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Keywords:

  • androgen;
  • estrogen;
  • gender;
  • immediate hypersensitivity;
  • progesterone

Abstract

  1. Top of page
  2. Abstract
  3. Atopic eczema
  4. Allergic asthma
  5. Allergic rhinoconjunctivitis
  6. Food allergy
  7. Anaphylaxis, urticaria, and angioedema caused by hymenoptera venom
  8. Anaphylaxis, urticaria, and angioedema caused by neuromuscular blocking agents
  9. Anaphylaxis, urticaria, and angioedema caused by radiocontrast medium
  10. The influence of menstruation, pregnancy, oral contraceptive, and menopause on disease activity
  11. Experimental evidence of the influence of sex hormones on allergy development
  12. Acknowledgments
  13. References

Gender differences in the development and prevalence of human diseases have long been recognized. Immense interest grows in the understanding of the role of sex hormones in the homeostasis of immunity. Asthma predominates in boys before puberty and this gender preference reverses after puberty and in adulthood, when adult women tend to have a more severe disease, often recalcitrant to treatment. Atopic eczema in preschool children shows insignificant gender difference or male preponderance in different studies, with more adult females suffering from atopic eczema. The limited data on the prevalence of immediate hypersensitivity to hymenoptera venom show controversial results. Discrepancy exists regarding the gender difference in food allergy, with females reporting significantly more allergic reactions in questionnaire studies. In general, adverse reactions to nonionic iodinated radiocontrast media are more commonly observed in females. The course of allergic diseases varies unpredictably during pregnancy, whereas hormone replacement therapy in postmenopausal women usually has a favorable influence on the course of asthma. Experiments in rodents confirm an effect of estrogens on mast cell activation and allergic sensitization, while progesterone is shown to suppress histamine release but potentiate IgE induction. Dehydroepiandrosterone may antagonize the production of Th2 cytokines but the effect of testosterone and the other androgens remains less defined. Actual data from human studies are lacking.

The worldwide prevalence of allergy, especially IgE-mediated atopic diseases, has increased dramatically over the last decades (1). The genetic predispositions, environmental factors, and social behavior interplay to orchestrate the scenario of allergy manifestation. Several clinical and epidemiologic studies have indicated gender differences in the prevalence of allergic diseases. In a single-year analysis of adult cases in an emergency department from Australia, females outnumbered males in both acute allergic reactions and anaphylaxis (2). Adult women suffered from urticaria, angioedema, and anaphylaxis more frequently than men, although the gender difference was reversed among children (3). Chronic urticaria, characterized by the recurrence of hives with or without angioedema for more than six weeks, involved predominantly women (4). The cumulative prevalence of allergies in the Viennese population was higher in women (32.2%) than in men (27.6%) (5). The results of skin prick tests in 981 children at age four from UK confirmed that boys were more often atopic than girls at this age with a male preponderance observed with most allergens, but this was statistically significant only for house dust mite and grass pollen (6). In the age group 6–7, the general increase in clinical symptoms of asthma, allergic rhinoconjunctivitis and atopic eczema (AE) was similar in boys and girls, while in the age group 13–14, the increase was generally more marked among boys (7). In a questionnaire study on Japanese adolescents aged 12–15 years, male gender was independently associated with an increased prevalence of wheezing and a decreased prevalence of AE (8). Female predominance of eczema seems to be limited to the reproductive period of 15–49 years (9).

Laboratory studies further suggest a dynamic change of the gender-specific distribution in atopic diseases. The overall sensitization rate and sensitization to mites, grass and tree pollens were significantly higher in male gender, especially in children under the age of 8 years. After 8 years of age, the male predominance persisted but a significant increase in sensitized females occurred (10). In an Israeli study, specific IgE antibodies to aero-allergens and food were significantly higher in males than in females under 20 years of age, while more women were positive than men above the age 21 years (11).

This paper reviews the state of knowledge on epidemiologic and experimental evidence regarding the influence of gender differences or sex hormones on the development of allergic reactions and diseases. Analysis of disease characteristics and course before and after puberty, during menstruation and gestation, in pre- and postmenopausal period will also help elucidate the effect of sex hormones on allergy. The term ‘gender’ and ‘sex’ will be used interchangeably and indiscriminately in the text, although the former may refer more to psychosocial influence and the latter to biological vulnerability which very likely exert a synergistic effect on allergy sensitization and manifestation.

Atopic eczema

  1. Top of page
  2. Abstract
  3. Atopic eczema
  4. Allergic asthma
  5. Allergic rhinoconjunctivitis
  6. Food allergy
  7. Anaphylaxis, urticaria, and angioedema caused by hymenoptera venom
  8. Anaphylaxis, urticaria, and angioedema caused by neuromuscular blocking agents
  9. Anaphylaxis, urticaria, and angioedema caused by radiocontrast medium
  10. The influence of menstruation, pregnancy, oral contraceptive, and menopause on disease activity
  11. Experimental evidence of the influence of sex hormones on allergy development
  12. Acknowledgments
  13. References

Conflicting evidence exists with respect to gender preference in the prevalence of AE in children and adolescents. Some authors suggest that the natural history of AE points towards male predominance in childhood and female predominance from adolescence onwards (12). In a prospective cohort study of pregnant women and their offspring in USA, male gender was associated with increased risk of AE in the first 6 months of life (13). In a prospective, population-based case-control study of 2-year-old children from Sweden, more boys than girls had ongoing AE and positive IgE-sensitization was more common in boys than in girls with ongoing AE (14). The prevalence of AE among 2-year-old children in Trondheim, Norway showed a higher prevalence in boys, without significant gender difference in disease severity (15). The point prevalence and the severity of AE in children younger than 4 years in central Netherlands also showed male preponderance particularly marked at the age younger than 2 years (16). In another prospective birth cohort study of children followed for 5 years from Western Australia, extrinsic AE was more common in boys while intrinsic AE was more common in girls (17). Similar results were found in preschool children aged 5–7 years from Germany, of them boys were more often atopic, whereas girls suffered significantly more often from nonatopic ‘intrinsic’ eczema (18). In studies conducted during 1992–2001, in cross-sectional surveys in 5–7-year-old children in Switzerland, rates of AE symptoms showed a significant increase in girls but remained stable in boys, while the increase in the prevalence of asthma and rhinoconjunctivitis might have ceased (19).

In contrast, a prospective study of AE in children aged 0–42 months in England showed no gender difference in either the incidence or prevalence of the disease (20). Similar findings were observed in another case-control study of children at age 3.5 years in New Zealand (21). In a prospective, longitudinal, birth cohort study of Danish children born to mothers with a history of asthma, the prevalence rate peaked at age 2 years for boys and at age 2.5 years for girls, but there was no gender difference in the proportion of children developing AE, and girls and boys did not differ in AE severity measured by the SCORAD index (22). Male gender was a nonsignificant risk factor in a multiple logistic regression analysis of 3–5-year-old children from Italy (23). In a dermatologist-directed inspective survey of school children aged 6–11 years from Taiwan, no gender difference existed in the point prevalence of AE (24). A population-based cross-sectional study on children aged 5–7 and 9–11 years from Germany showed even more girls than boys suffering from AE (25).

After puberty, there appears no more gender difference or even female predominance in adolescents with AE, as demonstrated in many recent ISAAC questionnaire-based surveys (26, 27). In adults, limited studies showed a higher prevalence of eczema in female gender (28–30).

Allergic asthma

  1. Top of page
  2. Abstract
  3. Atopic eczema
  4. Allergic asthma
  5. Allergic rhinoconjunctivitis
  6. Food allergy
  7. Anaphylaxis, urticaria, and angioedema caused by hymenoptera venom
  8. Anaphylaxis, urticaria, and angioedema caused by neuromuscular blocking agents
  9. Anaphylaxis, urticaria, and angioedema caused by radiocontrast medium
  10. The influence of menstruation, pregnancy, oral contraceptive, and menopause on disease activity
  11. Experimental evidence of the influence of sex hormones on allergy development
  12. Acknowledgments
  13. References

The gender differences and related patterns are more definitive in allergic asthma (31–33). In childhood, boys are disproportionately more often affected by allergic asthma, while this difference disappears in pre-adolescence when females have a much higher incidence after puberty (34–36). In many studies using the ISAAC questionnaire, significantly more female than male students attending grades 7–12 reported asthma, wheezing, rhinitis, and hay fever (37). In a large cohort of subjects at age ≥ 12 years with severe or difficult-to-treat asthma, females reported obviously more asthma-control problems, lower asthma-related quality of life and more allergic comorbidities, such as allergic rhinitis and AE (38). In a self-reported longitudinal study throughout childhood into adult life in Finland, boys tended to have a higher incidence rate of asthma than girls in childhood before age 16 years, while gender preference was reversed at age 17–22 years, and in early adulthood at age 23–32 years, incidence rates were equal in both genders (39), and definitely greater in women aged 23–64 years (40). On the other hand, analysis of children at 9–11 years of age in Norway showed that the prevalence of asthma in girls has reached a plateau and even decreased from 1995 to 2000, which was in contrast to the asthma prevalence in boys that appeared to increase on a continuing basis (41).

Allergic rhinoconjunctivitis

  1. Top of page
  2. Abstract
  3. Atopic eczema
  4. Allergic asthma
  5. Allergic rhinoconjunctivitis
  6. Food allergy
  7. Anaphylaxis, urticaria, and angioedema caused by hymenoptera venom
  8. Anaphylaxis, urticaria, and angioedema caused by neuromuscular blocking agents
  9. Anaphylaxis, urticaria, and angioedema caused by radiocontrast medium
  10. The influence of menstruation, pregnancy, oral contraceptive, and menopause on disease activity
  11. Experimental evidence of the influence of sex hormones on allergy development
  12. Acknowledgments
  13. References

In a questionnaire study on preschool children aged 3–5 years, male gender was one of the significant risk factors for rhinitis (42). The male gender was also prevalent for rhinitis among 6–7-year-old children from the western districts of São Paulo city, Brazil (43). Studies from Norway showed the prevalence of allergic rhinoconjunctivitis increased steadily from 1985, 1995 to 2000 (41). In Finland, the incidence rate for allergic rhinitis in males at age 16–32 was 13.4/per 1000 person-years, slightly greater than that in females with 11.4/per 1000 person-years (39). Among both genders, the highest incidence rate of allergic rhinitis was between 17 and 22 years. In another self-report questionnaire study on adults from Stockholm, Sweden, there were no statistically significant gender differences in the prevalence of either allergic or nonallergic symptoms (44). However, women reported more severe psychosocial effects such as social embarrassment and depression/irritation in both perennial allergic rhinitis and nonallergic rhinitis (45).

Food allergy

  1. Top of page
  2. Abstract
  3. Atopic eczema
  4. Allergic asthma
  5. Allergic rhinoconjunctivitis
  6. Food allergy
  7. Anaphylaxis, urticaria, and angioedema caused by hymenoptera venom
  8. Anaphylaxis, urticaria, and angioedema caused by neuromuscular blocking agents
  9. Anaphylaxis, urticaria, and angioedema caused by radiocontrast medium
  10. The influence of menstruation, pregnancy, oral contraceptive, and menopause on disease activity
  11. Experimental evidence of the influence of sex hormones on allergy development
  12. Acknowledgments
  13. References

The data regarding gender difference in food allergy are inconsistent, especially those between questionnaire studies and detection of specific IgE antibodies or skin prick test. In questionnaire studies, a gender bias may exist with significantly more females reporting self-diagnosed food allergy than males (46, 47). With reference to asthma and food allergy, prevalence is higher in boys before puberty, while this gender ratio is reportedly reversed after puberty (48). No gender difference could be identified in the prevalence of food allergy in schoolchildren from Toulouse, France (49), or in children with severe allergic reaction to cashew nut in England (50). In a study on specific IgE to peanut in patients with a history of nut sensitivity from England, there was no difference in age or gender, but males seemed to develop the immediate hypersensitivity at an earlier age (median age 5.8 years) as compared with females (median age 8.8 years) (51). However, another study on specific IgE antibodies to peanut in children (median age 10.4 years) from Western Sweden showed a significantly higher percentage of positive results in males (23%) than in females (18%) (52). Perceived prevalence of peanut allergy in the general population in Great Britain showed an overall female predominance, while male outnumbered female only in the age group 0–14 years, but reversed in age group 15–44 years or above 45 years (53). A Norwegian study on severe allergic reactions to food found that the gender distribution of severe reactions showed a female-over-male dominance at 60/40 in adolescence and adulthood, while this gender difference was not apparent in early life at the age of 18 months (54). In a population-based, nested, case–control study using a standardized interview with skin prick testing, a significantly greater number of adult women (27.5%) than men (14%) were suffering from food allergy/intolerance, most frequently associated with nuts, fruits, and milk (55). In an analysis of food-allergic and anaphylactic events in the National Electronic Injury Surveillance System collecting samples from hospital emergency departments in USA, the majority of reported events occurred in white persons (58%) and female subjects (63%) (age range 1 month to 86 years, median 26 years) (56), which was consistent with the national food allergy data (57).

Food-associated, exercise-induced anaphylaxis might account for up to one-half of the cases of exercised-induced anaphylaxis and is most common in female patients 15–35 years of age (57). In a questionnaire study on Japanese junior-high-school students, however, the frequency of food-dependent, exercise-induced anaphylaxis was significantly higher in boys than in girls, while the frequency of exercise-induced anaphylaxis showed no gender difference (58).

Anaphylaxis, urticaria, and angioedema caused by hymenoptera venom

  1. Top of page
  2. Abstract
  3. Atopic eczema
  4. Allergic asthma
  5. Allergic rhinoconjunctivitis
  6. Food allergy
  7. Anaphylaxis, urticaria, and angioedema caused by hymenoptera venom
  8. Anaphylaxis, urticaria, and angioedema caused by neuromuscular blocking agents
  9. Anaphylaxis, urticaria, and angioedema caused by radiocontrast medium
  10. The influence of menstruation, pregnancy, oral contraceptive, and menopause on disease activity
  11. Experimental evidence of the influence of sex hormones on allergy development
  12. Acknowledgments
  13. References

There is no gender difference in a multivariate regression analysis of 1,175 Italian children (age 74–162 months) regarding positive skin prick test to Hymenoptera venoms (59). In Sweden, however, sensitization to bee or wasp correlated positively with atopy, male gender, and age (60). In a study on a rural Mediterranean population from Eastern Spain, the prevalence of systemic reactions and local reactions to Hymenoptera venom was similar among both genders, but men experienced predominantly large local reactions (61). There was no gender difference in the severity of systemic reaction to bee sting in a Turkish study (62). On the other hand, female patients appeared to experience more reactions than the male patients regarding the adverse reactions to injection immunotherapy in bee and wasp venom allergy (63).

Anaphylaxis, urticaria, and angioedema caused by neuromuscular blocking agents

  1. Top of page
  2. Abstract
  3. Atopic eczema
  4. Allergic asthma
  5. Allergic rhinoconjunctivitis
  6. Food allergy
  7. Anaphylaxis, urticaria, and angioedema caused by hymenoptera venom
  8. Anaphylaxis, urticaria, and angioedema caused by neuromuscular blocking agents
  9. Anaphylaxis, urticaria, and angioedema caused by radiocontrast medium
  10. The influence of menstruation, pregnancy, oral contraceptive, and menopause on disease activity
  11. Experimental evidence of the influence of sex hormones on allergy development
  12. Acknowledgments
  13. References

The most common causes of anaphylaxis during anesthetics were neuromuscular blocking agents (>50%), antibiotics and latex. Succinylcholine, rocuronium and vecuronium were most frequently incriminated in recent literature (64, 65). A significant female predominance was observed in both immune-mediated anaphylactic and nonimmune-mediated anaphylactoid reactions irrespective of the causal agent (66). In Norway, IgE-mediated anaphylaxis was found in 71.1% of the cases, and neuromuscular blocking agents were by far the most frequent allergen (93.2%) (65). Moreover, significant gender differences were observed between drugs, with males reacting more likely to atracurium and females experiencing more adverse reaction to suxamethonium. Although more women than men reported allergic reactions (73%vs 27%), the mortality associated with suxamethonium was significantly higher in males than in females (22%vs 9%). The female preponderance, however, was reversed for subjects under 10 years of age as compared with the peak age during life decade 31–40 years (67).

Hospital-based studies suggested a female predominance regarding drug-induced anaphylaxis or a history of immediate penicillin allergy with a positive skin prick test to at least one of the penicillin-related determinants used (68, 69).

Anaphylaxis, urticaria, and angioedema caused by radiocontrast medium

  1. Top of page
  2. Abstract
  3. Atopic eczema
  4. Allergic asthma
  5. Allergic rhinoconjunctivitis
  6. Food allergy
  7. Anaphylaxis, urticaria, and angioedema caused by hymenoptera venom
  8. Anaphylaxis, urticaria, and angioedema caused by neuromuscular blocking agents
  9. Anaphylaxis, urticaria, and angioedema caused by radiocontrast medium
  10. The influence of menstruation, pregnancy, oral contraceptive, and menopause on disease activity
  11. Experimental evidence of the influence of sex hormones on allergy development
  12. Acknowledgments
  13. References

The frequency of reactions to radiocontrast media was reported to be equally distributed between males and females in the USA (70). There was no gender difference in the incidence of adverse reactions to high-osmolality ionic monomeric contrast medium sodium iothalamate or sodium meglumine diatrizoate in Indian patients (71). However, a majority of deaths was found in women (60%) in a study on the deaths attributed to X-ray contrast media based on U.S. Death Certificates from 1999 through 2001 (72). In an analysis of spontaneous reporting data about adverse reactions to contrast media from Italy, there was no significant difference in gender distribution in 100 collected cases, but females appeared to be vulnerable to serious reactions, especially in fatal cases (73). In patients undergoing intravenous urography with the nonionic monomeric contrast medium iobitridol, significantly more females displayed associated adverse events when compared with males (74), while no gender difference existed in the frequency of serious adverse events. Noteworthy was the different pre-existing risk factors; the coronary artery disease was more often observed in male patients, while asthma and/or allergies and a previous reaction to contrast media were more often observed in females (75). In a study of iodinated contrast medium hypersensitivity, the male/female ratio for the immediate and nonimmediate reactions was 1 : 1.5 and 1 : 4.5, respectively (76). The death cases and delayed/late adverse reactions induced by intravenous iodinated contrast media were more common in women than in men (77). Delayed adverse events were seen significantly more often in female patients in the nonionic dimeric group, while there was no gender-related difference in the monomeric or control group (78). Seventy percent of the patients were found to be girls in a retrospective evaluation of medical records concerning acute allergy-like reaction to intravenous nonionic iodinated contrast medium in children (79). A similar study on acute allergy-like reactions to gadolinium-containing intravenous contrast media showed 63% of the adult and 83% of the pediatric patients were females (80).

The influence of menstruation, pregnancy, oral contraceptive, and menopause on disease activity

  1. Top of page
  2. Abstract
  3. Atopic eczema
  4. Allergic asthma
  5. Allergic rhinoconjunctivitis
  6. Food allergy
  7. Anaphylaxis, urticaria, and angioedema caused by hymenoptera venom
  8. Anaphylaxis, urticaria, and angioedema caused by neuromuscular blocking agents
  9. Anaphylaxis, urticaria, and angioedema caused by radiocontrast medium
  10. The influence of menstruation, pregnancy, oral contraceptive, and menopause on disease activity
  11. Experimental evidence of the influence of sex hormones on allergy development
  12. Acknowledgments
  13. References

Pregnancy is well recognized to influence the course of asthma and AE (81, 82). Overall, an equal number of women have asthma or eczematous symptoms that improve, worsen, or are unchanged through pregnancy (83). The mechanisms involved remain ill-defined, but the interaction of increased levels of cortisone, estradiol and progesterone is supposed to play a pivotal role. Although the course in an individual woman is largely unpredictable, severe asthma tends to get worse during pregnancy (84). If symptoms worsen, it usually occurs in the second and third trimesters, with the peak in the sixth month. Generally, there is improvement in asthma in the last four weeks of pregnancy. Asthma tends to return to the pre gestational state within 3 months postpartum. Successive pregnancies tend to have a similar course in each individual. Early studies showed sex steroid hormones have little or no effect on humoral IgE levels during pregnancy (85). However, a recent observation suggested that the risk of asthma in adult women increased with the number of births but decreased by the use of oral contraceptives (86). In an analysis of lifetime prevalence of atopic diseases in elderly people (mean age 62 years) from Germany, the lifetime prevalence of AE and asthma among women as well as the lifetime prevalence of hay fever among both genders strongly decreased with age (87). A greater reduction in estrogen secretion was found in postmenopausal asthmatic women than in postmenopausal healthy women (88). Hormone replacement therapy in postmenopausal asthmatic women has a favorable influence on the course of asthma, reducing daily use of glucocorticosteroids and frequency of asthma exacerbations and normalizing serum concentrations of estradiol, cortisol, and dehydroepiandrosterone (DHEA), which were lower before hormone replacement (89). Table 1 summarizes the prevalence rate of the aforementioned allergic diseases.

Table 1.   Age-dependent gender differences in the prevalence of some allergic diseases in general population
DiseasesAge/gender
Preschool children (age < 6 years, M/F)Schoolchildren (age 6–11 years, M/F)Adolescent (age 12–17 years, M/F)Adult (age > 18 years, M/F)
  1. Values other than in the parenthesis are expressed in percentages. Numbers in the parenthesis refer to the citation in reference.

  2. *Atopic status: at least one positive skin prick test or presence of allergen-specific IgE values of 0.35 KU/l (class I) or greater.

  3. †Hospital-based or case–control studies.

Atopic eczema
 Questionnaire17.6/18.7 (23) 18.1/15.0 (15)8.3/12.3 (25) 21.1/23.8 (7)4.15/3.91 (27) 19.6/19.3 (7) 17.0/25.7 (117)6.04/8.01 (28) 4.6/5.5 (29) 3.7/4.8 (87)
 Doctor’s diagnosis15.6/15.4 (23) 19.1/22.2 (15) 3/2.3 (16)5.7/7.7 (25) 16.8/20.7 (118)5.6/7.7 (117) 3.8/3.4 (117) 14.1/16.5 (118)5.1/9.3 (30)†
 Atopic status*11.7/4.2 (10) 1.5/1 (112)10.8–16.4/3.2–13.4 (10)18.0/12.5 (10)32.9/25.0 (119)
Allergic asthma39.0/28.1 (32) 12.7/9.2 (33)17.0/10.5 (41)11.0/10.5 (33) 32/44 (33) 12.8/10.7 (117)1/1.86 (40)†
Food allergy1.27/1 (51)† 0.91/0.63 (peanut; 53) 0.28/0.79 (peanut; 53) 14/27.5 (55) 
Neuromuscular blocking agents†1.8/1 (64)† 1/2.3 (64)† 1/3 (63)† 
Radiocontrast media1/2.3 (79)† 0.024/0.055 (75) 1/1.5–4.5 (76)† 

Experimental evidence of the influence of sex hormones on allergy development

  1. Top of page
  2. Abstract
  3. Atopic eczema
  4. Allergic asthma
  5. Allergic rhinoconjunctivitis
  6. Food allergy
  7. Anaphylaxis, urticaria, and angioedema caused by hymenoptera venom
  8. Anaphylaxis, urticaria, and angioedema caused by neuromuscular blocking agents
  9. Anaphylaxis, urticaria, and angioedema caused by radiocontrast medium
  10. The influence of menstruation, pregnancy, oral contraceptive, and menopause on disease activity
  11. Experimental evidence of the influence of sex hormones on allergy development
  12. Acknowledgments
  13. References

The influence of sex hormones on mast cell activation

In general, estrogens can enhance humoral immunity and antibody synthesis, while androgens and progesterone seem to suppress immunity and inflammation (90, 91). Mast cells express estrogen receptor-α (92), and estradiol treatment augments its expression, while tamoxifen inhibits the same (93). Some environmental estrogens, alone or in combination with physiological concentration of 17β-estradiol, could cause a rapid, dose-related enhancement of IgE-mediated release of β-hexosaminidase from a human mast cell line and primary culture of bone marrow-derived murine mast cells (92). Physiological concentration of estradiol alone induced a probably nongenomic, estrogen receptor-α-mediated release of β-hexosaminidase from RBL-2H3, BMMC, and HMC-1 mast cell lines. Estradiol also enhanced IgE-induced degranulation and potentiated leukotriene C4 production in RBL-2H3 cells (94). Estradiol preincubation of the rat uterine mast cells could enhance the histamine release induced by anti-IgE but such enhancement was not induced by substance P or compound 48/80 (95). On the other hand, the sex hormones, estrogen, and testosterone, in contrast to glucocorticoids, could neither inhibit the IgE-dependent IL-4 generation in human basophils at transcriptional level (96) nor the post-transcriptional expression of FcεRI in mouse mast cells (97). However, castration in pubertal male rats could markedly reduce the peritoneal but not the lung histamine concentration, which was restored to the normal level in the testosterone-replacement group (98). In clinical skin prick testing, male allergic subjects were found to have higher histamine reactivity (99).

Progesterone at 100 nM was able to suppress the histamine secretion from purified rat peritoneal mast cells stimulated immunologically or activated by substance P (93). Pregnenolone, DHEA, and DHEA-sulfate (DHEAS) were found to cause rapid degranulation of β-hexosaminidase release from RBL-2H3 (100). In patients with hormone-related exacerbation of recurrent idiopathic anaphylaxis or in control subjects, progesterone and estradiol did not appear to influence the histamine release from basophils (101).

The chemokine ratio of CXCL10 (formerly interferon-gamma-inducible protein-10) to eotaxin declined over the course of pregnancy and was associated with more pronounced asthma symptoms, while both CXCL10 and eotaxin serum level increased postpartum. Alterations of Th1/Th2 chemokine balance during pregnancy may help identify women who are prone to more severe asthma during pregnancy (102). In nonpregnant women, healthy or asthmatic, the numbers of IL-4- and IFN-γ+ T cells in the blood were very low. Within the asthmatic pregnant group, significant negative correlation existed between the highly increased numbers of IFN-γ+ or IL-4+ T cells and maternal peak expiratory flow (103).

The influence of sex hormones on allergic sensitization

Female mice developed a more pronounced allergic airway inflammation than male mice after ovalbumin aerosol challenge with reduced percentage of regulatory T cells in the lungs (104). In CBA/J mice sensitized with phospholipase A2, females produced significantly higher levels of phospholipase A2-specific IgE than males. On the other hand, both titers of phospholipase A2-specific IgG1 and nasal eosinophilia did not differ significantly between the two groups. As compared with sham-treated male mice, castrated male mice produced significantly higher amounts of phospholipase A2-specific IgE, which decreased in castrated mice treated with testosterone. Gender differences in the production of antigen-specific IgE were not seen in BALB/c mice after the sensitization with Schistosoma mansoni egg antigen (105). A single subcutaneous injection of estradiol was shown to partially abrogate the tolerance induction of IgE antibody formation and promote allergic sensitization in mice or rats by repeated inhalation of low levels of ovalbumin (106). When exposed to aerosolized house dust mite allergen, the progesterone-treated mice showed significantly greater levels of serum total IgE as compared with the untreated group. Upon stimulation with Concanavalin A, significantly more IL-4 was produced in lung homogenate cells from animals treated with house dust mite allergen plus progesterone compared with placebo-treated animals (107).

The airway inflammation and blood eosinophilia induced by Dermatophagoides farinae was significantly reduced in DHEA-fed mice, which was associated with a decrease in serum IL-4, IL-5, and INF-γ levels. Total IgE antibody concentrations in serum and bronchoalveolar lavage fluids were not affected by the DHEA treatment. These results demonstrated that DHEA could suppress pre-existing allergic airway inflammation and that the suppressive effect of DHEA was associated with a downregulation of Th2 response (108). The administration of DHEA profoundly suppressed the spontaneous elevation of both serum IgE and IL-6 levels in NC/Nga mice, a model animal of human AE (109). Serum DHEA concentrations in adult male patients aged 19–30 years with AE were significantly lower than those of age-matched healthy male controls. Preincubation of peripheral blood mononuclear cells with DHEA reduced IL-4 and IL-5 production stimulated by concanavalin A (110). However, as there is no known specific hormone receptor for DHEA, it remains to be determined if the effect of DHEA is mediated through its quantitative conversion into testosterone or estradiol in men vs women.

In cultures of mononuclear cells from atopic patients, production of IgE and IgG4 was enhanced by hydrocortisone, but not by testosterone, 17β-estradiol, or progesterone (111). Dexamethasone induced a time-dependent increase in cellular histamine amount in mouse bone marrow-derived mast cells. Sex steroids, such as 17β-estradiol, androsterone, and testosterone, did not alter the histamine content of the cultured cells, whereas progesterone induced a moderate increase (112). In vivo, higher testosterone levels during pregnancy were associated with a lower IgE production in boys (113). The effect in boys was even stronger in the absence of maternal atopic disease. No gender difference was observed between the testosterone levels and positive skin testing results or atopic diseases. PHA-induced IFN-γ responses were higher in boys at age 1 and 3. Among children who wheezed during the third year of life, boys had increased IFN-γ, IL-5, and IL-13 responses and also demonstrated increased rates of sensitization, total IgE levels, and peripheral eosinophils (114).

In conclusion, experimental data showed that estradiol may enhance mast cell activation and allergic sensitization in rodent model, which is probably degranulator-selective or allergen-specific, respectively. Progesterone, on the other hand, has a discrepant effect in suppressing the histamine release but potentiate the IgE formation. DHEA appears to be able to downregulate the production of Th2 cytokines but not really the IgE levels. More studies are needed to clarify the regulatory effect of sex hormones in the allergy development in humans (Table 2).

Table 2.   Experimental data of the influence of sex hormones on allergy development
HormonesAllergy
SensitizationElicitation
  1. Numbers in parenthesis represent the references.

EstradiolFemale mice developed a more pronounced ovalbumin-induced allergic airway inflammation than male mice (105) Promote allergic sensitization and IgE production in mice or rats induced by inhalation of low levels of ovalbumin (106)Enhance IgE-mediated or direct release of β-hexosaminidase from RBL-2H3, BMMC, and HMC-1 mast cell lines Enhance IgE-mediated histamine release from rat uterine mast cells Do not influence the IgE-dependent IL-4 generation in human basophils (92–97)
ProgesteroneIncrease a higher level of serum total IgE in mice allergic to house dust mite Enhance the concanavalin A-stimulated IL-4 production in lung homogenate cells from animals treated with house dust mite allergen plus progesterone (107)Suppress histamine release from purified rat peritoneal mast cells (93)
TestosteroneSuppress phospholipase A2-specific IgE in CBA/J mice (105)Do not influence the IgE-dependent IL-4 generation in human basophils (96)
DehydroepiandrosteroneReduce the airway inflammation and blood eosinophilia, but not the total IgE antibody in BALB/c mice induced by Dermatophagoides farinae (108) Suppress the spontaneous elevation of both serum IgE and IL-6 levels in NC/Nga mice (109)Induce rapid degranulation of β-hexosaminidase in RBL-2H3 (100)

In clinical studies, clear gender differences in prevalence exist in asthma and probably also other atopic diseases with a male preponderance before puberty and a reversal of this gender preference after adolescence. Elucidating the mechanism underlying this switch in gender prevalence should provide new insights into atopy development. The challenge is to match the epidemiologic and pathophysiologic data with the accumulating scientific knowledge on gender differences in immune responses (36). Androgens appear to have immunosuppressive effect and are likely to be protective, while estrogens are proinflammatory and might increase the susceptibility to atopy. In analogous situation to autoimmune diseases, the immune imbalance or disturbance in atopic diseases may involve interaction between immunity, infection, inflammation, and hormones. It is unclear why estrogens predispose in some women to autoimmune diseases while in others to atopic diseases, which uncommonly concur in clinical settings (115, 116). A better understanding of the effect of sex hormones on sensitization and elicitation of allergic reactions may initiate new strategies for therapy and prevention of atopy.

References

  1. Top of page
  2. Abstract
  3. Atopic eczema
  4. Allergic asthma
  5. Allergic rhinoconjunctivitis
  6. Food allergy
  7. Anaphylaxis, urticaria, and angioedema caused by hymenoptera venom
  8. Anaphylaxis, urticaria, and angioedema caused by neuromuscular blocking agents
  9. Anaphylaxis, urticaria, and angioedema caused by radiocontrast medium
  10. The influence of menstruation, pregnancy, oral contraceptive, and menopause on disease activity
  11. Experimental evidence of the influence of sex hormones on allergy development
  12. Acknowledgments
  13. References