Abstract
‘The coining of the term ‘gender dermatology’ heralds a shift in focus from research directed mainly at women's health to a more comprehensive approach to the biological features of health and illness in each gender.’
Gender-specific research in dermatology, as in other medical fields, has gained popularity in recent years as differences in the pathogenesis, clinical course and outcomes of diseases are documented. The coining of the term ‘gender dermatology’ heralds a shift in focus from research directed mainly at women's health to a more comprehensive approach to the biological features of health and illness in each gender. The goal: to ensure good clinical practice and research based on reliable data that take into account the unique features of each sex [1]. Gender differences are found at many biological levels:
Genetic (karyotype size, X-chromosome inactivation or mosaics, mitochondrial inheritance exclusive in women);
The gonadal formation and conversion of sex hormones, their bloodstream levels and transportation;
Extragonadal peripheral events through aromatase and dihydrotestosterone enzyme activity on organ- and cellular-specific receptors;
Intracellular hormone action and metabolism with coactivators or corepressors on cell target DNA [2].
The area investigated most extensively is immunology. There is a dramatic difference in the prevalence of most inflammatory and autoimmune dermatoses in men and women, with female predominance in most subtypes [3]. Women generally show a greater immune response to exogenic insults and stronger autoimmune reactions than men, and mount higher antibody levels and more potent responses to infectious agents. This gender gap becomes even more prominent in women during the childbearing years.
Studies on both mice and humans indicate that females are more prone to develop autoimmune diseases such as the prototype models systemic lupus erythematosus and multiple sclerosis. Indeed, more than 75% of patients with autoimmune diseases are women. Female:male sex ratios in collagen diseases range from 3:1 for scleroderma and dermatomyositis to 9:1 for lupus erythematosus and Sjogren's disease. Pemphigus and pemphigoid, other examples of autoimmune blistering disorders, were once reported in the literature with equal or near-equal frequencies in men and women, while more recent reports show a clear female predominance [4].
These striking gender differences have been attributed to the immunopathogenesis of the diseases that makes women more susceptible to autoimmune disorders, with origins in the dimorphic effect of sex steroids on the development and function of the immune system in men and women [5]. According to the current view of this gender dimorphism, androgens are anti-inflammatory and depress both cellular and humoral immunity, while estrogens enhance it in a more complex way. Estrogens activate the immune system, ameliorate T helper (Th) 1 responses, and induce or accelerate Th 2 responses.
‘The goal is to ensure good clinical practice and research based on reliable data that take into account the unique features of each sex.’
The hyperestrogenic immunosetting of pregnancy, when many autoimmune diseases are altered and some disorders make their appearance, is of special interest. The previous view that the fetus is an allograft to the immunologically inert mother has been replaced by the more modern concept that distinguishes between innate and adaptive immune systems, and between Th 1 and 2 arms. Innate and adaptive Th 2 responses fit the immune milieu of pregnancy [6], and account for the appearance and/or progression of certain dermatological disorders during pregnancy and postpartum.
The immune system is exposed to estrogens via a number of routes: the endogenous route, for example, the production of natural estrogenic hormones in states such as pregnancy; the exogenous route, whereby estrogen hormones are ingested for medical reasons, such as in replacement therapy or contraception; or via external products such as plastics, pesticides and plants. Whatever the route, estrogens act by binding to specific receptors, both on the cell membrane and intracellularly [7,8].
Society at large, not just the medical community, is becoming increasingly aware of the greater burden of illness on women.
These receptors, like other hormonal receptors, such as thyroid hormone, steroids and retinoids, are members of a broad family of nuclear transcription factors responsible for major biological processes in reproductive, cognitive, cardiovascular system, skeletal and immune function. Estrogen acts in the skin by modulating keratinocyte growth and differentiation, and the production of growth factor and ground substance. When estrogen binds to its receptor, it acts in two ways: through a genomic pathway, by which it enters the nucleus and modulates the transcription of genes involved in homeostasis, angiogenesis, cell cycle and survival; or via the ligand–receptor complex that functions in the nongenomic pathway via cytoplasmatic or synaptic messengers. Chronic cross-talk between estrogen and the nuclear factor κB transcription factor family results in increased activity of the latter, which may be implicated in atherosclerosis, Alzheimer's disease, cancers and, of course, autoimmune diseases.
One of the latest proposed immunogenetic links contends that hormones exert their activity through distinct specialized loci on genes of the major histocompatibility complexes [9]. This specific immunological milieu that favors autoimmune phenomena is in line with the strikingly high proportion of hormone replacement therapy (HRT) users found among postmenopausal women. Nowadays, almost every second woman after menopause is using some form of exogenous sex hormones, a statistic that coincides with the high figures of hormone supplement consumption documented in the general population over the last decade. According to a publication in 2001, some 30% of all adult women in the USA and UK were current users of HRT, with the highest use in the postmenopausal age group, where the peak prevalence of 52% was in women aged 55–59 years [10]. More alarming results came from The Women's Health Initiative and the Million Women Study [11], pivotal works published since 2002, reporting increased rates of breast cancer, coronary heart disease, venous thromboembolism and dementia in postmenopausal women using long-term HRT, especially in the form of estrogen–progestagen preparations. Nevertheless, these alerts led to only a modest decrease in prescribing HRT in postmenopausal women [11].
Differences in the incidence and course of diseases in the two genders can also be attributed to differences in lifestyles and occupations of men and women. Cases in point are: the prevalence among women of irritant hand dermatitis from frequent exposure to water and detergents; the high rate of actinic dermatitis in men with outdoor occupations (such as sailors, lifeguards and construction workers) chronically exposing them to ultraviolet radiation; and the prevalence of mycosis fungoides in men with jobs in manufacturing and construction that entail exposure to metals, plastics, cutting oils and the like [12].
The advent of the new ‘metrosexual’ look in men means that allergic contact dermatitis, once seen mainly in women from long-term use of perfumes, is now seen in men availing themselves of perfumed aftershave lotions and colognes. Cosmetic acne or pomade acne, stemming from the use of comedogenic oil and greasy products, especially for hair, once restricted to women, is seen increasingly in young men.
Following the sexual revolution, sexually transmitted diseases such as HIV and syphilis, once prevalent mainly in the homosexual community, are now transmitted almost equally in women.
‘We are just beginning to see the fruits of the gender approach applied to dermatology.’
Society at large, not just the medical community, is becoming increasingly aware of the greater burden of illness on women. In some cultures, young women who contract diseases such as leprosy are hidden from public view and left untreated for fear they will be unsuitable for marriage. Women may experience physical abuse and disfigurement by family members, genital mutilation, or simple relegation to a second-class status that means no schooling, no participation in community affairs and no say in matters of their own sexuality. Perhaps this is why 2.8-times more females than males present at dermatology clinics with self-inflicted skin disorders [13].
We are just beginning to see the fruits of the gender approach applied to dermatology. The results are already producing better-honed diagnostic and treatment protocols for our patients, and gender-informed, evidence-based research that offers a better accounting of health and illness.