Hormonal Effects on Asthma, Rhinitis, and Eczema

Abstract

Hormones significantly influence the pathogenesis of asthma, rhinitis, and eczema. This review aims to summarize relevant clinical considerations for practicing allergists/immunologists. The first section reviews the effects of sex hormones: estrogen, progesterone, and testosterone. The second concerns insulin production in the context of type 1 and type 2 diabetes. The third concludes with a discussion of thyroid and adrenal pathology in relationship to asthma, rhinitis and eczema.

1. Introduction

Variations of hormones, whether physiologic or pathologic, have effects on atopic diseases. It is of value to the practicing allergist/immunologist to appreciate these associations to provide tailored therapies and educate patients. The effects of estrogen, progesterone, testosterone, insulin, thyroxine and cortisol on asthma, rhinitis and eczema are reviewed (Figure 1).

Figure 1:

Visual representation of the endocrine glands with a table outlining the hormonal effects on allergy, rhinitis and eczema.

2. Estrogen, Progesterone and Testosterone

2.1. ASTHMA

Fluctuations in sex hormones across the reproductive stages of life can impact asthma prevalence and severity. For example, asthma prevalence and asthma-related hospitalizations are higher in pre-pubertal males compared to females^{1, 2}. Similarly, fluctuations in asthma exacerbations occur during the menstrual cycle, with higher rates in the perimenstrual phase ^{3, 4}. Pregnancy can also impact asthma severity, with a subset of pregnant asthmatic subjects experiencing a decline in symptom control and an increase in the rate of hospitalizations and oral corticosteroid use^{5, 6}. In addition, both early menarche and multiparity increase the risk of asthma ^{7, 8}. The effects of hormonal contraceptives on asthma are less clear. Some show that oral contraceptive use is associated with an increased risk of asthma and asthma symptoms amongst normal weight and overweight women (BMI 20 to 30kg/m2), but not in lean women (BMI<20mg/kg2)⁹. In contrast, others report that hormonal contraceptives reduce the risk of physician-diagnosed asthma¹⁰. Finally, researchers also demonstrated that postmenopausal women who have never used hormone replacement therapy have a lower risk of asthma compared to premenopausal women. Likewise, the use of conjugated estrogen after menopause increases the risk of asthma in a dose-dependent manner¹¹. Collectively, these studies suggest a strong influence of sex hormones on asthma pathogenesis.

Sex hormones can regulate key aspects of asthma pathogenesis, including airway inflammation, mucus production, and airway hyperresponsiveness. Ovarian hormones tend to exacerbate several of these cardinal features. In contrast, androgens have marked anti-inflammatory effects on asthma.

Various cell types, including airway epithelial cells, airway smooth muscle (ASM) cells, lymphocytes, eosinophils, and mast cells express estrogen receptors and play a pivotal role in the pathogenesis of asthma^12–19. Estrogen causes various cell-specific genomic and nongenomic actions. For example, estrogen promotes the production of nitric oxide²⁰ and mucus ²¹ from bronchial epithelial cells. In addition, it prevents the store-operated calcium entry (SOCE) into airway epithelial cells by inhibiting the phosphorylation of the stromal interaction molecule 1 (STIM1)²². These alterations in calcium homeostasis can impact ion transport and goblet cell biology, which are highly relevant to asthma pathogenesis. Estrogen also can regulate ASM function, e.g., estrogen treatment inhibits histamine-induced intracellular calcium increases in ASM¹⁹ and decreases airway responsiveness via an epithelium-dependent increase in acetylcholinesterase activity²³.

Estrogen also affects the biology of several immune cells relevant to the pathogenesis of asthma. For example, it regulates dendritic cell differentiation and cytokine production^{24, 25}, stimulates IL-4 production from CD4+ T cells²⁶, and promotes cell survival¹³,²⁷. It favors the adhesion of eosinophils to endothelial cells²⁸, their recruitment into airways ^{12, 29}, and degranulation³⁰. Likewise, it promotes mast cell degranulation ^{18, 31–34}.

Progesterone also can significantly impact asthma pathogenesis. It inhibits ciliary beat frequency in airway epithelial cells, which can impact mucus clearance ³⁵. Likewise, it attenuates airway remodeling, especially in combination with budesonide ³⁶. The effect of progesterone on mast cell degranulation is contradictory, one study indicates that it promotes activation¹⁵, another, inhibition³⁷.

Several clinical studies highlight the effects of testosterone on asthma prevalence and severity. A 2020 study demonstrates that serum testosterone levels inversely correlate with asthma prevalence³⁸. In addition, this study and others show that testosterone levels are positively associated with better forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) across different races and ethnic groups^38–40. Higher expression of the androgen receptor (AR) in human asthmatic airways is also associated with better lung function and lower fractional exhaled nitric oxide (FeNO) levels⁴¹. Finally, nebulized dehydroepiandrosterone-3-sulfate improves asthma control scores in subjects with moderate-to-severe asthma⁴².

Mechanistically, the beneficial effects of androgens in asthma occurs at multiple levels. For example, dehydroepiandrosterone induces the relaxation of ASM via an epithelial and nitric oxide (NO)-dependent pathway⁴³. Androgens also inhibit the function of group 2 innate lymphoid cells (ILC2), which are an important source of IL-5 and IL-13. Specifically, androgens attenuate the differentiation of ILC2 and decrease ILC2 numbers in the lung ^{44, 45}. In addition, testosterone decreases the adhesion of eosinophils to endothelial cells and their viability²⁸. Finally, androgens also can suppress B cell development and immunoglobulin E (IgE) production^{46, 47}.

2.2. RHINITIS

Several observational studies suggest that sex hormones impact the incidence of rhinitis. For example, late-onset menarche protects against the onset of allergic rhinitis⁴⁸. In addition, as the levels of estrogen increase during the peri-ovulatory stage of the normal menstrual cycle, there is an associated increase in nasal congestion⁴⁹. Other studies show that the nasal mucosa becomes more reactive to histamine during ovulation⁵⁰. Even though higher estrogen levels are associated with more pronounced symptoms of rhinitis, lower estrogen levels are associated with an increased risk of nasal polyposis⁵¹. Perhaps the most compelling evidence for the effects of sex hormones on rhinitis comes from studies in pregnancy. New onset rhinitis occurs in approximately 20% of pregnant women⁵², and changes in sex hormones are considered to be the primary reason for the rhinitis. However, other studies indicate that higher levels of placental growth hormones could also be implicated. The exact mechanism remains unknown^{53, 54}.

The mechanisms by which sex hormones influence rhinitis are varied. Estrogen, progesterone, and androgen receptors are all expressed in the human nasal mucosa⁵⁵. Estrogen exposure can lead to significant nasal histopathological changes, including squamous metaplasia, interepithelial edema, glandular hyperplasia, fibrous tissue deposition and increased vascularity with endothelial proliferation^{56, 57}. In addition, both estrogen and progesterone can significantly increase the H1 histamine receptor mRNA expression in nasal epithelial cells⁵⁸. Nasal mucosa exposure to estrogen or progesterone can trigger immediate hypersensitivity reactions, which suggests that these hormones can induce mast cell degranulation⁵⁹. Estrogen can also regulate the eosinophilic adhesion to human mucosal endothelial cells; both estrogen and progesterone increase their degranulation²⁸. Finally, sex hormones can regulate antibody production. In a mouse model of allergic rhinitis, antigen-specific IgE levels were higher in castrated male versus sham-operated control mice. Importantly, the levels of antigen-specific IgE decreased when the castrated mice were treated with androgens⁴⁷.

2.3. ECZEMA

Sex hormones can also regulate several skin processes highly relevant to eczema. Overall, estrogen has a positive impact on skin barrier formation and recovery, while progesterone and testosterone have detrimental effects. The prevalence of atopic dermatitis (AD) varies, as does asthma, with the onset of puberty⁶⁰. Furthermore, research shows that sex hormones cause fluctuations in transepidermal water loss, alter cutaneous blood flow during the menstrual cycle^{61, 62}, and impact skin barrier integrity and perhaps the development of AD^{63, 64}.

Several studies address the mechanisms by which sex hormones influence AD. They indicate that estrogen promotes, while androgen impairs, skin barrier integrity⁶⁵. For example, bilateral oophorectomy decreases skin hydration and the integrity of the stratum corneum, reversed by estrogen treatment⁶⁶. Other studies indicate that bilateral oophorectomy results in the downregulation of filaggrin, a filament-associated protein key to epidermal homeostasis⁶⁷. Finally, estrogen promotes the production of ceramides, key epidermal lipids, by increasing the activity of β-glucocerebrosidase⁶⁸.

In contrast, androgen impairs skin barrier formation⁶⁹. Castrated and flutamide (an AR antagonist) treated mice have improved skin barrier recovery when compared to controls. Furthermore, these effects are reversed with testosterone replacement⁷⁰. The authors suggest that testosterone alters skin barrier formation by decreasing the formation and secretion of epidermal lamellar bodies, which are critical regulators of skin permeability. Moreover, studies with topical dehydroepiandrosterone (DHEA) indicate that androgens modulate collagen synthesis and the differentiation and cornification of keratinocytes ⁷¹. Even though the above studies suggest that androgens are implicated in the pathogenesis of AD, other studies do not⁷².

Progesterone can also impact AD. Progesterone impairs skin barrier recovery, an effect potentiated by estrogen⁶⁹. Investigators propose that progesterone influences skin barrier homeostasis via an interaction with the keratocyte cell membrane, but further studies are needed. Finally, maternal sex hormones also impact AD, as illustrated by an inverse association between maternal progesterone levels and the risk of AD in girls⁷³.

3. Insulin

Diabetes mellitus (DM,) a disorder of glucose regulation⁷⁴, is categorized as type 1 (DM1) and 2 (DM2), the former by autoimmune destruction of pancreatic islet cells leading to deficient insulin production, and the latter because of insulin resistance, followed by pancreatic islet beta cell failure and loss of compensatory hyperinsulinemia. The relationship between these two DM types and atopic conditions is discussed below.

3.1. DM1

T helper (Th) 1 cells are implicated in the pancreatic islet cell destruction characteristic of DM1. Children with DM1 and their siblings versus controls have less asthma⁷⁵ raising the possibility that a predisposition towards Th1- over Th2-mediated immunity protects against the development of childhood asthma, predominantly a Th2-mediated disease⁷⁶. Conflicting evidence also is reported, where prior DM1 may reduce⁷⁷ or increase⁷⁸ the risk of subsequent asthma. A 2020 prospective study of children, ages 9–11 years, at high risk for DM1 indicates that the presence of DM1-related autoantibodies protects against subsequent asthma⁷⁹. However, in a longitudinal Dutch cohort study, similar rates of asthma exacerbations and asthma medication use over a 5-year follow-up were found both in children with and without DM1⁸⁰. Children with DM1 had similar lung function independent of atopic status with predicted values comparable to the general population⁸¹. These data suggest that the association between DM1 and asthma is complex and may be limited to specific populations.

In contrast to asthma, DM1-related autoantibodies do not protect against the subsequent development of allergic rhinitis⁷⁹. A meta-analysis did not detect an association between DM1 and this disease⁸².

AD is typically a Th2-mediated disease versus DM1, a Th1-mediated. However, Th1 cytokines are implicated in certain AD subsets⁶⁰. There is conflicting evidence of an association between DM1 and AD. An international epidemiological study found that DM1 correlates with the prevalence of AD among adolescents after adjusting for latitude⁸³. Similarly, an analysis of a Taiwanese healthcare claims database shows that children with DM1 are at higher risk to develop AD⁸⁴. In contrast, a large study of Danish twins, after appropriate consideration of sex and age, indicates that subjects with versus those without DM1 have a lower risk of self-reported AD. Furthermore, among discordant twins, the twin with versus those without DM1 had a lower risk of AD⁸⁵. Differences in geographic location and study design could account for these discrepant results. An association between DM1 and AD is not reliably established.

The mechanisms linking DM1 with atopic conditions may be unrelated to Th1-Th2 polarization and may instead relate to the effects of insulin or its deficiency on allergic inflammation or airway structural cells, not yet well understood ^86–89.

3.2. DM2

Rats and mice administered exogenous insulin exhibit enhanced bronchoconstriction⁹⁰, possibly due to increased laminin expression in airway smooth muscle extracellular matrices⁹¹. DM2 is associated with more severe asthma outcomes in adults. Insulin resistance characterizes DM2 and correlates with worse lung function ⁹². Obesity is associated with both DM2 and asthma, and insulin resistance potentiates the association between obesity and asthma⁹³. Individuals with high glycated hemoglobin in the diabetic range (HbA1C levels ≥6.5%) versus normals exhibit 33% higher rates of asthma exacerbations⁹⁴. HbA1C levels are directly associated with greater odds of asthma hospitalizations⁹⁵, and individuals with asthma and DM versus controls experience longer hospitalization rates and greater costs and risk of readmission⁹⁶. These findings indicate that DM2 has adverse effects on asthma severity outcomes. Epidemiologic studies also indicate that anti-diabetic drugs, such as metformin⁹⁷ and glucagon-like peptide-1 receptor agonists⁹⁸, may ameliorate asthma exacerbations. Clinical trials are needed to confirm this hypothesis.

Similar to asthma, many subjects with chronic rhinosinusitis (CRS) exhibit a Th2-dominant, allergic phenotype⁹⁹. Therefore, a potential relationship between DM2 and CRS has been investigated. A 2020 study, using the Korean National Health and Nutrition Examination Survey, found that both DM and HbA1C levels were associated with lower odds of allergic rhinitis¹⁰⁰. Elevated fasting blood glucose levels were associated with higher odds of allergic rhinitis in Japanese adults¹⁰¹. In contrast, elevated HbA1C levels were associated with greater odds of MRI-ascertained paranasal sinus disease. This suggests that the relationship between DM2 and CRS may vary by phenotype. The impact of DM2 on the surgical management of complicated CRS is unclear, with one retrospective study indicating a higher incidence of post-operative infections and less substantial improvements in sinonasal outcomes for individuals with DM2 versus those without¹⁰². In contrast, a case-control study described similar symptomatic improvement post-surgically between individuals with and without DM2¹⁰³. Prospective studies on the impact of DM2 on the surgical management of CRS are necessary.

The relationship between DM2 and AD remains controversial. A 2015 US survey-based study found that adults with AD have a higher incidence of DM¹⁰⁴. Similar results were reported in a large Israeli cross-sectional study of adults with moderate-severe AD. The study was adjusted for age, sex, socioeconomic status, comorbidities and smoking¹⁰⁵. In contrast, a 2018 meta-analysis did not detect an association between hyperglycemia and AD¹⁰⁶. Furthermore, a 2017 longitudinal Danish study found no relationship between DM2 and AD, and instead, proposed that associations between these two diseases was mediated by factors such as age, alcohol use, smoking, and use of topical and systemic corticosteroids¹⁰⁷. However, it is hypothesized that gestational DM could be a risk factor for childhood AD¹⁰⁸.

4. Thyroid Hormone

4.1. Asthma

Hyperthyroidism is associated with asthma exacerbations¹⁰⁹. The etiology is speculated to be related to alterations in the formation of reactive oxygen species^{110, 111}. Symptoms improve once a euthyroid state is achieved. Obtaining screening thyroid labs in asthmatics with exacerbations should be done if there are clinical signs and symptoms of hyperthyroidism¹¹² It is important not to confuse the clinical signs of hyperthyroidism, such as palpitations, anxiety, and tremors, with side effects from bronchodilators^{111, 113, 114}.

Conversely, hypothyroidism is linked to milder asthma symptoms, possibly from reduced metabolic processes from the lower T4 and T3 hormones leading to decreased oxygen consumption^115–117. During an asthma exacerbation, as with any acute illness, subjects with normal thyroid function can experience a similar protective reduction of their metabolism from a decreased conversion of the inactive T4 to the biologically active T3 hormone while maintaining normal Thyroid Stimulating Hormone (TSH) levels, a condition known as sick euthyroid syndrome ¹¹⁸. Hypothyroidism is identified more frequently in women and those older than 65 years ¹¹⁹. Women, particularly those with non-allergic asthma, have a higher prevalence of positive thyroid peroxidase (TPO) antibody levels diagnostic of Hashimoto’s thyroiditis^{120, 121}. The higher prevalence of hypothyroidism in adult females does not imply a causation of asthma, as the latter is also independently more prevalent in this gender¹²². A population based-cohort study of Danish national registers shows an increased incidence of asthma in children born to mothers with hypothyroidism. The highest risk occurs among mothers not receiving treatment for hypothyroidism during pregnancy¹²³.

History of excessive iodine intake or thyroid gland pathology raise additional considerations in asthmatics. Large iodine doses, such as from amiodarone or following CT scans, are associated with thyroid dysfunction¹²⁴. Supersaturated potassium iodide (SSKI), historically used as an expectorant by subjects with asthma, can still be obtained from compounding pharmacies. Several case reports link asthma exacerbations with SSKI-induced hyperthyroidism^{125, 126}. Tracheobronchomalacia (TBM) (weakening of the airway) or excessive dynamic airway collapse (EDAC) (bulging of the posterior wall of the trachea that moves forward to touch the anterior wall during breathing) were associated with a history of past thyroidectomy, thyroiditis, goiter, or thyroid malignancies in bronchoscopies of 34 out 264 subjects. Though these results are limited by sample size and selection bias, it remains an important consideration as subjects with TBM or EDAC can present with poorly controlled asthma despite optimal therapeutic escalation¹²⁷.

4.2. Rhinitis

Subjects with allergic rhinitis have a higher incidence of hypothyroidism versus normals¹²⁸. Hypothyroidism leads to prolonged mucociliary clearance that increases the risk of upper respiratory and sinonasal infections¹²⁹, sometimes referred to as “hormonal rhinopathy”. Clinically significant improvement in turbinate hypertrophy, mucosal pallor, clearance time and nasal peak flow were noted in 25 hypothyroid subjects with allergic rhinitis following the initiation of levothyroxine and achieving a TSH < 4.0mlU/L¹³⁰. Concomitant treatment of allergic rhinitis and hypothyroidism is more effective for the rhinitis than just hypothyroid treatment alone¹³¹. The inflammatory effect of seasonal allergic rhinitis led to exacerbations of existing and new onset Grave’s disease in case reports from Japan^{132, 133}.

4.3. Eczema

The literature does not support a cause-and-effect relationship between atopic eczema and hypothyroidism, but hypothyroidism could exacerbate it. Nummular eczema (or asteatotic eczema, a much more severe form) are characteristic of hypothyroidism. It is associated with dry skin and pruritus, subject to scratching. It presents with round, pruritic lesions (Figure 2)^{134, 135}. The more severe asteatotic eczema, also known as eczema craquelé, presents with dry, cracked and scaling skin with irregular fissuring¹³⁶. Management of both include treatment of the hypothyroidism. With autoimmune hyperthyroidism (Grave’s disease), pretibial myxedema or thyroid dermopathy, presents as non-pitting nodules caused by accumulation of glycosaminoglycans (Figure 3). Treatment of the Grave’s disease does not resolve the problem; management is supportive¹³⁷.

Figure 2:

Nummular Eczema. Image used with permission of the American Academy of Dermatology National Library of Dermatologic Teaching Slides.

Figure 3:

Pretibial Myxedema in patient with Grave’s disease.

5. Cortisol

Cortisol release is dictated by the hypothalamic-pituitary-adrenal (HPA) axis. The hypothalamus responds to complex environmental and hormonal stimuli through the neuroendocrine system. Some of these complex associations are reviewed followed by the specifics on the effects of hypo- and hypercortisolism.

There are multiple studies which show a connection between psychological stress and asthma exacerbations. Activation of the anterior cingulate cortex, insula and limbic structures in the hypothalamus initiate signal transduction directly affecting the lungs and indirectly affecting the HPA axis and the Sympathetic-Adrenal-Medullary (SAM) axis^{138, 139}. This results in amplification of Th2-type inflammation in the lungs and can lead to immune dysregulation and suppression¹⁴⁰. Early life, including prenatal stress, is linked to an increased incidence of asthma^{141, 142}.

Seasonal allergic rhinitis, a concept dubbed as “allergic mood”, is linked to depression and anxiety¹⁴³. High levels of vasoactive intestinal peptide (VIP) and substance P in the mucosal tissue of subjects with allergic rhinitis likely play a role in its pathogenesis¹⁴⁴. Alterations in the response of the HPA axis in cases of atopic eczema in subjects with depression and attention deficit hyperactivity disorders are documented^145–147. Finally, the circadian rhythm related neuroendocrine factors are associated with nocturnal pruritus in subjects with atopic eczema¹⁴⁸.

Adrenal insufficiency (AI) can be primary, from adrenal destruction, or secondary, from hypothalamic-pituitary pathology or suppression from prolonged glucocorticoid use. Although AI does not cause asthma, severe exacerbations of asthma are associated with it and can potentially trigger an adrenal crisis manifested as hypoglycemia, decreased consciousness/coma, convulsions, hypotension, abdominal pain, syncope, and death^149–151. Chronic AI can present with vague symptoms: fatigue, decreased appetite, nausea, weakness, anhedonia, and weight loss. Hyperpigmentation and salt wasting are exclusive to primary adrenal destruction. Eosinophilia can be present and resolves with corticosteroids¹⁵². If AI is suspected, a random 8–9 AM cortisol level should be performed with a low cortisol, ≤ 5 micrograms/dL, highly suspicious for the disease¹⁵³. A cosyntropin stimulation test is used to confirm the diagnosis¹⁵⁴.

Endogenous hypercortisolism, known as Cushing’s syndrome, causes extreme catabolic and anti-inflammatory effects. The latter can result in resolution of asthma¹⁵⁵. Surgical treatment of Cushing’s can lead to reoccurrence of asthma and asthma exacerbations¹⁵⁶.

6. Conclusion

Physiologic and pathologic hormonal fluctuations can impact asthma, rhinitis and eczema (Figure 1). Guidelines to screen for these endocrine disorders are lacking. Recognizing these hormonal associations and, when necessary, appropriately treating them will improve asthma, rhinitis and eczema outcomes as well as the underlying endocrinopathy. An endocrinologist, where necessary, should be consulted.

List of Abbreviations:

AD

atopic Dermatitis

AR

Androgen Receptor

ASM

airway smooth muscle

CRS

chronic rhinosinusitis

DHEA

dehydroepiandrosterone

DM

diabetes mellitus

DM1

type 1 diabetes mellitus

DM2

type 2 diabetes mellitus

FeNO

fractional exhaled nitric oxide

FEV1

forced expiratory volume in one second

FVC

forced vital capacity

HPA

hypothalamic-pituitary and adrenal axis

IgE

immunoglobulin E

ILC2

innate lymphoid cells group 2

NO

nitric oxide

SAM

Sympathetic-Adrenal-Medullary axis

SOCE

store-operated calcium Entry

SSKI

Supersaturated potassium iodide

STIM1

stromal Interaction molecule 1

Th

T helper

TPO

Thyroid peroxidase

VIP

Vasoactive intestinal peptide