Clinical Biochemistry 44 (2011) 10351040

Contents lists available at ScienceDirect

Clinical Biochemistry
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c l i n b i o c h e m

Review

Role of hormones in acne vulgaris

Megha Kataria Arora , Amita Yadav, Vandana Saini
Department of Biochemistry, Lady Hardinge Medical College, New Delhi, India

a r t i c l e

i n f o

a b s t r a c t
Objective: To elucidate the role of endogenous hormones like testosterone, progesterone, estrogen, insulinlike growth factor, insulin and glucocorticoids in a common skin condition acne vulgaris. Design and methods: We conducted a systematic review of the literature and abstracted the data for every published cut point. Results: We screened more than 1000 studies and found that serum testosterone, progesterone, glucocorticoids, insulin and insulin-like growth factors are increased in patients with acne vulgaris and serum estrogen levels are low in patients. Conclusions: Various endogenous hormones play important role in the pathogenesis of acne vulgaris. Thus, in the clinical practice it is important to evaluate serum levels of these hormones and patients must be treated accordingly to avoid serious endocrine disorders at an early age. 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Article history: Received 23 February 2011 Received in revised form 26 May 2011 Accepted 20 June 2011 Available online 6 July 2011 Keywords: Acne vulgaris Serum testosterone Estrogen Progesterone Glucocorticoids Insulin Insulin-like growth factor

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of androgens . . . . . . . . . . . . . . . . . . . . . . . . . . . . Androgen synthesis and localization of androgen receptors in skin . . . . . Mechanism by which androgens lead to acne vulgaris . . . . . . . . . . . Recent reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of estrogen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Localization of estrogen receptors in skin . . . . . . . . . . . . . . . . . Recent reports and mechanism by which estrogens improve acne vulgaris . Role of progesterone . . . . . . . . . . . . . . . . . . . . . . . . . . . Localization of progesterone receptor . . . . . . . . . . . . . . . . . . . Recent reports and mechanism by which progesterone leads to acne vulgaris Role of glucocorticoid . . . . . . . . . . . . . . . . . . . . . . . . . . Localization of the glucocorticoid receptor in skin . . . . . . . . . . . . . Mechanism by which glucocorticoids lead to acne vulgaris . . . . . . . . . Role of insulin and insulin-like growth factor 1(IGF-1) . . . . . . . . . . . Localization of receptors . . . . . . . . . . . . . . . . . . . . . . . . . Mechanism by which insulin/IGF-1 leads to acne vulgaris . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1035 1036 1036 1037 1037 1037 1037 1037 1038 1038 1038 1038 1038 1038 1038 1039 1039 1039 1040

Introduction Acne is a chronic inammatory disease of the pilosebaceous unit, characterized by seborrhea, formation of comedones, erythematous papules and pustules, less frequently by nodules, deep pustules, or pseudocysts and, in some cases, it is accompanied by scarring [1]. Follicular hyperkeratinization, excessive sebum production,

Corresponding author at: H.NO: B7, Ground oor, Southend oors, Sector 49, Sohna Road, Gurgaon, India. E-mail address: aroramegha26@gmail.com (M.K. Arora).

0009-9120/$ see front matter 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.clinbiochem.2011.06.984

1036

M.K. Arora et al. / Clinical Biochemistry 44 (2011) 10351040

hypercolonization of the duct by Propionibacterium acnes, direct or indirect inammation and recently, Matrix metalloproteinases (MMPs) have been included to have role in the pathogenesis of acne vulgaris [2,3]. Several hormones implicated in the regulation of sebaceous gland activity have been linked to acne. They include androgens, estrogens, progesterone, growth hormone, insulin, insulin-like growth factor-1 (IGF-1), corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), melanocortins and glucocorticoids [4]. The link between sebaceous gland activity and puberty has been recognized for many years [1]. Acne vulgaris rst develops at the onset of puberty as a result of hormonal changes [5].

Review Acne vulgaris is a common skin disease, affecting more than 85% of adolescents, women being affected more frequently than men [6]. It is seen in nearly 100% of individuals at some time during their lives [7]. For some, it is temporary and resolves by the mid-20s; however, more severe cases often take longer to resolve, and it can persist into adult years in as many as 50% of individuals [2,7]. Although it does not affect overall health, its impact on emotional well-being and function can be critical, especially active acne and its sequel, like permanent scarring, leaves psychological stress that do not always correlate with the clinician's assessment of severity at one point in time [8,9]. The psychological fallout in acne patients includes much higher rates of clinical depression, anxiety, anger, suicidal thoughts, and even suicide itself [10]. Increasing age of afiction with acne can proportionately affect the quality of life in various ways, including employment, social behavior, and body dissatisfaction [9]. The more severe the acne, the greater the negative impact on quality of life (QOL) [7]. The impact of acne on a patient's psychological and emotional well-being is comparable with that of chronic systemic disease processes such as diabetes, asthma, arthritis, and epilepsy [9]. Acne is often a chronic disease and not just a self-limiting disorder of teenagers. The following characteristics have been used to dene its chronic state: a prolonged course, a pattern of recurrence or relapse, manifestation as acute outbreaks or slow onset, and a psychological and social impact that affects the individual's quality of life. Factors that have been linked to a chronic course include stress-related production of adrenal androgens, P. acnes colonization, familial background, and specic subtypes of acne (conglobata, keloidal, inversa, androgenic, scalp folliculitis, and chloracne) [2]. Acne is a pleomorphic disorder of the pilosebaceous unit, characterized by both inammatory (papules, pustules, nodules) and noninammatory (comedones, open and closed) lesions [8]. Sebaceous glands are found all over the human body, with the exception of the palms and soles, and are most numerous on the scalp and the face. The embryologic development of the human sebaceous gland is closely related to the differentiation of the hair follicle and the epidermis [11]. Together with the hair follicles, they comprise the pilosebaceous unit [12]. The number of sebaceous glands remains approximately the same throughout life, whereas their size tends to increase with age. The development and function of the sebaceous gland in the fetal and neonatal periods appear to be regulated by maternal androgens and by endogenous steroid synthesis. The most apparent function of the glands is to excrete sebum. Patients with acne have larger sebaceous glands and produce more sebum than do those without acne [11]. There are 4 primary pathogenic factors, which interact in a complex manner to produce acne lesions [2]: 1) 2) 3) 4) Follicular hyperkeratinization, Excessive sebum production, Hypercolonization of the duct by P. acnes, Direct or indirect inammation.

Lastly, included in the pathogenesis of acne vulgaris is the role of Matrix metalloproteinases (MMPs) [3]. Papakonstantinou and coworkers investigated the role of MMPs in acne. Sebum includes several MMPs, which are thought to originate in keratinocytes and sebocytes. These enzymes, which include collagenases, gelatinases, stromelysins, and matrilysins, have a prominent role in both inammatory matrix remodeling and proliferative skin disorders. In addition, oral isotretinoin targets all the four primary follicular changes observed in acne vulgaris and also reduces concentration of MMPs in sebum, in parallel with clinical improvement [2,13]. A recent hypothesis has suggested that a relative nuclear deciency of the metabolic sensor and nuclear transcription factor FoxO1 appears to play a key role in the pathogenesis of acne vulgaris. FoxO1 has been identied as an important regulator of androgen receptor, cell proliferation, apoptosis, lipogenesis, oxidative stress regulation, innate and acquired immunity, all important aspects involved in the pathogenesis of acne. Reduced nuclear levels of FoxO1 may increase the expression of important acne target genes and derepress nuclear receptors, suggested to be involved in the clinical manifestation of acne. There is indirect evidence supporting the role of growth factor and growth factor like acneigenic stimuli in posttranslational modication of nuclear FoxO1 and strengthens the hypothesis of a nuclear FoxO1 deciency as the possible underlying cause of acne vulgaris and clinical acne variants [14]. The improved understanding of acne development on a molecular level suggests that acne is a disease that involves the innate and adaptive immune system and inammatory events [2]. Using a human keratinocyte cell line, Ottaviani and associates showed that peroxidation of sebum lipids can activate inammatory mediators, including IL-6 and lipoxygenases. Oxidized squalene can also stimulate hyperproliferative behavior of keratinocytes, suggesting that this lipid may be partly responsible for comedo formation [15]. Jeremy and coworkers investigated the initiating events for acne lesions, and found that immune changes and inammatory responses occur before hyperproliferation of keratinocytes, with a pattern similar to a type IV delayed hypersensitivity. The immune response is led by CD4 + lymphocytes and macrophages. The subsequent production of cytokines activates local endothelial cells, up-regulating inammatory vascular markers (E-selectin, vascular cell adhesion molecule-1 [VCAM-1], intercellular adhesion molecule-1 [ICAM-1], and human leukocyte antigen-DR [HLA-DR] in the vasculature around the pilosebaceous follicle. The entire process is initiated by interleukin (IL)-1, which is up-regulated in response to a relative linoleic acid deciency caused by excess sebum and perturbation of barrier function within the follicle [16]. Role of androgens The link between sebaceous gland activity and puberty has been recognized for many years [1]. With the onset of puberty, androgenmediated stimulation of the sebaceous gland results in increased sebum production in both sexes. They are without doubt the most important hormones controlling sebaceous gland activity [17]. Androgens are thought to play a crucial role in the pathogenesis of acne [18]. The relevance of hyperandrogenism in male acne patients is often not considered, whereas in women or prepubertal children suffering from acne, disorders of androgen metabolism are readily suspected. Extensive investigations have documented that in women, acne is accompanied by hyperandrogenemia [19]. This notion is also supported by clinical observation of acne onset around puberty and are during menstruation or hyperandrogenic states. Studies have also shown a statistically signicant increase in circulating androgen levels in women with acne as compared to healthy controls. Though the majorities of the female patients with acne have androgen levels within normal limits and do not have an underlying endocrinopathy. Nonetheless, the possibility of a hyperandrogenic state in female

M.K. Arora et al. / Clinical Biochemistry 44 (2011) 10351040

1037

patients with acne in certain clinical settings must be excluded. Suspicion should be high in women with signs of virilization and irregular menses. The most commonly considered endocrinopathies in this setting are polycystic ovary syndrome (PCOS), late-onset adrenal hyperplasia, or a virilizing tumor (adrenal or ovarian) [18]. Androgen synthesis and localization of androgen receptors in skin Androgens leading to acne vulgaris are produced within the sebaceous gland from dehydroepiandrosterone sulfate DHEAS, an adrenal precursor hormone which is converted to DHEA by steroid sulfatase. Androgen receptors are expressed in the basal layer of sebaceous glands and in the outer root sheath keratinocytes of the hair follicle [17]. Functional androgen receptors are required for sebum production and men without functional androgen receptors do not develop acne. Individual variability in the response of the sebaceous gland androgen receptor to circulating androgens has been reported [20]. Mechanism by which androgens lead to acne vulgaris Three predominant steroid metabolizing enzymes are expressed in sebaceous glands: (1) 3-hydroxysteroid dehydrogenase; (2) 17-hydroxysteroid dehydrogenase; and (3) 5- reductase. 3hydroxysteroid dehydrogenase, which is proven to localize in the sebaceous gland, acts on dehydroepiandrosterone (DHEA) to convert it to androstenedione. [17]. There are 2 forms of 3-hydroxysteroid dehydrogenase. Type I is active in the skin, placenta, and mammary tissue, whereas type II is concentrated in the gonads and adrenal glands. The reversible enzyme 17-hydroxysteroid dehydrogenase is responsible for converting androstenedione to testosterone. Testosterone is then taken up by the cell and rapidly converted by type 1, 5-reductase to 5-dihydrotestosterone (DHT). There are 11 isozymes of 17-hydroxysteroid dehydrogenase, which vary in their tissue localization and ability to reduce or oxidize androgens and estrogens [17]. This may represent a regulatory point in androgen and estrogen metabolism as the type 2 isozyme appears to be the most active in the sebaceous gland, where it prefers to oxidize testosterone back to androstenedione. The net effect of the activity of these two enzymes is the greater production of potent androgens, such as testosterone and DHT, within sebaceous glands of facial areas, which may partially account for the development of acne in these areas [21].

It has been hypothesized that patients with acne have more active 5-reductase type 1 in the infrainfundibulum and those without acne have greater activity of 17-hydroxysteroid dehydrogenase the activity. Increased activity of 5-reductase type 1 is associated with the abnormal hyperproliferation of keratinocytes leading to formation of microcomedones which is important for acne lesions. However, no statistically signicant difference in enzyme activity has been observed to date between those with and without acne, but subject numbers have been very low [22]. The exact mechanisms by which androgens increase the size and secretion of sebaceous glands are unknown. Testosterone and DHT form complexes with nuclear androgen receptors. The androgen receptor complex then interacts with DNA in the nuclei of sebaceous cells to regulate genes involved in cell growth and lipid production. Androgens may act directly, indirectly, or both on epithelial cells within the pilosebaceous unit by regulating the production of growth factors by dermal broblasts. The stromalepithelial interaction of sex steroid hormones and growth factors is an important phenomenon in the local regulation of other endocrine-responsive tissues, including the prostate, breast, endometrium, and ovary. Evidence exists for the importance of these autocrine and paracrine effects of androgens and growth factors in the regulation of sebaceous glands [17]. Peroxisome proliferator-activated receptors (PPAR) receptors , , have been identied in sebocytes with the form being the most important. Fatty acids and linoleic acid and androgens act through these receptors. These are nuclear receptors which act in concert with retinoid X receptors to regulate epidermal growth and terminal sebocyte differentiation. They are therefore involved in maturation of the sebaceous gland and initiation of the inammatory reaction in acne. The PPAR present in the sebaceous gland could provide a new target for acne treatments [23]. Recent reports In a study done by Lawrence and colleagues acne patients with moderate and severe acne had increased free testosterone and free dihydrotestosterone whereas total testosterone and dihydrotestosterone, androstenedione, or SHBG values were not signicantly different from those in control group [24]. In various studies it has been revealed that although androgens do play a role in the pathogenesis of acne vulgaris but the circulating levels of these hormones are often within the normal range. Probably hypertestosteronemia occurs because of defect in the afnity for receptors, number of receptors, avidity with which they are bound, and metabolism at the receptor site [25]. Theca cells of ovary are the source of androstenedione and testosterone leading to increased total testosterone levels in blood [26]. Elevated levels of testosterone as compared to controls have also been reported in the study conducted by Marynick [27]. Role of estrogen It is well known that exogenous estrogens in the form of oral contraceptive pill given in sufcient amounts will suppress sebum production and decrease acne lesions by increasing sex hormone binding globulin and decreasing circulating free testosterone, but the role of endogenous estrogens in the pathophysiology of acne is not very well dened [1]. Localization of estrogen receptors in skin Estrogen receptor (ER) is localized in sebocytes only and ER is found to be highly expressed in the epidermal and outer root sheath keratinocytes, melanocytes, dermal broblasts, dermal papilla cells, sebocytes, endothelial cells and adipocytes. Either androgens or

Steroid hormone metabolism in the sebaceous gland.

1038

M.K. Arora et al. / Clinical Biochemistry 44 (2011) 10351040

estrogens can activate the non-genomic signaling pathways of ER, ER and the androgen receptor [28]. Recent reports and mechanism by which estrogens improve acne vulgaris Testosterone is a prohormone for estradiol and many effects of testosterone are facilitated through the peripheral conversion of testosterone to estrogen by aromatase. It has also been shown that target tissues for androgens contain not only an androgen receptor but in most instances also the receptor for estradiol. Local modulation of the balance of androgen/estrogen action could be envisioned to regulate target cell function [12] and [29]. Russell analyzed that unlike male hormone androgens, female hormone estrogens have a benecial effect on acne that is why some doctors recommend birth control pills for women who have acne. A case control study conducted in north Indian population reported low serum estrogen levels in patients with acne vulgaris as compared to controls. Also, when a woman's estrogen levels decline, as they do just before the beginning of a menstrual cycle, acne may worsen [30]. This is also supported by the fact that acne is commonest at puberty because of the low level of estrogens and progesterone during the rst few menstrual cycles [19]. It has been hypothesized that estrogens may act by reducing endogenous androgen production in acne vulgaris lesions by one of several mechanisms, including (1) direct opposition of androgens within the sebaceous gland, (2) inhibition of androgen production by the gonads through a negative feedback loop on gonadotrophin release, or (3) regulation of genes involved in sebaceous gland growth or lipid production [17,21]. The view that estrogen suppresses gonadotropin secretion by the pituitary receives support from the nding that sebum suppressing doses of estrogen reduce the levels of testosterone in plasma and urine of normal men. In humans, estrogens are very likely to inuence hormonal levels by some systemic action through the pituitary gonadal axis [1]. The above data suggests that estrogen plays an anti-inammatory role in acne vulgaris. In human sebaceous glands the 17-Estradiol plays an important role by inhibiting the chemokine RANTES and an interferon--induced 10 kDa protein produced in human keratinocytes [31,32]. Estrogen receptor activation also plays an important anti-inammatory role by inhibiting matrix metalloproteinase-9 (MMP-9), the role of which is implicated in the pathogenesis of acne vulgaris. Estrogen protective role in acne vulgaris could also occur by blocking resident inammatory cell production of proinammatory cytokines (IL-1, IL-6 and TNF-) and cell differentiation agents (receptor activator of NF-kB ligand, RANKL). It also suppresses monocyte recruitment and/or macrophage activation at the inammatory site. Many observations have indicated that estradiol directly inhibits the expression of pro-inammatory genes via a receptormediated mechanism, in spite of the lack of canonical estrogen responsive elements in the promoter region of these genes. Because of the capability of hormone-activated ERs to interact with other classes of transcription factors coupled to membrane receptor signaling molecules (such as Sp-1, Jun/Fos, NF-kB and Stat), it is postulated that estrogen-dependent inhibition of transcription occurs without a physical interaction of the ligandreceptor complex with the proinammatory gene promoters. The receptor could in fact alter the dynamics of the association of other transcription factors with the transcription machinery (a mechanism known as transrepression) [33]. Role of progesterone The effect of progesterone on sebaceous glands has been a matter of dispute. The uctuation of sebum production in women during the

menstrual cycle has been blamed on progesterone, but this has not been proved experimentally. Progesterone administration can produce acne, and when given to elderly women it increases sebum production, but no such effect could be demonstrated in young women [1]. Localization of progesterone receptor Progesterone receptors are expressed in basal epidermal keratinocytes only [28]. Recent reports and mechanism by which progesterone leads to acne vulgaris Progesterone is a competitive inhibitor of 5- reductase and might be expected to reduce sebaceous gland activity but in humans its sebosupressive effect is minimal [1]. There's paucity of literature regarding relationship of acne vulgaris and serum progesterone levels. In one study serum progesterone levels were found to be higher in females with severe acne vulgaris and the probable reason explained was increase in serum cholesterol, the immediate precursor of progesterone [34]. Possible mechanism by which progesterone aggravates acne lesions is by increasing sebum secretion and stimulation of proliferation of keratinocytes [35]. Progestins can also potentially stimulate monocyte production of proinammatory cytokines as has been demonstrated IL-6 concentrations increase during the luteal phase of the menstrual cycle, possibly being responsible for the increase in acne lesions during this time [36,37]. Role of glucocorticoid Skin is also a source of corticosteroids [28]. Evaluation of the skin layer-specic prednicarbate biotransformation has shown that epidermal keratinocytes can hydrolyze the double ester prednicarbate at position 21 to the monoester prednisolone 17-ethylcarbonate which nonenzymatically transforms to prednisolone 21-ethylcarbonate. This metabolite is enzymatically cleaved to prednisolone, the main biotransformation corticosteroid product [38]. Proopiomelanocortin (POMC) is produced by the anterior pituitary gland in response to corticotrophin releasing hormone (CRH) released from the hypothalamus. Its cleavage yields melanocortins, ACTH and melanocytestimulating hormone (MSH). Melanocortins regulate lipogenesis in sebocytes expressing both melanocortin-1 receptor (MC-1R) and MC5R through which ACTH and MSH produce various effects on the sebaceous gland. ACTH also stimulates the production of cortisol in the adrenal gland. It is well known that the use of topical or systemic glucocorticoids promotes acneiform eruptions. In vitro studies have demonstrated that hydrocortisone stimulates sebocyte proliferation in a dose-dependent manner, and that cortisol is essential for sebocyte differentiation [3941]. Localization of the glucocorticoid receptor in skin Glucocorticoid receptors are mainly expressed in basal keratinocytes, langerhan cells and dermal broblasts [28]. Mechanism by which glucocorticoids lead to acne vulgaris In acne vulgaris, gram-positive bacillus, P. acnes, plays an important role in the inammation. P. acnes produce low-molecular weight, serum-independent chemotactic factors that attract neutrophils through the epithelium wall, into the lumen of sebaceous follicles. It also activates the classical and alternative complement pathways, leading to the formation of C5a, an anaphylotoxin that induces the secretion of pro-inammatory cytokines, including tumor

M.K. Arora et al. / Clinical Biochemistry 44 (2011) 10351040

1039

necrosis factor alpha (TNF ), IL-1, and IL-8 by monocytes [39,42]. One of the major components of P. acnes cell wall is a very distinctive peptidoglycan, which is an exogenous ligand for Toll-like receptors TLR-2. TLRs are a group of glycoprotein cell surface receptors on keratinocytes involved in the innate and acquired immune response to invading microorganisms. Large amounts of TLR-2 have been found to be expressed on perifollicular and peribulbar macrophages in acne lesions. In addition, it has been shown that there is a positive correlation between the severity of acne lesions and the concentration of cells expressing TLR-2. The production of the inammatory cytokines IL-6, IL-8, and IL-12 is clearly dependent on the interaction of P. acnes and TLR-2. Proinammatory cytokines secreted by monocytes, IL-8 in particular, are induced through the activation of TLR-2 by P. acnes, leading to the recruitment of neutrophils to the pilosebaceous unit. TLR-2 activation by P. acnes may induce skin inammation via induction of various proinammatory molecules that stimulate the invasion of inammatory cells [39,43,44]. Although corticosteroids themselves exert immunosuppressive or anti inammatory effects, it is well known clinically that systemic or topical glucocorticoid treatment provokes an acneiform reaction. Nevertheless, the effect of steroids on TLR2 expression in human keratinocytes remains unknown. Shibata and coworkers found that the addition of glucocorticoids, such as dexamethasone and cortisol, to cultured human keratinocytes increased their TLR2 gene expression. Moreover, these glucocorticoids markedly enhanced TLR2 gene expression, which was further stimulated by P. acnes, tumor necrosis factor- and IL-1. Gene expression of mitogen-activated protein kinase (MAPK) phosphatase-1 was also increased by the addition of dexamethasone. By using several inhibitors and activators, we found that TLR2 gene induction by glucocorticoids was mediated by the suppression of p38 MAPK activity following induction of MAPK phosphatase-1. These ndings strongly suggest that steroid-induced TLR2 together with P. acnes existing as normal resident ora plays an important role in the exacerbation of acne vulgaris as well as in possible induction of corticosteroid-induced acne [39,43,4547]. Nicotinamide, adapalene, and zinc have been successfully used for the treatment of acne. Recent research ndings have elucidated additional mechanisms of action related to these agents through their important antagonization of the TLR-dependent inammatory reactions induced by P. acnes in the host [48]. Proopiomelanocortin, corticotropin-releasing hormone (CRH), and corticotropin-releasing hormone receptor(CRHR) genes are present in the skin [28]. CRH has been reported to promote lipogenesis and to enhance mRNA expression of -5, 3--hydroxysteroid dehydrogenase, the enzyme that coverts dehydroepiandrosterone to testosterone, in human sebocytes [49]. Ganceviciene et al. studied the involvement of CRH system in acne pathogenesis. Facial biopsies were obtained from 33 acne patients and were compared to noninvolved thigh skin of the same patients and normal skin of eight age matched healthy volunteers. Strong CRH expression was seen in sebocytes, of all differentiation stages, of acne-involved skin whereas the CRH expression in uninvolved and normal skin was dependent on the differentiation stage of the sebocyte. The authors hypothesized that CRH may interact with immune factors causing a release of inammatory mediators in acne. CRHBP expression was intense in differentiating sebocytes of acneinvolved skin, which may be as a result of local stress reaction in acne. The authors concluded that CRH acts as a central director, via the CRHR-1, for behavioral and neuroendocrine response to stress and is involved in stress-induced exacerbation of acne [50]. Moreover, acne ares have been seen during periods of stress. Although objective data are limited, stress is known to increase the output of adrenal steroids, which may affect the sebaceous gland. The sebaceous gland also regulates independent endocrine functions of the skin and has a signicant role in hormonally induced aging of skin. They have control centre for a complex regulatory neuropeptide program that acts like the hypothalamus pituitary-adrenal axis. This

aspect of sebaceous gland function is primarily inuenced by corticotrophin-releasing hormone, its binding protein, and corticotrophin receptors. Corticotrophin-releasing hormone levels change in response to stress, and its role in regulating sebaceous gland function is likely a link in the brain-skin connection that is thought to explain the relationship between stress and skin disorders with an inammatory component such as acne [2]. Role of insulin and insulin-like growth factor 1(IGF-1) Acne vulgaris has been proposed to be an IGF-1 mediated disease. IGF-1 rises during puberty by the action of increased GH secretion and correlates well with the clinical course of acne [51]. Localization of receptors Insulin/insulin-like growth factor I (IGF-I) receptor are expressed in epidermal keratinocytes and belong to the single-transmembrane domain receptors that harbor intrinsic tyrosine kinase activity [28]. Mechanism by which insulin/IGF-1 leads to acne vulgaris In acne patients, associations between serum levels of IGF-1, dehydroepiandrosterone sulphate, dihydrotestosterone, acne lesion counts and facial sebum secretion rate have been reported. IGF-1 stimulates 5-reductase, adrenal and gonadal androgen synthesis, androgen receptor signal transduction, sebocyte proliferation and lipogenesis. IGF-1 also increases lipogenesis by activating PI3K Akt and MAPK ERK signal transduction pathways and induction of sterol response element-binding protein-1 (SREBP-1), which preferentially regulates genes of fatty acid synthesis. SREBP-1c is also regulated by insulin at the transcriptional level [51]. Insulin sensitivity and sex hormone-binding globulin (SHBG) have been reported to be directly correlated, such that decrease in insulin sensitivity increases the free androgen index (FAI). The highest incidence of acne has been noticed to occur when IGF-1 levels peak and also adult women with acne have high levels of IGF-1 [52]. Edmondson and coworkers reported that interventions reducing fasting and postprandial insulin and IGF-1 concentration decreases sebum production and keratinocyte proliferation thus reducing acne lesions [26]. The GH-IGF-1 axis also plays an important role for the ACTH-dependent production of DHEAS of the human adrenal gland. IGF-1 enhances the sensitivity of the adrenal for ACTH, and induces the expression and activity of key enzymes of adrenal androgen biosynthesis. In healthy prepubertal girls as well as prepubertal girls with premature adrenarche, a positive correlation between IGF-1 and DHEAS serum levels has been reported. Serum IGF-1 levels rise and fall in a pattern similar to serum DHEAS, and normal puberty is characterized by a state of transient insulin resistance associated with an increase in gonadal sex steroid production and adrenal androgens [51]. Blood glucose levels have also been reported to be elevated in patients of acne vulgaris when compared to healthy controls. This occurs primarily because increase in blood glucose levels stimulates the secretion of insulin which decreases binding protein for IGF-I, facilitating the effect of IGF-I on cell proliferation. This may lead to increased proliferation of basal keratinocytes within the pilosebaceous duct, abnormal desquamation of follicular corneocytes. Insulin may also increase androgen production and activity due to decrease in the levels of sex hormone-binding globulin, thus, facilitating acne formation [53]. The role of insulin in acne development is also supported by the high prevalence of acne in women with polycystic ovary syndrome (PCOS), a condition associated with insulin resistance, hyperinsulinemia, and hyperandogenism. Insulin resistance is believed to be the underlying disturbance in PCOS, because it generally precedes and

1040

M.K. Arora et al. / Clinical Biochemistry 44 (2011) 10351040 [24] Lawrence D, Shaw M, Katz M. Elevated free testosterone concentration in men and women with acne vulgaris. Clin Exp Dermatol 1986;11:26373. [25] Bershad SV. Diet and acneslim evidence, again. J Am Acad Dermatol 2005;53: 11023. [26] Peter AM, Kathleen MB. Lipid transport & storage. In: Murray RK, Granner DK, Mayes PA, Rodwell VW, editors. Harper's Illustrated Biochemistry. 28th ed. New Delhi: Lange Medical Books; 2009. p. 1101. [27] Marynick SP. Androgen excess in cystic acne. N Engl J Med 1983;308:981. [28] Zouboulis CC. Hormones. Int J Endocrinol Metab 2004;3(1):926. [29] Jerzy KW, Iwona CZ, Marcin RA, Piotr KA. The relationship between sex hormones and lipid prole in men with coronary artery disease. Int J Cardiol 2005;101: 10510. [30] Russell JJ. Topical therapy for acne. Am Fam Physician 2000;61(2):35766. [31] Kanda N, Watanabe S. 17-estradiol inhibits the production of RANTES in human keratinocytes. J Invest Dermatol 2003;120:4207. [32] Kanda N, Watanabe S. 17-estradiol inhibits the production of interferon-induced protein of 10 kDa by human keratinocytes. J Invest Dermatol 2003;120:4119. [33] Vegeto E, Ciana P, Maggi A. Estrogen and inammation: hormone generous action spreads to the brain. Mol Psychiatry 2002;7:2368. [34] Arora MK, Seth S, Dayal S. The relationship of lipid prole and menstrual cycle with acne vulgaris. Clin Biochemistry 2010;43:141520. [35] Kanda N, Watanabe S. Regulatory roles of sex hormones in cutaneous biology and immunology. J Dermatol Sci 2005;38:17. [36] Konecna L, Yan MS, Miller LE, Scholmerich J, Falk W, Straub RH. Modulation of IL-6 production during the menstrual cycle in vivo and in vitro. Brain Behav Immun 2000;14:4961. [37] Rutanen EM, Teppo AM, Stenman UH, Tiitinen A, Fyhrquist F, Ylikorkala O. Recurrent fever associated with progesterone action and persistently elevated serum levels of immunoreactive tumor necrosis factor- and interleukin-6. J Clin Endocrinol Metab 1993;76:15948. [38] Gysler A, Lange K, Korting HC, Schfer-Korting M. Prednicarbate biotransformation in human foreskin keratinocytes and broblasts. Pharm Res 1997;14:7937. [39] Shibata M, Katsuyama M, Onodera T, Ehama R, Hosoi J, Tagami H. Glucocorticoids enhance Toll-Like Receptor 2 expression in human keratinocytes stimulated with Propionibacterium acnes or proinammatory cytokines. J Invest Dermatol 2009;129:37582. [40] Bhm M, Luger TA. The role of melanocortins in skin homeostasis. Horm Res 2000;54:28793. [41] Scholzen TE, Brzoska T, Kalden DH. Expression of functional melanocortin receptors and proopiomelanocortin peptides by human dermal microvascular endothelial cells. Ann N Y Acad Sci 1999;885:23953. [42] Oeff MK, Seltmann H, Hiroi N, Nastos A, Makrantonaki E, Bornstein SR, et al. Differential regulation of Toll-like receptor and CD14 pathways by retinoids and corticosteroids in human sebocytes. Dermatology 2006;213:66. [43] Kim J, Ochoa MT, Krutzik SR, Takeuchi O, Uematsu S, Legaspi AJ, et al. Activation of toll-like receptor 2 in acne triggers inammatory cytokine responses. J Immunol 2002;169:153541. [44] Nagy I, Pivarcsi A, Kis K, Koreck A, Bodai L, Dowell A, et al. Propionibacterium acnes and lipopolysaccharide induce the expression of antimicrobial peptides and proinammatory cytokines/chemokines in human sebocytes. Microbes Infect 2006;8:2195205. [45] McInturff JE, Kim J. The role of toll-like receptors in the pathophysiology of acne. Semin Cutan Med Surg 2005;24(2):738. [46] Marta Guarna M, Coulson R, Rubinchik E. Anti-inammatory activity of cationic peptides: application to the treatment of acne vulgaris. FEMS Microbiol Lett 2006;257(1):16. [47] Jugeau S, Tenaud I, Knol AC, Jarrousse V, Quereux G, Khammari A, et al. Induction of toll-like receptors by Propionibacterium acnes. Br J Dermatol 2005;153(6): 110513. [48] Grange PA, Raingeaud J, Calvez V, Dupin N. Nicotinamide inhibits Propionibacterium acnes-induced IL-8 production in keratinocytes through the NF-kappaB and MAPK pathways. J Dermatol Sci 2009;56(2):10612. [49] Zouboulis CC, Seltmann H, Hiroi N, Chen W, Young M, Oeff M, et al. Corticotropinreleasing hormone: an autocrine hormone that promotes lipogenesis in human sebocytes. Proc Natl Acad Sci USA 2002;99(10):714853. [50] Ganceviciene R, Graziene V, Fimmel S, Zouboulis CC. Involvement of the corticotropin-releasing hormone system in the pathogenesis of acne vulgaris. Br J Dermatol 2008;160(2):34552. [51] Bodo CM, Gerd S. Role of insulin, insulin-like growth factor-1, hyperglycaemic food and milk consumption in the pathogenesis of acne vulgaris. Exp Dermatol 2009;1: 19. [52] Rebecca CR, Stephen L, James YJ, Fiona SA, Karola SS, Peter P, et al. Effect of the glycemic index of carbohydrates on acne vulgaris. Nutrients 2010;2:106072. [53] Edmondson SR, Thumiger SP, Werther GA, Wraight CJ. Epidermal homeostasis: the role of the growth hormone and insulin-like growth factor systems. Endocr Rev 2003;24:73764. [54] Robyn NS, Neil JM, Anna B, Henna M, George AV. A low-glycemic-load diet improves symptoms in acne vulgaris patients: a randomized controlled trial. Am J Clin Nutr 2007;86:10715.

gives rise to the cluster of endocrine abnormalities that characterize PCOS (elevated androgen and IGF-I concentrations and low sex hormonebinding globulin. Treatment for PCOS includes oral hypoglycemic agents, which improves insulin sensitivity, restore fertility, and alleviate acne [54]. Severe, persistent acne in males has also been associated with an increased frequency of prostate carcinoma. There are further acneassociated diseases exhibiting increased IGF-1 serum levels and increased incidence of cancer. Patients with acromegaly and PCOS have an increased prevalence of cancer Increased serum insulin and IGF-1 levels are associated with an increased incidence of a variety of cancers. In this regard, persistent acne in adulthood with insulin resistance and high IGF-1 serum levels should be regarded as a clinical indicator of increased risk for tumor promotion. Treatment of these patients with insulin-sensitizing agents will not only improve acne, but may also reduce the risk of cancer development [53]. References
[1] Simpson NB, Cunliffe WJ. Disorders of sebaceous glands. In: Burns T, Breathnach S, Cox N, Grifth C, editors. Rook's textbook of dermatology. 7th ed. Massachusetts, USA: Blackwell Publishing Company; 2004. p. 43.143.78. [2] Thiboutot D, Gollnick H, Bettoli V, Dreno B, Kang S, Leyden JJ, et al. New insights into the management of acne: an update from the global alliance to improve outcomes in acne group. J Am Acad Dermatol 2009;60(5):S1S50. [3] Rigopoulos D, Ioannides D, Kalogeromitros D, Katsambas AD. Comparison of topical retinoids in treatment of acne. Clin Dermatol 2004;22(5):40811. [4] Melnik BC, Schmitz G. Role of insulin, insulin-like growth factor-1, hyperglycaemic food and milk consumption in the pathogenesis of acne vulgaris. Exp Dermatol 2009;1:19. [5] Leyden JJ. New understandings of the pathogenesis of acne. J Am Acad Dermatol 1995;32:S1525. [6] Collier CN, Harper CJ, Cantrell WC. The prevalence of acne in adults 20 years and older. J Am Acad Dermatol 2007;58:569. [7] Sandra LH, Davidson S, Smith CB. Cause and effect: the relationship between acne and self-esteem in adolescent years. J Nurs Pract 2008;4:595600. [8] Katsambas AD, Stefanaki C, Cunliffe WJ. Guidelines for treating acne. Clin Dermatol 2004;22(5):43944. [9] Munavalli GS, Weiss RA. Evidence for laser- and light-based treatment of acne vulgaris. Semin Cutan Med Surg 2008;27(3):20711. [10] Katzman M, Logan AC. Acne vulgaris: nutritional factors may be inuencing psychological sequelae. Med Hypotheses 2007;69(5):10804. [11] Zouboulis CC. Acne and sebaceous gland function. Clin Dermatol 2004;22(5): 3606. [12] Lucky AW. Quantitative documentation of a premenstrual are of facial acne in adult women. Arch Dermatol 2004;140:4234. [13] Papakonstantinou E, Aletras AJ, Glass E, Tsogas P, Dionyssopoulos A, Adjaye J, et al. Matrix metalloproteinases of epithelial origin in facial sebum of patients with acne and their regulation by isotretinoin. J Invest Dermatol 2005;125:67384. [14] Melnik Bodo C. Acneigenic stimuli converge in phosphoinositol-3 kinase/ Akt/ Foxo1 signal transduction. J Clin Exp Dermatol 2010:18. [15] Ottaviani M, Alestas T, Flori E, Mastrofrancesco A, Zouboulis CC, Picardo M. Peroxidated squalene induces the production of inammatory mediators in HaCaT keratinocytes: a possible role in acne vulgaris. J Invest Dermatol 2006;126:24307. [16] Jeremy AH, Holland DB, Roberts SG, Thomson KF, Cunliffe WJ. Inammatory events are involved in acne lesion initiation. J Invest Dermatol 2003;121:207. [17] George R, Clarke S, Thiboutot D. Hormonal therapy for acne. Semin Cutan Med Surg 2008;27(3):18896. [18] Olutunmbi Y, Paley K, English JC. The effect of a high-protein, low glycemic-load diet versus a conventional, high glycemic-load diet on biochemical parameters associated with acne vulgaris; A randomized, investigator-masked, controlled trial. J Pediatr Adolesc Gynecol 2008;21(4):1716. [19] Placzek M, Arnold B, Schmidt H, Gaube S, Keller E, Plewig G, et al. Elevated 17hydroxyprogesterone serum values in male patients with acne. J Am Acad Dermatol 2005;53(6):9558. [20] Harper JC. An update on the pathogenesis and management of acne vulgaris. J Am Acad Dermatol 2004;51(1):368. [21] Thiboutot D. Acne: hormonal concepts and therapy. Clin Dermatol 2004;22:41928. [22] Thiboutot D, Harris G, Iles V. Activity of the type 1 5 alpha-reductase exhibits regional differences in isolated sebaceous glands and whole skin. J Invest Dermatol 1995;105:20914. [23] Roseneld RL, Deplewski D, Kentsis A, Ciletti N. Mechanisms of androgen induction of sebocyte differentiation. Dermatology 1998;196:436.