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Adult onset asthma is often progressive1 and the cause of considerable morbidity. Some asthma developing de novo in adults can be attributed to environmental factors, such as occupational sensitisers. When such an association is recognised, asthma can often be prevented, so searching for aetiological factors is well worthwhile. Hormone replacement therapy (HRT) may be one such factor.
Postmenopausal HRT was used widely until recently, being seen as the way for women not only to appear more youthful and glamorous following the menopause but also to be healthier. Various observational studies had suggested a reduced risk of diseases such as osteoporosis, heart disease and possibly dementia. However, when the results of prospective studies became available the picture was, alas, rather less positive. Not only did these studies fail to confirm many of the alleged benefits of HRT, they suggested or confirmed important adverse effects including an increased risk of breast cancer, ovarian cancer, venous thrombo-embolism, heart disease, cognitive decline and, more recently, mortality from lung cancer.2–8 Should late-onset asthma be on this list?
Cross-sectional studies have shown an association between the use of HRT and a diagnosis of asthma and asthma symptoms.9–11 The studies have varied in design and in how asthma was diagnosed, but the findings have been fairly consistent in showing a modest association between HRT use and reported asthma, with ORs ranging from 1.38 to 1.57.9–11 The associations with symptoms and asthma medication were of similar magnitude.9–11 Two studies found the strongest association in never smokers9 11 and two showed an interaction with body mass index (BMI), in that the effects of HRT were seen largely in women with a low BMI.9 10 Having a high BMI per se was associated with asthma,9 but there was no additional effect from HRT in these more overweight women. Cross-sectional studies have limitations, and none of these studies looked at the type of HRT used, nor did they distinguish between new-onset and established asthma.
Data from the large US Nurses Health Study were published in 199512 and 2004.13 This was the first prospective study to look at the relationship of postmenopausal hormone use to the development of new cases of physician-diagnosed asthma, using biennial questionnaires to determine HRT use. The analyses covered a quarter12 and half13 a million person-years of follow-up, respectively, with some overlap for the middle period. Both analyses showed an increased risk of developing asthma in association with current use of HRT, and this was similar for oestrogen alone and oestrogen/progestin preparations. The increased risk with unopposed oestrogen showed a dose–response relationship in the first study.12 In the more recent study, by Barr et al,13 the rate ratio for newly diagnosed asthma amongst current users of oestrogen only was 2.29 (95% CI 1.59 to 3.29), and this tended to be greater in women with a low BMI. HRT was not a risk factor for developing chronic obstructive pulmonary disease.13
This issue of Thorax contains a further prospective study, from Romieu et al (see page 292), looking at the relationship of HRT use to new-onset asthma amongst postmenopausal women in the E3N study, a cohort of 98 995 French women using a health insurance plan that covers predominantly teachers.14 The analysis is based on 57 664 women who said at the time of the menopause that they had never had asthma, and who had adequate follow-up data. The women were aged 40–65 years when the study was initiated in 1990, and data on medical history, menopausal status and aspects of lifestyle were obtained subsequently from two-yearly self-completed questionnaires. Recent use of HRT was observed for 56% of person study years, with 11.2% of women taking oestrogen alone as last treatment and most of the remainder a combination of oestrogen and some form of progestogen. A third of the 19% of women who had had a hysterectomy had taken oestrogen alone.
Amongst the 57 664 women there were 569 incident cases of asthma over the 12 years of the study (1.15/1000 women/year).14 Overall there was a small increased risk of asthma developing amongst recent users of HRT, of borderline statistical significance (HR 1.2 (95% CI 0.98 to 1.46)). The risk of a new diagnosis of asthma was, however, increased amongst women who reported taking oestrogen alone as their last treatment, with a HR of 1.54 (95% CI 1.13 to 2.09). This increased risk amongst oestrogen users was seen mainly in women who had never smoked (HR 1.8 (95% CI 1.15 to 2.8)) and in women who had a history of allergic disease prior to asthma onset (HR 1.86 (95% CI 1.18 to 2.93)). There was no increased risk for new asthma onset for women taking oestrogen/progestogen preparations overall, although amongst non-smokers and people with previous allergic disease there was a small increase, of borderline statistical significance. Higher BMI was associated with an increased risk of asthma, but the effects of HRT on the risk of developing asthma did not vary with BMI.
The data from the current study by Romieu et al14 are broadly in keeping with the prospective US Nurses Study12 13 for women taking unopposed oestrogen, with an OR for recent users in the French study14 of 1.67, compared with rate ratios of 1.4212 and 2.2913 for current users in the US studies. The main difference between the two studies is that combined oestrogen/progestogen preparations were associated with a similar risk of developing asthma to oestrogen alone in the US studies12 13 but with no increased risk in the French study,14 apart from subgroups of non-smokers and people with previous allergic disorders. The finding that being overweight is a risk factor for developing asthma is in keeping with several previous studies,15–18 but the findings of an interaction between BMI and the effects of HRT have been less consistent.9–14
Differences in outcome between cross-sectional and longitudinal studies are not too surprising, but the reason for the different findings for combined oestrogen and progestin preparations between the two large prospective studies is a bit more puzzling since they were of similar size and both collected data prospectively. The French teachers studied by Romieu et al14 were considerably less likely to take unopposed oestrogens than the nurses in the US study13 (11.2% vs 44%) and they had a lower median BMI. Both studies were prospective but observational rather than randomised controlled trials, and so the possibility of bias due to residual confounding cannot be excluded. The reasons why women choose to take or not take HRT, and which preparation, are complex and likely to be affected by social factors, educational attainment, availability and medical advice. The differences between the two studies may reflect differences in the population studied or the type or dose of HRT used. Despite the large numbers and long follow-up (around half a million years in both studies), some of the analyses are based on fairly small numbers because the number of new cases of asthma is relatively small. Furthermore, categorising HRT is inevitably untidy and very much larger numbers would be needed to try to disentangle the effects of the different preparations, formulations and doses used, and which are likely to differ between countries and could well have affected study outcomes. If, for example, oestrogen was the main driver of the increase in asthma with progestogens having a modifying effect, differences in the relative doses of oestrogen and progestogens might explain the differences in outcome between the two studies. Understanding the mechanism underlying the effects of oestrogen and progestogens in the lung might help but, as Romieu et al14 discuss, these are complicated, with oestrogen, for example, having actions that could be either proinflammatory or anti-inflammatory.
So what can we conclude from these studies? Unopposed oestrogen appears to be associated with an increased risk of developing asthma, and this risk appears to be greater in non-smokers and women with a history of allergic disease. There is less agreement about the risk of asthma associated with combined oestrogen/progestogen preparations and the role of a low BMI in enhancing this risk, which might relate to differences in the nature and dose of the oestrogen and progestogens used in the combination product in different studies. The two most recent prospective studies13 14 provide some estimate of the likely risk of asthma from HRT in postmenopausal women and, although this may not be seen as being as serious as some of the adverse effects associated with HRT, it adds to the downside when women consider the pros and cons of hormone treatment.