,16] Active tobacco smokers were excluded. Participants maintained medications for asthma as prescribed by their care provider. Study procedures were approved by the IRB at each institution and an independent Data Safety Monitoring Board (Additional File 1: Figure S1). All subjects provided written informed consent and/or assent. The study is listed on ClinicalTrials.gov.

Supplementary Figure S1.

Participating institutions, involved Institutional Review Boards (IRB) and IRB numbers.

Criteria for Enrollment

Enrollees met criteria for current asthma based on responsiveness to β-agonist (≥12% increase in FEV1 from baseline post-albuterol) and/or positive methacholine bronchoprovocation. Severe asthma was defined according to the ERS/ATS consensus definition.[17] Children whose asthma required treatment with high-dose inhaled corticosteroids (≥440 mcg of fluticasone equivalents per day for children 6–11 years of age; ≥880 mcg fluticasone equivalents per day ≥12 years of age) plus a second controller and/or systemic corticosteroids to maintain asthma control or which was uncontrolled despite these medications were assigned to the severe sub-group. Medications at this level were required for at least 6 of the previous 12 months and the 3 months prior to enrollment for participants to qualify for the severe sub-group. Those who did not meet criteria for severe asthma were assigned to the non-severe sub-group.

Characterization

Characterization procedures extended from the SARP I and II protocols[18–20] for SARP III included detailed history and physical examination, vital signs, height, weight, characterization questionnaires, assessment of four-week symptom control (asthma control questionnaire; ACQ6[21]), and spirometry with maximal β-agonist reversibility testing (dose escalation protocol at 180 mcg albuterol increments up to 720 mcg).

Blood was drawn during the visit but not with systematic timing related to the timing of the spirometry. Pubertal stage was determined by study coordinators and investigators certified a priori to enrollment by a pediatric endocrinologist (MDD) with the method of Marshall and Tanner.[12] To identify central (CNS) puberty, Tanner stage for males was based on pubic hair and for females breast development. Females were also separated into pre−/early adrenarche and mid−/late adrenarche based on Tanner stages of pubic hair.

Spirometry, maximum bronchodilator challenge and methacholine challenge were performed by study coordinators certified after standard training and completion of an examination administered by the SARP III Data Coordinating Center on ATS-compatible equipment. Quality analysis of lung function tests and validation of results was accomplished by inspection of randomly sampled flow volume plots by a central over-reader. Population reference standards adjusted for age, height, and sex were from the Global Lung Initiative (GLI).[22]

Sex Hormone Assays

Sex hormone and SHBG levels were analyzed at the University of Virginia Center for Research in the Reproduction Ligand Core Laboratory. Estradiol levels were assessed with Calbiotech ELISA and all other metabolites were assessed using the Siemens Immulite 2000. Free testosterone was calculated from total testosterone and SHBG as previously described.[23] The lower limit of detection for assays were: testosterone 20 ng/dL; DHEAS 15 μg/dL; progesterone 0.20 ng/mL; and SHBG 10 nmol/L. For the purpose of mathematical analyses, individuals with measurements below the limit of detection were counted as having a value just below the lower limit of detection. Intra−/inter-assay coefficients of variation (CVs, %) were as follows: estradiol 6.3/8.1, testosterone 4.4/7.5, DHEAS 5.4/6.5, progesterone 4.4/7.8, and SHBG 2.7/5.2.

Data Analysis

The analysis was restricted to enrollees with complete data sets with regards to Tanner stage and lung function. Because of natural variation in recruitment, mid-Tanner stages were relatively under-represented (Table 1). To examine the effects of pubertal maturation, participants were assigned to sub-groups including those with pre−/early puberty (Tanner 1–2) and mid-late puberty (Tanner 3–5).

Categorical data are presented as count and percentage, and continuous data as means ± standard deviations. Comparisons of differences by pubertal stage between males and females (both adrenarche and breast development) was performed by testing the stage by sex interaction term in a simple regression model. PC20 was evaluated on a log base 2 scale, with two zero values replaced by 0.016, or half of the minimum non-zero value. Univariable linear regression was used to evaluate relationships between measures of lung function or ACQ6 and individual 5-level Tanner stage. Multivariable linear regression tested associations of clinical outcomes (lung function and ACQ6) with sex hormone levels (for males, testosterone and DHEA-S; for females, estradiol, progesterone, free testosterone and DHEAS) as co-variates. With a backward selection method, hormones that were not significantly associated with the outcome were removed in steps and only significant associations were reported. These analyses were then further stratified based on BMI ≥85th percentile and < 85th percentile. P-values are unadjusted in these exploratory post hoc analyses.

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