Association between asthma and female sex hormones

The relationship between sex hormones and asthma has been evaluated in several studies. The aim of this review article was to investigate the association between asthma and female sex hormones, under different conditions (premenstrual asthma, use of oral contraceptives, menopause, hormone replacement therapy and pregnancy).

DESIGN AND SETTING:

Narrative review of the medical literature, Universidade Federal do Tocantins (UFT) and Universidade Federal de São Paulo (Unifesp).

METHODS:

We searched the CAPES journal portal, a Brazilian platform that provides access to articles in the MEDLINE, PubMed, SciELO, and LILACS databases. The following keywords were used based on Medical Subject Headings: asthma, sex hormones, women and use of oral contraceptives.

RESULTS:

The associations between sex hormones and asthma remain obscure. In adults, asthma is more common in women than in men. In addition, mortality due to asthma is significantly higher among females. The immune system is influenced by sex hormones: either because progesterone stimulates progesterone-induced blocking factor and Th2 cytokines or because contraceptives derived from progesterone and estrogen stimulate the transcription factor GATA-3.

CONCLUSIONS:

The associations between asthma and female sex hormones remain obscure. We speculate that estrogen fluctuations are responsible for asthma exacerbations that occur in women. Because of the anti-inflammatory action of estrogen, it decreases TNF-α production, interferon-γ expression and NK cell activity. We suggest that further studies that highlight the underlying physiopathological mechanisms contributing towards these interactions should be conducted.

KEY WORDS:
Asthma; Gonadal steroid hormones; Women; Contraceptives, oral; Cytokines

Authors	Method	Results and conclusions
Hellings et al.⁶³63. Hellings PW, Vandekerckhove P, Claeys R, et al. Progesterone increases airway eosinophilia and hyper-responsiveness in a murine model of allergic asthma. Clin Exp Allergy. 2003;33(10):1457-63.	BALB/c male mice of 6 weeks of age were sensitized to ovalbumin (Ova) using intraperitoneal injections. Medroxyprogesterone or placebo was instilled daily into the esophagus before and during the inhalatory Ova challenge phase.	Progesterone worsened allergic airway inflammation in Ova-challenged mice. Progesterone increased IL-5 levels and elevated airway eosinophilia. Progesterone did not influence allergen-specific IgE production. Progesterone aggravates the phenotype of eosinophilic airway inflammation in mice by enhancing systemic IL-5 production.
Degano et al.⁶⁴64. Degano B, Mourlanette P, Valmary S, et al. Differential effects of low and high-dose estradiol on airway reactivity in ovariectomized rats. Respir Physiol Neurobiol. 2003;138(2-3):265-74.	Ovariectomized seven-week-old female Wistar rats received either placebo or 17β-estradiol (E2) (10 to 100 mcg/kg/day) for 21 days. They were administered an aerosol of saline and increasing concentrations of acetylcholine (Ach) until lung resistance was observed.	Rats treated with low-dose E2 were less responsive to Ach than rats given either placebo or high-dose E2 were. Treatment with E2 had a differential, dose-dependent effect on airway responsiveness to Ach.
de Oliveira et al.⁶⁵65. de Oliveira AP, Domingos HV, Cavriani G, et al. Cellular recruitment and cytokine generation in a rat model of allergic lung inflammation are differentially modulated by progesterone and estradiol. Am J Physiol Cell Physiol. 2007;293(3):C1120-8.	The authors evaluated the roles of estradiol and progesterone in allergic lung inflammation. Female Wistar rats were ovariectomized (Ovx) and then sensitized with ovalbumin (OA). They received estradiol and progesterone.	In Ovx-allergic rats, treatment with estradiol decreased the amount of IL-10 and increased the amount of IL-4 produced by bone marrow (BM) cells. Estradiol increased IL1β and TNFα levels in BAL (bronchoalveolar lavage) cells. Progesterone increased the release of IL-10, IL-1β and TNFα by BAL cells and increased the production of IL-4 by BM cells. The existence of such dual hormonal effects suggests that hormone therapy in asthmatic postmenopausal women and women who suffer from premenstrual asthma should take into account the possibility that these treatments may worsen pulmonary conditions.
Mitchell et al.⁶⁶66. Mitchell VL, Van Winkle LS, Gershwin LJ. Environmental tobacco smoke and progesterone alter lung inflammation and mucous metaplasia in a mouse model of allergic airway disease. Clin Rev Allergy Immunol. 2012;43(1-2):57-68.	Adult female BALB/c mice were ovariectomized and implanted with time-release progesterone pallets. They were housed in filtered air or ETS (environmental tobacco smoke) for 6 weeks and exposed to HDMA (house dust mite allergen) by inhalation.	Progesterone alone did not increase mucous cell mass or abundance of eosinophils, but ETS coupled with progesterone exposure resulted in a significant increase in mucous cell metaplasia and increased accumulation of eosinophils in the asthma model. Progesterone, in the absence of estrogen, exacerbated the airway inflammation and airway remodeling that was induced by the toxicant ETS.
Matsubara et al.⁶⁷67. Matsubara S, Swasey CH, Loader JE, et al. Estrogen determines sex differences in airway responsiveness after allergen exposure. Am J Respir Cell Mol Biol. 2008;38(5):501-8.	The authors compared sex differences in the development of airway hyperresponsiveness (AHR) following allergen exposure exclusively via the airways. Ovalbumin was administered via nebulization on 10 consecutive days in 8 to 10-week male and female BALB/c mice. After methacholine challenge, signiﬁcant AHR developed in male mice but not in female mice. Ovariectomized female mice showed signiﬁcant AHR after 10 days of Ova inhalation. ICI182,780, an estrogen antagonist, similarly enhanced airway responsiveness even when administered 1 hour before the assay.	The results showed that 17 beta-estradiol dose-dependently suppressed AHR in male mice. In all cases, airway responsiveness was inhibited by administration of a neurokinin 1 receptor antagonist. The neurokinin 1 receptor antagonist attenuated the effect that the estrogen receptor antagonist had in enhancing AHR in female mice in vivo. Endogenous estrogen may regulate the neurokinin 1-dependent prejunctional activation of airway smooth muscles in allergen-exposed mice.

Authors and type of study	Method	Results and conclusions
Macsali et al.⁷7. Macsali F, Real FG, Omenaas ER, et al. Oral contraception, body mass index, and asthma: a cross-sectional Nordic-Baltic population survey. J Allergy Clin Immunol. 2009;123(2):391-7. Cross-sectional survey	Postal questionnaires were sent to subjects in Denmark, Estonia, Iceland, Norway and Sweden from 1999 to 2001 (response rate in women, 77%). The analyses included 5791 women who were 25 to 44 years old, of whom 961 (17%) used oral contraceptives.	Oral contraceptive pills were associated with an increased risk of asthma, asthma with hay fever, wheezing and shortness of breath, hay fever and ≥ 3 asthma symptoms. Associations were present. Women using oral contraceptive pills had more asthma. This was found only in the normal weight and overweight women and not in lean women, thus indicating an interplay between sex hormones and metabolic status in their effects on airways.
Guthikonda et al.⁴⁷47. Guthikonda K, Zhang H, Nolan VG, et al. Oral contraceptives modify the effect of GATA3 polymorphisms on the risk of asthma at the age of 18 years via DNA methylation. Clin Epigenetics. 2014;6(1):17. Cohort	Blood samples were collected from 245 female participants aged 18 years old.	Subjects with genotype AG showed an increase in the average risk ratio (RR) from 0.31 (95% CI: 0.10 to 0.8) to 11.65 (95% CI: 1.71 to 79.5) when the methylation level increased from 0.02 to 0.12 relative to the risk in genotype AA. A two-stage model that takes into account genetic variants of the GATA-3 gene, oral contraceptive use, age at menarche and DNA-methylation may explain how sex hormones can increase the prevalence of asthma after puberty.
Erkoçoğlu et al.⁴⁵45. Erkoçoglu M, Kaya A, Azkur D, et al. The effect of oral contraceptives on current wheezing in young women. Allergol Immunopathol (Madr). 2013;41(3):169-75. Cross-sectional	The ISAAC questionnaire was provided to 487 women between 11.3 and 25.6 years of age. Questions on oral contraceptives were also asked.	In this study, n = 487 (ages ranged from 11.3 to 25.6 years old), 196 (40%) reported using an oral contraceptive, 7.4% had a diagnosis of asthma from a physician and 10.3% of them were active smokers. Young women taking oral contraceptives had a higher rate of current wheezing, thus suggesting that sex steroids may be important for respiratory health.
Dratva et al.³⁹39. Dratva J, Schindler C, Curjuric I, et al. Perimenstrual increase in bronchial hyperreactivity in premenopausal women: results from the population-based SAPALDIA 2 cohort. J Allergy Clin Immunol. 2010;125(4):823-9. SPALDIA 2 Cohort	571 women aged 28 to 58 years who had menstrual periods without hormone treatment were subjected to methacholine challenge. In a second step, 130 women taking oral contraceptives were subjected to methacholine challenge.	An effect of modification according to asthma status and oral contraceptive use was found, with a lower odds ratio (OR) among subjects without asthma. An OR < 1 was found among woman taking oral contraceptives. Oral contraceptives appeared to have a protective effect through which they decreased bronchial hyperreactivity.
Vélez-Ortega et al.³⁷37. Vélez-Ortega AC, Temprano J, Reneer MC, et al. Enhanced generation of suppressor T cells in patients with asthma taking oral contraceptives. J Asthma. 2013;50(3):223-30. Cohort	Thirteen patients were included in this pilot study. During three distinct phases of their menstrual cycles, the authors measured exhaled nitric oxide (eNO) levels, forced expiratory volume at 1 second (FEV₁), asthma control test (ACT) scores, sex steroid hormone levels in serum, natural Tregs levels in peripheral blood, and the ability of CD4⁺ T cells to generate iTregs ex vivo.	Patients taking oral contraceptives showed reduced serum sex hormone levels in association with higher levels of iTreg induction, better ACT scores and a tendency to have lower eNO levels. The impact of sex hormones on the capacity of T cells to polarize towards a regulatory phenotype suggests that regulation of peripheral T cell lineage plasticity is a potential mechanism that may underlie the beneficial effects of oral contraceptives among women with asthma.
Tan et al.³³33. Tan KS, McFarlane LC, Lipworth BJ. Beta2-adrenoceptor regulation and function in female asthmatic patients receiving the oral combined contraceptive pill. Chest. 1998;113(2):278-82. Cohort with intragroup analysis	The study population comprised 11 women aged 19 to 40 years with stable and moderate asthma. The patients were evaluated while on (day 20 to 21) and off (day 5 to 7) oral contraceptives during a 28-day calendar period.	Baseline FEV₁ did not differ between patients who were on and off oral contraceptives. These did not alter beta2-adrenoreceptor regulation or function in stable female asthmatic patients.
Tan et al.⁴⁸48. Tan KS, McFarlane LC, Lipworth BJ. Paradoxical down-regulation and desensitization of beta2-adrenoceptors by exogenous progesterone in female asthmatics. Chest. 1997;111(4):847-51. Trial	Seven nonsmoking females aged 26 years with mild asthma completed the study. They were evaluated through two successive menstrual cycles during the follicular phase (days 1 to 6). They were randomized to receive single oral doses of either ethinyl estradiol or medroxyprogesterone.	The results showed that exogenous progesterone, but not estrogen, when given during the follicular phase, decreased beta2- adrenoreceptor density and cyclic-adenosine monophosphate (AMP) responses in female asthmatics. The beta2-adrenoreceptor was abnormally regulated in female asthmatics, and this might be a potential mechanism through which premenstrual asthma could be triggered when progesterone levels are high.
Salam et al.²⁶26. Salam MT, Wenten M, Gilliland FD. Endogenous and exogenous sex steroid hormones and asthma and wheeze in young women. J Allergy Clin Immunol. 2006;117(5):1001-7. Cohort	905 women who had undergone menarche were included. The subjects ranged in age from 13 to 28 years and had participated in the Children's Health Study.	In women without asthma, oral contraceptive use was associated with higher risk of current wheezing. In contrast, oral contraceptive use was associated with reduced prevalence of current wheezing in women with asthma. These associations showed significant trends with duration of oral contraceptive use. Age at menarche was associated with new-onset asthma after puberty. Compared with women who had their menarche after they were 12 years old, women who reached their menarche before they were 12 years old were at higher risk of asthma after puberty. Because women have a higher risk of asthma after puberty, and because oral contraceptive use is common among young women, clinicians should inform women with asthma about the potential effects of oral contraceptives on asthma-related respiratory symptoms.
Jenkins et al.⁴⁶46. Jenkins MA, Dharmage SC, Flander LB, et al. Parity and decreased use of oral contraceptives as predictors of asthma in young women. Clin Exp Allergy. 2006;36(5):609-13. Cohort	681 women aged 29-32 years were randomly sampled from participants who were first surveyed at the age of 7 years in the 1968 Tasmanian Asthma Survey, which was a study of all children born in 1961 who attended school. Current asthma was defined as reporting asthma or wheezy breathing during the past 12 months.	The risk of current asthma in individuals who were parous increased with the number of births, while women with one birth were at lower risk than nulliparous women. Independent of parity, the risk decreased by 7% per year of oral contraceptive pill use. In women who had asthma or wheezy breathing by the age of 7 years old, neither reproductive history nor oral contraceptive pill use predicted current asthma. Parity and decreased oral contraceptive use predicted asthma in women, and these results are consistent with the hypothesis that the asthma that develops after childhood is in part a response to endogenous and exogenous female hormones.
Nwaru and Sheikh³⁸38. Nwaru BI, Sheikh A. Hormonal contraceptives and asthma in women of reproductive age: analysis of data from serial national Scottish Health Surveys. J R Soc Med. 2015;108(9):358-71. Cross-sectional survey	A population-based analysis using serial data from the Scottish general population. A total of 3257 non- pregnant, 16-45-year-old women were included.	The use of any hormonal contraceptive was associated with a reduced risk of current physician-diagnosed asthma. The use of a hormonal contraceptive may reduce asthma exacerbations. Overweight and obese non-contraceptive-using women may be at increasing risk of asthma.
Lange et al.⁴²42. Lange P, Parner J, Prescott E, Ulrik CS, Vestbo J. Exogenous female sex steroid hormones and risk of asthma and asthma-like symptoms: a cross sectional study of the general population. Thorax. 2001;56(8):613-6. Cross-sectional	Data from a study on women who were selected from the general population were used to correlate the effect of treatment with oral contraceptives and hormonal replacement therapy (HRT) with asthma indications. 377 women were on oral contraceptives (24.5% of the premenopausal women) and 458 were on HRT (15.2% of the postmenopausal women). The age span of the premenopausal women was 21-49 years and of the postmenopausal women, 27-90 years.	A weak association was observed between HRT and self-reported asthma. No relationship was found between the use of oral contraceptives and asthma, although an association was observed between asthma and HRT.

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