1. Asthma in Young Female Adolescents
Globally, in people aged 10 to 24 years, respiratory disorders are the sixth leading cause of disability; in 2011, it was estimated that asthma was responsible for 346,000 deaths worldwide each year
[1][2]. In pediatric age, the prevalence of asthma is higher in males than in females; however, in adulthood, the prevalence is approximately 20% higher in females than in males, indicating a change that occurs during puberty
[3][4]. The higher prevalence in boys is, in part due, to their smaller airways relative to lung size compared with young girls; however, this is a characteristic that reverses during adolescence
[3].
The Global Initiative for Asthma (GINA) guidelines describe asthma as a heterogeneous disease
[5], usually characterized by chronic airway inflammation
[6]. Variability in symptoms and airflow limitation is a feature of asthma that can vary in time and intensity
[5]. Clusters of demographic, clinical, and pathophysiologic characteristics identify asthma phenotypes and endotypes. No strong relationship has been found between specific pathological features and peculiar clinical patterns and treatment responses; however, in patients with more severe asthma, some phenotype guided treatments have become available
[5][7][8][9].
Epidemiologic evidences have shown that the overall prevalence and incidence of asthma are increased in obese individuals, and obesity is a risk factor for airway inflammation
[1][10][11][12][13][14]. A recent meta-analysis, including six prospective cohort studies on the effect of body weight on future asthma risk, found a twice-higher risk in obese children compared with normal-weight ones, suggesting that obesity is an independent asthma risk factor for the youngest
[15][16]. Clinical studies also suggest that obesity-related asthma is distinct from normal-weight asthma: it is associated to decreased responsiveness to medications
[17] and poor disease control
[14][15][18], particularly among ethnic-minority children
[18][19], contributing to increased healthcare expenditures
[15]. In terms of ethnic and gender differences, it has been observed that Hispanics and African Americans, who have a higher burden of obesity-related asthma, tend to have central obesity more frequently, for the same body weight, than Caucasians
[15][20], and obese girls are more symptomatic
[21][22] than boys
[23]. Visceral obesity is responsible for a picture of mechanical obstruction in the lungs, resulting in airflow obstruction and altered lung volumes
[15]. The relationship between obesity and asthma is complex
[10][24]. In the Severe Asthma Research Program, an age/phenotype-dependent association was found: children with early onset asthma became obese, whereas there was no significant relationship between overweight/obesity and asthma duration in cases of late-onset asthma
[1][25]. In the Asthma Adiposity Study conducted by Kattan et al.
[19] among 368 adolescents aged 12 to 20 years living in urban areas of the United States, the main finding was the association between adiposity and asthma morbidity
[19]. In female adolescents, higher BMI and body fat correlated with worse asthma control, more disease exacerbations, and a lower Tiffenau index (forced expiration, FEV1/forced vital capacity, FVC)
[19]. In addition, obese girls, in contrast to boys, lacked the anti-inflammatory properties of serum adiponectin. Indeed, although there were higher serum levels of adiponectin in females, its protective role was observed only in males: one plausible interpretation is that adiponectin receptors are downregulated with elevated adiposity in female adolescents
[19]. Adipokines produced by the adipose tissue are likely to mediate the association between obesity and asthma in a gender-specific manner, and asthma outcome seems to be adversely influenced by obesity in girls but not in boys
[1][19].
Despite a worldwide reduction in asthma mortality in adults and children over the past 25 years, largely attributable to increased use of inhaled corticosteroids, a wide global disparity in life years lost due to asthma remains
[3].
It is much easier to diagnose asthma in teenagers than in younger children. A narrower range of conditions should be considered in the differential diagnosis of the adolescent who presents with recurrent cough, dyspnea, or wheezing
[26]. In contrast to preschoolers, it is possible to assess lung function at baseline and in response to bronchodilators or exercise for objective evidence of reversible airway narrowing. However, both under-diagnosis and under-treatment are common
[26][27]. Of note, in a Danish study, it has been shown that girls were 50% more likely to have underdiagnosed asthma than boys (69% vs. 33%), and coughing rather than wheezing or breathlessness was the major symptom
[28].
Remission of asthma frequently occurs, especially in late adolescence, with reported rates of 16% to 60%
[29]. In several population-based studies, remission probability of asthmatic disease in late adolescence was commonly observed and showed a relationship with mild disease, male sex, and absence of atopic trait, particularly sensitization to fur-bearing animals at the age of 7 or 8 years
[1][30]. In a prospective study conducted in Sweden since 1996 in people followed from 7 or 8 to 19 years of age, 21% of those with asthma at age 7 were in remission at 19 years old, 38% had periodic asthma, and 41% had persistent asthma
[30]; these results were similar to those of other studies
[29][31][32][33][34]. Conversely, sensitization and female sex have been identified as important predictors of persistent asthma in several studies
[31][35] In addition, along with a higher incidence among girls
[36], the higher remission rate among boys contributes to the change in asthma prevalence ratio between boys and girls. That notwithstanding, puberty is the turning point with male prevalence in early childhood and a more prevalent asthma among women later in life
[30]. Other relevant risk factors for pubertal asthma include early airway obstruction, sensitization to fur-bearing animals, more severe asthma in childhood, family history of atopy, being the first-born child, perinatal family stress, extreme preterm birth (23–27 gestational weeks), and low birth weight per gestational age
[1][30][35][37][38][39][40]. In young females, early menarche (before 12 years of age) has been associated with an up to two-fold increased risk of new onset asthma
[41][42]. However, the role of heredity, sex, smoking, and sensitization to specific allergens remains to be further investigated
[1][43][44][45][46][47].
As far as the role of sex is concerned, both incidence and prevalence of asthma vary accordingly; in addition, age-related changes in sex prevalence are observed
[1][48]. Sex differences play a key role in driving numerous conditions, including cardiovascular diseases and, specifically, atherosclerosis
[49]; bone metabolism disorders, such as osteoporosis
[50]; and some neurological pathologies
[51]. Sex hormones are responsible for the expression of such gender differences at the phenotypic and genotypic level
[52], including the regulation of airway function and inflammation
[52]. Indeed, it has been observed that estrogens are able to prevent cholinergic constriction of asthmatic tracheal rings in vitro
[53], and estrogen treatment decreases airway responsiveness to acetylcholine in ovariectomized rats
[54]. Female rats appear to be more susceptible than males to allergen-induced airway inflammation
[55][56][57]. By examining sex differences in a scenario of allergen exposure delivered exclusively through the airway and in the absence of systemic sensitization and adjuvant, thus dependent solely on IgE, Fc epsilon receptor (FceRI), and mast cells
[52], the inhibitory effects of estrogen on airway hyper-responsiveness (AHR) development are evident
[53][54][58][59]. In contrast, when dual allergen sensitization with systemic adjuvant and airway sensitization occurs, female mice develop greater AHR, with estrogen increasing airway inflammation
[56][57][60]. Carey et al. also demonstrated that estrogen receptor deficiency led to increased AHR
[58].
Unquestionably, female sex hormones, particularly estrogens, play a key role in the pathophysiology of asthma and the development AHR.
Estrogens participate in various biological processes through different molecular actions. They may show either pro- or anti-inflammatory properties depending on the circumstances and the involved tissues.
Lowered levels of estrogens increase the concentration of reactive oxygen species, along with the inhibition of NF-KB transcription factor, indicating their prevalent anti-inflammatory properties.
On the other hand, estrogen therapy in ovariectomyzed mice reduces reactive oxygen species-induced by ovariectomy in bone marrow
[61][62], attenuating the phosphorylation of PKC β (redox-sensitive cytoplasmic kinase)
[61][62].
It is well-known that female patients of all ages endure remarkably lower rates of infection and resultant mortality than male subjects.
Immunological evidences suggest that female sex hormones are key factors in the etiology and course of chronic inflammatory diseases, being linked to significant influencing reproductive stages, such as menstrual cycle, pregnancy, perimenopause, and postmenopausal status
[63][64][65][66]. Estrogens and their specific receptors influence systemic immune response by reducing the cytokine-driven cortisol and ACTH release, by increasing substance P signaling and responsiveness to noxious stimulation (increase of neurogenic inflammation).
Estrogen receptors α and β could have different effects depending on the cell type. The connection between estrogens and their receptors acts on monocyte differentiation along with inflammatory mediator production by macrophages
[67][68][69]. Estrogens, in particular, 17 β-estradiol (E2), protect neuronal cells against toxic insults, inducing the expression of growth factors and their receptors, as well as proteins and cells involved in apoptosis
[67][68][69].
The prevalence of asthma is higher in males before puberty, with a reversal in adulthood, when it is more common in women, who have a higher risk of having severe asthma, as well as greater susceptibility to the harmful effects of smoking
[1][70][71][72]. There is no single direct mechanism responsible for gender differences, but several etiologies have been proposed, including gender-specific dysinaptic lung growth, female and male hormonal influences, genetic susceptibility, immune response, and differences in consultation practices
[1][58][73][74][75]. Studies showing changes in lung structure and function at key life stages, such as puberty, suggest a modulatory role of sex steroids in the phenomenon of asthma transitions
[1]. Indeed, sex hormones are known to have both biological and pathophysiological actions on several non-reproductive organs, including the lung
[76]. Moreover, pulmonary function appears to undergo alterations during the menstrual cycle, with worsening of asthma when sex hormones decline premenstrually
[77][78]. Moreover, a number of women who have moderate asthma report relief of their premenstrual exacerbations by taking oral contraceptives, which suppress wide fluctuations in circulating sex hormones
[75]. Although these preliminary clinical data seem to indicate that the hormonal milieu correlates with prevalence and severity of asthma, the role of specific hormones in determining these changes is unclear. In particular, the effects of estrogens in asthma have been discordant
[56][57][58]. On one side, supplementation with estrogens has been used beneficially as sparing steroids in women with asthma. Conversely, postmenopausal estrogen therapy increased the subsequent risk of asthma, and several lines of evidence report worsening of asthma during the premenstrual and intra-menstrual periods
[47][77][79][80][81][82].
Even progesterone may play a role in the exacerbation of asthma symptoms
[83]. Indeed, progesterone can influence airway smooth muscle tone and inflammation. Moreover, a progestogen hypersensitivity, characterized by a spectrum of symptoms ranging from urticaria to asthma and systemic anaphylaxis, has been described
[83].
In addition, from a therapeutic point of view, there is evidence suggesting that the response to inhaled corticosteroid may be gender-specific: in particular, women are less likely to have uncontrolled persistent asthma
[84]; the underlying rational is currently not understood
[1][85].
Besides the intrinsic risk factors mentioned above, extrinsic risk factors, such as environmental pollution and cigarette smoking, also play a major role on asthma incidence and severity
[86][87][88]. Furthermore, females seem to have a greater susceptibility to the effects of smoking
[1], which, whether occasional or not, is a serious risk factor for adolescents with asthma, and smoking rates in this vulnerable population remain high
[1][89]. Early exposure to secondhand smoke, whether in utero or during childhood, influences the development of allergic disease into adolescence
[90]. Guerra et al., who conducted a prospective study from birth to age 26, recently demonstrated that active and parental smoking act synergistically to influence early deficits in lung function in young adulthood
[91]. In addition, in asthmatic individuals, tobacco smoking is associated with accelerated decline in lung function, decreased disease control, and reduced benefit from corticosteroid treatment
[92]. Although electronic cigarettes (e-cigs), as compared to traditional ones, contain fewer carcinogens and cause fewer acute lung effects in both healthy individuals and asthmatics, they are still not totally harmless, as they contain formaldehyde and other toxins that are still poorly understood
[93][94]. Moreover, e-cigs could offer an alternative to cannabis use for youth
[1][95]. However, due to the absence of complete scientific studies related to cannabinoid vaping, health consequences remain largely unknown and hypothetical; therefore, the most significant health concerns are for children and adolescents
[95]. In addition, smoking cannabinoids could lead to environmental and passive contamination
[95].
Adolescence is a period fraught with expectation for the youngest, in which social, sexual, and intellectual maturation occurs, followed by a progressive greater level of autonomy
[96]. Nevertheless, this autonomy is frustrated by parental and physician dependence for asthma care, medication, and the need for continued follow-up
[96]. Asthma, and how it is managed, can impede these processes and intensify the stress that is already an integral part of ordinary adolescence
[26].
Anxiety and depression are clinically linked to asthma in this life period
[97][98][99], being typically associated with lower adherence to daily monitoring of asthma symptoms
[98][100][101]. Social anxiety disorder (SAD), one of the most common anxiety disorders in adolescents, is typically characterized by intense fear of social situations, anxiety, or avoidance; all of which lead to significant impairment (e.g., few friends, loneliness, depressed mood, poor school performance, and difficulty with interpersonal relationships)
[101][102]. SAD can be particularly disabling during adolescence because peers play a critical role in social and identity development at this stage
[101][103]. Adolescents with asthma are then at high risk for social anxiety. These youth report feeling different and isolated from their peers, fearing peer rejection and having poor social competence
[102][104][105][106][107]. In addition, social anxiety may decrease compliance with treatment regimens that require taking medications in front of others (e.g., taking rapid-release medications before exercise or exposure to other triggers), because adolescents are worried about being accepted by peers
[101]. Overall, anxiety disorders, such as panic disorder (PD), are up to twice as prevalent in females as in males
[108], and it appears that a gender-specific susceptibility is responsible for their development. Sex hormonal changes occurring in the premenstrual phase represent a neuromodulatory signal in the onset and maintenance of maladaptive or clinical anxiety and other mental disorders in the female sex
[109][110][111][112][113]. Indeed, in some
[80][114][115] but not in all
[77] studies, women with PMA showed a higher incidence of premenstrual syndrome if compared with a control asthma group
[116]. Dysphoric symptoms or general discomfort preceding menstruation
[114] could contribute to self-reported perimenstrual worsening of asthma: women with PMS might have an altered perception of asthmatic symptoms in the premenstrual phase, and emotional changes may influence lung function up to precipitation of asthmatic attacks
[116]. In a study conducted by Richardson et al.
[98], involving subjects aged 11–17 years, youth with an anxiety or depressive disorder were, among other things, more frequently girls and had a more recent diagnosis of asthma. Furthermore, in the same research by Richardson et al.
[98], youth with an anxiety or depressive disorder reported, on average, more days of symptoms than the other participants without either of these disorders (5.4 vs. 3.5 days). Among other factors significantly and independently associated with increased symptom days, there was the female sex.
Figure 1 summarizes risk factors for asthma in young female adolescents.
Figure 1. Risk factors for asthma in young female adolescents.
3. Perimenstrual Asthma and Sex Hormones
Various studies, including the PIAMA (Prevention and Incidence of Asthma and Mite Allergy) study, have shown that there is a gender difference in asthma that varies with age
[130].
The PIAMA study
[112] enlisted 4146 pregnant women and assessed 3308 of their children yearly for wheezing and asthma, using questionnaires. Males showed an increased incidence of wheezing compared to females. At the age of 8, 15.1% of the male patients and 10.8% of the female patients had asthma, suggesting that the gender difference in asthma could begin early in infancy. Males also showed more atopic symptoms, measured by specific IgE or skin-prick testing to common allergens, compared to female patients prior to adolescence
[48][130][131][132][133][134]. Another study showed that phytohemagglutinin-induced mononuclear cells from males, compared to females, have remarkably increased IFN-γ, IL-5, and IL-13 in children that showed wheezing at 3 years of life. Increased rates of sensitization, total IgE levels, and blood eosinophil counts were higher in males. The disproportionate growth between lung size and airway caliber has also been detected more often in male patients
[132][135]. Therefore, a more robust immune response and a decreased airway size likely contribute to increased wheezing in young males compared to females.
Various studies have shown that hospital admissions for asthma are similar by sex in the early teenage years (10 to 13 years of age), but they are up to three times higher in females than males between 20 to 50 years. It is also reported that, after menopause, the incidence of asthma decreases balancing again with men
[70][123][124].
Sex hormones are known to be effective modulators of immune responses and inflammatory-associated diseases
[136][137][138].
Estrogens play a key role in influencing the course of various autoimmune diseases, as well as infectious processes (viral, bacterial, and others), exerting their actions through the estrogen receptor alpha and beta, as ultimately expressed by several immune cells
[138].
Classical estrogen receptors (ER) ERα and ERβ are members of the superfamily of nuclear receptors. The binding of a ligand to ERα or ERβ triggers receptor activation, dimerization, and translocation from the cytoplasm to the nucleus. Here, the hormone-receptor complex recruits co-regulators and binds to estrogen receptor elements (ERE) of targeted genes, thus modulating gene transcription (genomic mechanism)
[139]. More recently, researchers identified the membrane estrogen receptor GPR30 or GPER, a 7-transmembrane G-protein-coupled receptor that activates intracellular signaling cascades, including MAPK, ERK1/2, and PI3K pathways
[76][140]. Thus, rapid nongenomic mechanisms through secondary messengers determine variations in cellular enzymatic pathways, ion channel, and intracellular calcium levels, and they also result in transcriptional modulation
[76][141].
Experimental evidence suggests that ERs are involved in lung development
[141]. Indeed, ERα modulates alveolar regeneration and alveolar size and number, while ERβ induces normal elastic tissue recoil through regulation of extracellular matrix
[142]. In human lung tissue, ERα and ERβ are expressed in bronchial epithelial cells
[76], as well as in various immune cells, including macrophages, lymphocyte, and dendritic cells
[143]. It has been demonstrated that ERβ activation modulates airway inflammation and negatively regulates eosinophilic airway infiltration during asthma
[144]. GPER also exerts a negative control on airway inflammation through IL-10
[145]. ERs activation in both vascular endothelial cells (especially ERα) and bronchial epithelial cells (especially ERβ) leads to nitric oxide synthesis and subsequent vasodilation or bronchodilation, respectively
[76]. ERα and ERβ are expressed also in human airway smooth muscle (ASM) cells: it was observed that asthmatic subjects manifest an increased ERs expression in ASM which concerns especially ERβ subtype
[146]. A murine model of asthma revealed pronounced airway fibrosis and ASM hypertrophy, leading to airway hyper-reactivity (AHR) and remodeling. Interestingly, this condition reversed with ERβ activation
[144][147] and downregulation of extracellular matrix proteins
[148]. Furthermore, it was observed that ERβ activation diminishes ASM thickness through the negative regulation of PDGF (platelet derived growth factor)-induced proliferation in human ASM cells
[147]. According to these evidences, in a recent study on mice, it was confirmed that asthmatic phenotype was associated to airway remodeling and subsequent AHR. In that context, ERs may play a major downregulating role, in which the activation of ERβ (but not ERα) resulted in decreased remodeling and AHR
[144].
Patients with asthma generally show allergic airway inflammation characterized by type-2-mediated airway inflammation, but some patients show low type-2-mediated airway inflammation with increased neutrophils concentration caused by type 1 or IL17-mediated airway inflammation
[149][150]. Type 2 allergic airway inflammation starts with exposures to allergens, including dust, pollen, mammalian antigens, cockroach antigens, and others, resulting in increased production of inflammatory cytokines, such as thymic IL-4, IL-25, and IL-33. Increased concentration of these co-stimulatory cytokines results in enhanced expression of proinflammatory cytokines; IL-4, IL-5, IL-13, and IL-9 produced by TCD4+ cells helper; group-2 innate lymphoid cells (ILCs); eosinophils; basophils; mast cells; macrophages; and others. The release of these cytokines leads to increased IgE-triggered hypersensitivity to allergens, activation of airway epithelial cells, activation and infiltration of eosinophils, mucus production, and AHR. Increased secretion of IL-17A, a cytokine secreted by CD4+ Th17 cells and other cell types, also leads to increased airway inflammation and hyper-responsiveness
[151].
Such an immune response can be modulated by hormonal milieu during different stages in life, from puberty to menopause
[136][137][138]. Thus, sex-hormone fluctuations seem to play a key role in respiratory health, leading to asthma exacerbations, suggesting the need of monitoring hormonal changes in asthmatic female patients.
During puberty, testes increase testosterone production, along with adrenal glands producing androgens, leading reproductive organs to mature and muscle and bone to grow. For what concerns females, there is an increase in the production of estrogen from the ovaries (driving thelarche and menarche), along with FSH and LH, and androgens (androstenedione and DHEA-S) from the adrenal glands.
Hyperandrogenism may be present in some adolescents more likely suffering from polycystic ovary syndrome (PCOS), a medical condition showing a certain degree of comorbidity with asthma
[152], especially in overweight and obese adolescents
[153].
The androgen overproduction with puberty seems to confer protection on lung growth in both males and females, while estrogens may well have negative effects in females extending into adulthood.
It has been observed that progesterone is the pivotal hormone in the perimenstrual phase, which is also when this specific asthma phenotype occurs
[154]. Patients with PMA frequently show impairment in periodic fluctuations in serum progesterone concentrations
[155][156]. Progesterone, as well as all other steroid hormones, is synthesized from pregnenolone. Progesterone is an aldosterone precursor, which, in turn, can be converted into testosterone
[157]. Some data have shown that low testosterone levels can significantly impair immune responses and airway smooth-muscle reactivity, either through genomic or non-genomic mechanisms
[125][158].
De Boer et al.
[125] studied 116 males and 71 females, showing that female patients had post-bronchodilator FEV1% and FVC% significantly lower (by 8.9% and 9.1% respectively) than the same values seen in male patients from pre-/early to mid-/late puberty, as determined by breast development (differences attributed by Tanner stage). For what concerned female patients between 6 and 18 years of age, androgens correlated positively with lung function, whereas estrogens did not. Free testosterone had a favorable connection with post-bronchodilator FEV1%. On the other hand, estradiol showed negative coefficients for pre- and post-bronchodilator FEV1% and FVC%.
Moreover, DHEAS, which works as an inhibitor of the airway smooth muscle and fibroblast proliferation, influences airway epithelial-to-mesenchymal transition and even prevents airway remodeling observed in severe asthma. All of these effects, in association with the increased levels of DHEA-S reported in male subjects during late adolescence, may explain lower symptoms in case of hyperandrogenism.
These data suggest that the high rate of asthma exacerbations in females during late adolescence is due to the negative role of estradiol; it also consolidates the benefit of androgens, which are quite low in females
[125].
Studies showed reacutization of asthma symptoms, reduced peak flow rates, and increased use of quick-relief medications in nearly 40% of female patients with asthma during the pre- or perimenstrual phase of the cycle
[77][78][115][159][160].
As far as the use of contraceptive measures is concerned, some studies, such as the SAPALDIA (Swiss cohort study on Air Pollution And Lung Disease in Adults)
[161], showed a reduction in methacoline-induced airway hyper-responsiveness in pill users. DHEA, which is ultimately converted into androgens and estrogens, has been tested in animal studies in order to explore its asthma-related role. It happened to lower the airway eosinophils, along with IL-4 and -5 serum levels in mice fed with it
[162][163]. Nebulized dehydroepiandrosterone-3-sulfate, when used as a medication in moderate-to-severe asthmatic patients seemed to improve asthma control. Surely, further studies are needed in order to evaluate the possible therapeutic use of such hormonal compounds in asthmatic patients
[164].
It appears clear that sex hormones have an important role in the immune system in many autoimmune and/or allergic diseases, including asthma. Therefore, gender differences in asthma prevalence coincide with modifications in sex hormones levels, highlighting their key role in regulating PMA asthma pathogenesis.