Allergies are the most common chronic inflammatory disorders worldwide; triggered by immune reactions to specific allergens, which can be proteins or glycoproteins and vary widely in nature and origin (e.g., pollen, dust mite dander, food) (1). Vary allergic conditions (e.g., urticaria, asthma, atopic dermatitis, rhinoconjunctivitis, allergies to food or drugs, and anaphylaxis) share common pathogenic mechanisms, though the precise pathways remain not entirely clear (2). Additionally, epidemiological data indicate notable differences in the incidence, prevalence, and severity of allergies between sexes (3).

Globally, the prevalence of allergies is rising, with documented cases indicating that 400 million people suffer from rhinitis, 300 million from asthma, between 200 and 250 million from food allergies, and approximately 10% of the world population from drug allergies (4). Although the precise mechanisms underlying this rapid increase in prevalence are unknown, many factors can influence allergic responses; emerging evidence suggests that genetics, environment, microbiota, diet, and sex-related factors may play a significant role (5).

Allergies are generally mediated by expanding populations of helper T cells subtype 2 (Th2), which produce type 2 cytokines such as interleukin IL-4, IL-5, IL-9, and IL-13. These cytokines influence the pathology of allergies; IL-4 helps B cells differentiate into IgE-producing plasma cells, triggering an immediate allergic reaction after binding to high-affinity IgE FcεRI receptor on mast cells (6). It also promotes Th2 cell differentiation. IL-5 induces differentiation, recruitment, and activation of eosinophils (7), while IL-13 increases mucus production in the bronchial epithelium and participates in B cell activation (8).

The allergic response can be divided into two phases: sensitization and effector. During the sensitization phase, allergens can break through the body's protective mucosal barrier and be taken in by an antigen-presenting cell (APC). The APC degrades the allergen into peptide fragments and presents them to major histocompatibility complex (MHC) class II molecules. This interaction activates CD4+ T cells or Th2 cells, which, in turn, stimulate naïve B cells to differentiate into IgE-producing plasma cells (9). Upon re-exposure, allergens bind to IgE on sensitized mast cells or basophils, inducing cross-linking of IgE-FcεRI complexes, which triggers cell activation and degranulation. During the effector phase, degranulation results in the release of histamine and proinflammatory cytokines from these cells. The release of these mediators produces allergy symptoms in various organ systems and tissues, including the alveoli (Figure 1). These symptoms include upregulating inflammation, eosinophilia, smooth muscle contraction, excessive mucus secretion, vasodilation, and tissue damage; thus, persistent exposure to allergens causes the disease to become chronic (10).

Interestingly, hormonal variations have been identified to affect the immune system. After puberty, males are believed to maintain higher or similar total serum IgE and allergen-specific IgE levels compared to females. As adults, both sexes experience a decrease in IgE levels. In addition to age-related changes, menstrual cycles and pregnancy can also influence IgE levels, suggesting the role of estrogens in their regulation (11).

Clinical data supports the role of sex in the sensitization process, indicating that women may be more prone to allergies than men, including conditions such as urticaria, anaphylaxis, food allergy, and asthma (12). Additionally, clinical investigations and longitudinal studies have highlighted the higher prevalence of systemic allergic reactions in women, who are more susceptible than men to both idiopathic allergic reactions and those induced by food, drugs, and radiocontrast agents (13, 14).

Specific associations have been reported between pregnancy, hormonal therapies, and the severity of allergic reactions (15). Therefore, differences among sexes can significantly affect allergy prevention, detection, diagnosis, and treatment (16). Immunological sexual dimorphism can cause discrepancies in allergic responses in men and women because of a dynamic and complex combination of hyperreactivity, deregulated immune response, chronic inflammation, and tissue remodeling in affected organs (17).

Regarding asthma, global reports indicate variations between sexes. It is observed that men have a higher incidence of asthma until puberty. Still, after puberty, there is a switch in the ratio, and the prevalence and severity of asthma increase in women (3, 18). Furthermore, approximately 30 to 40% of asthmatic women report cyclical changes in the disease during pre and perimenstrual phases, leading to a reduction in lung function, severe asthma attacks, needing more bursts of corticosteroid, and having to be hospitalized (2, 11). Moreover, hormonal fluctuations during pregnancy and menopause may be responsible for exacerbations of asthma in women (19).

In addition to asthma, Eczema is more common among boys during childhood, but girls are more likely to have it after puberty. This indicates a switch from male to female predominance by early adulthood (20). Another example is what happened in Vernal keratoconjunctivitis, a severe ocular allergy that mainly affects boys but almost disappears after puberty (21). Even in the cases of peanut allergy, females are more affected than males (22). This could have occurred because androgens produced in more significant amounts in men after puberty generally suppress the responsiveness of immune cells (23). In this sense, changes in the sex hormones, such as those occurring at puberty, may influence the development of allergic diseases.

Although the effect of sex hormones on immune cell function, innate immune sensing in the airways, development, T-cell activation, and B-cell responses have been extensively studied, the mechanisms by which sex hormones specifically influence the sensitization process in individuals of different age groups, such as young people, adolescents, and adults remain unclear.

Age-related and sex-based differences in allergic disease prevalence highlight the significant roles of biological sex and gender-related factors in allergy development and progression. Boys tend to have a higher incidence of allergic conditions in childhood, but this trend reverses at puberty, leading to a higher prevalence in women throughout adulthood. This shift likely arises from complex interactions involving sex hormones, genetic and epigenetic regulation, lifestyle factors, microbiota diversity, and environmental exposures. Such insights emphasize the need for further studies to better understand the underlying mechanisms and the influence of gender-specific factors in the sensitization and development of allergic diseases across different life stages (24).

The term sex hormone typically refers to sex steroid hormones, which are derived from cholesterol metabolism (25). However, other non-steroidal hormones, like prolactin (PRL), which plays a vital role associated with sex, are not usually considered within this category (26, 27).

Although sex hormones have well-known effects on sexual differentiation and reproduction, they also influence the immune system and cause sexual dimorphism in the immune response (28). Thus, women often develop more robust immune responses than men, making them more resistant to certain infections (29).

However, increased immunity has significant drawbacks, particularly the high prevalence of autoimmune and allergic diseases among women. Over 80% of patients with antibody-mediated autoimmune conditions, such as systemic lupus erythematosus, Sjögren's syndrome, and Hashimoto's thyroiditis, are women. This suggests that the immunological mechanisms underlying sex differences in infectious diseases and acquired immunity to pathogens may also contribute to the higher rates of autoimmune and allergic diseases observed in women (5). These findings suggest that hormonal differences between sexes may modulate the normal and dysfunctional regulation of the immune system.

Allergic inflammation of the airways, characterized by the presence of the Th2 cytokines profile (19), is stronger in women, probably because estrogens could enhance it (30). In contrast to the drop in asthma incidence observed in and around puberty in males, the increased number of remissions observed intensely suggests the protective action of male sex hormones (31).

Some asthmatic patients present a reduced (or no) Th2-mediated airway profile; however, they present an increase in neutrophils driven by airway inflammation mediated by Th1 or Th17 cytokines profiles. These cases may respond to different causes, e.g., non-allergic asthma, corticosteroid resistance, and genetic or environmental factors, such as high levels of hormones like testosterone (32, 33).

Animal studies suggest that pregnancy is associated with cytokine polarization towards a Th2 profile, with early increases in several cytokines followed by a decrease in Th1 cytokines, such as IL-2 and Interferon gamma (IFN-γ), and an increase in Th2-like cytokines, such as IL-4, as pregnancy progresses. Thus, the physiological increase in cortisol, progesterone, estradiol, and testosterone concentrations observed during the third trimester of pregnancy could be involved in Th2-like cytokine polarization (34).

These findings suggest that sex hormones could have essential implications in immunological pathogenesis, such as asthma and hypersensitivity reactions. However, the underlying mechanisms must be fully elucidated (19, 35).

Hormones also regulate the thymus's structure and function, affecting B and T lymphocytes, mast cells, natural killer (NK) cell activity, phagocytic cells, and cytokine production (36). Additionally, they regulate type 2 innate lymphoid cells (ILC2), which are more abundant in asthmatic women than in men's peripheral blood (37).

Hormones can make these effects by binding to their receptors, triggering intracellular signaling cascades that can induce the expression of immunomodulatory genes in the pathophysiology of allergies (38).

The sex hormone receptors could be present on the surface of immune cells like transmembrane proteins or, more classically, in the cytoplasm. These receptors trigger specific cellular-type responses; for example, they can modulate antigen presentation mediated by dendritic cells, mast cells, or monocytes/macrophages, which is why they are crucial to determining the type of adaptive immune response under normal or pathological conditions (39).

Scientific evidence suggests that female sex hormones act as enhancers of autoimmunity, mast cell reactivity, and delayed-type IV allergic reactions. At the same time, male hormones and glucocorticoids may have an immunosuppressive effect (40, 41).

The following sections summarize the specific effects of sex steroid hormones and PRL on allergic reactions in humans and some animal models.

Sex hormones and corticosteroids are complex organic molecules of four rings produced in several organs, such as the adrenal glands, gonads, placenta, and adipose tissue. They all originate from cholesterol through the same steroidogenic pathway. Sex hormones include androgens (such as testosterone and androstenedione), estrogens (like estradiol, estrone, and estriol), and progesterone (42).

Other non-steroid sexual hormones, like follicle-stimulating hormone (FSH) and luteinizing hormone (LH), have low levels during menopause and are associated with allergies, such as asthma (35). Additionally, PRL is involved in allergic lung inflammation (43).

The steroid hormones function as endogenous endocrine hormones, exerting physiological effects in cells by binding to and activating specific intracellular proteins called nuclear receptors (NRs). Class I NRs include estrogen receptors alpha (ERα) and beta (ERβ), androgen receptor (AR), glucocorticoid receptor (GR), progesterone receptor (PR), and mineralocorticoid receptor (MR) (44).

Hormones readily penetrate the cell membrane to the cytosol; NRs are located mainly in an inactive state, forming an inactive complex with heat shock proteins (HSP) (27). When a steroid ligand binds to its receptor, it dimerizes, then translocate to the nucleus and binds to specific palindromic sites called hormone response elements (HRE) located in the promoters of target genes; NRs can activate or repress their transcription, which means that they act as transcription factors (30, 31, 36).

The effects mediated by hormones are also due to their ability to regulate gene expression without direct binding to DNA but rather through protein interactions with other transcription factors that bind to DNA, including nuclear factor -κB (NF- κB), specific protein 1 (Sp1), CCAAT-enhancer-binding protein β (C/EBP β), or Fos/Jun AP-1 complex (activator protein-1); which are all involved in the synthesis of proinflammatory cytokines by innate immune cells (45, 46).

Glucocorticosteroids (GCs), also known as corticosteroids or steroids, are natural regulators that play a vital role in regulating various biological processes such as the hypothalamic-pituitary-adrenal axis, immunity, and energy metabolism to maintain balance within the body. Cortisol, the primary glucocorticoid synthesized and secreted by the adrenal cortex, interacts with the GC receptor (GR) to regulate multiple human signaling pathways (142). Synthetic GCs are immunosuppressive drugs for treating immune-related disorders, including allergies (143). The most common treatments for asthma are inhaled glucocorticoids for suppression of inflammatory gene expression and β2-adrenergic receptor agonists for inhibition of bronchoconstriction (144).

Synthetic GCs bind to its cognate intracellular receptor GR with higher affinity than endogenous glucocorticoids, which means synthetic glucocorticoids are more potent immunoregulators than cortisol because they are not subject to endogenous inhibitors of cortisol activity (143).

The mechanisms by which natural or synthetic GCs mediate their genomic effects involve binding the GCs to GR homodimers in the cytoplasm, forming the GC/GR complex. This complex translocates to the nucleus, where it interacts with glucocorticoid response elements (GRE), which are 15 bp in length and consist of two pseudo-palindromic hexameric sites separated by a three bp spacer: GGAACAnnnTGTTCT (where n, is any nucleotide) (145). GRE is present in the promoter regions of steroid-sensitive genes (transactivation), or it can inhibit the activity of transcription factors (transrepression) (Figure 3) (146). Moreover, GCs have non-genomic effects that involve the direct interaction of liganded GR with diverse intracellular mediators, modulating several signaling pathways, including protein kinase C (PKC), phosphatidylinositol-specific phospholipase C (PI-PLC), and SRC kinase pathways (38).

The GR is encoded by a nine-exon NR3C1 gene, positioned at 5q31–32 in humans. GR is a 777-amino acid multidomain protein like the other NRs; the GRs comprise the domains: a variable N-terminal domain, a C-terminal domain, and a DNA-binding domain containing zinc fingers capable of binding to DNA (122). GRs are expressed by nearly all nucleated cells, but the functional effects of glucocorticoids differ by cell type. The variety in GR signaling arises from the influence of distinct GREs and numerous receptor isoforms that emerge through alternative splicing and the commencement of alternative translations (147).

The GCs are the primary therapy for managing airway inflammation in asthma (148). The GC/GR complex leads to the expression of anti-inflammatory genes and suppression of pro-inflammatory gene expression, thus inhibiting Th2 cell-mediated inflammation in the airways. Additionally, GR interacts with coactivator molecules to suppress the expression of inflammatory genes by inhibiting the action of proinflammatory transcription factors such as NF-kB and activating protein 1 (AP-1) (149) to suppress the production and release of cytokines, proinflammatory chemokines, and airway epithelial cell adhesion molecules, which are crucial in the pathogenesis of asthma (150).

GATA3 is the master transcription factor of Th2 cells. It helps differentiate them from CD4+ lymphocytes to Th2 cells. It promotes the expression of IL-4, IL-5, and IL-13, which mediate allergic inflammation. Furthermore, it is essential for developing ILC2 progenitors (ILC2p) in the bone marrow and maintaining mature ILC2 populations in the periphery (151).

The GC/GR complex competes with GATA-3 for nuclear import via importin-α. Higher concentrations of GC increase the expression of MAP kinase phosphatase (MKP)-1, which inhibits p38 MAP kinase activity and prevents GATA-3 phosphorylation. This phosphorylation is necessary for GATA-3's interaction with importin-α and subsequent nuclear import (151). Moreover, GCs reduce the immune response and inflammation and trigger the differentiation toward Type 1 regulatory T (TR1) cells by a FOXP3-dependent mechanism (152).

PRL is a 23 kD peptide hormone primarily produced by lactotroph cells in the anterior pituitary gland. It is named for its ability to promote lactation in response to the suckling stimulus of hungry young mammals. However, it can also be produced in the ovaries, prostate, mammary gland, brain, and immune cells (153).

Cytokines that promote PRL production, including IL-1, IL-2, and IL-6, regulate it, while endothelin-3 and IFN-γ have inhibitory effects. Post-translational modifications can result in different isoforms of PRL (153), including small, large, and macro PRL. Among these isoforms, the small one, which consists of 199 amino acids and weighs 23 kDa, is the most biologically potent (154).

PRL plays a significant role in regulating both innate and adaptive immune responses. It affects the maturation of CD4-CD8- thymocytes into CD4+ CD8+ T cells by regulating the expression of the IL-2 receptor (155). Studies suggest that PRL is involved in deregulating B cell activation, which can lead to autoimmunity (156). Moreover, PRL has been found to either promote or regulate the production of cytokines, including Th1 and Th2 type cytokines, IL-6, IFN-γ, and IL-2 (157, 158).

The PRL receptor (PRLR), which belongs to the type 1 cytokine/hematopoietic superfamily, is expressed in various immune cells, including monocytes, lymphocytes, macrophages, NK cells, granulocytes, thymic epithelial cells, and Treg cells (159). Therefore, the interaction of PRL with its receptor plays a critical role in regulating immune cell proliferation, differentiation, secretion, and survival through signaling pathways (Figure 4) (160, 161).

PRL has been shown to promote the transcription of interferon regulatory factor 1 (IRF-1), a critical factor in the maturation of T and B cells. Additionally, it can trigger the production of inducible NO synthase (iNOS), an enzyme that generates NO and participates in immune responses and inflammation. Furthermore, PRL can enhance the synthesis of IFN-γ in both T and NK cells (162).

PRL is also a modulating apoptosis agent that regulates the expression of genes such as BAX and BCL2. This allows it to have an immunological maintenance function in stress states and can counteract the apoptotic effects of GCs on lymphocytes (163).

In allergies, such as eosinophilic esophagitis, PRL has been studied from the point of view of the T cells involved in inflammation: CD3+, CD4+, and CD8+, which are of great importance because they produce cytokines of the Th2 profile, PRL can regulate the production of these cytokines (164).

In addition, it has been observed that patients with allergic fungal sinusitis may present hyperprolactinemia. This rhinological disease is relatively new and is characterized by polyposis, fungal remnants, and hypersensitivity (165). Until now, the relationship of PRL with this pathology has mainly been due to the compression of the pituitary gland, which stimulates the deregulation of the synthesis of hormones (166).

On the other hand, in asthma, it has been evaluated and reported in murine models that domperidone-induced hyperprolactinemia exhibits a decrease in lymphocytes in bronchial lavage, a cellular decrease in femoral marrow lavage fluid, and mucus. Furthermore, it has been related to an increase in IL-4, IL-6, IL-10, TNF-α, and IFN-γ in the lungs, causing the allergic inflammatory response of the lungs to decrease (43).

A study conducted by Tugrul Ayanoğlu et al. compared the serum PRL levels of patients with atopic dermatitis and controls. They suggest that PRL may not play a role in disease pathogenesis (167).

Overall, while PRL's role extends beyond lactation to significant immunological functions, its exact impact on various allergic conditions remains an area of ongoing research, warranting further studies to elucidate its full spectrum of biological activities.

Paradoxically, steroid hormones can trigger what is yet a rarely diagnosed disease, which is hormonal allergy (168). Several studies have suggested that sensitization to steroid sex hormones may cause clinical symptoms such as dermatitis, dysmenorrhea, rhinitis, pruritus, and erythema multiforme (169). In severe cases of hypersensitivity to sex hormones, anaphylaxis, a life-threatening allergic reaction with rapid onset, has been observed (170). Case studies have shown that patients suffer unexplained anaphylactic reactions for years before sex hormone allergy is diagnosed correctly (171–175).

Hormone hypersensitivity can be triggered by pregnancy, exogenous hormone intake, oral contraceptives, and in vitro fertilization. These factors indicate multiple potential causes, including hormone administration, elevated hormone levels during pregnancy, and increased hormone sensitivity (168). The underlying mechanism remains unclear; however, it may involve IgE antibodies, T cells, an inappropriate cytokine response, natural killer (NK) cell activity, or drug hypersensitivity (176).

Progesterone hypersensitivity (PH) can occur due to natural progesterone production or after allergic sensitization to progestins used for contraception and fertility treatment, which may be recognized as foreign by the immune system (177). Thus, progestogen-specific IgE antibodies may be formed in susceptible patients following exposure to exogenous progestins. PH mainly affects young females, with fewer than 200 cases reported to date (178). As we mentioned before, one of the risk factors includes exposure to exogenous progestins and high-dose progesterone for in vitro fertilization. The exact cause of PH is unknown, but it is likely multifactorial due to its varied symptoms, including skin issues like dermatitis, urticaria, erythema multiforme, and other immediate reactions (179).

Allergies are the most common worldwide diseases with an increasing prevalence and incidence. The influence of sex hormones (i.e., estrogens and androgens) on the allergic response is relevant in the appearance of autoimmune diseases and allergies in women and men (5). However, female hormones give more susceptibility to developing allergies like asthma, food allergies, or hypersensitivity than males (180). This gap in the prevalence of allergies in women and men may be regulated by hormones derived from cholesterol or peptides. Women often develop stronger immune responses, and during menstrual cycles, pregnancy, or menopause, allergic inflammation appears, perhaps because estrogens enhance the production of the Th2 cytokine profile (19, 30).

Cytokines produced by the immune system mediate the pathophysiology of allergies. About the Th2 cytokines IL-4/IL-13, some inhibitory monoclonal treatments contribute to decreasing asthma symptoms (181). However, the antibodies of the treatment show different therapeutic effects in the groups of patients, and this could be explained by the fact that some genetic alterations within the cytokines coding genes were not contemplated (182). The US Food and Drug Administration (FDA) has approved several anti-IL-5 therapies targeting eosinophilic disorders. For eosinophilic asthma, all three biologics—mepolizumab, benralizumab, and reslizumab—are approved for adults aged 18 and older, with both mepolizumab and benralizumab additionally approved for patients aged 6 and above (183).

Several research groups around the world have documented the complex connection of steroid sex hormones with menstrual cycle and allergies (168). In the case of HRT, estrogens trigger asthma symptoms due to the activation of the immune system in postmenopausal women (98). On the other hand, the treatment with Tamoxifen (estrogen receptor blocker) has reported good results in neutrophilic inflammation in animal models (184). However, its usage may cause fertility problems in the long term and some other cardiovascular side effects in both sexes (185, 186).

The use of Pg as a pro-inflammatory cytokines suppressor has shown promising results in animal models with allergic lung inflammation (114–116). However, the cases of Pg hypersensitivity are increasing because of contraceptives and fertility treatments (187). Exposure to exogenous Pg may present symptoms like dermatitis, urticaria, angioedema, asthma, or anaphylaxis. In these cases, it has been reported that the Pg desensitization protocol is effective (177, 188).

As we described above, allergic diseases are associated with low levels of testosterone and high levels of estrogen (189). In this context, replacement therapy with testosterone in men with allergies due to hypogonadism impacts positively on the anti-inflammatory cytokines stimulation and Treg differentiation (190). This replacement therapy in women with allergies has been considered, but several side effects data must be obtained before releasing a safety therapy (191).

Other hormones, like GCs, are primary immunosuppressive drugs for inflammation in asthma. However, some adverse effects are registered in patients with chronic treatments, and they are indicated only in anaphylaxis crises or emergencies associated with pro-inflammatory effects. Nevertheless, contradictory data on the severity of allergies have been shown; some studies have associated hyperprolactinemia with a decrease in asthma symptoms (43), but others have reported no differences in PRL serum levels in dermatitis (167, 192).

Hypersensitivity to hormones may include several allergic responses with different symptoms. These allergic reactions may be treated with monoclonal antibodies such as Omalizumab, which avoids anaphylaxis (193, 194).

Finally, it is essential to acknowledge the significant controversy surrounding findings on each hormone's role in either alleviating or worsening allergic symptoms. Research that considers genetic, epigenetic, and environmental factors is needed to advance the development of precision medicine tailored to individual patients. This approach will deepen our understanding of the diversity across various allergic conditions.