Twenty to thirty-five percent of women with asthma have pre- or perimenstrual worsening of asthma, but asthma exacerbations were independent of cyclic hormonal changes [40–44]. Estrogen and progesterone concentrations oscillate throughout with menstrual cycle, and these fluctuations in hormonal concentrations are thought to be potentially linked to changes in asthma symptoms. As shown in Fig. 4.3, estrogen concentrations peak on day 13 of a 28-day menstrual cycle, just prior to ovulation, and progesterone concentrations peak at days 22–24, four to six days prior to menses. Asthma symptoms are increased in the premenstrual phase of the cycle (days 25–28) when both estrogen and progesterone concentrations are low (Fig. 4.3). Clinical studies tracking asthma symptoms and peak expiratory flow rates in women through at least two menstrual cycles found increased symptoms and decreased peak flow rates in the morning during the premenstrual and perimenstrual phases of the cycle compared to other phases of the cycle [40, 43]. Women with premenstrual asthma symptoms had increased fractional exhaled nitric oxide (FeNO) , a noninvasive measure of epithelial induced nitric oxide that correlates with eosinophilic inflammation [45], and eosinophils in the sputum in the premenstrual phase compared to the seventh day of their cycle [46]. However, no difference in the phase of the menstrual cycle of women requiring emergency department visits for asthma symptoms was reported [44]. Combined, these studies suggest a subset of women with asthma have increased premenstrual asthma symptoms and decreased peak expiratory flow rates, but no change in asthma exacerbations during premenstrual phase of their cycle.

Use of certain hormonal birth controls pills reduced the fluctuations of hormone levels and could potentially reduce pre- and perimenstrual asthma symptoms in women with asthma.

However, only a few studies, with small patient sizes, have been conducted to determine the effect of hormonal birth control medications on asthma symptoms through the menstrual cycle. One study followed 18 women with asthma through two menstrual cycles. Women not taking oral contraceptives (n = 9) had increased AHR to adenosine monophosphate during the luteal phase and reduced diurnal peak expiratory flow rates. However, women taking oral contraceptives medications (n = 9) did not have a significant increase in AHR to adenosine monophosphate or significant changes in morning and afternoon peak flow rates [47]. Another study followed 28 women with asthma for 12 weeks (2–4 menstrual cycles) and found no difference in asthma symptoms in women taking oral contraceptives versus women not taking oral contraceptives [48]. Therefore, additional studies, with larger patient populations that stratify different types of hormonal birth control medications, are needed to fully delineate if asthma symptoms are reduced in women taking hormonal contraceptives.

Asthma is a common chronic condition present during pregnancy with a 3.7–8.4 % prevalence among pregnant women [49]. Variations in asthma symptoms and asthma control during pregnancy are common. Two studies from the late 1980s reported that in pregnant women with asthma approximately one-third had decreased asthma symptoms, one-third had increased asthma symptoms, and one-third had no change in asthma symptoms [50, 51]. Since that time, there has been little improvement on predicting if asthma symptoms will increase, decrease, or remain the same in pregnant women. Researchers have shown that compared to women with mild asthma phenotypes, women with severe asthma were more likely to experience increased asthma symptoms later in the pregnancy, in the second and third trimesters [52]. Pregnant women with asthma were also more susceptible to respiratory viral infections, including rhinovirus and influenza, and viral infections increase asthma exacerbations [53, 54]. Variations in asthma symptoms and control in pregnant women are not fully understood, but are likely related to various phenotypes of asthma, hormonal changes during pregnancy, and adherence to asthma medications. Many pregnant women with asthma decide, either individually or as advised by their medical provider, to reduce or stop asthma medications to prevent adverse side effects on the fetus. However, National Heart , Lung, and Blood Institute and the Global Initiative for Asthma (GINA) guidelines indicate that pregnant women should maintain their current regimen of asthma medications, including inhaled corticosteroids, long-acting beta agonist, leukotriene modifiers, theophylline, and oral corticosteroids [55, 56]. Use of asthma medications during pregnancy was not associated with fetal abnormalities [57], and maintaining asthma control during pregnancy is important. More severe asthma, poorly controlled asthma, and asthma exacerbations during pregnancy are associated with increased risk for development of preeclampsia and gestational diabetes in the mother and preterm birth, low birth weight, and perinatal mortality for the baby [55, 57, 58].

As described above, ovarian hormones are associated with asthma. Therefore, one would predict that the decline in circulating ovarian hormones that occurs with menopause leads to decreased asthma in women. However, studies in menopausal women report variable findings, with asthma symptoms increasing, decreasing, or remaining the same when compared to premenopausal women or postmenopausal women on hormone replacement therapy (HRT) (as reviewed in [59]). The US Nurses’ Health Study was a prospective study which followed 41,202 premenopausal women and 23,035 postmenopausal women from 1980 until 1990 [6]. Women were reclassified as pre- or postmenopausal every 2 years based on questionnaire responses. At the end of the study, 582,135 person-years were documented with 726 new cases of asthma. The US Nurses’ Health Study determined that postmenopausal women who never used HRT had a significant decrease in the risk of developing asthma compared to premenopausal women [6]. Further, postmenopausal women who used HRT had an increased age-adjusted risk for asthma compared to postmenopausal women who never used HRT [6]. The European Community Respiratory Healthy Surveys (ECRHS I) also conducted a study and reported no difference in self-reported asthma between premenopausal and postmenopausal women not taking HRT [60]. However, the ECRHSII cross-sectional study reported increased asthma symptoms in women during the menopause transition (amenorrhea for 6+ months) compared to premenopausal women [61]. Further, the ECRHSII study reported increased asthma severity in women diagnosed with asthma during or after menopause [62]. Combined, these studies suggest menopause and HRT are involved in asthma pathogenesis, but the mechanisms are not completely understood. Co-variables, including BMI, genetic factors, estrogen production from adipose tissue, and insulin sensitivity, need to also be considered in future study design.

At baseline naïve mice have very few lymphocytes, neutrophils, and eosinophils in the bronchoalveolar lavage (BAL) fluid [63], and there is no sexual dimorphism in the percentages of baseline leukocytes in naïve mice [64]. However, baseline AHR is increased in male mice compared to female mice in both the BALB/c and C57BL/6 strains of mice [64]. ER-α-deficient mice (ER-α KO) have increased AHR compared to WT female mice [65, 66], and using an estrogen antagonist increased AHR compared to vehicle control [67]. Conversely, administering 17β-estradiol to male mice decreased AHR compared to vehicle control [67].

Researchers speculated that the increased AHR in male mice is due to male mice having decreased numbers of alveoli and decreased alveolar surface area compared to female mice [68]. To test this hypothesis, female mice were ovariectomized just after weaning (approximately 21 days) and similar alveolar structures were seen in ovariectomized female and male mice, suggesting sex hormones were important in the development of alveoli [68, 69]. Additional studies in ER-α and ER-β KO mice showed ER-α and ER-β signaling is required for fully developing alveolar structures in female mice, and that ER-β KO mice have decreased elastic recoil compared to WT female mice [69]. Increased numbers of alveoli and alveolar surface area may be responsible for the observed sex difference in AHR, and normalization for lung volume and size in a statistical model resulted in no difference in AHR between males and females.

Other factors including variations in vagal nerve-mediated pathways and smooth muscle contractility may also contribute to sex differences in AHR after stimulation. Vagal nerve-mediated pathways are increased in response to methacholine and carbachol, chemicals known to increase smooth muscle contractility, in male mice compared to female mice [70]. Gonadectomized male mice also had similar vagal nerve responses as intact female mice, and restoring androgens to gonadectomized male mice increased the vagal nerve response and AHR to methacholine [70], suggesting androgens increased the vagal nerve response. However, no difference in ex vivo smooth muscle contractility assays to carbachol was reported in tracheal rings from male and female mice. Further, ER-α KO mice and WT female mice had similar smooth muscle contractility to carbachol [70]. Combined, these results suggest sex hormones affect baseline AHR in mice independent of smooth muscle constriction.

Dryness of the throat and vaginal dryness are symptoms reported by women during menopause. These symptoms suggest that sex hormones may affect mucous cell metaplasia and mucus production in the airway and the reproductive system. Therefore, researchers became interested in the role of estrogen and progesterone on mucus production in the nasal and airway epithelial cells . In 1975, Helmi and colleagues administered 10 μg/day ethynyl estradiol, a downstream hormone of the 17β-estradiol, to guinea pigs and measured mucous cell hyperplasia and metaplasia in nasal epithelial cells by histochemical staining. Guinea pigs administered ethynyl estradiol had increased mucous cell hyperplasia and metaplasia compared to vehicle-treated animals [71]. In vitro studies in human airway or nasal epithelial cells also showed that estrogen or progesterone increased mucus production and the expression of the mucus proteins, Muc5AC and Muc5B, compared to vehicle-treated cells [72, 73]. In summary, sex hormones regulate baseline airway responsiveness to methacholine as well as mucus production. Acknowledging baseline differences is vital for experiment design and interpretation of data as normalizing experimental results to percent baseline may not provide the most accurate interpretation of data.

During ongoing allergic airway inflammation the role of sex hormones varies based on the protocol used to induce allergic airway inflammation and the endpoint measured. The results discussed in the paragraphs below are summarized in Table 4.2. Two widely used models of allergic airway inflammation are: (1) ovalbumin (OVA) sensitization followed by OVA challenge and (2) exposure to house dust mite (HDM) antigen. Both these models increase airway inflammation, AHR, and mucus hypersecretion through a CD4+ Th2 cell-mediated mechanism. Female mice undergoing the OVA sensitized and challenged protocol or the HDM protocols had increased eosinophilic infiltration and IgE serum levels compared to male mice undergoing the same protocol [74–76]. Female mice with OVA-induced allergic airway inflammation also had significantly increased lung IL-4, IL-5, and IL-13 protein expression, mucous cell metaplasia, and airway remodeling compared to male mice [74–76]. Further, castration of male mice prior to OVA sensitization and challenge increased eosinophils and lymphocytes in the BAL fluid, mucous cell metaplasia, and airway inflammation compared to sham-operated mice [75]. However, an ovariectomy prior to OVA sensitization decreased OVA-induced airway inflammation and AHR compared to intact female BALB/c mice [77]. These results suggest that ovarian sex hormones increased, while testosterone decreased, allergic airway inflammation, AHR, and mucous cell metaplasia.