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Gender-related differences in chronic urticaria
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Nicoletta CASSANO, Delia COLOMBO, Gilberto BELLIA, Emanuela ZAGNI, Gino
Antonio VENA
G Ital Dermatol Venereol 2015 Jun 19 [Epub ahead of print]
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA

Rivista di Dermatologia e Malattie Sessualmente Trasmesse
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Differenze legate al genere nell’orticaria cronica
Nicoletta Cassano,1 Delia Colombo,2 Gilberto Bellia,2 Emanuela Zagni,2 Gino A. Vena1
1Dermatology and Venereology Private Practice, Bari and Barletta, Italy; 2 Novartis Farma,
Origgio, Varese, Italy
Corresponding author: Nicoletta Cassano; Dermatology and Venereology Private Practice,
Bari and Barletta; E-mail: nicoletta.cassano@yahoo.com
Word count: 4106
65 References
1 Table
1
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Summary
Chronic urticaria (CU) is a common skin disorder with important repercussion on the quality
of life and a relevant socioeconomic impact. CU is included among the skin diseases that
exhibit a significant female preponderance, with an average female to male ratio of nearly 2-
4/1. In recent years, an ever-growing interest in gender medicine has been registered and the
assessment of gender differences has increasingly become an attractive issue in clinical
research. Unfortunately, there are only limited data relative to the study of CU in the
perspective of gender medicine. However, apart from the predilection for females, an in-depth
evaluation of the available literature shows the existence of other interesting gender-related
differences in CU. The aim of this article is to review the current knowledge on gender
differences in CU under different points of view, including pathophysiology, epidemiology,
clinical and prognostic features, association with comorbidities, psychological aspects and
quality of life.
KEY WORDS: Chronic urticaria – Chronic spontaneous urticaria – Gender – Gender differences
– Gender medicine - Epidemiology – Quality of life.
Introduction
Urticaria is a group of skin diseases characterized by pruritic wheals, angioedema or both.
Chronic urticaria (CU) is defined on the basis of a duration of more than 6 weeks.1 Although
usually without life-threatening consequences, CU is a disabling and frustrating disease that
has substantial repercussions on the quality of life (QoL) and healthcare costs.2 Chronic
spontaneous urticaria (CSU) is the most common type of non-acute urticaria, and consists in
the spontaneous occurrence of clinical manifestations, that are not therefore evoked by
physical and/or environmental factors as happens in physical and other inducible urticarias.3
Autoimmune pathomechanisms have been implicated in a relevant proportion of CSU
patients, in whom histamine release has been attributed to circulating IgG antibodies specific
for the high-affinity IgE receptor (Fc RI) expressed on the surface of mast cells and
basophils.4 A screening test supportive of autoreactivity is the autologous serum skin test
(ASST), whose positivity suggests the presence of circulating histamine-releasing factors of
any type, and not only of functional autoantibodies.1 The frequent association with thyroid
autoimmunity along with the predilection for women is believed to represent further indirect
evidence of a possible autoimmune origin of CSU.4
CU is included among the skin diseases that exhibit a significant female predominance, with
an overall female/male ratio of approximately 2-4/1.5
In recent years, an increasing interest in gender medicine has been acquired and the study of
gender differences has progressively become an attractive issue in clinical research. The
possibility of different clinical presentation of human diseases between the two genders may
be due to differences in various factors, including anatomy, physiology, immunity, genetics,
sociocultural aspects, with complex interactions among such factors. In this context, sex
hormones play a fundamental role, bearing in mind that these hormones have a relevant
influence on the immune and inflammatory responses, thus contributing to the pathogenesis
of immune-mediated human diseases.5
The objective of this article is to review the current knowledge on gender differences in CU
from various perspectives and with special emphasis on pathophysiology, epidemiology,
clinical, prognostic and psychological aspects, as well as comorbidities and QoL.
Sex-related pathophysiological peculiarities and role of sex hormones
There are well-established differences between women and men in the structure and function
of the skin, immune responses, and molecular biology, while no functional differences seem
to exist in the cutaneous microvascular response to histamine.5
Significant gender differences have been detected in pruritogen-induced scratching behaviour
in mice, with more intense scratching in females, 6 whereas similar aspects have not been
explored in human beings. Serum IgE levels were shown to be much higher in allergic female
mice compared to male mice.7 Female mice were also prone to develop more severe
anaphylactic responses. This effect has been related to the estrogen-induced increased tissue
expression of endothelial nitric oxide synthase and nitric oxide production, leading to vascular
hyperpermeability.8
As concerns the immunological effects of sex hormones, it is known that androgens tend to
have an immunosuppressive action through multiple mechanisms, and progesterone similarly
seems to suppress immunity and inflammation. In contrast, estrogens can stimulate humoral
immunity and antibody synthesis.5 The susceptibility of mast cells to the activity of sex
hormones is highlighted by the expression of receptors for these hormones on their cell
surface.7,9 Testosterone however proved unable to induce mast cell degranulation. 9,10
Experimental studies showed that estradiol may activate mast cells and enhance IgE-induced
degranulation.11,12 Progesterone may preferentially act as a negative regulator of mast cell
degranulation but it potentiates IgE formation.11,13,14
5
The available data on the effect of sex hormones on CU disclose contradictory results. It has
been reported that urticaria may be associated with some conditions characterized by
hormonal changes, including endocrinopathy, menstrual cycle, menopause and hormonal
contraceptives or hormone replacement therapy.15 Bork et al16 suggested however that any
impact of oral contraceptives and hormone replacement therapy on CU worsening is probably
very marginal. Urticaria/angioedema syndrome may appear or worsen in some pregnant
women while it can improve during pregnancy in others.17
Hormonal fluctuations during the menstrual cycle are also thought to influence urticaria
expression. Progesterone- or estrogen-dependent urticaria should be suspected in women who
present with cyclic appearance of hives with each menses or CU lesions with periodic
exacerbations.15 Hypersensitivity reactions to endogenous or exogenous female sex hormones
have been implicated in the pathogenesis of these forms. Autoimmune progesterone
dermatitis is a rare cyclic disease that can be characterized by premenstrual exacerbation of
urticaria and angioedema. Urticaria typically appears at the end of the luteal phase and
spontaneously disappears or improves a few days after menses. Estrogen-related urticaria
shows an unremitting chronic course, with constant premenstrual peaks in disease activity.
An association between wheals and menstruation was observed in 4.8% of the 1,113 female
patients with CSU evaluated in the study of Zhong et al.18 A recent case report suggested the
relationship between irregular menstrual cycle and CU symptoms, which resolved after
commencement of oral contraceptive therapy.19
Dehydroepiandrosterone (DHEA) and its sulphate ester (DHEA-S) are secretory products of
adrenal glands, that are converted to either androgens and estrogens in the periphery. DHEA
may antagonize the production of Th2 cytokines.11 A reduced concentration of DHEA-S,
likely to be the consequence of psychological distress, has been demonstrated in CU patients,
regardless of their gender and response to ASST.20
Epidemiological aspects
CU is known to be more common among middle-aged women. In previous studies, with the
exception of only isolated reports, most authors found male/female ratios of 1:2.21-25 In a
representative cross-sectional survey of the population of the city of Berlin, 26 women were
more likely than men to have CU (70.3% vs. 29.7%). In a population-based study among
adults in Spain,27 the comparison between sexes disclosed a clear-cut female preponderance,
with an odds ratio (OR) of 3.82. The age of onset followed the same profile in men as in
women. A cross-sectional analysis using insurance claims in the United States showed that
two-thirds of patients with claims consistent with CSU/chronic idiopathic urticaria were
females.28
A descriptive prospective study carried out in Brazil enrolled a total of 125 patients with CU
to obtain sociodemographic and clinical data.29 Of these patients, 76% were female, giving a
male/female ratio of 1:3. Among the patients’ occupations, 52.8% were classified as inactive
(32% housewives). In accordance with literature data, the authors noted that the
predominance among females was between the ages of 30 and 40 years, whereas, among
males, it was between 10 and 30 years. On the contrary, Helgreen and Hersle30 reported
predominance among males between 30 and 40 years old. A Swedish study in 330 CU
patients showed a different age distribution between women and men: in particular, most
women were aged 24-38 years with a clear peak at age 29, while most of the men were aged
18–54 years with no peak in the age distribution at all.21 Another study suggested a somewhat
later age of onset in men affected with CU as compared to female patients.31
Interestingly, a case series in CU elderly patients consisted of a lower proportion of females
as compared to adult non-elderly subjects with CU (46.7% vs 69.2%).32
A prospective, cross-sectional, questionnaire-based epidemiologic investigation analyzed the
7
clinical and laboratory features of 3,027 patients diagnosed with CU recruited at 19 tertiary
referral hospitals in China over 9 months.18 Again, female preponderance was observed
(female/male ratio, 1.46:1), although it was not seen in patients <20 years of age. The most
common type of CU was CSU, and among CSU patients, 60.3% were females. Women
accounted for 58.4% of patients with physical urticarias. More females were affected with
cold contact urticaria (65.9%) and dermographism (57.8%), while females suffered less
frequently from cholinergic urticaria (15.6%).
Associations with other conditions
The autoimmune paradigm supporting the pathogenesis of a subset of CSU cases implies the
possible link with other autoimmune diseases due to the increased susceptibility for
autoimmunity, in terms of clinical associations, as well as overlapping pathomechanisms and
genetic background.
CSU has been associated with thyroid disorders and in particular with those of autoimmune
nature. This association has long been recognized as significant on various occasions, in spite
of some methodological bias in various studies, such as the heterogeneity of the criteria used
to diagnose thyroid autoimmunity, the small sample size and/or the absence of a well-
controlled design in many of these studies. In a study of CSU,33 the OR for hypothyroidism
was 4.6 (CI = 1.00-21.54) and for hyperthyroidism 3.3 (CI = 0.38-28.36), while autoimmune
thyroid disorders were detected in 19.1% of CSU patients. According to previous results, 12-
37% (median, 26%) of CU patients have thyroid autoantibodies.34 A recent meta-analysis has
confirmed that the prevalence of positive thyroid autoantibodies is higher in CU patients than
controls.35 The pathophysiology of the association between CU and thyroid autoimmunity is
not well understood, but anti-thyroid antibodies are believed to act only as a non-specific
indicator of autoimmunity.33
It is well known that thyroid disorders, in all clinical variants with the inclusion of
autoimmune forms, are much more common among women than men. 36 Some investigators
have also shown that the risk of association between CSU and thyroid autoimmunity is higher
in females.37,38 In a recent large study of 12,778 CU patients,38 hypothyroidism was the most
commonly detected thyroid disease in patients with CU, found in 9.8% of patients and 0.6%
in the control group. Females were more likely to be affected by the combination of
hypothyroidism and CU than their male counterparts.
Consistent with other reports, among 257 CSU patients examined by Asero,39 ASST positivity
was observed in 65% of cases, whereas the overall prevalence of thyroid autoimmunity and
thyroid dysfunction were 26% and 15%, respectively. ASST positivity was more frequently
detected in female patients, as well as in the presence of thyroid autoantibodies. Therefore
thyroid autoimmunity appeared to be strictly associated with autoreactivity on ASST. Based
on these findings, Asero postulated the possible role of different CSU pathomechanims in the
two sexes, with a predominant autoimmune basis in female patients, while most male patients
may have an idiopathic disease.39 Anyway, it is likely that thyroid autoimmunity and
histamine-releasing activity are simple epiphenomena associated with CSU but that they are
not directly involved in the pathogenesis of the disease.37 Nevertheless, an intriguing
hypothesis was recently raised from the observation that a subgroup of CSU patients
expresses IgE antibodies against thyroid peroxidase. These autoantibodies could cause an
“autoallergic” mast cell activation, a novel pathogenic mechanism proposed for CSU.40
Najib et al37 studied the frequency of thyroid autoimmunity and serum basophil activation
testing (BAT-CD203) in 236 patients with CSU. BAT-CD203 (measuring CD203 expression)
was used as an indirect marker to identify functional histamine-releasing autoantibodies
taking into account the presumed correlation of BAT-CD203 with histamine-releasing
activity.41 The frequency of thyroid autoimmunity was particularly high in this cohort of CSU
9
patients, amounting to 30% of cases. The frequency of thyroid autoimmunity and BAT-
CD203 positivity was higher in females. In this study, 37 there was however no correlation
between BAT-CD203 and thyroid autoimmunity, as well as between antinuclear antibodies
(ANA) and BAT-CD203, or ANA levels and thyroid autoimmunity.
Females are more susceptible to develop various autoimmune disorders in addition to those
involving the thyroid gland. Female patients with CU were shown to have a significantly
higher incidence of rheumatoid arthritis, Sjogren’s syndrome, celiac disease, type I diabetes
mellitus, and systemic lupus erythematosus, mostly diagnosed during the 10 years after the
diagnosis of CU.38
The association of CU and cancer is still controversial, although a recent population-based
cohort study in Taiwan has evidenced an increased risk of malignancies, especially of
hematological malignant tumors and particularly of non-Hodgkin lymphomas, in patients with
CU.42 Most cancers were detected within the first year following diagnosis of CU. The risk of
developing cancers was not influenced by gender.
Clinical features and prognostic aspects
Most findings appear to indicate the absence of a relevant influence of gender on CU severity.
In fact, a hospital-based epidemiological study did not reveal any significant differences by
gender in the mean urticaria activity score (UAS),18 a well-established composite score that
incorporates the number of wheals and itch intensity.3 However, in an internet patients’
survey, women were found to have worse Skindex symptoms scores than men, and to be more
often bothered by symptoms on several body parts.43,44 Legs, wrists⁄hands/palms, face and
scalp were more often affected in women than men, whereas armpits and ears were more
frequently affected in men. These observations might have important treatment implications
and reflect differences in anatomical distribution of symptoms or in underlying
pathomechanisms.39,43-45 In fact, it has been hypothesized that CU may have a different
etiology or more severe pathogenesis in women, leading to a more severe outbreak of
symptoms,39 or can show symptoms with different anatomical patterns in men and women,
thereby affecting more sensitive body parts in women. 43 Furthermore, an alternative
speculation takes into account that women’s skin and/or mental perception can be more
sensitive to CU symptoms.45
A Swedish study of 209 women and 121 men with CU found that only 24% and 41% had
only urticaria without angioedema, respectively. 21 In a case series of Brazilian patients with
CSU, physical urticaria and mixed forms,46 women were more likely to have angioedema than
men (84.4% versus 52.9%; p=0.024). Interestingly, a case-control study showed that the risk
of angioedema among CSU patients with autoimmune thyroid disease was 16.2 times greater
than among those without this thyroid abnormality. 33 This observation can therefore justify
the increased prevalence of angioedema among female patients described in some
circumstances.21,46
There are only very few reports regarding prognostic features in CU patients. A retrospective
study analyzed 100 children aged ≤ 18 years (male/female ratio 1.27) followed for CSU
during an 8-year period.47 ASST was performed in 45 of these 100 children and was positive
in 46.7% of them, with a female predominance (71.4%). In 13.8% of the children, ANA titers
were over 1/100. ASST results were not associated with ANA positivity and/or high levels of
inflammatory markers. CSU had a favorable prognosis and half of the children with CSU
recovered without any relapse within 5 years. The median recovery time was 4.0 years for
boys and 5.8 years for girls; however, the results were not statistically significant (p = 0.351).
Risk analysis regarding the prognosis was performed with univariate and multivariate
analyses, and several factors were considered, including age, gender, abnormal laboratory
results, ASST positivity, a family history of autoimmunity, or the presence of angioedema or
11
other allergic diseases. Though in multivariate analysis none of these factors predicted the
prognosis in children with CU, in univariate analysis being female and being older than 10
years of age increased the risk of an unfavorable prognosis.47 These findings corroborated
results previously obtained in adult patients with CU. In particular, in a study investigating
2,523 CU patients with a negative ASST, multiple regression analysis showed that female
gender was defined as a risk factor for poor prognosis, along with a long duration of the
disorder at the initial examination, and the presence of angioedema and physical urticarias.48
Some findings led to support that CU duration is associated with the presence of both ASST
and anti-thyroid antibodies, with ASST but not anti-thyroid antibodies significantly associated
with CU severity.49 Autoreactivity has been repeatedly detected in a higher proportion of
females with CU as compared to the male counterparts. 39,46,47 It is therefore plausible that the
risk of a poor prognosis in CU may be increased by the female gender, being related to a
higher susceptibility to autoreactive and autoimmune mechanisms, although specific studies
are needed to define this issue.
Patients with CU may experience wheal flares when exposed to aspirin and other nonsteroidal
anti-inflammatory drugs (NSAIDs). Hypersensitivity to NSAIDs is being observed with
increasing frequency, mainly because of the large size of the exposed (at risk) population.
Some predisposing factors for these cutaneous reactions have been identified, among them
atopic diathesis, young adulthood, a history of CU, the use of the NSAID for the relief of
acute pains and finally female sex.50
Very few studies have evaluated the effect of gender on therapeutic outcome in CU patients.
A retrospective analysis of clinical and laboratory characteristics of patients with
antihistamine-responsive CSU and antihistamine-resistant CSU disclosed a similar female
preponderance, without significant differences between the two groups.51 Another
retrospective study demonstrated that age, disease duration from the onset to the first visit,
and treatment steps were the significant prognostic factors for the improvement of CSU.52 On
the contrary, there was no statistical significance with respect to gender.
In a retrospective chart review in adult CU patients treated with cyclosporine, multiple
variables were analyzed independently for their influence on response to cyclosporine.53
Overall, 53 (78%) of the patients in this cohort were able to achieve a complete remission on
cyclosporine therapy. Having a shorter duration of urticaria and a history of hives were was
found to be predictive of the effectiveness of cyclosporine in these patients. Variables such as
age, response to steroids, presence of anti-thyroid antibodies, and ASST results were not
found to be significant. Of note, male sex and a positive ANA more or equal 1:80 status
approached significance.
Quality of life and psychological aspects
CU frequently results in severely impaired QoL, with effects somehow comparable to those
experienced by patients suffering from ischaemic heart disease.54 CU patients generally
experience difficulties attributable to their skin condition in relation to many facets of
everyday life including home management, personal care, social and sex life, recreation,
mobility, emotional factors, sleep, rest and work. Many studies, most of which using the
Dermatology Life Quality Index (DLQI) questionnaire, consistently gave rise to scores
suggestive of a moderate to severe impairment of QoL.18,46,55,56
A large variation within different urticarial subsets has been however found. In the study of
O’Donnell et al,54 patients with delayed pressure urticaria complained of more pain, had more
difficulties with work, hobbies, and choice of clothing than the uncomplicated CU patients.
According to Poon et al,57 the association of angioedema and dermographism did not confer a
significant increase in morbidity, whereas subjects with delayed pressure urticaria and
cholinergic urticaria endured the most QoL impairment. A Chinese report indicates that the
13
high DLQI scores were detected in patients with CSU than those with other CU forms, and in
presence of angioedema and ASST reactivity.18 Some authors55 reported that the presence of
angioedema was the only variable that was significantly associated with worst scores on
DLQI. Other authors,58 who measured QoL by means of Skindex-29, noted that QoL
impairment was not influenced by the age or sex of patients, the absence or presence of
angioedema, or the duration or cause of CU.
There are controversial data on the presence of gender differences in CU-related QoL. Some
studies using the DLQI questionnaire documented that the total DLQI scores were not
influenced by gender.18,57 No significant differences were observed between males and
females for each question score of the DLQI questionnaire.18 On the contrary, Poon et al57
reported that men were significantly more disabled in the subdomains of leisure and work
compared with women.
A Brazilian study examined the impact of CU on QoL of 100 outpatients using the DLQI
questionnaire.55 Female patients reported greater impact on clothing, while male patients
reported more frequently interference with work and study, and problems with treatment (p <
0.05). Another Brazilian study was conducted in 62 patients with CU, consisting in CSU,
physical urticaria and mixed forms, using both DLQI and SF-36.46 QoL was found to be more
impaired in women, in patients of up to 30 years of age, in those with higher education levels,
in patients who had had the disease for up to one year and in those with angioedema. In
women, there were statistically worst scores compared to men in the daily activities domain
of the DLQI (p=0.003). More specifically, this domain may involve situations that lead to
greater negative repercussions on women (i.e., difficulties in shopping or taking care of the
house, or the influence on choice of clothing). In the SF-36, the effects on the vitality
(p=0.038), role-emotional (p=0.018) and mental health (p=0.020) domains were more
impaired in women. This indicates a possible psychological and emotional vulnerability in
women coping with CU.
The impact of CSU on QoL was evaluated in 125 Australian and Sri Lankan patients, 59 using
the chronic urticaria quality of life questionnaire (CU-Q2oL), a new specific tool with a good
level of validity, internal consistency and reliability.60 There were no differences between
sexes in all the items explored by the questionnaire, with the only exception of sleep
disturbances, as females had more difficulty falling asleep.59 Previous reports have however
indicated that women, in general, have a higher prevalence of sleep disturbances compared to
men.61
Another study performed in Germany by means of the CU-Q2oL assessed the QoL in a
sample of 157 subjects with CU of different severity and duration. 45 Sex significantly
predicted itching/embarrassment (P =0.048), and limits looks (cosmetics, limit clothes) (p <
0.001), being women more severely affected on both scales.
An internet survey was conducted with 321 randomly selected, representative adults in
Germany and France who were diagnosed with CU.44 The survey included the Skindex-29
questionnaire on QoL and questions about treatment usage and patients’ relation to their
physician. The survey confirmed that CU has substantial impact on QoL. Satisfaction and
trust were shown to be low in patients with CSU, thus impairing the adherence to prescribed
treatment. There was a tendency for women (OR = 1.88, p = 0.051) to not be under a
physician’s care for their CU. None of the sociodemographic variables significantly predicted
the Skindex functioning or emotions scores. The regression analysis identified sex as the only
significant predictor of the Skindex symptoms score (p < 0.001), as women were found to be
more affected than men. Sex was also the only sociodemographic determinant that
significantly predicted the physician discussing emotions (p < 0.001), since men were more
prone than women (OR = 3.4) to report that their physician discussed the emotional impact of
CU with them. Furthermore, the significant sociodemographic predictors of trust in physician
15
were sex (p = 0.02) and employment status (p = 0.03). In particular, high trust levels were
more frequently reported by women and fully employed subjects.
Physical health and psychological health were found to be the areas of QoL most affected in
CSU patients. Moreover, CSU patients can frequently suffer from depression and anxiety.
The severity of these parameters was found to be positively correlated with the extent of QoL
deterioration. Some studies that explored the relationship between psychological disorders
and QoL recruited more females in the study sample, without however determining the effect
of gender.62
Interestingly, psychiatric morbidity seems to be pronounced among CU patients and is
detrimental to their QoL, as QoL was shown to be more impaired in patients with CSU who
concomitantly exhibit mental disorders.58,63 Moreover, levels of emotional distress were
significantly higher in CSU patients with mental disorders.64 A recent study has assessed the
prevalence and spectrum of mental disorders and levels of emotional distress in 100 patients
with CSU.64 Forty-eight percent of patients with CSU were diagnosed with one or more
psychosomatic disorders. The most common mental disorders were anxiety disorders (30%),
followed by depressive and somatoform disorders (17% each). Mental disorders were of
similar prevalence in male and female patients with CSU.
Ozkan et al63 also described a high prevalence of psychiatric morbidity, with a psychiatric
diagnosis made in 60% of the patients in their series. In terms of the distribution of
psychiatric diagnoses, the most frequently occurring diagnosis was depressive disorders
(40%), followed by anxiety disorder (12%), and somatoform disorder (6%). The subdomains
on the SF-36 measurements were significantly lower than those of the control subjects. The
physical function, vitality, and mental health subdomains of the SF-36 in the patients with a
psychiatric diagnosis were significantly lower. The scores on physical function, bodily pain,
vitality, and role-emotional in women were significantly lower than those of men.
The assessment of the personality traits and psychological status of patients with CSU by
means of the Minnesota Multiphasic Personality Inventory (MMPI) revealed a mean score of
hysteria significantly higher in women, while the remaining scales were not affected by
gender.65
Conclusions
There are limited data derived from a systematic assessment of gender-related differences in
patients with CU. Nevertheless, the literature review appears to suggest the existence of some
intriguing gender-specific differences among CU patients (the main aspects are summarized
in Table I).
In our opinion, this issue should deserve more attention and further studies are certainly
needed for a better understanding of these aspects, also in the consideration of the potential
impact that gender-specific characteristics may have on the pathophysiological, clinical and
prognostic aspects of CU, as well as on the disease management.
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21
TABLE I. Main findings concerning the effect of gender on different CU aspects.
Epidemiology Predilection for middle- aged wome n (various reports).

Minor differences in prevalence between sexes in the extre me age groups
in some case series.
Later age of onset in men in a case series.
Possible differences in the frequenc y of some inducible urticarias (i.e.,
cold contact urticaria and dermographism more common in fe males, and
cholinergic urticaria less frequent in wo men).
Clinical Risk of association with th yroid autoi mmu nit y and with h ypoth yr oi dism
associations higher in females.
Significantl y higher incidence of rheumatoid arthritis, Sjogren’s synd ro me ,
celiac disease, type I diabetes mellitus, and syste mic lupus er yt he matosus
in fe male patients.
No influence of gender on the risk of developing cancers.
Clinical, Autoreactivit y (positivit y of ASST and serum basophil activation BAT-

prognostic CD203 test) more frequentl y detected in female patients.
and No relevant influence of gender on CU severit y, defined by the mean UAS.
therapeutic Women more often bothered b y s ymp to ms on several bod y parts and with
aspects worse Skindex s ymptoms.
Legs, wrists⁄hands/palms, face and scalp reported as more often affected
in women; ar mpits and ears more frequentl y affected in men.
In some case series, women more likel y to have angioede ma or less wo men
presenting with urticaria alone (without angioedema) .
Female gender defined as a risk factor for poor prognosis in a few series of
children and adults.
No apparent relevant effect of gender on the response to therapy (however,
in a study assessing the predictors of c yclosporine effectiveness, male sex
approached significance).
QoL and Existence of controversial data, with some reports based on diverse
ps ychological questionnaires excluding a relevant influence of gender, and others
status documenting the opposite.
In some studies with DLQI, QoL found to be more i mpaired in women,
with men reporting mo re frequent interference with work, leisure and
study, and more problems with treat ment, or wome n with worst scores in
the dail y activities domain and with greater impact on clothing.
In a study with the SF-36, greater impact on the vitalit y, role-e motional
and mental health domains in women. In another report, lower scores on
phys ical function, bodil y pain, vitalit y, and role-emotional in women.
Using the CU-Q2oL, females with more difficult y falling asleep in a stud y,
and, in another report, women more severel y affected in the scales
concerning itching/e mbarrass ment, and li mits looks.
In an internet surve y, wo me n more likel y to not be under a ph ysician’s
care for their CU and to report high trust levels; men mo re likel y to report
that their physician discussed the emotional i mpact of CU with the m.
Mean score of hys teria significantl y higher in women.
ASST= autologous serum skin test; CU= chronic urticaria; CU-Q2oL= chronic urticaria quality of life questionnaire;
DLQI= Dermatology Life Quality Index; QoL= quality of life; UAS= urticaria activity score
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Gender-related differences in chronic urticaria

Article in Giornale Italiano di Dermatologia e Venereologia · June 2015

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Gender-related differences in chronic urticaria

G Ital Dermatol Venereol 2015 Jun 19 [Epub ahead of print]

GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA

The online version of this article is located at http://www.minervamedica.it

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COPYRIGHT© 2015 EDIZIONI MINERVA MEDICA

Gender-related differences in chronic urticaria

Differenze legate al genere nell’orticaria cronica

Origgio, Varese, Italy

Corresponding author: Nicoletta Cassano; Dermatology and Venereology Private Practice,

Bari and Barletta; E-mail: nicoletta.cassano@yahoo.com

Word count: 4106

assessment of gender differences has increasingly become an attractive issue in clinical

differences in CU under different points of view, including pathophysiology, epidemiology,

– Gender medicine - Epidemiology – Quality of life.

Urticaria is a group of skin diseases characterized by pruritic wheals, angioedema or both.

usually without life-threatening consequences, CU is a disabling and frustrating disease that

Autoimmune pathomechanisms have been implicated in a relevant proportion of CSU

(ASST), whose positivity suggests the presence of circulating histamine-releasing factors of

evidence of a possible autoimmune origin of CSU.4

an overall female/male ratio of approximately 2-4/1.5

be due to differences in various factors, including anatomy, physiology, immunity, genetics,

of immune-mediated human diseases.5

from various perspectives and with special emphasis on pathophysiology, epidemiology,

clinical, prognostic and psychological aspects, as well as comorbidities and QoL.

Sex-related pathophysiological peculiarities and role of sex hormones

to exist in the cutaneous microvascular response to histamine.5

Significant gender differences have been detected in pruritogen-induced scratching behaviour

have an immunosuppressive action through multiple mechanisms, and progesterone similarly

degranulation.11,12 Progesterone may preferentially act as a negative regulator of mast cell

degranulation but it potentiates IgE formation.11,13,14

hormonal changes, including endocrinopathy, menstrual cycle, menopause and hormonal

impact of oral contraceptives and hormone replacement therapy on CU worsening is probably

very marginal. Urticaria/angioedema syndrome may appear or worsen in some pregnant

women while it can improve during pregnancy in others.17

expression. Progesterone- or estrogen-dependent urticaria should be suspected in women who

exacerbations.15 Hypersensitivity reactions to endogenous or exogenous female sex hormones

have been implicated in the pathogenesis of these forms. Autoimmune progesterone

dermatitis is a rare cyclic disease that can be characterized by premenstrual exacerbation of

spontaneously disappears or improves a few days after menses. Estrogen-related urticaria

commencement of oral contraceptive therapy.19

may antagonize the production of Th2 cytokines.11 A reduced concentration of DHEA-S,

likely to be the consequence of psychological distress, has been demonstrated in CU patients,

regardless of their gender and response to ASST.20

later age of onset in men affected with CU as compared to female patients.31

Interestingly, a case series in CU elderly patients consisted of a lower proportion of females

as compared to adult non-elderly subjects with CU (46.7% vs 69.2%).32

A prospective, cross-sectional, questionnaire-based epidemiologic investigation analyzed the