Understanding the role of sex hormones in asthma

In childhood, asthma is more common in boys than girls. “Mechanistically, we don’t have a clear understanding as to why,” says Dawn Newcomb, an associate professor in allergy, pulmonary and critical care medicine at Vanderbilt University Medical Center in Nashville, Tennessee.

But around puberty, that trend reverses — dramatically. Women have an increased prevalence of asthma compared with men (9.6% versus 6.3%, respectively) and are three times more likely than men to be admitted to hospital with asthma-related complications^​1​. Women are also more likely to die from the disease^​2​.

For some women, their symptoms are particularly bad just before their period. “I’ve spoken to women who have virtually been in hospital 12 times a year,” says Samantha Walker, director of research and innovation at the charity Asthma + Lung UK.

Clearly, sex hormones are having an effect. “Female sex hormones are thought to be pro-inflammatory,” explains Joe Zein, a pulmonary physician at the Mayo Clinic, Phoenix, Arizona.

And yet, this issue is little discussed when it comes to the consulting room. “Generally, there’s a lack of awareness of the impact of hormonal changes [on asthma],” says Nazir Hussain, specialist respiratory pharmacist at Dudley Integrated Health and Care NHS Trust. “It hasn’t been on the radar.”  

Defining disease

Asthma is a slippery term. “In the past it was very simplistic,” says Hussain. “You have allergic asthma, you have non-allergic asthma.” While these terms can still be useful for patients who are understanding what triggers their symptoms, clinicians are starting to think more about the biological mechanisms underlying classic asthma symptoms, which include wheezing, chest tightness, shortness of breath and coughing.

“Type 2 high inflammation is classically associated with an eosinophilic asthma,” says Katherine Cahill, who works alongside Newcomb as an assistant professor in allergy, pulmonary and critical care medicine at Vanderbilt University Medical Center. It is also often seen in allergic asthma.

Type 2 low inflammation is “more identified with a neutrophilic inflammatory phenotype or, frankly, the absence of a clear inflammatory phenotype”, Cahill continues (see Box).

The hope is that understanding more about the underlying type of inflammation will help clinicians to target therapeutics better. For now, the reality is that the vast majority of patients are treated with inhaled corticosteroids in the first instance. “In most patients [this] is combined with some form of bronchodilation or they might have something like a leukotriene-receptor antagonist,” says Darush Attar-Zadeh, a clinical fellow respiratory pharmacist at North West London Integrated Care Board.

Hormones and inflammation

How do sex hormones feed into this already muddy picture? “Ovarian hormones seem to upregulate that type 2 eosinophilic inflammation,” says Newcomb, “but also increase the cells that drive neutrophilic airway inflammation.”

The result is that hormonal fluctuations during the menstrual cycle, in pregnancy or around the menopause, can impact symptoms (see Figure). “Mechanistically how we think this is happening is, in our models, mostly oestrogen working through the oestrogen receptor alpha,” she adds.

Human airway smooth muscle cells express both the alpha and beta forms of the oestrogen receptor. In contrast to oestrogen receptor alpha, there is some evidence from mouse models that oestrogen receptor beta has a protective role against pathological airway changes^​2​. In one study, mice lacking this receptor showed exacerbated airway hyperresponsiveness and remodelling^​3​.

Meanwhile, “we have a lot of clinical and preclinical model data suggesting … androgens are important in down-regulating these immune responses”, Newcomb says. This may explain the shift in prevalence post-puberty, when male and female sex hormones increase.

Times of change

Post-puberty, around 20–25% of women with asthma will experience pre-menstrual asthma flare-ups^​2​. When it comes to pregnancy, while around one-third of pregnant women with asthma will experience no change in their symptoms and one-third will see an improvement, the remaining third will experience a worsening in their asthma symptoms, “and this might have a negative effect on both the mother and the foetus”, Zein says.

Consequently, although “there are a lot of women who are concerned about the side effects of treatment”, Hussain says, “we certainly wouldn’t drop treatment during pregnancy without seeking specialist advice”.

Some women will see an increase in asthma symptoms during perimenopause, but women are less likely than men to develop asthma after they have been through menopause.

“It’s really clear from the data that the times of hormonal change have a real influence on your asthma severity,” Walker says. There is some evidence that transgender status may also increase asthma risk, with one cross-sectional study of a clinical dataset showing that those who have transitioned from male to female had a 3.5 times higher lifetime risk of asthma than the whole population^​4​.

Walker says that the trouble for women with asthma is that “mostly, doctors will only ask about something if they feel it’s going to influence the treatment that they offer”. And if an exacerbation is caused by hormones, the concern is that “the only way of stopping it would be to manipulate your hormones, which would not be a popular treatment option for women”, according to Walker.

Even so, there is some evidence that oral contraceptives can be helpful in asthma. Newcomb cites a 2015 study that used NHS survey data on 3,257 non-pregnant women aged 16–45 years in Scotland^​5​. “Use of oral contraceptives reduced the incidence or onset of asthma,” Newcomb says.  

However, the study authors did not differentiate between the type of oral contraceptive used. Zein says that “future research is needed to study the best contraceptive method in asthma” and cautions that “advice in that regard cannot be recommended at this point”.

The effect of hormone replacement therapy (HRT) on asthma in menopausal women is even less well understood. “HRT among postmenopausal women has been associated with worse asthma and poor lung function,” Zein says.

One 2006 study that looked at questionnaire data from 2,206 women aged 46–54 years, of which 884 women were menopausal and 540 women used HRT, showed that those taking HRT were at a higher risk of developing asthma^​5,6​. And, “if they were obese, they had worsening of symptoms compared to women with asthma who had BMIs of less than 30 that also started HRT,” Newcomb says.

Obesity does seem to be a particularly impactful comorbidity for women with asthma. In both men and women, “obesity seems to complicate our ability to treat asthma effectively”, Cahill says.

However, “women who are obese have about double the prevalence of asthma compared to their lean counterparts”, she continues. “We don’t see that increase in males.” More research is needed to understand the mechanisms behind this. “That’s an area of a lot of current investigation.”

Managing flare-ups

The picture around hormonal treatments may be complicated, but symptom exacerbations owing to hormonal changes can be managed as you would manage any other asthma trigger. “If you have poor asthma control, your lungs will be more hypersensitive to triggers,” Hussain explains, and this includes hormonal changes.

“We almost need to step back first,” Attar-Zadeh agrees, suggesting that clinicians look at whether patients are following their management plan, taking their inhaled corticosteroids regularly and have good inhaler technique.

It is also worth asking patients to keep a symptom diary. “Write down when your symptoms get worse, what stage of your cycle it is, what you’re doing at the time,” Hussain says, pointing out that there may be other things going on around the time of a patient’s period, such as increased use of non-steroidal anti-inflammatory drugs (itself a risk factor for worsening asthma symptoms). If a clear pattern is detected, clinicians can suggest that the patient increases their dose of inhaled corticosteroids in the run up to their period. “They can prepare in advance,” says Hussain.

Unfortunately, the NHS is already stretched when it comes to treating patients with asthma. “Some clinicians are only given ten minutes to do asthma reviews,” Attar-Zadeh says.

In that time, he adds, they may need to take a clinical history, do objective diagnostic tests and cover points including inhaler technique, a self-management plan and answer patient queries. “With asthma there are so many things to consider.”

Hussain agrees that it can be hard to identify any triggers during a short appointment, but “there are approaches that we should be encouraging”, he says, such as raising awareness to patients that hormonal changes can affect asthma “so they can look out for it”.

One intervention that might help is adding a prompt to online systems for healthcare practitioners to ask about hormonal triggers. This type of measure would raise awareness among clinicians and might also help women to be taken more seriously. “I’ve advised many women in my time to go and see the doctor and they do tend to get brushed off,” Walker says.

There are hopes that the way we manage asthma in the UK is set to improve. The National Institute for Health and Care Excellence (NICE) released updated guidelines for asthma treatment in November 2024^​7​. “We’ve got an opportunity with the new NICE guidance to transform the way we manage asthma,” Attar-Zadeh says.

Currently, the mainstay of asthma treatment is delivered in two separate inhalers: corticosteroids in a brown inhaler; bronchodilators in a blue. “Many patients like the blue reliever inhaler more because it works fast and it treats the symptoms,” Attar-Zadeh says. “The problem is it doesn’t treat the underlying cause of the asthma.”

New guidelines recommend switching patients over to a combined inhaler that delivers an inhaled corticosteroid in combination with formeterol, a long-acting bronchodilator. “[This] should hopefully tackle the issue we have of underuse of inhaler steroids in asthma,” Hussain says. “Patients get the best of both worlds.”

While this change in approach should help all patients, there is a conspicuous lack of targeted advice for women with asthma in the updated guidelines. Other than in pregnancy, there is no mention of women as a specific subgroup at all. When approached for comment about this, a spokesperson for NICE said: “This did not come up as an issue during scoping or consultation on the scope of the guideline.”

Research gap

Furthermore, examining sex differences in asthma was not listed as a research recommendation in the recent NICE guidelines. This is despite the fact that Asthma + Lung UK released a report on sex hormones and asthma in 2022, which — among other things — called for an immediate large-scale funding call to investigate the influence of sex and gender differences on adult asthma^​2​.

The report also suggested mandating analysing clinical trial data by sex to identify differences. For now, “most of the data … about therapeutic response assumes asthma in general, adjusting for any sex differences already,” Cahill says.

Unfortunately, “in the grand scheme of things, it’s not a priority”, Walker says, suggesting that one factor might be that pharmaceutical companies “can’t see a treatment at the end of it that isn’t a hormone replacement therapy of some description”.

New horizons

Nonetheless, there are new therapeutic possibilities for asthma stemming from the research being done on sex differences. One possible target is the oestrogen beta receptor. Another, which is currently being studied in both men and women, is using the upstream androgen, dehydroepiandrosterone (DHEA), as a treatment^​8,9​.

“DHEA does not have the systemic effects of testosterone and there’s ongoing research right now looking at whether or not DHEA administration may decrease asthma symptoms, asthma exacerbations and airway inflammation,” says Newcomb.

“This therapeutic is also very economical,” she adds. It is currently available in an oral slow-release tablet but can be delivered in a nebulised form as well.

Another approach that could be useful for women in asthma is mobilising the possibility of so-called ‘femtech’, such as period-tracking apps. Women already use these apps to input symptoms around the time of their period; adding a set of prompts for those with asthma should be a relatively easy addition.

According to Walker, Asthma + Lung UK are having these conversations “opportunistically” with companies and trying to persuade them that “this is a really important unmet need”.

“There’s also really interesting opportunities around passive sensors on phones,” she adds, suggesting that in the future our phones might be able to detect the way we cough or how we are breathing to prompt us to up our asthma medicines.

In the here and now, Hussain has some simple words of advice: “We don’t tend to distinguish between men and women when it comes to treating asthma. Perhaps that needs to change.”