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A systemic type I 5 α-reductase inhibitor is ineffective in the treatment of acne vulgaris
Abstract
Excessive sebum production is a central aspect of the pathophysiology of acne vulgaris. Sebaceous gland function is under androgen control and it is hypothesized that dihydrotestosterone is formed by the action of 5 alpha-reductase. Type I is the controlling isoenzyme. This study describes a 3-month, multicenter, randomized, placebo-controlled clinical trial with a potent, selective inhibitor of type I 5 alpha-reductase used alone and in combination with systemic minocycline. Inhibition of type I 5 alpha-reductase was not associated with clinical improvement of acne when used alone and did not enhance the clinical benefit of systemic minocycline. These results indicate the need for further work at the molecular level to better understand the action of androgens on sebaceous gland function.
... Sebum secretion by the sebaceous glands is accelerated by the conversion of testosterone to DHT by type I 5a-reductase, which is strongly expressed in the sebaceous glands. Therefore, it has been proposed that type I 5ARIs have the potential to improve acne vulgaris [20]. There are few publications regarding the use of 5ARIs and patients with acne. ...
... However, there was no additional improvement observed for patients receiving the combination treatment compared to those on minocycline alone. The lack of enhanced improvement with the combination treatment could be attributed to the direct stimulation of sebaceous production by testosterone and the expression of type II 5areductase in sebaceous glands associated with acne follicles [20]. ...
Finasteride and dutasteride are 5-alpha reductase selective inhibitors (5ARIs). They were introduced as therapeutic agents for the treatment of benign prostatic hyperplasia in 1992 and 2002, respectively; finasteride has also been approved for the treatment of androgenetic alopecia since early 2000. These agents inhibit the conversion of testosterone (T) to 5α-dihydrotestosterone (5α-DHT), limiting steroidogenesis and playing a crucial role in the physiological function of the neuroendocrine system. Therefore, it has been proposed that blocking androgen synthesis with the use of 5ARIs would be beneficial in the treatment of various diseases related to states of hyperandrogenism. This review describes the dermatological pathologies in which 5ARIs have been used as part of the treatment, evaluation of the efficacy, and knowledge of the safety profile. Specifically, we discuss the application of 5ARIs in androgenetic alopecia, acne, frontal fibrosing alopecia, hirsutism, and the implications of adverse events associated with its use to inform about the applications of 5ARIs in general dermatology practice.
... [36,37] A PubMed search from January 2000 to 15 November 2008 using the search terms 'acne,' 'minocycline,' and 'randomized controlled trial' found nine randomized controlled trials of minocycline for the treatment of acne (table IV). [29,[38][39][40][41][42][43][44][45] Table III. Non-antibacterial and anti-inflammatory effects of different tetracyclines [4,[14][15][16][17][18] Effect ...
... The therapeutic effects of minocycline were superior to placebo [41,[43][44][45] and zinc gluconate, [38] comparable to lymecycline, [29,40] and almost as effective as isotretinoin in severe nodulocystic acne in combination with azelaic acid, [39] but not more effective than oxytetracycline, topical benzoyl peroxide, or combinations of topical benzoyl peroxide with erythromycin in mild to moderate acne of the face. [42] In the latter study, minocycline was the least cost-effective drug; however, an assessment of quality of life using the Dermatology Quality of Life Scale ranked the drug higher than for efficacy. ...
Minocycline is a semi-synthetic, second-generation tetracycline. It was introduced in 1972 and has both antibacterial and anti-inflammatory properties. Minocycline is used for a variety of infectious diseases and in acne. Even today, new indications beyond the antibacterial indications are being investigated such as its use in neurologic diseases. Formerly, minocycline was thought to have a superior efficacy in the treatment of inflammatory acne, especially with respect to antibacterial-resistant Propionibacterium acnes. A thorough review of the literature, however, shows that minocycline is not more effective in acne than other tetracyclines. Compared with first-generation tetracyclines, minocycline has a better pharmacokinetic profile, and compared with doxycycline it is not phototoxic. However, minocycline has an increased risk of severe adverse effects compared with other tetracyclines. It may induce hypersensitivity reactions affecting the liver, lung, kidneys, or multiple organs (Drug Reaction with Eosinophilia and Systemic Symptoms [DRESS] syndrome) in the first weeks of treatment and, with long-term treatment, may cause autoimmune reactions (systemic lupus erythematosus, autoimmune hepatitis). In addition, CNS symptoms, such as dizziness, are more frequent compared with other tetracyclines. Long-term treatment may induce hyperpigmentation of the skin or other organs. Resistance of P. acnes to minocycline also occurs, dependent on the prescribing behavior.
Considering the aspects of efficacy, its adverse effect profile, resistance, price, and alternatives, minocycline is no longer considered the first-line antibacterial in the treatment of acne.
... Since the activity of the 5 -reductase system is elevated in skin from acne-prone areas, acne-bearing facial skin, pubic skin of hirsute women, and male bald scalp, its inhibition appears to be a promising target for treatment of androgen-dependent skin disorders [1,11,12] . However, the published clinical results on acne treatment are rather disappointing [13,14] . Aim of this study was to investigate the infl uence of a series of selective inhibitors of the 5 -reductase isotypes on the conversion of testosterone to 5 -DHT in human sebocytes and keratinocytes in vitro and to examine the biological activity of 5 -reductase inhibition within cultured human sebocytes. ...
... This illustrates that androgen receptor blockers only partially block the androgen receptor [35] and that the unblocked androgen receptor fraction is suffi cient to convey the weak testosterone effect on sebocyte proliferation. Our data and the rather disappointing results of 5 -reductase inhibitors in acne treatment [13,14] make it likely that acne aetiopathogenesis is not solely associated with increased androgen activity but has a complex background [36] . Nevertheless, since the clinical studies did not distinguish between male and female volunteers, the possibility remains that the therapeutic effi cacy may differ under prolonged therapy between men and women. ...
Inhibition of 5alpha-reductase type 1 has been considered to be a promising target for treatment of androgen-dependent skin disorders, however, currently published clinical results on acne treatment are rather disappointing. In this study, the influence of selective inhibitors of 5alpha-reductase on testosterone metabolism within SZ95 sebocytes and HaCaT keratinocytes IN VITRO was investigated. In both cell types, the isotype 1 inhibitor MK386 completely inhibited the conversion of testosterone to 5alpha-dihydrotestosterone in concentrations higher than 10 (-9) M. Inhibitors of the isotype 2 such as finasteride, dihydrofinasteride, and turosteride, were >100-fold less active, while, as expected, androgen receptor inhibitors did not affect the 5alpha-reductase activity. MK386, but not finasteride, reduced testosterone-stimulated proliferation and slightly reduced the testosterone-induced increase in the amount of SZ95 sebocyte proteins. The androgen receptor inhibitor cyproterone acetate exhibited no effect on testosterone-induced proliferation, but inhibited the 5alpha-dihydrotestosterone-induced sebocyte proliferation. Our experimental findings and the existing clinical results indicate that the inhibition of 5alpha-reductase activity alone may be insufficient to reduce overall sebocyte activity and improve acne lesions.
... Interestingly, the sebum production rate in patients with a type II 5a-reductase deficiency was similar to that in normal men [20], suggesting that DHT produced locally by type I 5α-reductase enhances the sebum production. However, in clinical and in vitro studies, selective inhibitors of type I 5α-reductase did not significantly reduce the sebum production or improve acne vulgaris [21,22], suggesting that the suppression of 5α-reductase alone is not sufficient to improve acne. There are several possibilities to explain this. ...
The association between acne and insulin resistance has not been investigated as thoroughly in males as it has been in women, despite the fact that in adult men, acne prevalence has grown. On the face, sebaceous glands produce and secrete sebum, which lubricates the skin and protects it from friction. Metformin, an insulin-sensitizing medication, may modify the association between acne vulgaris and insulin resistance (IR). Individuals with IR, metabolic syndrome or with impaired glucose tolerance are sometimes treated ‘off label’ with Metformin. In these conditions, IR may be a leading factor in the pathogenesis of acne, and in men, Metformin treatment may reduce the Global Acne Grading System (GAGS) score by enhancing insulin sensitivity. However, additional clinical studies are required to corroborate these assumptions.
... However, for the establishment of acne, androgenmediated sebum production is necessary but not sufficient. This was confirmed by studies that evaluated the efficacy of 5α-reductase inhibitors that did not significantly improve acne [50,51]. ...
The objective of this narrative review was to check the influence of the human microbiota in the pathogenesis of acne and how the treatment with probiotics as adjuvant or alternative therapy affects the evolution of acne vulgaris. Acne is a chronic inflammatory skin disease involving the pilosebaceous units. The pathogenesis of acne is complex and multifactorial involving genetic, metabolic, and hormonal factors in which both skin and gut microbiota are implicated. Numerous studies have shown the bidirectionality between the intestinal microbiota and skin homeostasis, a communication mainly established by modifying the immune system. Increased data on the mechanisms of action regarding the relevance of Cutibacterium acnes, as well as the importance of the gut–skin axis, are becoming known. Diverse and varied in vitro studies have shown the potential beneficial effects of probiotics in this context. Clinical trials with both topical and oral probiotics are scarce, although they have shown positive results, especially with oral probiotics through the modulation of the intestinal microbiota, generating an anti-inflammatory response and restoring intestinal integrity, or through metabolic pathways involving insulin-like growth factor I (IGF-1). Given the aggressiveness of some standard acne treatments, probiotics should continue to be investigated as an alternative or adjuvant therapy.
... Isotretinoin can inhibit sebum production and inhibit the size of the sebaceous glands [3]. Systemic type I 5a-reductase inhibitors did not improve acne in vivo [62]. Topical linoleic acid has shown some efficacy in acne, but there is no significant reduction in sebum [63]. ...
Previous approaches to acne management have focused on the four main factors implicated in acne, namely, androgen-mediated sebogenesis (considered integral to acne), hyperkeratinization, colonization with Cutibacterium acnes, and inflammation related to both innate and adaptive mechanisms. Recent advances have facilitated potential novel approaches to acne management, as the pathophysiology and the immunological aspects related to acne and wound healing have evolved. Particular targets that have been shown to be closely involved in acne pathophysiology and wound healing include interleukin (IL)-1β, IL-17, IL-23, and tumor necrosis factor alpha (TNFα). Biological antibodies targeting IL-1β, IL-17, IL-23, and TNFα could provide novel approaches for treating severe acne and related disorders. Acne is primarily a disease associated with sebogenesis. Monosaturated free acids are important components. Insulin growth factor 1 (IGF-1) promotes the proliferation and differentiation of sebocytes and IL-1β. Research into the microbiome may also provide insights into potential future therapeutic options for acne. Scars, both atrophic and hypertrophic, are common sequelae to acne. Risk factors associated with the development of acne scars include genetic, systemic, local, and lifestyle factors. Pro-inflammatory cytokines have been shown to play a crucial role in the development of acne-induced hypertrophic scars. Treatment for extensive inflammatory keloid scarring is limited. Surgery and postoperative radiotherapy are two possible options. Transforming growth factor-β (TGFβ), IL-6, matrix metalloproteinase (MMP), IGF-1, and B cells are found in keloid or hypertrophic scar tissues. Biological antibodies targeting these cytokines may be a potential strategy for the prevention and treatment of this type of scar in the future. Future treatment for acne should embrace approaches that target the main etiological factors of acne. In particular, specific emphasis on aggressive treatment in the acute inflammatory phase to reduce the likelihood of scarring and other clinical sequelae, such as pigmentary changes would be highly desirable. Treatment for established acne-induced sequelae should also be considered.
... Hence, sebum production is associated with DHT which changes from testosterone by 5α-reductase type 1. Therefore, 5α-reductase type 1 inhibitory activity decreases DHT that decreases sebum production and AV [18,36,37]. In this study, QML and PD showed great 5α-reductase type 1 inhibitory activity compare with the PC. ...
Quercus mongolica (QM)—a member of the Fagaceae family—has been used as traditional medicine in Korea, China and Mongolia as a treatment for inflammation of oral, genital or anal mucosa and for external inflammation of skin. To treat acne vulgaris (AV), we evaluated the inhibition of inflammatory cytokines (IL-6 and IL-8) of QM leaf extract (QML) and its main compound, pedunculagin (PD) in vitro and 5α-reductase inhibitory activity by western blotting. As results, QML and PD showed potent NO production inhibitory activity compared with the positive control (PC), NG-monomethyl-L-arginine (L-NMMA). QML and PD was also showed the decreases of IL-6 and IL-8 compared with the PC, EGCG and exhibited potent 5α-reductase type 1 inhibitory activities compared with the PC, dutasteride.
... Unfortunately, to date, there is no inhibitor able to selectively target the type 1 isoenzyme in humans. Some 5AR1 inhibitors have been developed for clinical trials for the treatment of acne vulgaris, but with no promising results (Leyden et al., 2004). Furthermore, these compounds do not bind to rat 5AR1 and, therefore, cannot be used to discern the role of this isoform in the 6-OHDA rat model of PD. ...
Although 1-3,4-dihydroxyphenylalanine (L-DOPA) is the mainstay therapy for treating Parkinson's disease (PD), its long-term administration is accompanied by the development of motor complications, particularly L-DOPA induced dyskinesia (LID), that dramatically affects patients' quality of life. LID has consistently been related to an excessive dopamine receptor transmission, particularly at the down-stream signaling of the striatal D1 receptors (D1R), resulting in an exaggerated stimulation of cAMP-dependent protein kinase and extracellular signal-regulated kinase (ERK) pathway. We previously reported that pharmacological blockade of 5alpha-reductase (5AR), the rate-limiting enzyme in neurosteroids synthesis, attenuates the severity of a broad set of behavioral alterations induced by D1R and D3R activation, without inducing extrapyramidal symptoms. In line with this evidence, in a recent study, we found that inhibition of 5AR by finasteride (FIN) produced a significant reduction of dyskinesia induced by L-DOPA and direct dopaminergic agonists in 6-OHDA-lesioned rats. In the attempt to further investigate the effect of 5AR inhibitors on dyskinesia and shed light on the mechanism of action, in the present study we compared the effect of FIN and dutasteride (DUTA), a potent dual 5AR inhibitor, on the development of LID, on the therapeutic efficacy of L-DOPA, on the molecular alterations downstream to the D1R, as well as on D1R-D3R interaction. The results indicated that both FIN and DUTA administration significantly reduced development and expression of LID; however, DUTA appeared more effective than FIN at a lower dose and produced its antidyskinetic effect without impacting the ability of L-DOPA to increase motor activation, or ameliorate forelimb use in parkinsonian rats. Moreover, this study demonstrates for the first time that 5AR inhibitors are able to prevent key events in the appearance of dyskinesia, such as L-DOPA-induced upregulation of striatal D1R-related cAMP/PKA/ERK signaling pathways and D1R-D3R coimmunoprecipitation, an index of heteromer formation. These findings are relevant as they confirm the 5AR enzyme as a potential therapeutic target for treatment of dyskinesia in PD, suggesting the first ever evidence that neurosteroidogenesis may affect functional interaction between dopamine D1R and D3R.
... Le type III a été plus récemment découvert (Uemura et al., 2008) et son implication sur la sécrétion sébacée est inconnue. Une déficience en 5α-réductase de type II ne modifie pas le taux de production de sébum, ce qui suggère que la 5α-DHT ( produite dans les sébocytes est fonction de la 5α-réductase de type I. Toutefois, des études cliniques (Leyden et al., 2004) et in vitro (Seiffert et al., 2007), avec des inhibiteur sélectifs de type I n'ont pas montré réduire de façon significative la production de sébum, ce qui indique que la suppression de la 5α-réductase seule pourrait ne pas être suffisante pour améliorer l'acné. De surcroît, l'activité de la 5α-réductase de type I ne semblait pas modifiée entre un sujet atteint d'acné et un sujet sain, ce qui devra être confirmé car le nombre de sujets étudiés est très faible (Arora et al., 2011). ...
L’acné représente l’un des motifs de consultation les plus fréquents en dermatologie, notamment chezl’adolescent et le jeune adulte. Cette pathologie est complexe et multiparamétrique et, à ce titre, cemémoire présente les mécanismes impliqués dans la pathogenèse de l’acné, les facteurs de risquesassociés et les effets des médicaments utilisés dans le traitement de l’acné en France.La pathogénie de l’acné fait intervenir plusieurs groupes de mécanismes que sont une hyperséborrhéeavec une modification de la composition du sébum, une hyperkératinisation des follicules pilosébacés,une amplification de la colonisation de ces follicules par la bactérie Propionibacterium acnesainsi qu’une réaction inflammatoire. La chronologie de ces événements reste incertaine. Cependant,l’activité de la glande sébacée et la qualité du sébum produits ont un rôle central dans cettepathogenèse et de fait sont sans doute le point de départ du développement de la pathologie.L’activité des sébocytes présents dans les glandes sébacées sont sous l’influence de nombreusesmolécules telles que des hormones, des facteurs de croissance ou des neuropeptides. La modificationdes taux de ces molécules chez le patient acnéique en comparaison aux sujets sains conditionne ledéveloppement de l’acné. Les androgènes et l’IGF-1 ont par exemple un rôle important dansl’apparition de l’acné à l’adolescence.Mais, ces mécanismes pathogéniques sont également sous l’influence de divers facteurs de risques(alimentation, stress, soleil, tabac…). Une mise au point des connaissances actuelles, de l’implicationet des mécanismes par lesquels le mode de vie et le patrimoine génétique influent sur ledéveloppement l’acné est présentée dans ce mémoireEnfin, il est également question de comprendre comment les médicaments permettent une réductiondes lésions d’acné, et de passer en revue les recommandations actuelles d’utilisation de cesmédicaments pour traiter le plus efficacement les patients acnéiques.
... The results in increased proliferation of sebaceous gland and increased sebum production; responsible genes are not identified up till now (figure -1) 21 . In most of the patients of seborrhea, despite of normal levels of androgens sebum production is high because of increased sensitivity of sebocytes towards androgen (it may be the cause) 22 . Hence seborrhea and acne can occur both at normal as well as higher levels of androgens. ...
The literature is full of disputes, contradictions and confusions regarding acne. This disease is more prevailing among the young people and often associated with suicide and depression. Acne starts appearing after the onset of puberty and can extend up to 40 to 50 years of age. As far as pathogenesis of acne is concerned it is not fully understood up till now. The main key factors responsible for the development of acne are: An increased production of sebum, Hypercornification, Colonization of bacteria in pilosebaceous duct and Inflammation. Although inflammation is not directly associated with the development of acne but it can results as a consequence of other factors for example, propionibacterium acnes when colonized into the ducts it cause the production of pro inflammatory cytokines and other antigens which initiate various cellular as well as non- cellular immune responses ultimately lead to inflammation. Treatment of acne is very frustrating and involves an understanding of etiopathological factors. The aim of this review is to study the various factors responsible for acne, there contribution towards the pathogenesis of acne and acne therapy.
... It has also been shown that the activity of 5αR1, which mainly converts T to DHT in human sebaceous glands, is greater in facial skin than in normal skin [54,124]. The use of selective inhibitors of 5αR1 did not improve the acne lesions [125]. ...
The skin is an important extra-gonadal steroidogenic organ, capable of metabolizing various hormones from their precursors, as well as of synthesizing de novo a broad palette of sex steroids and glucocorticoids from cholesterol. In this manuscript, we review the major steroidogenic properties of human skin and we suggest steroidogenesis’ impairment as a cardinal factor for various pathological conditions such as acne, rosacea, atopic dermatitis, and androgenic alopecia.
... In most of the patients of seborrhea, despite normal levels of androgens sebum production is high because of increased sensitivity of sebocytes toward androgen (it may be the cause) [15]. Hence, seborrhea and acne can occur both at normal as well as higher levels of androgens [16,17]. ...
Acne vulgaris is a disease associated with sebaceous follicle. It starts appearing after the onset of puberty and can extend up to 40-50 years of age. As far as the pathogenesis of acne is concerned, it is not fully understood up till now. Treatment of acne is very frustrating and involves an understanding of etiopathological factors. This review focuses on various factors accountable, pathogenesis, and therapy of acne. © 2016, Innovare Academics Sciences Pvt. Ltd. All rights reserved.
... Lesions may develop in oily as well as in dry facial areas. Although elevated sebum production is considered as one key element in acne pathogenesis (1,3), it only promotes the development of acne lesions but is no primary trigger (2,24,43). ...
Background:
Porphyrins are native fluorophores in the follicle openings, visible under ultraviolet-A light. Acne severity might be associated with increased Propionibacterium acnes colonization and porphyrin production. Aim of this study was to investigate whether the parameter fluorescence quantity can be used to measure acne severity.
Methods:
A validation study was conducted in 24 patients with acne using split-face design. Acne severity was measured using Investigator Static Global Assessment scores and lesion counts. Reliability, construct validity and sensitivity to change in fluorescence quantity were investigated.
Results:
Mean baseline Investigator Static Global Assessment score was 2.7 (SD 0.1). Mean baseline fluorescence quantities were 24.8 (SD 4.0) on the cheek and 20.3 (SD 4.6) on the chin. On day 25, values ranged from 6.0 (SD 6.0) to 18.1 (SD 18.4) on the cheek and from 2.6 (SD 4.4) to 14.7 (SD 16.2) on the chin. The intraclass correlation coefficients of fluorescence quantity ranged from 0.513 to 0.987. Effect sizes for fluorescence measurements were highest on the chin and cheek ranging from 0.24 to 0.77 and 0.32 to 0.75, respectively.
Conclusion:
Fluorescence quantity indicates acne severity, especially on the inner cheek and chin areas. Fluorescence quantity is reliable but is not as sensitive as manual lesion counting.
... 17HSD2 (which can inactivate potent androgens) and was found mostly in sebaceous glands of non-acne prone areas in comparison to facial skin [98]. Although 5R1 is the main enzyme converting T to DHT in human sebaceous glands, the use of selective inhibitors did not improve acne vulgaris lesions [200]. This might be interpreted to be due to reduced production of DHT by other 5R isozymes to the minimal quantity required to trigger cellular responses, and/or the idea that T rather than DHT plays the main role in stimulating sebaceous lipogenesis [106,201]. ...
... Intriguingly, the sebum production rate in patients with the deficiency of type II 5a-reductase was similar to that of normal males [52], suggesting that DHT produced locally by type I 5a-reductase enhanced sebum production. However, in the clinical and in vitro studies, selective inhibitors for type I 5a-reductase did not significantly reduce sebum production and improve acne vulgaris [62,97], indicating that suppression of 5a-reductase alone might not be sufficient to improve acne. There are several possibilities to explain this. ...
Androgen and androgen receptor (AR) may play important roles in several skin-related diseases, such as androgenetic alopecia and acne vulgaris. Current treatments for these androgen/AR-involved diseases, which target the synthesis of androgens or prevent its binding to AR, can cause significant adverse side effects. Based on the recent studies using AR knockout mice, it has been suggested that AR and androgens play distinct roles in the skin pathogenesis, and AR seems to be a better target than androgens for the treatment of these skin diseases. Here, we review recent studies of androgen/AR roles in several skin-related disorders, including acne vulgaris, androgenetic alopecia and hirsutism, as well as cutaneous wound healing.
... MK-386 was examined as a treatment for acne in a placebo-controlled trial and was found to be similar to placebo and inferior to systemic minocycline therapy. Furthermore, MK-386 did not enhance the therapeutic benefit of minocycline when used in combination [106]. In another study, finasteride decreased the severity of acne but was inferior to flutamide and cyproterone acetate with ethinyl estradiol [107]. ...
Despite the discovery of 5 alpha-reduction as an enzymatic step in steroid metabolism in 1951, and the discovery that dihydrotestosterone is more potent than testosterone in 1968, the significance of 5 alpha-reduced steroids in human diseases was not appreciated until the discovery of 5 alpha-reductase type 2 deficiency in 1974. Affected males are born with ambiguous external genitalia, despite normal internal genitalia. The prostate is hypoplastic, nonpalpable on rectal examination and approximately 1/10th the size of age-matched normal glands. Benign prostate hyperplasia or prostate cancer does not develop in these patients. At puberty, the external genitalia virilize partially, however, secondary sexual hair remains sparse and male pattern baldness and acne develop rarely. Several compounds have been developed to inhibit the 5 alpha-reductase isozymes and they play an important role in the prevention and treatment of many common diseases. This review describes the basic biochemical properties, functions, tissue distribution, chromosomal location, and clinical significance of the 5 alpha-reductase isozyme family.
... Unfortunately, to date, there is no inhibitor able to selectively target the type 1 isoenzyme in humans. Some 5AR1 inhibitors have been developed for clinical trials for the treatment of acne vulgaris, but with no promising results (Leyden et al., 2004). Furthermore, these compounds do not bind to rat 5AR1 and, therefore, cannot be used to discern the role of this isoform in the 6-OHDA rat model of PD. ...
... A recent study with orally administered type I 5a-reductase inhibitor, which suppresses facial sebum secre- tion, showed that the suppression of facial sebum production does not improve acne lesions. 14 This study supports our results. ...
It is generally accepted that the severity of acne is correlated with facial sebum secretion. However, previous studies on the relation between seborrhoea and the development of acne did not consider topographical differences in facial sebum secretion and used relatively vague acne severity grading systems.
To elucidate the relation between topographical variations in facial sebum secretion and the severity of acne in women.
Forty-six female controls and 46 women with acne were included in this study. The Sebumeter was used to measure facial sebum secretion in the following facial areas: forehead, nose, chin, and right and left cheek. We counted noninflammatory comedones and inflammatory acne lesions in the same areas. We compared sebum secretion between patients with acne and controls, and analysed the relation between the quantity of sebum secreted and the number of acne lesions.
Sebum secretions in the whole face and in the T- and U-zones (areas of high and low sebum secretion, respectively) were higher in patients with acne than in controls. There was no correlation between sebum quantity and acne lesion count in most facial regions.
Increased levels of facial sebum secretion were observed in patients with acne. Our findings indicate that increased sebum levels do not directly cause development of acne lesions.
... In addition, the suppression of facial sebum secretion may not directly prevent orTable 4 The pH (mean and SD) measured in five facial sites and p-value between two different sites Mean ± SD (lg cm –2 ) Nose tip (5.05 ± 0.452) Arch Dermatol Res reduce acne. Leyden et al. [9] demonstrated that the suppression of facial sebum secretion by a potent, selective inhibitor of type I 5 a-reductase did not improve acne lesions in a multicenter, placebo-controlled clinical trial. In respect to pH, none of the five areas differed significantly between the two groups (P > 0.05). ...
Differences of skin type and pH between subjects with and without acne have not been investigated. In addition, the relationship between sebum secretion and pH in these populations has not been determined. This study assessed the differences in objective and subjective skin types between these two groups. Secondly, this study evaluated the difference in pH on five facial areas (forehead, nose, chin, right and left cheeks) between the two populations. Lastly, the relationship between pH and sebum secretion was analyzed in each population. Sebum casual levels (CL) of the five facial areas in 36 Koreans with acne and 47 Koreans without acne were measured by using a Sebumeter SM 815® and subjects were classified into objective skin types by CL. Subjects reported the type of skin they believed they had, which determined the subjective skin type. The pH levels of the five facial areas were measured by the Skin-pH-Meter PH 905®. Data were assessed with adequate statistical tests depending on data type and distribution. Among the five areas, the nose of the subjects with acne showed a significantly higher CL, compared to the subjects without acne. This difference in CL on the nose resulted in the difference in CL on the T-zone and mean facial sebum excretions (MFSE). Although CL differed, objective skin types did not differ between the two groups (P > 0.05), but the subjective skin types differed significantly (P = 0.001). In addition, the objective skin types were significantly different than the subjective skin types in subjects with acne (P = 0.001), whereas the two skin types did not differ in subjects without acne. Subjects with acne actually overestimated their skin types and stated their skin types were “oilier” than they were. In respect to pH, none of the five areas differed significantly between the two groups. Among the five sites in subjects with acne, CL showed a significant negative correlation with pH on the left (r
2 = 0.12) and right (r
2 = 0.15) cheeks, which resulted in a significant negative correlation on the U-zone (r
2 = 0.14). In contrast, in subjects without acne, there was a significant negative correlation between CL and pH on the forehead (r
2 = 0.10) and chin (r
2 = 0.16), which led to a significant negative correlation on the T-zone (r
2 = 0.14).
... Therefore, it may aid the consumer by measuring the objective skin types when skin care products are selected in subjects with acne, rather than solely depending on the subjective feelings of the consumer. In addition, the suppression of facial sebum secretion may not directly prevent or [9] demonstrated that the suppression of facial sebum secretion by a potent, selective inhibitor of type I 5 a-reductase did not improve acne lesions in a multicenter, placebo-controlled clinical trial. In respect to pH, none of the five areas differed significantly between the two groups (P > 0.05). ...
Differences of skin type and pH between subjects with and without acne have not been investigated. In addition, the relationship between sebum secretion and pH in these populations has not been determined. This study assessed the differences in objective and subjective skin types between these two groups. Secondly, this study evaluated the difference in pH on five facial areas (forehead, nose, chin, right and left cheek) between the two populations. Lastly, the relationship between pH and sebum secretion was analyzed in each population. Sebum casual levels (CL) of the five facial areas in 36 Koreans with acne and 47 Koreans without acne were measured by using a Sebumeter SM 815((R)) and subjects were classified into objective skin types by CL. Subjects reported the type of skin they believed they had, which determined the subjective skin type. The pH levels of the five facial areas were measured by the Skin-pH-Meter PH 905((R)). Data was assessed with adequate statistical tests depending on data type and distribution. Among the five areas, the nose of the subjects with acne showed a significantly higher CL, compared to the subjects without acne. This difference in CL on the nose resulted in the difference in CL on the T-zone and mean facial sebum excretions (MFSE). Although CL differed, objective skin types did not differ between the two groups (P > 0.05), but the subjective skin types differed significantly (P = 0.001). In addition, the objective skin types were significantly different than the subjective skin types in subjects with acne (P = 0.001), whereas the two skin types did not differ in subjects without acne. Subjects with acne actually overestimated their skin types and stated their skin types were "oilier" than they were. In respect to pH, none of the five areas differed significantly between the two groups. Among the five sites in subjects with acne, CL showed a significant negative correlation with pH on the left (r (2 )=( )0.12) and right (r (2 )=( )0.15) cheeks, which resulted in a significant negative correlation on the U-zone (r (2 )=( )0.14). In contrast, in subjects without acne, there was a significant negative correlation between CL and pH on the forehead (r (2 )=( )0.10) and chin (r (2 )=( )0.16), which led to a significant negative correlation on the T-zone (r (2 )=( )0.14).
... In accordance with in vivo studies, treatment with LY191704 and either testosterone or LA did not show any inhibitory effect on 5a-DHT and sebaceous lipid synthesis. 21 However, LY191704 showed its inhibitory action when cells were exposed concurrently to testosterone and LA. Hence, we hypothesize that the 5a-reductase type I can be inhibited only after being activated by LA. ...
Despite the clinical evidence that androgens stimulate sebaceous lipids, androgens in vitro have shown no similar effects. This contradiction led to the assumption that cofactors may be required for lipid regulation and peroxisome proliferator-activated receptor (PPAR) ligands were suggested to be adequate candidates.
The influence of testosterone and linoleic acid, a PPAR ligand, as single agents and in combination with of LY191704, a 5alpha-reductase type I inhibitor, was examined on 5alpha-dihydrotestosterone (5alpha-DHT) synthesis and lipid content in human SZ95 sebocytes.
Cell proliferation and viability were measured by the 4-methylumbelliferyl heptanoate fluorescence assay and by the Boehringer Lactate Dehydrogenase Assay kit, respectively. 5alpha-DHT enzyme-linked immunosorbent assay was used for the detection of 5alpha-DHT synthesis in cell supernatants after treatment, whereas lipid production was documented by means of the Nile red lipid microassay and fluorescence microscopy.
Testosterone promoted 5alpha-DHT synthesis (P < 0.001), whereas linoleic acid increased sebaceous lipids (P < 0.001). The combination of testosterone and linoleic acid exhibited a synergistic effect on the synthesis of 5alpha-DHT (P < 0.01 vs. testosterone) and sebaceous lipids (P < 0.01 vs. linoleic acid). Furthermore, LY191704 reduced 5alpha-DHT and sebaceous lipid levels (P < 0.01 and P < 0.001 in comparison with testosterone/linoleic acid, respectively). Cell proliferation and viability remained unchanged under treatment with all compounds tested.
These data suggest a catalytic effect of PPAR ligands on cellular testosterone activation by 5alpha-reduction and the importance of the latter for the regulation of sebaceous lipids.
... However, although an exclusive predominance of type 1 5 -reductase has been demonstrated in sebaceous glands, with higher enzyme activity in facial skin than in nonacne-prone skin [27,69] , there seems to be no relationship between the activity of 5 -reductase or 17 -HSD in sebaceous glands and the presence or absence of acne in both sexes [70] . Moreover, in a 3-month, multicenter, randomized, placebo-controlled clinical trial, the use of a potent selective inhibitor of type 1 5 -reductase alone or in combination with systemic minocycline was not associated with clinical improvement of acne [71] . On the other hand, enhanced expression of type 2 5 -reductase was revealed in the hair follicle but not in the sebaceous glands in infl ammatory acne lesions [72] . ...
Local androgen excess has been associated with attenuation of wound healing in elderly individuals and with a decline in permeability barrier homeostasis in adult human skin. In this study we have applied specific antisense oligonucleotides, whose activity has already been investigated in SZ95 sebocytes, to inactivate transiently the androgen receptor in a reconstituted epidermis model and in primary human epidermal keratinocytes of different origin (breast, abdomen, foreskin) and donor age (females, 30- and 60-year-old). Further a possible interaction between blockage of androgen receptor and the expression of tissue inhibitors of matrix metalloproteinases was investigated. Androgen receptor levels were similar in pooled keratinocytes of the two age groups. Cell transfection with antisense oligonucleotides against the androgen receptor resulted in decreasing protein levels detected in all epidermal keratinocytes tested, whereas cells of aged donors (60-year-old) exhibited a stronger response than cells of young individuals (30-year-old). Keratinocytes from aged donors also responded to androgens with a stronger regulation of proliferation than keratinocytes of young individuals. The pattern of the androgen-induced response was dependent on the skin region of keratinocyte origin. The expression levels of tissue inhibitor of matrix metalloproteinase-1 were not age-related. Our results demonstrate an enhanced androgen sensitivity of keratinocytes from aged individuals associated with an origin-specific type of response.
... However, although an exclusive predominance of type 1 5 -reductase has been demonstrated in sebaceous glands, with higher enzyme activity in facial skin than in nonacne-prone skin [27,69] , there seems to be no relationship between the activity of 5 -reductase or 17 -HSD in sebaceous glands and the presence or absence of acne in both sexes [70] . Moreover, in a 3-month, multicenter, randomized, placebo-controlled clinical trial, the use of a potent selective inhibitor of type 1 5 -reductase alone or in combination with systemic minocycline was not associated with clinical improvement of acne [71] . On the other hand, enhanced expression of type 2 5 -reductase was revealed in the hair follicle but not in the sebaceous glands in infl ammatory acne lesions [72] . ...
The skin locally synthesizes significant amounts of sexual hormones with intracrine or paracrine actions. The local level of each sexual steroid depends upon the expression of each of the androgen- and estrogen-synthesizing enzymes in each cell type, with sebaceous glands and sweat glands being the major contributors. Sebocytes express very little of the key enzyme, cytochrome P450c17, necessary for synthesis of the androgenic prohormones dehydroepiandrosterone and androstenedione, however, these prohormones can be converted by sebocytes and sweat glands, and probably also by dermal papilla cells, into more potent androgens like testosterone and dihydrotestosterone. Five major enzymes are involved in the activation and deactivation of androgens in skin. Androgens affect several functions of human skin, such as sebaceous gland growth and differentiation, hair growth, epidermal barrier homeostasis and wound healing. Their effects are mediated by binding to the nuclear androgen receptor. Changes of isoenzyme and/or androgen receptor levels may have important implications in the development of hyperandrogenism and the associated skin diseases such as acne, seborrhoea, hirsutism and androgenetic alopecia. On the other hand, estrogens have been implicated in skin aging, pigmentation, hair growth, sebum production and skin cancer. Estrogens exert their actions through intracellular receptors or via cell surface receptors, which activate specific second messenger signaling pathways. Recent studies suggest specific site-related distribution of ERalpha and ERbeta in human skin. In contrast, progestins play no role in the pathogenesis of skin disorders. However, they play a major role in the treatment of hirsutism and acne vulgaris, where they are prescribed as components of estrogen-progestin combination pills and as anti-androgens. These combinations enhance gonadotropin suppression of ovarian androgen production. Estrogen-progestin treatment can reduce the need for shaving by half and arrest progression of hirsutism of various etiologies, but do not necessarily reverse it. However, they reliably reduce acne. Cyproterone acetate and spironolactone are similarly effective as anti-androgens in reducing hirsutism, although there is wide variability in individual responses.
Acne vulgaris is nothing but it is a skin condition that affects the sebaceous follicle. It begins to occur shortly just after the puberty and can last for up to 40-50 years. Up till now, the pathophysiology of acne has remained a mystery. Several anti-acne agents are currently available that affect one or more of these pathogenic factors and are effective against one or more acne lesion types. Acne treatment is difficult and necessitates an awareness of etiopathological variables. Treatment of acne vary according to the patients and the disease conditions they have. Treatment of acne in adult women specifically has its challenges due to the considerations of patient preferences, pregnancy, and lactation. Agents effective against inflammatory lesions include tretinoin, benzoyl peroxide, and topical and systemic antibiotics. Agents effective against nodules and cysts include oral antibiotics and isotretinoin. However, the successful utilization of the available agents and techniques is highly dependent on an accurate and thorough assessment of each patient's needs and concerns, followed by the implementation of an individualized treatment program that has been clearly communicated to the patient. Now a days Novel drug delivery system is used for the treatment of acne. This article examines the numerous elements that contribute to acne's occurrence, etiology, and treatment. INTRODUCTION:
The androgenic provoked stimulation of sebum production plays a crucial role in the pathogenesis of acne. Although numerous factors contribute to the development of acne, the requirement for androgens is absolute (1). Thiboutot et al. (2) and Fritsch et al. (3) demonstrated that human skin is indeed a steroidogenic tissue. The skin functions as an independent peripheral endocrine organ (4) expressing all the enzymes necessary for androgen synthesis and catabolism. It can synthesize cholesterol from acetate and can further metabolize steroids such as dehydroepiandrosterone sulfate into potent androgens such as testosterone and DHT. DHT itself further induces enzymes such as 3a-hydroxysteroid dehydrogenase and 17b-hydroxysteroid dehydrogenase (5).
• Hirsutism is related to hormonal factors, mainly an increase in androgen levels.
• In females, the main sources of androgens are the adrenal glands (dehydroepiandrosterone sulfate; DHEA-S) and the ovaries (Δ-4-androstenedione): dysfunction of these organs must be excluded when a patient present with hirsutism.
• The pituitary, the liver, ectopic hormones, certain drugs, and peripheral failure to convert androgens into estrogens may also be causes of hirsutism.
• If minimal or no hormonal abnormalities are found, the patient will be diagnosed as having a constitutional hirsutism (SAHA syndrome) or a familial hirsutism.
• As a general rule whenever there is hirsutism that appears abruptly and evolves quickly, one must first suspect that there is an ovarian, adrenal or pituitary tumor.
• When the hirsutism is mainly localized to the areola and the lateral surfaces of the face and neck, the androgens usually have an ovarian origin, whereas if the location is central, with a distribution from the pubic triangle to the upper abdominal area, between the breasts, to the neck and the chin, the origin is usually adrenal.
• The Ferriman and Gallwey score reflects functional hirsutism when the score is greater than 8 and an organic hirsutism when the score is greater than 15.
• A correct biochemical evaluation must request levels of free testosterone, 5-α-dihydrotestosterone (5-α-DHT), DHEA-S, 17-β-hydroxyprogesterone, Δ-4-androstenedione, prolactin, sex hormone binding globulin (SHBG), 3-α-androstanediol glucuronide, and prostate-specific antigen (PSA), a marker of hyperandrogenism. In ovarian hirsutism and HAIRAN syndrome, we expand the laboratory evaluation to include luteinizing hormone (LH), follicle-stimulating hormone (FSH), LH:FSH ratio, and insulin levels.
• Depending on the origin of the hirsutism, the treatment is based on antiandrogens, glucocorticosteroids, and contraceptives, in association with topical and dermato-cosmetic therapies.
Acne vulgaris is a chronic disorder connected with hyper-secretion of sebaceous glands affecting people between 12 and 40 years old. It is one of the most common dermatological problems. Treatment is a long process in which good cooperation between patient and doctor is necessary. Hormonal factors, essentially androgens, sex and growth hormones and melanocortin, play an important role in the pathogenesis of acne. Precise mechanisms which regulate normal function of sebaceous glands are still undear. The use of contraceptives among other forms of treatment in acne vulgaris is common. Spironolacton and flutamid can be used as elements of combined therapy. We present a review of the role of hormonal factors in the pathogenesis and therapy of acne.
Background:
Acne is treated according to the clinical observations and pathophysiologically relevant mechanisms, such as hyper--keratinization, seborrhea and bacterial proliferation. In mild and moderate forms of inflammatory acne, topical antimicrobials are recommended as a monotherapy or in combination with topical retinoids.
Objective:
To compare the clinical effectiveness, tolerability, impact on quality of life and effect on sebum excretion of three antimicrobial preparations: clindamycin phosphate, benzoyl peroxide and a combination of clindamycin phosphate plus benzoyl peroxide.
Methods:
In total, 240 patients were randomized into treatment groups for an 8--week study. Every two weeks the patients were evaluated using the following methods: photography, the Global Acne Grading System, sebumetric evaluation, and the Acne--Specific Quality of Life questionnaire. In addition, 80 healthy controls were enrolled for the sebumetric evaluation.
Results:
A significant improvement in acne and the quality of life was observed for all three therapies at the end of the study. The sebum excretion results for the three treatment groups displayed significant and unpredictable variation, whereas the controls groups exhibited no significant variation. The three treatments were well tolerated.
Conclusions:
The efficacy of the three antimicrobial preparations likely results from their anti--inflammatory and bacteriostatic activities. In contrast, seborrhoea seems to be minimally impacted.
From the first reliable descriptions of acne in the early 19th century, dermatologists recognized it as a disease of the pilosebaceous follicle. Until the middle of the 20th century, they hypothesized that seborrhoea, follicular keratosis and microorganisms could be individually responsible for the acne lesions. Inflammation was only regarded as the final and inescapable step of the acne process. Although the importance of these factors has been reevaluated, recent works still regarded them as mandatory. In the 1970s, the onset of isotretinoin dramatically improved acne management. It also provided great opportunities for a better understanding of the pathogenic factors of acne. This study analyzes their genesis and development from the seminal contributions until recent advances. © 2014 S. Karger AG, Basel.
Pathogenetisch sind bei der Entstehung der Akne verschiedene Faktoren von Bedeutung, unter anderem Seborrhö, follikuläre Hyperkeratose, Propionibakterien und entzündliche Vorgänge. Diese Übersichtsarbeit erläutert pathophysiologisch relevante Faktoren.
5α-reductase (5α-R) isozymes are ubiquitously expressed in human tissues. This enzyme family is composed of 3 members that perform several important biologic functions. 5α-R isozymes play an important role in benign prostate hyperplasia, prostate cancer, and androgen-stimulated skin disorders, which include androgenic alopecia, acne, and hirsutism. Discovery of 5α-R type 2 deficiency in 1974 sparked interest in development of pharmaceutical agents to inhibit 5α-R isozymes, and 2 such inhibitors are currently available for clinical use: finasteride and dutasteride. 5α-R inhibitors are US Food and Drug Administration (FDA)-approved for the treatment of benign prostate hyperplasia. Only finasteride is FDA-approved for treatment of male androgenic alopecia. This article reviews the pathophysiology of androgen-stimulated skin disorders and the key clinical trials using 5α-R inhibitors in the treatment of androgen-stimulated skin disorders. J Drugs Dermatol. 2013;12(2):e30-e35.
Background: A large body of evidence now exists showing how certain foods and food substances may directly or indirectly influence follicular keratinocyte proliferation, differentiation, inflammation, and the balance of steroid hormones, and hence the development of acne. A wide variety of food items have been postulated to be associated with acne, including milk and other dairy products, chocolate, and others.
Objective: To assess the relationship between the dietary intake of acne patients and acne severity.
Patients and methods: A food frequency sheet containing 32 food items was administered to 100 acne patients. The patients were asked whether or not these types of food were consumed and how frequently they consumed a typical portion size of these foods on average. A commonly used portion size was specified for each food. Correlation between the dietary intake of most of these food items and the degree of acne was made.
Results: A statistically significant positive correlation between the frequency of consumption of nuts, chocolate, candy, and red tea, and the severity of acne lesions was established. A statistically significant negative correlation between the frequency of consumption of fresh vegetables and the severity of acne was detected in our patients. However, unexpectedly, we did not find any correlation between the frequency of consumption of milk and other dairy products and the severity of acne lesions in our patients.
Conclusion: Certain foods may be implicated in acne flares in certain acne patients. The consumption of nuts, chocolate candy, and red tea could be associated with more severe forms of acne, whereas the consumption of fresh vegetables is associated with milder forms of acne.
Minocycline is an oral antibiotic used for acne vulgaris. Its use has lessened due to safety concerns (including potentially irreversible pigmentation), a relatively high cost, and no evidence of any greater benefit than other acne treatments. A modified-release version of minocycline is being promoted as having fewer side-effects.
To assess new evidence on the effects of minocycline for acne vulgaris.
Searches were updated in the following databases to November 2011: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library, MEDLINE (from 1946), EMBASE (from 1974), and LILACS (from 1982). We also searched trials registers and checked reference lists for further references to relevant randomised controlled trials (RCTs).The Cochrane Skin Group's Trials Search Co-ordinator undertook searches exploring minocycline's adverse effects in EMBASE and MEDLINE in February 2012.
We selected randomised controlled trials (RCTs) comparing minocycline, at any dose, to an active or a placebo control, in participants with inflammatory acne vulgaris. For adverse effects, we selected additional studies that reported the number of adverse effects and the number of participants treated.
Outcome measures used in the trials included lesion counts, acne grades/severity scores, doctors' and participants' global assessments, adverse effects, and dropout rates. Two authors independently assessed the quality of each study. Effect sizes were calculated, and meta-analyses were undertaken where possible.Sixteen studies met the inclusion criteria for the review of adverse effects.
We included 12 new RCTs for this update, giving a total of 39 RCTs (6013 participants). These additional 12 RCTs have not changed the original conclusions about the clinical efficacy of minocycline.The identified RCTs were generally small and poor quality. Meta-analysis was rarely possible because of the lack of data and different outcome measures and trial durations. Although minocycline was shown to be an effective treatment for moderate to moderately-severe acne vulgaris, there was no evidence that it is better than any of the other commonly-used acne treatments. One company-sponsored RCT found minocycline to be less effective than combination treatment with topical erythromycin and zinc. No trials have been conducted using minocycline in those participants whose acne is resistant to other therapies. Also, there is no evidence to guide what dose should be used.The adverse effects studies must be interpreted with caution. The evidence suggests that minocycline is associated with more severe adverse effects than doxycycline. Minocycline, but not other tetracyclines, is associated with lupus erythematosus, but the risk is small: 8.8 cases per 100,000 person-years. The risk of autoimmune reactions increases with duration of use. The evidence does not support the conclusion that the more expensive extended-release preparation is safer than standard minocycline preparations.
Minocycline is an effective treatment for moderate to moderately-severe inflammatory acne vulgaris, but there is still no evidence that it is superior to other commonly-used therapies. This review found no reliable evidence to justify the reinstatement of its first-line use, even though the price-differential is less than it was 10 years ago. Concerns remain about its safety compared to other tetracyclines.
Seborrhoe, follikuläre Hyperkeratose, Propionibakterien und entzündliche Vorgänge sind die wichtigsten Faktoren, die zu Akne
führen. Das Zusammenwirken von verstärktem Talgfluss und follikulärer Hyperkeratose begünstigt ein starkes Wachstum von Propionibacterium acnes. Dessen Stoffwechselprodukte fördern follikuläre und im Extremfall abszedierende perifollikuläre Entzündungen. Die Talgproduktion
wird von Androgenen gesteuert, und Störungen im Androgenhaushalt können Seborrhoe und Akne provozieren. Die follikuläre Hyperkeratose
wird durch ein relatives Linolsäuredefizit, Peroxide von Talgkomponenten und insbesondere auch von Entzündungsmediatoren wie
Interleukin-1 provoziert. Bakterielle Stoffwechselprodukte wie Lipasen, Proteasen oder chemotaktische Faktoren fördern die
perifollikuläre Entzündung. Entzündung ist aber nicht nur Resultat anderer pathogenetischer Faktoren, sondern auch Wegbereiter
der Akne: Eine initiale perifollikuläre Entzündungsbereitschaft fördert über Entzündungsmediatoren die Komedogenese und bereitet
hierdurch Akne vor. Der Bedeutung von Ernährungsgewohnheiten für die Entstehung und den Verlauf der Akne wird seit Kurzem
wieder mehr wahrgenommen. Vermutet werden insbesondere Zusammenhänge zwischen Akne und Nahrungsmitteln mit einem hohen glykämischen
Index sowie mit Milchprodukten.
Seborrhea, follicular hyperkeratosis, propionibacteria, and inflammatory reactions are the most important factors leading
to acne. The combination of increased sebum producation and follicular hyperkeratosis facilitates an increased growth of Propionibacterium
acnes. Its metabolic products lead to follicular inflammation and, in extreme cases, even to perifollicular abscesses. Sebum
production is influenced by androgens, so that abnormalities in androgen levels can produce seborrhea and acne. Follicular
hyperkeratosis may be triggered by a relative deficiency in linoleic acid, peroxides from sebum components, and especially
by inflammatory mediators such as interleukin-1. Bacterial metabolic products such as lipases, proteases, or chemotactic factors
lead to the perifollicular inflammation. This inflammation is not only a response to other pathogenetic factors, but also
a cause of acne. An initial mild perifollicular infammation can induce comedogenesis via a variety of mediators. The influence
of dietary factors on the initiation and course of acne has recently received increased recognition. A connection has been
postulated between acne and a high nutrients with glycemic index, as well as with milk products.
Topical use of systemic agents to treat cutaneous disorders is widely applied. However, there is a lack of articles summarizing the relevant literature in a systematic way.
We sought to review the published literature regarding topical use of systemic drugs that were categorized according to their mode of actions. Only drugs that are not yet commercially available in a topical preparation are included.
A PubMed search was performed, using as key words "topical," "extemporaneous," "compounding," and names of each generic drug, to identify all clinical reports (1966-2009).
Although many systemic drugs are used topically, randomized controlled trials were limited to a few agents.
Many of the reports consist only of small case series or are anecdotal in nature. As the level of evidence is limited, larger prospective trials are needed before firm conclusions can be drawn.
Extemporaneous compounding helps physicians to individualize treatment to the patient's specific needs and to create topical preparations that are not otherwise commercially available. However, comparative effectiveness studies are needed to determine whether or not topical use of systemic therapeutics is more beneficial than existing therapies.
Tesis Univ. Granada. Departamento de Bioquímica y Biología Molecular. Leída el 31 de mayo de 2007
The combination of lesion ablation with excellence in cosmetic outcome has allowed photodynamic therapy (PDT) an ever increasing role in the treatment of diseases of the skin. As currently practiced, PDT employs a photosensitizing agent that when activated by light energy creates a photodynamic reaction that is cytotoxic and vasculotoxic. The relative simplicity of therapy with its ability to achieve high response rates has brought PDT to a worldwide audience not only for oncologic indications but far more commonly to non oncologic indications. This paper will review the mechanism of action for PDT and highlight the versatile clinical outcomes reported from the peer reviewed literature.
An enhanced sebaceous gland activity with production of proinflammtory sebaceous lipids belongs to the major pathogenetic factors of acne. Hormonal antiandrogen treatment targets the androgen-metabolizing cells of the pilosebaceous unit, i. e. follicular kertinocytes and sebocytes, and leads to sebostasis, with a reduction of the sebum secretion rate of 12.5 to 65 %. Concerning their mechanism of action, hormonal antiandrogens are classified in androgen receptor blockers, inhibitors of circulating androgens by affecting the ovarial function (oral contraceptives), inhibitors of circulating androgens by affecting the pituitary (gonadotrophin-releasing hormone agonists and dopamin agonists in hyperprolactinemia), inhibitors of the adrenal function, and inhibitors of peripheral androgen metabolism (5-reductase inhibitors, inhibitors of other enzymes).
In this study, all original and review publications on hormonal antiandrogen treatment of acne as monotherapy or in combination included in MEDLINE, EMBASE and COCHRANE libraries were extracted by using the terms "acne", "seborrhea", "polycystic ovary syndrome", "hyperandrog*" and "treatment" and classified according to their level of evidence.
Antiandrogen treatment is overall active on acne lesions. The combinations of ethinyl estradiol with cyproterone acetate chlormadinone acetate, dienogest desogestrel and drospirenone have shown the strongest antiacne activity. Gestagens or estrogens as monotherapy, spironolactone, flutamide, gonadotrophin-releasing hormone agonists and inhibitors of peripheral androgen metabolism are not recommended according to the current stand of knowledge. Low dose prednisolone is to only be administered at late onset congenital adrenal hyperplasia and dopamine agonists at hyperprolactinemia. Treatment with hormonal antiandrogens requires missing of any contraindications.
Hormonal antiandrogen treatment is limited to female patients who present additional signs of peripheral hyperandrogenism or hyperandrogenemia. In addition, females with acne tarda, persistent acne recalcitrant to treatment, with parallel wish of contraception, and as a requirement for a systemic isotretinoin treatment can be treated with hormonal antiandrogens. Hormonal antiandrogen treatment is not a primary monotherapy for uncomplicated acne.
Female pattern hair loss (FPHL) is a clinical problem that is becoming more common in women. Female alopecia with androgen increase is called female androgenetic alopecia (FAGA) and without androgen increase is called female pattern hair loss. The clinical picture of typical FAGA begins with a specific "diffuse loss of hair from the parietal or frontovertical areas with an intact frontal hairline." Ludwig called this process "rarefaction." In Ludwig's classification of hair loss in women, progressive type of FAGA, 3 patterns were described: grade I or minimal, grade II or moderate, and grade III or severe. Ludwig also described female androgenetic alopecia with male pattern (FAGA.M) that should be subclassified according to Ebling's or Hamilton-Norwood's classification. FAGA.M may be present in 4 conditions: persistent adrenarche syndrome, alopecia caused by an adrenal or an ovarian tumor, posthysterectomy, and as an involutive alopecia. A more recent classification (Olsen's classification of FPHL) proposes 2 types: early- and late-onset with or without excess of androgens in each. The diagnosis of FPHL is made by clinical history, clinical examination, wash test, dermoscopy, trichoscan, trichograms and laboratory test, especially androgenic determinations. Topical treatment of FPHL is with minoxidil, 2-5% twice daily. When FPHL is associated with high levels of androgens, systemic antiandrogenic therapy is needed. Persistent adrenarche syndrome (adrenal SAHA) and alopecia of adrenal hyperandrogenism is treated with adrenal suppression and antiandrogens. Adrenal suppression is achieved with glucocorticosteroids. Antiandrogens therapy includes cyproterone acetate, drospirenone, spironolactone, flutamide, and finasteride. Excess release of ovarian androgens (ovarian SAHA) and alopecia of ovarian hyperandrogenism is treated with ovarian suppression and antiandrogens. Ovarian suppression includes the use of contraceptives containing an estrogen, ethinylestradiol, and a progestogen. Antiandrogens such as cyproterone acetate, always accompanied by tricyclic contraceptives, are the best choice of antiandrogens to use in patients with FPHL. Gonadotropin-releasing hormone agonists such as leuprolide acetate suppress pituitary and gonadal function through a reduction in luteinizing hormone and follicle-stimulating hormone levels. Subsequently, ovarian steroid levels also will be reduced, especially in patients with polycystic ovary syndrome. When polycystic ovary syndrome is associated with insulin resistance, metformin must be considered as treatment. Hyperprolactinemic SAHA and alopecia of pituitary hyperandrogenism should be treated with bromocriptine or cabergoline. Postmenopausal alopecia, with previous high levels of androgens or with prostatic-specific antigen greater than 0.04 ng/mL, improves with finasteride or dutasteride. Although we do not know the reason, postmenopausal alopecia in normoandrogenic women also improves with finasteride or dutasteride at a dose of 2.5 mg per day. Dermatocosmetic concealment with a hairpiece, hair prosthesis as extensions, or partial hairpieces can be useful. Lastly, weight loss undoubtedly improves hair loss in hyperandrogenic women.
Acne vulgaris is a common skin disorder among children and young adults that carries enormous financial and psychosocial impact. Contemporary therapies attempt to address factors underlying acne as a disorder of the pilosebaceous unit. These longstanding paradigms regarding pathogenesis and treatment continue to evolve in light of recent work on this ubiquitous disease.
This review focuses on new literature that has emerged regarding the biology of the folliculosebaceous unit, the identification of particular mediators responsible for inflammatory acne, the use of topical and systemic retinoids in acne therapy, and approaches to address the emergence of antibiotic-resistant Propionibacterium acnes strains. In addition, the use of several novel therapeutic avenues is discussed, including combination therapies, lipoxygenase inhibitors, and lasers.
As the understanding of the factors that initiate and exacerbate acne vulgaris continues to increase, so does the diversity of therapeutic options. Rational use of available treatment options based on the type and severity of acne lesions is a key component of successful acne therapy and allows the physician who treats adolescents with acne to provide optimum care.
Androgen hormones play an important role in common skin and hair conditions including acne vulgaris, hirsutism, and androgenetic alopecia. Blocking this androgen effect may lead to significant improvements in these conditions. Several medications that work through a variety of different mechanisms may be prescribed safely and effectively as antiandrogen therapies in the dermatology arena.
Acne vulgaris is a nearly universal phenomenon among adolescents in the western world and continues to remain problematic for a significant proportion of adults. During adolescence, emotional and physical changes must be successfully integrated into the emerging sense of self, and skin disorders such as acne, which alter that self-image, may engender distressing feelings of embarrassment, shame, and disgust. While most patients eventually achieve spontaneous remission, approximately one quarter of teenagers will show evidence of permanent acne scarring by 18 years of age. This article reviews current information regarding the pathophysiology, clinical manifestations, differential diagnosis, and therapy of the adolescent patient who has acne, and emphasizes recent advances in acne management.
The synthesis of dihydrotestosterone is catalyzed by steroid 5 alpha-reductase isozymes, designated types 1 and 2. Mutation of type 2 results in male pseudohermaphroditism, in which the external genitalia are phenotypically female at birth. Two striking and unexplained features of this disorder are that external genitalia of affected males undergo virilization during puberty and that these individuals have less temporal hair regression. The tissue-specific and developmental expression patterns of the 5 alpha-reductase isozymes were investigated by immunoblotting. The type 1 isozyme is not detectable in the fetus, is transiently expressed in newborn skin and scalp, and permanently expressed in skin from the time of puberty. There was no qualitative difference in 5 alpha-reductase type 1 expression between adult balding vs. nonbalding scalp. The type 2 isozyme is transiently expressed in skin and scalp of newborns. Type 2 is the predominant isozyme detectable in fetal genital skin, male accessory sex glands, and in the prostate, including benign prostatic hyperplasia and prostate adenocarcinoma tissues. Both isozymes are expressed in the liver, but only after birth. These results are consistent with 5 alpha-reductase type 1 being responsible for virilization in type 2-deficient subjects during puberty, and suggest that the type 2 isozyme may be an initiating factor in development of male pattern baldness.
Growth of sebaceous glands in the ears and flank organs of castrated male hamsters is dependent on androgen substitution. Taking this for granted, a study was done to compare the effects of topical antiandrogenic treatment in vivo on the morphology and size of sebaceous glands with the concomitant changes in in vitro metabolism of 3H-testosterone. The role of dihydrotestosterone in sebaceous gland stimulation was thereby investigated.
Background
This study examined the relationships of pubertal maturation and sex steroid hormones to the development of acne in young girls. Black (n=317) and white (n=306) premenarchal girls with a mean age of 9.97±0.62 years were evaluated for acne prevalence and severity, pubic hair and areolar maturation, and sex steroid hormone levels.
Results
Overall, 77.8% of the girls had some acne; of the whole group, 48.3% had only comedonal acne, 2.2% had only inflammatory acne, and 27.3% had both types. Although black girls matured at an earlier age than white girls, racial differences in acne were minimal when adjusted for pubertal maturation. Acne increased with advancing maturation; at Tanner pubic hair stages 1, 2, and 3, the prevalence of acne rose from 73.1% to 84.0% and to 90.6%, respectively. Acne lesion counts at seven facial locations revealed a predominance of midfacial acne on the middle aspect of the forehead, nose, and chin. Sex steroid hormone levels measured in 365 of the girls were found to increase significantly during maturation from prepuberty to early puberty. Testosterone-estrogen—binding globulin and the ratio of testosterone to estradiol decreased. In 118 prepubertal girls, estradiol, total and free testosterone, progesterone, testosterone to estradiol ratio, and testosterone-estrogen—bindingglobulin levels were no different whether in subjects with acne or without acne. However, the level of dehydroepiandrosterone sulfate, an androgen of adrenal origin, was significantly higher in prepubertal girls with acne.
Conclusion
Acne, especially the comedonal type, can be the first sign of pubertal maturation in girls, even preceding pubic hair and areolar development. Concentration of dehydroepiandrosterone sulfate is significantly and specifically associated with the initiation of acne in young girls.(Arch Dermatol. 1994;130:308-314)
The assumption that the metabolism of testosterone to 5α-dihydrotestosterone (5α-DHT) is required for androgen action in the skin was investigated by studying the uptake and metabolism of testosterone by skin and other tissues of the rat in vivo. The skin resembled the classical androgen target organs in the uptake and retention of radioactivity, but the proportions of the steroids present were markedly different. In the ventral prostate most of the testosterone was metabolized, mainly to 5α-DHT, after only 20 min. In the skin testosterone was always the predominant steroid identified and androstenedione, 5α-DHT, 5α-androstane-3α, 17β-diol, androsterone and 5α-androstane-3β, 17β-diol were only present in much smaller quantities, even after 5 h. Hypophysectomy, known to reduce the response of the sebaceous glands to testosterone in the rat, did not alter the steroid composition in the classical target organs, the preputial glands, or the plasma, but in the skin it increased testosterone metabolism without altering the levels of 5α-DHT or the 5α-androstane-diols. These results suggest that the 5α-reduction of testosterone to 5α-DHT may not be so important in the skin, or at least in the sebaceous glands, as it is in the prostate.
The presence of 5α-reductase (5α-R) in skin may indicate that the androgen regulation of sebaceous glands and sebum production requires the local conversion of testosterone to dihydrotestosterone. The goals of this study were to identify which isozyme of 5α-R (type 1 or type 2) is expressed in sebaceous glands from facial areas, scalp, and non-acne-prone areas; to determine if 5α-R activity is concentrated in sebaceous glands; to assess whether there are regional differences in this enzyme's activity; and to test the effects of azasteroid inhibitors and 13-cis retinoic acid on 5α-R in these tissues. Sebaceous glands were microdissected from facial skin, scalp, and non-acne-prone skin (arm, breast, abdomen, leg), and the activity of 5α-R was determined. A total of 49 samples from 23 male and 21 female subjects without acne (age range, 16 to 81 years, 56 ± 20 years [mean ± SD]) was analyzed. The biochemical properties of the enzyme in each of the samples tested are consistent with those of the type 1 5α-R. Minimal to no type 2 5α-R was detected. The level of 5α-R activity was significantly higher in the sebaceous glands compared to whole skin in facial skin (p = 0.047), scalp (p = 0.039), and non-acne-prone skin (p = 0.04). Enzyme activity in sebaceous glands from facial skin and scalp was significantly higher than in a comparable amount of sebaceous gland material obtained from non-acne-prone areas (32 ± 6 [mean ± SEM]), 35 ± 7 (mean ± SEM) versus 6.0 ± 3.0 (mean ± SEM) pmol/min/mg protein, p = 0.014 and 0.007, respectively). Finasteride and 13-cis retinoic acid were poor inhibitors of the enzyme with 50% inhibitory concentration values greater than 500 nM. These data demonstrate that in the skin from older patients without acne the type 1 isozyme of 5α-R predominates, its activity is concentrated in sebaceous glands and is significantly higher in sebaceous glands from the face and scalp compared to non-acne-prone areas, and the action of 13-cis retinoic acid in the control of acne is not at the level of 5α-R. Furthermore, we suggest that specific inhibition of the type 1 5α-R may offer a viable approach to the management of sebum production and, hence, acne.
Testosterone metabolism was investigated in fractions, of human skin, enriched in epidermis, dermis, sebaceous glands, and sweat glands, by histologic sectioning of skin punch biopsies, and the results were compared with two culturable skin cells, i.e., keratinocytes and fibroblasts. Since sebocytes could not be brought in culture, metabolism was also investigated in the hamster flank model. In the epidermal tissue of the skin biopsies the predominant metabolite was androstenedione, formed by the enzyme 17β- hydroxysteroid dehydrogenase. The same was true for cultured hair follicle keratinocytes. In the deeper skin layers the formation of androstenedione was markedly reduced, whereas the formation of 5α-reduced metabolites was highly increased, with a maximum in the skin fractions containing large sebaceous glands. Cultured shoulder skin fibroblasts showed a markedly different testosterone metabolism compared with the sectioned skin biopsies, suggesting that dermal fibroblasts play a less important role in the overall skin testosterone metabolism. The present approach, allowing the comparison of testosterone metabolism in different sub- structures of the same skin biopsy provides new evidence that the high 5α-reductase activity in the specific skin fractions must be mainly ascribed to the sebaceous glands. These results render a previous hypothesis, stating that the elevated level of 5α-reductase and subsequent formation of dihydrotestosterone in androgenetic alopecia and acne (usually accompanied by seborrhea) could therefore simply be the consequence of sebaceous gland enlargement, much stronger. This hypothesis is further evaluated by quantitative correlation of sebaceous gland size with enzyme activity in the hamster flank model.
In order to know the distribution of testosterone 5α-reductase activity in human skin, we developed a micro-method, in which we used 20–50 μg of various tissues microdissected from freeze-dried sections. The characteristics of this enzyme in the sebaceous gland are briefly described, as follows: the identified 5α-reduced metabolites are 5α-dihydrotestosterone, 5α-androstane-3β, 17β-diol and 5α-androstanedione; the optimal pH is about 7.5; and the apparent Km is approximately 2.4 × 10⁻⁵ M.
The measurement of 5α-reductase activity of various components of the skin obtained from 7 men and 5 women revealed that the sweat gland (probably apocrine) in the axillary skin possessed the highest activity of 5α-reductase: the value was nearly 400 pmoles/mg dry weight/hr in the standardized condition. The sebaceous gland also showed a high activity of 85–261 pmoles/mg/hr. The hair follicles exhibited a significantly lower activity than the sebaceous gland. The enzyme activity was negligible in the epidermis, while it was detected in the dermis though the values determined were variable probably because of contamination with other components such as sweat glands and hair follicles.
Thus, the present study demonstrates that the 5α-reductase activity is mainly located in the apocrine sweat gland and sebaceous gland. This suggests that 5α-reduction of testosterone is an important step in mediating the action of androgens in these tissues.
• To assess the prevalence and severity of acne vulgaris in young adolescent boys, we studied 219 black and 249 white boys in fifth through ninth grades in Cincinnati, Ohio. The mean age was 12.2 ± 1.4 years, with a range of 9 to 15 years. Pubertal maturation was scored as Tanner pubic hair stages (PH I to V) and pubertal stages (PS I to IV) that included testicular volume assessment. Acne was scored by number of comedonal (open plus closed comedones) and inflammatory (papules plus pustules) lesions. Comedonal and inflammatory lesions were analyzed separately and evaluated both as numerical scores and as grades (1, ≤10 lesions; 2,11 to 25 lesions; and 3, ≥26 lesions). Grades 2 and 3 were considered clinically significant acne. Acne became progressively more severe with advancing maturity. Mean acne scores correlated better with PS and pubic hair than with age. Black subjects were more mature than white subjects. Black boys in PS I and II had significantly more comedones than white boys; white boys had significantly more inflammatory lesions at PS I and III. Clinically significant comedonal acne was already present in PS I and occurred in 100% of boys in PS IV. In contrast, no boys at PS I and only 50% at PS IV had significant inflammatory acne. Midfacial acne dominated. We concluded that acne prevalence and severity correlate well with advancing pubertal maturation in young adolescent boys. Comedonal acne was more frequent and severe than inflammatory disease. Awareness of the extent and severity of acne in preadolescents and young adolescents may ultimately provide rationale for early intervention and thus prevention of severe acne vulgaris.
(Arch Dermatol. 1991;127:210-216)
Growth of sebaceous glands in the ears and flank organs of castrated male hamsters is dependent on androgen substitution. Taking this for granted, a study was done to compare the effects of topical antiandrogenic treatment in vivo on the morphology and size of sebaceous glands with the concomitant changes in in vitro metabolism of 3H-testosterone. The role of dihydrotestosterone in sebaceous gland stimulation was thereby investigated. Topical treatment was carried out with the androgen antagonist 17 alpha-propylmesterolone (PM), with 4-androsten-3-one-17 beta-carboxylic acid (17 beta-C), and 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one (4-MA), both described as specific 4-steroid-5 alpha-reductase inhibitors, and with progesterone (PRO), which is an androgen receptor antagonist with 5 alpha-reductase inhibiting properties. Regrowth of sebaceous glands after castration and substitution with testosterone propionate or dihydrotestosterone could be inhibited by topical PM and PRO. This occurred irrespective of the influence on testosterone metabolism and irrespective of the mode of substitution. 4-MA, on the other hand, while exhibiting strong 5 alpha-reductase inhibition in vitro, was ineffective in reducing sebaceous gland sizes in vivo. The compound 17 beta-C was ineffective in every respect. In no case were systemic antiandrogenic effects on prostates and seminal vesicles observed. Our results support the view that the DHT formation rate has no regulatory function for growth of sebaceous glands in hamsters and that PM and PRO counteract the androgenic stimulus by their competitive antagonistic binding to the androgen receptor, but not by their influence on testosterone metabolism.
In spite of an abundant literature on antiandrogen treatment with cyproterone acetate (CA) there have been no objectively measured results to prove statistically the possible superiority of CA over combined oral contraceptive pills in the treatment of acne vulgaris. A multicenter study was therefore done, in which two preparations containing CA in combination with ethinylestradiol (EE) were compared with a marketed combined oral contraceptive pill. The preparations studied were: CA 2 mg + EE 50 micrograms (Diane), CA 2 mg + EE 35 micrograms (Diane mite), Levonorgestrel 150 micrograms + EE 30 micrograms (Neovletta). A woman was eligible for the study if she was found by a dermatologist to have at least eight acne lesions (sum of papules, pustules, cysts and nodules) on her face, was otherwise healthy and without medication. After a primary assessment of the number of acne lesions by the dermatologist the woman was referred to a gynecologist and given one of the three test preparations double-blind and at random. The treatment was to continue for 6 months. 133 women were recruited at eight different centers. The groups thus constituted were of similar size and comparable with regard to age, degree of acne, and menstrual and contraceptive histories. As the number of acne lesions varied considerably between patients all data were converted into percentage change during treatment before they were processed in a computer. After only 4 months of treatment the patients on Diane and Diane mite had a significantly greater reduction in the number of acne lesions compared with those on Neovletta.(ABSTRACT TRUNCATED AT 250 WORDS)
A multicenter trial was conducted in 267 centers in Italy to evaluate the efficacy, acceptability and safety of a monophasic oral contraceptive containing 30 micrograms ethinyl estradiol and 150 micrograms desogestrel (Marvelon) 13,290 women were followed up for a total of 74,967 cycles. No pregnancies due to method failure were reported and only three because of patient failure. Cycle control was good. There was a decrease in the occurrence of irregular cycles and in the duration and amount of menstrual bleeding; the incidence of breakthrough bleeding and spotting was low. No severe side-effects occurred and the incidence of minor complaints was generally lower during treatment than in the pre-treatment cycle. Body weight and blood pressure were not significantly altered.
It is clear from the foregoing considerations that the development and secretory activity of the sebaceous gland of man is influenced by hormonal factors. Androgenic steroids, particularly of gonadal origin, are the hormones principally responsible for these effects and the only ones shown to have a direct stimulatory effect on glandular activity. Adrenal androgens may be responsible for early sebaceous gland maturation in late childhood, at a time when minor degrees of acne sometimes occur. Glucocorticoids appear to function in a permissive capacity, the anterior pituitary hormones primarily affecting the sebaceous gland indirectly through stimulation of their respective target organs, i.e., the gonads and the adrenal gland. The role of the thyroid and other endocrine glands is unknown and needs to be studied.
In order to know the distribution of testosterone 5 alpha-reductase activity in human skin, we developed a micro-method, in which we used 20-50 micrograms of various tissues microdissected from freeze-dried sections. The characteristics of this enzyme in the sebaceous gland are briefly described, as follows: the identified 5 alpha-reduced metabolites are 5 alpha-dihydrotestosterone, 5 alpha-androstane-3 beta, 17 beta-diol and 5 alpha-androstanedione; the optimal pH is about 7.5; and the apparent Km is approximately 2.4 x 10(-5) M. The measurement of 5 alpha-reductase activity of various components of the skin obtained from 7 men and 5 women revealed that the sweat gland (probably apocrine) in the axillary skin possessed the highest activity of 5 alpha-reductase: the value was nearly 400 pmoles/mg dry weight/hr in the standardized condition. The sebaceous gland also showed a high activity of 85-261 pmoles/mg/hr. The hair follicles exhibited a significantly lower activity than the sebaceous gland. The enzyme activity was negligible in the epidermis, while it was detected in the dermis though the values determined were variable probably because of contamination with other components such as sweat glands and hair follicles. Thus, the present study demonstrates that the 5 alpha-reductase activity is mainly located in the apocrine sweat gland and sebaceous gland. This suggests that 5 alpha-reduction of testosterone is an important step in mediating the action of androgens in these tissues.
This study examined the relationships of pubertal maturation and sex steroid hormones to the development of acne in young girls. Black (n = 317) and white (n = 306) premenarchal girls with a mean age of 9.97 +/- 0.62 years were evaluated for acne prevalence and severity, pubic hair and areolar maturation, and sex steroid hormone levels.
Overall, 77.8% of the girls had some acne; of the whole group, 48.3% had only comedonal acne, 2.2% had only inflammatory acne, and 27.3% had both types. Although black girls matured at an earlier age than white girls, racial differences in acne were minimal when adjusted for pubertal maturation. Acne increased with advancing maturation; at Tanner pubic hair stages 1, 2, and 3, the prevalence of acne rose from 73.1% to 84.0% and to 90.6%, respectively. Acne lesion counts at seven facial locations revealed a predominance of midfacial acne on the middle aspect of the forehead, nose, and chin. Sex steroid hormone levels measured in 365 of the girls were found to increase significantly during maturation from prepuberty to early puberty. Testosterone-estrogen-binding globulin and the ratio of testosterone to estradiol decreased. In 118 prepubertal girls, estradiol, total and free testosterone, progesterone, testosterone to estradiol ratio, and testosterone-estrogen-binding globulin levels were no different whether in subjects with acne or without acne. However, the level of dehydroepiandrosterone sulfate, an androgen of adrenal origin, was significantly higher in prepubertal girls with acne.
Acne, especially the comedonal type, can be the first sign of pubertal maturation in girls, even preceding pubic hair and areolar development. Concentration of dehydroepiandrosterone sulfate is significantly and specifically associated with the initiation of acne in young girls.
To evaluate the androgen control of sebum, subjects with complete androgen insensitivity and male pseudohermaphrodites with inherited 5 alpha-reductase deficiency and decreased dihydrotestosterone (DHT) production had sebum production studied. A hydrophobic polymeric film applied to the forehead was used to measure sebum production through the use of air filled micropores. Sebum scores of normal preadrenarchal children (ages 2-6), and normal age-matched adult males and females, were studied as well as males treated with the 5 alpha-reductase inhibitor, finasteride, for benign prostatic hyperplasia who were studied at baseline and after drug therapy. Androgen insensitive subjects had no sebum production by this methodology, and the results were identical to preadrenarchal children. In contrast, adult male pseudohermaphrodites with 5 alpha-reductase deficiency and a selective decrease in DHT production had sebum production scores identical to normal age-matched males. Males with benign prostatic hyperplasia treated with the 5 alpha-reductase inhibitor, finasteride, to lower DHT levels did not decrease the sebum score from baseline values. The lack of demonstrable sebum in androgen-insensitive subjects clearly demonstrates the absolute androgen control of sebum production. The DHT dependency of the sebaceous gland, however, could not be demonstrated in this study. Two 5 alpha-reductase isoenzymes 1 and 2, have been described. 5 alpha-reductase-2 is the gene responsible for inherited 5 alpha-reductase deficiency. Although the degree of inhibition of DHT in utero and in adulthood in male pseudohermaphrodites with a defect in 5 alpha-reductase-2 enzyme activity caused severe impairment of external genital and prostate differentiation and decreased facial and body hair, it had no demonstrable effect on sebaceous gland development or function. Furthermore, lowering DHT levels in adulthood had no effect on sebum production. If the gland is rich in the enzyme 5 alpha-reductase-2, it is proposed that the sebaceous gland is either exquisitely sensitive to DHT, requiring only small amounts for normal development and function, or that male levels of testosterone compensate for DHT and maintain normal sebaceous gland activity throughout life. It is also possible that 5 alpha-reductase-1 is the enzyme of the sebaceous gland and is unaffected in the inherited condition and by finasteride.
Two isozymes (types 1 and 2) of 5alpha-reductase (5alphaR; EC 1.3.99.5), with differential tissue distribution, catalyze the reduction of testosterone (T) to dihydrotestosterone (DHT) in humans. This study examined sequentially increasing oral doses of MK-386 (4,7beta-dimethyl-4-aza-5alpha-cholestan-3-one), an azasteroid that specifically inhibits the human 5alphaR1 isozyme in vitro. Finasteride, a selective inhibitor of 5alphaR2, was included for comparison. One hundred men were evaluated in a double blind, randomized, placebo-controlled, sequential, increasing dose, parallel group trial. Ten to 20 subjects received MK-386, and 2 to 5 received placebo in each of 6 panels. In 1 panel, 10 subjects received finasteride (5 mg), and 5 received placebo. Treatments were given once daily for 14 days, except in 1 panel in which MK-386 was administered 10 mg twice daily for comparison to 20 mg daily. Serum, sebum, and semen DHT concentrations and serum and sebum T concentrations were measured before and after treatment. The mean changes from baseline on day 14 for serum DHT after placebo and 0.1, 0.5, 5, 20, and 50 mg MK-386 were 6.9%, 4.6%, -2.7%, -1.2%, -14.1% (P < 0.05 vs. placebo), and -22.2% (P < 0.05 vs. placebo), respectively. No significant alterations in serum T were observed after any dose of MK-386. Serum DHT fell 65.8% from the baseline 14 days after finasteride treatment (P < 0.05 vs. placebo). The mean changes from baseline on day 14 in sebum DHT were 5.0%, 3.0%, -25.4% (P < 0.05 vs. placebo), -30.1% (P < 0.05 vs. placebo), and -49.1% (P < 0.05 vs. placebo) for the placebo and 0.5, 5, 20, and 50 mg MK-386 groups, respectively. Finasteride also reduced sebum DHT, but to a lesser extent (- 14.9%; P < 0.05 vs. placebo). Reciprocal increases in sebum T concentration were noted at doses of 5 mg or more of MK-386, but not with finasteride. The mean reduction in semen DHT with 5 mg finasteride was approximately 88% (P < 0.01 vs. placebo); no significant change in semen DHT was noted with 20 or 50 mg MK-386. Serum 3alpha-androstanediol glucuronide values were also reduced after the 20- and 50-mg MK-386 treatments in parallel with the changes in serum DHT. No meaningful changes were observed in serum LH after MK-386 treatment. MK-386 was generally well tolerated by all subjects; reversible aspartate aminotransferase/alanine aminotransferase elevations were observed in two subjects at the 50-mg dose. The differential responses in serum, sebum, and semen DHT concentrations associated with MK-386 and finasteride treatments are consistent with those changes anticipated for selective inhibitors of the human 5alphaR isozymes. Dose-dependent suppression of sebum DHT by a 5alphaR1 inhibitor suggests the potential utility of such compounds in the treatment of acne.
An excess of androgen is believed to contribute to development of acne in some patients. Because oral contraceptives (OCs) may reduce the active androgen level, hormonal therapy with OCs has been used successfully to treat patients with acne, although this treatment has previously not been studied in placebo-controlled trials.
Our purpose was to evaluate the efficacy of a triphasic, combination OC (ORTHO TRI-CYCLEN [Ortho-McNeil Pharmaceutical, Raritan, N.J.], norgestimate/ethinyl estradiol) compared with placebo in the treatment of moderate acne vulgaris.
Two hundred fifty-seven healthy female subjects, 15 to 49 years of age with moderate acne vulgaris, were enrolled in a multicenter, randomized, double-blind, placebo-controlled clinical trial. Each month for 6 months, subjects received either 3 consecutive weeks of the OC (i.e., tablets containing a fixed dose of ethinyl estradiol [0.035 mg] and increasing doses of norgestimate [0.180 mg, 0.215 mg, 0.250 mg]) followed by 7 days of inactive drug or placebo (color-matched tablets). Efficacy was assessed by facial acne lesion counts, an investigator's global assessment, a subject's self-assessment, and an analysis of within-cycle variation (cycle 6) in lesion counts.
Of the 160 subjects in whom efficacy could be evaluated, the OC group showed a statistically significantly greater improvement than the placebo group for all primary efficacy measures. The mean decrease in inflammatory lesion count from baseline to cycle 6 was 11.8 (62.0%) versus 7.6 (38.6%) (p = 0.0001), and the mean decrease in total lesion count was 29.1 (53.1%) versus 14.1 (26.8%) (p = 0.0001) in the OC and placebo groups, respectively. In the investigator's global assessment, 93.7% of the active treatment group versus 65.4% of the placebo group were rated as improved at the end of the study (p < 0.001). Six of the seven secondary efficacy measures (total comedones, open comedones, closed comedones, papules, pustules, and the subject's self-assessment of study treatment) were also significantly more favorable in the OC group compared with the placebo group.
An OC containing 0.035 mg of ethinyl estradiol combined with the triphasic regimen of norgestimate is a safe and effective treatment of moderate acne vulgaris in women with no known contraindication to OC therapy.
Dihydrotestosterone mediates androgen-dependent diseases, such as acne, hirsutism, and androgenetic alopecia. This hormone is produced from testosterone by the 5alpha-reductase enzyme. There are 2 isozymes of 5alpha-reductase (types 1 and 2) that differ in their localization within the body and even within the skin. Activity of the type 1 isozyme predominates in sebaceous glands, where it may be involved in regulation of sebum production. Since specific inhibition of 5alpha-reductase type 1 may represent a novel therapeutic approach to acne, it is important to define the localization of these isozymes in normal sebaceous follicles and acne lesions.
Skin biopsy specimens were obtained from the backs of 11 subjects: 8 with acne and 3 without acne. Sections of normal follicles, open comedones, closed comedones, and inflammatory lesions were incubated with antibodies to types 1 and 2 5alpha-reductase. In all samples, the type 1 antibody localized specifically to sebaceous glands, and the type 2 antibody localized to the companion layer of the hair follicle (the innermost layer of the outer root sheath) and granular layer of the epidermis. Localization of the type 2 isozyme was also noted within the walls of open and closed comedones and in endothelial cells from sections of inflammatory lesions.
The immunolocalization of 5alpha-reductase isozymes in normal sebaceous follicles and acne follicles is similar to the pattern described in terminal hair follicles and corresponds with the findings of biochemical studies that have demonstrated predominance of type 1 activity in sebaceous glands. The function of type 2 5alpha-reductase in comedones or endothelial cells in inflammatory lesions is unknown.
The Journal of Investigative Dermatology publishes basic and clinical research in cutaneous biology and skin disease.
Male hormone substance
- Hamilton
The effect of the triphasic oral contraceptive on acne vulgaris: an interim report of an open multicenter study. Elstein M, editor. Update on triphasic oral contraception
- N B Loudon
- S F Biddell
The androgen control of sebum production
- Imperato-McGinley
Acne vulgaris in early adolescent boys
- Lucky