Sex Hormones in Allergic Disease: Overview and Spotlight on Asthma in Pregnancy

Case Overview

A 27-year-old female, G0P0, presents for preconception counseling. She has a history of atopic dermatitis, allergic rhinitis, and asthma. Currently these conditions are under good control. She does note some fluctuation of asthma symptoms with her menstrual cycles. She is on single maintenance and reliever therapy (SMART) with a low-dose budesonide-formoterol inhaler, two scheduled puffs twice daily, and has only required one rescue puff over the past month for mild wheezing. She is wondering how becoming pregnant might affect her asthma and vice versa.

How do you counsel her? A.

Reassure her that pregnancy will not affect her asthma symptoms.

Background

Sex hormones are increasingly recognized for their physiological and pathological roles in allergic disease. Estrogen binding to receptors found on dendritic cells, macrophages, T-cells, and B-cells, which are key players in allergic inflammation, can enhance allergic pathways. ¹ Estrogen encourages naive T cells to become T helper 2 (Th2) cells, which produce allergic cytokines such as interleukin (IL)-4, IL-5, and IL-13. These cytokines help plasma cells switch to making immunoglobulin (Ig)E antibodies and promote eosinophil growth and activation. ² Mast cells (triggered by IgE cross-linking upon allergen exposure) and eosinophils release inflammatory mediators such as histamines, prostaglandins, and leukotrienes that result in clinical allergy. Estrogen may also activate non-Th2 pathways in asthma by increasing IL-17A production by T helper 17 cells, resulting in neutrophilic inflammation. ³ Meanwhile, androgens can ameliorate allergic inflammation by inhibiting the development and activity of group 2 innate lymphoid cells, B-cells, and eosinophils that typically participate in Th2 inflammation. ⁴

Impacts of estrogens and androgens on the pathogenesis of allergy manifest as sex differences in prevalence of allergic (“atopic triad”) diseases throughout life, including atopic dermatitis, asthma, and allergic rhinitis. In childhood, when estrogen (inflammatory) in girls and androgen (anti-inflammatory) in boys are relatively low, asthma and allergic rhinitis are more common in boys than in girls, while rates of eczema are similar between sexes. ⁵ With puberty, there is a marked rise of estrogen in females and androgens in males, corresponding to a shift towards female predominance in disease burden for all three atopic conditions. ⁵ The higher asthma burden in postpubertal women is also driven by dysanaptic airway growth leading to proportionally smaller airways relative to lung volume that become more prominent after puberty. Menopause, which is characterized by diminished estrogen levels, is protective against asthma and allergic rhinitis but has no relationship with nonallergic rhinitis. ^6,7

Sex Hormones in Asthma

Asthma may be dichotomized into Th2-high (more common, 50–70%) and Th2-low endotypes. ⁸ Th2-high asthma is typically more responsive to corticosteroids and Th2 axis inhibitors (e.g., omalizumab, dupilumab, mepolizumab) than Th2-low asthma, although a subset of steroid-resistant Th2-high asthma exists. ⁸ Estrogen promotes Th2-high asthma via eosinophil recruitment to the airways, IgE production, M2 polarization of macrophages, and degranulation of eosinophils, mast cells, and basophils. ¹ Meanwhile, estrogen may also potentiate Th2-low asthma via Th17 neutrophilic inflammation as mentioned above. In children (6–7 years old), the prevalence of asthma is 8% in females and 9–12% in males, with 0.8 times the odds of severe asthma symptoms in females versus males. ^5,9 By adolescence (13–14 years old), the prevalence changes to 12% in females and 10% in males, with 1.3 times the odds of severe asthma symptoms in females versus males.

The effects of estrogen on asthma may be observed in various contexts of estrogen fluctuation. Spirometric markers of asthma severity (forced expiratory volume over 1 second and forced vital capacity) worsen in girls during estrogen-dependent tanner stages of development (breast development) as compared to girls during androgen-dependent tanner stages (pubic hair growth) and boys during adrenarche. ¹⁰ Likewise, spirometric measures are worst in the luteal phase of menses when estradiol levels are high and best in the follicular phase when estradiol is low. ¹¹ Greater asthma prevalence and severity for women persists into adulthood, when females comprise 64% of asthma patients and experience higher rates of emergency department visits, hospitalizations, and mortality related to asthma as compared to men. ^12,13 Prospective data reveal that the protective effect of menopause against asthma is reversed by estrogen-containing menopausal hormone therapy. ⁶ However, combined hormonal contraceptives containing estrogen may protect against severe asthma exacerbations in younger women (ages 16–45 years old), ¹⁴ and more studies are needed to clearly define the impact of hormonal therapies in allergic disorders.

Asthma in Pregnancy

Approximately 11% of women have asthma, and 40% experience worsening of symptoms during pregnancy. ^15,16 This is secondary to a combination of hormonal, immunological, and anatomical changes. Pregnancy is characterized by increased estrogen and progesterone levels at the end of the first trimester. While estrogen drives both Th2 and non-Th2 inflammation, progesterone may increase airway reactivity and enhance eosinophilic airway inflammation in asthma. ¹⁷ Meanwhile, pregnancy is characterized by complex maternal immune shifts such as creating a pro-inflammatory decidual environment for successful trophoblastic invasion. ¹⁶ Anatomically, there is an upward displacement of the diaphragm accompanied by decreased expiratory reserve and residual volumes that may predispose to respiratory difficulty in pregnancy, especially with underlying asthma. ¹⁶ Poor maternal asthma control is associated with unfavorable maternal and fetal outcomes, including gestational diabetes, antepartum and postpartum hemorrhage, maternal intensive care admissions, preterm birth, spontaneous abortion, low birth weight, and small for gestational age status. ¹⁶ Notably, maternal asthma differentially affects placental gene expression by fetal sex, thereby reducing female but not male fetal growth. ¹⁸

Currently, most guidelines recommend step-up therapy for the management of asthma in pregnancy, which gradually increases the dose and type of medication. ¹⁹ Experts suggest SMART with a combination of inhaled corticosteroid-formoterol is safe in pregnancy when used up to 12 puffs per day. In clinical practice, if symptoms are well controlled, SMART is often continued in pregnancy. Similarly, while the data on biologics such as omalizumab and dupilumab in pregnancy is limited, guidelines support continued use, especially if a woman has shown a significant response to treatment before pregnancy. ¹⁹ Patients should also be counseled regarding comorbidities that may exacerbate asthma during pregnancy, including gastroesophageal reflux disease, respiratory viral infection, diabetes mellitus, obstructive sleep apnea, smoking, and alcohol consumption. ^16,20 Treatment of these risk factors should occur as part of the comprehensive approach to management of asthma in pregnancy. Close follow-up is advised in case therapy escalation is required to control asthma.

Explanations

Correct answer: B

A is incorrect, as approximately 40% of asthma worsens during pregnancy.

B is the correct answer. Although many women with asthma experience worsening of asthma symptoms during pregnancy, these symptoms can be effectively managed with STEP therapy. The data regarding safety and efficacy of SMART and biological therapies in pregnancy is growing, yet continuing these treatments in pregnancy is reasonable if providing good control of maternal asthma prior to pregnancy. Comorbidities that exacerbate asthma should also be addressed in a comprehensive approach.

C is incorrect, as asthma is not a contraindication to becoming pregnant.

D is incorrect since poorly controlled asthma negatively influences both maternal and fetal outcomes in pregnancy.