Sexual dimorphism is defined as differences in biological characteristics between male and female members of the same species. The presence of sexual dimorphism results from a complex relationship between evolution and genetics [1]. Genetics determines the formation of gonads within an organism. The timing with which gonadal androgens and estrogens reach their peak is also sexually dimorphic. Males experience a surge in testosterone early in life, while estrogen increases later in females [2].

Sex hormones have a significant impact on the immune system. Estrogen receptors (ERs) are expressed by many immune cells, including lymphocytes, macrophages, eosinophils, basophils, dendritic cells, mast cells, and B and T cells [3]. In high concentrations, estrogen encourages a Th2 response and aids B cell class switching to IgE [4, 5]. It can also promote mast cell and basophil degranulation [4]. Androgen receptors (ARs) are expressed in hematopoietic stem cells, lymphoid and myeloid progenitor cells, and cells from the bone marrow, thymus, and spleen [5, 6]. Unlike ERs, AR signaling typically suppresses the immune response [3], inhibiting both Th1 and Th2 responses [7]. Testosterone also reduces B cell number [8]. These effects make males generally less susceptible to inflammatory and autoimmune diseases [3].

In addition to sex-specific hormones, chromosomal expression differs between males and females. The female XX chromosomal pair undergoes incomplete X chromosome inactivation. However, ~ 15% of the 1100 genes encoded in the human X chromosome evade inactivation and can contribute to sexual dimorphism by yielding higher gene expression in females [9, 10]. For example, the innate inflammatory receptors TLR7 [11] and TLR8 [12] have been shown to escape X-inactivation. Likewise, the male-restricted Y-chromosome genes KDM5D [13] and UTY [14] have been linked to reduced inflammation, while the male gonad-determining gene SRY promotes [15] inflammation.

Interestingly, X chromosome inactivation itself promotes sexually dimorphic inflammation. The long non-coding RNA Xist is transcribed from the X chromosome only in females and generates a ribonucleoprotein complex used to inactivate the chromosome. This ribonucleoprotein includes antigenic components that can induce autoantibodies in mice. Transgenic expression of RNA Xist in males is sufficient to generate autoantibodies and reproduce female autoimmunity [16].

There is evidence of sexual dimorphism in type 2 (T2) inflammatory and allergic diseases [17]. An overactive T2 response can induce allergic diseases through the actions of epithelial cells, dendritic cells, T cells, innate lymphoid cells, eosinophils, mast cells, and basophils. Mechanisms include variations in the Th2 cytokines, interleukin (IL)−4, IL-5, IL-9, IL-13, and IL-31 [18]. Females may be predisposed to T2 inflammation due to estrogen effects. For example, a recent study showed that estrogen increases memory B cell production selectively in XX-karyotype individuals [19].

T2 allergic diseases include asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), allergic rhinitis, atopic dermatitis, chronic pruritus, eosinophilic esophagitis, food allergy, allergic conjunctivitis, chronic urticaria, and mast cell activation syndrome [20,21,22,23,24,25,26]. These inflammatory disorders can emerge in childhood or adulthood and greatly affect quality of life [27]. It is important to understand disease pathophysiology, which can be partly due to sexual dimorphism. Our aim in this review is to summarize the available literature describing sexual dimorphism in allergic disease.

Atopic dermatitis (AD) is a common condition characterized by chronic pruritus and inflammation of the skin, with a range of severity [28]. AD has become an increasingly relevant health concern, affecting > 200 M people globally, or approximately 2.5% of the population [29, 30].

AD development is related to environmental, genetic, and immunological triggers [31, 32]. Interestingly, AD is part of the “atopic march”, associated with asthma and chronic rhinitis. In this model, AD has the highest incidence rates in infancy, followed by a rise in asthma in adolescence, and allergic rhinitis after puberty [33]. AD severity varies widely, which can prove challenging for treatment. While a unified grading scale has not been established, severity indices can be used to quantify disease intensity, including the Eczema Area and Severity Index (EASI) and the SCORing Atopic Dermatitis (SCORAD) index [34, 35]. Recent treatment breakthroughs have made AD management and long-term remission more attainable.

Due to the prominent physical symptoms of the disease, AD remains a largely descriptive diagnosis. Acute (< 72-hour-old) lesions typically appear bright red and have exudate with little skin thickening. Chronic lesions are typically dull red, dry/scaly, and have thickened skin. Biomarkers such as elevated IgE levels, eosinophilia, and increased type 2 Th cell (Th2) cytokines including IL-4, IL-5, IL-13, and IL-31 are associated with AD pathogenesis [36,37,38]. A subset of AD patients (∼20%) shows normal IgE levels and no evidence of allergy. This is sometimes referred to as “intrinsic” AD [39, 40]. Progression from acute to chronic lesions has been ascribed to a transition from a largely Th2 response to a mixed Th1/Th17/Th22 response [41]. However, two RNA sequencing-based studies comparing non-lesional skin to acute and chronic AD lesions concluded that acute versus chronic lesions are largely distinguished by two features: a quantitatively greater inflammatory cytokine response and a qualitative shift to cellular repair and regeneration gene induction in late lesions [42, 43]. A unified view is that the acute-to-chronic transition is marked by enhanced cytokine responses that promote skin thickening through factors such as IL-22.

AD pathophysiology comprises interactions between the epidermis, immune system, and external environment that collectively determine disease progression [44]. Epidermal malfunction represents the most clinically distinctive characteristic of AD, with breaks in the epidermal layers associated with a Th2-dominant inflammatory response [45]. The most common malfunction in the epithelium is loss-of-function (LOF) mutation in the filaggrin (FLG) gene, which greatly increases AD incidence [46, 47]. A recent systematic review showed that the incidence of filaggrin LOF mutations varied with geographic latitude, from 15% of AD patients near the equator to > 25% in the Northern latitudes. Prevalence in the general population ranged from 2.5% near the equator to 7.5% in Northern latitudes [48]. Filaggrin is a protein produced by skin epithelial cells that maintains dermal homeostasis. Filaggrin promotes keratin filament aggregation for keratinocyte-to-corneocyte transition, enhances water retention, and maintains the skin microbiome by limiting Staphylococcus aureus growth [49,50,51]. Interestingly, IL-4 and IL-13 suppress filaggrin expression as well as compensatory tight junction proteins in filaggrin-deficient cells [52, 53]. Despite its role in AD, FLG LOF genetic testing is seldom utilized because it does not currently affect treatment [54,55,56].

Importantly, the Th2 response can promote skin barrier defects through additional mechanisms separate from filaggrin. This includes altering the lipid makeup of the dermal barrier, which contributes to stratum corneum dysfunction [57, 58]. IL-4 and IL-13 can also decrease skin acidity and decrease tight junction protein levels [53, 59, 60].

A global cohort of 6 to 7-year-olds showed varied AD incidence, from 0.9% in India to 22.5% in Ecuador [61]. In addition to variance by country, age- and sex-dependent differences are observed. Disease rates peak between the ages of 0 and 5 and gradually decrease until plateauing post-puberty. AD has no clear sex-based bias in preadolescence. However, after puberty, women have significantly higher rates of AD than men, with variations by region [29, 30, 62,63,64,65,66]. For example, the US CDC reported rates of 8.9% in women versus 5.7% for males in the US (1.5-fold), while Italy showed a female: male difference of 10% versus 6% [67]. In terms of disease severity, US- and Swedish-based studies found that females were not more likely than males to have severe AD [63, 64].

An interesting distinction is found when examining sex differences in the less common intrinsic (nonallergic) form of AD (IAD). These studies are small but show a striking female predominance. A German group showed that 16 of 18 IAD patients were female [68]. Similarly, a Japanese study showed 13 of 17 females among their IAD subjects, while in a Thai study, 6 of 7 were female [69]. Finally, a slightly larger Dutch study identified 34 IAD subjects, of which 70% were female, a rate similar to that in their extrinsic AD cohort [70]. Collectively, these studies found that 59 of 76 IAD subjects were female, a 3:1 ratio.

While AD severity does vary significantly between the sexes, sex hormones affect skin barrier permeability and hence symptomology. Testosterone impairs skin barrier function [71], while estrogen promotes it [72]. Mouse models using ovariectomy to mirror menopause showed decreased skin barrier integrity that correlated with more itch/scratch cycles and was inhibited by blocking IL-4 and IL-13 [73]. Ovariectomized mice also showed increased transdermal water loss correlated with decreased filaggrin and involucrin expression [74]. Skin barrier damage was compensated by estrogen replacement therapy [75]. In contrast, castrated male mice demonstrated increased barrier recovery that was suppressed by testosterone replacement therapy [71]. These mouse models support a common claim in the lay press that menopause worsens AD symptoms, which has not been shown in peer-reviewed studies.

Mast cells are a logical cellular target for studying AD sexual dimorphism. Estrogen has been shown to stimulate mast cell degranulation and enhance IgE-receptor induced degranulation [66, 76, 77]. On a transcriptional level, Mackey et al. observed that mast cells from female mice expressed elevated markers of allergic inflammation relative to their male counterparts. The female mast cells also had higher expression of granule-associated synthesis and storage genes, potentially contributing to higher concentrations of mediators promoting AD [78].

Innate Lymphoid 2 Cells (ILC2) are another cell type potentially driving AD sexual dimorphism. Although not strictly related to AD pathophysiology, previous findings have shown that androgens decrease ILC2 proliferation and IL-5 and IL-13 production in the lungs [79,80,81]. More recently, Chi et al. found that skin ILC2 cells express high levels of the androgen receptor and that androgens reduced skin ILC2 numbers in mice. In contrast, estrogen promotes dermal DC and Langerhans cell differentiation [82,83,84]. ILC2s produce granulocyte-macrophage colony-stimulating factor (GM-CSF), which increases skin DC numbers and hence antigen presentation [17]. Thus, estrogen could be promoting ILC2-to-DC communication that enhances Type 2 skin inflammation, while androgens suppress this cascade.

Characterized by rhinorrhea and nasal congestion, allergic rhinitis (also called hay fever) affects 13 million Americans [85] and > 500 million people worldwide [86, 87]. Global AR rates are highly variable, ranging from 1% to 60% incidence depending on the country [88,89,90]. Annual costs of AR treatment in the US totaled approximately $4.6 billion in 2022 [