Estradiol in Premenstrual Asthma: A Double-Blind, Randomized, Placebo-Controlled, Crossover Study

Estradiol in Premenstrual Asthma: A Double-Blind, Randomized, Placebo-Controlled, Crossover Study Mary H. H. Ensom, Pharm.D., FASHP, FCCP, FCSHP, Gina Chong, Danyi Zhou, M.D., Bev Beaudin, R.R.T., Stephen Shalansky, Pharm.D., FCSHP, and Tony R. Bai, M.D. Study Objectives. To characterize asthma symptoms and pulmonary function throughout two menstrual cycles, with and without exogenous estradiol administration, in women with premenstrual asthma, and to determine the effect of estradiol administration on asthma symptoms, pulmonary function, quality of life, and biomarkers of airway inflammation. Design. Double-blind, randomized, placebo-controlled, crossover study. Setting. Respiratory clinic and clinical research center. Subjects. Twelve women with documented premenstrual asthma (≥ 20% premenstrual worsening of asthma symptoms and/or of peak expiratory flow [PEF] during a 1-month screening phase). Intervention. Each woman received either estradiol 2 mg or placebo orally between cycle days 23 and 28 (i.e., premenstrually, or before the onset of menses) in the first cycle and then crossed over to the other arm in the second cycle. Throughout both cycles, the women recorded daily morning and evening PEF readings and asthma symptoms. Measurements and Main Results. Spirometry testing and measurement of serum estradiol and biomarkers of airway inflammation were performed on days 8 (follicular phase), 22 (luteal phase), and 28 (premenstrually) of both the estradiol and placebo cycles. During the two premenstrual visits, the Asthma Quality of Life Questionnaire was administered. No notable differences were observed between the estradiol and placebo cycles in daily PEF recordings or composite asthma symptoms scores. The area under the curve (AUC) for the composite asthma symptoms versus time profile was numerically, but not statistically, lower (denoting less severe symptoms) during the estradiol cycle than during the placebo cycle. Likewise, no significant difference in AUC values for morning PEF or evening PEF was found between the estradiol cycle and the placebo cycle. Despite differences (p0.05) were detected in quality-of-life scores (all domains 170

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Table 1. Demographics of the 12 Study Subjects Characteristic Value Age (yrs) 38.8 ± 7.1 Weight (kg) 76.7 ± 11.8 Height (cm) 163.2 ± 7.0 Baseline FEV1 (L) 2.60 ± 0.69 85.8 ± 21.6 Percentage of predicted FEV1 (L) FEV1:FVC ratio 0.74 ± 0.11

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Figure 2. Daily morning peak expiratory flow (PEF) recordings (A), evening PEF recordings (B), and composite asthma symptoms scores of estradiol and placebo cycles (C). Values are means. VAS = visual analog scales.

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Table 2. Select Parameters for Study Visits

Parameter Estradiol (pmol/L) Composite asthma symptoms scores FEV1 (L) PEF (L/min) Endothelin-1 (pg/ml) Serum EPX (ng/ml) Urine EPX (µg/mmol creatinine) Urine LTE4 (pg/mg creatinine)

Day 8 (visit 1) 332 ± 207 52 ± 49 2.58 ± 0.71 414 ± 75 3.04 ± 0.49 56 ± 95 79 ± 119 498 ± 599

Estradiol Cycle Day 22 (visit 2) 394 ± 139 52 ± 55 2.50 ± 0.66 423 ± 74 2.88 ± 0.47 47 ± 70 85 ± 124 541 ± 660

Day 28 (visit 3) 998 ± 159a 39 ± 38 2.53 ± 0.62 423 ± 78 2.80 ± 0.38 45 ± 78 87 ± 136 315 ± 129

Day 8 (visit 4) 271 ± 171 29 ± 29 2.49 ± 0.65 426 ± 78 3.11 ± 0.21 34 ± 37 74 ± 83 471 ± 539

Placebo Cycle Day 22 Day 28 (visit 5) (visit 6) 399 ± 157 263 ± 154 64 ± 58 46 ± 45 2.45 ± 0.63 2.51 ± 0.67 414 ± 80 422 ± 76 3.06 ± 0.30 3.03 ± 0.30 41 ± 47 46 ± 74 68 ± 83 65 ± 81 372 ± 192 315 ± 126

Data are mean ± SD. FEV1 = forced expiratory volume in 1 second; PEF = peak expiratory flow; EPX = eosinophil protein X; LTE4 = leukotriene E4. a p0.05) were detected other than for estradiol concentrations (p