WenChieh Chen

New developments in our understanding of acne pathogenesis and treatment

Abstract:  Interest in sebaceous gland physiology and its diseases is rapidly increasing. We provide a summarized update of the current knowledge of the pathobiology of acne vulgaris and new treatment concepts that have emerged in the last 3 years (2005–2008). We have tried to answer questions arising from the exploration of sebaceous gland biology, hormonal factors, hyperkeratinization, role of bacteria, sebum, nutrition, cytokines and toll‐like receptors (TLRs). Sebaceous glands play an important role as active participants in the innate immunity of the skin. They produce neuropeptides, excrete antimicrobial peptides and exhibit characteristics of stem cells. Androgens affect sebocytes and infundibular keratinocytes in a complex manner influencing cellular differentiation, proliferation, lipogenesis and comedogenesis. Retention hyperkeratosis in closed comedones and inflammatory papules is attributable to a disorder of terminal keratinocyte differentiation. Propionibacterium acnes, by acting on TLR‐2, may stimulate the secretion of cytokines, such as interleukin (IL)‐6 and IL‐8 by follicular keratinocytes and IL‐8 and ‐12 in macrophages, giving rise to inflammation. Certain P. acnes species may induce an immunological reaction by stimulating the production of sebocyte and keratinocyte antimicrobial peptides, which play an important role in the innate immunity of the follicle. Qualitative changes of sebum lipids induce alteration of keratinocyte differentiation and induce IL‐1 secretion, contributing to the development of follicular hyperkeratosis. High glycemic load food and milk may induce increased tissue levels of 5α‐dihydrotestosterone. These new aspects of acne pathogenesis lead to the considerations of possible customized therapeutic regimens. Current research is expected to lead to innovative treatments in the near future.

The International Criteria for Behcet's Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria

Behçets disease (BD) is a chronic, relapsing, inflammatory vascular disease with no pathognomonic test. Low sensitivity of the currently applied International Study Group (ISG) clinical diagnostic criteria led to their reassessment.

Corticotropin-releasing hormone: An autocrine hormone that promotes lipogenesis in human sebocytes

Sebaceous glands may be involved in a pathway conceptually similar to that of the hypothalamic-pituitary-adrenal (HPA) axis. Such a pathway has been described and may occur in human skin and lately in the sebaceous glands because they express neuropeptide receptors. Corticotropin-releasing hormone (CRH) is the most proximal element of the HPA axis, and it acts as central coordinator for neuroendocrine and behavioral responses to stress. To further examine the probability of an HPA equivalent pathway, we investigated the expression of CRH, CRH-binding protein (CRH-BP), and CRH receptors (CRH-R) in SZ95 sebocytes in vitro and their regulation by CRH and several other hormones. CRH, CRH-BP, CRH-R1, and CRH-R2 were detectable in SZ95 sebocytes at the mRNA and protein levels: CRH-R1 was the predominant type (CRH-R1/CRH-R2 = 2). CRH was biologically active on human sebocytes: it induced biphasic increase in synthesis of sebaceous lipids with a maximum stimulation at 10−7 M and up-regulated mRNA levels of 3β- hydroxysteroid dehydrogenase/Δ5–4 isomerase, although it did not affect cell viability, cell proliferation, or IL-1β-induced IL-8 release. CRH, dehydroepiandrosterone, and 17β-estradiol did not modulate CRH-R expression, whereas testosterone at 10−7 M down-regulated CRH-R1 and CRH-R2 mRNA expression at 6 to 24 h, and growth hormone (GH) switched CRH-R1 mRNA expression to CRH-R2 at 24 h. Based on these findings, CRH may be an autocrine hormone for human sebocytes that exerts homeostatic lipogenic activity, whereas testosterone and growth hormone induce CRH negative feedback. The findings implicate CRH in the clinical development of acne, seborrhea, androgenetic alopecia, skin aging, xerosis, and other skin disorders associated with alterations in lipid formation of sebaceous origin.

Gender difference, sex hormones, and immediate type hypersensitivity reactions

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.

Update and Future of Hormonal Therapy in Acne

Hormonal therapy is an important component in the treatment of women with acne who may or may not have elevated serum androgens. The mainstays of hormonal therapy include oral contraceptives and antiandrogens such as cyproterone acetate, flutamide or spironolactone. Recent research over the past several years has unraveled some of the details regarding the way that the skin and sebaceous glands synthesize and metabolize hormones. The knowledge gained from this work may provide an impetus for future drug discovery in the hormonal treatment of acne and lead to improvements in the care of our patients with acne.

Acne-associated syndromes: models for better understanding of acne pathogenesis.

Acne, one of the most common skin disorders, is also a cardinal component of many systemic diseases or syndromes. Their association illustrates the nature of these diseases and is indicative of the pathogenesis of acne. Congenital adrenal hyperplasia (CAH) and seborrhoea‐acne‐hirsutism‐androgenetic alopecia (SAHA) syndrome highlight the role of androgen steroids, while polycystic ovary (PCO) and hyperandrogenism‐insulin resistance‐acanthosis nigricans (HAIR‐AN) syndromes indicate insulin resistance in acne. Apert syndrome with increased fibroblast growth factor receptor 2 (FGFR2) signalling results in follicular hyperkeratinization and sebaceous gland hypertrophy in acne. Synovitis‐acne‐pustulosis‐hyperostosis‐osteitis (SAPHO) and pyogenic arthritis‐pyoderma gangrenosum‐acne (PAPA) syndromes highlight the attributes of inflammation to acne formation. Advances in the understanding of the manifestation and molecular mechanisms of these syndromes will help to clarify acne pathogenesis and develop novel therapeutic modalities.

Hormones and the pilosebaceous unit

Hormones can exert their actions through endocrine, paracrine, juxtacrine, autocrine and intracrine pathways. The skin, especially the pilosebaceous unit, can be regarded as an endocrine organ meanwhile a target of hormones, because it synthesizes miscellaneous hormones and expresses diverse hormone receptors. Over the past decade, steroid hormones, phospholipid hormones, retinoids and nuclear receptor ligands as well as the so-called stress hormones have been demonstrated to play pivotal roles in controlling the development of pilosebaceous units, lipogenesis of sebaceous glands and hair cycling. Among them, androgen is most extensively studied and of highest clinical significance. Androgen-mediated dermatoses such as acne, androgenetic alopecia and seborrhea are among the most common skin disorders, with most patients exhibiting normal circulating androgen levels. The “cutaneous hyperandrogenism” is caused by in stiu overexpression of the androgenic enzymes and hyperresponsiveness of androgen receptors. Regulation of cutaneous steroidogenesis is analogous to that in gonads and adrenals. More work is needed to explain the regional difference within and between the androgn-mediated dermatoses. The pilosebaceous unit can act as an ideal model for studies in dermato-endocrinology.

Human demodicosis: revisit and a proposed classification

Human Demodex mites (Demodex folliculorum and Demodex brevis) hold a high rank in the evolutionary and phylogenetic hierarchy of the skin microbiome, although in most people their presence is of no consequence. While human demodicosis is a skin disease sui generis, it can mimic many other inflammatory dermatoses, such as folliculitis, rosacea and perioral dermatitis, leading to unspecific and confusing descriptions in the literature. Here, we propose to classify human demodicosis into a primary form and a secondary form, which is associated mainly with immunosuppression. The clinical manifestations of primary demodicosis may include (i) spinulate demodicosis, currently known as pityriasis folliculorum, involving sebaceous hair follicles without visible inflammation; (ii) papulopustular/nodulocystic or conglobate demodicosis with pronounced inflammation affecting most commonly the perioral and periorbital areas of the face; (iii) ocular demodicosis, inducing chronic blepharitis, chalazia or, less commonly, keratoconjunctivitis; and (iv) auricular demodicosis causing external otitis or myringitis. Secondary demodicosis is usually associated with systemic or local immunosuppression. Treatment is only weakly evidence based, and the most effective concentrations of acaricides remain to be determined. Optimization of an in vitro or ex vivo culture model is necessary for future studies. Endosymbiosis between certain bacteria and Demodex mites in the pathogenesis of demodicosis deserves more attention. Further clinical observations and experiments are needed to prove our hypothesis.

Human mast cells express androgen receptors but treatment with testosterone exerts no influence on IgE-independent mast cell degranulation elicited by neuromuscular blocking agents

Please cite this paper as: Human mast cells express androgen receptors but treatment with testosterone exerts no influence on IgE‐independent mast cell degranulation elicited by neuromuscular blocking agents. Experimental Dermatology 2010; 19: 302–304.

Expression of sex-determining genes in human sebaceous glands and their possible role in the pathogenesis of acne.

Background  The human skin, especially the sebaceous gland, is a steroidogenic organ similar to the gonads and adrenal cortex, possessing all the enzymes required for steroid sex‐hormone synthesis and metabolism. Factors regulating cutaneous steroidogenesis associated with disease status remain largely unknown.