30 January, 2017: 

Asthma is basically an inflammatory disease, sometimes associated with allergy. Several publications have addressed recently the potential association between menopause and asthma. The latest study examined the possibility that there is a link between menopause and new-onset asthma [1]: the Respiratory Health in Northern Europe study provided questionnaire data pertaining to respiratory and reproductive health at baseline (1999–2001) and follow-up (2010–2012). The study cohort included women aged 45–65 years at follow-up, without asthma at baseline, and not using exogenous hormones (n = 2322). Menopausal status was defined as non-menopausal, transitional, early postmenopausal, and late postmenopausal. Associations with asthma (defined by the use of asthma medication, having asthma attacks, or both) and respiratory symptoms scores were analyzed by using logistic (asthma) and negative binomial (respiratory symptoms) regressions, adjusting for age, body mass index, physical activity, smoking, education, and study center. The odds (OR) of new-onset asthma were increased in women who were transitional (OR 2.4; 95% CI 1.09–5.30), early postmenopausal (OR 2.1; 95% CI 1.06–4.20), and late postmenopausal (OR 3.4; 95% CI 1.31–9.05) at follow-up compared with non-menopausal women. The risk of respiratory symptoms increased in early postmenopausal and late postmenopausal women as well.

Comment

Epidemiological data show that asthma prevalence, severity, exacerbation rate, hospitalizations and mortality are higher among women than men overall [2]. The transition from childhood to adulthood is characterized by a higher odds ratio of persistence of wheezing and asthma worsening in females. A growing body of clinical and experimental evidence indicates that female sex hormones, particularly estrogen, have significant effects on normal airway function. These effects are very complex and are exerted at several levels, directly on airway reactivity or indirectly through regulation of the immune and inflammatory responses in the lung. Asthma presents as a heterogeneous disease: in typical Th2-type allergic asthma, interleukin (IL)-4 and IL-13 predominate, driving IgE production and recruitment of eosinophils into the lungs. Chronic Th2-inflammation in the lung results in structural changes and activation of multiple immune cell types, leading to a deterioration of lung function over time. Most immune cells express estrogen receptors (ER alpha and beta, or the membrane-bound G-protein-coupled ER) to varying degrees and can respond to the hormone. Together these receptors have demonstrated the capacity to regulate a spectrum of immune functions. Kesselman and Heller reviewed the current understanding of estrogen signaling in allergic inflammation and discussed how this signaling may contribute to sex differences in asthma and allergy [3].

In view of the effect of estrogen on various parameters related to asthma, how does menopause fit in? There seems to be some controversy since, on the one hand, menopause was found to be associated with increased respiratory symptoms, lower forced vital capacity (FVC) and adjusted mean forced expiratory volume in one second (FEV1), but, on the other hand, there were reports suggesting that menopause is protective, pointing at asthma improvement in the climacterium [4]. A systematic review and meta-analysis on menopause and asthma noted that there were not too many large-scale and good-quality studies, yet once again pointed at conflicting data [5]. Overall, no significant association of menopause with asthma prevalence or incidence was found; however, asthma rates were increased in women reporting use of menopausal hormone therapy (RR 1.32, 95% CI 1.01–1.74), as compared with non-users. Another review reached similar conclusions that the administration of estrogen to menopausal women is associated with increased rates of newly diagnosed asthma but, conversely, estrogen may improve objective indexes of respiratory functionality [6]. An interesting study from Denmark looked into admission rates due to acute exacerbations or difficulties in controlling the asthma among 22,958 postmenopausal women, of whom a total of 11,487 (50.0%) women ever used HRT [7]. There were 476 (2.1%) incident asthma hospital admissions and 1161 (5.1%) incident chronic obstructive lung disease (COPD) admissions over 13.2 years of mean follow-up. Ever using HRT was associated with increased risk of hospital admission for asthma, with hazard ratio (HR) and 95% CI of 1.46 (1.21–1.76) in the fully adjusted model. Furthermore, the longer the use of hormones, the higher HR: 19% (95% CI 11–28%) increase in the risk of hospital admission for asthma for each 5-year use of HRT. The risk was significantly increased for all types of HRT regimens. Ever using HRT was also associated with hospital admission for COPD, but with an HR approximately half of that for asthma (1.19; 95% CI 1.06–1.34). A stronger association was observed with longer duration of HRT use. It therefore seems that postmenopausal hormone therapy poses a risk of worsening of existing asthma, and increases the chance of new-onset asthma. Prescribers of HRT should be aware of this adverse effect related to such a common disease. Those who wish to read about the potential interaction between oral contraceptives and asthma (bottom line: may reduce asthma exacerbations and number of care episodes) can start with the article of Nwaru & Sheikh [8].

Amos Pines

Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

References

1. Triebner K, Johannessen A, Puggini L, et al. Menopause as a predictor of new-onset asthma: A longitudinal Northern European population study. J Allergy Clin Immunol 2016;137:50-7
   http://www.ncbi.nlm.nih.gov/pubmed/26435006
2. Zein JG, Erzurum SC. Asthma is different in women. Curr Allergy Asthma Rep 2015;15:28
   http://www.ncbi.nlm.nih.gov/pubmed/26141573
3. Keselman A, Heller N. Estrogen signaling modulates allergic inflammation and contributes to sex differences in asthma. Front Immunol 2015;16;6:568
   http://www.ncbi.nlm.nih.gov/pubmed/26635789
4. Triebner K, Matulonga B, Johannessen A, et al. Menopause is associated with accelerated lung function decline. Am J Respir Crit Care Med 2016 Dec 1. Epub ahead of print
   http://www.ncbi.nlm.nih.gov/pubmed/27907454
5. Zemp E, Schikowski T, Dratva J, Schindler C, Probst-Hensch N. Asthma and the menopause: a systematic review and meta-analysis. Maturitas 2012;73:212-7
   http://www.ncbi.nlm.nih.gov/pubmed/22964072
6. Ticconi C, Pietropolli A, Piccione E. Estrogen replacement therapy and asthma. Pulm Pharmacol Ther 2013;26:617-23
   http://www.ncbi.nlm.nih.gov/pubmed/24035822
7. Bønnelykke K, Raaschou-Nielsen O, Tjønneland A, Ulrik CS, Bisgaard H, Andersen ZJ. Postmenopausal hormone therapy and asthma-related hospital admission. J Allergy and Clin Immunol 2015:135:813-16
   http://www.ncbi.nlm.nih.gov/pubmed/25579482
8. 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;108:358-71
   http://www.ncbi.nlm.nih.gov/pubmed/26152676