1. 1 Gender Dermatology ADAM and EVE Where is the apple ? ADAM and EVE Where is the apple ?

2. 2 Why mainstream the gender perspective ? Gender influences health and well being throughout the life of an individual. Everyone has a gender. Understanding the implications of gender differences is vital for: good clinical practice targeted options for treatment relevant medical education unbiased medical research

3. 3 Medical Evidence A lack of sex disaggregated data does not mean “there is no evidence of difference.” It means a lack of evidence – not a lack of difference.

4. 4 Gender Differences - Epidemiology

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6. 6 The Impact of gender Lifestyle Hormonal Genetics Occupation Age Immunology Psychology Lifestyle Hormonal Genetics Occupation Age Immunology Psychology

7. 7 OCCUPATION Housewife's eczema

8. 8 OCCUPATION Sailor’s skin

9. 9 OCCUPATION Mycosis fungoides

10. 10 LIFESTYLE Contact dermatitis - fragrance

11. 11 LIFESTYLE HIV

12. 12 LIFESTYLE Sexually transmitted diseases

13. 13 LIFESTYLE Cosmetic acne

14. 14 LIFESTYLE Sex hormones

15. 15 IMMUNOLOGY Collagen vascular diseases - SLE

16. 16 Sex hormones are immunomodulators Associations in humans More than 75% of autoimmune patients are women. Exacerbation of lupus with pregnancy, postpartum, exogenous estrogen. Males with Kleinfelter’s syndrome develop SLE. Hypoandrogenism is found in some males with SLE. Associations in animal models (NZB mice) Female mice fare worse than male mice. Administration of estrogen to mice results in the production of inflammatory cytokines - IL6, IL10. Molecular observations Estrogen increases the secretion of Ig in vitro. Estradiol acts on the genome as a transcriptor factor. Associations in humans More than 75% of autoimmune patients are women. Exacerbation of lupus with pregnancy, postpartum, exogenous estrogen. Males with Kleinfelter’s syndrome develop SLE. Hypoandrogenism is found in some males with SLE. Associations in animal models (NZB mice) Female mice fare worse than male mice. Administration of estrogen to mice results in the production of inflammatory cytokines - IL6, IL10. Molecular observations Estrogen increases the secretion of Ig in vitro. Estradiol acts on the genome as a transcriptor factor.

17. 17 Sex hormones and autoimmunity The genetic link Human MHC encodes for class I proteins, class II proteins, complement proteins, TNF alpha, heat shock proteins – all part of the immune system. MHC alleles combinations are present in half of autoimmune patients. Specific MHC background in multiple sclerosis mice model (EAE) is associated with specific steroid/ hormonal and complement loci. The genetic link Human MHC encodes for class I proteins, class II proteins, complement proteins, TNF alpha, heat shock proteins – all part of the immune system. MHC alleles combinations are present in half of autoimmune patients. Specific MHC background in multiple sclerosis mice model (EAE) is associated with specific steroid/ hormonal and complement loci. Source: Sex, MHC and C4 in autoimmune disease, Trends in Immunology, 2004

18. 18 The dimorphic immunomodulator paradigm Androgens depress cellular and humoral immunity Estrogens enhance humoral immunity cellular immunity Enhancement of TH2 Amelioration of TH1 Androgens depress cellular and humoral immunity Estrogens enhance humoral immunity cellular immunity Enhancement of TH2 Amelioration of TH1 Sources: Science 1995 ● Immunopharmacol 2001 ● Ann N Y Acad Sci 2002 ● J Immunol 2002 ● Immunol Letters 2005

19. 19 Hyperestrogenic settings Pregnancy Exogenous intake – HRT, OCs Environmental exposure plastics (bisphenol A, phthalates) detergents (octylphenol) pesticides (methoxychlor, DDT, dieldrin) phytoestrogens mycoestrogens – Fusarium sp.

20. 20 Immune system in pregnancy “The baby is an allogeneic allograft” The fetus can survive and thrive by the following mechanisms Anatomic separation of fetus from its mother The antigenic immaturity of the fetus The immunologic inertness of the mother Source: Sir Peter Medawar – Symp Soc Exp Biol, 1953

21. 21 Immune system in pregnancy The prevailing concept Activation of innate immunity resulting in increased phagocytosis increased conscription of effector cells - granulocytes, monocytes, eosinophiles increased secretion of inflammatory mediators A shift in adaptive immunity arms: TH1 and TH2

22. 22 Dermatoses in pregnancy Aggravated Collagen diseases Immunoblistering Atopic dermatitis Neutrophilic disorders – EN, AGEP Gestational special variants: Herpes (pemphigoid) gestationis, impetigo herpetiformis Ameliorated Psoriasis Sarcoidosis Rheumatoid arthritis

23. 23 The estrogen receptor

24. 24 The nuclear receptor family Thyroid receptor (TR) Steroid receptors (glucocorticoid, mineralocorticoid) Retinoids receptors (RARs and RXRs) Vitamin D receptors (VDR) Estrogen receptors (ERa and ERb), androgens Prostaglandins Orphan receptors for which no ligand has been identified

25. 25 The nuclear receptor family (cont.) Belongs to the family of nuclear receptors / transcription factors responsible for biologic processes in reproduction, cardiovascular, skeletal, immune and neurocognitive functions In the skin, responsible for modulation of keratinocyte growth and differentiation, production of GF and ground substance

26. 26 Identifying medical issues through the gender lens Does the disease affect both men and women? Were both men and women included in the study? If not, why not? Is the data presented in a sex disaggregated way? Do the implications of the study for treatment differ for men and women?

27. 27 Thank you