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The role of female hormones on lung function in chronic lung diseases Tam, Anthony; Morrish, Don; Wadsworth, Samuel; Dorscheid, Delbert; Man, SF P; Sin, Don D Jun 3, 2011

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REVIEW Open AccessThe role of female hormones on lung function inchronic lung diseasesAnthony Tam1, Don Morrish2, Samuel Wadsworth1, Delbert Dorscheid1, SF Paul Man1 and Don D Sin1*AbstractBackground: The prevalence, morbidity, and mortality of inflammatory lung diseases such as asthma, chronicobstructive pulmonary disease (COPD) and cystic fibrosis (CF) are increasing in women. There is a dearth of dataon the biological mechanisms to explain such observations. However, some large epidemiologic studies suggestthat lung function fluctuates during the menstrual cycle in female patients with airways disease but not in womenwithout disease, suggesting that circulating estradiol and progesterone may be involved in this process.Discussion: In asthma, estradiol shuttles adaptive immunity towards the TH2 phenotype while in smokersestrogens may be involved in the generation of toxic intermediate metabolites in the airways of female smokers,which may be relevant in COPD pathogenesis. In CF, estradiol has been demonstrated to up-regulate MUC5B genein human airway epithelial cells and inhibit chloride secretion in the airways. Progesterone may augment airwayinflammation.Summary: Taken together, clinical and in-vivo data have demonstrated a sex-related difference in that femalesmay be more susceptible to the pathogenesis of lung diseases. In this paper, we review the effect of female sexhormones in the context of these inflammatory airway diseases.Keywords: lung function, menstrual cycle, sex hormones, asthma, cystic fibrosis, COPDBackgroundThe sex differences in the epidemiology of asthma, COPDand CFThere is an epidemic of inflammatory lung diseases suchas asthma, chronic obstructive pulmonary disease(COPD) and cystic fibrosis (CF). Although these condi-tions have distinct pathophysiologies, women for largelyunknown reasons are increasingly becoming more pre-valent and experiencing excess morbidity and mortalityfrom these disorders. For instance, in the United States(U.S.) and elsewhere, more than 60% of all adult patientswith asthma are women, and female compared to maleasthmatics are 50% more likely to have physician visits,35% more likely to experience hospitalizations and 40%more likely to die from asthma [1]. Although men havehigher prevalence of COPD than women, the increasedrates of cigarette smoking in females within the lastseveral decades have been associated with steadilyincreasing rates of COPD in females [2]. In 2000, forthe first time, the number of women dying of COPD inthe United States surpassed the number of men [3].Even in cases in which cigarette smoking is implicated,women develop COPD after smoking fewer number ofcigarettes per lifetime (i.e. less pack-years of smoking)[4] and are two to three times more likely to experiencehospitalization than are male patients [5]. Among first-degree relatives of patients with severe COPD, femalesmoking relatives demonstrate significantly lower lungfunction compared to male smoking relatives [6]. Inpatients with severe COPD with oxygen dependence,women have a 50% increase in the risk of mortalitycompared to men [7]. Finally, although CF is a raregenetic disorder that affects both men and women, forlargely unclear reasons, female patients have shorter lifeexpectancy compared to male patients (Figure 1). Col-lectively, these epidemiologic data suggest that femalegender is a significant risk factor for morbidity and mor-tality in inflammatory lung diseases and raise the possi-bility that sex-related hormones may be important in* Correspondence: don.sin@hli.ubc.ca1The UBC James Hogg Research Centre, Providence Heart + Lung Centre &Department of Medicine, University of British Columbia (UBC), Vancouver, BC,CanadaFull list of author information is available at the end of the articleTam et al. BMC Women?’?s Health 2011, 11:24http://www.biomedcentral.com/1472-6874/11/24© 2011 Tam et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.mediating disease progression in asthma, COPD and CF,though the mechanisms by which this occurs may differbetween these disorders. In this paper, we will examinethe potential role of estrogen and progesterone in thepathogenesis of these disorders.Biology of sex hormonesEstrogen and progesteroneSteroid hormones are primarily synthesized in thegonads, adrenal glands, and the feto-placental unit [9].Cholesterol is the common precursor of all steroid hor-mones where it is first converted to pregnenolone byP450-linked side chain cleaving enzyme (P450ssc)(Figure 2A). Pregnenolone is then converted to proges-terone, which is used to synthesize androgens and estro-gens [10]. Estrogens are derived from androgens by theaddition of an aromatic A ring, through a reaction thatis catalyzed by the enzyme aromatase [10,11]. Estrogenand progesterone are multi-ringed structures with dis-tinct functional groups (Figure 2B, C, D, E). Unlike pro-gesterone, there are three major naturally occurringestrogens in women: 1) estriol, 2) estradiol, and 3)estrone. In humans, estriol is the predominant estrogenin pregnant women, while estradiol is the predominantform in the non-pregnant premenopausal women andestrone is the predominant estrogen in the menopausalfemales. Sex steroid hormones act via their own uniquereceptors: estrogen receptor (ER-a or ER-b), progester-one receptor (PR-A or PR-B), and an androgen receptor(AR) [12]. Estradiol binds with a higher affinity to ERthan its metabolic products such as estrone and estriol[13]. All sex steroid hormone receptors have beenshown to be expressed in lung tissue [14,15].Sex hormones and menstrual cycleFour main hormones characterize the menstrual cycle:estradiol (E2), progesterone (P), luteinizing hormone,and follicle stimulating hormone. On average, the men-strual cycle is 28 days and is divided in two phases: thefollicular (Day 1-13) and the luteal phase (Day 14-28).The onset of ovulation is defined by a surge in estradiolon day 14. Menstruation and the late luteal phase arecharacterized by low serum levels of estradiol (~0.15nM) and progesterone (~9.54-31.81 nM); whereas ovula-tion is marked by high circulating levels of estradiol(~0.37-1.47 nM) and low levels of progesterone (~0.95-9.54 nM) (Table 1). During the luteal phase, estradiollevels range from 0.15-0.92 nM, whereas progesteronelevels increase from 9.54-31.81 nM and drop back tolower levels prior to menstruation. However duringmenopause, estradiol and progesterone levels in bothgenders significantly reduced to levels below those inthe menstruation phase.Figure 1 Median survival ages in both sexes in CF from 1977-2002. Obtained from the Canadian Cystic Fibrosis Foundation, Report of theCanadian Patient Data Registry 2002, Toronto, Ontario [8].Tam et al. BMC Women?’?s Health 2011, 11:24http://www.biomedcentral.com/1472-6874/11/24Page 2 of 9Delivery of sex hormones to estrogen receptors in the lungsvia SHBGSex hormone binding globulin (SHBG) is an importantsteroid hormone binding protein in human plasma andregulates sex hormone delivery to tissues and cells [17].Plasma SHBG is produced primarily in hepatocytes,which is a glycosylated isoform of SHBG [18] and isproduced by the Sertoli cells [19]. In biological fluids,SHBG exists as a homodimer with a separate steroid-binding pocket and a calcium-binding site in eachmonomer [20] and binds to both androgens and estra-diol with nanomolar affinities [21]. In normal men andwomen, between 40-65% of circulating testosterone (T)and between 20-40% of circulating estradiol (E2) isbound to SHBG [22]. SHBG regulates tissue delivery ofsex hormones by binding them and retaining them inthe circulatory pool, where they are relatively inert.However, once the sex hormones dissociate from SHBG,they can escape the blood stream, and bind with theintracellular androgen or estrogen receptors, causingchanges in gene expression of cells [17]. It is thus gener-ally accepted that only the non-bound hormone is biolo-gically active [23]. SHBG is considered as an estrogenamplifier because T preferentially binds with SHBG,causing more E2 to remain unbound [17].Sex hormone receptors: lung physiologyFor many years, we have known that estrogen and proges-terone receptors are responsible for sexual development[24] but their effect beyond the reproductive system isbecoming increasingly recognized. There are two types ofestrogen receptors (ER), two types of progesterone recep-tors (PR): ER-a, ER-b, PR-A and PR-B, all of which areexpressed in rats [25], mouse [26], and humans [27].While androgen receptor (AR) is expressed primarily inmammalian reproductive tissues [28], ER-a, ER-b, PR-Aand PR-B expression have been noted in not only in themammalian female and male reproductive tracts, but alsoin the female mammary glands, bone, cardiovascular tis-sues, lung, and the brain [14,24]. In the lungs, the expres-sion of ER-b protein is twice as that of ER-a [29]. Most ofFigure 2 Used with permission from the American Physiological Society. A) Overview of the sex steroid hormone biosynthetic pathwayand associated nuclear receptors. P450ssc, P450-linked side chain cleaving enzyme; CYP17, cytochrome P450 17; 3b-HSD, 3b-hydroxysteroiddehydrogenase; 17b-HSD, 17b-hydroxysteroid dehydrogenase; PR, progesterone receptor; AR, androgen receptor; ER, estrogen receptor. B)Progesterone, C) estriol, D) estradiol, E) estrone [9].Table 1 Female hormone levels throughout the menstrual cycle [16]Phases 17b-estradiol (nM) Progesterone (nM)Day 1-13 (follicular) ~0.15-0.37 (40-100 pg/ml) ~0.95 (300 pg/ml)Day 14 (Ovulation) ~0.37-1.47 (100-400 pg/ml) ~0.95-9.54 (300-3000 pg/ml)Day 15-28 (luteal) ~0.15-0.92 (40-250 pg/ml) ~9.54-31.81 (3000-10,000 pg/ml)Tam et al. BMC Women?’?s Health 2011, 11:24http://www.biomedcentral.com/1472-6874/11/24Page 3 of 9the expression is found in the cytoplasm but minorexpression has also been noted in the mitochondria andnucleus [29]. ER-a and ER-b belong to a super-family ofnuclear hormone receptors, many of which are ligand-acti-vated transcription factors that regulate gene expressionby binding to the promoter region of genes [24]. Thesereceptors contain an N-terminal DNA binding domainand a C-terminal ligand binding domain (LBD) for estro-gen [24]. Studies in mice in which ER-a and ER-b weredeleted revealed that both types of ER are required for theformation of complete alveolar units in females. ER-aensures that the lungs differentiate properly during devel-opment, leading to normal numbers of alveoli per surfacearea. ER-b, on the other hand, modulates development ofextracellular matrix, leading to normal elastic tissue recoilpressure in the lungs [30,31]. Furthermore, ER-a, but notER-b, has been demonstrated to mediate an anti-inflam-matory response when challenged by carrageenan (CAR)in mice [32]. Upon activation by E2, ER-a inhibited theintracellular trafficking of nuclear factor-B, thereby pre-venting the expression of inflammatory genes [33].Mechanism of estrogen receptor activation in the lungsThe exact mechanism by which E2 modulates cell signal-ing pathways is not completely known and there may bemultiple cell signaling pathways by which sex hormonesaffect gene regulation and expression. According to thefree hormone hypothesis, unbound sex steroids freely dif-fuse across cell surface membranes [23]. Binding of estro-gen to the ligand binding domain of the ER causes aconformational change in the receptor, which results indimerization of ER and translocation to the nucleus [24].The activated receptor/DNA complex then binds to speci-fic promoter sequences of DNA called hormone responseelements (HREs) and recruits other cofactors from thenucleus, which results in transcription of DNA down-stream from the HRE [24]. An alternate hypothesis sug-gests that even E2 bound to SHBG are metabolicallyactive. It is now well recognized that sex steroids target tis-sues containing membrane-binding sites that can bindwith SHBG [34]. In prostate [35] and breast cancer cells, ithas been shown that by binding to this site, SHBG triggerscAMP-dependent signaling causing upregulation of adenylcyclase and other downstream signaling molecules. It isimportant to note that these data were generated in vitrousing isolated epithelial cells and not in the context ofthese cells in vivo. Thus, the exact cell signaling pathwayof sex hormones remains unknown.DiscussionHow sex hormones may modulate COPDSex hormone on cigarette smoke metabolismA variety of animal models have been used to examinepotential sex-related differences in the risk of inflamma-tory lung diseases. For example, chronic exposure of miceto cigarette smoke has led to the development of emphy-sematous-like changes in alveolar structure, and thesechanges develop more rapidly in females than in males [9].It is important to note that cigarette smoke is made up ofmore than 4,000 different chemicals. After inhalation,these chemicals are metabolized in two different phases:Phase I and Phase II. Phase I is mediated largely by cyto-chrome P450 (CYP) enzymes, which are a family of xeno-biotic enzymes that are responsible for de-toxifyingcigarette smoke and other environmental irritants intointermediate metabolites. These metabolites in turn areconjugated by Phase II enzymes and excreted. The rate-limiting step in most cases is Phase II. Thus, if there isunder-expression of Phase II enzymes or complete satura-tion of their binding sites, CYP-based metabolites accumu-late in the lung. Because some intermediate metabolitesare as toxic and others are even more toxic than their par-ent constituents, lungs may suffer oxidant damage througha process called bioactivation unless there is excellent co-ordination of Phase I and Phase II enzymes. Estradiol up-regulates CYP enzymes without necessarily altering theexpression of Phase II enzymes, making the female lungsmore susceptible to oxidant damage in response to cigar-ette smoke. This concept is supported by animal experi-ments. For instance, Van Winkle et al. showed that thelungs of female mice were more susceptible to naphtha-lene, a prominent component of side stream cigarettesmoke, compared to male mice [36]. Female lungs of ratshad higher expression of CYP enzymes and demonstratedincreased accumulation of potent oxidants from naphtha-lene metabolites [37]. Interestingly, in humans, the twoCYP enzymes that are up-regulated by cigarette smoke areCYP1A1 and CYP1B1, which are regulated by ER-a [38].Stimulation of estrogen receptors in the lungs increasesprotein expression of CYP1A1 by twofold [39]. CYP1A1has been demonstrated to have high activity for 17b-estra-diol 2-hydroxylation, followed by 15a-, 6a-, 4-, and 7a-hydroxylation [40]. 2-hydroxylated estrogens are suggestedto be anti-carcinogens, whereas 4- and 16a-hydroxylatedestrogens may enhance cancer development [41-43]. Inter-estingly, 2-hydroxyestrogen but not 16a-hydroxyestrogenhas increased clearance rate from the circulation of pre-menopausal females smokers [44,45], suggesting a differ-ential effect of estrogen metabolism. The increased CYPexpression is related to increased levels of estradiol [46]and increased metabolism of cigarette smoke to generateoxidants/oxidizers [47], suggesting that female sex hor-mone contributes to oxidative stress and greater airwayinjury.How sex hormones may modulate asthmaAnimal Models for AsthmaWhen challenged with allergen, female compared tomale mice mount an enhanced allergic response,Tam et al. BMC Women?’?s Health 2011, 11:24http://www.biomedcentral.com/1472-6874/11/24Page 4 of 9characterized by increased serum levels of ovalbumin-specific IgG1 and IgE [48] and increased airway inflam-mation [49]. Ovariectomized rats, on the other hand, areprotected from increased airway inflammation related toallergens [50]. Estrogen replacement in these ovariecto-mized rats reestablishes airway inflammation to levelsfound in intact females [50]. Collectively, these data sug-gest that female hormones augment airway inflamma-tion in the presence of allergens. One potentialmechanism for this response is estrogen-mediated devia-tion in helper T cells towards a TH2 phenotype.Another mechanism is that female hormones down-reg-ulate the expression of regulatory T (Treg) cells [51],which play an important role in regulating TH2responses [52]. Estradiol may also up-regulate earlyphase pro-inflammatory cytokines such as IL-1b andTNF-a and down-regulate anti-inflammatory cytokinessuch as IL-10 [53]. Consistent with this notion, Huberand Pfaeffle showed that male mice transfected withCoxsackievirus B3 predominantly mounted a TH1 cellphenotypic response, while female mice mounted a vig-orousTH2 cell phenotypic response [54]. Interestingly,when male mice were given estradiol, the ratio of IL-2/IFN-g to IL-4-producing cells became nearly equal, sug-gesting that estrogen promotes a TH2 response [54].Progesterone, on the other hand, significantly increasesthe expression of IL-10, IL1-b, and TNF-a in the lungs,and augments the release of IL-4 by bone marrow cells[53], which may lead to eosinophilia. The existence ofsuch dual hormone effects suggests that the balancebetween estradiol and progesterone may be critical inhost responses to environmental allergens [53]. It shouldbe noted, however that the ovary generates a large num-ber of cytokines and other factors that modulate theinflammatory process and affect the actions of estradioland progesterone [55,56].Sex hormones and adaptive immunityDifferences in male and female immune responses havebeen recognized for some time [54]. Females generallymount better humoral immunity than males, whilemales demonstrate enhanced cellular immune responses[57,58]. These differential immune responses may beimportant in autoimmune diseases. Helper T cells origi-nate from hematopoietic stem cells in the bone marrow,mature in the thymus and act in many different tissuesand organs. The two major subsets of helper T cells areTH1 and TH2 cells. Naïve T cells differentiate into TH1cells in the presence of IFN-g and IL-12, which aresecreted by dendritic cells in response to bacterial andviral challenge. TH1 cells produce a variety of differentcytokines including IFN-g and IL-2 and regulate thecell-mediated immune response [59,60]. In response toextracellular parasites and allergens, dendritic cells pro-duce IL-4, which promotes the TH2 lineage. TH2 cells,dissimilar to TH1 cells, produce mostly IL-4, -5, -10 and-13 to promote IgG, IgA, and IgE antibody isotyperesponses [61].Unlike the animal models, immunological modulationby sex hormones in human inflammatory diseases ismore complex. However, there are data suggesting thatcertain inflammatory diseases can modulate the TH1/TH2 response in humans. For example, patients withsystemic lupus erythematosus (SLE) demonstrate aunique pattern of estrogen production and metabolism[62]. SLE is characterized by elevated aromatase enzymeactivity and cytochrome p450 isoenzyme (CYP1B1),increased expression of the CD4+ TH2 response and arelative under-expression of the CD4+ TH1 response[62]. Estrogen is known to be an inducer of aromatasethat converts androgen to estrogens. CYP1B1 then con-verts estrogen to 16a-hydroxyestrone, which is the mostbiologically active serum estrogen with the most potentimmunomodulatory effects [62]. Estrogen can also sti-mulate secretion of IL-4, -5, -6, and -10 by TH2 lympho-cytes, while androgens promote the production of IL-2by TH1 cells [62]. Taken together, the relative balancebetween estrogen and androgen in the circulation mayinfluence the TH1/TH2 lineage and modulate the overallinflammatory response.Clinical overview of asthmaIt is well known that before puberty the incidence ofasthma is higher in boys than in girls, but followingpuberty, the pattern switches such that by adulthood,the prevalence of asthma is nearly 50% higher in womenthan in men [63]. It is also well known that asthmaseverity fluctuates over the course of the menstrualcycle [64]. The incidence of asthma tends to decreaseafter menopause [65] but hormone replacement therapyfollowing menopause is associated with an increasedrisk of asthma in non-smokers but not with newly diag-nosed COPD [66,67], suggesting that sex hormones mayplay a more important role in the development and pro-gression of asthma.Sex hormones on lung function in asthmaBoth forced expiratory volume in one second (FEV1)and forced vital capacity (FVC) are the lowest followingovulation in the peri-ovulatory phase of the menstrualcycle. During this phase, circulating estradiol levels arerelatively high and progesterone levels are moderate.FEV1 and FVC are the greatest during the peri-men-strual period when estradiol and progesterone levels areat their lowest [68]. Consistent with the observation,Zimmerman and colleagues showed that the highestrates of emergency department visits for asthmaoccurred during the pre-ovulatory phase of the men-strual cycle [69]. Although the exact mechanism forthese observations are unknown, as previously stated,both progesterone (at any concentration) and estrogenTam et al. BMC Women?’?s Health 2011, 11:24http://www.biomedcentral.com/1472-6874/11/24Page 5 of 9at high physiological concentrations promote a TH2phenotype, which is likely to be important in asthmapathogenesis.Sex hormones on exhaled nitric oxide in womenAn important biomarker of airway inflammation inasthma is nitric oxide (NO). NO is synthesized by acti-vated alveolar macrophages (AM) through the actions ofan inducible form of nitric oxide synthase (iNOS) [70].AM effects bacterial and viral killing by releasing NOand other reactive oxygen and nitrogen species [71].However, in asthma, this process is dysregulated suchthat even the absence of microbial products, NO path-ways in the airways are enhanced.Provocatively, in a small study of pre-menopausalwomen not using oral contraceptives, Mandhane et al.showed that exhaled NO concentrations were positivelyrelated to serum progesterone (p < 0.05) but inverselyrelated to serum 17b-estradiol levels [72]. Similarly, Farhaet al showed that exhaled NO concentrations were highestin the luteal phase (when serum progesterone levels areexpected to reach their peak). Suppression of the men-strual cycle with the use of oral contraceptives, on theother hand, abolished these relationships. Together, thesedata suggested that progesterone may be a very importantregulator of airway inflammation in female asthmatics.How sex hormones may modulate Cystic FibrosisSex hormone on mucus productionAccumulation of thick, tenacious mucus is a hallmark ofcystic fibrosis (CF) and has a central role in CF patho-physiology [73]. Mucus clearance plays an importantrole in innate immunity in the mammalian lung [74].Excess sputum production in the lung is one of the keyfactors in overwhelming ciliary clearance and obstruct-ing the airways, thereby contributing to morbidity andmortality in CF and other inflammatory lung diseases[75]. Mucins are upregulated by pathogens, inflamma-tory mediators, and toxins, which when dysregulatedcan exacerbate chronic airway diseases [76,77]. Expres-sion of mucin genes is increased by inflammatory med-iators, such as lipopolysaccharide (LPS) [78], TNF-a[79], IL-1 [79], IL-17 [80] and b neutrophil elastase [81].In addition to these inflammatory mediators, it isknown that sex hormones such as estrogen can also up-regulate MUC5B gene expression in normal human air-way epithelial cells [82]. MUC5B is one of the majormucins in the human airway submucosal glands [83].Estrogen is not the only regulator of MUC5B but alsoregulates a wide diversity of genes involved in extracel-lular matrix, general cell growth, and differentiation pro-cesses [24]. Taken together, estradiol may have thepotential to augment mucin production resulting inreduced clearance in CF.Sex hormone on Ca+2-activated Cl- secretionAn in-vitro study [84] has shown that high circulatinglevels of estradiol reduces Ca+2-activated Cl- secretionby airway epithelial cells in culture, thereby disruptingion and water balance and leading to thick, tenaciousmucus. Clinical studies have confirmed that Ca+2-acti-vated Cl- secretion is decreased in women with CF attimes when 17b-estradiol levels are high [69]. Estadiolmediates this effect by inhibiting Ca+2 influx and sig-naling in both non-CF and CF airway epithelia [74].Moreover, estrogen also appears to inhibit the uridinetriphosphate-mediated Cl- secretion in both womenwith CF and normal, healthy women [74]. Experimentsrevealed that a four-fold increase in estradiol wasaccompanied by a 50% inhibition of UTP-stimulatedCl- secretion in vivo [74]. Since the CF lung disease ischaracterized by poor Cl- secretion and water retentionin the airways [74], it is likely that the estrogen-relateddisturbance in Cl- secretion via the Ca+2-activatedchannels and other pathways can cause marked pertur-bations in mucociliary clearance, and accumulation ofthick mucus in the airway, resulting in disease progres-sion [85].Sex hormones on lung function in CFAs with asthma, menstrual cycles may also affect lungfunction in female patients with CF but not in thesame phasic manner [86]. Unlike in asthmatics whodemonstrate best lung function in the peri-menstrualperiod, female CF patients have the highest lung func-tion during the luteal phase and the lowest lung func-tion during the pre-ovulatory phase [87]. Johannessonshowed that FEV1 was 66% of predicted in female CFpatients during the luteal phase, while it was only 63%during ovulation (P < 0.01) [86], which interestingly isassociated with increasing levels of estradiol. The dif-ferences in the swings in lung function during themenstrual period between asthmatics and CF patientsmay relate to the relative importance of mucus pro-duction in their pathophysiology. Although mucusproduction and clearance are thought to be importantboth diseases, in CF, it is has a pre-eminent role,while in asthma, it is believed to have a more comple-mentary role in disease progression. By up-regulatingMUC5B expression, high estradiol levels during thepre-ovulatory phase may significantly enhance mucusproduction (through the mechanisms discussed in theprevious section) and lead to worsening of airflowlimitation in CF. Furthermore, 17b-estradiol in highphysiological concentrations inhibits local productionof IL-8 by up-regulating secretory leucoprotease inhi-bitors [88], which may diminish the ability of thefemale respiratory tract to contain bacterial infectionsin CF.Tam et al. BMC Women?’?s Health 2011, 11:24http://www.biomedcentral.com/1472-6874/11/24Page 6 of 9SummaryWomen are relatively more prevalent in the epidemiologyof asthma, CF and COPD and appear in general to haveworse prognosis than their male counterparts. The exactmechanism of this process is still uncertain. Emergingdata suggest that female sex hormones play a role inthese inflammatory airway conditions, through differentbut related mechanisms. Studies have shown that estro-gen promotes a TH2 response, while androgen promotesa TH1 response, which may be relevant in asthma. Estra-diol inhibits Cl- secretion in the CF lung and up-regulatesmucus production, which may be very relevant in CF.Cigarette smoke is de-toxified through Phase I and PhaseII enzymes and estrogens may preferentially up-regulatePhase I enzymes, leading to accumulation of toxic meta-bolites through a process called bioactivation. This maybe relevant in the pathophysiology of COPD. Althoughless well studied than estrogen, progesterone may alsoplay relevant roles in inflammatory airway disease byamplifying airway inflammation. With the rise in the bur-den of these diseases in women worldwide, there is apressing need to better understand the biological roles ofsex hormones in modulating airway inflammation,mucus production and cigarette de-toxification and otherprocesses relevant to COPD, asthma and CF.Abbreviation ListCF: cystic fibrosis; COPD: chronic obstructive pulmonary disease; E2: estradiol;ER: estrogen receptor; HRE: hormone response element; IL: interleukin;MUC5B: mucin 5B; NO: nitric oxide; PR: progesterone receptor; SHBG: sexhormone binding globulin; TNF: tumor necrosis factorAuthor details1The UBC James Hogg Research Centre, Providence Heart + Lung Centre &Department of Medicine, University of British Columbia (UBC), Vancouver, BC,Canada. 2Department of Medicine, The University of Alberta, Edmonton, AB,Canada.Authors’ contributionsAT participated in drafting the manuscript. DM, SW, DD, SFPM, and DDSparticipated in critical revisions. All authors read and approved the finalmanuscript.Competing interestsAnthony Tam - declared no competing interestsDon Morrish - received funding from GSK/CIHR, and Wyeth Pharmaceuticals.Samuel Wadsworth - declared no competing interestsDelbert Dorscheid - declared no competing interestsPaul S F Man - received educational grants from Glaxo-Smith-Kline andAstro-Zenecca to support researchDon D Sin - holds a Canada Research Chair in COPD and a senior clinicalscholarship with the Michael Smith Foundation for Health Research (MSFHR)and has received grants from Wyeth Pharmaceuticals, GlaxoSmithKline,AstraZeneca and Pfizer.Received: 30 August 2010 Accepted: 3 June 2011Published: 3 June 2011References1. Centers for Disease Control and Prevention: Asthma prevalence, healthcare use and mortality. 2010 [http://www.cdc.gov/nchs/data/hestat/asthma/asthma.htm], Date last updated: Feb 3 2010. Date last accessed:Feb 3.2. 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Kharitonov SA, Logan-Sinclair RB, Busset CM, Shinebourne EA: Peakexpiratory nitric oxide differences in men and women: relation to themenstrual cycle. Br Heart J 1994, 72:243-5.88. Chotirmall SH, Greene CM, Oglesby IK, Thomas W, O’Neill SJ, Harvey BJ,McElvaney NG: 17{beta}-Estradiol Inhibits IL-8 in Cystic Fibrosis by Up-Regulating Secretory Leucoprotease Inhibitor. Am J Respir Crit Care Med2010.Pre-publication historyThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6874/11/24/prepubdoi:10.1186/1472-6874-11-24Cite this article as: Tam et al.: The role of female hormones on lungfunction in chronic lung diseases. BMC Women’s Health 2011 11:24.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitTam et al. BMC Women?’?s Health 2011, 11:24http://www.biomedcentral.com/1472-6874/11/24Page 9 of 9


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